TW202217000A - Sars-cov-2 mrna domain vaccines - Google Patents

Abstract

The disclosure relates to coronavirus ribonucleic acid (RNA) vaccines as well as methods of using the vaccines and compositions comprising the vaccines. The RNA vaccines encode domains and subunits of coronavirus.

Description

SARS-COV-2 mRNA domain vaccine

Human coronavirus is a highly contagious mantle positive single-stranded RNA virus of the family Coronaviridae. Two subfamilies of the coronavirus family are known to cause disease in humans. The most important are beta-coronaviruses (beta-coronaviruses, betacoronaviruses). Beta-coronavirus is a common causative agent of mild to moderate upper respiratory tract infections. However, outbreaks of novel coronavirus infections, such as those caused by a coronavirus originally identified from Wuhan, China in December 2019, are associated with high mortality. This recently identified coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as "2019 novel coronavirus" or "2019-nCoV", has rapidly infected hundreds of thousands of people. The pandemic caused by the SARS-CoV-2 virus has been named COVID-19 (Coronavirus Disease 2019) by the World Health Organization (WHO). The first genome sequence of the SARS-CoV-2 isolate (Wuhan-Hu-1) was published on January 10, 2020 by researchers at the Chinese CDC in Beijing in Virological, a department for virus analysis and interpretation UK-based discussion forum for molecular evolution and epidemiology. The sequence was then deposited in GenBank on January 12, 2020, with GenBank accession number MN908947.1.

Currently, there is no specific treatment for COVID-19 or a vaccine against SARS-CoV-2 infection. The ongoing health problems and mortality associated with coronavirus infections, especially the SARS-CoV-2 pandemic, are of great international concern. The public health crisis caused by SARS-CoV-2 reinforces the importance of rapidly developing effective and safe vaccine candidates against these viruses.

In some embodiments, provided herein are compositions (eg, vaccines) comprising one or more messenger ribonucleic acid (mRNA) molecules encoding a potent medium capable of eliciting an antigen against SARS-CoV-2 Highly immunogenic antigens that react with antibodies. The mRNA molecules described herein are used to express the key neutralizing domain of the SARS-CoV-2 coronavirus spike (S) protein, which is effective in inducing protective properties when used individually or in combination as an immunogenic composition or vaccine Immunization to protect a person from natural viral infection and/or reduce symptoms if infected.

The envelope S protein of betacoronaviruses is known to determine viral host tropism and entry into host cells and is critical for SARS-CoV-2 infection. The organization of the S protein in betacoronaviruses such as SARS-CoV-2, SARS-CoV, MERS-CoV, HKU1-CoV, MHV-CoV and NL63-CoV (including two subunits S1 and S2, which mediate attachment and membrane fusion)). The S1 subunit includes an N-terminal domain (NTD) and a receptor binding domain (RBD).

The presentation of subunit antigens focuses the immune response on specific subunits, with minimal stimulation of memory B and T cells specific for other domains of antigens shared by other related viruses. The data presented herein demonstrate that administration of mRNA encoding a membrane-bound or soluble SARS-CoV-2 S1 subunit antigen produces targeting of the SARS-CoV-2 RBD antigen, NTD antigen, wild-type full-length S protein, and a bisproline mutation to Antibody titers for each of the S proteins that stabilized the prefusion conformation. As shown herein, at all doses tested, the two-dose regimen (ie, including the booster dose) was effective in inducing antibodies that recognize and bind to the SARS-CoV-2 WT S protein. Surprisingly, even though no bisproline mutation was found in the S1 subunit (the bisproline mutation occurred in S2, which was not present in the tested immunogens), when targeting the bisproline stable form When the S protein was measured, the induction titer was the highest.

In addition, both NTD and RBD are known to be sites of binding of antibodies that neutralize viral activity. In the case of SARS-CoV-2, RBD is the receptor binding site for the spike protein, which binds vasoconstrictor peptide converting enzyme 2 (ACE2). The function of NTD is not fully understood, but it appears to play a role in binding the sugar moiety and promoting the conformational transition of the spike protein from the prefusion to the postfusion conformation. Regardless, both the NTD and RBD domains induce high binding and neutralizing antibody titers as shown herein.

For example, it is rather surprising that the data presented in some of the examples herein show that although sera from administration of mRNA encoding membrane-bound RBD antigen (RBD-TM) or membrane-bound NTD antigen (NTD-TM) show Immunogenic for the SARS-CoV-2 S1/S2 spike protein, but a 50:50 combination of the two mRNAs (and thus the two antigens) yields unexpectedly high levels of the SARS-CoV-2 S1/S2 spike protein The synergistic neutralizing antibody titer.

Accordingly, some aspects of the present disclosure provide compositions comprising mRNA encoding a functional domain of the SARS-CoV-2 S protein capable of inducing an immune response, such as a neutralizing antibody response, against SARS-CoV-2 . In some embodiments, the mRNA is formulated in lipid nanoparticles.

In some aspects, an mRNA comprising an open reading frame (ORF) that encodes at least two domains of the SARS-CoV-2 spike protein and is smaller than the full-length spike protein is provided. Spike proteins that are smaller than the full-length spike protein are those that have one or more domains and/or subunits of the spike protein that are at least one amino acid fewer than the full-length spike protein, or have a non-native order or sequence linked together A fusion protein of one or more domains. In some embodiments, one of the two domains is the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. In some embodiments, one of the two domains is the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. In some embodiments, the ORF encodes a transmembrane domain (TD) linked to NTD and/or RBD. In some embodiments, the TD is an influenza hemagglutinin transmembrane domain. In some embodiments, the ORF comprises NTD-RBD-TM. In some embodiments, at least two domains are linked via a cleavable or non-cleavable linker. In some embodiments, the non-cleavable linker system glycine-serine (GS) linker. In some embodiments, the GS linkage system is 4-15 amino acids. In some embodiments, the linking system is a pan HLA DR-binding epitope (PADRE). In some embodiments, the ORF encodes a signal peptide. In some embodiments, the signal peptide is linked to the NTD. In some embodiments, the signal peptide is linked to the RBD. In some embodiments, the signal peptide is heterologous to SARS-CoV-2. In some embodiments, at least two domains are soluble. In some embodiments, the ORF encodes a trafficking signaling domain. In some embodiments, the trafficking signaling domain is a macrophage marker. In some embodiments, the macrophage markers are CD86 and/or CD11b. In some embodiments, the trafficking signaling domain is a VSV-G cytoplasmic tail (VSVGct). In some embodiments, one of the two domains is the first repeat heptapeptide of the SARS-CoV-2 spike protein: HPPHCPC (HR1). In some embodiments, one of the two domains is the second repeat heptapeptide of the SARS-CoV-2 spike protein: HPPHCPC (HR2). In some embodiments, the ORF encodes a transmembrane domain (TD) linked to HR1 and/or HR2. In some embodiments, the TD is an influenza hemagglutinin transmembrane domain. In some embodiments, the ORF encodes a fusion peptide (FP). In some embodiments, the ORF encodes a CT tail.

In some aspects, an mRNA comprising an open reading frame (ORF) encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein is provided. In some embodiments, the RBD is soluble. In some embodiments, the RBD is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain.

The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will become apparent from the following drawings and detailed description of several embodiments and appended claims.

related applications

This application claims U.S. Provisional Application No. 63/044,330, filed June 25, 2020, and U.S. Provisional Application No. 63/063,137, filed August 7, 2020, under 35 U.S.C. § 119(e) The rights and interests of each application are incorporated herein by reference in their entirety.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged respiratory virus with high morbidity and mortality. Compared with SARS-CoV, which emerged in 2002, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which emerged in 2012, SARS-CoV-2 has spread rapidly around the world. The World Health Organization (WHO) reports that as of July 6, 2020, the current outbreak of COVID-19 has nearly 11.5 million confirmed cases worldwide, with more than 530,000 deaths. New cases of COVID-19 infections are on the rise and are still increasing rapidly. Therefore, it is crucial to develop various safe and effective vaccines and drugs to prevent and treat COVID-19 and reduce the severe impact of COVID-19 worldwide. There is a need for vaccines and drugs prepared using a variety of methods, as well as vaccines with improved safety and efficacy. There is still a need to accelerate advanced design and development of vaccines and therapeutics for the coronavirus disease 2019 (COVID-19).

On January 7, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the causative agent of a novel pneumonia that appeared in Wuhan, Hubei Province, China in December 2019 (Lu H et al. (2020) J Med Virol. Apr;92(4):401-402.). Soon, the virus caused an outbreak in China and spread around the world. According to the analysis of the genome structure of SARS-CoV-2, it belongs to beta-coronavirus (CoV) (Chan et al., 2020 Emerg Microbes Infect .; 9(1):221-236).

The key protein on the surface of the coronavirus is the spike protein. A number of mRNA constructs have been designed and are disclosed herein. When formulated in an appropriate delivery vehicle, mRNA encoding the spike antigen, subunits and domains are capable of inducing a potent immune response against SARS-CoV-2, resulting in an effective and potent mRNA vaccine. Administration of mRNA encoding various Spike antigens, particularly Spike subunit and domain antigens, results in delivery of the mRNA to immune tissues and cells of the immune system, where it is rapidly translated into protein antigens. Other immune cells, such as B cells and T cells, are then able to recognize and initiate, and the immune response develops an immune response against the encoded protein and ultimately a durable protective response against the coronavirus. Low immunogenicity (a disadvantage of protein vaccine development due to poor presentation to the immune system or incorrect folding of the antigen) is avoided by using the highly efficient mRNA vaccines disclosed herein encoding the spike protein, its subunits and domains.

The present disclosure provides compositions (eg, mRNA vaccines) that elicit potent neutralizing antibodies against coronavirus antigens. In some embodiments, the composition includes mRNA encoding at least one (eg, one, two, or more) coronavirus antigens, such as SARS-CoV-2 antigens. In some embodiments, the mRNA encodes a spike protein domain, such as a receptor binding domain (RBD), an N-terminal domain (NTD), or a combination of RBD and NTD.

Some aspects of the present disclosure provide messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the receptor binding domain (RBD) and protein transmembrane structure of the SARS-CoV-2 spike protein domains, such as naturally occurring or heterologous transmembrane domains.

In some embodiments, the protein transmembrane domain is an influenza hemagglutinin transmembrane domain.

In some embodiments, the fusion protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the fusion protein comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 77 amino acid sequence.

In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO:77.

In some embodiments, the open reading frame comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO:76.

In some embodiments, the open reading frame comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or Nucleotide sequences that are at least 99% identical.

In some embodiments, the open reading frame comprises the nucleotide sequence of SEQ ID NO:76.

Other aspects of the present disclosure provide messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the amino (N) terminal domain and the transmembrane domain of the SARS-CoV-2 spike protein .

In some embodiments, the transmembrane domain is an influenza hemagglutinin transmembrane domain.

In some embodiments, the fusion protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47.

In some embodiments, the fusion protein comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 47 amino acid sequence.

In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO:47.

In some embodiments, the open reading frame comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 46.

In some embodiments, the open reading frame comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or Nucleotide sequences that are at least 99% identical.

In some embodiments, the open reading frame comprises the nucleotide sequence of SEQ ID NO:46.

Other aspects of the disclosure provide messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising, optionally via a linker, the amine (N) terminus of the SARS-CoV-2 spike protein Domain-linked receptor-binding domains of the SARS-CoV-2 spike protein.

In some embodiments, the fusion protein further comprises a transmembrane domain.

In some embodiments, the fusion protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 92.

In some embodiments, the fusion protein comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 92 amino acid sequence.

In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO:92.

In some embodiments, the open reading frame comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 91.

In some embodiments, the open reading frame comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or Nucleotide sequences that are at least 99% identical.

In some embodiments, the open reading frame comprises the nucleotide sequence of SEQ ID NO:91.

In some embodiments, the mRNA further comprises a 5' untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO: 131 or 2, as appropriate.

In some embodiments, the mRNA further comprises a 3' untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO: 132 or 4, as appropriate.

In some embodiments, the mRNA further comprises a 5' end cap, optionally 7mG(5')ppp(5')NlmpNp.

In some embodiments, the mRNA further comprises a poly-A tail, optionally having a length of about 100 nucleotides.

In some embodiments, the mRNA comprises a chemical modification, optionally 1-methylpseudouridine.

Some aspects of the present disclosure provide compositions comprising the mRNA of any of the preceding paragraphs.

Other aspects of the present disclosure provide compositions comprising at least two mRNAs of any of the preceding paragraphs.

Other aspects of the present disclosure provide compositions comprising: (a) messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising a receptor for the SARS-CoV-2 spike protein Binding domain (RBD) and protein transmembrane domain; (b) mRNA comprising an open reading frame encoding a fusion protein comprising the amino (N) terminal domain and transmembrane domain of the SARS-CoV-2 spike protein membrane domain. In some embodiments, the ratio of mRNA of (a) to mRNA of (b) is about 1:1, eg, 1:2, 1:3, 2:1, or 3:1. In some embodiments, at least 50% of the mRNA of the composition is the mRNA of (a). For example, at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the mRNA of the composition is the mRNA of (a). In some embodiments, at least 50% of the mRNA of the composition is the mRNA of (b). For example, at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the mRNA of the composition is the mRNA of (b).

In some embodiments, the protein transmembrane domain is an influenza hemagglutinin transmembrane domain.

In some embodiments, the fusion protein of (a) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the fusion protein of (a) comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least the amino acid sequence of SEQ ID NO: 77 99% identical amino acid sequence.

In some embodiments, the fusion protein of (a) comprises the amino acid sequence of SEQ ID NO:77.

In some embodiments, the open reading frame of (a) comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 76.

In some embodiments, the open reading frame of (a) comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 97% of the nucleotide sequence of SEQ ID Nucleotide sequences that are at least 98% or at least 99% identical.

In some embodiments, the open reading frame of (a) comprises the nucleotide sequence of SEQ ID NO:76.

In some embodiments, the fusion protein of (b) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47.

In some embodiments, the fusion protein of (b) comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least the amino acid sequence of SEQ ID NO: 47 99% identical amino acid sequence.

In some embodiments, the fusion protein of (b) comprises the amino acid sequence of SEQ ID NO:47.

In some embodiments, the open reading frame of (b) comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 46.

In some embodiments, the open reading frame of (b) comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 97% of the nucleotide sequence of SEQ ID NO: 46, Nucleotide sequences that are at least 98% or at least 99% identical.

In some embodiments, the open reading frame of (b) comprises the nucleotide sequence of SEQ ID NO:46.

In some embodiments, the mRNA is formulated in lipid nanoparticles.

In some embodiments, the composition further comprises lipid nanoparticles.

In some embodiments, the mRNA of (a) is formulated in lipid nanoparticles, and the mRNA of (b) is formulated in lipid nanoparticles.

In some embodiments, the lipid nanoparticles comprise cationic lipids.

In some embodiments, the lipid nanoparticles further comprise neutral lipids.

In some embodiments, the lipid nanoparticle further comprises a sterol.

In some embodiments, the lipid nanoparticles further comprise polyethylene glycol (PEG) modified lipids.

In some embodiments, lipid nanoparticles comprise ionizable cationic lipids, neutral lipids, sterols, and PEG-modified lipids.

In some embodiments, the ionizable cationic lipid is 8-((2-hydroxyethyl)(6-oxy-6-(undecyloxy)hexyl)amino)octanoic acid heptadecan-9 - base ester (compound 1).

In some embodiments, the neutral lipid is 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC).

In some embodiments, the sterol is cholesterol.

In some embodiments, the PEG-modified lipid is 1,2 dimyristoyl-sn-glycero-methoxypolyethylene glycol (PEG2000 DMG).

In some embodiments, the lipid nanoparticles comprise 20-60 mol% ionizable cationic lipids, 5-25 mol% neutral lipids, 25-55 mol% sterols, and 0.5-15 mol% PEG-modified lipids.

In some embodiments, the lipid nanoparticles comprise: 47 mol% ionizable cationic lipids; 11.5 mol% neutral lipids; 38.5 mol% sterols; and 3.0 mol% PEG-modified lipids; 48 mol% ionizable lipids 11 mol% neutral lipids; 38.5 mol% sterols; and 2.5 mol% PEG-modified lipids; 49 mol% ionizable cationic lipids; 10.5 mol% neutral lipids; 38.5 mol% sterols; and 2.0 mol% PEG-modified lipids; 50 mol% ionizable cationic lipids; 10 mol% neutral lipids; 38.5 mol% sterols; and 1.5 mol% PEG-modified lipids; or 51 mol% ionizable cationic lipids; 9.5 mol% neutral lipids; 38.5 mol% sterols; and 1.0 mol% PEG-modified lipids.

In some embodiments, the lipid nanoparticle comprises 47 mol% Compound 1; 11.5 mol% DSPC; 38.5 mol% cholesterol; and 3.0 mol% PEG2000 DMG; 48 mol% Compound 1; 11 mol% DSPC; 38.5 mol% cholesterol; and 2.5 mol% PEG2000 DMG; 49 mol% Compound 1; 10.5 mol% DSPC; 38.5 mol% cholesterol; and 2.0 mol% PEG2000 DMG; 50 mol% Compound 1; 10 mol% DSPC; 38.5 mol% cholesterol; and 1.5 mol% PEG2000 DMG; or 51 mol% Compound 1; 9.5 mol% DSPC; 38.5 mol% cholesterol; and 1.0 mol% PEG2000 DMG.

Other aspects of the present disclosure provide a method comprising administering to an individual an mRNA or combination of any of the following claims in an amount effective to induce a neutralizing antibody response against SARS-CoV-2 in the individual thing.

Other aspects of the present disclosure provide a method comprising administering to an individual an mRNA or combination of any of the following claims in an amount effective to induce a T cell immune response against SARS-CoV-2 in the individual thing.

Some aspects of the present disclosure provide messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding a coronavirus antigen capable of inducing an immune response (such as a neutralizing antibody response) against SARS-CoV-2 , wherein the antigen comprises a protein fragment or functional protein domain of SARS-CoV-2, optionally wherein the RNA is formulated in lipid nanoparticles.

In some embodiments, the antigen is a functional protein domain.

In some embodiments, the protein domain is the N-terminal domain (NTD) of the SARS-CoV-2 spike protein.

In some embodiments, the NTD is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 47 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:47.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 46.

In some embodiments, the protein domain is the receptor binding domain (RBD) of the SARS-CoV-2 spike protein.

In some embodiments, the RBD is soluble.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 62 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:62.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 61.

In some embodiments, the RBD is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 77 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:77.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:76.

In some embodiments, the NTD is linked to the RBD of the SARS-CoV-2 spike protein to form an NTD-RBD fusion protein.

In some embodiments, the NTD-RBD fusion is linked to a transmembrane domain (TM), optionally linked to an influenza hemagglutinin transmembrane domain, to form an NTD-RBD-TM protein.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 92 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:92.

In some embodiments, an open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 91.

In some embodiments, the NTD-RBD fusion comprises a C-terminal truncation.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 107 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 107.

In some embodiments, an open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 97%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 106.

In some embodiments, NTDs and/or RBDs include extension regions.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95% of the amino acid sequence of any one of SEQ ID NOs: 59, 86, 89, 116, 119, or 122 , at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, optionally wherein the antigen comprises any one of SEQ ID NOs: 59, 86, 89, 116, 119 or 122 the amino acid sequence.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 70%, at least 75%, at least 80%, at least the 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises SEQ ID NOs: 58, 85, 88, 115, The nucleotide sequence of any of 118 or 121.

In some embodiments, the protein domain is the S1 subunit domain of the SARS-CoV-2 spike protein.

In some embodiments, the S1 subunit is soluble.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 5 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:5.

In some embodiments, an open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 3.

In some embodiments, the S1 subunit is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 17 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 17.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 16.

In some embodiments, the S1 subunit is modified to remove the RBD or a portion of the RBD of the S protein.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95% of the amino acid sequence of any one of SEQ ID NOs: 20, 23, 26, 29, 32, or 35 , at least 96%, at least 97%, at least 98% or at least 99% identical amino acid sequences, optionally wherein the antigen comprises any one of SEQ ID NOs: 20, 23, 26, 29, 32 or 35 the amino acid sequence.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises SEQ ID NOs: 19, 22, 25, 28, The nucleotide sequence of any of 31 or 34.

In some embodiments, the S1 subunit is linked to the S2 subunit of the S protein.

In some embodiments, the S2 subunit is from the SARS-CoV-2 S protein.

In some embodiments, the S1 subunit is from the HKU1 S protein.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 38 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:38.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:37.

In some embodiments, the S1 subunit is from an OC43 S protein.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of SEQ ID NO: 41 % identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 41.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, A nucleotide sequence that is at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 40.

In some embodiments, the antigen further comprises a scaffold domain, optionally selected from the group consisting of ferritin, lumazine synthetase, and foldon.

In some embodiments, the scaffold domain is ferritin.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or An amino acid sequence of at least 99% identity wherein the antigen comprises the amino acid sequence of SEQ ID NO: 8 or 65, as appropriate.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97% of the nucleotide sequence of SEQ ID NO: 7 or 64 %, at least 98%, or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 7 or 64.

In some embodiments, the scaffold domain is a dioxytetrahydropteridine synthase.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96% of the amino acid sequence of any one of SEQ ID NOs: 11, 14, 68, or 71 , an amino acid sequence of at least 97%, at least 98%, or at least 99% identity, optionally wherein the antigen comprises the amino acid sequence of any one of SEQ ID NOs: 11, 14, 68, or 71.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least A nucleotide sequence that is 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises any one of SEQ ID NOs: 10, 13, 67 or 70 the nucleotide sequence.

In some embodiments, the scaffold domain is a foldon.

In some embodiments, the antigen comprises at least 80%, at least 85%, at least 90% of the amino acid sequence of any one of SEQ ID NOs: 44, 50, 74, 80, 83, 101, 104, or 113 , at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, optionally wherein the antigen comprises SEQ ID NOs: 44, 50, 74, 80, 83, 101, The amino acid sequence of any of 104 or 113.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 70%, at least 75%, at least 70%, at least A nucleotide sequence that is 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises SEQ ID NOs: 43, 49, The nucleotide sequence of any of 73, 79, 82, 100, 103 or 112.

In some embodiments, the antigen further comprises a trafficking signal, optionally selected from macrophage markers, optionally CD86, CD11B and/or VSVGct.

In some embodiments the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least An amino acid sequence that is 97%, at least 98%, or at least 99% identical, as appropriate, wherein the antigen comprises the amino acid sequence of any of SEQ ID NOs: 95, 98, or 110.

In some embodiments, the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95% of the nucleotide sequence of any one of SEQ ID NOs: 94, 97, or 109 , a nucleotide sequence of at least 96%, at least 97%, at least 98%, or at least 99% identity, optionally wherein the open reading frame comprises the nucleotides of any one of SEQ ID NOs: 94, 97, or 109 sequence.

In some embodiments, the mRNA is formulated in lipid nanoparticles.

In some embodiments, the lipid nanoparticles comprise cationic lipids (optionally ionizable cationic lipids), neutral lipids, sterols, and/or polyethylene glycol (PEG) modified lipids. Ionizable cationic lipids are used interchangeably herein with ionizable lipids and cationic lipids to refer to ionizable lipids. In some embodiments, the lipid nanoparticle comprises 40-50 mol% ionizable lipid, optionally 45-50 mol%, eg, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48 -49 mol% or 49-50 mol%, such as about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol% or 49.5 mol%. In some embodiments, the lipid nanoparticle comprises 30-45 mol% sterol, optionally 35-40 mol%, eg, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol% mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 38-38 mol%, 38-39 mol%, or 39-40 mol%. In some embodiments, the lipid nanoparticle comprises 5-15 mol% helper lipid, optionally 10-12 mol%, eg, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8-9 mol% mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol% or 14-15 mol%. In some embodiments, lipid nanoparticles comprise 1-5% PEG lipid, optionally 1-3 mol%, eg, 1.5-2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol% % or 4-5 mol%.

In some embodiments, the ionizable cationic lipid is 8-((2-hydroxyethyl)(6-oxy-6-(undecyloxy)hexyl)amino)octanoic acid heptadecan-9 - base ester (compound 1), neutral lipid system 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC), sterol system cholesterol, and/or PEG-modified lipid system 1 , 2 dimyristyl-sn-glycerol-methoxy polyethylene glycol (PEG2000 DMG).

In some embodiments, the lipid nanoparticles comprise 20-60 mol% ionizable cationic lipids, 5-25 mol% neutral lipids, 25-55 mol% sterols, and 0.5-15 mol% PEG-modified lipids.

In some embodiments, the lipid nanoparticles comprise: 47 mol% ionizable cationic lipids; 11.5 mol% neutral lipids; 38.5 mol% sterols; and 3.0 mol% PEG-modified lipids; 48 mol% ionizable lipids 11 mol% neutral lipids; 38.5 mol% sterols; and 2.5 mol% PEG-modified lipids; 49 mol% ionizable cationic lipids; 10.5 mol% neutral lipids; 38.5 mol% sterols; and 2.0 mol% PEG-modified lipids; 50 mol% ionizable cationic lipids; 10 mol% neutral lipids; 38.5 mol% sterols; and 1.5 mol% PEG-modified lipids; or 51 mol% ionizable cationic lipids; 9.5 mol% neutral lipids; 38.5 mol% sterols; and 1.0 mol% PEG-modified lipids.

In some embodiments, the lipid nanoparticle comprises 47 mol% Compound 1; 11.5 mol% DSPC; 38.5 mol% cholesterol; and 3.0 mol% PEG2000 DMG; 48 mol% Compound 1; 11 mol% DSPC; 38.5 mol% cholesterol; and 2.5 mol% PEG2000 DMG; 49 mol% Compound 1; 10.5 mol% DSPC; 38.5 mol% cholesterol; and 2.0 mol% PEG2000 DMG; 50 mol% Compound 1; 10 mol% DSPC; 38.5 mol% cholesterol; and 1.5 mol% PEG2000 DMG; or 51 mol% Compound 1; 9.5 mol% DSPC; 38.5 mol% cholesterol; and 1.0 mol% PEG2000 DMG.

The entire contents of International Application No. PCT/US2016/058327 (Publication No. WO2017/070626) and International Application No. PCT/US2018/022777 (Publication No. WO2018/170347) are incorporated herein by reference. SARS-Cov-2

The genetic system of SARS-CoV-2 single-stranded positive-sense RNA (+ssRNA), 29.8-30 kb in size, encodes about 9860 amino acids (Chan et al., 2000, supra; Kim et al., 2020 Cell, May 14 Sun;181(4):914-921, e10). SARS-CoV-2 is a polycistronic mRNA with a 5'-end cap and a 3'-poly A tail. The SARS-CoV-2 genome is organized into specific genes encoding structural and nonstructural proteins (Nsp). The sequence of structural proteins in the genome is 5'-replicase (open reading frame (ORF) 1/ab)-structural protein [spike (S)-mantle (E)-membrane (M)-nucleoprotein shell ( N)]-3'. The genome of coronaviruses includes a variable number of open reading frames encoding accessory, nonstructural, and structural proteins (Song et al., 2019 Viruses; 11(1): p. 59). Most antigenic peptides are located in structural proteins (Cui et al., 2019 Nat. Rev. Microbiol.; 17(3):181-192). Spike surface glycoprotein (S), small envelope protein (E), matrix protein (M) and nucleic acid protein capsid protein (N) are four major structural proteins. Since the S-protein contributes to cell tropism, its ability to induce neutralizing antibodies (NAbs) and protective immunity, it can be regarded as one of the most important targets in coronavirus vaccine development among all other structural proteins. In addition, amino acid sequence analysis showed that the S-protein contains a conserved region in coronaviruses, which can be the basis for the development of a universal vaccine. antigen

Compositions (eg vaccine compositions) of the invention are characterized by nucleic acids designed to encode relevant antigens (eg, antigens derived from betacoronavirus structural proteins, particularly antigens derived from the SARS-CoV-2 spike protein) , especially mRNA. The compositions (eg vaccine compositions) of the invention do not comprise the antigen itself, but rather comprise nucleic acid, particularly mRNA, that encodes the antigen or antigenic sequence once delivered to a cell, tissue or individual. Delivery of nucleic acid molecules, particularly mRNA, is accomplished by formulating the nucleic acid molecules in a suitable carrier or delivery vehicle (eg, lipid nanoparticles) such that upon administration to a cell, tissue or individual, Nucleic acids are taken up by cells, which in turn express proteins encoded by nucleic acids (eg, mRNA). The term "antigen" as used herein refers to substances such as proteins (eg, glycoproteins), polypeptides, peptides, or the like, which elicit an immune response, eg, when present in an individual (eg, when present in a human or mammalian individual). time) triggers an immune response. The invention is based, at least in part, on the understanding that, when an mRNA-encoded antigen is self-administered to the expression of the mRNA in a cell or individual, the immune system can be induced to mount an immune response against the expressed antigen, for example, antibodies to the expressed antigen can be triggered (e.g., binding and The production of neutralizing antibodies) can trigger a B-cell and or T-cell response specific for the presented antigen and, ultimately, can elicit a protective or preventive response against subsequently encountered antigen or antigen-related pathogens. A preferred mRNA-encoded antigen is a "viral antigen". The term "viral antigen" as used herein refers to an antigen derived from a virus, eg, from a pathogenic virus. The term antigen as used herein may refer to a full-length protein, eg, a full-length viral protein, or may refer to a fragment (eg, a polypeptide or peptide fragment), subunit or domain of a protein, eg, a viral protein subunit or domain.

Many proteins have a quaternary or three-dimensional structure consisting of more than one polypeptide or several polypeptide chains associated into oligomeric molecules. The term "subunit" as used herein refers to a single protein molecule, eg, a polypeptide or polypeptide chain resulting from processing a nascent protein molecule, that assembles (or "co-assembles" with other protein molecules (eg, subunits or chains) ) to form protein complexes. A protein may have a relatively small number of subunits and thus be described as "oligomeric", or may consist of a large number of subunits and thus be described as "polymeric". Subunits of oligomeric or multimeric proteins can be identical, homologous or completely dissimilar, and dedicated to different tasks.

The protein or protein subunit may further comprise domains. The term "domain" as used herein refers to distinct functional and/or structural units within a protein. Typically, "domains" are responsible for specific functions or interactions that contribute to the overall functioning of the protein. Domains can exist in a variety of biological contexts. Similar domains (ie, domains that share structural, functional and/or sequence homology) may exist within a single protein or may exist within different proteins with similar or different functions. A protein domain is typically a conserved portion of a given protein's tertiary structure or sequence that can function and exist independently of the rest of the protein or its subunits.

In structural and molecular biology, identical, homologous, or similar subunits or domains can aid in the classification of newly identified or novel proteins, as was done immediately after the publication of the SARS-CoV-2 viral genome sequence.

The term antigen as used herein differs from the term "epitope," which is a substructure of an antigen, such as a polypeptide or carbohydrate structure, that is recognized by the antigen binding site, but is not sufficient to induce an immune response. Protein antigens, such as isolated protein, polypeptide or peptide antigens, are described in the art for delivery to an individual or immune cell in isolated form, however, the design, testing, validation and production of protein antigens can be expensive and time consuming, especially when produced on a large scale protein time. In contrast, mRNA technology can be used to rapidly design and test mRNA constructs encoding various antigens. In addition, rapid production of mRNA in combination with formulated in an appropriate delivery vehicle (eg, lipid nanoparticles) can be performed rapidly and mRNA vaccines can be produced rapidly on a large scale. Potential benefits also arise from the fact that the antigens encoded by the mRNAs of the invention are expressed by cells of the individual, eg, by the human body, and thus, the individual (eg, the human body) acts as a "factory" to generate antigens, which in turn elicit the desired immune response.

In preferred aspects, the antigen is a protein capable of inducing an immune response (eg, causing the immune system to produce antibodies against the antigen). As used herein, unless otherwise stated, the use of the term "antigen" includes immunogenic proteins as well as polypeptides or peptides derived from immunogenic proteins, such as immunogenic fragments that induce (or are capable of inducing) an immune response to the antigen the immunogenic fragment). It is to be understood that the term "protein" encompasses polypeptides and peptides, and the term "antigen" encompasses antigenic fragments. Other molecules may be antigenic, such as bacterial polysaccharides or combinations of proteins and polysaccharide structures, but for viral vaccines included herein, viral proteins, viral protein fragments and designs and/or mutations derived from betacoronavirus SARS-CoV-2 The protein is the antigen characterized herein. Nucleic acid /mRNA

The vaccine technologies described herein feature nucleic acids, particularly messenger RNA (mRNA), designed to encode relevant antigens (eg, betacoronavirus spike protein antigens, subunits, domains or fragments (eg, antigenic fragments)). The nucleic acid (eg, mRNA) of the present invention is preferably formulated in a suitable carrier or delivery vehicle (eg, lipid nanoparticle), making the nucleic acid (eg, mRNA) suitable for in vivo use. Nucleic acids (eg, mRNAs), when appropriately formulated, can be delivered to cells and/or tissues within an individual (eg, a human individual) to accomplish translation of the proteins encoded by the nucleic acids.

Nucleic acid molecules are macromolecules composed of linked nucleotides that carry genetic information and direct most, if not all, cellular functions by directing the process of protein synthesis. Nucleic acids comprise polymers of nucleotides (nucleotide monomers). Accordingly, nucleic acids are also known as polynucleotides (also known as polynucleotide chains). The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA constitutes the genetic material in all free-living organisms and in most viruses. RNA is the genetic material of some viruses, but is also found in all living cells where it plays an important role in cellular processes, most notably in the production of proteins.

Nucleosides are structural subunits of nucleic acids such as DNA and RNA. Nucleosides consist of a nitrogenous base (nucleobase), usually a pyrimidine (cytosine, thymine, or uracil), covalently attached to the five-carbon carbohydrate ribose or "sugar" (which is ribose or deoxyribose) or purine (adenine or guanine). Nucleotides consist of a nitrogenous base, a sugar (ribose or deoxyribose), and one to three phosphate groups. Essentially, nucleotides are simply nucleosides with one or more additional phosphate groups.

Nucleic acid molecules (DNA and RNA) are composed of nucleotides linked to each other in a chain by chemical bonds (called ester bonds) between the sugar bases of one nucleotide and the phosphate groups of adjacent nucleotides. The sugar is at the 3' end of each nucleotide and the phosphate is at the 5' end of each nucleotide. The phosphate group attached to the 5' carbon of the sugar on one nucleotide forms an ester bond with the free hydroxyl group on the 3' carbon of the next nucleotide. These bonds are called phosphodiester bonds, and when synthesizing the molecule, the sugar-phosphate backbone is illustrated as extending or growing in the 5' to 3' direction.

The nucleobase portion of nucleic acids is characterized by the purine bases: adenine (A) and guanine (G); and the pyrimidine bases: cytosine (C), thymine (T) in DNA, and uracil in RNA (U). The sugar moiety of nucleic acids is characterized by deoxyribose in DNA and ribose in RNA. The five nucleosides are commonly abbreviated by their one-letter codes A, G, C, T, and U, respectively. However, thymidine is more commonly written as "dT" ("d" stands for "deoxy") because it contains a 2'-deoxyribofuranose moiety rather than the ribofuranose ring found in uridine. This is due to the fact that thymidine is found in deoxyribonucleic acid (DNA) rather than ribonucleic acid (RNA). In contrast, uridine is found in RNA rather than DNA. The remaining three nucleosides can be found in both RNA and DNA. In RNA it will be denoted A, C and G, and in DNA it will be denoted dA, dC and dG.

It will be understood by those skilled in the art that unless otherwise stated, the nucleic acid sequences illustrated in this application may recite a "T" in a representative DNA sequence, but where the sequence represents mRNA, the "T" will be replaced by "U". Thus, any DNA disclosed and identified by a specific sequence identification number herein also discloses the corresponding mRNA sequence complementary to the DNA, wherein each "T" of the DNA sequence is substituted with a "U".

Nucleic acids can be or can include, for example, deoxyribonucleic acid (DNA), ribonucleic acid (RNA) (eg, mRNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), peptide nucleic acid (PNA), locked nucleic acid ( LNAs, including LNAs with a β-D-ribose configuration, α-LNAs with an α-L-ribose configuration (a mirror isomer of LNA), 2'-amine functionalized with a 2'-amine group -LNA and 2'-amino-α-LNA with 2'-amino functionalization), ethylene nucleic acid (ENA), cyclohexenyl nucleic acid (CeNA) and/or chimeras and/or combinations thereof.

The invention features messenger RNA (mRNA), particularly mRNA designed to encode a relevant antigen (eg, betacoronavirus spike protein antigen, subunits, domains or fragments (eg, antigenic fragments)). Messenger RNA (mRNA), a subtype of RNA, is a single-stranded RNA molecule that corresponds to the genetic sequence of a gene. mRNA is produced during transcription, in which single-stranded DNA is decoded by RNA polymerase, and mRNA is synthesized, ie, transcribed. mRNA is read by ribosomes during protein synthesis, ie, translation. Thus, messenger RNA (mRNA) is RNA that encodes (at least one) protein (naturally-occurring, non-naturally-occurring or modified amino acid polymer), and can be translated for in vitro, in vivo, original The encoded protein is produced in situ or ex vivo.

Compositions of the present disclosure comprise (at least one) mRNA having an open reading frame (ORF) encoding a coronavirus antigen. In some embodiments, the mRNA further comprises a 5ꞌ UTR, a 3ꞌ UTR, a poly(A) tail, and/or a 5ꞌ end cap or end cap analog. An open reading frame (ORF) is a continuous stretch of DNA or RNA that begins with a start codon (eg, methionine (ATG or AUG)) and ends with a stop codon (eg, TAA, TAG, or TGA, or UAA, UAG) or UGA) ends. ORFs usually encode proteins. It is understood that the sequences disclosed herein may further comprise additional elements, such as 5' and 3' UTRs, but unlike ORFs, these elements are not necessarily present in the mRNAs of the present disclosure. It should also be understood that the mRNAs of the present invention (eg, mRNAs characterized in the betacoronavirus vaccines of the present disclosure) may include any 5' untranslated region (UTR) and/or any 3' UTR. Exemplary UTR sequences are provided in the Sequence Listing (eg, SEQ ID NOs: 2, 4, 131, and 132); however, other UTR sequences may use or replace any of the UTR sequences described herein. UTRs can also be omitted from the mRNAs provided herein.

In some embodiments, the composition comprises mRNA comprising at least 70%, at least 75%, at least 80%, at least 85% of the nucleotide sequence of any one of SEQ ID NOs: 45, 75 or 90 , at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical nucleotide sequences. In some embodiments, the composition comprises mRNA comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 70%, at least 75%, at least 80%, at least 85%, at least a nucleotide sequence of any of the sequences in Tables 1-15 Nucleotide sequences that are 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical.

In some embodiments, the composition comprises mRNA comprising at least 70%, at least 75%, at least 80%, at least 85% of the nucleotide sequence of any one of SEQ ID NOs: 46, 76, or 91 , at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical ORFs. In some embodiments, the composition comprises mRNA comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 70%, at least 75%, at least 80%, at least 85%, at least a nucleotide sequence of any of the sequences in Tables 1-15 ORFs of 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity.

Exemplary sequences of coronavirus antigens and mRNA encoding coronavirus antigens of the compositions of the present disclosure are provided in Tables 1-15.

It will be appreciated that any of the antigens encoded by the mRNAs described herein may or may not contain a signal sequence. Encoded coronavirus spike (S) protein antigen

The known mantle spike (S) protein of betacoronaviruses determines viral host tropism and entry into host cells. The coronavirus spike (S) protein is the antigen of choice for vaccine design because it induces neutralizing antibodies and protective immunity. The S protein is essential for SARS-CoV-2 infection. The organization of the S protein is similar in betacoronaviruses such as SARS-CoV-2, SARS-CoV, MERS-CoV, HKU1-CoV, MHV-CoV and NL63-CoV.

The term "spike protein" as used herein refers to a glycoprotein that forms a homotrimer protruding from the envelope (viral surface) of viruses, including betacoronaviruses. Trimeric spike proteins facilitate viral entry into host cells by binding to receptors on the host cell surface, followed by fusion of the viral and host cell membranes. The S protein is a large, highly glycosylated type I transmembrane fusion protein consisting of 1,160 to 1,400 amino acids, depending on the type of virus. Betacoronavirus spike proteins comprise approximately 1100 to 1500 amino acids and comprise the structure (i.e., domain composition and organization) as illustrated in Figure 1 . The SARS-CoV-2 spike (S) protein is the antigen of choice for vaccine design because of its ability to induce neutralizing antibodies and protective immunity. The mRNA of the invention is designed to produce the SARS-CoV-2 spike protein (ie, encodes the spike protein such that the spike protein behaves when the mRNA is delivered to a cell or tissue (eg, a cell or tissue of an individual)), and its antigenic variants. Those skilled in the art will appreciate that although substantially full-length or intact spike proteins may be necessary for a virus (eg, betacoronavirus) to perform its intended function of facilitating viral entry into host cells, when primary elicitation of targeting of the spike protein is sought. A quantitative change in the structure and/or sequence of the spike protein is tolerated during an immune response. For example, minor truncations such as one to several, possibly up to 5 or up to 10 amino acids from the N-terminus or C-terminus of the encoded spike protein (eg, the encoded spike protein antigen) can be tolerated , without changing the antigenic properties of the protein. Likewise, one to several, possibly up to 5 or up to 10 amino acid (or more) changes (eg, conservative substitutions) in the encoded spike protein (eg, the encoded spike protein antigen) are tolerated, while Does not alter the antigenic properties of the protein. In exemplary embodiments, the spike protein (eg, the encoded spike protein antigen) has the amino acid sequence (eg, derived from, eg, SEQ ID NO: 125) as set forth in any of the sequences of Tables 1-15 the amino acid sequence explained). In other embodiments, with a spike protein having the amino acid sequence set forth in any of the sequences of Tables 1-15 (eg, derived from the amino acid sequence set forth as SEQ ID NO: 125) Compared (when aligned to) the spike protein (eg, the encoded spike protein antigen) has no greater than 100, no greater than 90, no greater than 80, no greater than 70, no greater than 60, no greater than 50, no greater than 40 , no more than 30, no more than 20, no more than 10, or no more than 5 amino acid substitutions and/or deletions. Where minor changes are made in the encoded spike protein sequence, the variant preferably has the same activity and/or the same immunospecificity as the reference spike protein sequence, as for example in an immunoassay ( For example, as determined in an enzyme-linked immunosorbent assay (ELISA assay).

The S protein of coronavirus can be divided into two important functional subunits, including the N-terminal S1 subunit, which forms the globular head of the S protein; and the C-terminal S2 region, which forms the stem of the protein and directly embeds the viral jacket in the membrane. When interacting with a potential host cell, the S1 subunit will recognize and bind to receptors on the host cell, especially the vasoconstrictor peptide-converting enzyme 2 (ACE2) receptor, while the S2 subunit, the most conserved component of the S protein The unit will be responsible for fusing the viral envelope with the host cell membrane. (See eg, Shang et al., PLoS Pathog. 2020 Mar;16(3):e1008392.). Each monomer of the trimerized S protein trimer contains two subunits, S1 and S2, which mediate attachment and membrane fusion, respectively. See e.g. Figure 1 . As part of the in vivo infection process, the two subunits are separated from each other by an enzymatic cleavage process. The S protein is first cleaved at the S1/S2 site in infected cells by furin-mediated cleavage, followed by serine protease-mediated cleavage at the S2' site within S1 in vivo event. In SARS-CoV2, the S1/S2 cleavage site is at amino acid 676 - TQTNSPRRAR/SVA - 688 (refer to SEQ ID NO: 127). The S2' cleavage site is at amino acid 811 - KPSKR/SFI - 818 (refer to SEQ ID NO: 126).

As used herein, eg, in the context of designing a SARS-CoV-2 S protein antigen encoded by a nucleic acid (eg, mRNA) of the invention, the term "S1 subunit" (eg, S1 subunit antigen) refers to the N of the spike protein The terminal subunit, starting at the N-terminus of the S protein and ending with the S1/S2 cleavage site, and the term "S2 subunit" (e.g., the S2 subunit antigen) refers to the C-terminal subunit of the spike protein, beginning with S1/S2 The cleavage site begins and ends with the C-terminus of the spike protein. As noted above, those skilled in the art will appreciate that while substantially full-length or complete Spike protein S1 or S2 subunits may be required for receptor binding or membrane fusion, respectively, when the primary goal is to elicit targeting of the Spike protein subunits Quantitative changes in S1 or S2 structure and/or sequence are tolerated during the immune response of the unit. For example, one to several, possibly up to 4, 5, 6, 7, 8, 9 or 10 amines can be tolerated, eg, from the N or C terminus of the encoded subunit (eg, the encoded S1 or S2 protein antigen) Minor truncations of amino acids without altering the antigenic properties of the protein. Likewise, one to several, possibly up to 4, 5, 6, 7, 8, 9, or 10 amino acids (or more) of the encoded spike protein subunit (eg, the encoded S1 or S2 protein antigen) may be tolerated. multiple) changes (such as conservative substitutions) without changing the antigenic properties of the protein. In exemplary embodiments, the spike protein (eg, the encoded spike protein antigen) has the amino acid sequence (eg, derived from, eg, SEQ ID NO: 125) as set forth in any of the sequences of Tables 1-15 the amino acid sequence explained). In other embodiments, with a spike protein S1 subunit comprising or consisting of amino acids 1-685 of a spike protein having the amino acid sequence set forth in SEQ ID NO: 125 or Spike protein subunits (eg, the encoded S1 or S2 protein antigens) have different properties compared to (when aligned with) the spike protein S2 subunits comprising or consisting of amino acids 686-1273. More than 50, no more than 40, no more than 30, no more than 20, no more than 10, or no more than 5 amino acid substitutions and/or deletions. When minor changes are made in the encoded Spike subunit sequence, the variant preferably has the same activity and/or the same immunospecificity as the reference Spike subunit sequence, such as For example, as determined in an immunoassay, such as an enzyme-linked immunosorbent assay (ELISA assay).

The S1 and S2 subunits of the SARS-CoV-2 spike protein further include domains that are easily discernible by structure and function, and are further characterized by designing antigens encoded by nucleic acid vaccines, especially mRNA vaccines of the present invention. Within the S1 subunit, the domains include an N-terminal domain (NTD) and a receptor binding domain (RBD), which further includes a receptor binding motif (RBM). The wild-type S1 subunit also includes a signal peptide (SD) at the N-terminus of the NTD domain and a first subdomain (SD1) and a second subdomain (SD2). Within the S2 subunit, the domains include fusion peptide (FP), heptapeptide repeat 1 (HR1), heptapeptide repeat 2 (HR2), transmembrane domain (TM), and the cytoplasmic domain, also known as the cytoplasmic domain Tail region (CT) (Lu R. et al, supra; Wan et al, J. Virol. Mar 2020, 94(7) e00127-20). The HR1 and HR2 domains may be referred to as the "fusion core region" of SARS-CoV-2 (Xia et al., 2020 Cell Mol Immunol. Jan; 17(1): 1-12.). Figure 1 depicts the domain architecture in the SARS-CoV-2 spike protein. The S1 subunit includes an N-terminal domain (NTD), a linker region, a receptor binding domain (RBD), a first subdomain (SD1), and a second subdomain (SD2). The S1 subunit can be modified to add a C-terminal transmembrane domain (TM), or it can be soluble. The S2 subunit includes, inter alia, the first heptapeptide repeat region (HR1), the second heptapeptide repeat region (HR2), the transmembrane domain (TM), and the cytoplasmic tail region. Soluble S2 subunits can be produced without the TM domain.

The NTD and RBD of S1 are good antigens for use in the vaccine design methods of the present invention, as these domains have been shown to be targets for neutralizing antibodies in betacoronavirus-infected individuals. As used herein, for example, in the context of antigen design (the antigen is encoded by the mRNA of the invention and expressed, for example, by the mRNA vaccine of the invention), the term "N-terminal domain" or "NTD" refers to SARS-CoV-2 S1 time The domain within the unit, comprising about 290 amino acids in length, is identical to amino acids 1-290 of the S1 subunit of the spike protein having the amino acid sequence set forth in SEQ ID NO: 125. As used herein, eg, in the context of antigen design (the antigen is encoded by the mRNA of the invention and expressed, eg, by the mRNA vaccine of the invention), the term "receptor binding domain" or "RBD" refers to the A domain within the S1 subunit comprising about 175-225 amino acids in length with amino acids 316-517 of the S1 subunit of the spike protein having the amino acid sequence set forth in SEQ ID NO: 125 Consistent. The term "receptor binding motif" as used herein refers to the portion of the RBD that directly contacts the ACE2 receptor. The RBDs predicted to appear specifically bind to vasoconstrictor peptide converting enzyme 2 (ACE2) as its receptor and/or react specifically with RBD binding and/or neutralizing antibodies (eg, CR3022).

Compositions provided herein include mRNAs that can encode any or more full-length or partial (truncated or other sequence deletions) S protein subunits (eg, S1 or S2 subunits), one or more of S protein subunits Domains or combinations of domains (eg, NTD, RBD or NTD-RBD fusions, with or without SD1 and/or SD2) or chimeras of full or partial S1 and S2 protein subunits. Other S protein subunit and/or domain configurations are contemplated herein.

2 and 6 depict exemplary domains and subunit antigens derived from the SARS - CoV-2 spike protein. 2A and 2B depict soluble and transmembrane RBD antigens, respectively. Transmembrane NTD antigens are shown in Figure 2C. The domain antigens shown in Figures 2D-2F and 2I represent exemplary fusion proteins of NTD and RBD, each with SP and TM domains. Both of the constructs also have terminal trafficking domains (CD86 and/or CD11b). The domains are linked via linkers, in particular GS linkers or PADRE linkers (Figure 2I). Domain constructs with the RBD domain at the N-terminus of the NTD domain are depicted in Figures 2G and 2H. Each construct may also include SP and/or TM domains. encoded subunit antigen

Some aspects of the present disclosure provide compositions comprising mRNA encoding (at least one) subunit of the SARS-CoV-2 S protein. In some embodiments, the mRNA encodes the S1 subunit (eg, full-length or partial). In other embodiments, the mRNA encodes the S2 subunit (eg, full-length or partial). In other embodiments, the mRNA encodes a chimeric S1-S2 protein, wherein one subunit is from the SARS-CoV-2 S protein and the other subunit is from another organism, eg, a virus, such as influenza virus. The SARS-CoV-2 subunits (S1 and/or S2) encoded by the mRNAs of the present disclosure may be soluble or membrane bound (eg, linked to a transmembrane domain). An exemplary antigen design based on S2 is shown in FIG. 6 . Figure 6A depicts full-length S2, including FP, HRl, HR2, TM and CT domains. One form of S2 consisting of links between subunits is shown in Figure 6B. Domain antigens without the CT domain are shown in Figures 6C and 6D. soluble subunit antigen

Soluble proteins are present in the cytoplasm of cells or secreted from cells (eg, do not bind membranes). Soluble antigens secreted by cells can be opsonized by complement and captured by follicular dendritic cells in lymph nodes, where they are recognized by B cells specific for epitopes present on the expressed protein. The presentation of subunit antigens further allows to focus the immune response on specific subunits with minimal stimulation of memory B and T cells specific for other domains of antigens shared by other related viruses. Without being bound by theory, it is believed that presentation of the SARS-CoV-2 S1 subunits (including NTDs, RBDs, and in some cases intervening polypeptides of the SARS-CoV-2 S1 subunits) in a soluble form yields S1 subunit-specific Sexual immune response. Thus, in some embodiments, the mRNA provided herein encodes a soluble SARS-CoV-2 S1 subunit antigen and/or a soluble SARS-CoV-2 S2 subunit antigen. Non-limiting examples of soluble SARS-CoV-2 S1 subunit antigens and mRNAs encoding them are provided in Tables 1A and 1B below . Additional examples of soluble SARS-CoV-2 subunit antigens are provided herein. Table 1A. Soluble Subunit Antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 soluble S1 subunit 3 5 Table 1B. Soluble Subunit Antigens SARS-CoV-2 soluble S1 subunit SEQ ID NO: 1 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 3 and 3' UTR SEQ ID NO: 4. 1 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGG CGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCA 3 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNS 5 Poly A tail 100nt membrane bound subunit antigen

Membrane-bound proteins are anchored in the cell membrane (insoluble). Without being bound by theory, it is believed that antigen presenting cells carry embedded antigen to draining lymph nodes to generate a strong immune response. Germinal center responses occurring in draining lymph nodes include prolonged contacts between CD4 ⁺ TFH cells and B cells, allowing for co-stimulation and local intercellular signaling, such as IL-4 and IL-21, which favors antigen specificity for presented antigens. Replication and class switching of B cells to the production of IgGl, each of which promotes the production of long-lived plasma cells and memory B cells. Thus, in some embodiments, the mRNA encodes a membrane-bound SARS-CoV-2 S1 subunit antigen and/or a membrane-bound SARS-CoV-2 S2 subunit antigen. In some embodiments, a membrane-bound antigen (eg, S1 subunit, S2 subunit, NTD, RBD, or any combination thereof) is associated with a transmembrane domain (eg, a naturally occurring transmembrane domain or a heterologous transmembrane domain ( derived from a heterologous protein), which is responsible for anchoring the protein in the cell membrane) ligation. Non-limiting examples of membrane-bound SARS-CoV-2 S1 subunit antigens and SARS-CoV-2 S2 subunit antigens and mRNAs encoding them are provided in Tables 2A and 2B below . Other membrane-bound SARS-CoV-2 S1 subunit antigens are considered here. Table 2A. Membrane-bound subunit antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 S1 subunit linked to transmembrane domain (S1-666-TM) 16 17 SARS-CoV-2 S2 subunit (S2-TM) linked to the transmembrane domain 145 146 Table 2B. Membrane-bound subunit antigens SARS-CoV-2 S1 subunit linked to transmembrane domain (S1-666-TM) SEQ ID NO: 15 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 16 and 3' UTR SEQ ID NO: 4. 15 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGG CGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCAUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 16 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSGGGSILAIYSTVASSLVLLVSLGAISF 17 Poly A tail 100nt SARS-CoV-2 S2 subunit (S2-TM) comprising a transmembrane domain SEQ ID NO: 147 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 145 and 3' UTR SEQ ID NO: 4. 147 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGUACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACCCUCCCGAGGCCGAGGUGCAGAUCGACCGGCUGAUCACUGGCCGGCUGCAGAGCCUGCAGACCUACGUGACCCAGCAGC UGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCAGCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCACUACACC 145 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MYSMQLASCVTLTLVLLVNSQGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 146 Poly A tail 100nt Subunit antigen truncation and RBD deletion

In some embodiments, the composition comprises an mRNA encoding an S1 subunit that has been modified to remove an RBD or a portion of an RBD. Truncation of the S1 subunit provides the immune system with fewer epitopes to recognize, thereby biasing the immune response to the remaining epitopes, which select antibodies against specific epitopes important for virus neutralization. Truncation or partial deletion of the RBD prevents the expressed protein or cells carrying it from interacting with the receptor ACE2, making it more likely to reach lymph nodes and stimulate the desired immune response. In addition, removal of RBD prevents epitope masking by cross-reactive antibodies previously raised against related viruses, and thus focuses the elicited immune response specifically to the desired antigen. In addition, removal of RBD alters the conformation of the expressed subunit, allowing B cells specific for these alternative conformational epitopes to uptake and present linear peptides to T cells, thereby indirectly enhancing the ability of CD4 ⁺ T cells to remain viable. The reaction of those epitopes in their native conformation.

In some embodiments, the composition comprises mRNA encoding an S1 subunit that has been modified to remove an RBD or a portion of an RBD, wherein the S2 subunit contains a glycan. Glycans are attached to proteins by N-linked glycosylation via asparagine residues or O-linked glycosylation on serine or threonine residues. The presence of glycan shields on some components of a protein can mask peptide epitopes, thereby focusing antibody responses on other exposed peptide epitopes. In addition, glycosylated proteins also elicit antibodies that recognize coated glycans. B cells recognizing the glycan epitope will take up the linear peptide epitope and present it to CD4 ⁺ T cells, thereby enhancing the CD4 ⁺ T cell response to the linear epitope found on ubiquitin.

Non-limiting examples of truncated SARS-CoV-2 S1 subunit antigens and mRNAs encoding them are provided in Tables 3A and 3B below .

