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PE20221756A1 - Vacunas de arn contra el coronavirus - Google Patents

Vacunas de arn contra el coronavirus

Info

Publication number
PE20221756A1
PE20221756A1 PE2022001511A PE2022001511A PE20221756A1 PE 20221756 A1 PE20221756 A1 PE 20221756A1 PE 2022001511 A PE2022001511 A PE 2022001511A PE 2022001511 A PE2022001511 A PE 2022001511A PE 20221756 A1 PE20221756 A1 PE 20221756A1
Authority
PE
Peru
Prior art keywords
vaccines against
rna vaccines
against coronavirus
vaccines
coronavirus
Prior art date
Application number
PE2022001511A
Other languages
English (en)
Inventor
Guillaume Stewart-Jones
Elisabeth Narayanan
Hamilton Bennett
Andrea Carfi
Mihir Metkar
Vladimir Presnyak
Original Assignee
Modernatx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Modernatx Inc filed Critical Modernatx Inc
Publication of PE20221756A1 publication Critical patent/PE20221756A1/es

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20071—Demonstrated in vivo effect

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La descripcion se refiere a vacunas de acido ribonucleico (ARN) contra el coronavirus, asi como a metodos de uso de las vacunas y composiciones que comprenden las vacunas
PE2022001511A 2020-01-28 2021-01-26 Vacunas de arn contra el coronavirus PE20221756A1 (es)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202062967006P 2020-01-28 2020-01-28
US202062971825P 2020-02-07 2020-02-07
US202063002094P 2020-03-30 2020-03-30
US202063009005P 2020-04-13 2020-04-13
US202063016175P 2020-04-27 2020-04-27
PCT/US2021/015145 WO2021154763A1 (en) 2020-01-28 2021-01-26 Coronavirus rna vaccines

Publications (1)

Publication Number Publication Date
PE20221756A1 true PE20221756A1 (es) 2022-11-11

Family

ID=74669543

Family Applications (1)

Application Number Title Priority Date Filing Date
PE2022001511A PE20221756A1 (es) 2020-01-28 2021-01-26 Vacunas de arn contra el coronavirus

Country Status (15)

Country Link
US (1) US20230108894A1 (es)
EP (1) EP4096710A1 (es)
JP (1) JP2023511633A (es)
KR (1) KR20220133224A (es)
CN (1) CN115175698A (es)
AU (1) AU2021213108A1 (es)
BR (1) BR112022014837A2 (es)
CA (1) CA3168902A1 (es)
CO (1) CO2022011685A2 (es)
DO (1) DOP2022000152A (es)
IL (1) IL295016A (es)
MX (1) MX2022009280A (es)
PE (1) PE20221756A1 (es)
TW (1) TW202142556A (es)
WO (1) WO2021154763A1 (es)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10953089B1 (en) 2020-01-27 2021-03-23 Novavax, Inc. Coronavirus vaccine formulations
BR112022014808A2 (pt) * 2020-01-31 2022-09-20 Beth Israel Deaconess Medical Ct Inc Composições e métodos para vacinas para prevenir e tratar infecção pelo coronavírus-sars-cov-2
EP4147717A1 (en) 2020-02-04 2023-03-15 CureVac SE Coronavirus vaccine
US12194089B2 (en) 2020-02-04 2025-01-14 CureVac SE Coronavirus vaccine
US20230242591A1 (en) * 2020-02-14 2023-08-03 Epivax, Inc. Regulatory t cell epitopes and detolerized sars-cov-2 antigens
US20240269266A1 (en) * 2020-04-14 2024-08-15 The Regents Of The University Of California Broad-spectrum multi-antigen pan-coronavirus vaccine
AU2021261471B2 (en) 2020-04-22 2024-10-24 BioNTech SE Coronavirus vaccine
WO2021159130A2 (en) * 2020-05-15 2021-08-12 Modernatx, Inc. Coronavirus rna vaccines and methods of use
AU2021379090A1 (en) * 2020-11-16 2023-06-15 BioNTech SE Lnp compositions comprising rna and methods for preparing, storing and using the same
WO2022218503A1 (en) * 2021-04-12 2022-10-20 BioNTech SE