Non-limiting examples of SARS-CoV-2 S1 subunits with RBD deletions and mRNAs encoding them are provided in Tables 4A and 4B below . Table 3A. Subunit antigenic truncations name SEQ ID NO: mRNA ORF protein Truncated SARS-CoV-2 S1 subunit linked to the transmembrane domain (S1-531-TM) 19 20 Truncated SARS-CoV-2 S1 subunit linked to the transmembrane domain (S1-594-TM) twenty two twenty three SARS-CoV-2 S1 subunit truncated by poly-G and linked to the transmembrane domain (S1-594-poly-G-TM) 25 26 SARS-CoV-2 S1 subunit truncated by polyG/DS and linked to the transmembrane domain (S1-594-polyG-DS-TM) 28 29 Truncated SARS-CoV-2 S1 subunit linked to the transmembrane domain (S1-666-TM) 150 151 Table 3B. Subunit antigenic truncations Truncated SARS-CoV-2 S1 subunit linked to the transmembrane domain (S1-531-TM) SEQ ID NO: 18 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 19 and 3' UTR SEQ ID NO: 4. 18 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 19 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTsgggsilaiystvasslvllvslgaisf 20 Poly A tail 100nt Truncated SARS-CoV-2 S1 subunit linked to the transmembrane domain (S1-594-TM) SEQ ID NO: 21 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 22 and 3' UTR SEQ ID NO: 4. twenty one Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC twenty two 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGsgggsilaiystvasslvllvslgaisf twenty three Poly A tail 100nt SARS-CoV-2 S1 subunit truncated by poly- G and linked to the transmembrane domain (S1-594 -poly -G-TM) SEQ ID NO: 24 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 25 and 3' UTR SEQ ID NO: 4. twenty four Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGGCAGCGGCGGCGGCAGCGGCGGAGGCAGCGGAGGAGGCAGCGGCGGAGGCAGUGGAGGCCAGCCCACCGAGAGCA UCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 25 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVGSGGGSGGGSGGGSGGGSGGQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGsgggsilaiystvasslvllvslgaisf 26 Poly A tail 100nt SARS-CoV-2 S1 subunit truncated by polyG /DS and linked to the transmembrane domain (S1-594 - polyG -DS-TM) SEQ ID NO: 27 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 28 and 3' UTR SEQ ID NO: 4. 27 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUGCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGGCAGCGGCGGCGGCAGCGGCGGAGGCAGCGGAGGAGGCAGCGGCGGAGGCAGUGGAGGCCAGCCCACCGAGAGCA UCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUUGCCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 28 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVCRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVGSGGGSGGGSGGGSGGGSGGQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFCQFGRDIADTTDAVRDPQTLEILDITPCSFGGsgggsilaiystvasslvllvslgaisf 29 Poly A tail 100nt Truncated SARS-CoV-2 S1 subunit linked to the transmembrane domain (S1-666-TM) SEQ ID NO: 149 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 150 and 3' UTR SEQ ID NO: 4. 149 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGG CGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCA 150 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNS 151 Poly A tail 100nt Table 4A. Subunit antigen RBD deletion name SEQ ID NO: mRNA ORF protein SARS-CoV-2 S1 subunit with RBD deletion and S2 subunit with added glycan 31 32 SARS-CoV-2 S1 subunit with deletion of RBD and NTD and S2 subunit with added glycan 34 35 Table 4B. Subunit antigen RBD deletion SARS-CoV-2 S1 subunit with RBD deletion and S2 subunit with added glycan SEQ ID NO: 30 consists of the following from 5' to 3': 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 31 and 3' UTR SEQ ID NO: 4. 30 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCGGCGGCAGCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCA GCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGGCGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCACCCCGGAGGGCAAGGAGCGUGGCCAGCCAGAGCAUCAUCGCCUACACCAUGAGCCUGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGUACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCU GAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACCCUCCCAACGCCACCGUGCAGAUCGACCGGCUGAUCACUGGCCGGCUGCAGAGCCUGCAGACCUACGUGACCCAGCAGCUGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCAGCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCAC UACACC 31 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFGGSGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPNATVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLH YT 32 Poly A tail 100nt SARS-CoV-2 S1 subunit with deletion of RBD and NTD and S2 subunit with added glycan SEQ ID NO: 33 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 34 and 3' UTR SEQ ID NO: 4. 33 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCGGCGGCAGCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGGCGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCACCCCGGAGGGCAAGGAGCGUGGCCAGCCAGAGCAUCAUCGCCUACACCAUGAGCCUGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGAACUACACCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGU ACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACCCUCCCAACGCCACCGUGCAGAUCGACCGGCUGAUCACUGGCCGGCUGCAGAGCCUGCAGACCUACGUGACCCAGCAGCUGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUA CGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCAGCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCACUACACC 34 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFGGSGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLNYTSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPNATVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 35 Poly A tail 100nt Chimeric S1-S2 subunit antigen

In some embodiments, the composition comprises mRNA encoding a chimeric protein (eg, a chimeric S1-S2 protein having the S1 subunit of the S protein from one virus and the S2 subunit of the S protein from a different virus). For example, the S2 subunit can be from SARS-CoV-2, and the S1 subunit can be from HKU1. As another example, the S2 subunit can be from SARS-CoV-2, and the S1 subunit can be from OC43. These chimeric proteins may be opsonized by circulating antibodies specific for the S1 subunit of HKU1 or OC43 generated by prior exposure to promote efficient uptake of the SARS-CoV-2 S2 subunit peptide by macrophages and dendritic cells and to It is cross-presented to CD4 ⁺ T cells. Opsonization by circulating antibodies also facilitates capture by follicular dendritic cells for presentation to B cells with receptors specific for the SARS-CoV-2 S2 subunit epitope. Non-limiting examples of chimeric S1/S2 subunit constructs and the mRNAs encoding them are provided in Table 5A and Table 5B below. Table 5A. Chimeric S1 Subunit - S2 Subunit Antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 S2 subunit linked to HKU1 S1 subunit 37 38 SARS-CoV-2 S2 subunit linked to OC43 S1 subunit 40 41 Table 5B. Chimeric S1 Subunit - S2 Subunit Antigens SARS-CoV-2 S2 subunit linked to HKU1 S1 subunit SEQ ID NO: 36 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 37 and 3' UTR SEQ ID NO: 4. 36 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCCUGAUCAUCUUCAUCCUGCCCACCACCCUGGCCGUGAUCGGCGACUUCAACUGCACCAACAGCUUCAUCAACGACUACAACAAGACCAUCCCUCGGAUCAGCGAAGACGUGGUGGACGUGUCCCUGGGCCUGGGCACCUACUACGUGCUGAACCGGGUGUACCUGAACACCACACUGCUGUUCACCGGCUACUUCCCCAAGAGCGGCGCCAACUUCCGGGACCUGGCCCUGAAGGGCAGCAUCUACCUGAGCACCUUGUGGUACAAGCCUCCCUUCCUGAGCGACUUCAAUAACGGCAUCUUCUCUAAGGUGAAGAACACCAAGCUGUACGUAAACAACACCCUGUACAGCGAGUUCAGCACCAUCGUGAUCGGCAGCGUGUUCGUCAACACCAGCUACACCAUCGUGGUGCAGCCCCACAACGGCAUCCUGGAGAUCACCGCCUGCCAGUACACCAUGUGCGAGUACCCUCACACCGUGUGCAAGAGCAAGGGCUCCAUCCGGAACGAGAGCUGGCACAUCGACAGCAGCGAGCCGCUGUGCCUGUUCAAGAAGAACUUCACCUACAACGUGAGCGCCGACUGGCUGUACUUCCACUUCUACCAGGAGCGGGGCGUGUUCUACGCCUACUACGCCGACGUGGGCAUGCCAACCACCUUCCUGUUCAGCCUGUACCUGGGCACCAUCCUGAGCCACUACUACGUGAUGCCCCUGACCUGCAACGCCAUCAGCUCAAACACCGACAACGAGACCCUGGAGUACUGGGUGACUCCACUGAGCCGGCGGCAGUACCUGCUGAACUUCGACGAGCACGGCGUGAUCACCAACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCGGCUUCACCGUGAAGCCCGUAGCCACCGUGUACCGGCGGAUCCCCAACCUGCCCGACUGCGACAUCGACAACUGGCUGA ACAACGUCAGCGUGCCCAGCCCACUGAACUGGGAGCGGCGGAUCUUCAGCAACUGCAACUUCAAUCUGAGCACCCUGCUGCGGCUGGUGCACGUGGACAGCUUCAGCUGCAACAACCUGGACAAGAGCAAGAUCUUCGGUAGCUGCUUCAACAGCAUCACCGUGGACAAGUUCGCCAUCCCUAACCGGCGGCGGGACGAUCUGCAGCUGGGCAGCAGCGGCUUCCUGCAGAGCAGCAACUACAAGAUCGACAUCAGCAGCUCAAGCUGCCAGCUGUACUACAGCCUGCCCCUGGUGAACGUGACCAUCAACAACUUCAACCCCAGCAGCUGGAACCGGCGGUACGGCUUCGGCAGCUUCAACCUGAGCAGCUACGACGUGGUGUACAGCGACCACUGCUUCAGCGUGAACAGCGACUUCUGCCCCUGUGCCGACCCUAGCGUGGUGAACAGCUGCGCCAAGAGCAAGCCUCCCAGCGCCAUUUGCCCCGCCGGCACCAAGUACCGGCACUGCGACCUGGACACCACCCUGUACGUGAAGAACUGGUGCCGGUGCAGCUGCCUGCCCGACCCCAUCAGCACCUACAGCCCCAACACCUGUCCCCAGAAGAAGGUGGUGGUGGGUAUCGGCGAGCACUGUCCCGGCCUGGGCAUCAACGAGGAGAAGUGCGGCACCCAGCUGAACCACAGCAGCUGCUUCUGUAGCCCCGACGCCUUCCUGGGCUGGAGCUUCGACAGCUGCAUCAGCAACAACCGGUGCAACAUCUUUAGCAACUUCAUCUUCAACGGAAUCAACAGCGGCACCACCUGCAGCAACGACCUGCUGUAUAGCAACACCGAGAUCAGCACCGGCGUGUGCGUGAACUACGACCUGUACGGCAUCACCGGCCAGGGCAUCUUCAAGGAGGUGAGCGCCGCCUACUACAACAACUGGCAGAACCUGCUGUACGACAGCAACGGCAACAUCAUCGGCUUCAAGGACUUUCUGACCAACAAGACCUA CACCAUCCUGCCCUGCUACAGCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGGCGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCACCCCGGAGGGCAAGGAGCGUGGCCAGCCAGAGCAUCAUCGCCUACACCAUGAGCCUGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGUACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUGUACGAG AACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACCCUCCCGAGGCCGAGGUGCAGAUCGACCGGCUGAUCACUGGCCGGCUGCAGAGCCUGCAGACCUACGUGACCCAGCAGCUGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCA GCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCACUACACC 37 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFLIIFILPTTLAVIGDFNCTNSFINDYNKTIPRISEDVVDVSLGLGTYYVLNRVYLNTTLLFTGYFPKSGANFRDLALKGSIYLSTLWYKPPFLSDFNNGIFSKVKNTKLYVNNTLYSEFSTIVIGSVFVNTSYTIVVQPHNGILEITACQYTMCEYPHTVCKSKGSIRNESWHIDSSEPLCLFKKNFTYNVSADWLYFHFYQERGVFYAYYADVGMPTTFLFSLYLGTILSHYYVMPLTCNAISSNTDNETLEYWVTPLSRRQYLLNFDEHGVITNAVDCALDPLSETKCTLKSFTVEKGIYQTSGFTVKPVATVYRRIPNLPDCDIDNWLNNVSVPSPLNWERRIFSNCNFNLSTLLRLVHVDSFSCNNLDKSKIFGSCFNSITVDKFAIPNRRRDDLQLGSSGFLQSSNYKIDISSSSCQLYYSLPLVNVTINNFNPSSWNRRYGFGSFNLSSYDVVYSDHCFSVNSDFCPCADPSVVNSCAKSKPPSAICPAGTKYRHCDLDTTLYVKNWCRCSCLPDPISTYSPNTCPQKKVVVGIGEHCPGLGINEEKCGTQLNHSSCFCSPDAFLGWSFDSCISNNRCNIFSNFIFNGINSGTTCSNDLLYSNTEISTGVCVNYDLYGITGQGIFKEVSAAYYNNWQNLLYDSNGNIIGFKDFLTNKTYTILPCYSGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYE NQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 38 Poly A tail 100nt SARS-CoV-2 S2 subunit linked to OC43 S1 subunit SEQ ID NO: 39 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 40 and 3' UTR SEQ ID NO: 4. 39 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCCUGAUCCUGCUGAUCAGCCUGCCCACCGCCUUCGCCGUGAUCGGCGACCUGAAGUGCACCAGCGACAACAUCAACGACAAGGACACCGGCCCACCACCCAUCAGCACCGACACCGUGGACGUGACCAACGGCCUGGGCACCUACUACGUGCUGGACCGGGUGUACCUGAACACCACCCUGUUCCUGAACGGCUACUACCCCACCAGCGGCAGCACCUACCGGAAUAUGGCCCUGAAGGGCAGCGUGCUGCUGAGCCGGCUGUGGUUCAAGCCACCAUUCCUGAGCGACUUCAUCAACGGAAUCUUCGCCAAGGUGAAGAACACCAAGGUGAUCAAGGACCGGGUGAUGUACAGCGAGUUCCCCGCCAUCACCAUUGGCAGUACCUUCGUGAACACCAGCUACAGCGUGGUGGUGCAGCCCCGGACCAUCAACAGCACCCAGGACGGCGACAACAAGCUGCAGGGCCUGCUGGAGGUGAGCGUGUGCCAGUACAACAUGUGCGAGUACCCUCAGACCAUCUGCCACCCCAACCUGGGCAACCACCGGAAGGAGCUGUGGCACCUGGACACCGGCGUGGUGAGCUGCCUGUACAAGCGGAACUUCACCUACGACGUAAACGCCGACUACCUGUACUUCCACUUCUACCAGGAGGGCGGCACCUUCUACGCCUACUUCACCGACACGGGCGUGGUGACCAAGUUCCUGUUCAACGUGUACCUGGGCAUGGCCCUGAGCCACUACUACGUGAUGCCCCUGACCUGUAACAGCAAGCUGACCCUGGAGUACUGGGUGACCCCUCUGACCAGCCGGCAGUACCUGCUGGCCUUCAACCAGGACGGCAUCAUCUUCAACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAACGGCUACACCGUGCAGCCCAUCGCCGACGUGUACCGGCGGAAGCCCAACCUGCCCA ACUGCAACAUCGAGGCCUGGCUGAACGACAAGAGCGUGCCCUCGCCCCUGAACUGGGAGCGGAAGACCUUCAGCAACUGCAACUUCAACAUGAGCAGUCUGAUGAGCUUCAUCCAGGCCGACAGCUUCACCUGCAACAACAUCGACGCCGCCAAGAUCUACGGCAUGUGCUUCAGCAGCAUCACCAUCGACAAGUUUGCCAUCCCCAACGGCCGGAAGGUGGACCUGCAGCUGGGCAACCUGGGCUACCUGCAGAGCUUCAACUACCGGAUCGACACCACCGCCACCUCUUGCCAGCUGUACUACAACCUGCCCGCCGCCAACGUGAGCGUGAGCCGGUUCAACCCCAGCACCUGGAACAAGCGGUUCGGCUUCAUUGAGGACAGCGUGUUCAAACCCCGGCCCGCAGGAGUACUGACCAACCACGACGUGGUGUACGCCCAGCACUGCUUCAAGGCACCCAAGAACUUCUGCCCCUGCAAGCUGAACGGCAGCUGUGUGGGCUCUGGCCCCGGUAAGAACAACGGCAUAGGGACUUGCCCGGCAGGGACCAACUACCUGACCUGCGACAACCUGUGCACACCCGACCCCAUCACCUUCACCGGCACCUACAAGUGUCCCCAGACCAAGAGCCUGGUGGGCAUCGGCGAGCACUGCAGCGGCCUGGCCGUGAAGAGCGACUACUGCGGCGGCAACAGCUGCACCUGUCGGCCCCAGGCCUUCCUGGGCUGGAGCGCCGACAGCUGCCUGCAGGGCGACAAGUGCAACAUCUUUGCCAACUUCAUCCUGCACGACGUGAACAGCGGCCUGACCUGCAGCACCGACCUGCAGAAGGCCAACACCGACAUCAUCCUGGGCGUGUGCGUGAACUACGACUUGUACGGCAUCCUGGGCCAGGGCAUCUUCGUGGAGGUGAACGCCACCUACUACAACAGCUGGCAGAACCUGCUGUACGACAGCAACGGCAACCUGUACGGCUUCCGGGACUACAUCAUCAACCG GACCUUCAUGAUCCGGAGCUGCUACAGCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGGCGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCACCCCGGAGGGCAAGGAGCGUGGCCAGCCAGAGCAUCAUCGCCUACACCAUGAGCCUGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGUACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUG UACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACCCUCCCGAGGCCGAGGUGCAGAUCGACCGGCUGAUCACUGGCCGGCUGCAGAGCCUGCAGACCUACGUGACCCAGCAGCUGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCU GCGGCAGCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCACUACACC 40 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFLILLISLPTAFAVIGDLKCTSDNINDKDTGPPPISTDTVDVTNGLGTYYVLDRVYLNTTLFLNGYYPTSGSTYRNMALKGSVLLSRLWFKPPFLSDFINGIFAKVKNTKVIKDRVMYSEFPAITIGSTFVNTSYSVVVQPRTINSTQDGDNKLQGLLEVSVCQYNMCEYPQTICHPNLGNHRKELWHLDTGVVSCLYKRNFTYDVNADYLYFHFYQEGGTFYAYFTDTGVVTKFLFNVYLGMALSHYYVMPLTCNSKLTLEYWVTPLTSRQYLLAFNQDGIIFNAVDCALDPLSETKCTLKSFTVEKGIYQTNGYTVQPIADVYRRKPNLPNCNIEAWLNDKSVPSPLNWERKTFSNCNFNMSSLMSFIQADSFTCNNIDAAKIYGMCFSSITIDKFAIPNGRKVDLQLGNLGYLQSFNYRIDTTATSCQLYYNLPAANVSVSRFNPSTWNKRFGFIEDSVFKPRPAGVLTNHDVVYAQHCFKAPKNFCPCKLNGSCVGSGPGKNNGIGTCPAGTNYLTCDNLCTPDPITFTGTYKCPQTKSLVGIGEHCSGLAVKSDYCGGNSCTCRPQAFLGWSADSCLQGDKCNIFANFILHDVNSGLTCSTDLQKANTDIILGVCVNYDLYGILGQGIFVEVNATYYNSWQNLLYDSNGNLYGFRDYIINRTFMIRSCYSGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVL YENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 41 Poly A tail 100nt encoded domain antigen

Other aspects of the disclosure provide compositions comprising mRNA encoding a (at least one) subdomain of the SARS-CoV-2 S1 subunit of the S protein. A subdomain can be an N-terminal domain (NTD) or a receptor binding domain (RBD) (with or without SD1 and/or SD2). In some embodiments, the mRNA encodes a combination (eg, a non-natural combination) of NTD and RBD (with or without SD1 and/or SD2). In some embodiments, the NTD and/or RBD is linked to the transmembrane domain (with or without SD1 and/or SD2). In some embodiments, the mRNA encodes two subdomains (NTD and RBD) of the SARS-CoV-2 S1 subunit of the S protein, which are mutated to include cysteine residues. In some embodiments, the mutations result in the formation of disulfide bonds. As an example, an mRNA can encode an NTD comprising the F43C mutation and an RBD comprising the Q563C mutation, ultimately resulting in an NTD linked to the RBD via a disulfide bond. N -terminal domain (NTD) construct

In some embodiments, the mRNA provided herein encodes the NTD of the S1 subunit of the SARS-CoV-2 S protein. Certain betacoronavirus NTDs elicit protective levels of antibodies. Antibodies specific for the NTD of other betacoronaviruses, such as MERS, function by preventing membrane fusion and viral entry (Zhou H et al., Nat Commun. 2019; 3068), providing a second alternative to preventing viral attachment to ACE2 Neutralization mechanism. The SARS-CoV-2 NTDs encoded by the mRNAs of the present disclosure may be soluble or membrane bound. Non-limiting examples of membrane-bound SARS-CoV-2 NTD antigens and mRNAs encoding them are provided in Tables 6A and 6B below . Table 6A. Membrane bound NTD antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 NTD linked to transmembrane domain (NTD-TM) 46 47 Table 6B. Membrane bound NTD antigens SARS-CoV-2 NTD linked to transmembrane domain (NTD-TM) SEQ ID NO: 45 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 46 and 3' UTR SEQ ID NO: 4. 45 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 46 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDSGGGSILAIYSTVASSLVLLVSLGAISF 47 Poly A tail 100nt Receptor binding domain (RBD) construct

In other embodiments, the mRNA provided herein encodes the RBD of the S1 subunit of the SARS-CoV-2 S protein. RBD binds to ACE2 receptors on host cells, which mediate viral attachment to cells. Attachment is necessary for virus entry into cells and replication lines. Thus, RBD-targeted antibody responses that block viral attachment into cells effectively neutralize extracellular viral particles, preventing proliferation and promoting further immune responses to other components of the neutralized viral particles. The SARS-CoV-2 RBD encoded by the mRNA of the present disclosure can be soluble or membrane bound (eg, linked to a transmembrane domain). soluble RBD antigen

In some embodiments, the mRNA encodes a soluble SARS-CoV-2 RBD. Dendritic cells sample soluble proteins by pinocytosis and, upon migration to draining lymph nodes, present linear peptides containing the sampled proteins to CD4 ⁺ T cells. These CD4 ⁺ T cells provide proliferative signals to B cells that have recognized, taken up and presented epitopes from RBDs, so administration of specific RBDs without other components of the SARS-CoV-2 spike protein is expected to result in an immune response Focus on epitopes present in RBD. Non-limiting examples of soluble SARS-CoV-2 RBDs and mRNAs encoding them are provided in Tables 7A and 7B below . Table 7. Soluble RBD Antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 soluble RBD 61 62 Table 7B. Soluble RBD Antigens SARS-CoV-2 soluble RBD SEQ ID NO: 60 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 61 and 3' UTR SEQ ID NO: 4. 60 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAG 61 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MYSMQLASCVTLTLVLLVNSQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPK 62 Poly A tail 100nt Membrane bound RBD antigen

In some embodiments, the mRNA encodes a membrane-bound SARS-CoV-2 RBD. Cells expressing membrane-bound RBDs are expected to carry these membrane-bound antigens to draining lymph nodes and promote efficient recognition of epitopes by RBD-specific B cells. Since B cells contain many surface-bound antibodies on the surface and expressing cells contain many copies of membrane-bound RBDs, it is expected that cross-linking of B cell receptors occurs after initial recognition of antigen by B cells, thereby stimulating strong responses via affinity effects. Non-limiting examples of membrane-bound SARS-CoV-2 RBDs and the mRNAs encoding them are provided in Tables 8A and 8B below . Table 8A. Membrane bound RBD antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 RBD linked to transmembrane domain (RBD-TM) 76 77 Table 8B. Membrane bound RBD antigens SARS-CoV-2 RBD linked to transmembrane domain (RBD-TM) SEQ ID NO: 75 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 76 and 3' UTR SEQ ID NO: 4. 75 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 76 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MYSMQLASCVTLTLVLLVNSQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGAISFPKSGGGAI 77 Poly A tail 100nt domain fusion antigen

In other embodiments, the mRNA provided herein encodes a SARS-CoV-2 NTD-RBD fusion protein. For example, the NTD and RBD of the SARS-CoV-2 S1 subunit of the S protein can be linked to each other via a linker, such as a short amino acid (eg, glycine-serine) linker, to allow the domains Flexibility/hinged and space between. In another embodiment, linkers comprising antigenic epitopes (eg, class II universal T cell epitopes such as PADRE) can be used. In some embodiments, the transmembrane region is linked to the NTD-RBD fusion, eg, via another short amino acid (eg, glycine-serine or PADRE) linker to obtain flexibility and allow for the separation between the membrane and the antigen A reasonable distance exists. Without being bound by theory, it is believed that this membrane-bound tandem configuration presents most, if not all, known neutralizing and protective epitopes in one open reading frame. Administration of the fusion protein should then focus the immune response on known protective epitopes and reduce unwanted production of antibodies and T cells specific for non-protective epitopes. In addition, antibodies directed against different domains can neutralize viral particles through different mechanisms, such as by blocking attachment to the host cell or preventing the bound virus from undergoing membrane fusion and entering the host cell. Thus, the broad response elicited by fusion proteins comprising different domains may be evolutionarily stronger, requiring multiple distinct mutations to evade vaccine-induced immunity. Non-limiting examples of SARS-CoV-2 NTD-RBD fusion proteins and mRNAs encoding them are provided in Table 9A and Table 9B below. linker

A variety of linkers can be used in accordance with the present disclosure. Linkers as provided herein are simply amino acid sequences that artificially link together two other amino acid sequences. Linkers as used herein can be cleavable or non-cleavable. The cleavable linker allows translation of the mRNA into a polypeptide, followed by cleavage of the linker, allowing each individual component to be released independently. Non-cleavable linkers remain linked to one or more protein subunits, allowing the entire protein to perform functions that require close proximity of the subunits. Non-limiting examples of such linkers include glycine-serine (GS) linkers (non-cleavable); and F2A linkers, P2A linkers, T2A linkers, and E2A linkers (cleavable). Other connection methods may be used in this article.

In some embodiments, the ligation system is a GS linker. The GS linker system includes polypeptide linkers of glycine and serine amino acid repeats. These contain flexible and hydrophilic residues and can be used to effect fusion of protein subunits without interfering with the folding and function of the protein domains and without forming secondary structures. In some embodiments, the mRNA encodes a fusion protein comprising a 3 to 20 amino acid long GS linker. For example, a GS linker can have a length of (or have a length of at least) 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids. In some embodiments, the GS linker is (or at least is) 15 amino acids long (eg, GGSGGSGGSGGSGGGG (SEQ ID NO: 133)). In some embodiments, the GS linker is (or at least is) 8 amino acids long (eg, GGGSGGGS (SEQ ID NO: 134)). In some embodiments, the GS linker is (or at least is) 7 amino acids long (eg, GGGSGGG (SEQ ID NO: 135)). In some embodiments, the GS linker is (or at least is) 4 amino acids long (eg, GGGS (SEQ ID NO: 136)). In some embodiments, the GS linker comprises (GGGS)n (SEQ ID NO: 136), wherein n is any integer from 1-5. In some embodiments, the GS linker is (or at least is) 4 amino acids long (eg, GSGG (SEQ ID NO: 152)). In some embodiments, the GS linker comprises (GSGG)n (SEQ ID NO: 152), wherein n is any integer from 1-5.

In some embodiments, the linking system is a glycine linker, eg, having a length of 3 amino acids (or at least 3 amino acids in length) (eg, GGG).

In some embodiments, the protein encoded by the mRNA vaccine includes more than one linker, which may be the same or different from each other (e.g., GGGSGGG (SEQ ID NO: 135) and GGGS (SEQ ID NO: 135) in the same S protein construct 136)).

In some embodiments, the linker comprises mRNA encoding a pan-HLA DR-binding epitope (PADRE) (eg, AKFVAAWTLKAAA (SEQ ID NO: 148)). PADRE is an immunodominant helper CD4 T cell epitope and potent immunogen (see, eg, Alexander J. et al., J of Immuno. 164(3): 1625-33, incorporated herein by reference). Table 9A. Domain fusion antigens name SEQ ID NO: mRNA ORF protein SARS-CoV-2 NTD-RBD linked to transmembrane domain (NTD-RBD-TM) 91 92 SARS-CoV-2 RBD-NTD linked to transmembrane domain (RBD-NTD-TM) 139 140 SARS-CoV-2 NTD-PADRE-RBD linked to transmembrane domain (NTD-PADRE-RBD-TM) 142 143 Table 9B. Domain fusion antigens SARS-CoV-2 NTD-RBD linked to transmembrane domain (NTD-RBD-TM) SEQ ID NO: 90 consists of the following from 5' to 3': 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 91 and 3' UTR SEQ ID NO: 4. 90 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 91 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiystvasslvllvslgaisf 92 Poly A tail 100nt SARS-CoV-2 RBD-NTD linked to transmembrane domain (RBD-NTD-TM) SEQ ID NO: 141 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 139 and 3' UTR SEQ ID NO: 4. 141 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCGGAGGCGGAAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGC UGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 139 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MYSMQLASCVTLTLVLLVNSQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKSGGGSGGGSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDSGGGSILAIYSTVASSLVLLVSLGAISF 140 Poly A tail 100nt SARS-CoV-2 NTD-PADRE-RBD linked to transmembrane domain (NTD-PADRE-RBD-TM) SEQ ID NO: 144 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 142 and 3' UTR SEQ ID NO: 4. 144 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGCCAAGUUCGUGGCCGCCUGGACUCUGAAGGCCGCAGCCGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGA AGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 142 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDGGAKFVAAWTLKAAAGGPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKSGGGSILAIYSTVASSLVLLVSLGAISF 143 Poly A tail 100nt transport signal

In some embodiments, the mRNA encodes a SARS-CoV-2 S protein domain (eg, NTD, RBD, or NTD-RBD fusion) linked to a Golgi trafficking signal. Non-limiting examples of such signals include macrophage markers, such as CD86 and/or CD11b, which are highly expressed and the intracellular domain that controls efficient export from the Golgi to the cell surface. Other cellular trafficking signals (sequences) such as the VSV-G cytoplasmic tail (VSVGct) can be used herein. More efficient transport of the encoded protein to the cell surface is expected to increase B cell recognition of the antigen and thus facilitate the production of antibodies against the encoded SARS-CoV-2 S protein domain. Non-limiting examples of SARS-CoV-2 antigens linked to trafficking signals and mRNAs encoding them are provided in Table 10A and Table 10B below. Table 10A. Domain fusion antigens linked to trafficking signals name SEQ ID NO: mRNA ORF protein SARS-CoV-2 NTD-RBD linked to transmembrane domain and huCD86 (NTD-RBD-TM-CD86) 94 95 SARS-CoV-2 NTD-RBD linked to transmembrane domain and huCD11B (NTD-RBD-TM-CD11B) 97 98 SARS-CoV-2 NTD-RBD linked to VSVGct (NTD-RBD-VSVGct) 109 110 Table 10B. Domain fusion antigens linked to trafficking signals SARS-CoV-2 NTD-RBD linked to transmembrane domain and huCD86 (NTD-RBD-TM-CD86) SEQ ID NO: 93 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 94 and 3' UTR SEQ ID NO: 4. 93 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUCAAGAAGAAGAAGCGGCCACGGAACUCCUACAAGUGCGGCACCAACACCAUGGAGCGGGAGGAGAGCGAGCAGACCAAGAAGCGGGAGAAGAUCCACAUUCCUGAACGGUCCGACGAAGCCCAGCGGGUGUUCAAGAGCAGCAAGACCAGCAGCUGCGACAAGAGCGACACCUGCUUC 94 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiystvasslvllvslgaisfKKKKRPRNSYKCGTNTMEREESEQTKKREKIHIPERSDEAQRVFKSSKTSSCDKSDTCF 95 Poly A tail 100nt SARS-CoV-2 NTD-RBD linked to transmembrane domain and huCD11B (NTD-RBD-TM-CD11B) SEQ ID NO: 96 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 97 and 3' UTR SEQ ID NO: 4. 96 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUCAAGCGGCAGUACAAGGACAUGAUGAGCGAGGGAGGACCACCUGGCGCUGAGCCACAG 97 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiystvasslvllvslgaisfKRQYKDMMSEGGPPGAEPQ 98 Poly A tail 100nt SARS-CoV-2 NTD-RBD linked to VSVGct ( NTD-RBD-VSVGct) SEQ ID NO: 108 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 109 and 3' UTR SEQ ID NO: 4. 108 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAGCAGCAUCGCCAGCUUCUUCUUCAUCAUCGGGCUGAUCAUCGGCCUCUUCCUGGUGCUGCGGGUGGGCAUCCACCUGUGCAUCAAGCUGAAGCACACCAAGAAGAGACAGAUCUACACCGACAUCGAGAUGAACCGGCUGGGCAAG 109 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK 110 Poly A tail 100nt Domain fusion C- terminal truncation

In other embodiments, the mRNA provided herein encodes a SARS-CoV-2 NTD-RBD fusion protein in which a certain portion of the C-terminal domain has been truncated/deleted. In one embodiment, 13 (or at least 13) amino acids are deleted from the C-terminal domain of the NTD-RBD fusion protein. Deletion of these amino acids is expected to increase epitope exposure in the antibody, thereby stimulating a stronger immune response to the protective epitopes present on the NTD and RBD domains.

Non-limiting examples of SARS-CoV-2 domain fusion antigens with C-terminal truncations and mRNAs encoding them are provided in Table 11A and Table 11B below. Table 11A. Domain fusion C- terminal truncation name SEQ ID NO: mRNA ORF protein SARS-CoV-2 NTD-RBD with C-terminal truncation of 13 amino acids (NTD-RBD-∆13) 106 107 Table 11B. Domain fusion C- terminal truncation SARS-CoV-2 NTD-RBD with C - terminal truncation of 13 amino acids (NTD-RBD- ∆ 13) SEQ ID NO: 105 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 106 and 3' UTR SEQ ID NO: 4. 105 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCAGCUGCUGCAAGUUCGACGAGGACGAC 106 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiysLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDD 107 Poly A tail 100nt domain extension

In some embodiments, the SARS-CoV-2 S protein domain antigen includes an "extended" region that includes sequences adjacent to and/or flanking an NTD or RBD domain as understood in the art. The RBD_EXT family covers SD1 (subdomain 1). The NTD_EXT series covers the C-terminal helix in NTD. Some B cells and antibodies recognize conformational epitopes found only in properly folded, non-denatured forms of the SARS-CoV-2 S protein NTD and RBD. Including sequences adjacent to and/or flanking the NTD and RBD domains can not only provide additional B-cell epitopes to the antigen, but can potentially achieve more optimal folding of those domains, and use pairs that can be used in either domain. Antibodies specific for epitopes found on the edge stimulate B cells. In addition, the inclusion of these extended sequences can thus increase the distance between the NTD or RBD and the expressed cell membrane, thereby increasing the exposure of both domains to the antibody, which binds less efficiently if the expressed protein is too close to the cell surface. Finally, the inclusion of extended sequences increases the collection of peptides that can potentially be presented to CD4 ⁺ T cells by B cells recognizing NTD or RBD epitopes, followed by processing of the intact protein for antigen presentation, thereby increasing NTD or RBD specificity Sexual B cells receive adequate T cell help. Non-limiting examples of SARS-CoV-2 domain extensions and mRNAs encoding them are provided in Table 12A and Table 12B below. Table 12. Domain extensions name SEQ ID NO: mRNA ORF protein SARS-CoV-2 NTD DS extension linked to transmembrane domain (NTD-EXT-F43C-TM) 52 53 SARS-CoV-2 NTD DS extension linked to transmembrane domain (NTD-F43C-EXT-TM) 55 56 SARS-CoV-2 NTD extension linked to transmembrane domain (NTD-EXT-TM) 58 59 SARS-CoV-2 RBD extension linked to transmembrane domain (RBD-EXT-TM) 85 86 SARS-CoV-2 RBD DS extension linked to transmembrane domain (RBD-Q563D-EXT-TM) 88 89 SARS-CoV-2 NTD-RBD extension linked to transmembrane domain (NTD-RBD-EXT-TM) 115 116 SARS-CoV-2 NTD extension-RBD linked to transmembrane domain (NTD-EXT-RBD-TM) 118 119 SARS-CoV-2 NTD extension-RBD- extension linked to transmembrane domain (NTD-EXT-RBD-EXT-TM) 121 122 Table 12B. Domain extensions SARS-CoV-2 NTD DS extension linked to transmembrane domain (NTD-EXT-F43C-TM) SEQ ID NO: 51 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 52 and 3' UTR SEQ ID NO: 4. 51 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUGCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 52 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVCRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDsgggsilaiystvasslvllvslgaisf 53 Poly A tail 100nt SARS-CoV-2 NTD DS extension linked to transmembrane domain (NTD-F43C-EXT-TM) SEQ ID NO: 54 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 55 and 3' UTR SEQ ID NO: 4. 54 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUGCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCA GCUUC 55 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVCRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTsgggsilaiystvasslvllvslgaisf 56 Poly A tail 100nt SARS-CoV-2 NTD extension linked to transmembrane domain (NTD-EXT-TM) SEQ ID NO: 57 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 58 and 3' UTR SEQ ID NO: 4. 57 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCA GCUUC 58 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTsgggsilaiystvasslvllvslgaisf 59 Poly A tail 100nt SARS-CoV-2 RBD extension linked to transmembrane domain (RBD-EXT-TM) SEQ ID NO: 84 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 85 and 3' UTR SEQ ID NO: 4. 84 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 85 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence mysmqlascvtltlvllvnsQRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSsgggsilaiystvasslvllvslgaisf 86 Poly A tail 100nt SARS-CoV-2 RBD DS extension linked to transmembrane domain (RBD-Q563D-EXT-TM) SEQ ID NO: 87 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 88 and 3' UTR SEQ ID NO: 4. 87 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUUGCCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 88 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence mysmqlascvtltlvllvnsQRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFCQFGRDIADTTDAVRDPQTLEILDITPCSsgggsilaiystvasslvllvslgaisf 89 Poly A tail 100nt SARS-CoV-2 NTD-RBD extension linked to transmembrane domain (NTD-RBD-EXT-TM) SEQ ID NO: 114 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 115 and 3' UTR SEQ ID NO: 4. 114 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACAGCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGA ACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 115 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggQRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSsgggsilaiystvasslvllvslgaisf 116 Poly A tail 100nt SARS-CoV-2 NTD extension - RBD linked to transmembrane domain (NTD-EXT-RBD-TM) SEQ ID NO: 117 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 118 and 3' UTR SEQ ID NO: 4. 117 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCA GCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 118 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiystvasslvllvslgaisf 119 Poly A tail 100nt SARS-CoV-2 NTD extension - RBD- extension linked to transmembrane domain (NTD-EXT-RBD-EXT-TM) SEQ ID NO: 120 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 121 and 3' UTR SEQ ID NO: 4. 120 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGGAGGCGGAUCGGGAGGCGGACAGCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCAACCUGUGCC CCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 121 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTgggsgggQRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSsgggsilaiystvasslvllvslgaisf 122 Poly A tail 100nt domain mixture

In some aspects, the present disclosure provides compositions comprising mixtures of mRNAs encoding SARS-CoV-2 S protein subdomains. In one example, the composition comprises a mixture of mRNA encoding NTD (with or without SD1, SD2 and/or transmembrane domains) and mRNA encoding RBD (with or without SD1, SD2 and/or transmembrane domains). In some embodiments, the composition comprises an mRNA (e.g., SEQ ID NO: 45 or 46) encoding an NTD (e.g., SEQ ID NO: 47) linked to a transmembrane domain and an RBD (e.g., SEQ ID NO: 45 or 46) encoding a transmembrane domain SEQ ID NO: 77) mRNA (eg, SEQ ID NO: 75 or 76).

The ratio of the concentration of one mRNA to the other mRNA in the composition may be 1:1 (50:50), 1:2, 1:3, 1:4 or 1:5. In some embodiments, the ratio is 1:1. For example, a composition may comprise a 1:1 ratio of mRNA (eg, SEQ ID NO: 45 or 46) encoding an NTD linked to a transmembrane domain (eg, SEQ ID NO: 47) to a pair encoding the NTD linked to the transmembrane domain mRNA (eg, SEQ ID NO: 75 or 76) of the RBD (eg, SEQ ID NO: 77). In some embodiments, the ratio is 1:2. For example, a composition may comprise a 1:2 ratio of mRNA (eg, SEQ ID NO: 45 or 46) encoding an NTD linked to a transmembrane domain (eg, SEQ ID NO: 47) to a pair encoding the NTD linked to the transmembrane domain mRNA (eg, SEQ ID NO: 75 or 76) of the RBD (eg, SEQ ID NO: 77). As another example, a composition may comprise a 1:2 ratio of mRNA (e.g., SEQ ID NO: 75 or 76) encoding an RBD (e.g., SEQ ID NO: 77) linked to the transmembrane domain to the encoding and transmembrane structure mRNA (eg, SEQ ID NO: 45 or 46) of a domain-linked NTD (eg, SEQ ID NO: 47). Different mRNAs encoding different antigens can stimulate immune responses of different strengths (Magini D et al., PLoS ONE. 2016; 11:e0161193), and administration of two mRNAs encoding two different antigens in equimolar ratios can elicit a one-to-one response immune response to one but not the other (John S et al., Vaccine. 2018; 36:1689-1699). Manipulation of the ratio of co-delivered mRNAs can be used to elicit a broad immune response targeting the desired antigen with equal efficacy. Encoded Nanoparticle Antigen

In some embodiments, the mRNA vaccines provided herein encode fusion proteins comprising a coronavirus antigen linked to a scaffold domain. In some embodiments, the scaffold domain confers desirable properties to the antigen encoded by the mRNA of the present disclosure. For example, scaffold domains can improve the immunogenicity of an antigen, eg, by altering the structure of the antigen, altering the uptake and processing of the antigen, and/or binding the antigen to another molecule. In some embodiments, the scaffold domain linked to the antigen promotes self-assembly of the antigen into viral nanoparticles or larger protein-folded immunogens. Non-limiting examples of scaffold domains that can be used as provided herein include ferritin domains, dioxytetrahydropteridine synthase domains, foldon domains, and encapsulin domains. Other scaffold domains can be used. Ferritin

In some embodiments, a ferritin domain is used as a scaffold domain. Ferritin is a protein whose main function is to store iron in cells. Ferritin consists of twenty-four (24) subunits, each consisting of four alpha helical bundles that self-assemble into a quaternary structure with octahedral symmetry (Cho KJ et al., J Mol Biol. 2009; 390: 83-98; Granier T. et al, J Biol Inorg Chem. 2003; 8: 105-111; and Lawson DM et al, Nature. 1991; 349: 541-544). Ferritin self-assembles into nanoparticles with strong thermal and chemical stability. Encapsulation of antigens within ferritin nanoparticles in this manner is expected to both delay degradation of the antigens and aggregate individual antigens, each nanoparticle containing twenty-four (24) antigenic subunits. Aggregation of multiple copies of the same antigen enhances antigen uptake and migration by dendritic cells, and stronger CD4 ⁺ and CD8 ⁺ T cell responses (Kastenmüller K et al, J Clin Invest. 2011; 121(5):1782-96 ). Therefore, ferritin nanoparticles are very suitable platforms for antigen presentation and vaccine development.

In some embodiments, the mRNA provided herein encodes an RBD linked to a ferritin domain, eg, via a glycine (eg, GGG) linker domain. Other linkers can be used.

In other embodiments, the mRNA provided herein encodes the S1 domain of the S protein, eg, linked to the ferritin domain via a glycine (eg, GGG) linker. Other linkers can be used as indicated elsewhere herein.

Non-limiting examples of SARS-CoV-2 antigens linked to ferritin domains and mRNAs encoding them are provided in Table 13A and Table 13B below. Table 13A. Antigens linked to ferritin domains name SEQ ID NO: mRNA ORF protein SARS-CoV-2 S1 subunit linked to ferritin (S1-ferritin) 7 8 SARS-CoV-2 RBD linked to ferritin (RBD-ferritin) 64 65 Table 13B. Antigens linked to ferritin domains SARS-CoV-2 S1 subunit linked to ferritin (S1-ferritin) SEQ ID NO: 6 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 7 and 3' UTR SEQ ID NO: 4. 6 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGG CGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCAGGAGGAGGCAGCGGCGGCGAUAUCAUCAAGCUUCUGAACGAGCAAGUUAACAAGGAAAUGCAGAGCAGUAAUCUCUACAUGAGCAUGAGCAGCUGGUGCUACACCCACUCCCUGGACGGAGCAGGCCUCUUCCUGUUCGACCACGCAGCCGAGGAGUACGAGCACGCUAAGAAGUUGAUCAUUUUCUUGAACGAGAACAACGUGCCCGUGCAGCUAACGUCAAUCAGCGCACCUGAGCACAAGUUCGAGGGCCUGACCCAGAUCUUCCAGAAGGCCUACGAACACGAACAGCACAUCUCCGAGAGCAUCAACAAUAUUGUGGAUCACGCUAUCAAGUCCAAGGACCACGCUACCUUCAACUUCCUGCAGUGGUACGUGGCCGAGCAACAUGAGGAGGAGGUGCUGUUCAAGGACAUCCUGGACAAGAUCGAGCUGAUCGGUAAUGAGAAUCACGGCCUGUACCUGGCCGACCAGUACGUGAAGGGCAUCGCCAAGAGCCGGAAGUCAGGCUCA 7 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSgggSGGDIIKLLNEQVNKEMQSSNLYMSMSSWCYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKSGS 8 Poly A tail 100nt SARS-CoV-2 RBD linked to ferritin (RBD - ferritin ) SEQ ID NO: 63 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 64 and 3' UTR SEQ ID NO: 4. 63 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGGGAGGAGGCAGCGGCGGCGAUAUCAUCAAGCUUCUGAACGAGCAAGUUAACAAGGAAAUGCAGAGCAGUAAUCUCUACAUGAGCAUGAGCAGCUGGUGCUACACCCACUCCCUGGACGGAGCAGGCCUCUUCCUGUUCGACCACGCAGCCGAGGAGUACGAGCACGCUAAGAAGUUGAUCAUUUUCUUGAACGAGAACAACGUGCCCGUGCAGCUAACGUCAAUCAGCGCACCUGAGCACAAGUUCGAGGGCCUGACCCAGAUCUUCCAGAAGGCCUACGAACACGAACAGCACAUCUCCGAGAGCAUCAACAAUAUUGUGGAUCACGCUAUCAAGUCCA AGGACCACGCUACCUUCAACUUCCUGCAGUGGUACGUGGCCGAGCAACAUGAGGAGGAGGUGCUGUUCAAGGACAUCCUGGACAAGAUCGAGCUGAUCGGUAAUGAGAAUCACGGCCUGUACCUGGCCGACCAGUACGUGAAGGGCAUCGCCAAGAGCCGGAAGUCAGGCUCA 64 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MYSMQLASCVTLTLVLLVNSQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKGGGSGGDIIKLLNEQVNKEMQSSNLYMSMSSWCYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKSGS 65 Poly A tail 100nt dioxytetrahydropteridine synthase

In some embodiments, a dioxytetrahydropteridine synthase domain is used as a scaffold domain. Dioxytetrahydropteridine synthase is an enzyme responsible for the penultimate catalytic step of riboflavin biosynthesis in a variety of organisms including archaea, bacteria, fungi, plants and eubacteria. Dioxytetrahydropteridine synthase is composed of homo-oligomers that vary in size and number of subunits according to the type of source, including pentamers, decamers, and icosahedral hexamers ( icosahedral sixty-mer). The dioxytetrahydropteridine synthase monomer is 150 amino acids in length and includes a β-sheet with flanking tandem α-helices. Different quaternary structures of dioxytetrahydropteridine synthases have been reported, illustrating their morphological diversity: symmetrical assembly of twelve (12) pentamers ranging from homopentamers to form 150 Å diameter capsids. Antigen presentation on the surface of dioxytetrahydropteridine synthase results in high local concentrations of antigen displayed in ordered arrays. These repeating structures enable cross-linking of B cell receptors and lead to strong immune responses via affinity effects.

In some embodiments, the mRNA provided herein encodes an RBD linked to a dioxytetrahydropteridine synthase domain, eg, via a glycine-serine (eg, GGS). Other linkers can be used.

In other embodiments, the mRNA provided herein encodes the S1 domain of the S protein linked, eg, via a glycine-serine (eg, GGS) linker to a dioxytetrahydropteridine synthase domain. Other linkers can be used as indicated elsewhere herein.

Non-limiting examples of SARS-CoV-2 antigens linked to the foldon domains and mRNAs encoding them are provided in Table 14A and Table 14B below. Table 14A. Antigens linked to dioxytetrahydropteridine synthase domains name SEQ ID NO: SARS-CoV-2 soluble S1 (LS-S1) linked to the C-terminus of dioxytetrahydropteridine synthase 10 11 SARS-CoV-2 soluble S1 (S1-LS) linked to the N-terminus of dioxytetrahydropteridine synthase 13 14 SARS-CoV-2 RBD linked to the C-terminus of dioxytetrahydropteridine synthase (LS-RBD) 67 68 SARS-CoV-2 RBD linked to the N-terminus of dioxytetrahydropteridine synthase (RBD-LS) 70 71 Table 14B. Antigens linked to dioxytetrahydropteridine synthase domains SARS-CoV-2 soluble S1 (LS-S1) linked to the C-terminus of dioxytetrahydropteridine synthase SEQ ID NO: 9 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 10 and 3' UTR SEQ ID NO: 4. 9 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGGGCAUCCUGCCCAGCCCUGGCAUGCCCGCUCUGCUGAGCCUGGUGAGCCUGCUGAGCGUGCUGCUGAUGGGCUGCGUGGCUGAGACCGGCAUGCAGAUCUACGAGGGCAAGCUGACCGCAGAGGGCCUGCGGUUCGGCAUCGUGGCCAGCCGCGCCAACCACGCUCUGGUGGACCGGCUUGUGGAGGGCGCUAUCGACGCCAUCGUGAGACACGGCGGCCGGGAAGAGGACAUCACCCUGGUGCGGGUGUGCGGCAGCUGGGAGAUUCCCGUCGCCGCCGGAGAACUGGCCCGGAAGGAGGACAUCGACGCCGUGAUCGCCAUCGGCGUGCUGUGCAGAGGCGCCACGCCCAGCUUCGACUACAUCGCCAGCGAGGUGAGCAAGGGCCUGGCCGACCUGAGCCUGGAGCUGCGGAAGCCCAUCACCUUCGGCGUGAUCACCGCCGACACCCUGGAGCAGGCCAUCGAGGCCGCAGGCACCUGCCACGGCAACAAGGGCUGGGAAGCCGCCCUGUGCGCCAUCGAGAUGGCCAACCUGUUCAAGAGCCUGCGGGGCGGAAGUGGAGGCUCUGGUGGCAGCGGAGGAUCUGGCGGCGGCACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCU GGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGG CUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGGCGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCA 10 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MGILPSPGMPALLSLVSLLSVLLMGCVAETGMQIYEGKLTAEGLRFGIVASRANHALVDRLVEGAIDAIVRHGGREEDITLVRVCGSWEIPVAAGELARKEDIDAVIAIGVLCRGATPSFDYIASEVSKGLADLSLELRKPITFGVITADTLEQAIEAAGTCHGNKGWEAALCAIEMANLFKSLRGGSGGSGGSGGSGGGTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNS 11 Poly A tail 100nt SARS-CoV-2 soluble S1 (S1-LS) linked to the N-terminus of dioxytetrahydropteridine synthase SEQ ID NO: 12 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 13 and 3' UTR SEQ ID NO: 4. 12 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGG CGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCAGGAGGAGGCUCCGGAGGCGGUAGCGCUGAGACCGGCAUGCAGAUCUACGAGGGCAAGCUGACCGCAGAGGGCCUGCGGUUCGGCAUCGUGGCCAGCCGCGCCAACCACGCUCUGGUGGACCGGCUUGUGGAGGGCGCUAUCGACGCCAUCGUGAGACACGGCGGCCGGGAAGAGGACAUCACCCUGGUGCGGGUGUGCGGCAGCUGGGAGAUUCCCGUCGCCGCCGGAGAACUGGCCCGGAAGGAGGACAUCGACGCCGUGAUCGCCAUCGGCGUGCUGUGCAGAGGCGCCACGCCCAGCUUCGACUACAUCGCCAGCGAGGUGAGCAAGGGCCUGGCCGACCUGAGCCUGGAGCUGCGGAAGCCCAUCACCUUCGGCGUGAUCACCGCCGACACCCUGGAGCAGGCCAUCGAGGCCGCAGGCACCUGCCACGGCAACAAGGGCUGGGAAGCCGCCCUGUGCGCCAUCGAGAUGGCCAACCUGUUCAAGAGCCUGCGG 13 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSgggsgggsAETGMQIYEGKLTAEGLRFGIVASRANHALVDRLVEGAIDAIVRHGGREEDITLVRVCGSWEIPVAAGELARKEDIDAVIAIGVLCRGATPSFDYIASEVSKGLADLSLELRKPITFGVITADTLEQAIEAAGTCHGNKGWEAALCAIEMANLFKSLR 14 Poly A tail 100nt SARS-CoV-2 RBD linked to the C - terminus of dioxytetrahydropteridine synthase (LS-RBD) SEQ ID NO: 66 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 67 and 3' UTR SEQ ID NO: 4. 66 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGGGCAUCCUGCCCAGCCCUGGCAUGCCCGCUCUGCUGAGCCUGGUGAGCCUGCUGAGCGUGCUGCUGAUGGGCUGCGUGGCUGAGACCGGCAUGCAGAUCUACGAGGGCAAGCUGACCGCAGAGGGCCUGCGGUUCGGCAUCGUGGCCAGCCGCGCCAACCACGCUCUGGUGGACCGGCUUGUGGAGGGCGCUAUCGACGCCAUCGUGAGACACGGCGGCCGGGAAGAGGACAUCACCCUGGUGCGGGUGUGCGGCAGCUGGGAGAUUCCCGUCGCCGCCGGAGAACUGGCCCGGAAGGAGGACAUCGACGCCGUGAUCGCCAUCGGCGUGCUGUGCAGAGGCGCCACGCCCAGCUUCGACUACAUCGCCAGCGAGGUGAGCAAGGGCCUGGCCGACCUGAGCCUGGAGCUGCGGAAGCCCAUCACCUUCGGCGUGAUCACCGCCGACACCCUGGAGCAGGCCAUCGAGGCCGCAGGCACCUGCCACGGCAACAAGGGCUGGGAAGCCGCCCUGUGCGCCAUCGAGAUGGCCAACCUGUUCAAGAGCCUGCGGGGCGGAAGUGGAGGCUCUGGUGGCAGCGGAGGAUCUGGCGGCGGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGA AGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUUGUGUGGCCCCAAG 67 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MGILPSPGMPALLSLVSLLSVLLMGCVAETGMQIYEGKLTAEGLRFGIVASRANHALVDRLVEGAIDAIVRHGGREEDITLVRVCGSWEIPVAAGELARKEDIDAVIAIGVLCRGATPSFDYIASEVSKGLADLSLELRKPITFGVITADTLEQAIEAAGTCHGNKGWEAALCAIEMANLFKSLRGGSGGSGGSGGSGGGQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPK 68 Poly A tail 100nt SARS-CoV-2 RBD linked to the N - terminus of dioxytetrahydropteridine synthase (RBD-LS) SEQ ID NO: 69 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 70 and 3' UTR SEQ ID NO: 4. 69 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGGGAGGAGGCUCCGGAGGCGGUAGCGCUGAGACCGGCAUGCAGAUCUACGAGGGCAAGCUGACCGCAGAGGGCCUGCGGUUCGGCAUCGUGGCCAGCCGCGCCAACCACGCUCUGGUGGACCGGCUUGUGGAGGGCGCUAUCGACGCCAUCGUGAGACACGGCGGCCGGGAAGAGGACAUCACCCUGGUGCGGGUGUGCGGCAGCUGGGAGAUUCCCGUCGCCGCCGGAGAACUGGCCCGGAAGGAGGACAUCGACGCCGUGAUCGCCAUCGGCGUGCUGUGCAGAGGCGCCACGCCCAGCUUCGACUACAUCGCCAGCGAGGUGAGCAAGGGCCUGGCCG ACCUGAGCCUGGAGCUGCGGAAGCCCAUCACCUUCGGCGUGAUCACCGCCGACACCCUGGAGCAGGCCAUCGAGGCCGCAGGCACCUGCCACGGCAACAAGGGCUGGGAAGCCGCCCUGUGCGCCAUCGAGAUGGCCAACCUGUUCAAGAGCCUGCGG 70 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MYSMQLASCVTLTLVLLVNSQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKgggsgggsAETGMQIYEGKLTAEGLRFGIVASRANHALVDRLVEGAIDAIVRHGGREEDITLVRVCGSWEIPVAAGELARKEDIDAVIAIGVLCRGATPSFDYIASEVSKGLADLSLELRKPITFGVITADTLEQAIEAAGTCHGNKGWEAALCAIEMANLFKSLR 71 Poly A tail 100nt folder

In some embodiments, the Foldon domain is used as a scaffold domain. The C-terminal domain (foldon) of T4 elastin is necessary for the formation of the elastin trimer structure and can be used as an artificial trimerization domain (see eg Meier S. et al, Journal of Molecular Biology 2004 12 Jun 3;344(4):1051-1069; Tao Y et al. Structure 1997 Jun 15;5(6):789-98). When fused to the S protein extracellular domain, the Foldon domain promotes correct trimerization of the S protein, thereby avoiding protein misfolding. This process leading to the production of the prefusion conformation of the S protein results in increased expression, conformational homogeneity, and elicits a potent neutralizing antibody response.

Without being bound by theory, it is believed that this configuration will result in the largely immunogenic silencing of the foldon on the intracellular region of the protein. Non-limiting examples of SARS-CoV-2 antigens linked to the foldon domains and mRNAs encoding them are provided in Table 15A and Table 15B below. Table 15A. Antigens linked to foldon domains name SEQ ID NO: mRNA ORF protein SARS-CoV-2 NTD linked to the foldon domain 43 44 SARS-CoV-2 NTD linked to transmembrane and foldon domains 49 50 SARS-CoV-2 RBD linked to the foldon domain 73 74 SARS-CoV-2 RBD Linked to Foldon and Transmembrane Domains (RBD-FD-TM) 79 80 SARS-CoV-2 RBD linked to transmembrane and foldon domains (RBD-TM-FD) 82 83 SARS-CoV-2 NTD-RBD linked to foldon and transmembrane domains (NTD-RBD-FD-TM) 100 101 SARS-CoV-2 NTD-RBD linked to transmembrane and foldon domains (NTD-RBD-TM-FD) 103 104 SARS-CoV-2 NTD-RBD linked to the foldon domain 112 113 Table 15B. Antigens linked to foldon domains SARS-CoV-2 NTD linked to the foldon domain SEQ ID NO: 42 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 43 and 3' UTR SEQ ID NO: 4. 42 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUCUGGCGGAGGCGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGC 43 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDsggggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLG 44 Poly A tail 100nt SARS-CoV-2 NTD linked to transmembrane and foldon domains SEQ ID NO: 48 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 49 and 3' UTR SEQ ID NO: 4. 48 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUCGGCGGAGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAG ACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGCAAG 49 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDsgggsilaiystvasslvllvslgaisfgggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLGk 50 Poly A tail 100nt SARS-CoV-2 RBD linked to the foldon domain SEQ ID NO: 72 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 73 and 3' UTR SEQ ID NO: 4. 72 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGC 73 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence mysmqlascvtltlvllvnsQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFELLHAPATFGGCGPKsggleapgg 74 Poly A tail 100nt SARS-CoV-2 RBD Linked to Foldon and Transmembrane Domains (RBD-FD-TM) SEQ ID NO: 78 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 79 and 3' UTR SEQ ID NO: 4. 78 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 79 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence mysmqlascvtltlvllvnsQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsggggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLGggsilaiystvasslvllvslgaisf 80 Poly A tail 100nt SARS-CoV-2 RBD linked to transmembrane and foldon domains (RBD-TM-FD) SEQ ID NO: 81 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 82 and 3' UTR SEQ ID NO: 4. 81 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUACAGCAUGCAGCUGGCUAGCUGCGUGACCCUGACCCUGGUGCUGCUGGUGAACAGCCAGCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUCGGCGGAGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGCAAG 82 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence mysmqlascvtltlvllvnsQPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiystvasslvllvslgaisfgggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLGk 83 Poly A tail 100nt SARS-CoV-2 NTD-RBD linked to foldon and transmembrane domains (NTD-RBD-FD-TM) SEQ ID NO: 99 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 100 and 3' UTR SEQ ID NO: 4. 99 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUC 100 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsggggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLGggsilaiystvasslvllvslgaisf 101 Poly A tail 100nt SARS-CoV-2 NTD-RBD linked to transmembrane and foldon domains (NTD-RBD-TM-FD) SEQ ID NO: 102 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 103 and 3' UTR SEQ ID NO: 4. 102 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCAGCAUCCUGGCCAUCUACAGCACCGUGGCCAGCAGCCUGGUGCUGCUGGUGAGCCUGGGCGCCAUCAGCUUCGGCGGAGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGCAAG 103 3' UTR UGAUAAUAGGCUGGAGCCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsgggsilaiystvasslvllvslgaisfgggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLGk 104 Poly A tail 100nt SARS-CoV-2 NTD-RBD linked to the foldon domain SEQ ID NO: 111 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 112 and 3' UTR SEQ ID NO: 4. 111 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACGGAGGCGGAUCGGGAGGCGGACCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACA GCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGUCUGGCGGAGGCGGCAGCGCCAUCGGCGGCUACAUCCCCGAGGCCCCUAGAGACGGCCAGGCCUACGUGCGGAAGGACGGCGAGUGGGUGCUGCUGAGCACCUUCCUGGGC 112 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDgggsgggPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKsggggSAIGGYIPEAPRDGQAYVRKDGEWVLLSTFLG 113 Poly A tail 100nt Encapsulated protein

In some embodiments, an encapsulated protein domain is used as a scaffold domain. The encapsulated protein is a protein cage-shaped nanoparticle isolated from thermotoga maritima . The encapsulated protein is assembled from 60 copies of the same 31 kDa monomer with a thin icosahedral T=1 symmetric cage with inner and outer diameters of 20 nm and 24 nm, respectively (Sutter M. et al., Nat Struct Mol Biol. 2008; 15: 939-947). Although the exact function of the encapsulating protein in Thermotoga maris is not clearly understood, its crystal structure has recently been solved and its function is postulated to encapsulate enzymes such as DyP (dye depigmenting peroxidase) and Flp (ferritin-like protein) and other proteins involved in the oxidative stress response 30 (Rahmanpour R. et al., FEBS J. 2013; 280: 2097-2104). Nanoparticle construction using encapsulated proteins enables protein antigens to be displayed on the nanoparticle surface and to encapsulate cargoes such as mRNA within the nanoparticles themselves. Previous vaccines based on encapsulated protein nanoparticles have elicited strong immune responses to surface displayed antigens and the cargo protein itself (Lagoutte P. et al., Vaccine. 2018;36(25):3622-3628).

In some embodiments, the mRNA provided herein encodes a S protein domain (eg, S1, S2, RBD, and/or NTD) linked to an encapsulate protein domain. fusion protein

In some embodiments, the compositions of the present disclosure include mRNA encoding an antigenic fusion protein. Thus, encoding one or more antigens can include two or more proteins (eg, proteins and/or protein fragments) joined together. Alternatively, the protein fused to the protein antigen does not promote a strong immune response to itself, but rather a strong immune response to the coronavirus antigen. In some embodiments, the antigenic fusion proteins retain functional properties from each original protein.

In some embodiments, the fusion protein comprises a receptor binding domain from the SARS-CoV-2 spike protein.

In some embodiments, the fusion protein comprises the N-terminal domain from the SARS-CoV-2 spike protein.

In some embodiments, the fusion protein comprises a transmembrane domain. In some embodiments, the transmembrane domain can be from a virus other than SARS-CoV-2. For example, the transmembrane domain can be derived from the influenza hemagglutinin transmembrane domain, which has been shown to efficiently anchor proteins to the cell surface. variant

In some embodiments, the compositions of the present disclosure include RNA encoding a coronavirus antigenic variant. An antigenic variant or other system of polypeptide variation refers to a molecule whose amino acid sequence differs from the wild-type, native, or reference sequence. Antigen/polypeptide variants may have substitutions, deletions and/or insertions at certain positions within the amino acid sequence compared to the native or reference sequence. Typically, the variant is at least 50% identical to the wild-type, native, or reference sequence. In some embodiments, the variant shares at least 80% or at least 90% identity with the wild-type, native or reference sequence.

The variant antigens/polypeptides encoded by the nucleic acids of the present disclosure may contain amino acid changes that confer any of a variety of desirable properties, eg, enhancing their immunogenicity, enhancing their performance, and/or improving their stability in an individual or PK/PD properties. Variant antigens/polypeptides can be prepared using conventional mutagenesis techniques and suitably analyzed to determine whether they have the desired properties. Assays to determine expression levels and immunogenicity are well known in the art, and exemplary such assays are illustrated in the Examples section. Similarly, the PK/PD properties of protein variants can be measured using art-recognized techniques, such as by measuring the performance of the antigen in vaccinated individuals over time and/or by observing the durability of the induced immune response . The stability of the protein encoded by the variant nucleic acid can be measured by analyzing thermal stability or stability upon urea denaturation, or can be measured using computer prediction. The methods used for these experiments and computer assays are known in the art.

In some embodiments, the composition comprises an mRNA or mRNA ORF comprising the nucleotide sequence of any of the sequences provided herein (see, eg, the Sequence Listing), or comprising any of the sequences provided herein The nucleotide sequences of these are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical.

The term "identity" refers to the relationship between the sequences of two or more polypeptides (eg, antigens) or polynucleotides (nucleic acids) as determined by comparing the sequences. Identity also refers to the degree of sequence relatedness between or among sequences as determined by the number of matches between strings of two or more amino acid residues or nucleic acid residues. A measure of identity is the percent identity match between the smaller of two or more sequences with gapped alignments, if any, processed by a particular mathematical model or computer program (eg, an "algorithm"). The identity of related antigens or nucleic acids can be readily calculated by known methods. "Percent identity (%)", when applied to polypeptide or polynucleotide sequences, is defined as the difference in the candidate amino acid or nucleic acid sequence with the The percentage of residues in which the amino acid sequence of the second sequence or the residues (amino acid residues or nucleic acid residues) in the nucleic acid sequence are identical. Methods and computer programs for alignment are well known in the art. It should be understood that agreement depends on the calculation of percent agreement, but the value of agreement may vary due to gaps and penalties introduced in the calculation. Typically, a variant of a particular polynucleotide or polypeptide (eg, an antigen) has the properties as determined by sequence alignment programs and parameters known to those skilled in the art as described herein and to that particular reference polynucleotide or polypeptide. At least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98%, 99% but less than 100% sequence identity. Such tools for alignment include those of the BLAST suite (Stephen F. Altschul et al. (1997), "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Res. 25: 3389-3402). Another commonly used local alignment technique is based on the Smith-Waterman algorithm (Smith, T.F. and Waterman, M.S. (1981) "Identification of common molecular subsequences." J. Mol. Biol. 147:195-197). A general global alignment technique based on dynamic programming is the Needleman-Wunsch algorithm (Needleman, S.B. and Wunsch, C.D. (1970) "A general method applicable to the search for similarities in the amino acid sequences of two proteins." J. Mol. Biol 48:443-453). Recently, a Fast Optimal Global Sequence Alignment Algorithm (FOGSAA) has been developed which is said to produce global alignments of nucleotide and protein sequences faster than other optimal global alignment methods, including the Needleman-Wunsch algorithm.

Accordingly, polynucleotides encoding peptides or polypeptides containing substitutions, insertions and/or additions, deletions, and covalent modifications relative to a reference sequence, particularly a polypeptide (eg, antigen) sequence disclosed herein are included within the scope of the present disclosure . For example, sequence tags or amino acids such as one or more lysines can be added to the peptide sequence (eg, at the N-terminus or C-terminus). Sequence tags can be used for peptide detection, purification or localization. Lysine can be used to increase the solubility of peptides or to allow biotinylation. Alternatively, amino acid residues located in the carboxyl and amino terminal regions of the amino acid sequence of a peptide or protein can optionally be deleted to provide a truncated sequence. Certain amino acids (eg, C-terminal or N-terminal residues) may or may not be deleted depending on the use of the sequence, eg, the representation of the sequence as part of a larger sequence that is soluble or linked to a solid support. In some embodiments, signal sequences, termination sequences, transmembrane domains, linkers, multimerization domains (such as foldon regions), and the like (or sequences encoding the same) may be used as alternative sequences that perform the same or similar functions replace. In some embodiments, stability can be improved by filling cavities in the protein core, eg, by introducing larger amino acids. In other embodiments, the embedded hydrogen bonding network can be replaced with hydrophobic residues to improve stability. In other embodiments, glycosylation sites can be removed and replaced with appropriate residues. Those skilled in the art can readily identify such sequences. It will also be understood that some of the sequences provided herein contain sequence tags or terminal peptide sequences (eg, at the N-terminus or C-terminus) that may be deleted, eg, prior to use in the preparation of mRNA vaccines.

As recognized by those skilled in the art, protein fragments, functional protein domains and homologous proteins are also considered to be within the scope of relevant coronavirus antigens. For example, provided herein is any protein fragment (meaning a polypeptide sequence that is at least one amino acid residue shorter than a reference antigen sequence, but otherwise identical) of a reference protein, provided that the fragment is immunogenic and confers a target to Protective immune response to coronavirus. In addition to identical but truncated variants of the reference protein, in some embodiments, as shown in any of the sequences provided or referenced herein, the antigens include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more mutations. Antigens/antigenic polypeptides can range in length from about 4, 6 or 8 amino acids to full length proteins. Stabilizing element

Naturally occurring eukaryotic mRNA molecules may also contain stabilizing elements, including but not limited to, at their 5' end (5' UTR ) and/or the untranslated region (UTR) at its 3' end (3' UTR). Both the 5' UTR and the 3' UTR are typically transcribed from genomic DNA and are elements of pre-mature mRNA. Structural features characteristic of mature mRNAs (such as 5'-end caps and 3'-poly(A) tails) are typically added to transcribed (pre-mature) mRNAs during mRNA processing.

In some embodiments, the composition includes an mRNA having an open reading frame encoding at least one antigenic polypeptide with at least one modification, at least one 5' end cap, and formulated within a lipid nanoparticle. 5'-end capping of polynucleotides can be accomplished simultaneously during in vitro transcription reactions according to the manufacturer's protocol using the following chemical RNA end cap analogs to generate 5'-guanosine end cap structures: 3´-O- Me-m7G(5')ppp(5')G [ARCA end caps]; G(5')ppp(5')A; G(5')ppp(5')G; m7G(5')ppp( 5')A; m7G(5')ppp(5')G (New England BioLabs, Ipswich, MA). 5'-end capping of the modified RNA can be accomplished post-transcriptionally using the vaccinia virus capping enzyme to generate the "end cap 0" structure: m7G(5')ppp(5')G (New England BioLabs, Ipswich , MA). The endcap 1 structure can be generated using vaccinia virus endcapase and 2'-O methyltransferase to produce: m7G(5')ppp(5')G-2'-O-methyl. The end cap 2 structure can be generated from the end cap 1 structure followed by 2'-O-methylation of the 5'-third to last nucleotide using a 2'-O methyltransferase. The end cap 3 structure can be generated from the end cap 2 structure followed by 2'-O-methylation of the 5'-fourth-to-last nucleotide using a 2'-O methyltransferase. Enzymes can be derived from recombinant sources.

The 3'-poly(A) tail is usually a stretch of adenine nucleotides added to the 3' end of the transcribed mRNA. In some cases, it may contain up to about 400 adenine nucleotides. In some embodiments, the length of the 3'-poly(A) tail may be an essential element for the stability of the individual mRNA.

In some embodiments, the composition includes a stabilizing element. Stabilizing elements may include, for example, histone stem-loops. Stem-loop binding protein (SLBP), a 32 kDa protein, has been identified. It binds to the histone stem-loop at the 3' end of histone messengers in both the nucleus and cytoplasm. Its level of expression is regulated by the cell cycle; it peaks in S phase, when histone mRNA levels are also elevated. This protein has been shown to be critical for efficient 3' end processing of histone pre-mRNA by U7 snRNP. SLBP continues to bind to the stem-loop after processing and then stimulates the translation of mature histone mRNA into histones in the cytoplasm. The RNA binding domain of SLBP is conserved in metazoans and protozoa; its binding to the histone stem-loop depends on the structure of the loop. The minimal binding site includes at least three nucleotides 5' and two nucleotides 3' relative to the stem loop.

In some embodiments, the mRNA includes a coding region, at least one histone stem-loop, and optionally a poly(A) sequence or a polyadenylation signal. The poly(A) sequence or polyadenylation signal should generally enhance the level of expression of the encoded protein. In some embodiments, the encoded protein is not a histone, reporter protein (eg, luciferase, GFP, EGFP, β-galactosidase, EGFP) or marker or selectin (eg, α-globulin, Galactokinase and xanthine:guanine phosphoribosyltransferase (GPT)).

In some embodiments, the mRNA includes a poly(A) sequence or a polyadenylation signal in combination with at least one histone stem-loop, even though the two represent alternative mechanisms in nature, but act synergistically to increase protein expression over using either A level observed by another component. The synergistic effect of the combination of poly(A) and at least one histone stem-loop is independent of the order of the elements or the length of the poly(A) sequence.

In some embodiments, the mRNA does not include histone downstream elements (HDEs). "Histone Downstream Elements" (HDEs) include stretches of purine-rich polynucleotides of approximately 15 to 20 nucleotides 3' to naturally occurring stem loops that represent the binding site for U7 snRNA, the U7 snRNA is involved in the processing of histone pre-mRNA into mature histone mRNA. In some embodiments, the nucleic acid does not include introns.

mRNA may or may not contain enhancer and/or promoter sequences, which may or may not be modified, or which may or may not be activated. In some embodiments, a histone stem-loop is typically derived from a histone gene and includes intramolecular base pairing of two adjacent partially or fully reverse complementary sequences separated by a spacer formed by a structural A short sequence of loops. Unpaired loop regions are generally unable to base pair with any of the stem-loop elements. It occurs more frequently in RNA as it is a key component of many RNA secondary structures, but can also be found in single-stranded DNA. The stability of the stem-loop structure generally depends on the length, the number of mismatches or bulges, and the base composition of the paired regions. In some embodiments, rocking base pairing (non-Watson-Crick base pairing) can be generated. In some embodiments, the at least one histone stem-loop sequence comprises a length of 15 to 45 nucleotides.

In some embodiments, the mRNA removes one or more AU-rich sequences. These sequences, sometimes referred to as AURES, are unstable sequences found in the 3'UTR. AURES can be removed from RNA vaccines. Alternatively, AURES can be retained in the RNA vaccine. signal peptide

In some embodiments, the composition comprises mRNA with an ORF encoding a signal peptide fused to a coronavirus antigen. Signal peptides comprising the N-terminal 15-60 amino acids of proteins are generally required for transmembrane translocation on the secretory pathway, and thus, generally control the entry of most proteins into the secretory pathway in eukaryotes and prokaryotes. In eukaryotes, the signal peptide of a nascent precursor protein (pioneer protein) guides ribosomes to the crude endoplasmic reticulum (ER) membrane, and the growth-initiating peptide chain is transported across it for processing. ER processing produces mature proteins in which the signal peptide is typically cleaved from the precursor protein by the host cell's ER-resident signal peptidase, or it remains uncleaved and functions as a membrane anchor. Signal peptides can also facilitate protein targeting to the cell membrane.

The signal peptide can be 15-60 amino acids in length. For example, the length of the signal peptide can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 amino acids. In some embodiments, the length of the signal peptide is 20-60, 25-60, 30-60, 35-60, 40-60, 45-60, 50-60, 55-60, 15-55, 20-55 , 25-55, 30-55, 35-55, 40-55, 45-55, 50-55, 15-50, 20-50, 25-50, 30-50, 35-50, 40-50, 45 -50, 15-45, 20-45, 25-45, 30-45, 35-45, 40-45, 15-40, 20-40, 25-40, 30-40, 35-40, 15-35 , 20-35, 25-35, 30-35, 15-30, 20-30, 25-30, 15-25, 20-25, or 15-20 amino acids.

Signal peptides from heterologous genes that regulate the expression of genes other than coronavirus antigens in nature are known in the art and can be tested for their desired properties and then incorporated into the nucleic acids of the present disclosure. sequence optimization

In some embodiments, ORFs encoding antigens of the present disclosure are codon-optimized. Codon optimization methods are known in the art. For example, the ORF of any one or more of the sequences provided herein may be codon-optimized. In some embodiments, codon optimization can be used to match codon frequencies in the target and host organisms to ensure correct folding; bias toward GC content to increase mRNA stability or reduce secondary structure; minimize damage to gene architecture or Representation of tandem repeat codons or base runs; custom transcription and translation control regions; insertion or removal of protein trafficking sequences; removal/addition of post-translational modification sites (eg, glycosylation sites) in the encoded protein ); add, remove, or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translation rates to allow correct folding of various domains of the protein; or reduce or eliminate polynucleation Problematic secondary structure within nucleotides. Codon optimization tools, algorithms and services are known in the art - non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park CA) and/or proprietary methods. In some embodiments, an optimization algorithm is used to optimize open reading frame (ORF) sequences.

In some embodiments, the codon-optimized sequence shares less than 95% sequence identity with a naturally-occurring or wild-type sequence ORF (eg, a naturally-occurring or wild-type mRNA sequence encoding a coronavirus antigen). In some embodiments, the codon-optimized sequence shares less than 90% sequence identity with a naturally-occurring or wild-type sequence (eg, a naturally-occurring or wild-type mRNA sequence encoding a coronavirus antigen). In some embodiments, the codon-optimized sequence shares less than 85% sequence identity with a naturally-occurring or wild-type sequence (eg, a naturally-occurring or wild-type mRNA sequence encoding a coronavirus antigen). In some embodiments, the codon-optimized sequence shares less than 80% sequence identity with a naturally-occurring or wild-type sequence (eg, a naturally-occurring or wild-type mRNA sequence encoding a coronavirus antigen). In some embodiments, the codon-optimized sequence shares less than 75% sequence identity with a naturally-occurring or wild-type sequence (eg, a naturally-occurring or wild-type mRNA sequence encoding a coronavirus antigen).

In some embodiments, the codon-optimized sequence shares between 65% and 85% (eg, between 65% and 85%) with a naturally occurring or wild-type sequence (eg, a naturally occurring or wild-type mRNA sequence encoding a coronavirus antigen). between about 67% and about 85% or between about 67% and about 80%) sequence identity. In some embodiments, the codon-optimized sequence shares between 65% and 75% or about 80% with a naturally occurring or wild-type sequence (eg, a naturally occurring or wild-type mRNA sequence encoding a coronavirus antigen) sequence consistency.

In some embodiments, the antigen encoded by the codon-optimized sequence is as immunogenic as, or more immunogenic (eg, at least higher than the coronavirus antigen encoded by the non-codon-optimized sequence) 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 200%).

The modified mRNA is stable when transfected into a mammalian host cell for between 12-18 hours or greater than 18 hours, such as 24 hours, 36 hours, 48 hours, 60 hours, 72 hours or greater than 72 hours, and Can be expressed by mammalian host cells.

In some embodiments, the codon-optimized RNA can be an RNA in which the level of G/C is increased. The G/C content of a nucleic acid molecule (eg, mRNA) can affect RNA stability. RNAs with increased amounts of guanine (G) and/or cytosine (C) residues are functionally more functional than mRNAs that contain larger amounts of adenine (A) and thymine (T) or uracil (U) nucleotides more stable. As an example, WO02/098443 discloses a pharmaceutical composition containing mRNA stabilized by sequence modifications in the translation region. Due to the degeneracy of the genetic code, modifications work by replacing existing codons with those that promote greater RNA stability without altering the resulting amino acid. This method is limited to the coding region of RNA. Chemically unmodified nucleotides

In some embodiments, the mRNA is not chemically modified and comprises standard ribonucleotides consisting of adenosine, guanosine, cytosine, and uridine. In some embodiments, the nucleotides and nucleosides of the present disclosure comprise standard nucleoside residues, such as those found in transcribed RNA (eg, A, G, C, or U). In some embodiments, the nucleotides and nucleosides of the present disclosure comprise standard deoxyribonucleosides, such as those found in DNA (eg, dA, dG, dC, or dT). chemical modification

In some embodiments, the compositions of the present disclosure comprise mRNA having an open reading frame encoding a coronavirus antigen, wherein the nucleic acid comprises nucleotides that may be standard (unmodified) or modified as known in the art and/or or nucleosides. In some embodiments, the nucleotides and nucleosides of the present disclosure comprise modified nucleotides or nucleosides. Such modified nucleotides and nucleosides can be naturally occurring modified nucleotides and nucleosides or non-naturally occurring modified nucleotides and nucleosides. Such modifications may include such modifications in the sugar, backbone or nucleobase moieties of nucleotides and/or nucleosides, as recognized in the art.

In some embodiments, the naturally-occurring modified nucleotides or nucleosides of the present disclosure are nucleotides or nucleosides generally known or recognized in the art. Non-limiting examples of such naturally occurring modified nucleotides and nucleosides can be found, inter alia, in the widely recognized MODOMICS database.

In some embodiments, the non-naturally occurring modified nucleotides or nucleosides of the present disclosure are nucleotides or nucleosides generally known or recognized in the art. Non-limiting examples of such non-naturally occurring modified nucleotides and nucleosides can be found in, inter alia, Published US Application Nos. PCT/US2012/058519; PCT/US2013/075177; PCT/US2014/058897; PCT/US2014 /058891; PCT/US2014/070413; PCT/US2015/36773; PCT/US2015/36759; PCT/US2015/36771; or PCT/IB2017/051367, all of which are incorporated herein by reference.

Accordingly, nucleic acids (eg, DNA nucleic acids and RNA nucleic acids, such as mRNA nucleic acids) of the present disclosure can include standard nucleotides and nucleosides, naturally occurring nucleotides and nucleosides, non-naturally occurring nucleotides and nucleosides or any combination thereof.

In some embodiments, nucleic acids (eg, DNA nucleic acids and RNA nucleic acids, such as mRNA nucleic acids) of the present disclosure comprise multiple (more than one) different types of standard and/or modified nucleotides and nucleosides. In some embodiments, a particular region of a nucleic acid contains one, two or more (as appropriate) types of standard and/or modified nucleotides and nucleosides.

In some embodiments, the modified RNA nucleic acid (eg, modified mRNA nucleic acid) introduced into the cell or organism is in the cell or organism, respectively, relative to the unmodified nucleic acid comprising standard nucleotides and nucleosides Shows reduced degradation.

In some embodiments, a modified RNA nucleic acid (eg, a modified mRNA nucleic acid) introduced into a cell or organism, relative to an unmodified nucleic acid comprising standard nucleotides and nucleosides, can be used in the cell or organism, respectively. A reduced immunogenicity is exhibited in vivo (eg, a reduced innate response).

In some embodiments, nucleic acids (eg, RNA nucleic acids, such as mRNA nucleic acids) comprise non-naturally modified nucleotides that are introduced during or after synthesis of the nucleic acid to achieve a desired function or property. Modifications can exist on internucleotide linkages, purine or pyrimidine bases, or sugars. Modifications can be introduced at the end of the chain or anywhere else in the chain by chemical synthesis or with a polymerase. Any region of a nucleic acid can be chemically modified.

The present disclosure provides modified nucleosides and nucleotides of nucleic acids (eg, RNA nucleic acids, such as mRNA nucleic acids). "Nucleoside" refers to a compound containing a sugar molecule (eg, pentose or ribose) or a derivative thereof in combination with an organic base (eg, purine or pyrimidine) or a derivative thereof (also referred to herein as a "nucleobase") . "Nucleotide" refers to a nucleoside that includes a phosphate group. Modified nucleotides can be synthesized by any useful method, such as chemical, enzymatic or recombinant methods, to include one or more modified or non-natural nucleosides. Nucleic acids may comprise one or more regions of linked nucleosides. The regions may have variable backbone linkages. The linkage can be a standard phosphodiester linkage, in which case the nucleic acid will comprise a region of nucleotides.

Modified nucleotide base pairings encompass not only standard adenosine-thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also include nucleotides and/or include non-standard or modified base pairs. A base pair formed between modified nucleotides of bases in which the hydrogen bond donor and hydrogen bond acceptor are arranged to allow between a non-standard base and a standard base or between two complementary non-standard bases Hydrogen bonds between structures, such as in those nucleic acids with at least one chemical modification. An example of such non-standard base pairing is the base pairing between the modified nucleotides inosine and adenine, cytosine or uracil. Any combination of bases/sugars or linkers can be incorporated into the nucleic acids of the present disclosure.

In some embodiments, the modified nucleobases in nucleic acids (eg, RNA nucleic acids, such as mRNA nucleic acids) comprise 1-methyl-pseudouridine (m1ψ), 1-ethyl-pseudouridine (e1ψ), 5- Methoxy-uridine (mo5U), 5-methyl-cytidine (m5C) and/or pseudouridine (ψ). In some embodiments, the modified nucleobases in nucleic acids (eg, RNA nucleic acids, such as mRNA nucleic acids) comprise 5-methoxymethyluridine, 5-methylthiouridine, 1-methoxymethyl Pseudouridine, 5-methylcytidine and/or 5-methoxycytidine. In some embodiments, the polyribonucleotide includes a combination of at least two (eg, 2, 3, 4, or more) any of the above-mentioned modified nucleobases, including but not limited to chemical modifications .

In some embodiments, the mRNA of the present disclosure comprises a 1-methyl-pseudouridine (m1ψ) substitution at one or more or all uridine positions of the nucleic acid.

In some embodiments, the mRNA of the present disclosure comprises a 1-methyl-pseudouridine (m1ψ) substitution at one or more or all uridine positions of the nucleic acid and at one or more or all cytidine positions of the nucleic acid 5-methylcytidine substitution.

In some embodiments, the mRNAs of the present disclosure comprise pseudouridine (ψ) substitutions at one or more or all uridine positions of the nucleic acid.

In some embodiments, mRNAs of the present disclosure comprise pseudouridine (ψ) substitutions at one or more or all uridine positions of the nucleic acid and a 5-methyl group at one or more or all cytidine positions of the nucleic acid Cytidine substitution.

In some embodiments, the mRNA of the present disclosure comprises uridine at one or more or all uridine positions of the nucleic acid.

In some embodiments, for a particular modification, the mRNA is modified uniformly (eg, fully modified, modified throughout the sequence). For example, nucleic acids can be uniformly modified with 1-methyl-pseudouridine, which means that all uridine residues in the mRNA sequence are replaced with 1-methyl-pseudouridine. Similarly, nucleic acids can be uniformly modified for any type of nucleoside residue present in the sequence by replacement with modified residues, such as those explained above.

Nucleic acids of the present disclosure can be partially or fully modified along the entire length of the molecule. For example, in a nucleic acid of the present disclosure, or in a predetermined sequence region thereof (eg, in an mRNA that includes or does not include a poly(A) tail), one or more or all or a given type can be modified uniformly nucleotides (eg, purines or pyrimidines, or any or more or all of A, G, U, C). In some embodiments, all nucleotides X in the nucleic acids of the present disclosure (or in their sequence regions) are modified nucleotides, wherein X can be one of nucleotides A, G, U, C Any, or a combination of A+G, A+U, A+C, G+U, G+C, U+C, A+G+U, A+G+C, G+U+C, or A+ Any of G+C.

Nucleic acids may contain from about 1% to about 100% modified nucleotides (relative to total nucleotide content, or to one or more types of nucleotides, ie, any of A, G, U, or C). one or more) or any intermediate percentage (eg, 1% to 20%, 1% to 25%, 1% to 50%, 1% to 60%, 1% to 70%, 1% to 80%, 1% to 90%, 1% to 95%, 10% to 20%, 10% to 25%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90% %, 10% to 95%, 10% to 100%, 20% to 25%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 20% to 95%, 20% to 100%, 50% to 60%, 50% to 70%, 50% to 80%, 50% to 90%, 50% to 95%, 50% to 100%, 70% to 80%, 70% to 90%, 70% to 95%, 70% to 100%, 80% to 90%, 80% to 95%, 80% to 100%, 90% to 95%, 90% to 100 % and 95% to 100%). It should be understood that the presence of unmodified A, G, U or C accounts for any remaining percentages.

mRNA may contain a minimum of 1% and a maximum of 100% modified nucleotides or any intermediate percentages, such as at least 5% modified nucleotides, at least 10% modified nucleotides, at least 25% modified nucleotides Modified nucleotides, at least 50% modified nucleotides, at least 80% modified nucleotides, or at least 90% modified nucleotides. For example, nucleic acids can contain modified pyrimidines, such as modified uracil or cytosine. In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90%, or 100% of the uracils in the nucleic acid consist of modified uracils (eg, 5-substituted uracils pyrimidine) replacement. The modified uracil can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (eg, 2, 3, 4, or more unique structures). In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90%, or 100% of the cytosines in the nucleic acid are modified cytosines (eg, 5-substituted cytosines) pyrimidine) replacement. Modified cytosines can be replaced by compounds with a single unique structure, or can be replaced by multiple compounds with different structures (eg, 2, 3, 4, or more unique structures). Untranslated Region (UTR)

The mRNAs of the present disclosure may comprise one or more regions or portions that serve or function as untranslated regions. When the mRNA is designed to encode at least one relevant antigen, the nucleic acid may comprise one or more of these untranslated regions (UTRs). The wild-type untranslated region of the nucleic acid is transcribed, not translated. In mRNA, the 5'UTR begins at the transcription initiation site and continues to, but not including, the initiation codon; while the 3'UTR begins immediately after the stop codon and continues to the transcription termination signal. There is increasing evidence that UTRs play a regulatory role in the stability and translation of nucleic acid molecules. Regulatory features of UTRs can be incorporated into the polynucleotides of the present disclosure to, inter alia, enhance the stability of the molecule. Specific features may also be incorporated to ensure controlled downregulation of transcripts in the event that they are misdirected to undesired organ sites. Various 5'UTR and 3'UTR sequences are known and available in the art.

The 5ꞌ UTR is the region of the mRNA immediately upstream (5ꞌ) of the initiation codon (the first codon of the ribosome-translated mRNA transcript). 5ꞌ UTR does not encode protein (it is non-coding). The native 5'UTR is characterized by a role in translation initiation. It has a signature like the Kozak sequence, which is generally known to be involved in the process by which the ribosome initiates the translation of many genes. The Kozak sequence has a consensus CCR(A/G)CCAUGG (SEQ ID NO: 128), where R is a purine (adenine or guanine) three bases upstream of the initiation codon (AUG), and the initiation codon ( AUG) followed by another "G". The 5'UTR is also known to form secondary structures involved in elongation factor binding.

In some embodiments of the present disclosure, the 5' UTR is a heterologous UTR, ie, a UTR that is found in nature to be associated with a different ORF. In another embodiment, the 5' UTR is a synthetic UTR, ie, does not occur in nature. Synthetic UTRs include UTRs that have been mutated to improve their properties, eg, UTRs that increase gene expression, as well as fully synthetic UTRs. Exemplary 5' UTRs include Xenopus or human derived a-globulin or b-globin (8278063; 9012219), human cytochrome b-245a polypeptide and hydroxysteroid (17b) dehydrogenase and tobacco etch Streak virus (US8278063, 9012219). The CMV immediate early 1 (IE1) gene (US20140206753, WO2013/185069), sequence GGGAUCCUACC (SEQ ID NO: 129) (WO2014144196) can also be used. In another embodiment, the 5' UTR of the TOP gene is the 5' UTR of the TOP gene lacking the 5' TOP motif (oligopyrimidine tract) (eg, WO/2015101414, WO2015101415, WO/2015/062738, WO2015024667, WO2015024667 ); the 5' UTR element derived from the ribosomal protein large 32 (L32) gene (WO/2015101414, WO2015101415, WO/2015/062738), the hydroxysteroid (17-beta) dehydrogenase 4 gene (HSD17B4) can be used ) of the 5' UTR element (WO2015024667) or the 5' UTR element derived from the 5' UTR of ATP5A1 (WO2015024667). In some embodiments, an internal ribosome entry site (IRES) is used in place of the 5' UTR.

In some embodiments, the 5' UTR of the present disclosure comprises a sequence selected from the group consisting of SEQ ID NO: 131 and SEQ ID NO: 2.

The 3ꞌ UTR is the region of the mRNA immediately downstream (3ꞌ) of the stop codon (the codon that signals the termination of translation of the mRNA transcript). 3ꞌ UTRs do not encode proteins (are non-coding). Natural or wild-type 3'UTRs are known to have stretches of adenosine and uridine embedded therein. These AU-rich markers are particularly prevalent in genes with high turnover. AU-rich elements (AREs) can be divided into three classes based on their sequence characteristics and functional properties (Chen et al., 1995): Class I AREs contain scattered copies of the AUUUA motif within the U-rich region. C-Myc and MyoD contain class I AREs. Class II AREs have two or more overlapping UUAUUUA(U/A)(U/A) (SEQ ID NO: 130) nonamers. Molecules containing AREs of this type include GM-CSF and TNF-alpha. Class III AREs are less well-defined. These U-rich regions do not contain AUUUA primitives. c-Jun and myogenin are two well-studied examples of this class. Most proteins that bind to AREs are known to destabilize messengers, while members of the ELAV family, most notably HuR, have been documented to increase mRNA stability. HuR binds to all three classes of AREs. Engineering a HuR-specific binding site into the 3'UTR of a nucleic acid molecule will result in HuR binding and thus in vivo messenger stabilization.

Introduction, removal or modification of 3'UTR AU-rich elements (AREs) can be used to modulate the stability of nucleic acids (eg, RNAs) of the present disclosure. When engineering a particular nucleic acid, one or more copies of the ARE can be introduced to make the nucleic acid of the present disclosure more unstable, thereby curtailing translation and reducing the production of the resulting protein. Likewise, AREs can be identified and removed or mutated to increase intracellular stability, thereby increasing translation and production of the resulting protein. Transfection experiments using the nucleic acids of the present disclosure can be performed in relevant cell lines, and protein production can be analyzed at various time points after transfection. For example, the molecules can be engineered with different AREs and cells can be transfected by using an ELISA kit for the relevant protein and analyzing the protein produced at 6 hours, 12 hours, 24 hours, 48 hours and 7 days after transfection.

The 3' UTR can be heterologous or synthetic. Regarding 3' UTRs, globulin UTRs (including Xenopus β-globin UTR and human β-globin UTR) are known in the art (8278063, 9012219, US20110086907). By colonizing two consecutive human β-globin 3' UTRs end-to-end, modified β-globin constructs with enhanced stability in some cell types have been developed and are well known in the art ( US2012/0195936, WO2014/071963). In addition, a2-globulin, a1-globulin, UTR and mutants thereof are also known in the art (WO2015101415, WO2015024667). Other 3' UTRs described in mRNA constructs in the non-patent literature include CYBA (Ferizi et al., 2015) and albumin (Thess et al., 2015). Other exemplary 3' UTRs include bovine or human growth hormone (wild type or modified) (WO2013/185069, US20140206753, WO2014152774), rabbit beta globulin and the 3' UTR of hepatitis B virus (HBV), alpha-globulin 3' UTR and viral VEEV 3' UTR sequences are also known in the art. In some embodiments, the sequence UUUGAAUU (WO2014144196) is used. In some embodiments, the 3'UTRs of human and mouse ribosomal proteins are used. Other examples include rps9 3'UTR (WO2015101414), FIG4 (WO2015101415) and human albumin 7 (WO2015101415).

In some embodiments, the 3ꞌ UTR of the present disclosure comprises a sequence selected from the group consisting of SEQ ID NO: 132 and SEQ ID NO: 4.

Those skilled in the art will understand that a heterologous or synthetic 5'UTR can be used with any desired 3'UTR sequence. For example, a heterologous 5' UTR can be used with a synthetic 3' UTR or a heterologous 3' UTR.

Non-UTR sequences can also be used as regions or subregions within a nucleic acid. For example, introns or portions of intron sequences can be incorporated into regions of the nucleic acids of the present disclosure. Incorporation of intron sequences can increase protein production and nucleic acid content.

Combinations of features may be included in flanking regions and may be included within other features. For example, the ORF can be flanked by a 5' UTR, which can contain a strong Kozak translation initiation signal; and/or a 3' UTR, which can include an oligo (dT) sequence for adding a poly-A tail as a template. The 5'UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different genes, such as the 5'UTRs described in US Patent Application Publication No. 20100293625 and PCT/US2014/069155 , these publications are incorporated herein by reference in their entirety.

It is understood that any UTR from any gene can be incorporated into a region of nucleic acid. In addition, multiple wild-type UTRs for any known gene can be utilized. Artificial UTRs that are not variants of the wild-type region are also provided within the scope of this disclosure. The UTRs or portions thereof may be placed in the same orientation as the transcripts from which the UTRs were selected, or the orientation or position may be altered. Thus, a 5' or 3' UTR can be inverted, shortened, elongated, and prepared with one or more other 5' UTRs or 3' UTRs. The term "altered" as used herein in reference to a UTR sequence means that the UTR has been altered in some way relative to the reference sequence. For example, a 3' UTR or 5' UTR can be altered relative to a wild-type or native UTR by a change in orientation or position as taught above, or by the inclusion of additional nucleotides, deletions of nucleotides, exchanges or change by transposition of nucleotides. Any of these changes that result in an "altered" UTR (whether 3' or 5') comprises a variant UTR.

In some embodiments, double, triple or quadruple UTRs may be used, eg, 5' UTRs or 3' UTRs. A "double" UTR as used herein is a UTR in which two copies of the same UTR are encoded in tandem or substantially in tandem. For example, dual beta-globin 3' UTRs can be used, as described in US Patent Publication 20100129877, which is incorporated herein by reference in its entirety.

It is also within the scope of this disclosure to have a patterned UTR. As used herein, "patterned UTRs" reflect repeating or alternating patterns of those UTRs, such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than three times. In these patterns, each letter A, B or C represents a different UTR at the nucleotide level.

In some embodiments, the flanking regions are selected from a family of transcripts whose proteins share a common function, structure, characteristic or property. For example, related polypeptides may belong to a family of proteins that are expressed in a particular cell, tissue, or at some point during development. UTRs from any of these genes can be exchanged for any other UTRs of the same or different protein families to generate new polynucleotides. A "family of proteins" as used herein is used in the broadest sense to refer to a group of two or more related polypeptides that share at least one function, structure, characteristic, localization, origin, or mode of expression.

Untranslated regions may also include translational enhancer elements (TEEs). By way of non-limiting example, TEEs may include those TEEs set forth in US Application No. 20090226470 and those TEEs known in the art, incorporated herein by reference in its entirety. In vitro transcription of RNA

cDNAs encoding the polynucleotides described herein can be transcribed using an in vitro transcription (IVT) system. In vitro transcription of RNA is known in the art and described in International Publication WO 2014/152027, which is incorporated herein by reference in its entirety. In some embodiments, the RNAs of the present disclosure are prepared according to any one or more of the methods set forth in WO 2018/053209 and WO 2019/036682, each of which is incorporated herein by reference.

In some embodiments, RNA transcripts are produced in an in vitro transcription reaction using a non-amplified linearized DNA template to generate RNA transcripts. In some embodiments, the template DNA is isolated DNA. In some embodiments, the template DNA is cDNA. In some embodiments, cDNA is formed by reverse transcription of mRNA, such as, but not limited to, coronavirus mRNA. In some embodiments, cells, eg, bacterial cells, eg, E. coli, eg, DH-1 cells, are transfected with a plastid DNA template. In some embodiments, the transfected cells are cultured to replicate plastid DNA, followed by isolation and purification of the plastid DNA. In some embodiments, the DNA template includes an RNA polymerase promoter, such as the T7 promoter located 5' to and operably linked to the gene of interest.

In some embodiments, the in vitro transcription template encodes a 5' untranslated (UTR) region, contains an open reading frame, and encodes a 3' UTR and a poly(A) tail. The specific nucleic acid sequence composition and length of an in vitro transcribed template will depend on the mRNA encoded by the template.

A "5' untranslated region" (UTR) refers to the mRNA that does not encode a polypeptide that is directly upstream (ie, 5') of the initiation codon (ie, the first codon of a ribosome-translated mRNA transcript). area. When producing RNA transcripts, the 5' UTR may contain a promoter sequence. Such promoter sequences are known in the art. It will be understood that such promoter sequences will not be present in the vaccines of the present disclosure.

A "3' untranslated region" (UTR) refers to the region of an mRNA that does not encode a polypeptide that is immediately downstream (ie, 3') of a stop codon (ie, the codon of the mRNA transcript that signals translation termination).

An "open reading frame" is a contiguous stretch of DNA that begins with a start codon (eg, methionine (ATG)) and ends with a stop codon (eg, TAA, TAG, or TGA), and encodes a polypeptide.

A "poly(A) tail" is a region of an mRNA that is located downstream, eg, immediately downstream (ie, 3') of the 3' UTR containing multiple consecutive adenosine monophosphates. Poly A tails can contain from 10 to 300 adenosine monophosphates. For example, poly(A) tails can contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 , 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 adenosine monophosphates. In some embodiments, the poly(A) tail contains 50 to 250 adenosine monophosphates. In relevant biological contexts (eg, in cells, in vivo), poly(A) tails are used to protect mRNA from enzymatic degradation, eg, in the cytoplasm, and to aid in transcription termination, and/or mRNA export from the nucleus and translate.

In some embodiments, the nucleic acid includes 200 to 3,000 nucleotides. For example, the nucleic acid can include 200 to 500, 200 to 1000, 200 to 1500, 200 to 3000, 500 to 1000, 500 to 1500, 500 to 2000, 500 to 3000, 1000 to 1500, 1000 to 2000, 1000 to 3000 , 1500 to 3000 or 2000 to 3000 nucleotides.

In vitro transcription systems typically include transcription buffers, nucleotide triphosphates (NTPs), RNase inhibitors, and polymerases.

NTPs can be manufactured in-house, can be selected from suppliers, or can be synthesized as described herein. NTPs can be selected from, but are not limited to, those NTPs described herein, including natural and non-natural (modified) NTPs.

Any number of RNA polymerases or variants can be used in the methods of the present disclosure. The polymerase may be selected from, but not limited to, bacteriophage RNA polymerases, such as T7 RNA polymerase, T3 RNA polymerase, SP6 RNA polymerase, and/or mutant polymerases, such as, but not limited to, capable of incorporating modified nucleic acids and/or modified nucleic acids. Polymerases of modified nucleotides, including chemically modified nucleic acids and/or nucleotides. Some embodiments exclude the use of DNase.

In some embodiments, RNA transcripts are end-capped by enzymatic end-capping. In some embodiments, the RNA comprises a 5' end cap, eg, 7mG(5')ppp(5')NlmpNp. chemical synthesis

Solid-phase chemical synthesis. Nucleic acids of the present disclosure can be produced in whole or in part using solid phase techniques. Solid-phase chemical synthesis of nucleic acids is an automated method in which molecules are immobilized on solid supports and synthesized stepwise in reactant solutions. Solid phase synthesis can be used to site-specifically introduce chemical modifications in nucleic acid sequences.

Liquid phase chemical synthesis. Synthesis of nucleic acids of the present disclosure by sequential addition of monomeric building blocks can be performed in the liquid phase.

A combination of synthetic methods. The synthetic methods discussed above each have their own advantages and limitations. Attempts have been made to combine these approaches to overcome these limitations. Combinations of these methods are within the scope of this disclosure. The combined use of solid-phase or liquid-phase chemical synthesis and enzymatic ligation provides an efficient way to generate long-chain nucleic acids that cannot be obtained by chemical synthesis alone. Linking nucleic acid regions or subregions

Assembly of nucleic acids by ligases can also be used. DNA or RNA ligase facilitates the intermolecular ligation of the 5' and 3' ends of polynucleotide chains through the formation of phosphodiester bonds. Nucleic acids, such as chimeric polynucleotides and/or circular nucleic acids, can be prepared by linking one or more regions or subregions. DNA fragments can be joined by ligase-catalyzed reactions to generate recombinant DNA with different functions. Two oligodeoxynucleotides (one with a 5' phosphonium group and the other with a free 3' hydroxyl group) were used as substrates for DNA ligase. purification

Purification of nucleic acids described herein can include, but is not limited to, nucleic acid purification, quality assurance, and quality control. Purification can be performed by methods known in the art such as, but not limited to, AGENCOURT® beads (Beckman Coulter Genomics, Danvers, MA), poly-T beads, LNATM oligo-T capture probes (EXIQON® Corporation, Vedbaek , Denmark) or HPLC-based purification methods such as but not limited to strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC) and hydrophobic interaction HPLC (HIC-HPLC). The term "purified" when used in reference to nucleic acid, such as "purified nucleic acid," refers to nucleic acid that has been separated from at least one contaminant. A "contaminant" is any substance that renders another substance unsuitable, impure or inferior. Thus, purified nucleic acids (eg, DNA and RNA) exist in a form or environment different from the form or environment in which they are found in nature, or in a form or environment different from the form or environment in which they existed prior to processing or purification methods.

Quality assurance and/or quality control checks can be performed using methods such as, but not limited to, gel electrophoresis, UV absorbance, or analytical HPLC.

In some embodiments, nucleic acids can be sequenced by methods including, but not limited to, reverse transcriptase-PCR. Quantitative

In some embodiments, nucleic acids of the present disclosure can be quantified in exosomes or when derived from one or more body fluids. Body fluids include peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, ear wax, breast milk, bronchoalveolar lavage fluid, semen, prostatic fluid, Cowper's fluid or pre-ejaculate fluid, sweat, excrement, hair, tears, cystic fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyle, chyle, bile, interstitial fluid, menstrual blood, pus , sebum, vomit, vaginal secretions, mucosal secretions, fecal water, pancreatic juice, sinus lavage fluid, bronchopulmonary aspirates, blastocyst fluid and umbilical cord blood. Alternatively, the exosomes can be recovered from an organ selected from the group consisting of lung, heart, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colon, breast, prostate, brain, esophagus, liver and placenta.

Analysis can be performed using construct-specific probes, cytometry, qRT-PCR, real-time PCR, PCR, flow cytometry, electrophoresis, mass spectrometry, or a combination thereof, while immunohistochemical methods such as enzyme-linked immunosorbent assay can be used. assay (ELISA)) method to isolate exosomes. Exosomes can also be isolated by particle size chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunosorbent capture, affinity purification, microfluidic separation, or a combination thereof.

These methods allow researchers to monitor the level of nucleic acid remaining or delivered in real time. This is possible because, in some embodiments, the nucleic acids of the present disclosure differ from the endogenous form due to structural or chemical modifications.

In some embodiments, nucleic acids can be quantified using methods such as, but not limited to, ultraviolet visible spectroscopy (UV/Vis). A non-limiting example of a UV/Vis spectrometer is the NANODROP® spectrometer (ThermoFisher, Waltham, MA). The quantified nucleic acid can be analyzed to determine if the nucleic acid is of the correct size and to check that the nucleic acid has not been degraded. Degradation of nucleic acids can be checked by methods such as but not limited to agarose gel electrophoresis; HPLC based purification methods such as but not limited to strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC) and hydrophobic Interaction HPLC (HIC-HPLC); Liquid Chromatography-Mass Spectrometry (LCMS), Capillary Electrophoresis (CE) and Capillary Gel Electrophoresis (CGE). Lipid Nanoparticles (LNPs)

In some embodiments, the mRNAs of the present disclosure are formulated in lipid nanoparticles (LNPs). Lipid nanoparticles typically contain ionizable cationic lipids, non-cationic lipids, sterol and PEG lipid components, and related nucleic acid cargoes. The lipid nanoparticles of the present disclosure can be produced using components, compositions and methods generally known in the art, eg, see PCT/US2016/052352; PCT/US2016/068300; PCT/US2017/037551; PCT/US2015/027400; PCT/US2016/047406; PCT/US2016000129; PCT/US2016/014280; PCT/US2016/014280; PCT/US2017/038426; 069610; PCT/US2017/027492; PCT/US2016/059575 and PCT/US2016/069491, all of which are incorporated herein by reference in their entirety.

The vaccines of the present disclosure are typically formulated in lipid nanoparticles. In some embodiments, the lipid nanoparticles comprise at least one ionizable cationic lipid, at least one non-cationic lipid, at least one sterol, and/or at least one polyethylene glycol (PEG)-modified lipid.

In some embodiments, the lipid nanoparticle comprises 40-50 mol% ionizable lipid, optionally 45-50 mol%, eg, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48 -49 mol% or 49-50 mol%, such as about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol% or 49.5 mol%.

In some embodiments, the lipid nanoparticle comprises 30-45 mol% sterol, optionally 35-40 mol%, eg, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol% mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 38-38 mol%, 38-39 mol%, or 39-40 mol%.

In some embodiments, the lipid nanoparticle comprises 5-15 mol% helper lipid, optionally 10-12 mol%, eg, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8-9 mol% mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol% or 14-15 mol%.

In some embodiments, lipid nanoparticles comprise 1-5% PEG lipid, optionally 1-3 mol%, eg, 1.5-2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol% % or 4-5 mol%.

In some embodiments, the lipid nanoparticles comprise 20-60 mol% ionizable cationic lipids. For example, lipid nanoparticles can comprise 20-50 mol%, 20-40 mol%, 20-30 mol%, 30-60 mol%, 30-50 mol%, 30-40 mol%, 40-60 mol% %, 40-50 mol% or 50-60 mol% ionizable cationic lipids. In some embodiments, the lipid nanoparticles comprise 20 mol %, 30 mol %, 40 mol %, 50 mol %, or 60 mol % of ionizable cationic lipids. In some embodiments, the lipid nanoparticles comprise 35 mol%, 36 mol%, 37 mol%, 38 mol%, 39 mol%, 40 mol%, 41 mol%, 42 mol%, 43 mol%, 44 mol% , 45 mol%, 46 mol%, 47 mol%, 48 mol%, 49 mol%, 50 mol%, 51 mol%, 52 mol%, 53 mol%, 54 mol%, or 55 mol% of ionizable cationic lipids .

In some embodiments, the lipid nanoparticles comprise 5-25 mol% non-cationic lipids. For example, lipid nanoparticles can comprise 5-20 mol%, 5-15 mol%, 5-10 mol%, 10-25 mol%, 10-20 mol%, 10-25 mol%, 15-25 mol% %, 15-20 mol% or 20-25 mol% non-cationic lipids. In some embodiments, the lipid nanoparticle comprises 5 mol%, 10 mol%, 15 mol%, 20 mol%, or 25 mol% non-cationic lipid.

In some embodiments, the lipid nanoparticles comprise 25-55 mol% sterols. For example, lipid nanoparticles can comprise 25-50 mol%, 25-45 mol%, 25-40 mol%, 25-35 mol%, 25-30 mol%, 30-55 mol%, 30-50 mol% %, 30-45 mol%, 30-40 mol%, 30-35 mol%, 35-55 mol%, 35-50 mol%, 35-45 mol%, 35-40 mol%, 40-55 mol%, 40-50 mol%, 40-45 mol%, 45-55 mol%, 45-50 mol% or 50-55 mol% sterol. In some embodiments, the lipid nanoparticles comprise 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, or 55 mol% sterols.

In some embodiments, the lipid nanoparticles comprise 0.5-15 mol% PEG-modified lipids. For example, lipid nanoparticles can comprise 0.5-10 mol%, 0.5-5 mol%, 1-15 mol%, 1-10 mol%, 1-5 mol%, 2-15 mol%, 2-10 mol% %, 2-5 mol%, 5-15 mol%, 5-10 mol% or 10-15 mol%. In some embodiments, the lipid nanoparticles comprise 0.5 mol%, 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol% , 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol% or 15 mol% PEG-modified lipids.

In some embodiments, the lipid nanoparticles comprise 20-60 mol% ionizable cationic lipids, 5-25 mol% non-cationic lipids, 25-55 mol% sterols, and 0.5-15 mol% PEG-modified lipids.

， 或其鹽或異構物，其中： R ₁選自由C _5-30烷基、C _5-20烯基、-R*YR''、-YR''及-R''M'R'組成之群； R ₂及R ₃獨立地選自由H、C _1-14烷基、C _2-14烯基、-R*YR''、-YR''及-R*OR''組成之群，或R ₂及R ₃與其所附接之原子一起形成雜環或碳環； R ₄選自由C _3-6碳環、-(CH ₂) _nQ、-(CH ₂) _nCHQR、-CHQR、-CQ(R) ₂及未經取代之C _1-6烷基組成之群，其中Q選自碳環、雜環、-OR、-O(CH ₂) _nN(R) ₂、-C(O)OR、-OC(O)R、-CX ₃、-CX ₂H、-CXH ₂、-CN-、N(R) ₂、-C(O)N(R) ₂、-N(R)C(O)R、-N(R)S(O) ₂R、-N(R)C(O)N(R) ₂、-N(R)C(S)N(R) ₂、-N(R)R ₈、-O(CH ₂) _nOR、-N(R)C(=NR ₉)N(R) ₂、-N(R)C(=CHR ₉)N(R) ₂、-OC(O)N(R) ₂、-N(R)C(O)OR、-N(OR)C(O)R、-N(OR)S(O) ₂R、-N(OR)C(O)OR、-N(OR)C(O)N(R) ₂、-N(OR)C(S)N(R) ₂、-N(OR)C(=NR ₉)N(R) ₂、-N(OR)C(=CHR ₉)N(R) ₂、-C(=NR ₉)N(R) ₂、-C(=NR ₉)R、-C(O)N(R)OR及-C(R)N(R) ₂C(O)OR，且每一n獨立地選自1、2、3、4及5； 每一R ₅獨立地選自由C _1-3烷基、C _2-3烯基及H組成之群； 每一R ₆獨立地選自由C _1-3烷基、C _2-3烯基及H組成之群； M及M'獨立地選自-C(O)O-、-OC(O)-、-C(O)N(R')-、-N(R')C(O)-、-C(O)-、-C(S)-、-C(S)S-、-SC(S)-、-CH(OH)-、-P(O)(OR')O-、-S(O) ₂-、-S-S-、芳基及雜芳基； R ₇選自由C _1-3烷基、C _2-3烯基及H組成之群； R ₈選自由C _3-6碳環及雜環組成之群； R ₉選自由H、CN、NO ₂、C _1-6烷基、-OR、-S(O) ₂R、-S(O) ₂N(R) ₂、C _2-6烯基、C _3-6碳環及雜環組成之群； 每一R獨立地選自由C _1-3烷基、C _2-3烯基及H組成之群； 每一R'獨立地選自由C _1-18烷基、C _2-18烯基、-R*YR''、-YR''及H組成之群； 每一R''獨立地選自由C _3-14烷基及C _3-14烯基組成之群； 每一R*獨立地選自由C _1-12烷基及C _2-12烯基組成之群； 每一Y獨立地係C _3-6碳環； 每一X獨立地選自由F、Cl、Br及I組成之群；且 m選自5、6、7、8、9、10、11、12及13。 In some embodiments, the ionizable cationic lipids of the present disclosure comprise a compound of formula (I):

, or a salt or isomer thereof, wherein: R ₁ is selected from the group consisting of C _5-30 alkyl, C _5-20 alkenyl, -R*YR'', -YR'' and -R''M'R' the group; R ₂ and R ₃ are independently selected from the group consisting of H, C _1-14 alkyl, C _2-14 alkenyl, -R*YR'', -YR'' and -R*OR'', or R ₂ and R ₃ together with the atoms to which they are attached form a heterocycle or carbocycle; R ₄ is selected from C _3-6 carbocycle, -(CH ₂ ) _n Q, -(CH ₂ ) _n CHQR, -CHQR, The group consisting of -CQ(R) ₂ and unsubstituted C _1-6 alkyl, wherein Q is selected from carbocycle, heterocycle, -OR, -O(CH ₂ ) _n N(R) ₂ , -C( O)OR, -OC(O) _R , -CX3, -CX2H, _-CXH2 , -CN-, N(R) ₂ , -C(O)N(R _{)2 ,} -N(R) C(O)R, -N(R)S(O) ₂ R, -N(R)C(O)N(R) ₂ , -N(R)C(S)N(R) ₂ , -N (R)R ₈ , -O(CH ₂ ) _n OR, -N(R)C(=NR ₉ )N(R) ₂ , -N(R)C(=CHR ₉ )N(R) ₂ , - OC(O)N(R) ₂ , -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O) ₂ R, -N(OR)C (O)OR, -N(OR)C(O)N(R) ₂ , -N(OR)C(S)N(R) ₂ , -N(OR)C(=NR ₉ )N(R) ₂ , -N(OR)C(=CHR ₉ )N(R) ₂ , -C(=NR ₉ )N(R) ₂ , -C(=NR ₉ )R, -C(O)N(R) OR and -C(R)N(R) _2C (O)OR, and each n is independently selected from 1, 2, 3, 4, and ₅ ; each R5 is independently selected from _C1-3 alkyl , C _2-3 alkenyl and the group consisting of H; each R ₆ is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; M and M' are independently selected from -C (O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)- , -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O) ₂ -, -SS-, aryl and Heteroaryl; R ₇ is selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; R ₈ is selected from the group consisting of C _3-6 carbocycle and heterocycle; R ₉ is selected from H, CN, NO ₂ , C _1-6 alkyl, -OR, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , C _2-6 alkenyl, C _3-6 carbocycle and The group consisting of heterocycles; each R is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; each R' is independently selected from C _1-18 alkyl, C _{2- 18} The group consisting of alkenyl, -R*YR'', -YR'' and H; each R'' is independently selected from the group consisting of C _3-14 alkyl and C _3-14 alkenyl; each R *is independently selected from the group consisting of _C1-12 alkyl and _C2-12 alkenyl; each Y is independently a _C3-6 carbocycle; each X is independently selected from F, Cl, Br, and I and m is selected from 5, 6, 7, 8, 9, 10, 11, 12 and 13.

In some embodiments, the subgroup of compounds of formula (I) includes those compounds wherein when R4 is _- ( _CH2 )nQ, -( _CH2 ) _nCHQR , _-CHQR or -CQ(R) ₂ , then (i) when n is 1, 2, 3, 4, or 5, Q is not -N(R) ₂ , or (ii) when n is 1 or 2, Q is not 5-membered, 6-membered or 7-membered heterocycloalkyl.

In some embodiments, another subset of compounds of formula (I) includes those compounds wherein R ₁ is selected from C _5-30 alkyl, C _5-20 alkenyl, -R*YR'', - The group consisting of YR'' and -R''M'R'; R ₂ and R ₃ are independently selected from H, C _1-14 alkyl, C _2-14 alkenyl, -R*YR'', -YR '' and -R*OR'', or R ₂ and R ₃ together with the atoms to which they are attached form a heterocycle or carbocycle; R ₄ is selected from C _3-6 carbocycle, -(CH ₂ ) _n The group consisting of Q, -(CH ₂ ) _n CHQR, -CHQR, -CQ(R) ₂ and unsubstituted C _1-6 alkyl, wherein Q is selected from C _3-6 carbocyclic ring, having one or more 5- to 14-membered heteroaryl selected from heteroatoms of N, O and S, -OR, -O( _CH2 ) _nN (R) ₂ , -C(O)OR, -OC(O)R, - CX ₃ , -CX ₂ H, -CXH ₂ , -CN, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)S(O) ₂ R, - N(R)C(O)N(R) ₂ , -N(R)C(S)N(R) ₂ , -CRN(R) ₂ C(O)OR, -N(R)R ₈ , - O(CH ₂ ) _n OR, -N(R)C(=NR ₉ )N(R) ₂ , -N(R)C(=CHR ₉ )N(R) ₂ , -OC(O)N(R ) ₂ , -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O) ₂ R, -N(OR)C(O)OR, -N (OR)C(O)N(R) ₂ , -N(OR)C(S)N(R) ₂ , -N(OR)C(=NR ₉ )N(R) ₂ , -N(OR) C(=CHR ₉ )N(R) ₂ , -C(=NR ₉ )N(R) ₂ , -C(=NR ₉ )R, -C(O)N(R)OR and having one or more 5- to 14-membered heterocycloalkyl of heteroatoms selected from N, O and S, substituted with one or more substituents selected from: pendant oxy (=O), OH, amine, monoalkylamine group or dialkylamine group and C _1-3 alkyl group, and each n is independently selected from 1, 2, 3, 4 and 5; each R ₅ is independently selected from C _1-3 alkyl group, C ₂ The group consisting of _-3 alkenyl and H _; each R is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; M and M' are independently selected from -C(O) O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C (S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O) _2- , -SS-, aryl and heteroaryl ; R ₇ is chosen from C The group consisting of _1-3 alkyl, C _2-3 alkenyl and H; R ₈ is selected from the group consisting of C _3-6 carbocycle and heterocycle; R ₉ is selected from H, CN, NO ₂ , C _1-6 The group consisting of alkyl, -OR, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , C _2-6 alkenyl, C _3-6 carbocycle and heterocycle; each R independently is selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl, and H; each R' is independently selected from C _1-18 alkyl, C _2-18 alkenyl, -R*YR'' , -YR'' and H; each R'' is independently selected from the group consisting of C _3-14 alkyl and C _3-14 alkenyl; each R* is independently selected from C _1-12 alkane each Y is independently a _C3-6 carbocycle; each X is independently selected from the group consisting of F, Cl, Br, and I; and m is selected from 5, ₆ , 7, 8, 9, 10, 11, 12 and 13, or salts or isomers thereof.

In some embodiments, another subgroup of compounds of formula (I) includes those compounds wherein R ₁ is selected from C _5-30 alkyl, C _5-20 alkenyl, -R*YR'', - The group consisting of YR'' and -R''M'R'; R ₂ and R ₃ are independently selected from H, C _1-14 alkyl, C _2-14 alkenyl, -R*YR'', -YR '' and -R*OR'', or R ₂ and R ₃ together with the atoms to which they are attached form a heterocycle or carbocycle; R ₄ is selected from C _3-6 carbocycle, -(CH ₂ ) _n The group consisting of Q, -(CH ₂ ) _n CHQR, -CHQR, -CQ(R) ₂ and unsubstituted C _1-6 alkyl, wherein Q is selected from C _3-6 carbocyclic ring, having one or more 5- to 14-membered heterocycle of heteroatoms selected from N, O and S, -OR, -O( _CH2 ) _nN (R) ₂ , -C(O)OR, -OC(O)R, -CX ₃ , -CX ₂ H, -CXH ₂ , -CN, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)S(O) ₂ R, -N (R)C(O)N(R) ₂ , -N(R)C(S)N(R) ₂ , -CRN(R) ₂ C(O)OR, -N(R)R ₈ , -O (CH ₂ ) _n OR, -N(R)C(=NR ₉ )N(R) ₂ , -N(R)C(=CHR ₉ )N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O) ₂ R, -N(OR)C(O)OR, -N( OR)C(O)N(R) ₂ , -N(OR)C(S)N(R) ₂ , -N(OR)C(=NR ₉ )N(R) ₂ , -N(OR)C (=CHR ₉ )N(R) ₂ , -C(=NR ₉ )R, -C(O)N(R)OR, and -C(=NR ₉ )N(R) ₂ , and each n independently is selected from 1, 2, 3, 4, and 5; and when Q is a 5- to 14-membered heterocycle and (i) R4 is _- ( _CH2 )nQ, wherein _n is 1 or ₂ , or (ii) R4 is -(CH ₂ ) _n CHQR, wherein n is 1, or (iii) R ₄ is -CHQR and -CQ(R) ₂ , then Q is a 5- to 14-membered heteroaryl or an 8- to 14-membered heterocycloalkane each R ₅ is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; each R ₆ is independently selected from C _1-3 alkyl, C _2-3 alkenyl and the group consisting of H; M and M' are independently selected from -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O )-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O) ₂ -, -SS-, aryl and heteroaryl; R ₇ is selected from C _1-3 alkyl, C _2-3 alkenyl and H The group consisting of; R ₈ is selected from the group consisting of C _3-6 carbocycles and heterocycles; R ₉ is selected from H, CN, NO ₂ , C _1-6 alkyl, -OR, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , C _2-6 alkenyl, C _3-6 carbocycle and heterocycle; each R is independently selected from C _1-3 alkyl, C _2-3 the group consisting of alkenyl and H; each R' is independently selected from the group consisting of C _1-18 alkyl, C _2-18 alkenyl, -R*YR'', -YR'', and H; each R '' is independently selected from the group consisting of C _3-14 alkyl and C _3-14 alkenyl; each R* is independently selected from the group consisting of C _1-12 alkyl and C _2-12 alkenyl; each Y is independently a _C3-6 carbocycle; each X is independently selected from the group consisting of F, Cl, Br, and I; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13 , or its salts or isomers.

In some embodiments, another subgroup of compounds of formula (I) includes those compounds wherein R ₁ is selected from C _5-30 alkyl, C _5-20 alkenyl, -R*YR'', - The group consisting of YR'' and -R''M'R'; R ₂ and R ₃ are independently selected from H, C _1-14 alkyl, C _2-14 alkenyl, -R*YR'', -YR '' and -R*OR'', or R ₂ and R ₃ together with the atoms to which they are attached form a heterocycle or carbocycle; R ₄ is selected from C _3-6 carbocycle, -(CH ₂ ) _n The group consisting of Q, -(CH ₂ ) _n CHQR, -CHQR, -CQ(R) ₂ and unsubstituted C _1-6 alkyl, wherein Q is selected from C _3-6 carbocyclic ring, having one or more Heteroatom 5- to 14-membered heteroaryl selected from N, O and S, -OR, -O(CH ₂ ) _n N(R) ₂ , -C(O)OR, -OC(O)R, -CX ₃ , -CX ₂ H, -CXH ₂ , -CN, -C(O)N(R) ₂ , -N(R)C(O)R, -N(R)S(O) ₂ R, -N (R)C(O)N(R) ₂ , -N(R)C(S)N(R) ₂ , -CRN(R) ₂ C(O)OR, -N(R)R ₈ , -O (CH ₂ ) _n OR, -N(R)C(=NR ₉ )N(R) ₂ , -N(R)C(=CHR ₉ )N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O) ₂ R, -N(OR)C(O)OR, -N( OR)C(O)N(R) ₂ , -N(OR)C(S)N(R) ₂ , -N(OR)C(=NR ₉ )N(R) ₂ , -N(OR)C (=CHR ₉ )N(R) ₂ , -C(=NR ₉ )R, -C(O)N(R)OR, and -C(=NR ₉ )N(R) ₂ , and each n independently selected from 1, 2, 3, 4, and ₅ ; each R is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl, and H _; each R is independently selected from C _1- The group consisting of ₃ alkyl, C _2-3 alkenyl and H; M and M' are independently selected from -C(O)O-, -OC(O)-, -C(O)N(R')- , -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, - P(O)(OR')O-, -S(O) ₂ -, -SS-, aryl and heteroaryl; R ₇ is selected from C _1-3 alkyl, C _2-3 alkenyl and H group; R ₈ is selected from the group consisting of C _3-6 carbocycle and heterocycle; R ₉ is selected from H, CN, NO ₂ , C _1-6 alkyl, -OR, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , the group consisting of C _2-6 alkenyl, C _3-6 carbocycle and heterocycle; each R is independently selected from C _1-3 alkyl, C The group consisting of _2-3 alkenyl and H; each R' is independently selected from the group consisting of C _1-18 alkyl, C _2-18 alkenyl, -R*YR'', -YR'' and H; Each R'' is independently selected from the group consisting of C _3-14 alkyl and C _3-14 alkenyl; each R* is independently selected from the group consisting of C _1-12 alkyl and C _2-12 alkenyl each Y is independently a _C3-6 carbocycle; each X is independently selected from the group consisting of F, Cl, Br, and I; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12 and 13, or their salts or isomers.

In some embodiments, another subgroup of compounds of formula (I) includes those compounds wherein R ₁ is selected from C _5-30 alkyl, C _5-20 alkenyl, -R*YR'', - The group consisting of YR'' and -R''M'R'; R ₂ and R ₃ are independently selected from H, C _2-14 alkyl, C _2-14 alkenyl, -R*YR'', -YR '' and -R*OR'', or R ₂ and R ₃ together with the atoms to which they are attached form a heterocyclic or carbocyclic ring; R ₄ is -(CH ₂ ) _n Q or -(CH ₂ ) _n CHQR, wherein Q is -N(R) ₂ , and n is selected from 3, 4, and 5; each R ₅ is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl, and H; each - R ₆ is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; M and M' are independently selected from -C(O)O-, -OC(O)-, - C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S) -, -CH(OH)-, -P(O)(OR')O-, -S(O) ₂ -, -SS-, aryl and heteroaryl; R ₇ is selected from C _1-3 alkyl , C _2-3 alkenyl and the group consisting of H; each R is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; each R' is independently selected from C _1- The group consisting of ₁₈ alkyl, C _2-18 alkenyl, -R*YR'', -YR'' and H; each R'' is independently selected from C _3-14 alkyl and C _3-14 alkenyl the group consisting of; each R* is independently selected from the group consisting of C _1-12 alkyl and C _1-12 alkenyl; each Y is independently C _3-6 carbocycle; each X is independently selected from F , Cl, Br, and I; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13, or a salt or isomer thereof.

In some embodiments, another subgroup of compounds of formula (I) includes those compounds wherein R ₁ is selected from C _5-30 alkyl, C _5-20 alkenyl, -R*YR'', - The group consisting of YR'' and -R''M'R'; R ₂ and R ₃ are independently selected from C _1-14 alkyl, C _2-14 alkenyl, -R*YR'', -YR'' and -R*OR'', or R ₂ and R ₃ together with the atoms to which they are attached form a heterocyclic or carbocyclic ring; R ₄ is selected from -(CH ₂ ) _n Q, -(CH ₂ ) _n CHQR The group consisting of , -CHQR and -CQ(R) ₂ , wherein Q is -N(R) ₂ , and n is selected from 1, 2, 3, 4, and 5; each R ₅ is independently selected from C _1-3 The group consisting of alkyl, C _2-3 alkenyl and H; each R ₆ is independently selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; M and M' are independently selected from -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S )-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O) ₂ -, -SS-, aromatic R is selected from the group consisting of C _1-3 alkyl, C _2-3 alkenyl and H; each R is _{independently} selected from C _1-3 alkyl, C _2-3 alkenyl and The group consisting of H; each R' is independently selected from the group consisting of C _1-18 alkyl, C _2-18 alkenyl, -R*YR'', -YR'' and H; each R'' is independently is selected from the group consisting of C _3-14 alkyl and C _3-14 alkenyl; each R* is independently selected from the group consisting of C _1-12 alkyl and C _1-12 alkenyl; each Y is independently is a _C3-6 carbocycle; each X is independently selected from the group consisting of F, Cl, Br, and I; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13, or salt or isomer.

， 或其鹽或異構物，其中l選自1、2、3、4及5；m選自5、6、7、8及9；M ₁係鍵或M'；R ₄係未經取代之C _1-3烷基，或-(CH ₂) _nQ，其中Q係OH、-NHC(S)N(R) ₂、-NHC(O)N(R) ₂、-N(R)C(O)R、-N(R)S(O) ₂R、-N(R)R ₈、-NHC(=NR ₉)N(R) ₂、-NHC(=CHR ₉)N(R) ₂、-OC(O)N(R) ₂、-N(R)C(O)OR、雜芳基或雜環烷基；M及M'獨立地選自-C(O)O-、-OC(O)-、-C(O)N(R')-、-P(O)(OR')O-、-S-S-、芳基及雜芳基；且R ₂及R ₃獨立地選自由H、C _1-14烷基及C _2-14烯基組成之群。 In some embodiments, a subgroup of compounds of formula (I) includes compounds of formula (IA):

, or a salt or isomer thereof, wherein l is selected from 1, 2, 3, 4 and 5; m is selected from 5, 6, 7, 8 and 9; M ₁ is a bond or M'; R ₄ is unsubstituted C _1-3 alkyl, or -(CH ₂ ) _n Q, wherein Q is OH, -NHC(S)N(R) ₂ , -NHC(O)N(R) ₂ , -N(R)C (O)R, -N(R)S(O) ₂ R, -N(R)R ₈ , -NHC(=NR ₉ )N(R) ₂ , -NHC(=CHR ₉ )N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, heteroaryl or heterocycloalkyl; M and M' are independently selected from -C(O)O-, -OC (O)-, -C(O)N(R')-, -P(O)(OR')O-, -SS-, aryl and heteroaryl; and R ₂ and R ₃ are independently selected from The group consisting of H, C _1-14 alkyl and C _2-14 alkenyl.

或其鹽或異構物，其中l選自1、2、3、4及5；M ₁係鍵或M'；R ₄係未經取代之C _1-3烷基，或-(CH ₂) _nQ，其中n為2、3或4，且Q為OH、-NHC(S)N(R) ₂、-NHC(O)N(R) ₂、-N(R)C(O)R、-N(R)S(O) ₂R、-N(R)R ₈、-NHC(=NR ₉)N(R) ₂、-NHC(=CHR ₉)N(R) ₂、-OC(O)N(R) ₂、-N(R)C(O)OR、雜芳基或雜環烷基；M及M'獨立地選自-C(O)O-、-OC(O)-、-C(O)N(R')-、-P(O)(OR')O-、-S-S-、芳基及雜芳基；且R ₂及R ₃獨立地選自由H、C _1-14烷基及C _2-14烯基組成之群。 In some embodiments, a subgroup of compounds of formula (I) includes compounds of formula (II):

or a salt or isomer thereof, wherein l is selected from 1, 2, 3, 4 and 5; M ₁ is a bond or M'; R ₄ is unsubstituted C _1-3 alkyl, or -(CH ₂ ) _n Q, where n is 2, 3, or 4, and Q is OH, -NHC(S)N(R) ₂ , -NHC(O)N(R) ₂ , -N(R)C(O)R, -N(R)S(O) ₂ R, -N(R)R ₈ , -NHC(=NR ₉ )N(R) ₂ , -NHC(=CHR ₉ )N(R) ₂ , -OC(O )N(R) ₂ , -N(R)C(O)OR, heteroaryl or heterocycloalkyl; M and M' are independently selected from -C(O)O-, -OC(O)-, -C(O)N(R')-, -P(O)(OR')O-, -SS-, aryl and heteroaryl; and R ₂ and R ₃ are independently selected from H, C _1- A group consisting of ₁₄ alkyl and C _2-14 alkenyl.

， 或其鹽或異構物，其中R ₄係如本文所述。 In some embodiments, a subgroup of compounds of formula (I) includes compounds of formula (IIa), (IIb), (IIc), or (IIe):

, or a salt or isomer thereof, wherein R ₄ is as described herein.

， 或其鹽或異構物，其中n為2、3或4；且m、R'、R''及R ₂至R ₆係如本文所述。舉例而言，R ₂及R ₃可各自獨立地選自由C _5-14烷基及C _5-14烯基組成之群。 In some embodiments, a subgroup of compounds of formula (I) includes compounds of formula (IId):

, or a salt or isomer thereof, wherein n is 2, 3, or 4; and m, R', R'', and R ₂ to R ₆ are as described herein. For example, R ₂ and R ₃ can each be independently selected from the group consisting of C _5-14 alkyl and C _5-14 alkenyl.

(化合物I)。 In some embodiments, the ionizable cationic lipids of the present disclosure comprise compounds having the following structure:

(Compound I).

(化合物II)。 In some embodiments, the ionizable cationic lipids of the present disclosure comprise compounds having the following structure:

(Compound II).

In some embodiments, the non-cationic lipids of the present disclosure comprise 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleyl-sn-glycero- 3-Phosphoethanolamine (DOPE), 1,2-Dilinoleyl-sn-glycero-3-phosphocholine (DLPC), 1,2-Dimyristyl-sn-glycero-phosphocholine (DMPC) ), 1,2-dioleyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- Di-undecanyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine ( OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinanoyl-sn-glycero-3-phosphocholine, 1,2-diarachis Tetraenyl-sn-glycero-3-phosphocholine, 1,2-di-docosahexaenyl-sn-glycero-3-phosphocholine, 1,2-diphytanyl- sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleo-sn-glycero-3-phosphate Ethanolamine, 1,2-Dilinanoyl-sn-glycero-3-phosphoethanolamine, 1,2-Diarachidonyl-sn-glycero-3-phosphoethanolamine, 1,2-di-docosyl Hexenyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleyl-sn-glycero-3-phosphate-racemic-(1-glycerol) sodium salt (DOPG), sphingomyelin and its mixture.

In some embodiments, the PEG-modified lipids of the present disclosure comprise PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified phosphatidic acid, Quality diacylglycerol, PEG-modified dialkylglycerol and mixtures thereof. In some embodiments, the PEG-modified lipids are DMG-PEG, PEG-c-DOMG (also known as PEG-DOMG), PEG-DSG, and/or PEG-DPG.

In some embodiments, the sterols of the present disclosure comprise cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassosterol, tomatine, ursolic acid, alpha - Tocopherols and mixtures thereof.

In some embodiments, the LNPs of the present disclosure comprise the ionizable cationic lipid of Compound 1, wherein the non-cationic lipid is DSPC, the structural lipid is cholesterol, and the PEG lipid is DMG-PEG.

In some embodiments, the lipid nanoparticles comprise 45-55 mole percent (mol %) of ionizable cationic lipids. For example, the lipid nanoparticle may comprise 45 mol%, 46 mol%, 47 mol%, 48 mol%, 49 mol%, 50 mol%, 51 mol%, 52 mol%, 53 mol%, 54 mol%, or 55 mol% ionizable cationic lipid.

In some embodiments, the lipid nanoparticles comprise 5-15 mol%, 5-10 mol%, or 10-15 mol% DSPC. For example, the lipid nanoparticle can comprise 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol% or 15 mol% DSPC.

In some embodiments, the lipid nanoparticles comprise 35-40 mol% cholesterol. For example, the lipid nanoparticle can comprise 35 mol%, 35.5 mol%, 36 mol%, 36.5 mol%, 37 mol%, 37.5 mol%, 38 mol%, 38.5 mol%, 39 mol%, 39.5 mol%, or 40 mol% cholesterol.

In some embodiments, the lipid nanoparticles comprise 1-2 mol%, 1-3 mol%, 1-4 mol%, or 1-5 mol% DMG-PEG. For example, lipid nanoparticles can comprise 1 mol%, 1.5 mol%, 2 mol%, 2.5 mol%, 3 mol%, or 3.5 mol% DMG-PEG.

In some embodiments, the lipid nanoparticles comprise 50 mol% ionizable cationic lipid, 10 mol% DSPC, 38.5 mol% cholesterol, and 1.5 mol% DMG-PEG.

In some embodiments, the lipid nanoparticles comprise 49 mol% ionizable cationic lipids, 10 mol% DSPC, 38.5 mol% cholesterol, and 2.5 mol% DMG-PEG.

In some embodiments, the lipid nanoparticles comprise 49 mol% ionizable cationic lipids, 11 mol% DSPC, 38.5 mol% cholesterol, and 1.5 mol% DMG-PEG.

In some embodiments, the lipid nanoparticles comprise 48 mol% ionizable cationic lipids, 11 mol% DSPC, 38.5 mol% cholesterol, and 2.5 mol% DMG-PEG.

In some embodiments, the LNPs of the present disclosure comprise an N:P ratio of about 2:1 to about 30:1.

In some embodiments, the LNPs of the present disclosure comprise an N:P ratio of about 6:1.

In some embodiments, the LNPs of the present disclosure comprise an N:P ratio of about 3:1.

In some embodiments, the LNPs of the present disclosure comprise a weight/weight ratio of ionizable cationic lipid component to RNA of about 10:1 to about 100:1.

In some embodiments, the LNPs of the present disclosure comprise a weight/weight ratio of ionizable cationic lipid component to RNA of about 20:1.

In some embodiments, the LNPs of the present disclosure comprise a weight/weight ratio of ionizable cationic lipid component to RNA of about 10:1.

In some embodiments, the LNPs of the present disclosure have an average diameter of about 50 nm to about 150 nm.

In some embodiments, the LNPs of the present disclosure have an average diameter of about 70 nm to about 120 nm. polyvalent vaccine

Compositions as provided herein can include RNA or RNAs encoding two or more antigens of the same or different species. In some embodiments, the composition includes mRNA or mRNAs encoding two or more coronavirus antigens. In some embodiments, the RNA can encode 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more coronaviruses antigen.

In some embodiments, two or more different antigen-encoding mRNAs can be formulated in the same lipid nanoparticle. In other embodiments, two or more different antigen-encoding RNAs can be formulated into separate lipid nanoparticles (each RNA is formulated into a single lipid nanoparticle). The lipid nanoparticles can then be combined and administered as a single vaccine composition (eg, comprising multiple RNAs encoding multiple antigens), or can be administered separately. combination vaccine

Compositions as provided herein can include mRNA or multiple RNAs encoding two or more antigens of the same or different virus strains. Also provided herein are combination vaccines comprising RNA encoding one or more coronaviruses and one or more antigens from different organisms. Thus, the vaccines of the present disclosure may be combination vaccines targeting one or more antigens of the same strain/species or one or more antigens of different strains/species, eg to induce response to organisms found in the same geographic area with a high risk of coronavirus infection Antigens of immunity of an organism or an organism to which an individual may be exposed when exposed to the coronavirus. Pharmaceutical formulations

Provided herein are compositions (eg, pharmaceutical compositions), methods, kits, and reagents for the prevention or treatment of, eg, human and other mammalian coronaviruses. The compositions provided herein can be used as therapeutic or prophylactic agents. It can be used in medicine to prevent and/or treat coronavirus infection.

In some embodiments, an RNA-containing coronavirus vaccine as described herein can be administered to an individual (eg, a mammalian individual, such as a human individual), and the mRNA is translated in vivo to produce an antigenic polypeptide (antigen).

An "effective amount" of a composition (e.g., comprising RNA) is based, at least in part, on the target tissue, target cell type, mode of administration, physical characteristics of the RNA (e.g., length, nucleotide composition, and/or degree of modified nucleosides) , other components of the vaccine and other determinants such as the age, weight, height, sex and general health of the individual. Typically, an effective amount of the composition provides for induction or enhancement of an immune response as a function of antigen production in the cells of the individual. In some embodiments, an effective amount of a composition containing mRNA with at least one chemical modification is more effective than a composition containing the corresponding unmodified polynucleotide encoding the same antigen or peptide antigen. Increased antigen production can be achieved by increased cell transfection (percentage of cells transfected with RNA vaccine), increased protein translation and/or expression from polynucleotides, decreased nucleic acid degradation (eg, as by modified polynucleotides). This is evidenced by an increase in the duration of protein translation of nucleotides) or by changes in the antigen-specific immune response of the host cell.

The term "pharmaceutical composition" refers to a combination of an active agent and an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use. A "pharmaceutically acceptable carrier" does not cause undesired physiological effects after or when administered to a subject. A carrier in a pharmaceutical composition must also be "acceptable" in the sense that it is compatible with and capable of stabilizing the active ingredient. One or more solubilizers can be used as pharmaceutical carriers for delivery of active agents. Examples of pharmaceutically acceptable carriers include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to obtain compositions useful as dosage forms. Examples of other carriers include colloidal silica, magnesium stearate, cellulose and sodium lauryl sulfate. Additional suitable pharmaceutical carriers and diluents and the medical necessities for their use are described in Remington's Pharmaceutical Sciences.

In some embodiments, compositions according to the present disclosure (including polynucleotides and their encoded polypeptides) can be used to treat or prevent coronavirus infection. The compositions may be administered prophylactically or therapeutically to healthy individuals as part of an active immunization regimen or early in infection during the incubation phase or during active infection following the onset of symptoms. In some embodiments, the amount of RNA provided to the cell, tissue or individual may be an amount effective for immunoprophylaxis.

The compositions can be administered with other prophylactic or therapeutic compounds. By way of non-limiting example, a prophylactic or therapeutic compound can be an adjuvant or booster. As used herein, when referring to a prophylactic composition (such as a vaccine), the term "booster" refers to the additional administration of the prophylactic (vaccine) composition. A booster (or booster vaccine) can be administered after an earlier administration of the prophylactic composition. The administration time between the initial administration of the prophylactic composition and the booster can be, but is not limited to, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours , 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years , 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 25 years, 30 years, 35 years, 40 years, 45 years, 50 years years, 55 years, 60 years, 65 years, 70 years, 75 years, 80 years, 85 years, 90 years, 95 years or more than 99 years. In exemplary embodiments, the administration time between the initial administration of the prophylactic composition and the booster can be, but is not limited to, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months , 6 months or 1 year.

In some embodiments, the composition may be administered intramuscularly, intranasally, or intradermally, similar to the administration of inactivated vaccines known in the art.

The compositions can be used in a variety of settings depending on the prevalence of infection or the degree or level of unmet medical need. By way of non-limiting example, RNA vaccines can be used to treat and/or prevent a variety of infectious diseases. RNA vaccines have superior properties because they generate much larger antibody titers, better neutralize immunity, generate more durable immune responses, and/or generate responses earlier than commercially available vaccines.

Provided herein are pharmaceutical compositions comprising RNA and/or complexes, optionally in combination with one or more pharmaceutically acceptable excipients.

RNA can be formulated or administered alone, or in combination with one or more other components. For example, the composition may contain other components including, but not limited to, adjuvants.

In some embodiments, the composition does not contain an adjuvant (it does not contain an adjuvant).

RNA can be formulated or administered in combination with one or more pharmaceutically acceptable excipients. In some embodiments, the vaccine composition comprises at least one additional active, eg, a therapeutic active, a prophylactic active, or a combination of the two. Vaccine compositions can be sterile, pyrogen-free, or sterile and pyrogen-free. General considerations in the formulation and/or manufacture of pharmaceutical agents such as vaccine compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed. Lippincott Williams & Wilkins, 2005 (incorporated by reference in its entirety). manner is incorporated herein).

In some embodiments, the composition is administered to a human, human patient or individual. For the purposes of this disclosure, the phrase "active ingredient" generally refers to an RNA vaccine or a polynucleotide contained therein, such as mRNA encoding an antigen.

Formulations of the vaccine compositions described herein can be prepared by any method known or later developed in the art of pharmacology. In general, such methods of preparation include associating the active ingredient (eg, mRNA) with excipients and/or one or more other auxiliary ingredients and then, if necessary and/or desired, dividing, shaping and/or packaging the product into a Single-dose or multiple-dose unit procedures are desired.

The relative amounts of active ingredients, pharmaceutically acceptable excipients and/or any additional ingredients in the pharmaceutical compositions of the present disclosure will depend on the identity, size and/or condition of the individual being treated and further on the composition to be administered change with the way. For example, the composition may comprise between 0.1% and 100%, such as between 0.5% and 50%, between 1% and 30%, between 5% and 80%, at least 80% (w/w) active ingredient.

In some embodiments, mRNA is formulated with one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) allow sustained or delayed release (eg, from a depot formulation); (4) alter biodistribution (eg, target specific tissues or cell types); (5) increase translation of the encoded protein in vivo; and/or (6) alter the release profile of the encoded protein (antigen) in vivo . In addition to conventional excipients such as any and all solvents, dispersion media, diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic, thickening or emulsifying agents, preservatives, Excipients may also include, but are not limited to, lipidoids, liposomes, lipid nanoparticles, polymers, lipid complexes, core-shell nanoparticles, peptides, proteins, cells transfected with RNA (e.g., with transplantation into an individual), hyaluronidase, nanoparticle mimics, and combinations thereof. dosing / administration

Provided herein are compositions (eg, RNA vaccines), methods, kits and reagents for preventing and/or treating coronavirus infections in humans and other mammals. Immunological compositions can be used as therapeutic or prophylactic agents. In some embodiments, the compositions are used to provide prophylactic protection against coronavirus infection. In some embodiments, the composition is used to treat a coronavirus infection. In some embodiments, the compositions are used to elicit immune effector cells, eg, ex vivo activated peripheral blood mononuclear cells (PBMCs), which are then infused (re-infused) into an individual.

The subject can be any mammal, including non-human primates and human subjects. Typically, the individual is a human individual.

In some embodiments, a composition (eg, an RNA vaccine) is administered to an individual (eg, a mammalian individual, such as a human individual) in an amount effective to induce an antigen-specific immune response. The RNA encoding the coronavirus antigen is expressed and translated in vivo to produce the antigen, which in turn stimulates an immune response in the individual.

Preventive protection against coronaviruses can be achieved following administration of the compositions of the present disclosure. The immunizing composition may be administered once, twice, three times, four times or more, although one administration of the vaccine may suffice (optionally followed by a single boost). Although less desirable, the composition can be administered to an infected individual to achieve a therapeutic response. Dosing may need to be adjusted accordingly.

In aspects of the present disclosure, methods of eliciting an immune response against a coronavirus antigen (or antigens) in an individual are provided. In some embodiments, the method comprises administering to the individual a composition comprising mRNA having an open reading frame encoding a coronavirus antigen, thereby inducing in the individual an immune response specific for the coronavirus antigen, wherein relative to using a prophylactically effective dose The anti-antigen antibody titers in individuals traditionally vaccinated against the antigen increased after vaccination. "Anti-antigen antibodies" are serum antibodies that specifically bind to an antigen.

A prophylactically effective dose is a dose effective at a clinically acceptable level to prevent viral infection. In some embodiments, the effective dose is the dose listed on the package insert of the vaccine. As used herein, traditional vaccines refer to vaccines other than the mRNA vaccines of the present disclosure. For example, conventional vaccines include, but are not limited to, live microbial vaccines, killed microbial vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, virus-like particle (VLP) vaccines, and the like. In exemplary embodiments, conventional vaccines are vaccines that have been approved by regulatory authorities and/or registered with a national drug regulatory agency, such as the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

In some embodiments, the anti-antigen antibody titer in a vaccinated individual increases by 1 relative to the anti-antigen antibody titer in an individual vaccinated with a prophylactically effective dose of traditional vaccine against coronavirus or an unvaccinated individual log to 10 log. In some embodiments, the anti-antigen antibody titer in a vaccinated individual increases by 1 relative to the anti-antigen antibody titer in an individual vaccinated with a prophylactically effective dose of traditional vaccine against coronavirus or an unvaccinated individual log, 2 log, 3 log, 4 log, 5 log or 10 log.

In other aspects of the present disclosure, methods of eliciting an immune response against a coronavirus in an individual are provided. The method comprises administering to an individual a composition comprising mRNA comprising an open reading frame encoding a coronavirus antigen, thereby inducing in the individual an immune response specific to the coronavirus, wherein the immune response in the individual is equivalent to that relative to the composition Immune responses in individuals vaccinated with conventional vaccines against coronavirus at 2-fold to 100-fold dose levels.

In some embodiments, the immune response in an individual is equivalent to that in an individual vaccinated with conventional vaccines at dose levels that are twice relative to the compositions of the present disclosure. In some embodiments, the immune response in an individual is equivalent to that in an individual vaccinated with conventional vaccines at dose levels three times relative to the compositions of the present disclosure. In some embodiments, the immune response in an individual is equivalent to that in an individual vaccinated with conventional vaccines at dose levels 4-, 5-, 10-, 50-, or 100-fold relative to the compositions of the present disclosure. In some embodiments, the immune response in an individual is equivalent to that in an individual vaccinated with conventional vaccines at dose levels 10- to 1000-fold relative to the compositions of the present disclosure. In some embodiments, the immune response in an individual is equivalent to that in an individual vaccinated with conventional vaccines at dose levels 100- to 1000-fold relative to the compositions of the present disclosure.

In other embodiments, the immune response is assessed by measuring [protein] antibody titers in the individual. In other embodiments, sera or antibodies from immunized individuals are tested for their ability to neutralize viral uptake or reduce coronavirus transformation of human B lymphocytes. In other embodiments, the ability to promote a strong T cell response is measured using art-recognized techniques.

Other aspects of the present disclosure provide for inducing an immune response specific to a coronavirus antigen in an individual by administering to the individual a composition comprising mRNA having an open reading frame encoding a coronavirus antigen, eliciting in an individual A method of an immune response against a coronavirus wherein the immune response is induced in an individual 2 days to 10 weeks earlier than that induced in an individual vaccinated with a prophylactically effective dose of a conventional vaccine against the coronavirus. In some embodiments, an immune response in an individual is induced in an individual vaccinated with a prophylactically effective dose of a conventional vaccine at a dose level of 2- to 100-fold relative to a composition of the present disclosure.

In some embodiments, the immune response is induced in an individual 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 5 weeks earlier than the immune response induced in the individual vaccinated with a prophylactically effective dose of the traditional vaccine or 10 weeks.

Also provided herein are methods of eliciting an immune response against a coronavirus in an individual by administering to the individual mRNA having an open reading frame encoding a first antigen, wherein the RNA does not include stabilizing elements, and wherein the adjuvant is not co-formulated with the vaccine or co-investment.

The compositions can be administered by any route that produces therapeutically effective results. Such routes include, but are not limited to, intradermal, intramuscular, intranasal and/or subcutaneous administration. The present disclosure provides methods comprising administering RNA vaccines to individuals in need. The exact amount required will vary from individual to individual, depending on the individual's species, age and general condition, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. RNA is usually formulated in dosage unit form for ease of administration and uniformity of dosage. It should be understood, however, that the total daily amount of RNA can be determined by the attending physician within the scope of sound medical judgment. The particular therapeutically, prophylactically, or appropriate imaging dose level for any particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the particular compound employed; the particular composition employed; the patient age, weight, general health, sex, and diet; time of administration, route of administration, and rate of excretion of the particular compound employed; duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and Similar factors are well known in the medical field.

An effective amount of RNA as provided herein can be as low as 20 μg, eg, administered in a single dose or in two 10 μg doses. In some embodiments, the effective amount is a total dose of 20 μg-300 μg or 25 μg-300 μg. For example, an effective amount can be 20 µg, 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, 55 µg, 60 µg, 65 µg, 70 µg, 75 µg, 80 µg, 85 µg, Total dose of 90 µg, 95 µg, 100 µg, 110 µg, 120 µg, 130 µg, 140 µg, 150 µg, 160 µg, 170 µg, 180 µg, 190 µg, 200 µg, 250 µg or 300 µg. In some embodiments, the effective amount is a total dose of 20 μg. In some embodiments, the effective amount is a total dose of 25 μg. In some embodiments, the effective amount is a total dose of 50 μg. In some embodiments, the effective amount is a total dose of 75 μg. In some embodiments, the effective amount is a total dose of 100 μg. In some embodiments, the effective amount is a total dose of 150 μg. In some embodiments, the effective amount is a total dose of 200 μg. In some embodiments, the effective amount is a total dose of 250 μg. In some embodiments, the effective amount is a total dose of 300 μg.

The RNAs described herein can be formulated into dosage forms described herein, such as intranasal, intratracheal, or injectable (eg, intravenous, intraocular, intravitreal, intramuscular, intradermal, intracardiac, intraperitoneal, and subcutaneous). vaccine efficacy

Some aspects of the present disclosure provide formulations of compositions (eg, RNA vaccines) in which the RNA is formulated in an effective amount to generate an antigen-specific immune response (eg, to generate antibodies specific to a coronavirus antigen) in an individual. An "effective amount" is an amount of RNA effective to generate an antigen-specific immune response. Also provided herein are methods of inducing an antigen-specific immune response in an individual.

As used herein, an immune response to a vaccine or LNP of the present disclosure is the production of a humoral and/or cellular immune response in an individual to the coronavirus protein(s) present in the vaccine. For the purposes of this disclosure, a "humoral" immune response refers to an immune response mediated by antibody molecules, including, for example, secretory (IgA) or IgG molecules, while a "cellular" immune response is one mediated by T lymphocytes (eg, CD4 ⁺ helper cells and/or CD8 ⁺ T cells (eg CTL)) and/or other leukocyte-mediated immune responses. An important aspect of cellular immunity involves antigen-specific responses elicited by cytolytic T cells (CTLs). CTLs are specific for peptide antigens presented in association with proteins encoded by the major histocompatibility complex (MHC) and expressed on the cell surface. CTLs help to induce and promote the destruction of intracellular microorganisms or the lysis of cells infected with such microorganisms. Another aspect of cellular immunity involves antigen-specific responses elicited by helper T cells. Helper T cells are used to help stimulate function and focus the activity of nonspecific effector cells on cells displaying peptide antigens associated with MHC molecules on their surface. The cellular immune response also results in the production of interleukins, chemokines, and other such molecules (including those derived from CD4 ⁺ and CD8 ⁺ T cells) produced by activated T cells and/or other white blood cells.

In some embodiments, an antigen-specific immune response is characterized by measuring the anti-coronavirus antigen antibody titers produced in an individual administered a composition as provided herein. Antibody titer is a measure of the amount of antibody (eg, antibody specific for a particular antigen or epitope of an antigen) in an individual. Antibody titers are usually expressed as the reciprocal of the largest dilution that gave a positive result. For example, enzyme-linked immunosorbent assay (ELISA) is a common assay used to determine antibody titers.

A variety of serological tests can be used to measure antibodies against encoded relevant antigens, such as SAR-CoV-2 virus or SAR-CoV-2 viral antigens, such as the SAR-CoV-2 spike or S protein, or domains thereof. Such tests include hemagglutination inhibition test, complement fixation test, fluorescent antibody test, enzyme-linked immunosorbent assay (ELISA) and plaque reduction neutralization test (PRNT). Each of these tests measures a different antibody activity. In exemplary embodiments, plaque reduction neutralization tests or PRNTs (eg, PRNT50 or PRNT90) are used as serological correlates of protection. PRNT measures the biological parameter of virus neutralization in vitro and is the most serological virus-specific test among certain classes of viruses, and is closely related to the serum level of protection against viral infection.

The basic design of PRNT allows for virus-antibody interactions to take place in test tubes or microtiter plates, and then to measure the effect of the antibody on virus infectivity by plating the mixture on virus susceptible cells, preferably cells of mammalian origin . Cells were overlaid with semi-solid medium that would limit transmission of progeny virus. Each virus that causes a productive infection produces localized areas of infection (plaques) that can be detected in a variety of ways. Plaques were counted and compared to the starting concentration of virus to determine the percent reduction in total virus infectivity. In PRNT, serial dilutions of the tested serum samples are typically made before mixing with a standard amount of virus. The concentration of virus is kept constant so that when added to susceptible cells and covered with semi-solid medium, individual plaques can be identified and counted. In this manner, the PRNT endpoint titer for each serum sample can be calculated at any selected percent reduction in viral activity.

In functional assays intended to assess vaccine immunogenicity, dilution series of serum samples for antibody titration should ideally begin at titers below the "seroprotective" threshold value. With respect to SARS-CoV-2 neutralizing antibodies, the "seroprotective" threshold titer is still unknown; however, in certain embodiments, a seropositivity threshold of 1:10 may be considered a seroprotective threshold.

PRNT endpoint titers are expressed as the reciprocal of the final serum dilution showing the desired percent reduction in plaque counts. PRNT titers can be calculated based on a 50% or greater reduction in plaque count (PRNT50). For vaccine sera, PRNT50 titers are better than those using higher cutoffs (eg, PRNT90), providing more accurate results from the linear portion of the titration curve.

There are several ways to calculate PRNT titers. The simplest and most widely used way to calculate titers is to count plaques, and to report titers as the reciprocal of the final serum dilution based on a back-titration of input plaques showing a >50% reduction in input plaque counts. Using a curve fitting method from several serum dilutions may allow more accurate results to be calculated. Various computer analysis programs exist for this purpose (eg, SPSS or GraphPad Prism).

In some embodiments, antibody titers are used to assess whether an individual is already infected or to determine whether immunization is required. In some embodiments, antibody titers are used to determine the strength of an autoimmune response, to determine the need for booster immunization, to determine whether previous vaccines are effective, and to identify any recent or previous infection. According to the present disclosure, antibody titers can be used to determine the strength of an immune response induced in an individual by a composition (eg, an RNA vaccine).

In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by at least 1 log relative to a control. For example, the anti-coronavirus antigen antibody titer produced in an individual can be increased by at least 1.5, at least 2, at least 2.5, or at least 3 logs relative to a control. In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by 1, 1.5, 2, 2.5, or 3 logs relative to a control. In some embodiments, the anti-coronavirus antigen antibody titers produced in the individual are increased by 1-3 logs relative to a control. For example, the anti-coronavirus antigen antibody titer produced in an individual can be increased by 1-1.5, 1-2, 1-2.5, 1-3, 1.5-2, 1.5-2.5, 1.5-3, 2- 2.5, 2-3 or 2.5-3 log.

In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by at least 2-fold relative to a control. For example, the anti-coronavirus antigen antibody titer produced in the individual can be increased by at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold relative to a control times. In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold relative to a control. In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by 2-10 fold relative to the control. For example, the anti-coronavirus antigen antibody titer produced in an individual can be increased by 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2- 3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7- 8, 8-10, 8-9 or 9-10 times.

In some embodiments, the antigen-specific immune response is measured as the ratio of the geometric mean titers (GMT) of the titers of coronavirus serum neutralizing antibodies, referred to as the geometric mean ratio (GMR). Geometric mean titers (GMT) are calculated by multiplying all values together and taking the n root of the number, where n is the number of individuals with available data.

In some embodiments, the control is an anti-coronavirus antigen antibody titer produced in individuals not administered the composition (eg, RNA vaccine). In some embodiments, the control is an anti-coronavirus antigen antibody titer produced in an individual administered a recombinant or purified protein vaccine. Recombinant protein vaccines typically include protein antigens produced in heterologous expression systems (eg, bacteria or yeast) or purified from a number of pathogenic organisms.

In some embodiments, the ability of a composition (eg, an RNA vaccine) to be effective is measured in a murine model. For example, the composition can be administered to a murine model and assayed for the induction of neutralizing antibody titers in the murine model. Viral challenge studies can also be used to evaluate the efficacy of the vaccines of the present disclosure. For example, the composition can be administered to a murine model, challenged with a virus, and the murine model analyzed for survival and/or immune responses (eg, neutralizing antibody responses, T cell responses (eg, interleukin responses) )).

In some embodiments, an effective amount of a composition (eg, an RNA vaccine) is a reduced dose compared to a standard-of-care dose of a recombinant protein vaccine. "Standard of care" as provided herein refers to medical or psychotherapy guidelines, and can be general or specific. "Standard Care" prescribes appropriate treatment based on scientific evidence and collaboration between medical professionals involved in the treatment of a given condition. It is the process of diagnosis and treatment that a physician/clinician should follow for a certain type of patient, disease or clinical condition. "Standard of Care Dosage" provided herein refers to the amount that a physician/clinician or other medical professional would administer to an individual to treat or prevent coronavirus while following standard of care guidelines for the treatment or prevention of coronavirus infection or related conditions Doses of recombinant or purified protein vaccines, or live attenuated or inactivated vaccines, or VLP vaccines for infections or related conditions.

In some embodiments, the anti-coronavirus antigen antibody titers produced in an individual administered an effective amount of the composition are equivalent to those administered a standard-of-care dose of recombinant or purified protein vaccines, or live attenuated or inactivated vaccines , or the anti-coronavirus antigen antibody titers produced in control individuals of VLP vaccine.

Vaccine efficacy can be assessed using standard assays (see, eg, Weinberg et al., J Infect Dis. 2010 Jun 1;201(11):1607-10). For example, vaccine efficacy can be measured by double-blind, randomized, controlled clinical trials. Vaccine efficacy can be expressed as the proportional reduction in disease attack rate (AR) between unvaccinated (ARU) and vaccinated (ARV) study cohorts, and can be derived from the relative risk of disease in the vaccinated group using the following formula ( RR) calculation: Performance = (ARU - ARV)/ARU × 100; and Efficacy = (1-RR) × 100.

Likewise, vaccine efficacy can be assessed using standard assays (eg, see Weinberg et al., J Infect Dis. 2010 Jun 1;201(11):1607-10). Vaccine efficacy is the evaluation of how well a vaccine, which may have demonstrated high vaccine efficacy, reduces disease in a population. This measure evaluates the net balance of benefits and adverse effects of a vaccination regimen, not just the vaccine itself, under natural field conditions rather than in controlled clinical trials. Vaccine effectiveness is proportional to vaccine potency (efficacy), but is also influenced by the extent of target herd immunity in the population and other non-vaccine-related factors that affect the "real-world" outcome of hospitalizations, ambulatory visits, or costs. For example, a retrospective case-control analysis can be used in which vaccination rates are compared between a group of infected cases and appropriate controls. Vaccine effectiveness can be expressed as a ratio difference, using the odds ratio (OR) for infection despite vaccination: Validity = (1 - OR) × 100.

In some embodiments, the efficacy of the composition (eg, RNA vaccine) is at least 60% relative to unvaccinated control individuals. For example, the efficacy of the composition can be at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 95%, at least 98%, or 100% relative to unvaccinated control individuals.

Eliminating immunity . Eliminating immunity refers to a unique immune state that prevents efficient infection of a pathogen into a host. In some embodiments, an effective amount of a composition of the present disclosure is sufficient to provide eliminating immunity in an individual for at least 1 year. For example, an effective amount of a composition of the present disclosure is sufficient to provide eliminating immunity in an individual for at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In some embodiments, an effective amount of a composition of the present disclosure is sufficient to provide depleting immunity in an individual at a dose that is at least 5-fold lower relative to a control. For example, an effective amount can be sufficient to provide depleting immunity in an individual at a dose that is at least 10-fold, 15-fold or 20-fold lower relative to a control.

Detectable antigens . In some embodiments, an effective amount of a composition of the present disclosure is sufficient to produce detectable levels of coronavirus antigens, as measured in the serum of an individual 1-72 hours after administration.

Titer . Antibody titer is a measure of the number of antibodies (eg, antibodies specific for a particular antigen (eg, an anti-coronavirus antigen)) in an individual. Antibody titers are usually expressed as the reciprocal of the largest dilution that gave a positive result. For example, enzyme-linked immunosorbent assay (ELISA) is a common assay used to determine antibody titers.

In some embodiments, an effective amount of a composition of the present disclosure is sufficient to produce 1,000-10,000 neutralizing antibody titers produced by neutralizing antibodies directed against a coronavirus antigen, such as in the serum of an individual 1-72 hours after administration Measured in. In some embodiments, an effective amount of a composition of the present disclosure is sufficient to generate 1,000-5,000 neutralizing antibody titers produced by neutralizing antibodies directed against a coronavirus antigen, such as in the serum of an individual 1-72 hours after administration Measured in. In some embodiments, the effective amount is sufficient to generate a titer of 5,000-10,000 neutralizing antibodies produced by neutralizing antibodies directed against a coronavirus antigen, as measured in the serum of the individual 1-72 hours after administration.

In some embodiments, the neutralizing antibody titer is at least 100 NT ₅₀ . For example, the neutralizing antibody titer can be at least 200, 300, 400, ₅₀₀ , 600, 700, 800, 900, or 1000 NT50. In some embodiments, the neutralizing antibody titer is at least 10,000 _NT50 .

In some embodiments, the neutralizing antibody titer is at least 100 neutralizing units per milliliter (NU/mL). For example, the neutralizing antibody titer can be at least 200, 300, 400, 500, 600, 700, 800, 900, or 1000 NU/mL. In some embodiments, the neutralizing antibody titer is at least 10,000 NU/mL.

In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by at least 1 log relative to a control. For example, the anti-coronavirus antigen antibody titer produced in an individual can be increased by at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 logs relative to a control.

In some embodiments, the anti-coronavirus antigen antibody titer produced in the individual is increased by at least 2-fold relative to a control. For example, the anti-coronavirus antigen antibody titer produced in the individual is increased by at least 3, 4, 5, 6, 7, 8, 9 or 10 fold relative to the control.

In some embodiments, the geometric mean, the nth root of the product of n numbers, is often used to describe proportional growth. In some embodiments, the geometric mean is used to describe the antibody titer produced in an individual.

Controls can be, for example, unvaccinated individuals, or individuals administered a live attenuated virus vaccine, an inactivated virus vaccine, or a protein subunit vaccine. Additional Embodiments

The following numbered paragraphs cover additional embodiments of the present disclosure: 1. A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the receptor binding structure of the SARS-CoV-2 spike protein domain (RBD) and protein transmembrane domain. 2. The mRNA of paragraph 1, wherein the protein transmembrane domain is an influenza hemagglutinin transmembrane domain. 3. The mRNA of paragraph 2, wherein the fusion protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 77. 4. The mRNA of paragraph 3, wherein the fusion protein comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least the amino acid sequence of SEQ ID NO: 77 99% identical amino acid sequence. 5. The mRNA of paragraph 4, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:77. 6. The mRNA of any of the preceding paragraphs, wherein the open reading frame comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 76. 7. The mRNA of paragraph 6, wherein the open reading frame comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, with the nucleotide sequence of SEQ ID NO: 76. Nucleotide sequences that are at least 98% or at least 99% identical. 8. The mRNA of paragraph 7, wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:76. 9. A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising an amino (N) terminal domain and a transmembrane domain of a SARS-CoV-2 spike protein. 10. The mRNA of paragraph 9, wherein the transmembrane domain is an influenza hemagglutinin transmembrane domain. 11. The mRNA of paragraph 10, wherein the fusion protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47. 12. The mRNA of paragraph 11, wherein the fusion protein comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least the amino acid sequence of SEQ ID NO: 47 99% identical amino acid sequence. 13. The mRNA of paragraph 12, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:47. 14. The mRNA of any of the preceding paragraphs, wherein the open reading frame comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 46. 15. The mRNA of paragraph 14, wherein the open reading frame comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, with the nucleotide sequence of SEQ ID NO: 46. Nucleotide sequences that are at least 98% or at least 99% identical. 16. The mRNA of paragraph 15, wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:46. 17. A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising a SARS-CoV-2 spike protein linked to the receptor binding domain of the SARS-CoV-2 spike protein. Amine (N) terminal domain. 18. The mRNA of paragraph 17, wherein the fusion protein further comprises a transmembrane domain. 19. The mRNA of paragraph 18, wherein the fusion protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 92. 20. The mRNA of paragraph 18, wherein the fusion protein comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least the amino acid sequence of SEQ ID NO: 92 99% identical amino acid sequence. 21. The mRNA of paragraph 20, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:92. 22. The mRNA of any of the preceding paragraphs, wherein the open reading frame comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 91. 23. The mRNA of paragraph 22, wherein the open reading frame comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, with the nucleotide sequence of SEQ ID NO: 91. Nucleotide sequences that are at least 98% or at least 99% identical. 24. The mRNA of paragraph 23, wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:91. 25. The mRNA of any of the preceding paragraphs, further comprising a 5' untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO: 131 or 2 as appropriate. 26. The mRNA of any of the preceding paragraphs, further comprising a 3' untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO: 132 or 4 as appropriate. 27. The mRNA of any of the preceding paragraphs, further comprising a 5' end cap, optionally 7mG(5')ppp(5')NlmpNp. 28. The mRNA of any of the preceding paragraphs, further comprising a poly-A tail, the poly-A tail optionally having a length of about 100 nucleotides. 29. The mRNA of any preceding paragraph, wherein the mRNA comprises a chemical modification, optionally 1-methylpseudouridine. 30. A composition comprising the mRNA of any one of paragraphs 1-29. 31. A composition comprising the mRNA of any of paragraphs 1-8 and the mRNA of any of paragraphs 9-16. 32. A composition comprising the mRNA of any one of paragraphs 17-29. 33. A composition comprising: (a) a messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and a protein transmembrane domain; and (b) an mRNA comprising an open reading frame encoding a fusion protein comprising the amino (N) terminal domain and the transmembrane domain of the SARS-CoV-2 spike protein. 34. The composition of paragraph 33, wherein the protein transmembrane domain is an influenza hemagglutinin transmembrane domain. 35. The composition of paragraph 34, wherein the fusion protein of (a) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 77. 36. The composition of paragraph 35, wherein the fusion protein of (a) comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 97% with the amino acid sequence of SEQ ID NO: 77 Amino acid sequences that are 98% or at least 99% identical. 37. The composition of paragraph 36, wherein the fusion protein of (a) comprises the amino acid sequence of SEQ ID NO:77. 38. The composition of any of paragraphs 34 to 37, wherein the open reading frame of (a) comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 76. 39. The composition of paragraph 38, wherein the open reading frame of (a) comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, with the nucleotide sequence of SEQ ID NO: 76. Nucleotide sequences that are at least 97%, at least 98%, or at least 99% identical. 40. The composition of paragraph 39, wherein the open reading frame of (a) comprises the nucleotide sequence of SEQ ID NO:76. 41. The composition of any one of paragraphs 34 to 40, wherein the fusion protein of (b) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47. 42. The composition of paragraph 41, wherein the fusion protein of (b) comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least Amino acid sequences that are 98% or at least 99% identical. 43. The composition of paragraph 42, wherein the fusion protein of (b) comprises the amino acid sequence of SEQ ID NO:47. 44. The composition of any one of paragraphs 34 to 43, wherein the open reading frame of (b) comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 46. 45. The composition of paragraph 44, wherein the open reading frame of (b) comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, with the nucleotide sequence of SEQ ID NO:46. Nucleotide sequences that are at least 97%, at least 98%, or at least 99% identical. 46. The composition of paragraph 45, wherein the open reading frame of (b) comprises the nucleotide sequence of SEQ ID NO:46. 47. The composition of any of paragraphs 33-46, wherein the ratio of mRNA of (a) to mRNA of (b) is about 1:1. 48. The composition of any of paragraphs 1-29, formulated in lipid nanoparticles. 49. The composition of any of paragraphs 30-47, further comprising lipid nanoparticles. 50. The composition of paragraph 49, wherein the mRNA is formulated in lipid nanoparticles. 51. The composition of any of paragraphs 33-47, wherein the mRNA of (a) is formulated in lipid nanoparticles, and the mRNA of (b) is formulated in lipid nanoparticles. 52. The composition of paragraph 51, wherein the mRNAs of (a) and (b) are in the same lipid nanoparticle, or wherein the mRNAs of (a) and (b) are each formulated in separate nanoparticles relative to each other. 53. The mRNA of paragraph 48 or the composition of any of paragraphs 49-52, wherein the lipid nanoparticle comprises a cationic lipid. 54. The mRNA or composition of paragraph 53, wherein the lipid nanoparticle further comprises neutral lipids. 55. The mRNA or composition of paragraph 53 or 54, wherein the lipid nanoparticle further comprises a sterol. 56. The mRNA or composition of any of paragraphs 53-55, wherein the lipid nanoparticle further comprises polyethylene glycol (PEG) modified lipids. 57. The mRNA or composition of any of paragraphs 53-56, wherein the lipid nanoparticle comprises ionizable cationic lipids, neutral lipids, sterols, and PEG-modified lipids. 58. The mRNA or composition of paragraph 57, wherein the ionizable cationic lipid is 8-((2-hydroxyethyl)(6-oxygen-6-(undecyloxy)hexyl)amino ) heptadecan-9-yl octanoate (compound 1). 59. The mRNA or composition of paragraph 57 or 58, wherein the neutral lipid is 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). 60. The mRNA or composition of any of paragraphs 57-59, wherein the sterol is cholesterol. 61. The mRNA or composition of any of paragraphs 57-60, wherein the PEG-modified lipid is 1,2 dimyristyl-sn-glycerol-methoxypolyethylene glycol (PEG2000 DMG). 62. The mRNA or composition of any one of paragraphs 57 to 61, wherein the lipid nanoparticle comprises 20-60 mol% ionizable cationic lipids, 5-25 mol% neutral lipids, 25-55 mol% solid lipids Lipids modified with alcohol and 0.5-15 mol% PEG. 63. The mRNA or composition of paragraph 62, wherein the lipid nanoparticle comprises: 47 mol% ionizable lipids; 11.5 mol% neutral lipids; 38.5 mol% sterols; and 3.0 mol% PEG-modified lipids; 48 mol% ionizable lipids; 11 mol% neutral lipids; 38.5 mol% sterols; and 2.5 mol% PEG-modified lipids; 49 mol% ionizable lipids; 10.5 mol% neutral lipids; 38.5 mol% solids alcohol; and 2.0 mol% PEG-modified lipid; 50 mol% ionizable lipid; 10 mol% neutral lipid; 38.5 mol% sterol; and 1.5 mol% PEG-modified lipid; or 51 mol% ionizable lipid Lipids; 9.5 mol% neutral lipids; 38.5 mol% sterols; and 1.0 mol% PEG-modified lipids. 64. The mRNA or composition of paragraph 63, wherein the lipid nanoparticle comprises: 47 mol% Compound 1; 11.5 mol% DSPC; 38.5 mol% cholesterol; and 3.0% PEG2000DMG; 48 mol% Compound 1; 11.5 mol% DSPC 38.5 mol% cholesterol; and 2.5% PEG2000DMG; 49 mol% Compound 1; 11.5 mol% DSPC; 38.5 mol% cholesterol; and 2.0% PEG2000DMG; 50 mol% Compound 1; 11.5 mol% DSPC; % PEG2000DMG; or 51 mol% Compound 1; 11.5 mol% DSPC; 38.5 mol% cholesterol; and 1.0% PEG2000DMG. 65. A method comprising administering to an individual the mRNA or composition of any of the preceding paragraphs in an amount effective to induce a neutralizing antibody response against SARS-CoV-2 in the individual. 66. A method comprising administering to an individual the mRNA or composition of any of the preceding paragraphs in an amount effective to induce a T cell immune response against SARS-CoV-2 in the individual. 67. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding a coronavirus antigen capable of inducing an immune response against SARS-CoV-2 (such as a neutralizing antibody response), wherein the antigen A protein fragment or functional protein domain comprising SARS-CoV-2, optionally in which RNA is formulated in lipid nanoparticles. 68. The mRNA of paragraph 67, wherein the antigen is a functional protein domain. 69. The mRNA of paragraph 68, wherein the protein domain is the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. 70. The mRNA of paragraph 69, wherein the NTD is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain. 71. The mRNA of paragraph 70, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 47 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 47. 72. The mRNA of paragraph 70 or 71, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 46 %, at least 97%, at least 98%, or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 46. 73. The mRNA of paragraph 68, wherein the protein domain is the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. 74. The mRNA of paragraph 73, wherein the RBD is soluble. 75. The mRNA of paragraph 74, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 62 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 62. 76. The mRNA of paragraph 74 or 75, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 61 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 61. 77. The mRNA of paragraph 73, wherein the RBD is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain. 78. The mRNA of paragraph 77, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 77 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:77. 79. The mRNA of paragraph 77 or 78, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 76 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 76. 80. The mRNA of paragraph 69, wherein the NTD is linked to the RBD of the SARS-CoV-2 spike protein to form an NTD-RBD fusion protein. 81. The mRNA of paragraph 80, wherein the NTD-RBD fusion is linked to a transmembrane domain (TM), optionally linked to an influenza hemagglutinin transmembrane domain, to form an NTD-RBD-TM protein. 82. The mRNA of paragraph 81, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 92 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 92. 83. The mRNA of paragraph 81 or 82, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 91 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 91. 84. The mRNA of paragraph 80, wherein the NTD-RBD fusion comprises a C-terminal truncation. 85. The mRNA of paragraph 84, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 107 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 107. 86. The mRNA of paragraph 84 or 85, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 106 %, at least 97%, at least 98%, or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 106. 87. The mRNA of any of the preceding paragraphs, wherein the NTD and/or RBD comprises an extension. 88. The mRNA of paragraph 87, wherein the antigen comprises at least 80%, at least 85%, at least 90% with the amino acid sequence of any one of SEQ ID NOs: 59, 86, 89, 116, 119 or 122 , at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical amino acid sequences, optionally wherein the antigen comprises in SEQ ID NO: 59, 86, 89, 116, 119 or 122 The amino acid sequence of any one. 89. The mRNA of paragraph 87 or 88, wherein the open reading frame comprises at least 70%, at least 75% with the nucleotide sequence of any one of SEQ ID NOs: 58, 85, 88, 115, 118 or 121 , at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises SEQ ID NO: 58, The nucleotide sequence of any of 85, 88, 115, 118, or 121. 90. The mRNA of paragraph 68, wherein the protein domain is the S1 subunit domain of the SARS-CoV-2 spike protein. 91. The mRNA of paragraph 90, wherein the S1 subunit is soluble. 92. The mRNA of paragraph 91, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 5 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:5. 93. The mRNA of paragraph 91 or 92, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 3 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 3. 94. The mRNA of paragraph 90, wherein the S1 subunit is linked to a transmembrane domain, optionally an influenza hemagglutinin transmembrane domain. 95. The mRNA of paragraph 94, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 17 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 17. 96. The mRNA of paragraph 94 or 95, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 16 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 16. 97. The mRNA of paragraph 90, wherein the S1 subunit is modified to remove the RBD or a portion of the RBD of the S protein. 98. The mRNA of paragraph 97, wherein the antigen comprises at least 80%, at least 85%, at least 90% with the amino acid sequence of any one of SEQ ID NOs: 20, 23, 26, 29, 32 or 35 , at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical amino acid sequences, optionally wherein the antigen comprises in SEQ ID NO: 20, 23, 26, 29, 32 or 35 The amino acid sequence of any one. 99. The mRNA of paragraph 97 or 98, wherein the open reading frame comprises at least 70%, at least 75% with the nucleotide sequence of any one of SEQ ID NOs: 19, 22, 25, 28, 31 or 34 , at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises SEQ ID NO: 19, The nucleotide sequence of any of 22, 25, 28, 31 or 34. 100. The mRNA of paragraph 90, wherein the S1 subunit is linked to the S2 subunit of the S protein. 101. The mRNA of paragraph 100, wherein the S2 subunit is derived from the SARS-CoV-2 S protein, and in some embodiments wherein the S2 subunit comprises an open reading frame comprising the SEQ ID NO: 145 Nucleotide sequences having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity, as appropriate wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:145. 102. The mRNA of paragraph 101, wherein the S1 subunit is from the HKU1 S protein. 103. The mRNA of paragraph 102, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 38 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:38. 104. The mRNA of paragraph 102 or 103, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 37 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 37. 105. The mRNA of paragraph 101, wherein the S1 subunit is from an OC43 S protein. 106. The mRNA of paragraph 105, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% with the amino acid sequence of SEQ ID NO: 41 % or at least 99% identical amino acid sequence, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 41. 107. The mRNA of paragraph 105 or 106, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 40 %, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 40. 108. The mRNA of any of the preceding paragraphs, wherein the antigen further comprises a scaffold domain, optionally selected from the group consisting of ferritin, lumazine synthetase, and foldon. 109. The mRNA of paragraph 108, wherein the scaffold domain is ferritin. 110. The mRNA of paragraph 109, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, with the amino acid sequence of SEQ ID NO: 8 or 65, An amino acid sequence that is at least 98% or at least 99% identical, as appropriate, wherein the antigen comprises the amino acid sequence of SEQ ID NO: 8 or 65. 111. The mRNA of paragraph 109 or 110, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, with the nucleotide sequence of SEQ ID NO:7 or 64. A nucleotide sequence that is at least 96%, at least 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 7 or 64. 112. The mRNA of paragraph 108, wherein the scaffold domain is a lumazine synthase. 113. The mRNA of paragraph 112, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95% with the amino acid sequence of any one of SEQ ID NOs: 11, 14, 68 or 71 , at least 96%, at least 97%, at least 98% or at least 99% identical amino acid sequences, optionally wherein the antigen comprises an amino acid of any one of SEQ ID NOs: 11, 14, 68 or 71 sequence. 114. The mRNA of paragraph 112 or 113, wherein the open reading frame comprises at least 70%, at least 75%, at least 80% with the nucleotide sequence of any one of SEQ ID NOs: 10, 13, 67 or 70 , at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises SEQ ID NO: 10, 13, 67 or The nucleotide sequence of any of 70. 115. The mRNA of paragraph 108, wherein the scaffold domain is a foldon. 116. The mRNA of paragraph 115, wherein the antigen comprises at least 80%, at least 85% with the amino acid sequence of any one of SEQ ID NOs: 44, 50, 74, 80, 83, 101, 104 or 113 , at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, optionally wherein the antigen comprises SEQ ID NOs: 44, 50, 74, 80, The amino acid sequence of any of 83, 101, 104, or 113. 117. The mRNA of paragraph 115 or 116, wherein the open reading frame comprises at least 70% with the nucleotide sequence of any one of SEQ ID NOs: 43, 49, 73, 79, 82, 100, 103 or 112 , at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises SEQ ID The nucleotide sequence of any of NO: 43, 49, 73, 79, 82, 100, 103 or 112. 118. The mRNA of any of the preceding paragraphs, wherein the antigen further comprises a trafficking signal, optionally selected from macrophage markers, optionally CD86, CD11B and/or VSVGct. 119. The mRNA of paragraph 118, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least the amino acid sequence of any one of SEQ ID NOs: 95, 98 or 110 An amino acid sequence that is 96%, at least 97%, at least 98%, or at least 99% identical, as appropriate, wherein the antigen comprises the amino acid sequence of any one of SEQ ID NOs: 95, 98, or 110. 120. The mRNA of paragraph 118 or 119, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least the nucleotide sequence of any one of SEQ ID NOs: 94, 97 or 109 A nucleotide sequence that is 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises any of SEQ ID NOs: 94, 97 or 109 The nucleotide sequence of one. 121. The mRNA of any of paragraphs 67-120, formulated in a lipid nanoparticle. 122. The mRNA of paragraph 121, wherein the lipid nanoparticles comprise cationic lipids (optionally ionizable cationic lipids), neutral lipids, sterols, and/or polyethylene glycol (PEG) modified lipids. 123. The mRNA or composition of paragraph 108, wherein the ionizable cationic lipid is 8-((2-hydroxyethyl)(6-oxygen-6-(undecyloxy)hexyl)amino ) heptadecan-9-yl caprylate (compound 1), neutral lipids 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC), sterols cholesterol, and/or The PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol-methoxypolyethylene glycol (PEG2000 DMG). 124. The mRNA or composition of any one of paragraphs 121 to 123, wherein the lipid nanoparticle comprises 20-60 mol% ionizable cationic lipids, 5-25 mol% neutral lipids, 25-55 mol% solid lipids Lipids modified with alcohol and 0.5-15 mol% PEG. 125. The mRNA or composition of paragraph 124, wherein the lipid nanoparticle comprises: 47 mol% ionizable cationic lipids; 11.5 mol% neutral lipids; 38.5 mol% sterols; and 3.0 mol% PEG-modified lipids ; 48 mol% ionizable cationic lipids; 11 mol% neutral lipids; 38.5 mol% sterols; and 2.5 mol% PEG-modified lipids; 49 mol% ionizable cationic lipids; 10.5 mol% neutral lipids; 38.5 mol% mol% sterols; and 2.0 mol% PEG-modified lipids; 50 mol% ionizable cationic lipids; 10 mol% neutral lipids; 38.5 mol% sterols; and 1.5 mol% PEG-modified lipids; or 51 mol% % ionizable cationic lipids; 9.5 mol% neutral lipids; 38.5 mol% sterols; and 1.0 mol% PEG-modified lipids. 126. The mRNA or composition of paragraph 125, wherein the lipid nanoparticle comprises: 47 mol% Compound 1; 11.5 mol% DSPC; 38.5 mol% cholesterol; and 3.0 mol% PEG2000 DMG; 48 mol% Compound 1; 11 mol % DSPC; 38.5 mol % cholesterol; and 2.5 mol % PEG2000 DMG; 49 mol % Compound 1; 10.5 mol % DSPC; 38.5 mol % cholesterol; and 2.0 mol % PEG2000 DMG; 50 mol % Compound 1; 10 mol % DSPC; mol% cholesterol; and 1.5 mol% PEG2000 DMG; or 51 mol% Compound 1; 9.5 mol% DSPC; 38.5 mol% cholesterol; and 1.0 mol% PEG2000 DMG. 127. A method comprising administering to an individual the mRNA of any of paragraphs 67-126 in an amount effective to induce a neutralizing antibody response against SARS-CoV-2 in the individual. 128. A method comprising administering to an individual an mRNA or composition of any of paragraphs 67-126 in an amount effective to induce a T cell immune response against SARS-CoV-2 in the individual. Example Example 1. Performance Data

The mRNA used in this study was used to express the key neutralizing domains of the SARS-CoV-2 coronavirus spike (S) protein, and these neutralizing protein domains were evaluated individually or in combination as immunogenic compositions Or vaccines to protect people from live and circulating natural viruses are more effective in inducing protective immunity. The linear design of the protein encoded by the mRNA is shown in Figure 2 . The proteins also all contain the carboxy (C) terminal transmembrane domain (TM) of the influenza-derived hemagglutinin (HA).

Both NTD and RBD are known to bind to the site of antibodies that exhibit virus-neutralizing activity. In the case of SARS-CoV-2, RBD is the receptor binding site for the spike protein and binds vasoconstrictor peptide converting enzyme 2 (ACE2). The function of the amine (N) terminal domain, NTD, is not fully understood and appears to play a role in binding the carbohydrate moiety and promoting the conformational transition of the spike protein from the prefusion to the postfusion conformation. See Zhou H, Chen Y, Zhang S et al., Nat Commun. 2019;10(1):3068. Regardless, both the NTD and RBD domains induce high binding and neutralizing antibody titers as discussed below.

Antibodies specific for the receptor binding domain (RBD) (mAb1) of the SARS-CoV-2 spike protein and the N-terminal domain (NTD) (Ab2) of the SARS-CoV-2 spike protein were used, in Table 16 mRNA RBD-TM vaccine ("SARS-CoV-2 RBD-TM"; SEQ ID NO: 75-77), mRNA NTD-TM vaccine ("SARS-CoV-2 NTD-TM"; SEQ ID NO: 75-77) shown in and 17 : 45-47) and mRNA NTD-RBD-TM ("SARS-CoV-1 NTD-RBD-TM"; SEQ ID NO: 90-92) vaccine performance data. Table 16 shows the mean fold difference in MFI*Freq (over the dilution range) compared to WT SARS-CoV-2 spike protein mRNA at 24 hours (hr), 48 hr and 72 hr ( Table 16 ). Table 16. Fold change in total antigen expression (MFI*Freq) compared to S2P protein Monoclonal Antibody (mAb) Wild-type (WT) S mRNA RBD-TM mRNA NTD-TM mRNA NTD-RBD-TM mRNA blank 24 hours (hr) 1 – Specific to RBD 1.8 30.6 0.0 10.4 0.0 24 hours 2 – Specific to NTD 0.7 0.0 9.7 2.5 0.0 48 hours 1 1.2 40.1 0.0 7.3 0.0 48 hours 2 0.8 0.0 19.0 6.0 0.0 72 hours 1 0.8 32.5 0.1 11.6 0.0 72 hours 2 0.7 0 14.4 4.1 0.0 RBD = receptor binding domain NTD = N-terminal domain TM = transmembrane domain Example 2. Immunogenicity data and neutralization data at day 21 post single dose

Mice were administered mRNA NTD-TM and mRNA RBD-TM (described in Example 1 ) at the following doses: 0.001 μg, 0.01 μg, 0.1 μg or 1 μg (N=8). Mice were administered mRNA NTD-RBD-TM (described in Example 1 ) at the following doses: 0.1 μg or 1 μg (N=8). Mice were administered a 50:50 mixture of mRNA NTD-TM and mRNA RBD-TM containing 0.1 μg of each mRNA, 0.2 μg of mRNA in total, or 1 μg of each mRNA, 2 μg of mRNA in total (N=8). SARS-CoV-2 spike protein-specific IgG titers ( Table 17 ), SARS-CoV-2 RBD-specific IgG titers ( Table 18 ) and SARS-CoV were then measured by ELISA on day 21 post-vaccination -2 NTD-specific IgG titers ( Table 19 ). Data are provided in Tables 17-19 . mRNA NTD-RBD-TM at a dose of 0.1 μg and a 50:50 mixture of the composition of mRNA NTD-TM and mRNA RBD-TM at a dose of 0.2 μg elicited observable NTD-specific and RBD-specific IgG titers, and 0.1 μg Doses of RBD-TM and NTD-TM elicited measurable IgG titers against RBD and NTD antigens, respectively. Table 17. SARS-CoV-2 S1/S2 Spike Protein-Specific IgG Titers - Mean μg (per mRNA construct) RBD-TM NTD-TM NTD-RBD-TM 50:50 mix 0.001 13 13 - - 0.01 13 13 - - 0.1 13 13 13 19 1 225 13 379 707 Mean of N=8; PBS only = 1.1 Table 18. RBD domain specific IgG titers - mean μg (per mRNA construct) RBD-TM NTD-RBD-TM 50:50 mix 0.001 15 - - 0.01 14 - - 0.1 75 209 266 1 1947 7710 15530 Mean of N=8; PBS only = 1.1 Table 19. NTD domain specific IgG titers - mean μg (per mRNA construct) NTD-TM NTD-RBD-TM 50:50 mix 0.001 13 - - 0.01 14 - - 0.1 30 20 38 1 620 848 1075 Average of N=8; PBS only = 1.1

Neutralization titers of sera from mice vaccinated with a 1 μg dose of the RBD-TM and NTD-RBD-TM composition and a 50:50 mixture of the NTD-TM and RBD-TM composition at a 2 μg dose were measured, And the correlation between ELISA titer and neutralization titer was analyzed ( Fig. 7 ).

The titers elicited by a 1 μg dose of the NTD-RBD-TM composition or a 50:50 mixture of the NTD-TM and RBD-TM composition at 2 μg were greater than those elicited by a 1 μg dose of the RBD-TM composition price ( Table 20 ). There was a significant correlation between neutralizing titers and ELISA titers for spike-specific IgG, RBD-specific IgG, and NTD-specific IgG ( Figure 7 ). Table 20. Neutralizing potency - mean μg (per mRNA construct) RBD-TM NTD-RBD-TM 50:50 mix 1 238 504 - 2 - - 421 Average of N=8; PBS only = 1.1 SARS-CoV-2 pseudovirus neutralization assay based on recombinant VSVΔG

The codon-optimized wild-type or D614G spike gene (strain Wuhan-Hu-1; NC_045512.2) was cloned into the pCAGGS vector. To generate VSVΔG-based SARS-CoV-2 pseudoviruses, BHK-21/WI-2 cells were transfected with spike-expressing plastids and infected VSVΔG-firefly-luciferase as previously described (Whitt, 2010). . A549-hACE2-TMPRSS2 cells were used as target cells for the VSVΔG-based SARS-CoV-2 pseudovirus neutralization assay. A lentivirus encoding hACE2-P2A-TMPRSS2 was prepared to generate A549-hACE2-TMPRSS2 cells, which were maintained in DMEM supplemented with 10% fetal bovine serum and 1 μg/mL puromycin. A549-hACE2-TMPRSS2 cells were infected with pseudovirus for 1 hour at 37°C. The inoculum virus or virus-antibody mixture is removed after infection. After 18 hours, an equal volume of One-Glo reagent (Promega; E6120) was added to the medium and read using a BMG PHERastar-FS plate reader. The neutralization procedure and data analysis were the same as in the above-described lentivirus-based pseudovirus neutralization analysis. See Whitt, MA (2010). Journal of Virological Methods 169 , 365-374. Example 3. Immunogenicity data at day 36 after two doses

On day 22 after the first dose of the vaccine, the same dose of mRNA vaccine described in Example 2 was again administered to the mice as a booster dose. Serum from day 36 was measured by ELISA against RBD antigen, NTD antigen, wild-type (WT) Spike (S) protein and S2P protein (with bisproline mutation to stabilize the prefusion conformation against RBD antigen, NTD antigen) by ELISA The titers of antibodies to each of the S protein) are shown below. A 50:50 mixture of two immunogenic compositions of RBD-TM and NTD-TM encoded by mRNA in LNP was administered to mice on day 22 as a booster dose of 2 μg or 0.2 μg total mRNA, and on day 22. The titers were determined on day 36. See Table 21 .

An indication of WT S protein titer in mice immunized with RBD-TM, NTD-TM or NTD-RBD-TM encoded by mRNA in LNP, shown in Table 21 , recognizes and binds to SARS-CoV-2 upon induction For antibodies to the WT S protein, both doses were excellent at all doses tested. Table 21. SARS-CoV-2 WT S-specific IgG titers - geometric mean μg (mRNA construct) RBD-TM NTD-TM NTD-RBD-TM Day 21 (GMT) titer 0.001 13 13 - 0.01 13 13 - 0.1 13 13 14 1 225 13 379 Day 36 (GMT) titer 0.001 13 13 - 0.01 295 13 - 0.1 1,017 39 3879 1 27,674 6317 24,413 Average of N=8; PBS only = 1.1

Sera from mice immunized with two doses of RBD-TM, NTD-TM or NTD-RBD-TM encoded by mRNA in LNP were further analyzed for their ability to recognize and bind to the SARS-CoV-2 S2P protein. The titer of the SARS-CoV-2 S2P protein was determined by ELISA using S2P as the antigen on the plate and is shown in Table 22 below. When S2P was the antigen, each of these immunogens induced much higher antibody titers than when the WT S protein was the ELISA antigen. Compare Table 21 and Table 22 . Table 22. SARS-CoV-2 S2P-specific IgG titers - geometric mean μg (mRNA construct) RBD-TM NTD-TM NTD-RBD-TM Day 36 (GMT) titer 0.001 88 16 - 0.01 1,416 280 - 0.1 3,892 11,687 25,298 1 107,611 192,040 223,140 Average of N=8; PBS only = 1.1

In Table 23 , the immunogen was a 50:50 mixture of RBD-TM and NTD-TM encoded by mRNA in LNP, and was tested against WT after one dose (day 21) and two doses (day 36) The titers of S, RBD, NTD and S2P. These results show that when the immunogens are a combination of RBD-TM and NTD-TM in a 50:50 mix, the titers are significantly increased compared to the antibody titers induced by the same doses of the individual antigens. The 50:50 mixture induced good titers against the immunizing antigen, but surprisingly, the titers against the WT S protein were even better and the titers against the S2P protein were extremely high. See Table 23 . Table 23. SARS-CoV-2 antigen-specific IgG titers - geometric mean immunogen Antigen detection on ELISA plate μg (mRNA) 50:50 mixture RBD-TM LNP NTD-TM LNP anti-spike IgG anti-RBD IgG anti-NTD IgG Anti-S2P IgG Day 21 (GMT) titer 0.2 19 266 38 4,869 2 707 15,530 1,075 52,936 Day 36 (GMT) titer 0.2 7,259 15,957 4,869 74,718 2 75,871 186,740 52,936 2,726,948 Average of N=8; PBS only = 1.1

Table 24 shows the results of immunization with each of RBD-TM and NTD-TM as mRNA encoding their antigens. The geometric mean titers of 8 mice per group were measured using the protein encoded by the mRNA immunogen as the antigen on the ELISA plate. Likewise, both immunogenic compositions induced high titers to the immunizing antigen when the antigen was administered as mRNA formulated in LNP. In this case, both doses produced excellent antibody responses at all concentrations. However, on a per microgram (μg) basis, the 50:50 mixture of these antigens induced an antibody response that was about 10 times greater than when the antigen was administered alone. Compare Table 23 and Table 24 . Table 24. SARS-CoV-2 RBD and NTD domain-specific IgG titers - geometric mean μg (mRNA construct) Antigen on RBD-TM plate Antigen on NTD-TM plate Day 21 (GMT) titer 0.001 15 13 0.01 14 14 0.1 75 30 1 1,947 620 Day 36 (GMT) titer 0.001 25 13 0.01 1,357 123 0.1 4,678 6898 1 84,385 46,516 Average of N=8; PBS only = 1.1

On days 1 and 21, a fusion protein comprising NTD linked to RBD and encoded by mRNA in LNP was administered as an immunogenic composition to groups of 8 mice at 0.1 and 1 μg doses. See Table 25 below. Even the mRNA encoding the fusion protein form of NTD-RBD-TM induced excellent titers for the individual domains, which were higher than when the single domain was the immunizing antigen. The potency against the S2P protein was about 8 times the potency against the WT S protein. See Table 25 . Table 25. SARS-CoV-2 NTD-RBD-TM domain-specific IgG titers - geometric mean μg immunogen NTD-RBD-TM (mRNA construct) Antigen on RBD-TM plate Antigen on NTD-TM plate Antigen on wild-type spike plate Antigen on S2P Plate Day 21 (GMT) titer 0.1 209 20 13 NA 1 7,710 848 379 NA Day 36 (GMT) titer 0.1 5,769 2,875 3,878 25,298 1 111,747 41,876 24,413 223,140 Average of N=8; PBS only = 1.1

Neutralization data are shown in Table 26 . The S1-666-TM encoded by the mRNA uses the antigens of the S1 subdomain, specifically residues 1-666 of the SARS-CoV-2 spike protein attached to the transmembrane domain. Table 26. Mean neutralizing titers on day 36 after two immunizations on day 1 and day 22. μg (per mRNA construct) S1-666-TM 50:50 mixture of NTD-TM and RBD-TM RBD-TM NTD-TM NTD-RBD-TM 0.001 - - 40 40 - 0.01 508 - 70.5 40 - 0.1 11,561 1,336 260 205 865 1.0 - 25,208 7,402 4,669 57,891 Average of N=8; PBS only=1.1 Example 4. Immunogenicity of S1-666-TM

S1-666-TM (or S1 residues 1-666 of Spike protein S) encoded by mRNA in LNP was administered to mice as a prime immunization on day 1 and as a booster dose on day 22 0.01 μg and 0.1 μg (N = 8) groups. Serum from day 21 (pre-boost) and day 36 (post-boost) was measured by ELISA against mRNA RBD, mRNA NTD and mRNA wild-type (WT) Spike (S) protein by ELISA ( Figure 1 ) The antibody titers for each of these are shown in Table 27 below.

The WT S protein titer indications of mice immunized with S1-666-TM encoded by the mRNA in LNP, shown in Table 27 , were both effective in inducing antibodies that could recognize and bind to the SARS-CoV-2 WT S protein. This dose was excellent at all doses tested. Surprisingly, even though no 2P mutation was found in S1 (this is because the 2P mutation occurs in S2, which is not present in the immunogen), when measured against the S2P form of the spike protein, the titer of induction Also the highest. Similar to the other constructs, NTD titers required a second dose increase. Table 27. SARS-CoV-2 antigen-specific IgG titers - geometric mean immunogen Antigen detection on ELISA plate Micrograms (mRNA) S1-666-TM anti-spike IgG anti-RBD IgG anti-NTD IgG Anti-S2P IgG Day 21 (GMT) titer 0.01 13 30 13 NA 0.1 175 868 49 NA Day 36 (GMT) titer 0.01 2,450 12,952 112 186,561 0.1 17,066 69,969 9,015 874,609 Average of N=8; PBS only=1.1 Example 5. 50:50 mixture of RBD-TM , NTD-TM , NTD-RBD-TM and NTD-TM/RBD-TM composition at 36 after two doses day immunogenicity

In this replicate experiment, on day 22 after the first dose, mice were again administered the same dose of mRNA vaccine as described in the above example as a booster dose. The SARS-CoV-2 spike protein-specific IgG titers, SARS-CoV-2 S2P protein-specific IgG titers, SARS-CoV-2 RBD-specific IgG titers were then measured by ELISA on day 36 after the first dose of inoculation IgG titers and SARS-CoV-2 NTD-specific IgG titers.

The results show 1 μg and 0.1 μg doses of mRNA RBD-TM, mRNA NTD-TM, mRNA NTD-RBD-TM compositions and compositions containing 1 μg or 0.1 μg of each of mRNA RBD-TM and mRNA NTD-TM The 50:50 mixture elicited high ELISA titers against the SARS-CoV-2 spike or the SARS-CoV-2 S2P protein. Example 6. Immunogenicity studies

The immunogenicity of a 50:50 mixture of mRNA NTD-TM and mRNA RBD-TM was administered to mice at the following doses: 0.2 μg or 2 μg total mRNA (0.1 μg or 1 μg each mRNA) (N=8) . The prime dose was administered on day 1 and the booster dose was administered on day 22. On day 36, antibody binding to SARS-CoV-2 stable prefusion spike protein (SARS-CoV-2 pre-S) was assessed using ELISA. The following vaccine compositions including mRNA NTD-RBD-TM, mRNA RBD-TM and mRNA NTD-TM were administered to mice at the following doses: 0.1 μg and 0.01 μg (N=8). GMT data were determined and are shown in Table 28 below. Table 28. SARS-CoV-2 spike titers induced by S protein domain fusions and combinations vaccine immunogen Dose µg mRNA Day 21 GMT titer dose 1 after 3 weeks of S2P coating on plates Day 36 GMT titer dose 2 post 3 weeks S2P coating on plates 50:50 Mixture RBD-TM NTD-TM 1 5,913 301,881 50:50 Mixture RBD-TM NTD-TM 0.1 71 13,423 NTD-RBD-TM 1.0 3,329 177,499 NTD-RBD-TM 0.1 80 48947 RBD-TM 1.0 3198 593,730 RBD-TM 0.1 73 31,090 NTD-TM 1.0 593 74,777 NTD-TM 0.1 twenty one 23,916 Example 7. Determination of the ratio of IgG2a and IgG1 of NTD-RBD-TM

The composition of NTD-RBD-TM, mRNA NTD-RBD-TM was administered to mice at the following doses: 0.1 μg and 1 μg. The prime dose was administered on day 1 and the booster dose was administered on day 22. On day 36, S2P-specific IgG1 and IgG2a titers were assessed. See Figures 8A-8C . By day 36, the titer of IgG2a was higher than that of IgG1 at both dose levels. See Figure 8A . To determine whether T cell responses were biased towards Th1 or Th2 type responses, we plotted the ratio of IgG2a/IgG1 at the day 36 time point. As shown in Figure 8B , the NTD-RBD-TM composition induced an antibody immune response that was clearly in a Th1-type response. Th2-type responses are disadvantageous in vaccine development as they are associated with driving disease enhancement. Example 8. Immunogenicity studies

The mRNAs listed in Table 29 were administered to mice at the following doses: 0.1 μg and 1 μg (N = 8). The prime dose was administered on day 1 and the booster dose was administered on day 22. Serum IgG titers were analyzed on days 21 and 36 on S2P-coated plates. The results are shown in Table 29 . Table 29. Formulations / Materials Dose (μg) Day 21 _ Day 36 _ PBS 1.097 1.097 NTD-RBD-TM 1 4.237 6.036 0.1 2.711 5.106 S1-666-TM (SEQ ID NO: 16) 1 4.224 5.704 0.1 1.944 4.633 Mixed (50:50) NTD-EXT-F43C-TM (SEQ ID NO: 55) + RBD-Q563D-EXT-TM (SEQ ID NO: 88) 1 3.939 5.442 0.1 1.867 4.342 NTD-EXT-RBD-EXT-TM (SEQ ID NO: 121) 1 4.541 6.001 0.1 3.694 4.885 S1-594-TM (SEQ ID NO: 22) 1 4.027 5.517 0.1 3.313 4.780 S1-594-polyG-DS-TM (SEQ ID NO: 28) 1 3.974 5.531 0.1 2.551 4.425 S2-TM (SEQ ID NO: 145) 1 1.989 4.058 0.1 1.097 2.015 RBD-NTD-TM (SEQ ID NO: 139) 1 4.523 6.062 0.1 3.453 5.222 NTD-PADRE-RBD-TM (SEQ ID NO: 142) 1 4.489 6.040 0.1 3.386 5.301 extra sequence

SARS-CoV-2 野生型刺突 (S) 蛋白 SEQ ID NO: 123自5'端至3'端由以下組成：5' UTR SEQ ID NO: 2、mRNA ORF SEQ ID NO: 124及3' UTR SEQ ID NO: 4。 123 化學 1-甲基假尿苷    端帽 7mG(5')ppp(5')NlmpNp    5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 mRNA構築體之ORF (不包括終止密碼子) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCAACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGGCGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCACCCCGGAGGGCAAGGAGCGUGGCCAGCCAGAGCAUCAUCGCCUACACCAUGAGCCUGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGUACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACAAGGUGGAGGCCGAGGUGCAGAUCGACCGGCUGAUCACUGGCCGGCUGCAGAGCCUGCAGACCUACGUGACCCAGCAGCUGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCAGCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCACUACACC 124 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 相應之胺基酸序列 MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 125 聚A尾 100 nt    It is understood that any of the mRNA sequences described herein may include the 5' UTR and/or the 3' UTR. The UTR sequence can be selected from the following sequences, or other known UTR sequences can be used. It is also understood that any of the mRNA constructs described herein may further comprise a poly(A) tail and/or end cap (eg, 7mG(5')ppp(5')NlmpNp). In addition, although many of the mRNA and encoded antigen sequences described herein include signal peptides and/or peptide tags (eg, a C-terminal His tag), it should be understood that the indicated signal peptides and/or peptide tags may be used with different signal peptides and/or peptide tags. /or peptide tag substitution, or the signal peptide and/or peptide tag may be omitted.

SARS-CoV-2 wild-type spike (S) protein SEQ ID NO: 123 consists of the following from the 5' end to the 3' end: 5' UTR SEQ ID NO: 2, mRNA ORF SEQ ID NO: 124 and 3' UTR SEQ ID NO: 4. 123 Chemical 1-Methylpseudouridine end cap 7mG(5')ppp(5')NlmpNp 5' UTR GGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 2 ORF of mRNA construct (excluding stop codon) AUGUUCGUGUUCCUGGUGCUGCUGCCCCUGGUGAGCAGCCAGUGCGUGAACCUGACCACCCGGACCCAGCUGCCACCAGCCUACACCAACAGCUUCACCCGGGGCGUCUACUACCCCGACAAGGUGUUCCGGAGCAGCGUCCUGCACAGCACCCAGGACCUGUUCCUGCCCUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGAGCGGCACCAACGGCACCAAGCGGUUCGACAACCCCGUGCUGCCCUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGAGCAACAUCAUCCGGGGCUGGAUCUUCGGCACCACCCUGGACAGCAAGACCCAGAGCCUGCUGAUCGUGAAUAACGCCACCAACGUGGUGAUCAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCCUUCCUGGGCGUGUACUACCACAAGAACAACAAGAGCUGGAUGGAGAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGAGCCAGCCCUUCCUGAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGCGGGAGUUCGUGUUCAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCAAUCAACCUGGUGCGGGAUCUGCCCCAGGGCUUCUCAGCCCUGGAGCCCCUGGUGGACCUGCCCAUCGGCAUCAACAUCACCCGGUUCCAGACCCUGCUGGCCCUGCACCGGAGCUACCUGACCCCAGGCGACAGCAGCAGCGGGUGGACAGCAGGCGCGGCUGCUUACUACGUGGGCUACCUGCAGCCCCGGACCUUCCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGACUGCGCCCUGGACCCUCUGAGCGAGACCAAGUGCACCCUGAAGAGCUUCACCGUGGAGAAGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAGAGCAUCGUGCGGUUCCCCAACAUCACCA ACCUGUGCCCCUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCAGCGUGUACGCCUGGAACCGGAAGCGGAUCAGCAACUGCGUGGCCGACUACAGCGUGCUGUACAACAGCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGAGCCCCACCAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACAGCUUCGUGAUCCGUGGCGACGAGGUGCGGCAGAUCGCACCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGCGUGAUCGCCUGGAACAGCAACAACCUCGACAGCAAGGUGGGCGGCAACUACAACUACCUGUACCGGCUGUUCCGGAAGAGCAACCUGAAGCCCUUCGAGCGGGACAUCAGCACCGAGAUCUACCAAGCCGGCUCCACCCCUUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCUCUGCAGAGCUACGGCUUCCAGCCCACCAACGGCGUGGGCUACCAGCCCUACCGGGUGGUGGUGCUGAGCUUCGAGCUGCUGCACGCCCCAGCCACCGUGUGUGGCCCCAAGAAGAGCACCAACCUGGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUUACCGGCACCGGCGUGCUGACCGAGAGCAACAAGAAAUUCCUGCCCUUUCAGCAGUUCGGCCGGGACAUCGCCGACACCACCGACGCUGUGCGGGAUCCCCAGACCCUGGAGAUCCUGGACAUCACCCCUUGCAGCUUCGGCGGCGUGAGCGUGAUCACCCCAGGCACCAACACCAGCAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCCGUGGCCAUCCACGCCGACCAGCUGACACCCACCUGGCGGGUCUACAGCACCGGCAGCAACGUGUUCCAGACCCGGGCCGGUUGCCUGAUCGGCGCCGAGCACGUGAACAACAGCUACGAGUGCGACAUCCCCAUCGG CGCCGGCAUCUGUGCCAGCUACCAGACCCAGACCAAUUCACCCCGGAGGGCAAGGAGCGUGGCCAGCCAGAGCAUCAUCGCCUACACCAUGAGCCUGGGCGCCGAGAACAGCGUGGCCUACAGCAACAACAGCAUCGCCAUCCCCACCAACUUCACCAUCAGCGUGACCACCGAGAUUCUGCCCGUGAGCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGACAGCACCGAGUGCAGCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAACCGGGCCCUGACCGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUCUACAAGACCCCUCCCAUCAAGGACUUCGGCGGCUUCAACUUCAGCCAGAUCCUGCCCGACCCCAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAGGUGACCCUAGCCGACGCCGGCUUCAUCAAGCAGUACGGCGACUGCCUCGGCGACAUAGCCGCCCGGGACCUGAUCUGCGCCCAGAAGUUCAACGGCCUGACCGUGCUGCCUCCCCUGCUGACCGACGAGAUGAUCGCCCAGUACACCAGCGCCCUGUUAGCCGGAACCAUCACCAGCGGCUGGACUUUCGGCGCUGGAGCCGCUCUGCAGAUCCCCUUCGCCAUGCAGAUGGCCUACCGGUUCAACGGCAUCGGCGUGACCCAGAACGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACCGCUAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACCCUGGUGAAGCAGCUGAGCAGCAACUUCGGCGCCAUCAGCAGCGUGCUGAACGACAUCCUGAGCCGGCUGGACAAGGUGGAGGCCGAGGUGCAGAUCGACCGGCUGAUCACUGGCCGG CUGCAGAGCCUGCAGACCUACGUGACCCAGCAGCUGAUCCGGGCCGCCGAGAUUCGGGCCAGCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUGGGCCAGAGCAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUGAUGAGCUUUCCCCAGAGCGCACCCCACGGAGUGGUGUUCCUGCACGUGACCUACGUGCCCGCCCAGGAGAAGAACUUCACCACCGCCCCAGCCAUCUGCCACGACGGCAAGGCCCACUUUCCCCGGGAGGGCGUGUUCGUGAGCAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGAGCGGCAACUGCGACGUGGUGAUCGGCAUCGUGAACAACACCGUGUACGAUCCCCUGCAGCCCGAGCUGGACAGCUUCAAGGAGGAGCUGGACAAGUACUUCAAGAAUCACACCAGCCCCGACGUGGACCUGGGCGACAUCAGCGGCAUCAACGCCAGCGUGGUGAACAUCCAGAAGGAGAUCGAUCGGCUGAACGAGGUGGCCAAGAACCUGAACGAGAGCCUGAUCGACCUGCAGGAGCUGGGCAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUCAUCGCCGGCCUGAUCGCCAUCGUGAUGGUGACCAUCAUGCUGUGCUGCAUGACCAGCUGCUGCAGCUGCCUGAAGGGCUGUUGCAGCUGCGGCAGCUGCUGCAAGUUCGACGAGGACGACAGCGAGCCCGUGCUGAAGGGCGUGAAGCUGCACUACACC 124 3' UTR UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 4 Corresponding amino acid sequence MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGR LQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 125 Poly A tail 100nt

It is also understood that any of the open reading frames and/or corresponding amino acid sequences described herein may include or exclude signal sequences.

All references, patents, and patent applications disclosed herein are incorporated by reference, which in some cases may cover the entire document, with respect to the subject matter recited in each of them.

The indefinite articles "a (a and an)" as used in this specification and the scope of the claims should be understood to mean "at least one" unless the contrary meaning is expressly indicated.

It should also be understood that in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed, unless expressly indicated to the contrary.

In the scope of the patent application and in the above specification, all transitional phrases (such as "comprising", "including", "carrying", "having", "containing", "involving", "containing", "by. .. constitutes" and the like) shall be construed as open ended, that is, meant to include, but not be limited to. As stated in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures, only the transitional phrases "consisting of" and "consisting essentially of" should be closed or closed, respectively. Semi-closed transitional phrase.

The terms "about" and "substantially" preceding a numerical value mean ±10% of the recited numerical value.

Where a range of values is provided, each value between the upper and lower end of the range is specifically considered and set forth herein.

International application case numbers PCT/US2015/02740, PCT/US2016/043348, PCT/US2016/043332, PCT/US2016/058327, PCT/US2016/058324, PCT/US2016/058314, PCT/US2016/058310, PCT/US2016/ 058321, PCT/US2016/058297, PCT/US2016/058319, and PCT/US2016/058314 are incorporated herein by reference in their entirety.

Figure 1 Schematic representation of wild-type and 2P spike protein antigens encoded by mRNAs of the invention; signal peptide (SP), unfilled; N-terminal domain (NTD), dotted; receptor binding domain (RBD), down Diagonal band; subdomain 1 (SD1), horizontal band; subdomain 2 (SD2), vimentum; fusion peptide (FP), upward diagonal band; heptapeptide repeat 1 (HR1), braided ; heptapeptide repeat 2 (HR2), diagonal brick; (TM), vertical bars; and cytoplasmic tail (CT), brick. Figures 2A - 2I show exemplary linear designs of antigens encoded by mRNAs described in Examples 1-3. FIG. 3 shows a sequence alignment of the antigens depicted in FIG. 2 . Figure 4 shows an exemplary linear design of the antigens encoded by the mRNAs described in Examples 4-6. Figure 5 shows a sequence alignment of the various S1 subunit antigens described herein. 6A - 6D show exemplary linear designs of antigens encoded by mRNAs described in Examples 7 and 8. Figure 7 shows the correlation of neutralization with ELISA titers. Figures 8A - 8C show serum IgGl titers and IgG2a titers at day 36 after day 1 prime and day 21 booster doses in mice with mRNA encoding NTD-RBD-TM in LNP.

                         
           <![CDATA[ <110> ModernaTX, Inc.]]>
           <![CDATA[ <120> SARS-COV-2 mRNA domain vaccine]]>
           <![CDATA[ <130> M1378.70157]]>
           <![CDATA[ <140>TW 110123289]]>
           <![CDATA[ <141> 2021-06-25]]>
           <![CDATA[ <150> US 63/063,137]]>
           <![CDATA[ <151> 2020-08-07]]>
           <![CDATA[ <150> US 63/044,330]]>
           <![CDATA[ <151> 2020-06-25]]>
           <![CDATA[ <160> 152]]>
           <![CDATA[ <170> PatentIn Version 3.5]]>
           <![CDATA[ <210> 1]]>
           <![CDATA[ <211> 2216]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 1]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcg ugagcgugau caccccaggc 1860
          accaacacca gcaaccaggu ggccgugcug uaccaggacg ugaacugcac cgaggugccc 1920
          guggccaucc acgccgacca gcugacaccc accuggcggg ucuacagcac cggcagcaac 1980
          guguuccaga cccgggccgg uugccugauc ggcgccgagc acgugaacaa cagcuacgag 2040
          ugcgacaucc ccaucggcgc cggcaucugu gccagcuacc agacccagac caauucauga 2100
          uaauaggcug gagccucggu ggccuagcuu cuugccccuu gggccucccc ccagccccuc 2160
          cuccccuucc ugcacccgua cccccguggu cuuugaauaa agucugagug ggcggc 2216
           <![CDATA[ <210> 2]]>
           <![CDATA[ <211> 57]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 2]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccacc 57
           <![CDATA[ <210> 3]]>
           <![CDATA[ <211> 2040]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 3]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcgugagcgu gaucacccca 1800
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 1920
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 1980
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 2040
           <![CDATA[ <210> 4]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 4]]>
          ugauaauagg cuggagccuc gguggccuag cuucuugccc cuugggccuc cccccagccc 60
          cuccuccccu uccugcaccc guacccccgu ggucuuugaa uaaagucuga gugggcggc 119
           <![CDATA[ <210> 5]]>
           <![CDATA[ <211> 680]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 5]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
                  595 600 605
          Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
              610 615 620
          His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
          625 630 635 640
          Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
                          645 650 655
          Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
                      660 665 670
          Ser Tyr Gln Thr Gln Thr Asn Ser
                  675 680
           <![CDATA[ <210> 6]]>
           <![CDATA[ <211> 2729]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 6]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcg ugagcgugau caccccaggc 1860
          accaacacca gcaaccaggu ggccgugcug uaccaggacg ugaacugcac cgaggugccc 1920
          guggccaucc acgccgacca gcugacaccc accuggcggg ucuacagcac cggcagcaac 1980
          guguuccaga cccgggccgg uugccugauc ggcgccgagc acgugaacaa cagcuacgag 2040
          ugcgacaucc ccaucggcgc cggcaucugu gccagcuacc agacccagac caauucagga 2100
          ggaggcagcg gcggcgauau caucaagcuu cugaacgagc aaguuaacaa ggaaaugcag 2160
          agcaguaauc ucuacaugag caugagcagc uggugcuaca cccacucccu ggacggagca 2220
          ggccucuucc uguucgacca cgcagccgag gaguacgagc acgcuaagaa guugaucauu 2280
          uucuugaacg agaacaacgu gcccgugcag cuaacgucaa ucagcgcacc ugagcacaag 2340
          uucgagggcc ugacccagau cuuccagaag gccuacgaac acgaacagca caucuccgag 2400
          agcaucaaca auauugugga ucacgcuauc aaguccaagg accacgcuac cuucaacuuc 2460
          cugcaguggu acguggccga gcaacaugag gaggaggugc uguucaagga cauccuggac 2520
          aagaucgagc ugaucgguaa ugagaaucac ggccuguacc uggccgacca guacgugaag 2580
          ggcaucgcca agagccggaa gucaggcuca ugauaauagg cuggagccuc gguggccuag 2640
          cuucuugccc cuugggccuc cccccagccc cuccuccccu uccugcaccc guacccccgu 2700
          ggucuuugaa uaaagucuga gugggcggc 2729
           <![CDATA[ <210> 7]]>
           <![CDATA[ <211> 2553]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 7]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcgugagcgu gaucacccca 1800
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 1920
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 1980
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 2040
          ggaggaggca gcggcggcga uaucaucaag cuucugaacg agcaaguuaa caaggaaaug 2100
          cagagcagua aucucuacau gagcaugagc agcuggugcu acacccacuc ccuggacgga 2160
          gcaggccucu uccuguucga ccacgcagcc gaggaguacg agcacgcuaa gaaguugauc 2220
          auuuucuuga acgagaacaa cgugcccgug cagcuaacgu caaucagcgc accugagcac 2280
          aaguucgagg gccugaccca gaucuuccag aaggccuacg aacacgaaca gcacaucucc 2340
          gagagcauca acaauauugu ggaucacgcu aucaagucca aggaccacgc uaccuucaac 2400
          uuccugcagu gguacguggc cgagcaacau gaggaggagg ugcuguucaa ggacauccug 2460
          gacaagaucg agcugaucgg uaaugagaau cacggccugu accuggccga ccaguacgug 2520
          aagggcaucg ccaagagccg gaagucaggc uca 2553
           <![CDATA[ <210> 8]]>
           <![CDATA[ <211> 851]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 8]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
                  595 600 605
          Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
              610 615 620
          His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
          625 630 635 640
          Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
                          645 650 655
          Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
                      660 665 670
          Ser Tyr Gln Thr Gln Thr Asn Ser Gly Gly Gly Ser Gly Gly Asp Ile
                  675 680 685
          Ile Lys Leu Leu Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn
              690 695 700
          Leu Tyr Met Ser Met Ser Ser Trp Cys Tyr Thr His Ser Leu Asp Gly
          705 710 715 720
          Ala Gly Leu Phe Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala
                          725 730 735
          Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu
                      740 745 750
          Thr Ser Ile Ser Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile
                  755 760 765
          Phe Gln Lys Ala Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn
              770 775 780
          Asn Ile Val Asp His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn
          785 790 795 800
          Phe Leu Gln Trp Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe
                          805 810 815
          Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly
                      820 825 830
          Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys
                  835 840 845
          Ser Gly Ser
              850
           <![CDATA[ <210> 9]]>
           <![CDATA[ <211> 2762]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 9]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          ggcauccugc ccagcccugg caugcccgcu cugcugagcc uggugagccu gcugagcgug 120
          cugcugaugg gcugcguggc ugagaccggc augcagaucu acgagggcaa gcugaccgca 180
          gagggccugc gguucggcau cguggccagc cgcgccaacc acgcucuggu ggaccggcuu 240
          guggagggcg cuaucgacgc caucgugaga cacggcggcc gggaagagga caucacccug 300
          gugcgggugu gcggcagcug ggagauuccc gucgccgccg gagaacuggc ccggaaggag 360
          gacaucgacg ccgugaucgc caucggcgug cugugcagag gcgccacgcc cagcuucgac 420
          uacaucgcca gcgaggugag caagggccug gccgaccuga gccuggagcu gcggaagccc 480
          aucaccuucg gcgugaucac cgccgacacc cuggagcagg ccaucgaggc cgcaggcacc 540
          ugccacggca acaagggcug ggaagccgcc cugugcgcca ucgagauggc caaccuguuc 600
          aagagccugc ggggcggaag uggaggcucu gguggcagcg gaggaucugg cggcggcacc 660
          acccggaccc agcugccacc agccuacacc aacagcuuca cccggggcgu cuacuacccc 720
          gacaaggugu uccggagcag cguccugcac agcacccagg accuguuccu gcccuucuuc 780
          agcaacguga ccugguucca cgccauccac gugagcggca ccaacggcac caagcgguuc 840
          gacaaccccg ugcugcccuu caacgacggc guguacuucg ccagcaccga gaagagcaac 900
          aucauccggg gcuggaucuu cggcaccacc cuggacagca agacccagag ccugcugauc 960
          gugaauaacg ccaccaacgu ggugaucaag gugugcgagu uccaguucug caacgacccc 1020
          uuccugggcg uguacuacca caagaacaac aagagcugga uggagagcga guuccgggug 1080
          uacagcagcg ccaacaacug caccuucgag uacgugagcc agcccuuccu gauggaccug 1140
          gagggcaagc agggcaacuu caagaaccug cgggaguucg uguucaagaa caucgacggc 1200
          uacuucaaga ucuacagcaa gcacacccca aucaaccugg ugcgggaucu gccccagggc 1260
          uucucagccc uggagccccu gguggaccug cccaucggca ucaacaucac ccgguuccag 1320
          acccugcugg cccugcaccg gagcuaccug accccaggcg acagcagcag cggguggaca 1380
          gcaggcgcgg cugcuuacua cgugggcuac cugcagcccc ggaccuuccu gcugaaguac 1440
          aacgagaacg gcaccaucac cgacgccgug gacugcgccc uggacccucu gagcgagacc 1500
          aagugcaccc ugaagagcuu caccguggag aagggcaucu accagaccag caacuuccgg 1560
          gugcagccca ccgagagcau cgugcgguuc cccaacauca ccaaccugug ccccuucggc 1620
          gagguguuca acgccacccg guucgccagc guguacgccu ggaaccggaa gcggaucagc 1680
          aacugcgugg ccgacuacag cgugcuguac aacagcgcca gcuucagcac cuucaagugc 1740
          uacggcguga gccccaccaa gcugaacgac cugugcuuca ccaacgugua cgccgacagc 1800
          uucgugaucc guggcgacga ggugcggcag aucgcacccg gccagacagg caagaucgcc 1860
          gacuacaacu acaagcugcc cgacgacuuc accggcugcg ugaucgccug gaacagcaac 1920
          aaccucgaca gcaagguggg cggcaacuac aacuaccugu accggcuguu ccggaagagc 1980
          aaccugaagc ccuucgagcg ggacaucagc accgagaucu accaagccgg cuccaccccu 2040
          ugcaacggcg uggagggcuu caacugcuac uucccucugc agagcuacgg cuuccagccc 2100
          accaacggcg ugggcuacca gcccuaccgg gugguggugc ugagcuucga gcugcugcac 2160
          gccccagcca ccgugugugg ccccaagaag agcaccaacc uggugaagaa caagugcgug 2220
          aacuucaacu ucaacggccu uaccggcacc ggcgugcuga ccgagagcaa caagaaauuc 2280
          cugcccuuuc agcaguucgg ccgggacauc gccgacacca ccgacgcugu gcgggauccc 2340
          cagacccugg agauccugga caucaccccu ugcagcuucg gcggcgugag cgugaucacc 2400
          ccaggcacca acaccagcaa ccagguggcc gugcuguacc aggacgugaa cugcaccgag 2460
          gugcccgugg ccauccacgc cgaccagcug acacccaccu ggcgggucua cagcaccggc 2520
          agcaacgugu uccagacccg ggccgguugc cugaucggcg ccgagcacgu gaacaacagc 2580
          uacgagugcg acauccccau cggcgccggc aucugugcca gcuaccagac ccagaccaau 2640
          ucaugauaau aggcuggagc cucgguggcc uagcuucuug ccccuugggc cuccccccag 2700
          ccccuccucc ccuuccugca cccguacccc cguggucuuu gaauaaaguc ugagugggcg 2760
          gc 2762
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 2586]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 10]]>
          augggcaucc ugcccagccc uggcaugccc gcucugcuga gccuggugag ccugcugagc 60
          gugcugcuga ugggcugcgu ggcugagacc ggcaugcaga ucuacgaggg caagcugacc 120
          gcagagggcc ugcgguucgg caucguggcc agccgcgcca accacgcucu gguggaccgg 180
          cuuguggagg gcgcuaucga cgccaucgug agacacggcg gccgggaaga ggacaucacc 240
          cuggugcggg ugugcggcag cugggagauu cccgucgccg ccggagaacu ggcccggaag 300
          gaggacaucg acgccgugau cgccaucggc gugcugugca gaggcgccac gcccagcuuc 360
          gacuacaucg ccagcgaggu gagcaagggc cuggccgacc ugagccugga gcugcggaag 420
          cccaucaccu ucggcgugau caccgccgac acccuggagc aggccaucga ggccgcaggc 480
          accugccacg gcaacaaggg cugggaagcc gcccugugcg ccaucgagau ggccaaccug 540
          uucaagagcc ugcggggcgg aaguggaggc ucugguggca gcggaggauc uggcggcggc 600
          accacccgga cccagcugcc accagccuac accaacagcu ucacccgggg cgucuacuac 660
          cccgacaagg uguuccggag cagcguccug cacagcaccc aggaccuguu ccugcccuuc 720
          uucagcaacg ugaccugguu ccacgccauc cacgugagcg gcaccaacgg caccaagcgg 780
          uucgacaacc ccgugcugcc cuucaacgac ggcguguacu ucgccagcac cgagaagagc 840
          aacaucaucc ggggcuggau cuucggcacc acccuggaca gcaagaccca gagccugcug 900
          aucgugaaua acgccaccaa cguggugauc aaggugugcg aguuccaguu cugcaacgac 960
          cccuuccugg gcguguacua ccacaagaac aacaagagcu ggauggagag cgaguuccgg 1020
          guguacagca gcgccaacaa cugcaccuuc gaguacguga gccagcccuu ccugauggac 1080
          cuggagggca agcagggcaa cuucaagaac cugcgggagu ucguguucaa gaacaucgac 1140
          ggcuacuuca agaucuacag caagcacacc ccaaucaacc uggugcggga ucugccccag 1200
          ggcuucucag cccuggagcc ccugguggac cugcccaucg gcaucaacau cacccgguuc 1260
          cagacccugc uggcccugca ccggagcuac cugaccccag gcgacagcag cagcgggugg 1320
          acagcaggcg cggcugcuua cuacgugggc uaccugcagc cccggaccuu ccugcugaag 1380
          uacaacgaga acggcaccau caccgacgcc guggacugcg cccuggaccc ucugagcgag 1440
          accaagugca cccugaagag cuucaccgug gagaagggca ucuaccagac cagcaacuuc 1500
          cgggugcagc ccaccgagag caucgugcgg uuccccaaca ucaccaaccu gugccccuuc 1560
          ggcgaggugu ucaacgccac ccgguucgcc agcguguacg ccuggaaccg gaagcggauc 1620
          agcaacugcg uggccgacua cagcgugcug uacaacagcg ccagcuucag caccuucaag 1680
          ugcuacggcg ugagccccac caagcugaac gaccugugcu ucaccaacgu guacgccgac 1740
          agcuucguga uccguggcga cgaggugcgg cagaucgcac ccggccagac aggcaagauc 1800
          gccgacuaca acuacaagcu gcccgacgac uucaccggcu gcgugaucgc cuggaacagc 1860
          aacaaccucg acagcaaggu gggcggcaac uacaacuacc uguaccggcu guuccggaag 1920
          agcaaccuga agcccuucga gcgggacauc agcaccgaga ucuaccaagc cggcuccacc 1980
          ccuugcaacg gcguggaggg cuucaacugc uacuucccuc ugcagagcua cggcuuccag 2040
          cccaccaacg gcgugggcua ccagcccuac cggguggugg ugcugagcuu cgagcugcug 2100
          cacgccccag ccaccgugug uggccccaag aagagcacca accuggugaa gaacaagugc 2160
          gugaacuuca acuucaacgg ccuuaccggc accggcgugc ugaccgagag caacaagaaa 2220
          uuccugcccu uucagcaguu cggccgggac aucgccgaca ccaccgacgc ugugcgggau 2280
          ccccagaccc uggagauccu ggacaucacc ccuugcagcu ucggcggcgu gagcgugauc 2340
          accccaggca ccaacaccag caaccaggug gccgugcugu accaggacgu gaacugcacc 2400
          gaggugcccg uggccaucca cgccgaccag cugacaccca ccuggcgggu cuacagcacc 2460
          ggcagcaacg uguuccagac ccgggccggu ugccugaucg gcgccgagca cgugaacaac 2520
          agcuacgagu gcgacauccc caucggcgcc ggcaucugug ccagcuacca gacccagacc 2580
          aauuca 2586
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 862]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 11]]>
          Met Gly Ile Leu Pro Ser Pro Gly Met Pro Ala Leu Leu Ser Leu Val
          1 5 10 15
          Ser Leu Leu Ser Val Leu Leu Met Gly Cys Val Ala Glu Thr Gly Met
                      20 25 30
          Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile
                  35 40 45
          Val Ala Ser Arg Ala Asn His Ala Leu Val Asp Arg Leu Val Glu Gly
              50 55 60
          Ala Ile Asp Ala Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr
          65 70 75 80
          Leu Val Arg Val Cys Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu
                          85 90 95
          Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu
                      100 105 110
          Cys Arg Gly Ala Thr Pro Ser Phe Asp Tyr Ile Ala Ser Glu Val Ser
                  115 120 125
          Lys Gly Leu Ala Asp Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe
              130 135 140
          Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Ala Ala Gly
          145 150 155 160
          Thr Cys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Cys Ala Ile Glu
                          165 170 175
          Met Ala Asn Leu Phe Lys Ser Leu Arg Gly Gly Ser Gly Gly Ser Gly
                      180 185 190
          Gly Ser Gly Gly Ser Gly Gly Gly Thr Thr Arg Thr Gln Leu Pro Pro
                  195 200 205
          Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val
              210 215 220
          Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe
          225 230 235 240
          Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn
                          245 250 255
          Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val
                      260 265 270
          Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe
                  275 280 285
          Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn
              290 295 300
          Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp
          305 310 315 320
          Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu
                          325 330 335
          Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr
                      340 345 350
          Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe
                  355 360 365
          Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys
              370 375 380
          Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln
          385 390 395 400
          Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn
                          405 410 415
          Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr
                      420 425 430
          Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr
                  435 440 445
          Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn
              450 455 460
          Gly Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu
          465 470 475 480
          Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln
                          485 490 495
          Thr Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro
                      500 505 510
          Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg
                  515 520 525
          Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
              530 535 540
          Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys
          545 550 555 560
          Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
                          565 570 575
          Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile
                      580 585 590
          Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
                  595 600 605
          Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp
              610 615 620
          Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys
          625 630 635 640
          Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
                          645 650 655
          Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe
                      660 665 670
          Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln
                  675 680 685
          Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala
              690 695 700
          Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys
          705 710 715 720
          Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu
                          725 730 735
          Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala
                      740 745 750
          Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp
                  755 760 765
          Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr
              770 775 780
          Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr
          785 790 795 800
          Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg
                          805 810 815
          Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu
                      820 825 830
          Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile
                  835 840 845
          Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser
              850 855 860
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 2714]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 12]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcg ugagcgugau caccccaggc 1860
          accaacacca gcaaccaggu ggccgugcug uaccaggacg ugaacugcac cgaggugccc 1920
          guggccaucc acgccgacca gcugacaccc accuggcggg ucuacagcac cggcagcaac 1980
          guguuccaga cccgggccgg uugccugauc ggcgccgagc acgugaacaa cagcuacgag 2040
          ugcgacaucc ccaucggcgc cggcaucugu gccagcuacc agacccagac caauucagga 2100
          ggaggcuccg gaggcgguag cgcugagacc ggcaugcaga ucuacgaggg caagcugacc 2160
          gcagagggcc ugcgguucgg caucguggcc agccgcgcca accacgcucu gguggaccgg 2220
          cuuguggagg gcgcuaucga cgccaucgug agacacggcg gccgggaaga ggacaucacc 2280
          cuggugcggg ugugcggcag cugggagauu cccgucgccg ccggagaacu ggcccggaag 2340
          gaggacaucg acgccgugau cgccaucggc gugcugugca gaggcgccac gcccagcuuc 2400
          gacuacaucg ccagcgaggu gagcaagggc cuggccgacc ugagccugga gcugcggaag 2460
          cccaucaccu ucggcgugau caccgccgac acccuggagc aggccaucga ggccgcaggc 2520
          accugccacg gcaacaaggg cugggaagcc gcccugugcg ccaucgagau ggccaaccug 2580
          uucaagagcc ugcggugaua auaggcugga gccucggugg ccuagcuucu ugccccuugg 2640
          gccuccccccc agccccuccu ccccuuccug cacccguacc cccguggucu uugaauaaag 2700
          ucugaguggg cggc 2714
           <![CDATA[ <210> 13]]>
           <![CDATA[ <211> 2538]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 13]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcgugagcgu gaucacccca 1800
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 1920
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 1980
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 2040
          ggaggaggcu ccggaggcgg uagcgcugag accggcaugc agaucuacga gggcaagcug 2100
          accgcagagg gccugcgguu cggcaucgug gccagccgcg ccaaccacgc ucugguggac 2160
          cggcuugugg agggcgcuau cgacgccauc gugagacacg gcggccggga agaggacauc 2220
          acccuggugc gggugugcgg cagcugggag auucccgucg ccgccggaga acuggcccgg 2280
          aaggaggaca ucgacgccgu gaucgccauc ggcgugcugu gcagaggcgc cacgcccagc 2340
          uucgacuaca ucgccagcga ggugagcaag ggccuggccg accugagccu ggagcugcgg 2400
          aagcccauca ccuucggcgu gaucaccgcc gacacccugg agcaggccau cgaggccgca 2460
          ggcaccugcc acggcaacaa gggcugggaa gccgcccugu gcgccaucga gauggccaac 2520
          cuguucaaga gccugcgg 2538
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 846]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 14]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
                  595 600 605
          Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
              610 615 620
          His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
          625 630 635 640
          Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
                          645 650 655
          Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
                      660 665 670
          Ser Tyr Gln Thr Gln Thr Asn Ser Gly Gly Gly Ser Gly Gly Gly Ser
                  675 680 685
          Ala Glu Thr Gly Met Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly
              690 695 700
          Leu Arg Phe Gly Ile Val Ala Ser Arg Ala Asn His Ala Leu Val Asp
          705 710 715 720
          Arg Leu Val Glu Gly Ala Ile Asp Ala Ile Val Arg His Gly Gly Arg
                          725 730 735
          Glu Glu Asp Ile Thr Leu Val Arg Val Cys Gly Ser Trp Glu Ile Pro
                      740 745 750
          Val Ala Ala Gly Glu Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile
                  755 760 765
          Ala Ile Gly Val Leu Cys Arg Gly Ala Thr Pro Ser Phe Asp Tyr Ile
              770 775 780
          Ala Ser Glu Val Ser Lys Gly Leu Ala Asp Leu Ser Leu Glu Leu Arg
          785 790 795 800
          Lys Pro Ile Thr Phe Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala
                          805 810 815
          Ile Glu Ala Ala Gly Thr Cys His Gly Asn Lys Gly Trp Glu Ala Ala
                      820 825 830
          Leu Cys Ala Ile Glu Met Ala Asn Leu Phe Lys Ser Leu Arg
                  835 840 845
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 2300]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 15]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcg ugagcgugau caccccaggc 1860
          accaacacca gcaaccaggu ggccgugcug uaccaggacg ugaacugcac cgaggugccc 1920
          guggccaucc acgccgacca gcugacaccc accuggcggg ucuacagcac cggcagcaac 1980
          guguuccaga cccgggccgg uugccugauc ggcgccgagc acgugaacaa cagcuacgag 2040
          ugcgacaucc ccaucggcgc cggcaucugu gccagcuacc agacccagac caauucaucu 2100
          ggcggaggca gcauccuggc caucuacagc accguggcca gcagccuggu gcugcuggug 2160
          agccugggcg ccaucagcuu cugauaauag gcuggagccu cgguggccua gcuucuugcc 2220
          ccuugggccu ccccccagcc ccuccucccc uuccugcacc cguacccccg uggucuuuga 2280
          auaaagucug agugggcggc 2300
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 2124]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 16]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcgugagcgu gaucacccca 1800
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 1920
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 1980
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 2040
          ucuggcggag gcagcauccu ggccaucuac agcaccgugg ccagcagccu ggugcugcug 2100
          gugagccugg gcgccaucag cuuc 2124
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 707]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 17]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
                  595 600 605
          Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
              610 615 620
          His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
          625 630 635 640
          Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
                          645 650 655
          Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
                      660 665 670
          Ser Tyr Gln Thr Gln Thr Asn Ser Gly Gly Gly Ser Ile Leu Ala Ile
                  675 680 685
          Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala
              690 695 700
          Ile Ser Phe
          705
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 1853]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 18]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc ucuggcggag gcagcauccu ggccaucuac 1680
          agcaccgugg ccagcagccu ggugcugcug gugagccugg gcgccaucag cuucugauaa 1740
          uaggcuggag ccucgguggc cuagcuucuu gccccuuggg ccucccccca gccccucccuc 1800
          cccuuccugc acccguaccc ccguggucuu ugaauaaagu cugagugggc ggc 1853
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 1677]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 19]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accucuggcg gaggcagcau ccuggccauc 1620
          uacagcaccg uggccagcag ccuggugcug cuggugagcc ugggcgccau cagcuuc 1677
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 559]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 20]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val
              530 535 540
          Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
          545 550 555
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 2042]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 21]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcu cuggcggagg cagcauccug 1860
          gccaucuaca gcaccguggc cagcagccug gugcugcugg ugagccuggg cgccaucagc 1920
          uucugauaau aggcuggagc cucgguggcc uagcuucuug ccccuugggc cuccccccag 1980
          ccccuccucc ccuuccugca cccguacccc cguggucuuu gaauaaaguc ugagugggcg 2040
          gc 2042
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 1866]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 22]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcucuggcgg aggcagcauc 1800
          cuggccaucu acagcaccgu ggccagcagc cuggugcugc uggugagccu gggcgccauc 1860
          agcuuc 1866
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 622]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 23]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala
                  595 600 605
          Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
              610 615 620
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 2066]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 24]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu gggcagcggc ggcggcagcg gcggaggcag cggaggaggc 1020
          agcggcggag gcaguggagg ccagcccacc gagagcaucg ugcgguuccc caacaucacc 1080
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1140
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1200
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1260
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1320
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1380
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1440
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1500
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1560
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1620
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagaagag caccaaccug 1680
          gugaagaaca agugcgugaa cuucaacuuc aacggccuua ccggcaccgg cgugcugacc 1740
          gagagcaaca agaaauuccu gcccuuucag caguucggcc gggacaucgc cgacaccacc 1800
          gacgcugugc gggaucccca gacccuggag auccuggaca ucaccccuug cagcuucggc 1860
          ggcucuggcg gaggcagcau ccuggccauc uacagcaccg uggccagcag ccuggugcug 1920
          cuggugagcc ugggcgccau cagcuucuga uaauaggcug gagccucggu ggccuagcuu 1980
          cuugccccuu gggccucccc ccagccccuc cuccccuucc ugcacccgua cccccguggu 2040
          cuuugaauaa agucugagug ggcggc 2066
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 1890]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 25]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cgugggcagc ggcggcggca gcggcggagg cagcggagga 960
          ggcagcggcg gaggcagugg aggccagccc accgagagca ucgugcgguu ccccaacauc 1020
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 1080
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1140
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1200
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1260
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1320
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1380
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1440
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1500
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1560
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaagaa gagcaccaac 1620
          cuggugaaga acaagugcgu gaacuucaac uucaacggcc uuaccggcac cggcgugcug 1680
          accgagagca acaagaaauu ccugcccuuu cagcaguucg gccgggacau cgccgacacc 1740
          accgacgcug ugcgggaucc ccagacccug gagauccugg acaucacccc uugcagcuuc 1800
          ggcggcucug gcggaggcag cauccuggcc aucuacagca ccguggccag cagccuggug 1860
          cugcugguga gccugggcgc caucagcuuc 1890
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 630]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 26]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
          305 310 315 320
          Gly Ser Gly Gly Gly Ser Gly Gly Gln Pro Thr Glu Ser Ile Val Arg
                          325 330 335
          Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala
                      340 345 350
          Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn
                  355 360 365
          Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr
              370 375 380
          Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe
          385 390 395 400
          Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg
                          405 410 415
          Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys
                      420 425 430
          Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn
                  435 440 445
          Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
              450 455 460
          Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
          465 470 475 480
          Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys
                          485 490 495
          Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly
                      500 505 510
          Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala
                  515 520 525
          Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn
              530 535 540
          Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu
          545 550 555 560
          Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp
                          565 570 575
          Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile
                      580 585 590
          Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Ser Gly Gly Gly Ser Ile
                  595 600 605
          Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
              610 615 620
          Leu Gly Ala Ile Ser Phe
          625 630
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 2066]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 27]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          gugugccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu gggcagcggc ggcggcagcg gcggaggcag cggaggaggc 1020
          agcggcggag gcaguggagg ccagcccacc gagagcaucg ugcgguuccc caacaucacc 1080
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1140
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1200
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1260
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1320
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1380
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1440
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1500
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1560
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1620
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagaagag caccaaccug 1680
          gugaagaaca agugcgugaa cuucaacuuc aacggccuua ccggcaccgg cgugcugacc 1740
          gagagcaaca agaaauuccu gcccuuuugc caguucggcc gggacaucgc cgacaccacc 1800
          gacgcugugc gggaucccca gacccuggag auccuggaca ucaccccuug cagcuucggc 1860
          ggcucuggcg gaggcagcau ccuggccauc uacagcaccg uggccagcag ccuggugcug 1920
          cuggugagcc ugggcgccau cagcuucuga uaauaggcug gagccucggu ggccuagcuu 1980
          cuugccccuu gggccucccc ccagccccuc cuccccuucc ugcacccgua cccccguggu 2040
          cuuugaauaa agucugagug ggcggc 2066
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 1890]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 28]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aaggugugcc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cgugggcagc ggcggcggca gcggcggagg cagcggagga 960
          ggcagcggcg gaggcagugg aggccagccc accgagagca ucgugcgguu ccccaacauc 1020
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 1080
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1140
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1200
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1260
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1320
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1380
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1440
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1500
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1560
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaagaa gagcaccaac 1620
          cuggugaaga acaagugcgu gaacuucaac uucaacggcc uuaccggcac cggcgugcug 1680
          accgagagca acaagaaauu ccugcccuuu ugccaguucg gccgggacau cgccgacacc 1740
          accgacgcug ugcgggaucc ccagacccug gagauccugg acaucacccc uugcagcuuc 1800
          ggcggcucug gcggaggcag cauccuggcc aucuacagca ccguggccag cagccuggug 1860
          cugcugguga gccugggcgc caucagcuuc 1890
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 630]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 29]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Cys Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
          305 310 315 320
          Gly Ser Gly Gly Gly Ser Gly Gly Gln Pro Thr Glu Ser Ile Val Arg
                          325 330 335
          Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala
                      340 345 350
          Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn
                  355 360 365
          Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr
              370 375 380
          Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe
          385 390 395 400
          Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg
                          405 410 415
          Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys
                      420 425 430
          Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn
                  435 440 445
          Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
              450 455 460
          Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
          465 470 475 480
          Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys
                          485 490 495
          Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly
                      500 505 510
          Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala
                  515 520 525
          Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn
              530 535 540
          Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu
          545 550 555 560
          Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Cys Gln Phe Gly Arg Asp
                          565 570 575
          Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile
                      580 585 590
          Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Ser Gly Gly Gly Ser Ile
                  595 600 605
          Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
              610 615 620
          Leu Gly Ala Ile Ser Phe
          625 630
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 3182]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 30]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu cggcggcagc 1020
          ggcggcguga gcgugaucac cccaggcacc aacaccagca accagguggc cgugcuguac 1080
          caggacguga acugcaccga ggugcccgug gccauccacg ccgaccagcu gacacccacc 1140
          uggcgggucu acagcaccgg cagcaacgug uuccagaccc gggccgguug ccugaucggc 1200
          gccgagcacg ugaacaacag cuacgagugc gacaucccca ucggcgccgg caucugugcc 1260
          agcuaccaga cccagaccaa uucaccccgg agggcaagga gcguggccag ccagagcauc 1320
          aucgccuaca ccaugagccu gggcgccgag aacagcgugg ccuacagcaa caacagcauc 1380
          gccaucccca ccaacuucac caucagcgug accaccgaga uucugcccgu gagcaugacc 1440
          aagaccagcg uggacugcac cauguacauc ugcggcgaca gcaccgagug cagcaaccug 1500
          cugcugcagu acggcagcuu cugcacccag cugaaccggg cccugaccgg caucgccgug 1560
          gagcaggaca agaacaccca ggagguguuc gcccagguga agcagaucua caagaccccu 1620
          cccaucaagg acuucggcgg cuucaacuuc agccagaucc ugcccgaccc cagcaagccc 1680
          agcaagcgga gcuucaucga ggaccugcug uucaacaagg ugacccuagc cgacgccggc 1740
          uucaucaagc aguacggcga cugccucggc gacauagccg cccgggaccu gaucugcgcc 1800
          cagaaguuca acggccugac cgugcugccu ccccugcuga ccgacgagau gaucgcccag 1860
          uacaccagcg cccuguuagc cggaaccauc accagcggcu ggacuuucgg cgcuggagcc 1920
          gcucugcaga uccccuucgc caugcagaug gccuaccggu ucaacggcau cggcgugacc 1980
          cagaacgugc uguacgagaa ccagaagcug aucgccaacc aguucaacag cgccaucggc 2040
          aagauccagg acagccugag cagcaccgcu agcgcccugg gcaagcugca ggacguggug 2100
          aaccagaacg cccaggcccu gaacacccug gugaagcagc ugagcagcaa cuucggcgcc 2160
          aucagcagcg ugcugaacga cauccugagc cggcuggacc cucccaacgc caccgugcag 2220
          aucgaccggc ugaucacugg ccggcugcag agccugcaga ccuacgugac ccagcagcug 2280
          auccgggccg ccgagauucg ggccagcgcc aaccuggccg ccaccaagau gagcgagugc 2340
          gugcugggcc agagcaagcg gguggacuuc ugcggcaagg gcuaccaccu gaugagcuuu 2400
          ccccagagcg caccccacgg agugguguuc cugcacguga ccuacgugcc cgcccaggag 2460
          aagaacuuca ccaccgcccc agccaucugc cacgacggca aggcccacuu uccccgggag 2520
          ggcguguucg ugagcaacgg cacccacugg uucgugaccc agcggaacuu cuacgagccc 2580
          cagaucauca ccaccgacaa caccuucgug agcggcaacu gcgacguggu gaucggcauc 2640
          gugaacaaca ccguguacga uccccugcag cccgagcugg acagcuucaa ggaggagcug 2700
          gacaaguacu ucaagaauca caccagcccc gacguggacc ugggcgacau cagcggcauc 2760
          aacgccagcg uggugaacau ccagaaggag aucgaucggc ugaacgaggu ggccaagaac 2820
          cugaacgaga gccugaucga ccugcaggag cugggcaagu acgagcagua caucaagugg 2880
          cccugguaca ucuggcuggg cuucaucgcc ggccugaucg ccaucgugau ggugaccauc 2940
          augcugugcu gcaugaccag cugcugcagc ugccugaagg gcuguugcag cugcggcagc 3000
          ugcugcaagu ucgacgagga cgacagcgag cccgugcuga agggcgugaa gcugcacuac 3060
          accugauaau aggcuggagc cucgguggcc uagcuucuug ccccuugggc cuccccccag 3120
          ccccuccucc ccuuccugca cccguacccc cguggucuuu gaauaaaguc ugagugggcg 3180
          gc 3182
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 3006]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 31]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuucggcggc 960
          agcggcggcg ugagcgugau caccccaggc accaacacca gcaaccaggu ggccgugcug 1020
          uaccaggacg ugaacugcac cgaggugccc guggccaucc acgccgacca gcugacaccc 1080
          accuggcggg ucuacagcac cggcagcaac guguuccaga cccgggccgg uugccugauc 1140
          ggcgccgagc acgugaacaa cagcuacgag ugcgacaucc ccaucggcgc cggcaucugu 1200
          gccagcuacc agacccagac caauucaccc cggagggcaa ggagcguggc cagccagagc 1260
          aucaucgccu acaccaugag ccugggcgcc gagaacagcg uggccuacag caacaacagc 1320
          aucgccaucc ccaccaacuu caccaucagc gugaccaccg agauucugcc cgugagcaug 1380
          accaagacca gcguggacug caccauguac aucugcggcg acagcaccga gugcagcaac 1440
          cugcugcugc aguacggcag cuucugcacc cagcugaacc gggcccugac cggcaucgcc 1500
          guggagcagg acaagaacac ccaggaggug uucgcccagg ugaagcagau cuacaagacc 1560
          ccucccauca aggacuucgg cggcuucaac uucagccaga uccugcccga ccccagcaag 1620
          cccagcaagc ggagcuucau cgaggaccug cuguucaaca aggugacccu agccgacgcc 1680
          ggcuucauca agcaguacgg cgacugccuc ggcgacauag ccgcccggga ccugaucugc 1740
          gcccagaagu ucaacggccu gaccgugcug ccuccccugc ugaccgacga gaugaucgcc 1800
          caguacacca gcgcccuguu agccggaacc aucaccagcg gcuggacuuu cggcgcugga 1860
          gccgcucugc agauccccuu cgccaugcag auggccuacc gguucaacgg caucggcgug 1920
          acccagaacg ugcuguacga gaaccagaag cugaucgcca accaguucaa cagcgccauc 1980
          ggcaagaucc aggacagccu gagcagcacc gcuagcgccc ugggcaagcu gcaggacgug 2040
          gugaaccaga acgcccaggc ccugaacacc cuggugaagc agcugagcag caacuucggc 2100
          gccaucagca gcgugcugaa cgacauccug agccggcugg acccucccaa cgccaccgug 2160
          cagaucgacc ggcugaucac uggccggcug cagagccugc agaccuacgu gacccagcag 2220
          cugauccggg ccgccgagau ucgggccagc gccaaccugg ccgccaccaa gaugagcgag 2280
          ugcgugcugg gccagagcaa gcggguggac uucugcggca agggcuacca ccugaugagc 2340
          uuuccccaga gcgcacccca cggaguggug uuccugcacg ugaccuacgu gcccgcccag 2400
          gagaagaacu ucaccaccgc cccagccauc ugccacgacg gcaaggccca cuuuccccgg 2460
          gagggcgugu ucgugagcaa cggcacccac ugguucguga cccagcggaa cuucuacgag 2520
          ccccagauca ucaccaccga caacaccuuc gugagcggca acugcgacgu ggugaucggc 2580
          aucgugaaca acaccgugua cgauccccug cagcccgagc uggacagcuu caaggaggag 2640
          cuggacaagu acuucaagaa ucacaccagc cccgacgugg accugggcga caucagcggc 2700
          aucaacgcca gcguggugaa cauccagaag gagaucgauc ggcugaacga gguggccaag 2760
          aaccugaacg agagccugau cgaccugcag gagcugggca aguacgagca guacaucaag 2820
          uggcccuggu acaucuggcu gggcuucauc gccggccuga ucgccaucgu gauggugacc 2880
          aucaugcugu gcugcaugac cagcugcugc agcugccuga agggcuguug cagcugcggc 2940
          agcugcugca aguucgacga ggacgacagc gagcccgugc ugaagggcgu gaagcugcac 3000
          uacacc 3006
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 1002]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 32]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Gly Gly
          305 310 315 320
          Ser Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
                          325 330 335
          Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
                      340 345 350
          Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
                  355 360 365
          Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
              370 375 380
          Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
          385 390 395 400
          Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val
                          405 410 415
          Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
                      420 425 430
          Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
                  435 440 445
          Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
              450 455 460
          Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
          465 470 475 480
          Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
                          485 490 495
          Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
                      500 505 510
          Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
                  515 520 525
          Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
              530 535 540
          Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
          545 550 555 560
          Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
                          565 570 575
          Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
                      580 585 590
          Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
                  595 600 605
          Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
              610 615 620
          Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
          625 630 635 640
          Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
                          645 650 655
          Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser
                      660 665 670
          Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
                  675 680 685
          Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
              690 695 700
          Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Asn Ala Thr Val
          705 710 715 720
          Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
                          725 730 735
          Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
                      740 745 750
          Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg
                  755 760 765
          Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser
              770 775 780
          Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
          785 790 795 800
          Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala
                          805 810 815
          His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe
                      820 825 830
          Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn
                  835 840 845
          Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn
              850 855 860
          Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu
          865 870 875 880
          Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly
                          885 890 895
          Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile
                      900 905 910
          Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp
                  915 920 925
          Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr
              930 935 940
          Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr
          945 950 955 960
          Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys
                          965 970 975
          Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
                      980 985 990
          Val Leu Lys Gly Val Lys Leu His Tyr Thr
                  995 1000
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 2378]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 33]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagg gcaccaucac cgacgccgug 120
          gacugcgccc uggacccucu gagcgagacc aagugcaccc ugaagagcuu caccguggag 180
          aagggcaucu accagaccag caacuucggc ggcagcggcg gcgugagcgu gaucacccca 240
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 300
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 360
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 420
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 480
          ccccggaggg caaggagcgu ggccagccag agcaucaucg ccuacaccau gagccugggc 540
          gccgagaaca gcguggccua cagcaacaac agcaucgcca uccccaccaa cuucaccauc 600
          agcgugacca ccgagauucu gcccgugagc augaccaaga ccagcgugga cugcaccaug 660
          uacaucugcg gcgacagcac cgagugcagc aaccugcugc ugaacuacac cagcuucugc 720
          acccagcuga accgggcccu gaccggcauc gccguggagc aggacaagaa cacccaggag 780
          guguucgccc aggugaagca gaucuacaag accccuccca ucaaggacuu cggcggcuuc 840
          aacuucagcc agauccugcc cgaccccagc aagcccagca agcggagcuu caucgaggac 900
          cugcuguuca acaaggugac ccuagccgac gccggcuuca ucaagcagua cggcgacugc 960
          cucggcgaca uagccgcccg ggaccugauc ugcgcccaga aguucaacgg ccugaccgug 1020
          cugccuccccc ugcugaccga cgagaugauc gcccaguaca ccagcgcccu guuagccgga 1080
          accaucacca gcggcuggac uuucggcgcu ggagccgcuc ugcagauccc cuucgccaug 1140
          cagauggccu accgguucaa cggcaucggc gugacccaga acgugcugua cgagaaccag 1200
          aagcugaucg ccaaccaguu caacagcgcc aucggcaaga uccaggacag ccugagcagc 1260
          accgcuagcg cccugggcaa gcugcaggac guggugaacc agaacgccca ggcccugaac 1320
          acccugguga agcagcugag cagcaacuuc ggcgccauca gcagcgugcu gaacgacauc 1380
          cugagccggc uggacccucc caacgccacc gugcagaucg accggcugau cacuggccgg 1440
          cugcagagcc ugcagaccua cgugacccag cagcugaucc gggccgccga gauucgggcc 1500
          agcgccaacc uggccgccac caagaugagc gagugcgugc ugggccagag caagcgggug 1560
          gacuucugcg gcaagggcua ccaccugaug agcuuucccc agagcgcacc ccacggagug 1620
          guguuccugc acgugaccua cgugcccgcc caggagaaga acuucaccac cgccccagcc 1680
          aucugccacg acggcaaggc ccacuuuccc cgggagggcg uguucgugag caacggcacc 1740
          cacugguucg ugacccagcg gaacuucuac gagccccaga ucaucaccac cgacaacacc 1800
          uucgugagcg gcaacugcga cguggugauc ggcaucguga acaacaccgu guacgauccc 1860
          cugcagcccg agcuggacag cuucaaggag gagcuggaca aguacuucaa gaaucacacc 1920
          agccccgacg uggaccuggg cgacaucagc ggcaucaacg ccagcguggu gaacauccag 1980
          aaggagaucg aucggcugaa cgagguggcc aagaaccuga acgagagccu gaucgaccug 2040
          caggagcugg gcaaguacga gcaguacauc aaguggcccu gguacaucug gcugggcuuc 2100
          aucgccggcc ugaucgccau cgugauggug accaucaugc ugugcugcau gaccagcugc 2160
          ugcagcugcc ugaagggcug uugcagcugc ggcagcugcu gcaaguucga cgaggacgac 2220
          agcgagcccg ugcugaaggg cgugaagcug cacuacaccu gauaauaggc uggagccucg 2280
          guggccuagc uucuugcccc uugggccucc ccccagcccc uccuccccuu ccugcacccg 2340
          uacccccgug gucuuugaau aaagucugag ugggcggc 2378
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 2202]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 34]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agggcaccau caccgacgcc 60
          guggacugcg cccuggaccc ucugagcgag accaagugca cccugaagag cuucaccgug 120
          gagaagggca ucuaccagac cagcaacuuc ggcggcagcg gcggcgugag cgugaucacc 180
          ccaggcacca acaccagcaa ccagguggcc gugcuguacc aggacgugaa cugcaccgag 240
          gugcccgugg ccauccacgc cgaccagcug acacccaccu ggcgggucua cagcaccggc 300
          agcaacgugu uccagacccg ggccgguugc cugaucggcg ccgagcacgu gaacaacagc 360
          uacgagugcg acauccccau cggcgccggc aucugugcca gcuaccagac ccagaccaau 420
          ucaccccgga gggcaaggag cguggccagc cagagcauca ucgccuacac caugagccug 480
          ggcgccgaga acagcguggc cuacagcaac aacagcaucg ccauccccac caacuucacc 540
          aucagcguga ccaccgagau ucugcccgug agcaugacca agaccagcgu ggacugcacc 600
          auguacaucu gcggcgacag caccgagugc agcaaccugc ugcugaacua caccagcuuc 660
          ugcacccagc ugaaccgggc ccugaccggc aucgccgugg agcaggacaa gaacacccag 720
          gagguguucg cccaggugaa gcagaucuac aagaccccuc ccaucaagga cuucggcggc 780
          uucaacuuca gccagauccu gcccgacccc agcaagccca gcaagcggag cuucaucgag 840
          gaccugcugu ucaacaaggu gacccuagcc gacgccggcu ucaucaagca guacggcgac 900
          ugccucggcg acauagccgc ccgggaccug aucugcgccc agaaguucaa cggccugacc 960
          gugcugccuc cccugcugac cgacgagaug aucgcccagu acaccagcgc ccuguuagcc 1020
          ggaaccauca ccagcggcug gacuuucggc gcuggagccg cucugcagau ccccuucgcc 1080
          augcagaugg ccuaccgguu caacggcauc ggcgugaccc agaacgugcu guacgagaac 1140
          cagaagcuga ucgccaacca guucaacagc gccaucggca agauccagga cagccugagc 1200
          agcaccgcua gcgcccuggg caagcugcag gacgugguga accagaacgc ccaggcccug 1260
          aacacccugg ugaagcagcu gagcagcaac uucggcgcca ucagcagcgu gcugaacgac 1320
          auccugagcc ggcuggaccc ucccaacgcc accgugcaga ucgaccggcu gaucacuggc 1380
          cggcugcaga gccugcagac cuacgugacc cagcagcuga uccgggccgc cgagauucgg 1440
          gccagcgcca accuggccgc caccaagaug agcgagugcg ugcugggcca gagcaagcgg 1500
          guggacuucu gcggcaaggg cuaccaccug augagcuuuc cccagagcgc accccacgga 1560
          gugguguucc ugcacgugac cuacgugccc gcccaggaga agaacuucac caccgcccca 1620
          gccaucugcc acgacggcaa ggcccacuuu ccccgggagg gcguguucgu gagcaacggc 1680
          acccacuggu ucgugaccca gcggaacuuc uacgagcccc agaucaucac caccgacaac 1740
          accuucguga gcggcaacug cgacguggug aucggcaucg ugaacaacac cguguacgau 1800
          ccccugcagc ccgagcugga cagcuucaag gaggagcugg acaaguacuu caagaaucac 1860
          accagccccg acguggaccu gggcgacauc agcggcauca acgccagcgu ggugaacauc 1920
          cagaaggaga ucgaucggcu gaacgaggug gccaagaacc ugaacgagag ccugaucgac 1980
          cugcaggagc ugggcaagua cgagcaguac aucaaguggc ccugguacau cuggcugggc 2040
          uucaucgccg gccugaucgc caucgugaug gugaccauca ugcugugcug caugaccagc 2100
          ugcugcagcu gccugaaggg cuguugcagc ugcggcagcu gcugcaaguu cgacgaggac 2160
          gacagcgagc ccgugcugaa gggcgugaag cugcacuaca cc 2202
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 734]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 35]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Gly Thr
          1 5 10 15
          Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys
                      20 25 30
          Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser
                  35 40 45
          Asn Phe Gly Gly Ser Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn
              50 55 60
          Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu
          65 70 75 80
          Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val
                          85 90 95
          Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile
                      100 105 110
          Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly
                  115 120 125
          Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg
              130 135 140
          Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu
          145 150 155 160
          Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro
                          165 170 175
          Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met
                      180 185 190
          Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr
                  195 200 205
          Glu Cys Ser Asn Leu Leu Leu Asn Tyr Thr Ser Phe Cys Thr Gln Leu
              210 215 220
          Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln
          225 230 235 240
          Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys
                          245 250 255
          Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys
                      260 265 270
          Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr
                  275 280 285
          Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp
              290 295 300
          Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr
          305 310 315 320
          Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser
                          325 330 335
          Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly
                      340 345 350
          Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn
                  355 360 365
          Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile
              370 375 380
          Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser
          385 390 395 400
          Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn
                          405 410 415
          Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly
                      420 425 430
          Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro
                  435 440 445
          Asn Ala Thr Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser
              450 455 460
          Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg
          465 470 475 480
          Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly
                          485 490 495
          Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser
                      500 505 510
          Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr
                  515 520 525
          Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
              530 535 540
          Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly
          545 550 555 560
          Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile
                          565 570 575
          Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly
                      580 585 590
          Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser
                  595 600 605
          Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp
              610 615 620
          Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile
          625 630 635 640
          Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu
                          645 650 655
          Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys
                      660 665 670
          Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile
                  675 680 685
          Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys
              690 695 700
          Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp
          705 710 715 720
          Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr Thr
                          725 730
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 4241]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 36]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uuccugauca ucuucauccu gcccaccacc cuggccguga ucggcgacuu caacugcacc 120
          aacagcuuca ucaacgacua caacaagacc aucccucgga ucagcgaaga cgugguggac 180
          gugucccugg gccugggcac cuacuacgug cugaaccggg uguaccugaa caccacacug 240
          cuguucaccg gcuacuuccc caagagcggc gccaacuucc gggaccuggc ccugaagggc 300
          agcaucuacc ugagcaccuu gugguacaag ccucccuucc ugagcgacuu caauaacggc 360
          aucuucucua aggugaagaa caccaagcug uacguaaaca acacccugua cagcgaguuc 420
          agcaccaucg ugaucggcag cguguucguc aacaccagcu acaccaucgu ggugcagccc 480
          cacaacggca uccuggagau caccgccugc caguacacca ugugcgagua cccucacacc 540
          gugugcaaga gcaagggcuc cauccggaac gagagcuggc acaucgacag cagcgagccg 600
          cugugccugu ucaagaagaa cuucaccuac aacgugagcg ccgacuggcu guacuuccac 660
          uucuaccagg agcggggcgu guucuacgcc uacuacgccg acgugggcau gccaaccacc 720
          uuccuguuca gccuguaccu gggcaccauc cugagccacu acuacgugau gccccugacc 780
          ugcaacgcca ucagcucaaa caccgacaac gagacccugg aguacugggu gacuccacug 840
          agccggcggc aguaccugcu gaacuucgac gagcacggcg ugaucaccaa cgccguggac 900
          ugcgcccugg acccucugag cgagaccaag ugcacccuga agagcuucac cguggagaag 960
          ggcaucuacc agaccagcgg cuucaccgug aagcccguag ccaccgugua ccggcggauc 1020
          cccaaccugc ccgacugcga caucgacaac uggcugaaca acgucagcgu gcccagccca 1080
          cugaacuggg agcggcggau cuucagcaac ugcaacuuca aucugagcac ccugcugcgg 1140
          cuggugcacg uggacagcuu cagcugcaac aaccuggaca agagcaagau cuucgguagc 1200
          ugcuucaaca gcaucaccgu ggacaaguuc gccaucccua accggcggcg ggacgaucug 1260
          cagcugggca gcagcggcuu ccugcagagc agcaacuaca agaucgacau cagcagcuca 1320
          agcugccagc uguacuacag ccugccccug gugaacguga ccaucaacaa cuucaacccc 1380
          agcagcugga accggcggua cggcuucggc agcuucaacc ugagcagcua cgacguggug 1440
          uacagcgacc acugcuucag cgugaacagc gacuucugcc ccugugccga cccuagcgug 1500
          gugaacagcu gcgccaagag caagccuccc agcgccauuu gccccgccgg caccaaguac 1560
          cggcacugcg accuggacac cacccuguac gugaagaacu ggugccggug cagcugccug 1620
          cccgacccca ucagcaccua cagccccaac accugucccc agaagaaggu gguggugggu 1680
          aucggcgagc acugucccgg ccugggcauc aacgaggaga agugcggcac ccagcugaac 1740
          cacagcagcu gcuucuguag ccccgacgcc uuccugggcu ggagcuucga cagcugcauc 1800
          agcaacaacc ggugcaacau cuuuagcaac uucaucuuca acggaaucaa cagcggcacc 1860
          accugcagca acgaccugcu guauagcaac accgagauca gcaccggcgu gugcgugaac 1920
          uacgaccugu acggcaucac cggccagggc aucuucaagg aggugagcgc cgccuacuac 1980
          aacaacuggc agaaccugcu guacgacagc aacggcaaca ucaucggcuu caaggacuuu 2040
          cugaccaaca agaccuacac cauccugccc ugcuacagcg gcggcgugag cgugaucacc 2100
          ccaggcacca acaccagcaa ccagguggcc gugcuguacc aggacgugaa cugcaccgag 2160
          gugcccgugg ccauccacgc cgaccagcug acacccaccu ggcgggucua cagcaccggc 2220
          agcaacgugu uccagacccg ggccgguugc cugaucggcg ccgagcacgu gaacaacagc 2280
          uacgagugcg acauccccau cggcgccggc aucugugcca gcuaccagac ccagaccaau 2340
          ucaccccgga gggcaaggag cguggccagc cagagcauca ucgccuacac caugagccug 2400
          ggcgccgaga acagcguggc cuacagcaac aacagcaucg ccauccccac caacuucacc 2460
          aucagcguga ccaccgagau ucugcccgug agcaugacca agaccagcgu ggacugcacc 2520
          auguacaucu gcggcgacag caccgagugc agcaaccugc ugcugcagua cggcagcuuc 2580
          ugcacccagc ugaaccgggc ccugaccggc aucgccgugg agcaggacaa gaacacccag 2640
          gagguguucg cccaggugaa gcagaucuac aagaccccuc ccaucaagga cuucggcggc 2700
          uucaacuuca gccagauccu gcccgacccc agcaagccca gcaagcggag cuucaucgag 2760
          gaccugcugu ucaacaaggu gacccuagcc gacgccggcu ucaucaagca guacggcgac 2820
          ugccucggcg acauagccgc ccgggaccug aucugcgccc agaaguucaa cggccugacc 2880
          gugcugccuc cccugcugac cgacgagaug aucgcccagu acaccagcgc ccuguuagcc 2940
          ggaaccauca ccagcggcug gacuuucggc gcuggagccg cucugcagau ccccuucgcc 3000
          augcagaugg ccuaccgguu caacggcauc ggcgugaccc agaacgugcu guacgagaac 3060
          cagaagcuga ucgccaacca guucaacagc gccaucggca agauccagga cagccugagc 3120
          agcaccgcua gcgcccuggg caagcugcag gacgugguga accagaacgc ccaggcccug 3180
          aacacccugg ugaagcagcu gagcagcaac uucggcgcca ucagcagcgu gcugaacgac 3240
          auccugagcc ggcuggaccc ucccgaggcc gaggugcaga ucgaccggcu gaucacuggc 3300
          cggcugcaga gccugcagac cuacgugacc cagcagcuga uccgggccgc cgagauucgg 3360
          gccagcgcca accuggccgc caccaagaug agcgagugcg ugcugggcca gagcaagcgg 3420
          guggacuucu gcggcaaggg cuaccaccug augagcuuuc cccagagcgc accccacgga 3480
          gugguguucc ugcacgugac cuacgugccc gcccaggaga agaacuucac caccgcccca 3540
          gccaucugcc acgacggcaa ggcccacuuu ccccgggagg gcguguucgu gagcaacggc 3600
          acccacuggu ucgugaccca gcggaacuuc uacgagcccc agaucaucac caccgacaac 3660
          accuucguga gcggcaacug cgacguggug aucggcaucg ugaacaacac cguguacgau 3720
          ccccugcagc ccgagcugga cagcuucaag gaggagcugg acaaguacuu caagaaucac 3780
          accagccccg acguggaccu gggcgacauc agcggcauca acgccagcgu ggugaacauc 3840
          cagaaggaga ucgaucggcu gaacgaggug gccaagaacc ugaacgagag ccugaucgac 3900
          cugcaggagc ugggcaagua cgagcaguac aucaaguggc ccugguacau cuggcugggc 3960
          uucaucgccg gccugaucgc caucgugaug gugaccauca ugcugugcug caugaccagc 4020
          ugcugcagcu gccugaaggg cuguugcagc ugcggcagcu gcugcaaguu cgacgaggac 4080
          gacagcgagc ccgugcugaa gggcgugaag cugcacuaca ccugauaaua ggcuggagcc 4140
          ucgguggccu agcuucuugc cccuugggcc uccccccagc cccuccuccc cuuccugcac 4200
          ccguaccccc guggucuuug aauaaagucu gagugggcgg c 4241
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 4065]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 37]]>
          auguuccuga ucaucuucau ccugcccacc acccuggccg ugaucggcga cuucaacugc 60
          accaacagcu ucaucaacga cuacaacaag accaucccuc ggaucagcga agacguggug 120
          gacguguccc ugggccuggg caccuacuac gugcugaacc ggguguaccu gaacaccaca 180
          cugcuguuca ccggcuacuu ccccaagagc ggcgccaacu uccgggaccu ggcccugaag 240
          ggcagcaucu accugagcac cuugugguac aagccucccu uccugagcga cuucaauaac 300
          ggcaucuucu cuaaggugaa gaacaccaag cuguacguaa acaacacccu guacagcgag 360
          uucagcacca ucgugaucgg cagcguguuc gucaacacca gcuacaccau cguggugcag 420
          ccccacaacg gcauccugga gaucaccgcc ugccaguaca ccaugugcga guacccucac 480
          accgugugca agagcaaggg cuccauccgg aacgagagcu ggcacaucga cagcagcgag 540
          ccgcugugcc uguucaagaa gaacuucacc uacaacguga gcgccgacug gcuguacuuc 600
          cacuucuacc aggagcgggg cguguucuac gccuacuacg ccgacguggg caugccaacc 660
          accuuccugu ucagccugua ccugggcacc auccugagcc acuacuacgu gaugccccug 720
          accugcaacg ccaucagcuc aaacaccgac aacgagaccc uggaguacug ggugacucca 780
          cugagccggc ggcaguaccu gcugaacuuc gacgagcacg gcgugaucac caacgccgug 840
          gacugcgccc uggacccucu gagcgagacc aagugcaccc ugaagagcuu caccguggag 900
          aagggcaucu accagaccag cggcuucacc gugaagcccg uagccaccgu guaccggcgg 960
          auccccaacc ugcccgacug cgacaucgac aacuggcuga acaacgucag cgugcccagc 1020
          ccacugaacu gggagcggcg gaucuucagc aacugcaacu ucaaucugag cacccugcug 1080
          cggcuggugc acguggacag cuucagcugc aacaaccugg acaagagcaa gaucuucggu 1140
          agcugcuuca acagcaucac cguggacaag uucgccaucc cuaaccggcg gcgggacgau 1200
          cugcagcugg gcagcagcgg cuuccugcag agcagcaacu acaagaucga caucagcagc 1260
          ucaagcugcc agcuguacua cagccugccc cuggugaacg ugaccaucaa caacuucaac 1320
          cccagcagcu ggaaccggcg guacggcuuc ggcagcuuca accugagcag cuacgacgug 1380
          guguacagcg accacugcuu cagcgugaac agcgacuucu gccccugugc cgacccuagc 1440
          guggugaaca gcugcgccaa gagcaagccu cccagcgcca uuugccccgc cggcaccaag 1500
          uaccggcacu gcgaccugga caccacccug uacgugaaga acuggugccg gugcagcugc 1560
          cugcccgacc ccaucagcac cuacagcccc aacaccuguc cccagaagaa ggugguggug 1620
          gguaucggcg agcacugucc cggccugggc aucaacgagg agaagugcgg cacccagcug 1680
          aaccacagca gcugcuucug uagccccgac gccuuccugg gcuggagcuu cgacagcugc 1740
          aucagcaaca accggugcaa caucuuuagc aacuucaucu ucaacggaau caacagcggc 1800
          accaccugca gcaacgaccu gcuguauagc aacaccgaga ucagcaccgg cgugugcgug 1860
          aacuacgacc uguacggcau caccggccag ggcaucuuca aggaggugag cgccgccuac 1920
          uacaacaacu ggcagaaccu gcuguacgac agcaacggca acaucaucgg cuucaaggac 1980
          uuucugacca acaagaccua caccauccug cccugcuaca gcggcggcgu gagcgugauc 2040
          accccaggca ccaacaccag caaccaggug gccgugcugu accaggacgu gaacugcacc 2100
          gaggugcccg uggccaucca cgccgaccag cugacaccca ccuggcgggu cuacagcacc 2160
          ggcagcaacg uguuccagac ccgggccggu ugccugaucg gcgccgagca cgugaacaac 2220
          agcuacgagu gcgacauccc caucggcgcc ggcaucugug ccagcuacca gacccagacc 2280
          aauucacccc ggagggcaag gagcguggcc agccagagca ucaucgccua caccaugagc 2340
          cugggcgccg agaacagcgu ggccuacagc aacaacagca ucgccauccc caccaacuuc 2400
          accaucagcg ugaccaccga gauucugccc gugagcauga ccaagaccag cguggacugc 2460
          accauguaca ucugcggcga cagcaccgag ugcagcaacc ugcugcugca guacggcagc 2520
          uucugcaccc agcugaaccg ggcccugacc ggcaucgccg uggagcagga caagaacacc 2580
          caggaggugu ucgcccaggu gaagcagauc uacaagaccc cucccaucaa ggacuucggc 2640
          ggcuucaacu ucagccagau ccugcccgac cccagcaagc ccagcaagcg gagcuucauc 2700
          gaggaccugc uguucaacaa ggugacccua gccgacgccg gcuucaucaa gcaguacggc 2760
          gacugccucg gcgacauagc cgcccgggac cugaucugcg cccagaaguu caacggccug 2820
          accgugcugc cuccccugcu gaccgacgag augaucgccc aguacaccag cgcccuguua 2880
          gccggaacca ucaccagcgg cuggacuuuc ggcgcuggag ccgcucugca gauccccuuc 2940
          gccaugcaga uggccuaccg guucaacggc aucggcguga cccagaacgu gcuguacgag 3000
          aaccagaagc ugaucgccaa ccaguucaac agcgccaucg gcaagaucca ggacagccug 3060
          agcagcaccg cuagcgcccu gggcaagcug caggacgugg ugaaccagaa cgcccaggcc 3120
          cugaacaccc uggugaagca gcugagcagc aacuucggcg ccaucagcag cgugcugaac 3180
          gacauccuga gccggcugga cccucccgag gccgaggugc agaucgaccg gcugaucacu 3240
          ggccggcugc agagccugca gaccuacgug acccagcagc ugauccgggc cgccgagauu 3300
          cgggccagcg ccaaccuggc cgccaccaag augagcgagu gcgugcuggg ccagagcaag 3360
          cgggguggacu ucugcggcaa gggcuaccac cugaugagcu uuccccagag cgcaccccac 3420
          ggaguggugu uccugcacgu gaccuacgug cccgcccagg agaagaacuu caccaccgcc 3480
          ccagccaucu gccacgacgg caaggcccac uuuccccggg agggcguguu cgugagcaac 3540
          ggcacccacu gguucgugac ccagcggaac uucuacgagc cccagaucau caccaccgac 3600
          aacaccuucg ugagcggcaa cugcgacgug gugaucggca ucgugaacaa caccguguac 3660
          gauccccugc agcccgagcu ggacagcuuc aaggaggagc uggacaagua cuucaagaau 3720
          cacaccagcc ccgacgugga ccugggcgac aucagcggca ucaacgccag cguggugaac 3780
          auccagaagg agaucgaucg gcugaacgag guggccaaga accugaacga gagccugauc 3840
          gaccugcagg agcugggcaa guacgagcag uacaucaagu ggcccuggua caucuggcug 3900
          ggcuucaucg ccggccugau cgccaucgug auggugacca ucaugcugug cugcaugacc 3960
          agcugcugca gcugccugaa gggcuguugc agcugcggca gcugcugcaa guucgacgag 4020
          gacgacagcg agcccgugcu gaagggcgug aagcugcacu acacc 4065
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 1355]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 38]]>
          Met Phe Leu Ile Ile Phe Ile Leu Pro Thr Thr Leu Ala Val Ile Gly
          1 5 10 15
          Asp Phe Asn Cys Thr Asn Ser Phe Ile Asn Asp Tyr Asn Lys Thr Ile
                      20 25 30
          Pro Arg Ile Ser Glu Asp Val Val Asp Val Ser Leu Gly Leu Gly Thr
                  35 40 45
          Tyr Tyr Val Leu Asn Arg Val Tyr Leu Asn Thr Thr Leu Leu Phe Thr
              50 55 60
          Gly Tyr Phe Pro Lys Ser Gly Ala Asn Phe Arg Asp Leu Ala Leu Lys
          65 70 75 80
          Gly Ser Ile Tyr Leu Ser Thr Leu Trp Tyr Lys Pro Pro Phe Leu Ser
                          85 90 95
          Asp Phe Asn Asn Gly Ile Phe Ser Lys Val Lys Asn Thr Lys Leu Tyr
                      100 105 110
          Val Asn Asn Thr Leu Tyr Ser Glu Phe Ser Thr Ile Val Ile Gly Ser
                  115 120 125
          Val Phe Val Asn Thr Ser Tyr Thr Ile Val Val Gln Pro His Asn Gly
              130 135 140
          Ile Leu Glu Ile Thr Ala Cys Gln Tyr Thr Met Cys Glu Tyr Pro His
          145 150 155 160
          Thr Val Cys Lys Ser Lys Gly Ser Ile Arg Asn Glu Ser Trp His Ile
                          165 170 175
          Asp Ser Ser Glu Pro Leu Cys Leu Phe Lys Lys Asn Phe Thr Tyr Asn
                      180 185 190
          Val Ser Ala Asp Trp Leu Tyr Phe His Phe Tyr Gln Glu Arg Gly Val
                  195 200 205
          Phe Tyr Ala Tyr Tyr Ala Asp Val Gly Met Pro Thr Thr Phe Leu Phe
              210 215 220
          Ser Leu Tyr Leu Gly Thr Ile Leu Ser His Tyr Tyr Val Met Pro Leu
          225 230 235 240
          Thr Cys Asn Ala Ile Ser Ser Asn Thr Asp Asn Glu Thr Leu Glu Tyr
                          245 250 255
          Trp Val Thr Pro Leu Ser Arg Arg Gln Tyr Leu Leu Asn Phe Asp Glu
                      260 265 270
          His Gly Val Ile Thr Asn Ala Val Asp Cys Ala Leu Asp Pro Leu Ser
                  275 280 285
          Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr
              290 295 300
          Gln Thr Ser Gly Phe Thr Val Lys Pro Val Ala Thr Val Tyr Arg Arg
          305 310 315 320
          Ile Pro Asn Leu Pro Asp Cys Asp Ile Asp Asn Trp Leu Asn Asn Val
                          325 330 335
          Ser Val Pro Ser Pro Leu Asn Trp Glu Arg Arg Ile Phe Ser Asn Cys
                      340 345 350
          Asn Phe Asn Leu Ser Thr Leu Leu Arg Leu Val His Val Asp Ser Phe
                  355 360 365
          Ser Cys Asn Asn Leu Asp Lys Ser Lys Ile Phe Gly Ser Cys Phe Asn
              370 375 380
          Ser Ile Thr Val Asp Lys Phe Ala Ile Pro Asn Arg Arg Arg Asp Asp
          385 390 395 400
          Leu Gln Leu Gly Ser Ser Gly Phe Leu Gln Ser Ser Asn Tyr Lys Ile
                          405 410 415
          Asp Ile Ser Ser Ser Ser Cys Gln Leu Tyr Tyr Ser Leu Pro Leu Val
                      420 425 430
          Asn Val Thr Ile Asn Asn Phe Asn Pro Ser Ser Trp Asn Arg Arg Tyr
                  435 440 445
          Gly Phe Gly Ser Phe Asn Leu Ser Ser Tyr Asp Val Val Tyr Ser Asp
              450 455 460
          His Cys Phe Ser Val Asn Ser Asp Phe Cys Pro Cys Ala Asp Pro Ser
          465 470 475 480
          Val Val Asn Ser Cys Ala Lys Ser Lys Pro Pro Ser Ala Ile Cys Pro
                          485 490 495
          Ala Gly Thr Lys Tyr Arg His Cys Asp Leu Asp Thr Thr Leu Tyr Val
                      500 505 510
          Lys Asn Trp Cys Arg Cys Ser Cys Leu Pro Asp Pro Ile Ser Thr Tyr
                  515 520 525
          Ser Pro Asn Thr Cys Pro Gln Lys Lys Val Val Val Gly Ile Gly Glu
              530 535 540
          His Cys Pro Gly Leu Gly Ile Asn Glu Glu Lys Cys Gly Thr Gln Leu
          545 550 555 560
          Asn His Ser Ser Cys Phe Cys Ser Pro Asp Ala Phe Leu Gly Trp Ser
                          565 570 575
          Phe Asp Ser Cys Ile Ser Asn Asn Arg Cys Asn Ile Phe Ser Asn Phe
                      580 585 590
          Ile Phe Asn Gly Ile Asn Ser Gly Thr Thr Cys Ser Asn Asp Leu Leu
                  595 600 605
          Tyr Ser Asn Thr Glu Ile Ser Thr Gly Val Cys Val Asn Tyr Asp Leu
              610 615 620
          Tyr Gly Ile Thr Gly Gln Gly Ile Phe Lys Glu Val Ser Ala Ala Tyr
          625 630 635 640
          Tyr Asn Asn Trp Gln Asn Leu Leu Tyr Asp Ser Asn Gly Asn Ile Ile
                          645 650 655
          Gly Phe Lys Asp Phe Leu Thr Asn Lys Thr Tyr Thr Ile Leu Pro Cys
                      660 665 670
          Tyr Ser Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn
                  675 680 685
          Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val
              690 695 700
          Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr
          705 710 715 720
          Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu
                          725 730 735
          His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile
                      740 745 750
          Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser
                  755 760 765
          Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu
              770 775 780
          Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe
          785 790 795 800
          Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr
                          805 810 815
          Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser
                      820 825 830
          Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala
                  835 840 845
          Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe
              850 855 860
          Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly
          865 870 875 880
          Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys
                          885 890 895
          Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp
                      900 905 910
          Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala
                  915 920 925
          Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro
              930 935 940
          Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu
          945 950 955 960
          Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu
                          965 970 975
          Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly
                      980 985 990
          Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln
                  995 1000 1005
          Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr
              1010 1015 1020
          Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala
              1025 1030 1035
          Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly
              1040 1045 1050
          Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro
              1055 1060 1065
          Pro Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu
              1070 1075 1080
          Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala
              1085 1090 1095
          Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu
              1100 1105 1110
          Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly
              1115 1120 1125
          Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val
              1130 1135 1140
          Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr
              1145 1150 1155
          Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg
              1160 1165 1170
          Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln
              1175 1180 1185
          Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe
              1190 1195 1200
          Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
              1205 1210 1215
          Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu
              1220 1225 1230
          Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu
              1235 1240 1245
          Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys
              1250 1255 1260
          Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser
              1265 1270 1275
          Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys
              1280 1285 1290
          Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala
              1295 1300 1305
          Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys Cys
              1310 1315 1320
          Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe
              1325 1330 1335
          Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu His
              1340 1345 1350
          Tyr Thr
              1355
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 4247]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 39]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uuccugaucc ugcugaucag ccugcccacc gccuucgccg ugaucggcga ccugaagugc 120
          accagcgaca acaucaacga caaggacacc ggcccaccac ccaucagcac cgacaccgug 180
          gacgugacca acggccuggg caccuacuac gugcuggacc ggguguaccu gaacaccacc 240
          cuguuccuga acggcuacua ccccaccagc ggcagcaccu accggaauau ggcccugaag 300
          ggcagcgugc ugcugagccg gcugugguuc aagccaccau uccugagcga cuucaucaac 360
          ggaaucuucg ccaaggugaa gaacaccaag gugaucaagg accgggugau guacagcgag 420
          uuccccgcca ucaccauugg caguaccuuc gugaacacca gcuacagcgu gguggugcag 480
          ccccggacca ucaacagcac ccaggacggc gacaacaagc ugcagggccu gcuggaggug 540
          agcgugugcc aguacaacau gugcgaguac ccucagacca ucugccaccc caaccugggc 600
          aaccaccgga aggagcugug gcaccuggac accggcgugg ugagcugccu guacaagcgg 660
          aacuucaccu acgacguaaa cgccgacuac cuguacuucc acuucuacca ggagggcggc 720
          accuucuacg ccuacuucac cgacacgggc guggugacca aguuccuguu caacguguac 780
          cugggcaugg cccugagcca cuacuacgug augccccuga ccuguaacag caagcugacc 840
          cuggaguacu gggugacccc ucugaccagc cggcaguacc ugcuggccuu caaccaggac 900
          ggcaucaucu ucaacgccgu ggacugcgcc cuggacccuc ugagcgagac caagugcacc 960
          cugaagagcu ucaccgugga gaagggcauc uaccagacca acggcuacac cgugcagccc 1020
          aucgccgacg uguaccggcg gaagcccaac cugcccaacu gcaacaucga ggccuggcug 1080
          aacgacaaga gcgugcccuc gccccugaac ugggagcgga agaccuucag caacugcaac 1140
          uucaacauga gcagucugau gagcuucauc caggccgaca gcuucaccug caacaacauc 1200
          gacgccgcca agaucuacgg caugugcuuc agcagcauca ccaucgacaa guuugccauc 1260
          cccaacggcc ggaaggugga ccugcagcug ggcaaccugg gcuaccugca gagcuucaac 1320
          uaccggaucg acaccaccgc caccucuugc cagcuguacu acaaccugcc cgccgccaac 1380
          gugagcguga gccgguucaa ccccagcacc uggaacaagc gguucggcuu cauugaggac 1440
          agcguguuca aaccccggcc cgcaggagua cugaccaacc acgacguggu guacgcccag 1500
          cacugcuuca aggcacccaa gaacuucugc cccugcaagc ugaacggcag cugugugggc 1560
          ucuggccccg guaagaacaa cggcauaggg acuugcccgg cagggaccaa cuaccugacc 1620
          ugcgacaacc ugugcacacc cgaccccauc accuucaccg gcaccuacaa guguccccag 1680
          accaagagcc uggugggcau cggcgagcac ugcagcggcc uggccgugaa gagcgacuac 1740
          ugcggcggca acagcugcac cugucggccc caggccuucc ugggcuggag cgccgacagc 1800
          ugccugcagg gcgacaagug caacaucuuu gccaacuuca uccugcacga cgugaacagc 1860
          ggccugaccu gcagcaccga ccugcagaag gccaacaccg acaucauccu gggcgugugc 1920
          gugaacuacg acuuguacgg cauccugggc cagggcaucu ucguggaggu gaacgccacc 1980
          uacuacaaca gcuggcagaa ccugcuguac gacagcaacg gcaaccugua cggcuuccgg 2040
          gacuacauca ucaaccggac cuucaugauc cggagcugcu acagcggcgg cgugagcgug 2100
          aucaccccag gcaccaacac cagcaaccag guggccgugc uguaccagga cgugaacugc 2160
          accgaggugc ccguggccau ccacgccgac cagcugacac ccaccuggcg ggucuacagc 2220
          accggcagca acguguucca gacccgggcc gguugccuga ucggcgccga gcacgugaac 2280
          aacagcuacg agugcgacau ccccaucggc gccggcaucu gugccagcua ccagacccag 2340
          accaauucac cccggagggc aaggagcgug gccagccaga gcaucaucgc cuacaccaug 2400
          agccugggcg ccgagaacag cguggccuac agcaacaaca gcaucgccau ccccaccaac 2460
          uucaccauca gcgugaccac cgagauucug cccgugagca ugaccaagac cagcguggac 2520
          ugcaccaugu acaucugcgg cgacagcacc gagugcagca accugcugcu gcaguacggc 2580
          agcuucugca cccagcugaa ccgggcccug accggcaucg ccguggagca ggacaagaac 2640
          acccaggagg uguucgccca ggugaagcag aucuacaaga ccccucccau caaggacuuc 2700
          ggcggcuuca acuucagcca gauccugccc gaccccagca agcccagcaa gcggagcuuc 2760
          aucgaggacc ugcuguucaa caaggugacc cuagccgacg ccggcuucau caagcaguac 2820
          ggcgacugcc ucggcgacau agccgcccgg gaccugaucu gcgcccagaa guucaacggc 2880
          cugaccgugc ugccuccccu gcugaccgac gagaugaucg cccaguacac cagcgcccug 2940
          uuagccggaa ccaucaccag cggcuggacu uucggcgcug gagccgcucu gcagaucccc 3000
          uucgccaugc agauggccua ccgguucaac ggcaucggcg ugacccagaa cgugcuguac 3060
          gagaaccaga agcugaucgc caaccaguuc aacagcgcca ucggcaagau ccaggacagc 3120
          cugagcagca ccgcuagcgc ccugggcaag cugcaggacg uggugaacca gaacgcccag 3180
          gcccugaaca cccuggugaa gcagcugagc agcaacuucg gcgccaucag cagcgugcug 3240
          aacgacaucc ugagccggcu ggacccuccc gaggccgagg ugcagaucga ccggcugauc 3300
          acuggccggc ugcagagccu gcagaccuac gugacccagc agcugauccg ggccgccgag 3360
          auucgggcca gcgccaaccu ggccgccacc aagaugagcg agugcgugcu gggccagagc 3420
          aagcgggugg acuucugcgg caagggcuac caccugauga gcuuucccca gagcgcaccc 3480
          cacggagugg uguuccugca cgugaccuac gugcccgccc aggagaagaa cuucaccacc 3540
          gccccagcca ucugccacga cggcaaggcc cacuuucccc gggagggcgu guucgugagc 3600
          aacggcaccc acugguucgu gacccagcgg aacuucuacg agccccagau caucaccacc 3660
          gacaacaccu ucgugagcgg caacugcgac guggugaucg gcaucgugaa caacaccgug 3720
          uacgaucccc ugcagcccga gcuggacagc uucaaggagg agcuggacaa guacuucaag 3780
          aaucacacca gccccgacgu ggaccugggc gacaucagcg gcaucaacgc cagcguggug 3840
          aacauccaga aggagaucga ucggcugaac gagguggcca agaaccugaa cgagagccug 3900
          aucgaccugc aggagcuggg caaguacgag caguacauca aguggcccug guacaucugg 3960
          cugggcuuca ucgccggccu gaucgccauc gugaugguga ccaucaugcu gugcugcaug 4020
          accagcugcu gcagcugccu gaagggcugu ugcagcugcg gcagcugcug caaguucgac 4080
          gaggacgaca gcgagcccgu gcugaagggc gugaagcugc acuacaccug auaauaggcu 4140
          ggagccucgg uggccuagcu ucuugccccu ugggccuccc cccagccccu ccuccccuuc 4200
          cugcacccgu acccccgugg ucuuugaaua aagucugagu gggcggc 4247
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 4071]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 40]]>
          auguuccuga uccugcugau cagccugccc accgccuucg ccgugaucgg cgaccugaag 60
          ugcaccagcg acaacaucaa cgacaaggac accggcccac cacccaucag caccgacacc 120
          guggacguga ccaacggccu gggcaccuac uacgugcugg accgggugua ccugaacacc 180
          acccuguucc ugaacggcua cuaccccacc agcggcagca ccuaccggaa uauggcccug 240
          aagggcagcg ugcugcugag ccggcugugg uucaagccac cauuccugag cgacuucauc 300
          aacggaaucu ucgccaaggu gaagaacacc aagugauca aggaccgggu gauguacagc 360
          gaguuccccg ccaucaccau uggcaguacc uucgugaaca ccagcuacag cgugguggug 420
          cagccccgga ccaucaacag cacccaggac ggcgacaaca agcugcaggg ccugcuggag 480
          gugagcgugu gccaguacaa caugugcgag uacccucaga ccaucugcca ccccaaccug 540
          ggcaaccacc ggaaggagcu guggcaccug gacaccggcg uggugagcug ccuguacaag 600
          cggaacuuca ccuacgacgu aaacgccgac uaccuguacu uccacuucua ccaggagggc 660
          ggcaccuucu acgccuacuu caccgacacg ggcgugguga ccaaguuccu guucaacgug 720
          uaccugggca uggcccugag ccacuacuac gugaugcccc ugaccuguaa cagcaagcug 780
          acccuggagu acugggugac cccucugacc agccggcagu accugcuggc cuucaaccag 840
          gacggcauca ucuucaacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 900
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccaacggcua caccgugcag 960
          cccaucgccg acguguaccg gcggaagccc aaccugccca acugcaacau cgaggccugg 1020
          cugaacgaca agagcgugcc cucgccccug aacugggagc ggaagaccuu cagcaacugc 1080
          aacuucaaca ugagcagucu gaugagcuuc auccaggccg acagcuucac cugcaacaac 1140
          aucgacgccg ccaagaucua cggcaugugc uucagcagca ucaccaucga caaguuugcc 1200
          auccccaacg gccggaaggu ggaccugcag cugggcaacc ugggcuaccu gcagagcuuc 1260
          aacuaccgga ucgacaccac cgccaccucu ugccagcugu acuacaaccu gcccgccgcc 1320
          aacgugagcg ugagccgguu caaccccagc accuggaaca agcgguucgg cuucauugag 1380
          gacagcgugu ucaaaccccg gcccgcagga guacugacca accacgacgu gguguacgcc 1440
          cagcacugcu ucaaggcacc caagaacuuc ugccccugca agcugaacgg cagcugugug 1500
          ggcucuggcc ccgguaagaa caacggcaua gggacuugcc cggcagggac caacuaccug 1560
          accugcgaca accugugcac acccgacccc aucaccuuca ccggcaccua caaguguccc 1620
          cagaccaaga gccugguggg caucggcgag cacugcagcg gccuggccgu gaagagcgac 1680
          uacugcggcg gcaacagcug caccugucgg ccccaggccu uccugggcug gagcgccgac 1740
          agcugccugc agggcgacaa gugcaacauc uuugccaacu ucauccugca cgacgugaac 1800
          agcggccuga ccugcagcac cgaccugcag aaggccaaca ccgacaucau ccugggcgug 1860
          ugcgugaacu acgacuugua cggcauccug ggccagggca ucuucgugga ggugaacgcc 1920
          accuacuaca acagcuggca gaaccugcug uacgacagca acggcaaccu guacggcuuc 1980
          cgggacuaca ucaucaaccg gaccuucaug auccggagcu gcuacagcgg cggcgugagc 2040
          gugaucaccc caggcaccaa caccagcaac cagguggccg ugcuguacca ggacgugaac 2100
          ugcaccgagg ugcccguggc cauccacgcc gaccagcuga cacccaccug gcgggucuac 2160
          agcaccggca gcaacguguu ccagacccgg gccgguugcc ugaucggcgc cgagcacgug 2220
          aacaacagcu acgagugcga cauccccauc ggcgccggca ucugugccag cuaccagacc 2280
          cagaccaauu caccccggag ggcaaggagc guggccagcc agagcaucau cgccuacacc 2340
          augagccugg gcgccgagaa cagcguggcc uacagcaaca acagcaucgc cauccccacc 2400
          aacuucacca ucagcgugac caccgagauu cugcccgug gcaugaccaa gaccagcgug 2460
          gacugcacca uguacaucug cggcgacagc accgagugca gcaaccugcu gcugcaguac 2520
          ggcagcuucu gcacccagcu gaaccgggcc cugaccggca ucgccgugga gcaggacaag 2580
          aacacccagg agguguucgc ccaggugaag cagaucuaca agaccccucc caucaaggac 2640
          uucggcggcu ucaacuucag ccagauccug cccgacccca gcaagcccag caagcggagc 2700
          uucaucgagg accugcuguu caacaaggug acccuagccg acgccggcuu caucaagcag 2760
          uacggcgacu gccucggcga cauagccgcc cgggaccuga ucugcgccca gaaguucaac 2820
          ggccugaccg ugcugccucc ccugcugacc gacgagauga ucgcccagua caccagcgcc 2880
          cuguuagccg gaaccaucac cagcggcugg acuuucggcg cuggagccgc ucugcagauc 2940
          cccuucgcca ugcagauggc cuaccgguuc aacggcaucg gcgugaccca gaacgugcug 3000
          uacgagaacc agaagcugau cgccaaccag uucaacagcg ccaucggcaa gauccaggac 3060
          agccugagca gcaccgcuag cgcccugggc aagcugcagg acguggugaa ccagaacgcc 3120
          caggcccuga acacccuggu gaagcagcug agcagcaacu ucggcgccau cagcagcgug 3180
          cugaacgaca uccugagccg gcuggacccu cccgaggccg aggugcagau cgaccggcug 3240
          aucacuggcc ggcugcagag ccugcagacc uacgugaccc agcagcugau ccgggccgcc 3300
          gagauucggg ccagcgccaa ccuggccgcc accaagauga gcgagugcgu gcugggccag 3360
          agcaagcggg uggacuucug cggcaagggc uaccaccuga ugagcuuucc ccagagcgca 3420
          ccccacggag ugguguuccu gcacgugacc uacgugcccg cccaggagaa gaacuucacc 3480
          accgccccag ccaucugcca cgacggcaag gcccacuuuc cccgggaggg cguguucgug 3540
          agcaacggca cccacugguu cgugacccag cggaacuucu acgagcccca gaucaucacc 3600
          accgacaaca ccuucgugag cggcaacugc gacgugguga ucggcaucgu gaacaacacc 3660
          guguacgauc cccugcagcc cgagcuggac agcuucaagg aggagcugga caaguacuuc 3720
          aagaaucaca ccagccccga cguggaccug ggcgacauca gcggcaucaa cgccagcgug 3780
          gugaacaucc agaaggagau cgaucggcug aacgaggugg ccaagaaccu gaacgagagc 3840
          cugaucgacc ugcaggagcu gggcaaguac gagcaguaca ucaaguggcc cugguacauc 3900
          uggcugggcu ucaucgccgg ccugaucgcc aucgugaugg ugaccaucau gcugugcugc 3960
          augaccagcu gcugcagcug ccugaagggc uguugcagcu gcggcagcug cugcaaguuc 4020
          gacgaggacg acagcgagcc cgugcugaag ggcgugaagc ugcacuacac c 4071
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 1357]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 41]]>
          Met Phe Leu Ile Leu Leu Ile Ser Leu Pro Thr Ala Phe Ala Val Ile
          1 5 10 15
          Gly Asp Leu Lys Cys Thr Ser Asp Asn Ile Asn Asp Lys Asp Thr Gly
                      20 25 30
          Pro Pro Pro Ile Ser Thr Asp Thr Val Asp Val Thr Asn Gly Leu Gly
                  35 40 45
          Thr Tyr Tyr Val Leu Asp Arg Val Tyr Leu Asn Thr Thr Leu Phe Leu
              50 55 60
          Asn Gly Tyr Tyr Pro Thr Ser Gly Ser Thr Tyr Arg Asn Met Ala Leu
          65 70 75 80
          Lys Gly Ser Val Leu Leu Ser Arg Leu Trp Phe Lys Pro Pro Phe Leu
                          85 90 95
          Ser Asp Phe Ile Asn Gly Ile Phe Ala Lys Val Lys Asn Thr Lys Val
                      100 105 110
          Ile Lys Asp Arg Val Met Tyr Ser Glu Phe Pro Ala Ile Thr Ile Gly
                  115 120 125
          Ser Thr Phe Val Asn Thr Ser Tyr Ser Val Val Val Gln Pro Arg Thr
              130 135 140
          Ile Asn Ser Thr Gln Asp Gly Asp Asn Lys Leu Gln Gly Leu Leu Glu
          145 150 155 160
          Val Ser Val Cys Gln Tyr Asn Met Cys Glu Tyr Pro Gln Thr Ile Cys
                          165 170 175
          His Pro Asn Leu Gly Asn His Arg Lys Glu Leu Trp His Leu Asp Thr
                      180 185 190
          Gly Val Val Ser Cys Leu Tyr Lys Arg Asn Phe Thr Tyr Asp Val Asn
                  195 200 205
          Ala Asp Tyr Leu Tyr Phe His Phe Tyr Gln Glu Gly Gly Thr Phe Tyr
              210 215 220
          Ala Tyr Phe Thr Asp Thr Gly Val Val Thr Lys Phe Leu Phe Asn Val
          225 230 235 240
          Tyr Leu Gly Met Ala Leu Ser His Tyr Tyr Val Met Pro Leu Thr Cys
                          245 250 255
          Asn Ser Lys Leu Thr Leu Glu Tyr Trp Val Thr Pro Leu Thr Ser Arg
                      260 265 270
          Gln Tyr Leu Leu Ala Phe Asn Gln Asp Gly Ile Ile Phe Asn Ala Val
                  275 280 285
          Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser
              290 295 300
          Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Asn Gly Tyr Thr Val Gln
          305 310 315 320
          Pro Ile Ala Asp Val Tyr Arg Arg Lys Pro Asn Leu Pro Asn Cys Asn
                          325 330 335
          Ile Glu Ala Trp Leu Asn Asp Lys Ser Val Pro Ser Pro Leu Asn Trp
                      340 345 350
          Glu Arg Lys Thr Phe Ser Asn Cys Asn Phe Asn Met Ser Ser Leu Met
                  355 360 365
          Ser Phe Ile Gln Ala Asp Ser Phe Thr Cys Asn Asn Ile Asp Ala Ala
              370 375 380
          Lys Ile Tyr Gly Met Cys Phe Ser Ser Ile Thr Ile Asp Lys Phe Ala
          385 390 395 400
          Ile Pro Asn Gly Arg Lys Val Asp Leu Gln Leu Gly Asn Leu Gly Tyr
                          405 410 415
          Leu Gln Ser Phe Asn Tyr Arg Ile Asp Thr Thr Ala Thr Ser Cys Gln
                      420 425 430
          Leu Tyr Tyr Asn Leu Pro Ala Ala Asn Val Ser Val Ser Arg Phe Asn
                  435 440 445
          Pro Ser Thr Trp Asn Lys Arg Phe Gly Phe Ile Glu Asp Ser Val Phe
              450 455 460
          Lys Pro Arg Pro Ala Gly Val Leu Thr Asn His Asp Val Val Tyr Ala
          465 470 475 480
          Gln His Cys Phe Lys Ala Pro Lys Asn Phe Cys Pro Cys Lys Leu Asn
                          485 490 495
          Gly Ser Cys Val Gly Ser Gly Pro Gly Lys Asn Asn Gly Ile Gly Thr
                      500 505 510
          Cys Pro Ala Gly Thr Asn Tyr Leu Thr Cys Asp Asn Leu Cys Thr Pro
                  515 520 525
          Asp Pro Ile Thr Phe Thr Gly Thr Tyr Lys Cys Pro Gln Thr Lys Ser
              530 535 540
          Leu Val Gly Ile Gly Glu His Cys Ser Gly Leu Ala Val Lys Ser Asp
          545 550 555 560
          Tyr Cys Gly Gly Asn Ser Cys Thr Cys Arg Pro Gln Ala Phe Leu Gly
                          565 570 575
          Trp Ser Ala Asp Ser Cys Leu Gln Gly Asp Lys Cys Asn Ile Phe Ala
                      580 585 590
          Asn Phe Ile Leu His Asp Val Asn Ser Gly Leu Thr Cys Ser Thr Asp
                  595 600 605
          Leu Gln Lys Ala Asn Thr Asp Ile Ile Leu Gly Val Cys Val Asn Tyr
              610 615 620
          Asp Leu Tyr Gly Ile Leu Gly Gln Gly Ile Phe Val Glu Val Asn Ala
          625 630 635 640
          Thr Tyr Tyr Asn Ser Trp Gln Asn Leu Leu Tyr Asp Ser Asn Gly Asn
                          645 650 655
          Leu Tyr Gly Phe Arg Asp Tyr Ile Ile Asn Arg Thr Phe Met Ile Arg
                      660 665 670
          Ser Cys Tyr Ser Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr
                  675 680 685
          Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val
              690 695 700
          Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr
          705 710 715 720
          Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly
                          725 730 735
          Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala
                      740 745 750
          Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala
                  755 760 765
          Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly
              770 775 780
          Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr
          785 790 795 800
          Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr
                          805 810 815
          Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu
                      820 825 830
          Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn
                  835 840 845
          Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu
              850 855 860
          Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp
          865 870 875 880
          Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro
                          885 890 895
          Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu
                      900 905 910
          Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile
                  915 920 925
          Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val
              930 935 940
          Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala
          945 950 955 960
          Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala
                          965 970 975
          Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly
                      980 985 990
          Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala
                  995 1000 1005
          Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser
              1010 1015 1020
          Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln
              1025 1030 1035
          Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn
              1040 1045 1050
          Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu
              1055 1060 1065
          Asp Pro Pro Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly
              1070 1075 1080
          Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg
              1085 1090 1095
          Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met
              1100 1105 1110
          Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly
              1115 1120 1125
          Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly
              1130 1135 1140
          Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn
              1145 1150 1155
          Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe
              1160 1165 1170
          Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
              1175 1180 1185
          Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn
              1190 1195 1200
          Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn
              1205 1210 1215
          Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys
              1220 1225 1230
          Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val
              1235 1240 1245
          Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile
              1250 1255 1260
          Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn
              1265 1270 1275
          Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr
              1280 1285 1290
          Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu
              1295 1300 1305
          Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser
              1310 1315 1320
          Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys
              1325 1330 1335
          Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys
              1340 1345 1350
          Leu His Tyr Thr
              1355
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 1157]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 42]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuucuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacucu ggcggaggcg gcagcgccau cggcggcuac 960
          auccccgagg ccccuagaga cggccaggcc uacgugcgga aggacggcga gugggugcug 1020
          cugagcaccu uccugggcug auaauaggcu ggagccucgg uggccuagcu ucuugccccu 1080
          ugggccuccc cccagccccu ccuccccuuc cugcacccgu acccccgugg ucuuugaaua 1140
          aagucugagu gggcggc 1157
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 981]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 43]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ucuggcggag gcggcagcgc caucggcggc 900
          uacauccccg aggccccuag agacggccag gccuacgugc ggaaggacgg cgagugggug 960
          cugcugagca ccuuccuggg c 981
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 327]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 44]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Ser Gly Gly Gly Gly Ser Ala Ile Gly Gly Tyr Ile Pro Glu
              290 295 300
          Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val
          305 310 315 320
          Leu Leu Ser Thr Phe Leu Gly
                          325
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 1130]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 45]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuucuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacucu ggcggaggca gcauccuggc caucuacagc 960
          accguggcca gcagccuggu gcugcuggug agccugggcg ccaucagcuu cugauaauag 1020
          gcuggagccu cgguggccua gcuucuugcc ccuugggccu ccccccagcc ccuccucccc 1080
          uuccugcacc cguacccccg uggucuuuga auaaagucug agugggcggc 1130
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 954]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 46]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ucuggcggag gcagcauccu ggccaucuac 900
          agcaccgugg ccagcagccu ggugcugcug gugagccugg gcgccaucag cuuc 954
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 318]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 47]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala
              290 295 300
          Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
          305 310 315
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 1238]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 48]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacucu ggcggaggca gcauccuggc caucuacagc 960
          accguggcca gcagccuggu gcugcuggug agccugggcg ccaucagcuu cggcggaggc 1020
          agcgccaucg gcggcuacau ccccgaggcc ccuagagacg gccaggccua cgugcggaag 1080
          gacggcgagu gggugcugcu gagcaccuuc cugggcaagu gauaauaggc uggagccucg 1140
          guggccuagc uucuugcccc uugggccucc ccccagcccc uccuccccuu ccugcacccg 1200
          uacccccgug gucuuugaau aaagucugag ugggcggc 1238
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 1062]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 49]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ucuggcggag gcagcauccu ggccaucuac 900
          agcaccgugg ccagcagccu ggugcugcug gugagccugg gcgccaucag cuucggcgga 960
          ggcagcgcca ucggcggcua cauccccgag gccccuagag acggccaggc cuacgugcgg 1020
          aaggacggcg agugggugcu gcugagcacc uuccugggca ag 1062
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 354]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 50]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala
              290 295 300
          Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Gly Gly
          305 310 315 320
          Gly Ser Ala Ile Gly Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln
                          325 330 335
          Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
                      340 345 350
          Gly Lys
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 1130]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 51]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          gugugccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacucu ggcggaggca gcauccuggc caucuacagc 960
          accguggcca gcagccuggu gcugcuggug agccugggcg ccaucagcuu cugauaauag 1020
          gcuggagccu cgguggccua gcuucuugcc ccuugggccu ccccccagcc ccuccucccc 1080
          uuccugcacc cguacccccg uggucuuuga auaaagucug agugggcggc 1130
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 954]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 52]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aaggugugcc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ucuggcggag gcagcauccu ggccaucuac 900
          agcaccgugg ccagcagccu ggugcugcug gugagccugg gcgccaucag cuuc 954
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 318]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 53]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Cys Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala
              290 295 300
          Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
          305 310 315
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 1181]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 54]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          gugugccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccuc uggcggaggc agcauccugg ccaucuacag caccguggcc 1020
          agcagccugg ugcugcuggu gagccugggc gccaucagcu ucugauaaua ggcuggagcc 1080
          ucgguggccu agcuucuugc cccuugggcc uccccccagc cccuccuccc cuuccugcac 1140
          ccguaccccc guggucuuug aauaaagucu gagugggcgg c 1181
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 1005]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 55]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aaggugugcc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cucuggcgga ggcagcaucc uggccaucua cagcaccgug 960
          gccagcagcc uggugcugcu ggugagccug ggcgccauca gcuuc 1005
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 335]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 56]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Cys Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val
          305 310 315 320
          Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
                          325 330 335
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 1181]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 57]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccuc uggcggaggc agcauccugg ccaucuacag caccguggcc 1020
          agcagccugg ugcugcuggu gagccugggc gccaucagcu ucugauaaua ggcuggagcc 1080
          ucgguggccu agcuucuugc cccuugggcc uccccccagc cccuccuccc cuuccugcac 1140
          ccguaccccc guggucuuug aauaaagucu gagugggcgg c 1181
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 1005]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 58]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cucuggcgga ggcagcaucc uggccaucua cagcaccgug 960
          gccagcagcc uggugcugcu ggugagccug ggcgccauca gcuuc 1005
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 335]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 59]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val
          305 310 315 320
          Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
                          325 330 335
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 836]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 60]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaaguga 720
          uaauaggcug gagccucggu ggccuagcuu cuugccccuu gggccuccccc ccagccccuc 780
          cuccccuucc ugcacccgua cccccguggu cuuugaauaa agucugagug ggcggc 836
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 660]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 61]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 62]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
              210 215 220
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 1349]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 63]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaaggga 720
          ggaggcagcg gcggcgauau caucaagcuu cugaacgagc aaguuaacaa ggaaaugcag 780
          agcaguaauc ucuacaugag caugagcagc uggugcuaca cccacucccu ggacggagca 840
          ggccucuucc uguucgacca cgcagccgag gaguacgagc acgcuaagaa guugaucauu 900
          uucuugaacg agaacaacgu gcccgugcag cuaacgucaa ucagcgcacc ugagcacaag 960
          uucgagggcc ugacccagau cuuccagaag gccuacgaac acgaacagca caucuccgag 1020
          agcaucaaca auauugugga ucacgcuauc aaguccaagg accacgcuac cuucaacuuc 1080
          cugcaguggu acguggccga gcaacaugag gaggaggugc uguucaagga cauccuggac 1140
          aagaucgagc ugaucgguaa ugagaaucac ggccuguacc uggccgacca guacgugaag 1200
          ggcaucgcca agagccggaa gucaggcuca ugauaauagg cuggagccuc gguggccuag 1260
          cuucuugccc cuugggccuc cccccagccc cuccuccccu uccugcaccc guacccccgu 1320
          ggucuuugaa uaaagucuga gugggcggc 1349
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 1173]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 64]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ggaggaggca gcggcggcga uaucaucaag cuucugaacg agcaaguuaa caaggaaaug 720
          cagagcagua aucucuacau gagcaugagc agcuggugcu acacccacuc ccuggacgga 780
          gcaggccucu uccuguucga ccacgcagcc gaggaguacg agcacgcuaa gaaguugauc 840
          auuuucuuga acgagaacaa cgugcccgug cagcuaacgu caaucagcgc accugagcac 900
          aaguucgagg gccugaccca gaucuuccag aaggccuacg aacacgaaca gcacaucucc 960
          gagagcauca acaauauugu ggaucacgcu aucaagucca aggaccacgc uaccuucaac 1020
          uuccugcagu gguacguggc cgagcaacau gaggaggagg ugcuguucaa ggacauccug 1080
          gacaagaucg agcugaucgg uaaugagaau cacggccugu accuggccga ccaguacgug 1140
          aagggcaucg ccaagagccg gaaguccaggc uca 1173
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 391]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 65]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Gly Gly Gly Ser
              210 215 220
          Gly Gly Asp Ile Ile Lys Leu Leu Asn Glu Gln Val Asn Lys Glu Met
          225 230 235 240
          Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Cys Tyr Thr His
                          245 250 255
          Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala Glu Glu
                      260 265 270
          Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn Asn Val
                  275 280 285
          Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe Glu Gly
              290 295 300
          Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His Ile Ser
          305 310 315 320
          Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Ser Lys Asp His
                          325 330 335
          Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His Glu Glu
                      340 345 350
          Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile Gly Asn
                  355 360 365
          Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly Ile Ala
              370 375 380
          Lys Ser Arg Lys Ser Gly Ser
          385 390
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 1376]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 66]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          ggcauccugc ccagcccugg caugcccgcu cugcugagcc uggugagccu gcugagcgug 120
          cugcugaugg gcugcguggc ugagaccggc augcagaucu acgagggcaa gcugaccgca 180
          gagggccugc gguucggcau cguggccagc cgcgccaacc acgcucuggu ggaccggcuu 240
          guggagggcg cuaucgacgc caucgugaga cacggcggcc gggaagagga caucacccug 300
          gugcgggugu gcggcagcug ggagauuccc gucgccgccg gagaacuggc ccggaaggag 360
          gacaucgacg ccgugaucgc caucggcgug cugugcagag gcgccacgcc cagcuucgac 420
          uacaucgcca gcgaggugag caagggccug gccgaccuga gccuggagcu gcggaagccc 480
          aucaccuucg gcgugaucac cgccgacacc cuggagcagg ccaucgaggc cgcaggcacc 540
          ugccacggca acaagggcug ggaagccgcc cugugcgcca ucgagauggc caaccuguuc 600
          aagagccugc ggggcggaag uggaggcucu gguggcagcg gaggaucugg cggcggccag 660
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 720
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 780
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 840
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 900
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 960
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 1020
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 1080
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 1140
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 1200
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaaguga 1260
          uaauaggcug gagccucggu ggccuagcuu cuugccccuu gggccucccc ccagccccuc 1320
          cuccccuucc ugcacccgua cccccguggu cuuugaauaa agucugagug ggcggc 1376
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 1200]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 67]]>
          augggcaucc ugcccagccc uggcaugccc gcucugcuga gccuggugag ccugcugagc 60
          gugcugcuga ugggcugcgu ggcugagacc ggcaugcaga ucuacgaggg caagcugacc 120
          gcagagggcc ugcgguucgg caucguggcc agccgcgcca accacgcucu gguggaccgg 180
          cuuguggagg gcgcuaucga cgccaucgug agacacggcg gccgggaaga ggacaucacc 240
          cuggugcggg ugugcggcag cugggagauu cccgucgccg ccggagaacu ggcccggaag 300
          gaggacaucg acgccgugau cgccaucggc gugcugugca gaggcgccac gcccagcuuc 360
          gacuacaucg ccagcgaggu gagcaagggc cuggccgacc ugagccugga gcugcggaag 420
          cccaucaccu ucggcgugau caccgccgac acccuggagc aggccaucga ggccgcaggc 480
          accugccacg gcaacaaggg cugggaagcc gcccugugcg ccaucgagau ggccaaccug 540
          uucaagagcc ugcggggcgg aaguggaggc ucugguggca gcggaggauc uggcggcggc 600
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 660
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 720
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 780
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 840
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 900
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 960
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 1020
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 1080
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 1140
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 1200
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 400]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 68]]>
          Met Gly Ile Leu Pro Ser Pro Gly Met Pro Ala Leu Leu Ser Leu Val
          1 5 10 15
          Ser Leu Leu Ser Val Leu Leu Met Gly Cys Val Ala Glu Thr Gly Met
                      20 25 30
          Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile
                  35 40 45
          Val Ala Ser Arg Ala Asn His Ala Leu Val Asp Arg Leu Val Glu Gly
              50 55 60
          Ala Ile Asp Ala Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr
          65 70 75 80
          Leu Val Arg Val Cys Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu
                          85 90 95
          Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu
                      100 105 110
          Cys Arg Gly Ala Thr Pro Ser Phe Asp Tyr Ile Ala Ser Glu Val Ser
                  115 120 125
          Lys Gly Leu Ala Asp Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe
              130 135 140
          Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Ala Ala Gly
          145 150 155 160
          Thr Cys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Cys Ala Ile Glu
                          165 170 175
          Met Ala Asn Leu Phe Lys Ser Leu Arg Gly Gly Ser Gly Gly Ser Gly
                      180 185 190
          Gly Ser Gly Gly Ser Gly Gly Gly Gln Pro Asn Ile Thr Asn Leu Cys
                  195 200 205
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
              210 215 220
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
          225 230 235 240
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                          245 250 255
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                      260 265 270
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                  275 280 285
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
              290 295 300
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
          305 310 315 320
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                          325 330 335
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                      340 345 350
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                  355 360 365
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
              370 375 380
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
          385 390 395 400
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 1334]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 69]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaaggga 720
          ggaggcuccg gaggcgguag cgcugagacc ggcaugcaga ucuacgaggg caagcugacc 780
          gcagagggcc ugcgguucgg caucguggcc agccgcgcca accacgcucu gguggaccgg 840
          cuuguggagg gcgcuaucga cgccaucgug agacacggcg gccgggaaga ggacaucacc 900
          cuggugcggg ugugcggcag cugggagauu cccgucgccg ccggagaacu ggcccggaag 960
          gaggacaucg acgccgugau cgccaucggc gugcugugca gaggcgccac gcccagcuuc 1020
          gacuacaucg ccagcgaggu gagcaagggc cuggccgacc ugagccugga gcugcggaag 1080
          cccaucaccu ucggcgugau caccgccgac acccuggagc aggccaucga ggccgcaggc 1140
          accugccacg gcaacaaggg cugggaagcc gcccugugcg ccaucgagau ggccaaccug 1200
          uucaagagcc ugcggugaua auaggcugga gccucggugg ccuagcuucu ugccccuugg 1260
          gccuccicccc agccccuccu ccccuuccug cacccguacc cccguggucu uugaauaaag 1320
          ucugaguggg cggc 1334
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 1158]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 70]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ggaggaggcu ccggaggcgg uagcgcugag accggcaugc agaucuacga gggcaagcug 720
          accgcagagg gccugcgguu cggcaucgug gccagccgcg ccaaccacgc ucugguggac 780
          cggcuugugg agggcgcuau cgacgccauc gugagacacg gcggccggga agaggacauc 840
          acccuggugc gggugugcgg cagcugggag auucccgucg ccgccggaga acuggcccgg 900
          aaggaggaca ucgacgccgu gaucgccauc ggcgugcugu gcagaggcgc cacgcccagc 960
          uucgacuaca ucgccagcga ggugagcaag ggccuggccg accugagccu ggagcugcgg 1020
          aagcccauca ccuucggcgu gaucaccgcc gacacccugg agcaggccau cgaggccgca 1080
          ggcaccugcc acggcaacaa gggcugggaa gccgcccugu gcgccaucga gauggccaac 1140
          cuguucaaga gccugcgg 1158
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 386]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 71]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Gly Gly Gly Ser
              210 215 220
          Gly Gly Gly Ser Ala Glu Thr Gly Met Gln Ile Tyr Glu Gly Lys Leu
          225 230 235 240
          Thr Ala Glu Gly Leu Arg Phe Gly Ile Val Ala Ser Arg Ala Asn His
                          245 250 255
          Ala Leu Val Asp Arg Leu Val Glu Gly Ala Ile Asp Ala Ile Val Arg
                      260 265 270
          His Gly Gly Arg Glu Glu Asp Ile Thr Leu Val Arg Val Cys Gly Ser
                  275 280 285
          Trp Glu Ile Pro Val Ala Ala Gly Glu Leu Ala Arg Lys Glu Asp Ile
              290 295 300
          Asp Ala Val Ile Ala Ile Gly Val Leu Cys Arg Gly Ala Thr Pro Ser
          305 310 315 320
          Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys Gly Leu Ala Asp Leu Ser
                          325 330 335
          Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly Val Ile Thr Ala Asp Thr
                      340 345 350
          Leu Glu Gln Ala Ile Glu Ala Ala Gly Thr Cys His Gly Asn Lys Gly
                  355 360 365
          Trp Glu Ala Ala Leu Cys Ala Ile Glu Met Ala Asn Leu Phe Lys Ser
              370 375 380
          Leu Arg
          385
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 947]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 72]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaagucu 720
          ggcggaggcg gcagcgccau cggcggcuac auccccgagg ccccuagaga cggccaggcc 780
          uacgugcgga aggacggcga gugggugcug cugagcaccu uccugggcug auaauaggcu 840
          ggagccucgg uggccuagcu ucuugccccu ugggccuccc cccagccccu ccuccccuuc 900
          cugcacccgu acccccgugg ucuuugaaua aagucugagu gggcggc 947
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 771]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 73]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ucuggcggag gcggcagcgc caucggcggc uacauccccg aggccccuag agacggccag 720
          gccuacgugc ggaaggacgg cgagugggug cugcugagca ccuuccuggg c 771
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 257]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 74]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Ser Gly Gly Gly
              210 215 220
          Gly Ser Ala Ile Gly Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln
          225 230 235 240
          Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
                          245 250 255
          Gly
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 920]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 75]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaagucu 720
          ggcggaggca gcauccuggc caucuacagc accguggcca gcagccuggu gcugcuggug 780
          agccugggcg ccaucagcuu cugauaauag gcuggagccu cgguggccua gcuucuugcc 840
          ccuugggccu ccccccagcc ccuccucccc uuccugcacc cguacccccg uggucuuuga 900
          auaaagucug agugggcggc 920
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 744]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 76]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ucuggcggag gcagcauccu ggccaucuac agcaccgugg ccagcagccu ggugcugcug 720
          gugagccugg gcgccaucag cuuc 744
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 248]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 77]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Ser Gly Gly Gly
              210 215 220
          Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
          225 230 235 240
          Val Ser Leu Gly Ala Ile Ser Phe
                          245
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 1025]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 78]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaagucu 720
          ggcggaggcg gcagcgccau cggcggcuac auccccgagg ccccuagaga cggccaggcc 780
          uacgugcgga aggacggcga gugggugcug cugagcaccu uccugggcgg aggcagcauc 840
          cuggccaucu acagcaccgu ggccagcagc cuggugcugc uggugagccu gggcgccauc 900
          agcuucugau aauaggcugg agccucggug gccuagcuuc uugccccuug ggccuccccc 960
          cagccccuccc uccccuuccu gcacccguac ccccgugguc uuugaauaaa gucugagugg 1020
          gcggc 1025
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 849]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 79]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ucuggcggag gcggcagcgc caucggcggc uacauccccg aggccccuag agacggccag 720
          gccuacgugc ggaaggacgg cgagugggug cugcugagca ccuuccuggg cggaggcagc 780
          auccuggcca ucuacagcac cguggccagc agccuggugc ugcuggugag ccugggcgcc 840
          aucagcuuc 849
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 283]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 80]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Ser Gly Gly Gly
              210 215 220
          Gly Ser Ala Ile Gly Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln
          225 230 235 240
          Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
                          245 250 255
          Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu
                      260 265 270
          Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
                  275 280
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 1028]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 81]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaagucu 720
          ggcggaggca gcauccuggc caucuacagc accguggcca gcagccuggu gcugcuggug 780
          agccugggcg ccaucagcuu cggcggaggc agcgccaucg gcggcuacau ccccgaggcc 840
          ccuagagacg gccaggccua cgugcggaag gacggcgagu gggugcugcu gagcaccuuc 900
          cugggcaagu gauaauaggc uggagccucg guggccuagc uucuugcccc uugggccucc 960
          ccccagcccc uccuccccuu ccugcacccg uacccccgug gucuuugaau aaagucugag 1020
          ugggcggc 1028
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 852]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 82]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ucuggcggag gcagcauccu ggccaucuac agcaccgugg ccagcagccu ggugcugcug 720
          gugagccugg gcgccaucag cuucggcgga ggcagcgcca ucggcggcua cauccccgag 780
          gccccuagag acggccaggc cuacgugcgg aaggacggcg agugggugcu gcugagcacc 840
          uuccugggca ag 852
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 284]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 83]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Ser Gly Gly Gly
              210 215 220
          Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
          225 230 235 240
          Val Ser Leu Gly Ala Ile Ser Phe Gly Gly Gly Ser Ala Ile Gly Gly
                          245 250 255
          Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp
                      260 265 270
          Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly Lys
                  275 280
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 1142]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 84]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cgggugcagc ccaccgagag caucgugcgg uuccccaaca ucaccaaccu gugccccuuc 180
          ggcgaggugu ucaacgccac ccgguucgcc agcguguacg ccuggaaccg gaagcggauc 240
          agcaacugcg uggccgacua cagcgugcug uacaacagcg ccagcuucag caccuucaag 300
          ugcuacggcg ugagccccac caagcugaac gaccugugcu ucaccaacgu guacgccgac 360
          agcuucguga uccguggcga cgaggugcgg cagaucgcac ccggccagac aggcaagauc 420
          gccgacuaca acuacaagcu gcccgacgac uucaccggcu gcgugaucgc cuggaacagc 480
          aacaaccucg acagcaaggu gggcggcaac uacaacuacc uguaccggcu guuccggaag 540
          agcaaccuga agcccuucga gcgggacauc agcaccgaga ucuaccaagc cggcuccacc 600
          ccuugcaacg gcguggaggg cuucaacugc uacuucccuc ugcagagcua cggcuuccag 660
          cccaccaacg gcgugggcua ccagcccuac cggguggugg ugcugagcuu cgagcugcug 720
          cacgccccag ccaccgugug uggccccaag aagagcacca accuggugaa gaacaagugc 780
          gugaacuuca acuucaacgg ccuuaccggc accggcgugc ugaccgagag caacaagaaa 840
          uuccugcccu uucagcaguu cggccgggac aucgccgaca ccaccgacgc ugugcgggau 900
          ccccagaccc uggagauccu ggacaucacc ccuugcagcu cuggcggagg cagcauccug 960
          gccaucuaca gcaccguggc cagcagccug gugcugcugg ugagccuggg cgccaucagc 1020
          uucugauaau aggcuggagc cucgguggcc uagcuucuug ccccuugggc cuccccccag 1080
          ccccuccucc ccuuccugca cccguacccc cguggucuuu gaauaaaguc ugagugggcg 1140
          gc 1142
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 966]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 85]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcgggugc agcccaccga gagcaucgug cgguucccca acaucaccaa ccugugcccc 120
          uucggcgagg uguucaacgc cacccgguuc gccagcgugu acgccuggaa ccggaagcgg 180
          aucagcaacu gcguggccga cuacagcgug cuguacaaca gcgccagcuu cagcaccuuc 240
          aagugcuacg gcgugagccc caccaagcug aacgaccugu gcuucaccaa cguguacgcc 300
          gacagcuucg ugauccgugg cgacgaggug cggcagaucg cacccggcca gacaggcaag 360
          aucgccgacu acaacuacaa gcugcccgac gacuucaccg gcugcgugau cgccuggaac 420
          agcaacaacc ucgacagcaa ggugggcggc aacuacaacu accuguaccg gcuguuccgg 480
          aagagcaacc ugaagcccuu cgagcgggac aucagcaccg agaucuacca agccggcucc 540
          accccuugca acggcgugga gggcuucaac ugcuacuucc cucugcagag cuacggcuuc 600
          cagcccacca acggcguggg cuaccagccc uaccgggugg uggugcugag cuucgagcug 660
          cugcacgccc cagccaccgu guguggcccc aagaagagca ccaaccuggu gaagaacaag 720
          ugcgugaacu ucaacuucaa cggccuuacc ggcaccggcg ugcugaccga gagcaacaag 780
          aaauuccugc ccuuucagca guucggccgg gacaucgccg acaccaccga cgcugugcgg 840
          gauccccaga cccuggagau ccuggacauc accccuugca gcucuggcgg aggcagcauc 900
          cuggccaucu acagcaccgu ggccagcagc cuggugcugc uggugagccu gggcgccauc 960
          agcuuc 966
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 86]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe
                      20 25 30
          Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr
                  35 40 45
          Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys
              50 55 60
          Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe
          65 70 75 80
          Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr
                          85 90 95
          Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln
                      100 105 110
          Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu
                  115 120 125
          Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu
              130 135 140
          Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg
          145 150 155 160
          Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr
                          165 170 175
          Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr
                      180 185 190
          Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr
                  195 200 205
          Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro
              210 215 220
          Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys
          225 230 235 240
          Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr
                          245 250 255
          Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile
                      260 265 270
          Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu
                  275 280 285
          Asp Ile Thr Pro Cys Ser Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr
              290 295 300
          Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile
          305 310 315 320
          Ser Phe
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 1142]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 87]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cgggugcagc ccaccgagag caucgugcgg uuccccaaca ucaccaaccu gugccccuuc 180
          ggcgaggugu ucaacgccac ccgguucgcc agcguguacg ccuggaaccg gaagcggauc 240
          agcaacugcg uggccgacua cagcgugcug uacaacagcg ccagcuucag caccuucaag 300
          ugcuacggcg ugagccccac caagcugaac gaccugugcu ucaccaacgu guacgccgac 360
          agcuucguga uccguggcga cgaggugcgg cagaucgcac ccggccagac aggcaagauc 420
          gccgacuaca acuacaagcu gcccgacgac uucaccggcu gcgugaucgc cuggaacagc 480
          aacaaccucg acagcaaggu gggcggcaac uacaacuacc uguaccggcu guuccggaag 540
          agcaaccuga agcccuucga gcgggacauc agcaccgaga ucuaccaagc cggcuccacc 600
          ccuugcaacg gcguggaggg cuucaacugc uacuucccuc ugcagagcua cggcuuccag 660
          cccaccaacg gcgugggcua ccagcccuac cggguggugg ugcugagcuu cgagcugcug 720
          cacgccccag ccaccgugug uggccccaag aagagcacca accuggugaa gaacaagugc 780
          gugaacuuca acuucaacgg ccuuaccggc accggcgugc ugaccgagag caacaagaaa 840
          uuccugcccu uuugccaguu cggccgggac aucgccgaca ccaccgacgc ugugcgggau 900
          ccccagaccc uggagauccu ggacaucacc ccuugcagcu cuggcggagg cagcauccug 960
          gccaucuaca gcaccguggc cagcagccug gugcugcugg ugagccuggg cgccaucagc 1020
          uucugauaau aggcuggagc cucgguggcc uagcuucuug ccccuugggc cuccccccag 1080
          ccccuccucc ccuuccugca cccguacccc cguggucuuu gaauaaaguc ugagugggcg 1140
          gc 1142
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 966]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 88]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcgggugc agcccaccga gagcaucgug cgguucccca acaucaccaa ccugugcccc 120
          uucggcgagg uguucaacgc cacccgguuc gccagcgugu acgccuggaa ccggaagcgg 180
          aucagcaacu gcguggccga cuacagcgug cuguacaaca gcgccagcuu cagcaccuuc 240
          aagugcuacg gcgugagccc caccaagcug aacgaccugu gcuucaccaa cguguacgcc 300
          gacagcuucg ugauccgugg cgacgaggug cggcagaucg cacccggcca gacaggcaag 360
          aucgccgacu acaacuacaa gcugcccgac gacuucaccg gcugcgugau cgccuggaac 420
          agcaacaacc ucgacagcaa ggugggcggc aacuacaacu accuguaccg gcuguuccgg 480
          aagagcaacc ugaagcccuu cgagcgggac aucagcaccg agaucuacca agccggcucc 540
          accccuugca acggcgugga gggcuucaac ugcuacuucc cucugcagag cuacggcuuc 600
          cagcccacca acggcguggg cuaccagccc uaccgggugg uggugcugag cuucgagcug 660
          cugcacgccc cagccaccgu guguggcccc aagaagagca ccaaccuggu gaagaacaag 720
          ugcgugaacu ucaacuucaa cggccuuacc ggcaccggcg ugcugaccga gagcaacaag 780
          aaauuccugc ccuuuugcca guucggccgg gacaucgccg acaccaccga cgcugugcgg 840
          gauccccaga cccuggagau ccuggacauc accccuugca gcucuggcgg aggcagcauc 900
          cuggccaucu acagcaccgu ggccagcagc cuggugcugc uggugagccu gggcgccauc 960
          agcuuc 966
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 89]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe
                      20 25 30
          Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr
                  35 40 45
          Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys
              50 55 60
          Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe
          65 70 75 80
          Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr
                          85 90 95
          Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln
                      100 105 110
          Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu
                  115 120 125
          Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu
              130 135 140
          Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg
          145 150 155 160
          Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr
                          165 170 175
          Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr
                      180 185 190
          Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr
                  195 200 205
          Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro
              210 215 220
          Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys
          225 230 235 240
          Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr
                          245 250 255
          Glu Ser Asn Lys Lys Phe Leu Pro Phe Cys Gln Phe Gly Arg Asp Ile
                      260 265 270
          Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu
                  275 280 285
          Asp Ile Thr Pro Cys Ser Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr
              290 295 300
          Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile
          305 310 315 320
          Ser Phe
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 1748]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 90]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcagc 1560
          auccuggcca ucuacagcac cguggccagc agccuggugc ugcuggugag ccugggcgcc 1620
          aucagcuucu gauaauaggc uggagccucg guggccuagc uucuugcccc uugggccucc 1680
          ccccagcccc uccuccccuu ccugcacccg uacccccgug gucuuugaau aaagucugag 1740
          ugggcggc 1748
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 1572]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 91]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          agcauccugg ccaucuacag caccguggcc agcagccugg ugcugcuggu gagccugggc 1560
          gccaucagcu uc 1572
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 524]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 92]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser
                      500 505 510
          Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
                  515 520
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 1925]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 93]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcagc 1560
          auccuggcca ucuacagcac cguggccagc agccuggugc ugcuggugag ccugggcgcc 1620
          aucagcuuca agaagaagaa gcggccacgg aacuccuaca agugcggcac caacaccaug 1680
          gagcgggagg agagcgagca gaccaagaag cgggagaaga uccacauucc ugaacggucc 1740
          gacgaagccc agcggguguu caagagcagc aagaccagca gcugcgacaa gagcgacacc 1800
          ugcuucugau aauaggcugg agccucggug gccuagcuuc uugccccuug ggccuccccc 1860
          cagccccuccc uccccuuccu gcacccguac ccccgugguc uuugaauaaa gucugagugg 1920
          gcggc 1925
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 1749]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 94]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          agcauccugg ccaucuacag caccguggcc agcagccugg ugcugcuggu gagccugggc 1560
          gccaucagcu ucaagaagaa gaagcggcca cggaacuccu acaagugcgg caccaacacc 1620
          auggagcggg aggagagcga gcagaccaag aagcgggaga agauccacau uccugaacgg 1680
          uccgacgaag cccagcgggu guucaagagc agcaagacca gcagcugcga caagagcgac 1740
          accugcuuc 1749
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 583]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 95]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser
                      500 505 510
          Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Lys Lys Lys Lys
                  515 520 525
          Arg Pro Arg Asn Ser Tyr Lys Cys Gly Thr Asn Thr Met Glu Arg Glu
              530 535 540
          Glu Ser Glu Gln Thr Lys Lys Arg Glu Lys Ile His Ile Pro Glu Arg
          545 550 555 560
          Ser Asp Glu Ala Gln Arg Val Phe Lys Ser Ser Lys Thr Ser Ser Cys
                          565 570 575
          Asp Lys Ser Asp Thr Cys Phe
                      580
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 1805]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 96]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcagc 1560
          auccuggcca ucuacagcac cguggccagc agccuggugc ugcuggugag ccugggcgcc 1620
          aucagcuuca agcggcagua caaggacaug augagcgagg gaggaccacc uggcgcugag 1680
          ccacagugau aauaggcugg agccucggug gccuagcuuc uugccccuug ggccuccccc 1740
          cagccccuccc uccccuuccu gcacccguac ccccgugguc uuugaauaaa gucugagugg 1800
          gcggc 1805
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 1629]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 97]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          agcauccugg ccaucuacag caccguggcc agcagccugg ugcugcuggu gagccugggc 1560
          gccaucagcu ucaagcggca guacaaggac augaugagcg agggaggacc accuggcgcu 1620
          gagccacag 1629
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 543]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 98]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser
                      500 505 510
          Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Lys Arg Gln Tyr
                  515 520 525
          Lys Asp Met Met Ser Glu Gly Gly Pro Gly Ala Glu Pro Gln
              530 535 540
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 1853]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 99]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcggc 1560
          agcgccaucg gcggcuacau ccccgaggcc ccuagagacg gccaggccua cgugcggaag 1620
          gacggcgagu gggugcugcu gagcaccuuc cugggcggag gcagcauccu ggccaucuac 1680
          agcaccgugg ccagcagccu ggugcugcug gugagccugg gcgccaucag cuucugauaa 1740
          uaggcuggag ccucgguggc cuagcuucuu gccccuuggg ccucccccca gccccucccuc 1800
          cccuuccugc acccguaccc ccguggucuu ugaauaaagu cugagugggc ggc 1853
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 1677]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 100]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          ggcagcgcca ucggcggcua cauccccgag gccccuagag acggccaggc cuacgugcgg 1560
          aaggacggcg agugggugcu gcugagcacc uuccugggcg gaggcagcau ccuggccauc 1620
          uacagcaccg uggccagcag ccuggugcug cuggugagcc ugggcgccau cagcuuc 1677
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 559]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 101]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Gly Ser Ala Ile Gly Gly Tyr Ile Pro Glu Ala Pro
                      500 505 510
          Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu
                  515 520 525
          Ser Thr Phe Leu Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val
              530 535 540
          Ala Ser Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
          545 550 555
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 1856]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 102]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcagc 1560
          auccuggcca ucuacagcac cguggccagc agccuggugc ugcuggugag ccugggcgcc 1620
          aucagcuucg gcggaggcag cgccaucggc ggcuacaucc ccgaggcccc uagagacggc 1680
          caggccuacg ugcggaagga cggcgagugg gugcugcuga gcaccuuccu gggcaaguga 1740
          uaauaggcug gagccucggu ggccuagcuu cuugccccuu gggccuccccc ccagccccuc 1800
          cuccccuucc ugcacccgua cccccguggu cuuugaauaa agucugagug ggcggc 1856
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 1680]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 103]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          agcauccugg ccaucuacag caccguggcc agcagccugg ugcugcuggu gagccugggc 1560
          gccaucagcu ucggcggagg cagcgccauc ggcggcuaca uccccgaggc cccuagagac 1620
          ggccaggccu acgugcggaa ggacggcgag ugggugcugc ugagcaccuu ccugggcaag 1680
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 560]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 104]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser
                      500 505 510
          Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe Gly Gly Gly Ser
                  515 520 525
          Ala Ile Gly Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr
              530 535 540
          Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly Lys
          545 550 555 560
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 1826]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 105]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcagc 1560
          auccuggcca ucuacagccu gggcuucauc gccggccuga ucgccaucgu gauggugacc 1620
          aucaugcugu gcugcaugac cagcugcugc agcugccuga agggcuguug cagcugcggc 1680
          agcugcugca aguucgacga ggacgacuga uaauaggcug gagccucggu ggccuagcuu 1740
          cuugccccuu gggccuccccc ccagccccuc cuccccuucc ugcacccgua cccccguggu 1800
          cuuugaauaa agucugagug ggcggc 1826
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 1650]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 106]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          agcauccugg ccaucuacag ccugggcuuc aucgccggcc ugaucgccau cgugauggug 1560
          accaucaugc ugugcugcau gaccagcugc ugcagcugcc ugaagggcug uugcagcugc 1620
          ggcagcugcu gcaaguucga cgaggacgac 1650
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 550]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 107]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Leu Gly Phe Ile Ala
                      500 505 510
          Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr
                  515 520 525
          Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys
              530 535 540
          Lys Phe Asp Glu Asp Asp
          545 550
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 1826]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 108]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcagc 1560
          agcagcaucg ccagcuucuu cuucaucauc gggcugauca ucggccucuu ccuggugcug 1620
          cgggugggca uccaccugug caucaagcug aagcacacca agaagagaca gaucuacacc 1680
          gacaucgaga ugaaccggcu gggcaaguga uaauaggcug gagccucggu ggccuagcuu 1740
          cuugccccuu gggccuccccc ccagccccuc cuccccuucc ugcacccgua cccccguggu 1800
          cuuugaauaa agucugagug ggcggc 1826
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 1650]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 109]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          agcagcagca ucgccagcuu cuucuucauc aucgggcuga ucaucggccu cuuccuggug 1560
          cugcgggugg gcauccaccu gugcaucaag cugaagcaca ccaagaagag acagaucuac 1620
          accgacaucg agaugaaccg gcugggcaag 1650
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 550]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 110]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Ser Ser Ser Ile Ala Ser Phe Phe Phe Ile Ile Gly
                      500 505 510
          Leu Ile Ile Gly Leu Phe Leu Val Leu Arg Val Gly Ile His Leu Cys
                  515 520 525
          Ile Lys Leu Lys His Thr Lys Lys Arg Gln Ile Tyr Thr Asp Ile Glu
              530 535 540
          Met Asn Arg Leu Gly Lys
          545 550
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 1775]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 111]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggacc caacaucacc 960
          aaccugugcc ccuucggcga gguguucaac gccacccggu ucgccagcgu guacgccugg 1020
          aaccggaagc ggaucagcaa cugcguggcc gacuacagcg ugcuguacaa cagcgccagc 1080
          uucagcaccu ucaagugcua cggcgugagc cccaccaagc ugaacgaccu gugcuucacc 1140
          aacguguacg ccgacagcuu cgugauccgu ggcgacgagg ugcggcagau cgcacccggc 1200
          cagacaggca agaucgccga cuacaacuac aagcugcccg acgacuucac cggcugcgug 1260
          aucgccugga acagcaacaa ccucgacagc aaggugggcg gcaacuacaa cuaccuguac 1320
          cggcuguucc ggaagagcaa ccugaagccc uucgagcggg acaucagcac cgagaucuac 1380
          caagccggcu ccaccccuug caacggcgug gagggcuuca acugcuacuu cccucugcag 1440
          agcuacggcu uccagcccac caacggcgug ggcuaccagc ccuaccgggu gguggugcug 1500
          agcuucgagc ugcugcacgc cccagccacc guguguggcc ccaagucugg cggaggcggc 1560
          agcgccaucg gcggcuacau ccccgaggcc ccuagagacg gccaggccua cgugcggaag 1620
          gacggcgagu gggugcugcu gagcaccuuc cugggcugau aauaggcugg agccucggug 1680
          gccuagcuuc uugccccuug ggccuccccc cagccccuccc uccccuuccu gcacccguac 1740
          ccccgugguc uuugaauaaa gucugagugg gcggc 1775
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 1599]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 112]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acccaacauc 900
          accaaccugu gccccuucgg cgagguguuc aacgccaccc gguucgccag cguguacgcc 960
          uggaaccgga agcggaucag caacugcgug gccgacuaca gcgugcugua caacagcgcc 1020
          agcuucagca ccuucaagug cuacggcgug agccccacca agcugaacga ccugugcuuc 1080
          accaacgugu acgccgacag cuucgugauc cguggcgacg aggugcggca gaucgcaccc 1140
          ggccagacag gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugc 1200
          gugaucgccu ggaacagcaa caaccucgac agcaaggugg gcggcaacua caacuaccug 1260
          uaccggcugu uccggaagag caaccugaag cccuucgagc gggacaucag caccgagauc 1320
          uaccaagccg gcuccacccc uugcaacggc guggagggcu ucaacugcua cuucccucug 1380
          cagagcuacg gcuuccagcc caccaacggc gugggcuacc agcccuaccg ggugguggug 1440
          cugagcuucg agcugcugca cgccccagcc accgugugug gccccaaguc uggcggaggc 1500
          ggcagcgcca ucggcggcua cauccccgag gccccuagag acggccaggc cuacgugcgg 1560
          aaggacggcg agugggugcu gcugagcacc uuccugggc 1599
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 533]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 113]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu Cys
              290 295 300
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
          305 310 315 320
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                          325 330 335
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
                      340 345 350
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
                  355 360 365
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
              370 375 380
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
          385 390 395 400
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                          405 410 415
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
                      420 425 430
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
                  435 440 445
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
              450 455 460
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
          465 470 475 480
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                          485 490 495
          Ser Gly Gly Gly Gly Ser Ala Ile Gly Gly Tyr Ile Pro Glu Ala Pro
                      500 505 510
          Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu
                  515 520 525
          Ser Thr Phe Leu Gly
              530
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 1973]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 114]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcggaucgg gaggcggaca gcgggugcag 960
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1020
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1080
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1140
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1200
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1260
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1320
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1380
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1440
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1500
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1560
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1620
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1680
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1740
          cuggagaucc uggacaucac cccuugcagc ucuggcggag gcagcauccu ggccaucuac 1800
          agcaccgugg ccagcagccu ggugcugcug gugagccugg gcgccaucag cuucugauaa 1860
          uaggcuggag ccucgguggc cuagcuucuu gccccuuggg ccucccccca gccccuccuc 1920
          cccuuccugc acccguaccc ccguggucuu ugaauaaagu cugagugggc ggc 1973
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 1797]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 115]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcggau cgggaggcgg acagcgggug 900
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 960
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1020
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1080
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1140
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1200
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1260
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1320
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1380
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1440
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1500
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1560
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1620
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1680
          acccuggaga uccuggacau caccccuugc agcucuggcg gaggcagcau ccuggccauc 1740
          uacagcaccg uggccagcag ccuggugcug cuggugagcc ugggcgccau cagcuuc 1797
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 599]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 116]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Gly Ser Gly Gly Gly Gln Arg Val Gln Pro Thr Glu
              290 295 300
          Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
          305 310 315 320
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                          325 330 335
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
                      340 345 350
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
                  355 360 365
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
              370 375 380
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
          385 390 395 400
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                          405 410 415
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
                      420 425 430
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
                  435 440 445
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
              450 455 460
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
          465 470 475 480
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                          485 490 495
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn
                      500 505 510
          Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly
                  515 520 525
          Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln
              530 535 540
          Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln
          545 550 555 560
          Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Ser Gly Gly Gly Ser
                          565 570 575
          Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val
                      580 585 590
          Ser Leu Gly Ala Ile Ser Phe
                  595
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 1799]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 117]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgg aggcggaucg ggaggcggac ccaacaucac caaccugugc 1020
          cccuucggcg agguguucaa cgccacccgg uucgccagcg uguacgccug gaaccggaag 1080
          cggaucagca acugcguggc cgacuacagc gugcuguaca acagcgccag cuucagcacc 1140
          uucaagugcu acggcgugag ccccaccaag cugaacgacc ugugcuucac caacguguac 1200
          gccgacagcu ucgugauccg uggcgacgag gugcggcaga ucgcacccgg ccagacaggc 1260
          aagaucgccg acuacaacua caagcugccc gacgacuuca ccggcugcgu gaucgccugg 1320
          aacagcaaca accucgacag caaggugggc ggcaacuaca acuaccugua ccggcuguuc 1380
          cggaagagca accugaagcc cuucgagcgg gacaucagca ccgagaucua ccaagccggc 1440
          uccaccccuu gcaacggcgu ggagggcuuc aacugcuacu ucccucugca gagcuacggc 1500
          uuccagccca ccaacggcgu gggcuaccag cccuaccggg ugguggugcu gagcuucgag 1560
          cugcugcacg ccccagccac cguguguggc cccaagucug gcggaggcag cauccuggcc 1620
          aucuacagca ccguggccag cagccuggug cugcugguga gccugggcgc caucagcuuc 1680
          ugauaauagg cuggagccuc gguggccuag cuucuugccc cuugggccuc cccccagccc 1740
          cuccuccccu uccugcaccc guacccccgu ggucuuugaa uaaagucuga gugggcggc 1799
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 1623]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 118]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cggaggcgga ucgggaggcg gacccaacau caccaaccug 960
          ugccccuucg gcgagguguu caacgccacc cgguucgcca gcguguacgc cuggaaccgg 1020
          aagcggauca gcaacugcgu ggccgacuac agcgugcugu acaacagcgc cagcuucagc 1080
          accuucaagu gcuacggcgu gagccccacc aagcugaacg accugugcuu caccaacgug 1140
          uacgccgaca gcuucgugau ccguggcgac gaggugcggc agaucgcacc cggccagaca 1200
          ggcaagaucg ccgacuacaa cuacaagcug cccgacgacu ucaccggcug cgugaucgcc 1260
          uggaacagca acaaccucga cagcaaggug ggcggcaacu acaacuaccu guaccggcug 1320
          uuccggaaga gcaaccugaa gcccuucgag cgggacauca gcaccgagau cuaccaagcc 1380
          ggcuccaccc cuugcaacgg cguggagggc uucaacugcu acuucccucu gcagagcuac 1440
          ggcuuccagc ccaccaacgg cgugggcuac cagcccuacc gggugguggu gcugagcuuc 1500
          gagcugcugc acgccccagc caccgugugu ggccccaagu cuggcggagg cagcauccug 1560
          gccaucuaca gcaccguggc cagcagccug gugcugcugg ugagccuggg cgccaucagc 1620
          uuc 1623
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 541]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 119]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Gly Gly Gly Ser Gly Gly Gly Pro Asn Ile Thr Asn Leu
          305 310 315 320
          Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
                          325 330 335
          Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
                      340 345 350
          Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
                  355 360 365
          Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
              370 375 380
          Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
          385 390 395 400
          Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
                          405 410 415
          Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
                      420 425 430
          Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
                  435 440 445
          Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
              450 455 460
          Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
          465 470 475 480
          Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
                          485 490 495
          Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
                      500 505 510
          Lys Ser Gly Gly Gly Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser
                  515 520 525
          Ser Leu Val Leu Leu Val Ser Leu Gly Ala Ile Ser Phe
              530 535 540
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 2024]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 120]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgg aggcggaucg ggaggcggac agcgggugca gcccaccgag 1020
          agcaucgugc gguuccccaa caucaccaac cugugccccu ucggcgaggu guucaacgcc 1080
          acccgguucg ccagcgugua cgccuggaac cggaagcgga ucagcaacug cguggccgac 1140
          uacagcgugc uguacaacag cgccagcuuc agcaccuuca agugcuacgg cgugagcccc 1200
          accaagcuga acgaccugug cuucaccaac guguacgccg acagcuucgu gauccguggc 1260
          gacgaggugc ggcagaucgc acccggccag acaggcaaga ucgccgacua caacuacaag 1320
          cugcccgacg acuucaccgg cugcgugauc gccuggaaca gcaacaaccu cgacagcaag 1380
          gugggcggca acuacaacua ccuguaccgg cuguuccgga agagcaaccu gaagcccuuc 1440
          gagcgggaca ucagcaccga gaucuaccaa gccggcucca ccccuugcaa cggcguggag 1500
          ggcuucaacu gcuacuuccc ucugcagagc uacggcuucc agcccaccaa cggcgugggc 1560
          uaccagcccu accggguggu ggugcugagc uucgagcugc ugcacgcccc agccaccgug 1620
          uguggcccca agaagagcac caaccuggug aagaacaagu gcgugaacuu caacuucaac 1680
          ggccuuaccg gcaccggcgu gcugaccgag agcaacaaga aauuccugcc cuuucagcag 1740
          uucggccggg acaucgccga caccaccgac gcugugcggg auccccagac ccuggagauc 1800
          cuggacauca ccccuugcag cucuggcgga ggcagcaucc uggccaucua cagcaccgug 1860
          gccagcagcc uggugcugcu ggugagccug ggcgccauca gcuucugaua auaggcugga 1920
          gccucggugg ccuagcuucu ugccccuugg gccucccccc agccccuccu ccccuuccug 1980
          cacccguacc cccguggucu uugaauaaag ucugaguggg cggc 2024
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 1848]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 121]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cggaggcgga ucgggaggcg gacagcgggu gcagcccacc 960
          gagagcaucg ugcgguuccc caacaucacc aaccugugcc ccuucggcga gguguucaac 1020
          gccacccggu ucgccagcgu guacgccugg aaccggaagc ggaucagcaa cugcguggcc 1080
          gacuacagcg ugcuguacaa cagcgccagc uucagcaccu ucaagugcua cggcgugagc 1140
          cccaccaagc ugaacgaccu gugcuucacc aacguguacg ccgacagcuu cgugauccgu 1200
          ggcgacgagg ugcggcagau cgcacccggc cagacaggca agaucgccga cuacaacuac 1260
          aagcugcccg acgacuucac cggcugcgug aucgccugga acagcaacaa ccucgacagc 1320
          aaggugggcg gcaacuacaa cuaccuguac cggcuguucc ggaagagcaa ccugaagccc 1380
          uucgagcggg acaucagcac cgagaucuac caagccggcu ccaccccuug caacggcgug 1440
          gagggcuuca acugcuacuu cccucugcag agcuacggcu uccagcccac caacggcgug 1500
          ggcuaccagc ccuaccgggu gguggugcug agcuucgagc ugcugcacgc cccagccacc 1560
          guguguggcc ccaagaagag caccaaccug gugaagaaca agugcgugaa cuucaacuuc 1620
          aacggccuua ccggcaccgg cgugcugacc gagagcaaca agaaauuccu gcccuuucag 1680
          caguucggcc gggacaucgc cgacaccacc gacgcugugc gggaucccca gacccuggag 1740
          auccuggaca ucaccccuug cagcucuggc ggaggcagca uccuggccau cuacagcacc 1800
          guggccagca gccuggugcu gcuggugagc cugggcgcca ucagcuuc 1848
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 616]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 122]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Gly Gly Gly Ser Gly Gly Gly Gln Arg Val Gln Pro Thr
          305 310 315 320
          Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly
                          325 330 335
          Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg
                      340 345 350
          Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser
                  355 360 365
          Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu
              370 375 380
          Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg
          385 390 395 400
          Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala
                          405 410 415
          Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala
                      420 425 430
          Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr
                  435 440 445
          Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp
              450 455 460
          Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val
          465 470 475 480
          Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro
                          485 490 495
          Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe
                      500 505 510
          Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr
                  515 520 525
          Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr
              530 535 540
          Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln
          545 550 555 560
          Gln Phe Gly Arg Asp Ile Ala Asp Thr Asp Ala Val Arg Asp Pro
                          565 570 575
          Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Ser Gly Gly Gly
                      580 585 590
          Ser Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu
                  595 600 605
          Val Ser Leu Gly Ala Ile Ser Phe
              610 615
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 3995]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 123]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcg ugagcgugau caccccaggc 1860
          accaacacca gcaaccaggu ggccgugcug uaccaggacg ugaacugcac cgaggugccc 1920
          guggccaucc acgccgacca gcugacaccc accuggcggg ucuacagcac cggcagcaac 1980
          guguuccaga cccgggccgg uugccugauc ggcgccgagc acgugaacaa cagcuacgag 2040
          ugcgacaucc ccaucggcgc cggcaucugu gccagcuacc agacccagac caauucaccc 2100
          cggagggcaa ggagcguggc cagccagagc aucaucgccu acaccaugag ccugggcgcc 2160
          gagaacagcg uggccuacag caacaacagc aucgccaucc ccaccaacuu caccaucagc 2220
          gugaccaccg agauucugcc cgugagcaug accaagacca gcguggacug caccauguac 2280
          aucugcggcg acagcaccga gugcagcaac cugcugcugc aguacggcag cuucugcacc 2340
          cagcugaacc gggcccugac cggcaucgcc guggagcagg acaagaacac ccaggaggug 2400
          uucgcccagg ugaagcagau cuacaagacc ccucccauca aggacuucgg cggcuucaac 2460
          uucagccaga uccugcccga ccccagcaag cccagcaagc ggagcuucau cgaggaccug 2520
          cuguucaaca aggugacccu agccgacgcc ggcuucauca agcaguacgg cgacugccuc 2580
          ggcgacauag ccgcccggga ccugaucugc gcccagaagu ucaacggccu gaccgugcug 2640
          ccuccccugc ugaccgacga gaugaucgcc caguacacca gcgcccuguu agccggaacc 2700
          aucaccagcg gcuggacuuu cggcgcugga gccgcucugc agauccccuu cgccaugcag 2760
          auggccuacc gguucaacgg caucggcgug acccagaacg ugcuguacga gaaccagaag 2820
          cugaucgcca accaguucaa cagcgccauc ggcaagaucc aggacagccu gagcagcacc 2880
          gcuagcgccc ugggcaagcu gcaggacgug gugaaccaga acgcccaggc ccugaacacc 2940
          cuggugaagc agcugagcag caacuucggc gccaucagca gcgugcugaa cgacauccug 3000
          agccggcugg acaaggugga ggccgaggug cagaucgacc ggcugaucac uggccggcug 3060
          cagagccugc agaccuacgu gacccagcag cugauccggg ccgccgagau ucgggccagc 3120
          gccaaccugg ccgccaccaa gaugagcgag ugcgugcugg gccagagcaa gcggguggac 3180
          uucugcggca agggcuacca ccugaugagc uuuccccaga gcgcacccca cggaguggug 3240
          uuccugcacg ugaccuacgu gcccgcccag gagaagaacu ucaccaccgc cccagccauc 3300
          ugccacgacg gcaaggccca cuuuccccgg gagggcgugu ucgugagcaa cggcacccac 3360
          ugguucguga cccagcggaa cuucuacgag ccccagauca ucaccaccga caacaccuuc 3420
          gugagcggca acugcgacgu ggugaucggc aucgugaaca acaccgugua cgauccccug 3480
          cagcccgagc uggacagcuu caaggaggag cuggacaagu acuucaagaa ucacaccagc 3540
          cccgacgugg accugggcga caucagcggc aucaacgcca gcguggugaa cauccagaag 3600
          gagaucgauc ggcugaacga gguggccaag aaccugaacg agagccugau cgaccugcag 3660
          gagcugggca aguacgagca guacaucaag uggcccuggu acaucuggcu gggcuucauc 3720
          gccggccuga ucgccaucgu gauggugacc aucaugcugu gcugcaugac cagcugcugc 3780
          agcugccuga agggcuguug cagcugcggc agcugcugca aguucgacga ggacgacagc 3840
          gagcccgugc ugaagggcgu gaagcugcac uacaccugau aauaggcugg agccucggug 3900
          gccuagcuuc uugccccuug ggccuccccc cagccccuccc uccccuuccu gcacccguac 3960
          ccccgugguc uuugaauaaa gucugagugg gcggc 3995
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 3819]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 124]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcgugagcgu gaucacccca 1800
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 1920
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 1980
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 2040
          ccccggaggg caaggagcgu ggccagccag agcaucaucg ccuacaccau gagccugggc 2100
          gccgagaaca gcguggccua cagcaacaac agcaucgcca uccccaccaa cuucaccauc 2160
          agcgugacca ccgagauucu gcccgugagc augaccaaga ccagcgugga cugcaccaug 2220
          uacaucugcg gcgacagcac cgagugcagc aaccugcugc ugcaguacgg cagcuucugc 2280
          acccagcuga accgggcccu gaccggcauc gccguggagc aggacaagaa cacccaggag 2340
          guguucgccc aggugaagca gaucuacaag accccuccca ucaaggacuu cggcggcuuc 2400
          aacuucagcc agauccugcc cgaccccagc aagcccagca agcggagcuu caucgaggac 2460
          cugcuguuca acaaggugac ccuagccgac gccggcuuca ucaagcagua cggcgacugc 2520
          cucggcgaca uagccgcccg ggaccugauc ugcgcccaga aguucaacgg ccugaccgug 2580
          cugccuccccc ugcugaccga cgagaugauc gcccaguaca ccagcgcccu guuagccgga 2640
          accaucacca gcggcuggac uuucggcgcu ggagccgcuc ugcagauccc cuucgccaug 2700
          cagauggccu accgguucaa cggcaucggc gugacccaga acgugcugua cgagaaccag 2760
          aagcugaucg ccaaccaguu caacagcgcc aucggcaaga uccaggacag ccugagcagc 2820
          accgcuagcg cccugggcaa gcugcaggac guggugaacc agaacgccca ggcccugaac 2880
          acccugguga agcagcugag cagcaacuuc ggcgccauca gcagcgugcu gaacgacauc 2940
          cugagccggc uggacaaggu ggaggccgag gugcagaucg accggcugau cacuggccgg 3000
          cugcagagcc ugcagaccua cgugacccag cagcugaucc gggccgccga gauucgggcc 3060
          agcgccaacc uggccgccac caagaugagc gagugcgugc ugggccagag caagcgggug 3120
          gacuucugcg gcaagggcua ccaccugaug agcuuucccc agagcgcacc ccacggagug 3180
          guguuccugc acgugaccua cgugcccgcc caggagaaga acuucaccac cgccccagcc 3240
          aucugccacg acggcaaggc ccacuuuccc cgggagggcg uguucgugag caacggcacc 3300
          cacugguucg ugacccagcg gaacuucuac gagccccaga ucaucaccac cgacaacacc 3360
          uucgugagcg gcaacugcga cguggugauc ggcaucguga acaacaccgu guacgauccc 3420
          cugcagcccg agcuggacag cuucaaggag gagcuggaca aguacuucaa gaaucacacc 3480
          agccccgacg uggaccuggg cgacaucagc ggcaucaacg ccagcguggu gaacauccag 3540
          aaggagaucg aucggcugaa cgagguggcc aagaaccuga acgagagccu gaucgaccug 3600
          caggagcugg gcaaguacga gcaguacauc aaguggcccu gguacaucug gcugggcuuc 3660
          aucgccggcc ugaucgccau cgugauggug accaucaugc ugugcugcau gaccagcugc 3720
          ugcagcugcc ugaagggcug uugcagcugc ggcagcugcu gcaaguucga cgaggacgac 3780
          agcgagcccg ugcugaaggg cgugaagcug cacuacacc 3819
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 1273]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 125]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
                  595 600 605
          Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
              610 615 620
          His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
          625 630 635 640
          Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
                          645 650 655
          Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
                      660 665 670
          Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
                  675 680 685
          Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
              690 695 700
          Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
          705 710 715 720
          Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
                          725 730 735
          Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
                      740 745 750
          Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
                  755 760 765
          Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
              770 775 780
          Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
          785 790 795 800
          Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
                          805 810 815
          Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
                      820 825 830
          Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
                  835 840 845
          Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
              850 855 860
          Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
          865 870 875 880
          Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
                          885 890 895
          Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
                      900 905 910
          Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
                  915 920 925
          Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
              930 935 940
          Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
          945 950 955 960
          Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
                          965 970 975
          Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
                      980 985 990
          Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
                  995 1000 1005
          Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
              1010 1015 1020
          Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
              1025 1030 1035
          Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
              1040 1045 1050
          Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
              1055 1060 1065
          Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
              1070 1075 1080
          Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
              1085 1090 1095
          Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
              1100 1105 1110
          Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
              1115 1120 1125
          Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
              1130 1135 1140
          Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
              1145 1150 1155
          His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
              1160 1165 1170
          Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
              1175 1180 1185
          Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
              1190 1195 1200
          Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
              1205 1210 1215
          Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
              1220 1225 1230
          Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
              1235 1240 1245
          Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
              1250 1255 1260
          Val Leu Lys Gly Val Lys Leu His Tyr Thr
              1265 1270
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 126]]>
          Lys Pro Ser Lys Arg Ser Phe Ile
          1 5
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 127]]>
          Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
          1 5 10
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 128]]>
          ccrccaugg 9
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 129]]>
          gggauccuac c 11
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 130]]>
          uuauuuaww 9
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 47]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 131]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag agccacc 47
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 132]]>
          ugauaauagg cuggagccuc gguggccaug cuucuugccc cuugggccuc cccccagccc 60
          cuccuccccu uccugcaccc guacccccgu ggucuuugaa uaaagucuga gugggcggc 119
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 133]]>
          Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Gly
          1 5 10 15
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 134]]>
          Gly Gly Gly Ser Gly Gly Gly Ser
          1 5
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 135]]>
          Gly Gly Gly Ser Gly Gly Gly
          1 5
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 136]]>
          Gly Gly Gly Ser
          1               
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 137]]>
          Ser Gly Gly Ser
          1               
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 138]]>
          Ser Gly Gly Gly Ser
          1 5
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 1602]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 139]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagcccaaca ucaccaaccu gugccccuuc ggcgaggugu ucaacgccac ccgguucgcc 120
          agcguguacg ccuggaaccg gaagcggauc agcaacugcg uggccgacua cagcgugcug 180
          uacaacagcg ccagcuucag caccuucaag ugcuacggcg ugagccccac caagcugaac 240
          gaccugugcu ucaccaacgu guacgccgac agcuucguga uccguggcga cgaggugcgg 300
          cagaucgcac ccggccagac aggcaagauc gccgacuaca acuacaagcu gcccgacgac 360
          uucaccggcu gcgugaucgc cuggaacagc aacaaccucg acagcaaggu gggcggcaac 420
          uacaacuacc uguaccggcu guuccggaag agcaaccuga agcccuucga gcgggacauc 480
          agcaccgaga ucuaccaagc cggcuccacc ccuugcaacg gcguggaggg cuucaacugc 540
          uacuucccuc ugcagagcua cggcuuccag cccaccaacg gcgugggcua ccagcccuac 600
          cggguggugg ugcugagcuu cgagcugcug cacgccccag ccaccgugug uggccccaag 660
          ucuggcggag gcagcggagg cggaagccag ugcgugaacc ugaccacccg gacccagcug 720
          ccaccagccu acaccaacag cuucacccgg ggcgucuacu accccgacaa gguguuccgg 780
          agcagcgucc ugcacagcac ccaggaccug uuccugcccu ucuucagcaa cgugaccugg 840
          uuccacgcca uccacgugag cggcaccaac ggcaccaagc gguucgacaa ccccgugcug 900
          cccuucaacg acggcgugua cuucgccagc accgagaaga gcaacaucau ccggggcugg 960
          aucuucggca ccacccugga cagcaagacc cagagccugc ugaucgugaa uaacgccacc 1020
          aacgugguga ucaaggugug cgaguuccag uucugcaacg accccuuccu gggcguguac 1080
          uaccacaaga acaacaagag cuggauggag agcgaguucc ggguguacag cagcgccaac 1140
          aacugcaccu ucgaguacgu gagccagccc uuccugaugg accuggaggg caagcagggc 1200
          aacuucaaga accugcggga guucguguuc aagaacaucg acggcuacuu caagaucuac 1260
          agcaagcaca ccccaaucaa ccuggugcgg gaucugcccc agggcuucuc agcccuggag 1320
          ccccuggugg accugcccau cggcaucaac aucacccggu uccagacccu gcuggcccug 1380
          caccggagcu accugacccc aggcgacagc agcagcgggu ggacagcagg cgcggcugcu 1440
          uacuacgugg gcuaccugca gccccggacc uuccugcuga aguacaacga gaacggcacc 1500
          aucaccgacg ccguggacuc uggcggaggc agcauccugg ccaucuacag caccguggcc 1560
          agcagccugg ugcugcuggu gagccugggc gccaucagcu uc 1602
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 534]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 140]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
                      20 25 30
          Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
                  35 40 45
          Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
              50 55 60
          Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
          65 70 75 80
          Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
                          85 90 95
          Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
                      100 105 110
          Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
                  115 120 125
          Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
              130 135 140
          Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
          145 150 155 160
          Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
                          165 170 175
          Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
                      180 185 190
          Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
                  195 200 205
          Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Ser Gly Gly Gly
              210 215 220
          Ser Gly Gly Gly Ser Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu
          225 230 235 240
          Pro Pro Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp
                          245 250 255
          Lys Val Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu
                      260 265 270
          Pro Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly
                  275 280 285
          Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp
              290 295 300
          Gly Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp
          305 310 315 320
          Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val
                          325 330 335
          Asn Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys
                      340 345 350
          Asn Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp
                  355 360 365
          Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe
              370 375 380
          Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly
          385 390 395 400
          Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr
                          405 410 415
          Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu
                      420 425 430
          Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly
                  435 440 445
          Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr
              450 455 460
          Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala
          465 470 475 480
          Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn
                          485 490 495
          Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Ser Gly Gly Gly Ser Ile
                      500 505 510
          Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
                  515 520 525
          Leu Gly Ala Ile Ser Phe
              530
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 1778]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 141]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          cccaacauca ccaaccugug ccccuucggc gagguguuca acgccacccg guucgccagc 180
          guguacgccu ggaaccggaa gcggaucagc aacugcgugg ccgacuacag cgugcuguac 240
          aacagcgcca gcuucagcac cuucaagugc uacggcguga gccccaccaa gcugaacgac 300
          cugugcuuca ccaacgugua cgccgacagc uucgugaucc guggcgacga ggugcggcag 360
          aucgcacccg gccagacagg caagaucgcc gacuacaacu acaagcugcc cgacgacuuc 420
          accggcugcg ugaucgccug gaacagcaac aaccucgaca gcaagguggg cggcaacuac 480
          aacuaccugu accggcuguu ccggaagagc aaccugaagc ccuucgagcg ggacaucagc 540
          accgagaucu accaagccgg cuccaccccu ugcaacggcg uggagggcuu caacugcuac 600
          uucccucugc agagcuacgg cuuccagccc accaacggcg ugggcuacca gcccuaccgg 660
          gugguggugc ugagcuucga gcugcugcac gccccagcca ccgugugugg ccccaagucu 720
          ggcggaggca gcggaggcgg aagccagugc gugaaccuga ccacccggac ccagcugcca 780
          ccagccuaca ccaacagcuu cacccggggc gucuacuacc ccgacaaggu guuccggagc 840
          agcguccugc acagcaccca ggaccuguuc cugcccuucu ucagcaacgu gaccugguuc 900
          cacgccaucc acgugagcgg caccaacggc accaagcggu ucgacaaccc cgugcugccc 960
          uucaacgacg gcguguacuu cgccagcacc gagaagagca acaucauccg gggcuggauc 1020
          uucggcacca cccuggacag caagacccag agccugcuga ucgugaauaa cgccaccaac 1080
          guggugauca aggugugcga guuccaguuc ugcaacgacc ccuuccuggg cguguacuac 1140
          cacaagaaca acaagagcug gauggagagc gaguuccggg uguacagcag cgccaacaac 1200
          ugcaccuucg aguacgugag ccagcccuuc cugauggacc uggagggcaa gcagggcaac 1260
          uucaagaacc ugcgggaguu cguguucaag aacaucgacg gcuacuucaa gaucuacagc 1320
          aagcacaccc caaucaaccu ggugcgggau cugccccagg gcuucucagc ccuggagccc 1380
          cugguggacc ugcccaucgg caucaacauc acccgguucc agacccugcu ggcccugcac 1440
          cggagcuacc ugaccccagg cgacagcagc agcgggugga cagcaggcgc ggcugcuuac 1500
          uacgugggcu accugcagcc ccggaccuuc cugcugaagu acaacgagaa cggcaccauc 1560
          accgacgccg uggacucugg cggaggcagc auccuggcca ucuacagcac cguggccagc 1620
          agccuggugc ugcuggugag ccugggcgcc aucagcuucu gauaauaggc uggagccucg 1680
          guggccuagc uucuugcccc uugggccucc ccccagcccc uccuccccuu ccugcacccg 1740
          uacccccgug gucuuugaau aaagucugag ugggcggc 1778
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 1602]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 142]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ggaggcgcca aguucguggc cgccuggacu 900
          cugaaggccg cagccggcgg acccaacauc accaaccugu gccccuucgg cgagguguuc 960
          aacgccaccc gguucgccag cguguacgcc uggaaccgga agcggaucag caacugcgug 1020
          gccgacuaca gcgugcugua caacagcgcc agcuucagca ccuucaagug cuacggcgug 1080
          agccccacca agcugaacga ccugugcuuc accaacgugu acgccgacag cuucgugauc 1140
          cguggcgacg aggugcggca gaucgcaccc ggccagacag gcaagaucgc cgacuacaac 1200
          uacaagcugc ccgacgacuu caccggcugc gugaucgccu ggaacagcaa caaccucgac 1260
          agcaaggugg gcggcaacua caacuaccug uaccggcugu uccggaagag caaccugaag 1320
          cccuucgagc gggacaucag caccgagauc uaccaagccg gcuccacccc uugcaacggc 1380
          guggagggcu ucaacugcua cuucccucug cagagcuacg gcuuccagcc caccaacggc 1440
          gugggcuacc agcccuaccg ggugguggug cugagcuucg agcugcugca cgccccagcc 1500
          accgugugug gccccaaguc uggcggaggc agcauccugg ccaucuacag caccguggcc 1560
          agcagccugg ugcugcuggu gagccugggc gccaucagcu uc 1602
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 534]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 143]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Gly Gly Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala
              290 295 300
          Ala Gly Gly Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe
          305 310 315 320
          Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile
                          325 330 335
          Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe
                      340 345 350
          Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu
                  355 360 365
          Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu
              370 375 380
          Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn
          385 390 395 400
          Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser
                          405 410 415
          Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg
                      420 425 430
          Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr
                  435 440 445
          Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe
              450 455 460
          Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly
          465 470 475 480
          Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
                          485 490 495
          His Ala Pro Ala Thr Val Cys Gly Pro Lys Ser Gly Gly Gly Gly Ser Ile
                      500 505 510
          Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
                  515 520 525
          Leu Gly Ala Ile Ser Phe
              530
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 1778]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 144]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacgga ggcgccaagu ucguggccgc cuggacucug 960
          aaggccgcag ccggcggacc caacaucacc aaccugugcc ccuucggcga gguguucaac 1020
          gccacccggu ucgccagcgu guacgccugg aaccggaagc ggaucagcaa cugcguggcc 1080
          gacuacagcg ugcuguacaa cagcgccagc uucagcaccu ucaagugcua cggcgugagc 1140
          cccaccaagc ugaacgaccu gugcuucacc aacguguacg ccgacagcuu cgugauccgu 1200
          ggcgacgagg ugcggcagau cgcacccggc cagacaggca agaucgccga cuacaacuac 1260
          aagcugcccg acgacuucac cggcugcgug aucgccugga acagcaacaa ccucgacagc 1320
          aaggugggcg gcaacuacaa cuaccuguac cggcuguucc ggaagagcaa ccugaagccc 1380
          uucgagcggg acaucagcac cgagaucuac caagccggcu ccaccccuug caacggcgug 1440
          gagggcuuca acugcuacuu cccucugcag agcuacggcu uccagcccac caacggcgug 1500
          ggcuaccagc ccuaccgggu gguggugcug agcuucgagc ugcugcacgc cccagccacc 1560
          guguguggcc ccaagucugg cggaggcagc auccuggcca ucuacagcac cguggccagc 1620
          agccuggugc ugcuggugag ccugggcgcc aucagcuucu gauaauaggc uggagccucg 1680
          guggccuagc uucuugcccc uugggccucc ccccagcccc uccuccccuu ccugcacccg 1740
          uacccccgug gucuuugaau aaagucugag ugggcggc 1778
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 1785]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 145]]>
          auguacagca ugcagcuggc uagcugcgug acccugaccc uggugcugcu ggugaacagc 60
          cagggcgccg agaacagcgu ggccuacagc aacaacagca ucgccauccc caccaacuuc 120
          accaucagcg ugaccaccga gauucugccc gugagcauga ccaagaccag cguggacugc 180
          accauguaca ucugcggcga cagcaccgag ugcagcaacc ugcugcugca guacggcagc 240
          uucugcaccc agcugaaccg ggcccugacc ggcaucgccg uggagcagga caagaacacc 300
          caggaggugu ucgcccaggu gaagcagauc uacaagaccc cucccaucaa ggacuucggc 360
          ggcuucaacu ucagccagau ccugcccgac cccagcaagc ccagcaagcg gagcuucauc 420
          gaggaccugc uguucaacaa ggugacccua gccgacgccg gcuucaucaa gcaguacggc 480
          gacugccucg gcgacauagc cgcccgggac cugaucugcg cccagaaguu caacggccug 540
          accgugcugc cuccccugcu gaccgacgag augaucgccc aguacaccag cgcccuguua 600
          gccggaacca ucaccagcgg cuggacuuuc ggcgcuggag ccgcucugca gauccccuuc 660
          gccaugcaga uggccuaccg guucaacggc aucggcguga cccagaacgu gcuguacgag 720
          aaccagaagc ugaucgccaa ccaguucaac agcgccaucg gcaagaucca ggacagccug 780
          agcagcaccg cuagcgcccu gggcaagcug caggacgugg ugaaccagaa cgcccaggcc 840
          cugaacaccc uggugaagca gcugagcagc aacuucggcg ccaucagcag cgugcugaac 900
          gacauccuga gccggcugga cccucccgag gccgaggugc agaucgaccg gcugaucacu 960
          ggccggcugc agagccugca gaccuacgug acccagcagc ugauccgggc cgccgagauu 1020
          cgggccagcg ccaaccuggc cgccaccaag augagcgagu gcgugcuggg ccagagcaag 1080
          cgggguggacu ucugcggcaa gggcuaccac cugaugagcu uuccccagag cgcaccccac 1140
          ggaguggugu uccugcacgu gaccuacgug cccgcccagg agaagaacuu caccaccgcc 1200
          ccagccaucu gccacgacgg caaggcccac uuuccccggg agggcguguu cgugagcaac 1260
          ggcacccacu gguucgugac ccagcggaac uucuacgagc cccagaucau caccaccgac 1320
          aacaccuucg ugagcggcaa cugcgacgug gugaucggca ucgugaacaa caccguguac 1380
          gauccccugc agcccgagcu ggacagcuuc aaggaggagc uggacaagua cuucaagaau 1440
          cacaccagcc ccgacgugga ccugggcgac aucagcggca ucaacgccag cguggugaac 1500
          auccagaagg agaucgaucg gcugaacgag guggccaaga accugaacga gagccugauc 1560
          gaccugcagg agcugggcaa guacgagcag uacaucaagu ggcccuggua caucuggcug 1620
          ggcuucaucg ccggccugau cgccaucgug auggugacca ucaugcugug cugcaugacc 1680
          agcugcugca gcugccugaa gggcuguugc agcugcggca gcugcugcaa guucgacgag 1740
          gacgacagcg agcccgugcu gaagggcgug aagcugcacu acacc 1785
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 595]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 146]]>
          Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
          1 5 10 15
          Leu Val Asn Ser Gln Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn
                      20 25 30
          Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Glu Ile
                  35 40 45
          Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile
              50 55 60
          Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser
          65 70 75 80
          Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln
                          85 90 95
          Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys
                      100 105 110
          Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu
                  115 120 125
          Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu
              130 135 140
          Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly
          145 150 155 160
          Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys
                          165 170 175
          Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile
                      180 185 190
          Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp
                  195 200 205
          Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met
              210 215 220
          Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu
          225 230 235 240
          Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile
                          245 250 255
          Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp
                      260 265 270
          Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu
                  275 280 285
          Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser
              290 295 300
          Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr
          305 310 315 320
          Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg
                          325 330 335
          Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser
                      340 345 350
          Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly
                  355 360 365
          Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe
              370 375 380
          Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala
          385 390 395 400
          Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val
                          405 410 415
          Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr
                      420 425 430
          Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
                  435 440 445
          Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln
              450 455 460
          Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
          465 470 475 480
          His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala
                          485 490 495
          Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala
                      500 505 510
          Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
                  515 520 525
          Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala
              530 535 540
          Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr
          545 550 555 560
          Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys
                          565 570 575
          Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu
                      580 585 590
          His Tyr Thr
                  595
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 1961]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 147]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uacagcaugc agcuggcuag cugcgugacc cugacccugg ugcugcuggu gaacagccag 120
          ggcgccgaga acagcguggc cuacagcaac aacagcaucg ccauccccac caacuucacc 180
          aucagcguga ccaccgagau ucugcccgug agcaugacca agaccagcgu ggacugcacc 240
          auguacaucu gcggcgacag caccgagugc agcaaccugc ugcugcagua cggcagcuuc 300
          ugcacccagc ugaaccgggc ccugaccggc aucgccgugg agcaggacaa gaacacccag 360
          gagguguucg cccaggugaa gcagaucuac aagaccccuc ccaucaagga cuucggcggc 420
          uucaacuuca gccagauccu gcccgacccc agcaagccca gcaagcggag cuucaucgag 480
          gaccugcugu ucaacaaggu gacccuagcc gacgccggcu ucaucaagca guacggcgac 540
          ugccucggcg acauagccgc ccgggaccug aucugcgccc agaaguucaa cggccugacc 600
          gugcugccuc cccugcugac cgacgagaug aucgcccagu acaccagcgc ccuguuagcc 660
          ggaaccauca ccagcggcug gacuuucggc gcuggagccg cucugcagau ccccuucgcc 720
          augcagaugg ccuaccgguu caacggcauc ggcgugaccc agaacgugcu guacgagaac 780
          cagaagcuga ucgccaacca guucaacagc gccaucggca agauccagga cagccugagc 840
          agcaccgcua gcgcccuggg caagcugcag gacgugguga accagaacgc ccaggcccug 900
          aacacccugg ugaagcagcu gagcagcaac uucggcgcca ucagcagcgu gcugaacgac 960
          auccugagcc ggcuggaccc ucccgaggcc gaggugcaga ucgaccggcu gaucacuggc 1020
          cggcugcaga gccugcagac cuacgugacc cagcagcuga uccgggccgc cgagauucgg 1080
          gccagcgcca accuggccgc caccaagaug agcgagugcg ugcugggcca gagcaagcgg 1140
          guggacuucu gcggcaaggg cuaccaccug augagcuuuc cccagagcgc accccacgga 1200
          gugguguucc ugcacgugac cuacgugccc gcccaggaga agaacuucac caccgcccca 1260
          gccaucugcc acgacggcaa ggcccacuuu ccccgggagg gcguguucgu gagcaacggc 1320
          acccacuggu ucgugaccca gcggaacuuc uacgagcccc agaucaucac caccgacaac 1380
          accuucguga gcggcaacug cgacguggug aucggcaucg ugaacaacac cguguacgau 1440
          ccccugcagc ccgagcugga cagcuucaag gaggagcugg acaaguacuu caagaaucac 1500
          accagccccg acguggaccu gggcgacauc agcggcauca acgccagcgu ggugaacauc 1560
          cagaaggaga ucgaucggcu gaacgaggug gccaagaacc ugaacgagag ccugaucgac 1620
          cugcaggagc ugggcaagua cgagcaguac aucaaguggc ccugguacau cuggcugggc 1680
          uucaucgccg gccugaucgc caucgugaug gugaccauca ugcugugcug caugaccagc 1740
          ugcugcagcu gccugaaggg cuguugcagc ugcggcagcu gcugcaaguu cgacgaggac 1800
          gacagcgagc ccgugcugaa gggcgugaag cugcacuaca ccugauaaua ggcuggagcc 1860
          ucgguggccu agcuucuugc cccuugggcc uccccccagc cccuccuccc cuuccugcac 1920
          ccguaccccc guggucuuug aauaaagucu gagugggcgg c 1961
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 148]]>
          Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
          1 5 10
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 2216]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 149]]>
          gggaaauaag agagaaaaga agaguaagaa gaaauauaag accccggcgc cgccaccaug 60
          uucguguucc uggugcugcu gccccuggug agcagccagu gcgugaaccu gaccacccgg 120
          acccagcugc caccagccua caccaacagc uucacccggg gcgucuacua ccccgacaag 180
          guguuccgga gcagcguccu gcacagcacc caggaccugu uccugcccuu cuucagcaac 240
          gugaccuggu uccacgccau ccacgugagc ggcaccaacg gcaccaagcg guucgacaac 300
          cccgugcugc ccuucaacga cggcguguac uucgccagca ccgagaagag caacaucauc 360
          cggggcugga ucuucggcac cacccuggac agcaagaccc agagccugcu gaucgugaau 420
          aacgccacca acguggugau caaggugugc gaguuccagu ucugcaacga ccccuuccug 480
          ggcguguacu accacaagaa caacaagagc uggauggaga gcgaguuccg gguguacagc 540
          agcgccaaca acugcaccuu cgaguacgug agccagcccu uccugaugga ccuggagggc 600
          aagcagggca acuucaagaa ccugcgggag uucguguuca agaacaucga cggcuacuuc 660
          aagaucuaca gcaagcacac cccaaucaac cuggugcggg aucugcccca gggcuuca 720
          gcccuggagc cccuggugga ccugcccauc ggcaucaaca ucacccgguu ccagacccug 780
          cuggcccugc accggagcua ccugacccca ggcgacagca gcagcgggug gacagcaggc 840
          gcggcugcuu acuacguggg cuaccugcag ccccggaccu uccugcugaa guacaacgag 900
          aacggcacca ucaccgacgc cguggacugc gcccuggacc cucugagcga gaccaagugc 960
          acccugaaga gcuucaccgu ggagaagggc aucuaccaga ccagcaacuu ccgggugcag 1020
          cccaccgaga gcaucgugcg guuccccaac aucaccaacc ugugccccuu cggcgaggug 1080
          uucaacgcca cccgguucgc cagcguguac gccuggaacc ggaagcggau cagcaacugc 1140
          guggccgacu acagcgugcu guacaacagc gccagcuuca gcaccuucaa gugcuacggc 1200
          gugagcccca ccaagcugaa cgaccugugc uucaccaacg uguacgccga cagcuucgug 1260
          auccguggcg acgaggugcg gcagaucgca cccggccaga caggcaagau cgccgacuac 1320
          aacuacaagc ugcccgacga cuucaccggc ugcgugaucg ccuggaacag caacaaccuc 1380
          gacagcaagg ugggcggcaa cuacaacuac cuguaccggc uguuccggaa gagcaaccug 1440
          aagcccuucg agcgggacau cagcaccgag aucuaccaag ccggcuccac cccuugcaac 1500
          ggcguggagg gcuucaacug cuacuucccu cugcagagcu acggcuucca gcccaccaac 1560
          ggcgugggcu accagcccua ccggguggug gugcugagcu ucgagcugcu gcacgcccca 1620
          gccaccgugu guggccccaa gaagagcacc aaccugguga agaacaagug cgugaacuuc 1680
          aacuucaacg gccuuaccgg caccggcgug cugaccgaga gcaacaagaa auuccugccc 1740
          uuucagcagu ucggccggga caucgccgac accaccgacg cugugcggga uccccagacc 1800
          cuggagaucc uggacaucac cccuugcagc uucggcggcg ugagcgugau caccccaggc 1860
          accaacacca gcaaccaggu ggccgugcug uaccaggacg ugaacugcac cgaggugccc 1920
          guggccaucc acgccgacca gcugacaccc accuggcggg ucuacagcac cggcagcaac 1980
          guguuccaga cccgggccgg uugccugauc ggcgccgagc acgugaacaa cagcuacgag 2040
          ugcgacaucc ccaucggcgc cggcaucugu gccagcuacc agacccagac caauucauga 2100
          uaauaggcug gagccucggu ggccuagcuu cuugccccuu gggccucccc ccagccccuc 2160
          cuccccuucc ugcacccgua cccccguggu cuuugaauaa agucugagug ggcggc 2216
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 2040]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 150]]>
          auguucgugu uccuggugcu gcugccccug gugagcagcc agugcgugaa ccugaccacc 60
          cggacccagc ugccaccagc cuacaccaac agcuucaccc ggggcgucua cuaccccgac 120
          aagguguucc ggagcagcgu ccugcacagc acccaggacc uguuccugcc cuucuucagc 180
          aacgugaccu gguuccacgc cauccacgug agcggcacca acggcaccaa gcgguucgac 240
          aaccccgugc ugcccuucaa cgacggcgug uacuucgcca gcaccgagaa gagcaacauc 300
          auccggggcu ggaucuucgg caccacccug gacagcaaga cccagagccu gcugaucgug 360
          aauaacgcca ccaacguggu gaucaaggug ugcgaguucc aguucugcaa cgaccccuuc 420
          cugggcgugu acuaccacaa gaacaacaag agcuggaugg agagcgaguu ccggguguac 480
          agcagcgcca acaacugcac cuucgaguac gugagccagc ccuuccugau ggaccuggag 540
          ggcaagcagg gcaacuucaa gaaccugcgg gaguucgugu ucaagaacau cgacggcuac 600
          uucaagaucu acagcaagca caccccaauc aaccuggugc gggaucugcc ccagggcuuc 660
          ucagcccugg agccccuggu ggaccugccc aucggcauca acaucacccg guuccagacc 720
          cugcuggccc ugcaccggag cuaccugacc ccaggcgaca gcagcagcgg guggacagca 780
          ggcgcggcug cuuacuacgu gggcuaccug cagccccgga ccuuccugcu gaaguacaac 840
          gagaacggca ccaucaccga cgccguggac ugcgcccugg acccucugag cgagaccaag 900
          ugcacccuga agagcuucac cguggagaag ggcaucuacc agaccagcaa cuuccgggug 960
          cagcccaccg agagcaucgu gcgguucccc aacaucacca accugugccc cuucggcgag 1020
          guguucaacg ccacccgguu cgccagcgug uacgccugga accggaagcg gaucagcaac 1080
          ugcguggccg acuacagcgu gcuguacaac agcgccagcu ucagcaccuu caagugcuac 1140
          ggcgugagcc ccaccaagcu gaacgaccug ugcuucacca acguguacgc cgacagcuuc 1200
          gugauccgug gcgacgaggu gcggcagauc gcacccggcc agacaggcaa gaucgccgac 1260
          uacaacuaca agcugcccga cgacuucacc ggcugcguga ucgccuggaa cagcaacaac 1320
          cucgacagca aggugggcgg caacuacaac uaccuguacc ggcuguuccg gaagagcaac 1380
          cugaagcccu ucgagcggga caucagcacc gagaucuacc aagccggcuc caccccuugc 1440
          aacggcgugg agggcuucaa cugcuacuuc ccucugcaga gcuacggcuu ccagcccacc 1500
          aacggcgugg gcuaccagcc cuaccgggug guggugcuga gcuucgagcu gcugcacgcc 1560
          ccagccaccg uguguggccc caagaagagc accaaccugg ugaagaacaa gugcgugaac 1620
          uucaacuuca acggccuuac cggcaccggc gugcugaccg agagcaacaa gaaauuccug 1680
          cccuuucagc aguucggccg ggacaucgcc gacaccaccg acgcugugcg ggauccccag 1740
          acccuggaga uccuggacau caccccuugc agcuucggcg gcgugagcgu gaucacccca 1800
          ggcaccaaca ccagcaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
          cccguggcca uccacgccga ccagcugaca cccaccuggc gggucuacag caccggcagc 1920
          aacguguucc agacccgggc cgguugccug aucggcgccg agcacgugaa caacagcuac 1980
          gagugcgaca uccccaucgg cgccggcauc ugugccagcu accagaccca gaccaauuca 2040
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 680]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 151]]>
          Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
          1 5 10 15
          Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
                      20 25 30
          Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
                  35 40 45
          His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
              50 55 60
          Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
          65 70 75 80
          Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
                          85 90 95
          Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
                      100 105 110
          Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
                  115 120 125
          Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
              130 135 140
          Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
          145 150 155 160
          Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
                          165 170 175
          Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
                      180 185 190
          Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
                  195 200 205
          Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
              210 215 220
          Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
          225 230 235 240
          Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
                          245 250 255
          Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
                      260 265 270
          Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
                  275 280 285
          Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
              290 295 300
          Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
          305 310 315 320
          Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
                          325 330 335
          Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
                      340 345 350
          Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
                  355 360 365
          Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
              370 375 380
          Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
          385 390 395 400
          Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
                          405 410 415
          Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
                      420 425 430
          Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
                  435 440 445
          Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
              450 455 460
          Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
          465 470 475 480
          Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
                          485 490 495
          Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
                      500 505 510
          Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
                  515 520 525
          Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
              530 535 540
          Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
          545 550 555 560
          Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
                          565 570 575
          Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
                      580 585 590
          Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
                  595 600 605
          Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
              610 615 620
          His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
          625 630 635 640
          Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
                          645 650 655
          Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
                      660 665 670
          Ser Tyr Gln Thr Gln Thr Asn Ser
                  675 680
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis]]>
           <![CDATA[ <400> 152]]>
          Gly Ser Gly Gly
          1               
          
      

Claims (154)

A messenger ribonucleic acid (mRNA) comprising at least two domains encoding the SARS-CoV-2 spike protein and an open reading frame (ORF) smaller than the full-length spike protein. The mRNA of claim 1, wherein one of the two domains is the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The mRNA of claim 1 or 2, wherein one of the two domains is the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The mRNA of claim 2 or 3, wherein the ORF encodes a transmembrane domain (TD) linked to the NTD and/or the RBD. The mRNA of claim 4, wherein the TD is an influenza hemagglutinin transmembrane domain. The mRNA of claim 3 or 4, wherein the ORF comprises NTD-RBD-TM. The mRNA of any one of claims 1 to 6, wherein the at least two domains are linked via a cleavable linker or a non-cleavable linker. The mRNA of claim 7, wherein the non-cleavable linker is a glycine-serine (GS) linker. The mRNA of claim 8, wherein the GS linker comprises 4 to 15 amino acids. The mRNA of claim 6, wherein the linker system is a pan HLA DR-binding epitope (PADRE). The mRNA of any one of claims 1 to 10, wherein the ORF encodes a signal peptide. The mRNA of claim 11, wherein the signal peptide is linked to the NTD. The mRNA of claim 11, wherein the signal peptide is linked to the RBD. The mRNA of any one of claims 11 to 13, wherein the signal peptide is heterologous to SARS-CoV-2. The mRNA of any one of claims 1 to 3, wherein the at least two domains are soluble. The mRNA of any one of claims 1 to 14, wherein the ORF encodes a trafficking signaling domain. The mRNA of claim 16, wherein the trafficking signaling domain is a macrophage marker. The mRNA of claim 16, wherein the macrophage marker is CD86 and/or CD11b. The mRNA of claim 16, wherein the trafficking signaling domain is a VSV-G cytoplasmic tail (VSVGct). The mRNA of claim 1, wherein one of the two domains is the first repeat heptapeptide of the SARS-CoV-2 spike protein: HPPHCPC (HR1). The mRNA of claim 1, wherein one of the two domains is the second repeat heptapeptide of the SARS-CoV-2 spike protein: HPPHCPC (HR2). The mRNA of claim 20 or 21, wherein the ORF encodes a transmembrane domain (TD) linked to the HR1 and/or the HR2. The mRNA of claim 22, wherein the TD is an influenza hemagglutinin transmembrane domain. The mRNA of any one of claims 20 to 23, wherein the ORF encodes a fusion peptide (FP). The mRNA of any one of claims 20 to 23, wherein the ORF encodes a CT tail. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The mRNA of claim 26, wherein the RBD is soluble. The mRNA of claim 26, wherein the RBD is linked to a transmembrane domain, optionally linked to an influenza hemagglutinin transmembrane domain. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The mRNA of claim 29, wherein the NTD is linked to the RBD of the SARS-CoV-2 spike protein to form an NTD-RBD fusion protein. The mRNA of claim 30, wherein the NTD-RBD fusion is linked to a transmembrane domain (TM), optionally linked to an influenza hemagglutinin transmembrane domain, to form an NTD-RBD-TM protein. The mRNA of claim 30, wherein the NTD-RBD fusion comprises a C-terminal truncation. The mRNA of any one of claims 26 to 32, wherein the NTD and/or the RBD comprises an extension. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an S1 subunit, wherein the S1 subunit is linked to a transmembrane domain, optionally linked to an influenza hemagglutinin transmembrane domain. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an S1 subunit, wherein the S1 subunit is modified to remove the RBD or a portion of the RBD of the S protein. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an S1 subunit linked to an S2 subunit, wherein the S1 subunit is derived from the HKU1 S protein. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an S1 subunit linked to an S2 subunit, wherein the S1 subunit is derived from an OC43 S protein. The mRNA of any one of claims 34 to 37, further comprising a trafficking signal, optionally selected from macrophage markers, optionally CD86, CD11B and/or VSVGct. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding the S2 subunit of the SARS-CoV-2 spike protein. A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the receptor binding domain (RBD) and protein transmembrane domain of the SARS-CoV-2 spike protein. The mRNA of claim 40, wherein the protein transmembrane domain is an influenza hemagglutinin transmembrane domain. A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the amino (N) terminal domain (NTD) and transmembrane domain of the SARS-CoV-2 spike protein. The mRNA of claim 42, wherein the transmembrane domain is an influenza hemagglutinin transmembrane domain. A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the amine group of the SARS-CoV-2 spike protein linked to the receptor binding domain of the SARS-CoV-2 spike protein (N) Terminal domain. The mRNA of claim 44, wherein the fusion protein further comprises a transmembrane domain. The mRNA of any preceding claim, further comprising a 5' end cap, optionally 7mG(5')ppp(5')NlmpNp. The mRNA of any one of claims 1 to 46, further comprising a poly-A tail optionally about 100 nucleotides in length. The mRNA of any one of claims 1 to 47, wherein the mRNA comprises a chemical modification, optionally 1-methylpseudouridine. The mRNA of any one of claims 1 to 48, wherein each uridine in the mRNA is 1-methylpseudouridine. A composition comprising: (a) messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a fusion protein comprising the receptor binding domain (RBD) and protein transmembrane domain of the SARS-CoV-2 spike protein; and (b) mRNA comprising an open reading frame encoding a fusion protein comprising the amino (N) terminal domain (NTD) and transmembrane domain of the SARS-CoV-2 spike protein. The composition of claim 50, wherein the protein transmembrane domain is an influenza hemagglutinin transmembrane domain. The composition of claim 51, wherein the fusion protein of (a) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 77. The composition of claim 52, wherein the fusion protein of (a) comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least the amino acid sequence of SEQ ID NO: 77 Amino acid sequences that are 98% or at least 99% identical. The composition of claim 53, wherein the fusion protein of (a) comprises the amino acid sequence of SEQ ID NO:77. The composition of any one of claims 50 to 54, wherein the open reading frame of (a) comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 76. The composition of claim 55, wherein the open reading frame of (a) comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, and the nucleotide sequence of SEQ ID NO: 76. Nucleotide sequences that are at least 97%, at least 98%, or at least 99% identical. The composition of claim 56, wherein the open reading frame of (a) comprises the nucleotide sequence of SEQ ID NO:76. The composition of any one of claims 50 to 57, wherein the fusion protein of (b) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47. The composition of claim 58, wherein the fusion protein of (b) comprises at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least Amino acid sequences that are 98% or at least 99% identical. The composition of claim 59, wherein the fusion protein of (b) comprises the amino acid sequence of SEQ ID NO:47. The composition of any one of claims 50 to 60, wherein the open reading frame of (b) comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 46. The composition of claim 61, wherein the open reading frame of (b) comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, with the nucleotide sequence of SEQ ID NO: 46. Nucleotide sequences that are at least 97%, at least 98%, or at least 99% identical. The composition of claim 62, wherein the open reading frame of (b) comprises the nucleotide sequence of SEQ ID NO:46. The composition of any one of claims 50 to 63, wherein the ratio of the mRNA of (a) to the mRNA of (b) is about 1:1. The mRNA of any one of claims 1 to 49, further comprising lipid nanoparticles in the composition. The composition of any one of claims 50 to 63, further comprising lipid nanoparticles. The composition of claim 65 or 66, wherein the mRNA is in the lipid nanoparticle. The composition of any one of claims 50 to 63, wherein the mRNA of (a) is in lipid nanoparticles and the mRNA of (b) is in lipid nanoparticles. The composition of claim 68, wherein the mRNA of (a) and the mRNA of (b) are in the same lipid nanoparticle, or wherein the mRNA of (a) and the mRNA of (b) are each formulated relative to each other in individual nanoparticles. The composition of any one of claims 65 to 69, wherein the lipid nanoparticles comprise cationic lipids. The composition of claim 70, wherein the lipid nanoparticles further comprise neutral lipids. The composition of claim 70 or 71, wherein the lipid nanoparticle further comprises a sterol. The composition of any one of claims 70 to 72, wherein the lipid nanoparticles further comprise polyethylene glycol (PEG) modified lipids. The composition of any one of claims 70 to 73, wherein the lipid nanoparticles comprise ionizable cationic lipids, neutral lipids, sterols, and PEG-modified lipids. The composition of claim 74, wherein the ionizable cationic lipid is 8-((2-hydroxyethyl)(6-oxy-6-(undecyloxy)hexyl)amino)octanoic acid Heptan-9-yl ester (Compound 1). The composition of claim 74 or 75, wherein the neutral lipid is 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The composition of any one of claims 70 to 76, wherein the sterol is cholesterol. The composition of any one of claims 70 to 77, wherein the PEG-modified lipid is 1,2 dimyristyl-sn-glycerol-methoxypolyethylene glycol (PEG2000 DMG). The composition of any one of claims 70 to 78, wherein the lipid nanoparticles comprise 20-60 mol % ionizable cationic lipids, 5-25 mol % neutral lipids, 25-55 mol % sterols, and 0.5 mol % -15 mol% PEG-modified lipids. The composition of claim 79, wherein the lipid nanoparticles comprise: 40-50 mol% ionizable lipids, optionally 45-50 mol%; 30-45 mol% sterols, optionally 35-40 mol%; 5-15 mol% helper lipids, optionally 10-12 mol%; 1-5% PEG lipid, 1-3 mol% or 1.5-2.5 mol% as appropriate. The composition of claim 80, wherein the lipid nanoparticle comprises: 40-50 mol% compound 1, optionally 45-50 mol%; 30-45 mol% cholesterol, optionally 35-40 mol%; 5-15 mol% DSPC, optionally 10-12 mol%; 1 -5% PEG2000DMG, 1-3 mol% or 1.5-2.5 mol% as appropriate. A method comprising administering to an individual the mRNA or composition of any preceding claim in an amount effective to induce a neutralizing antibody response against SARS-CoV-2 in the individual. A method comprising administering to an individual the mRNA or composition of any preceding claim in an amount effective to induce a T cell immune response against SARS-CoV-2 in the individual. A method comprising administering to an individual the mRNA of any one of claims 1 to 49 in an amount effective to induce neutralizing antibody responses and T cell immune responses against SARS-CoV-2 in the individual. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding at least one domain of the SARS-CoV-2 spike protein. The mRNA of claim 85, wherein the mRNA is the mRNA of any one of claims 1 to 49. The mRNA of claim 85 or 86, wherein the ORF encodes an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 77. The mRNA of claim 85 or 86, wherein the ORF encodes at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least the amino acid sequence of SEQ ID NO: 77 99% identical amino acid sequence. The mRNA of claim 85 or 86, wherein the ORF encodes the amino acid sequence of SEQ ID NO:77. The mRNA of claim 85 or 86, wherein the ORF comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 76. The mRNA of claim 85 or 86, wherein the ORF comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least Nucleotide sequences that are 98% or at least 99% identical. The mRNA of claim 85 or 86, wherein the ORF comprises the nucleotide sequence of SEQ ID NO:76. The mRNA of claim 85 or 86, wherein the ORF encodes an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47. The mRNA of claim 85 or 86, wherein the ORF encodes at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least the amino acid sequence of SEQ ID NO: 47 99% identical amino acid sequence. The mRNA of claim 85 or 86, wherein the ORF encodes the amino acid sequence of SEQ ID NO:47. The mRNA of claim 85 or 86, wherein the ORF comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 46. The mRNA of claim 85 or 86, wherein the ORF comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 97%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least the Nucleotide sequences that are 98% or at least 99% identical. The mRNA of claim 85 or 86, wherein the ORF comprises the nucleotide sequence of SEQ ID NO:46. The mRNA of claim 85 or 86, wherein the ORF encodes at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least the amino acid sequence of SEQ ID NO: 62 An amino acid sequence that is 98% or at least 99% identical, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:62. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least the nucleotide sequence of SEQ ID NO: 61 A nucleotide sequence that is 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:61. The mRNA of claim 85 or 86, wherein the ORF encodes an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 92, 140 or 143. The mRNA of claim 85 or 86, wherein the ORF encodes at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 97% of the amino acid sequence of SEQ ID NO: 92, 140 or 143 Amino acid sequences that are 98% or at least 99% identical. The mRNA of claim 85 or 86, wherein the ORF encodes the amino acid sequence of SEQ ID NO: 92, 140 or 143. The mRNA of claim 85 or 86, wherein the ORF comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 91, 139 or 142. The mRNA of claim 85 or 86, wherein the ORF comprises at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least the nucleotide sequence of SEQ ID NO: 91, 139 or 142 Nucleotide sequences that are 97%, at least 98% or at least 99% identical. The mRNA of claim 85 or 86, wherein the ORF comprises the nucleotide sequence of SEQ ID NO: 91, 139 or 142. The mRNA of claim 85 or 86, wherein the ORF encodes at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least the amino acid sequence of SEQ ID NO: 107 An amino acid sequence that is 98% or at least 99% identical, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 107. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least A nucleotide sequence that is 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 106. The mRNA of claim 85 or 86, wherein the ORF encodes at least 80%, at least 85%, at least 90% of the amino acid sequence of any one of SEQ ID NOs: 59, 86, 89, 116, 119 or 122 %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, optionally wherein the antigen comprises SEQ ID NO: 59, 86, 89, 116, 119 or The amino acid sequence of any of 122. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80% with the nucleotide sequence of any one of SEQ ID NOs: 58, 85, 88, 115, 118 or 121 %, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises SEQ ID NOs: 58, 85, The nucleotide sequence of any of 88, 115, 118, or 121. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an S1 subunit antigen comprising at least 80%, at least 85%, at least 90%, at least 80%, at least 85%, at least 90%, with the amino acid sequence of SEQ ID NO: 5 An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:5. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least A nucleotide sequence that is 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 3. The mRNA of claim 85 or 86, wherein the antigen comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97% with the amino acid sequence of SEQ ID NO: 17 or 146 , an amino acid sequence of at least 98% or at least 99% identity, as appropriate wherein the antigen comprises the amino acid sequence of SEQ ID NO: 17 or 146. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96% with the nucleotide sequence of SEQ ID NO: 16 or 145 , a nucleotide sequence of at least 97%, at least 98%, or at least 99% identity, as the case may be, wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 16 or 145. The mRNA of claim 85 or 86, wherein the ORF encodes at least 80%, at least 85%, at least 90% of the amino acid sequence with any one of SEQ ID NOs: 20, 23, 26, 29, 32 or 35 %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, optionally wherein the antigen comprises SEQ ID NO: 20, 23, 26, 29, 32 or 35 The amino acid sequence of any of them. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80% with the nucleotide sequence of any one of SEQ ID NOs: 19, 22, 25, 28, 31 or 34 %, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises SEQ ID NOs: 19, 22, 25 The nucleotide sequence of any of , 28, 31 or 34. The mRNA of claim 85 or 86, wherein the ORF encodes at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least the amino acid sequence of SEQ ID NO: 38 An amino acid sequence that is 98% or at least 99% identical, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO:38. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least A nucleotide sequence that is 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO:37. The mRNA of claim 85 or 86, wherein the ORF encodes at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least the amino acid sequence of SEQ ID NO: 41 An amino acid sequence that is 98% or at least 99% identical, optionally wherein the antigen comprises the amino acid sequence of SEQ ID NO: 41. The mRNA of claim 85 or 86, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least A nucleotide sequence that is 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 40. The mRNA of any preceding claim, further comprising a 5' untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO: 131 or 2, as appropriate. The mRNA of any of the preceding claims, further comprising a 3' untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO: 132 or 4, as appropriate. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an antigen comprising at least 80%, at least 85%, at least 90%, at least 80% with the amino acid sequence of SEQ ID NO: 8 or 65 An amino acid sequence that is 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, as appropriate wherein the antigen comprises the amino acid sequence of SEQ ID NO: 8 or 65. The mRNA of claim 123, wherein the ORF comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least A nucleotide sequence that is 97%, at least 98%, or at least 99% identical, optionally wherein the open reading frame comprises the nucleotide sequence of SEQ ID NO: 7 or 64. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an antigen comprising at least 80% amino acid sequence with any one of SEQ ID NOs: 11, 14, 68 or 71, An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally wherein the antigen comprises SEQ ID NOs: 11, 14, 68 or the amino acid sequence of any of 71. The mRNA of claim 125, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90% with the nucleotide sequence of any one of SEQ ID NOs: 10, 13, 67 or 70 %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical nucleotide sequences, optionally wherein the open reading frame comprises one of SEQ ID NOs: 10, 13, 67 or 70 The nucleotide sequence of any one. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an antigen comprising an amine with any one of SEQ ID NOs: 44, 50, 74, 80, 83, 101, 104 or 113 an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to an amino acid sequence, optionally wherein the antigen comprises SEQ The amino acid sequence of any of ID NO: 44, 50, 74, 80, 83, 101, 104 or 113. The mRNA of claim 127, wherein the open reading frame comprises at least 70%, at least 75% with the nucleotide sequence of any one of SEQ ID NOs: 43, 49, 73, 79, 82, 100, 103 or 112 %, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleotide sequence, optionally wherein the open reading frame comprises SEQ ID NO: 43 The nucleotide sequence of any of , 49, 73, 79, 82, 100, 103, or 112. A messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding an antigen comprising at least 80%, at least 85%, at least 85%, at least 85%, at least 80%, at least 85%, at least 80%, at least 85%, at least 80%, at least 85%, at least 80%, at least 80%, 85%, %, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, optionally wherein the antigen comprises one of SEQ ID NOs: 95, 98 or 110 The amino acid sequence of any one. The mRNA of claim 129, wherein the open reading frame comprises at least 70%, at least 75%, at least 80%, at least 90%, at least 70%, at least 75%, at least 80%, at least 90% with the nucleotide sequence of any one of SEQ ID NOs: 94, 97 or 109, A nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical, optionally wherein the open reading frame comprises any one of SEQ ID NOs: 94, 97 or 109 Nucleotide sequence. The mRNA of any one of claims 85 to 130, further comprising lipid nanoparticles in the composition. The composition of claim 131, wherein the mRNA is in the lipid nanoparticle. The composition of claim 131 or 132, wherein the lipid nanoparticles comprise cationic lipids. The composition of claim 133, wherein the lipid nanoparticles further comprise neutral lipids. The composition of any one of claims 131 to 134, wherein the lipid nanoparticle further comprises a sterol. The composition of any one of claims 131 to 135, wherein the lipid nanoparticles further comprise polyethylene glycol (PEG) modified lipids. The composition of any one of claims 131 to 136, wherein the lipid nanoparticles comprise ionizable cationic lipids, neutral lipids, sterols, and PEG-modified lipids. The composition of claim 137, wherein the ionizable cationic lipid is 8-((2-hydroxyethyl)(6-oxy-6-(undecyloxy)hexyl)amino)octanoic acid Heptan-9-yl ester (Compound 1). The composition of claim 137 or 138, wherein the neutral lipid is 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The composition of any one of claims 131 to 139, wherein the sterol is cholesterol. The composition of any one of claims 131 to 140, wherein the PEG-modified lipid is 1,2 dimyristyl-sn-glycerol-methoxypolyethylene glycol (PEG2000 DMG). The composition of any one of claims 131 to 141, wherein the lipid nanoparticles comprise 20-60 mol % ionizable cationic lipids, 5-25 mol % neutral lipids, 25-55 mol % sterols, and 0.5 mol % -15 mol% PEG-modified lipids. The composition of claim 142, wherein the lipid nanoparticle comprises: 40-50 mol% ionizable lipids, optionally 45-50 mol%; 30-45 mol% sterols, optionally 35-40 mol%; 5-15 mol% helper lipids, optionally 10-12 mol%; 1-5% PEG lipid, 1-3 mol% or 1.5-2.5 mol% as appropriate. The composition of claim 143, wherein the lipid nanoparticle comprises: 40-50 mol% compound 1, optionally 45-50 mol%; 30-45 mol% cholesterol, optionally 35-40 mol%; 5-15 mol% DSPC, optionally 10-12 mol%; 1 -5% PEG2000DMG, 1-3 mol% or 1.5-2.5 mol% as appropriate. The mRNA of any one of claims 85 to 130, wherein the mRNA comprises a chemical modification, optionally 1-methylpseudouridine. The mRNA of any one of claims 85 to 130, wherein each uridine in the mRNA is 1-methylpseudouridine. The composition of any one of claims 131 to 144, wherein the mRNA comprises a chemical modification, optionally 1-methylpseudouridine. The composition of any one of claims 131 to 144, wherein each uridine in the mRNA is 1-methylpseudouridine. A method comprising administering to an individual the mRNA of any one of claims 85 to 130 in an amount effective to induce a neutralizing antibody response against SARS-CoV-2 in the individual. A method comprising administering to an individual the mRNA of any one of claims 85 to 130 in an amount effective to induce a T cell immune response against SARS-CoV-2 in the individual. A method comprising administering to an individual the mRNA of any one of claims 85 to 130 in an amount effective to induce neutralizing antibody responses and T cell immune responses against SARS-CoV-2 in the individual. A method comprising administering to an individual a composition of any one of claims 131 to 144 in an amount effective to induce a neutralizing antibody response against SARS-CoV-2 in the individual. A method comprising administering to an individual a composition of any one of claims 131 to 144 in an amount effective to induce a T cell immune response against SARS-CoV-2 in the individual. A method comprising administering to an individual the composition of any one of claims 131 to 144 in an amount effective to induce neutralizing antibody responses and T-cell immune responses against SARS-CoV-2 in the individual .

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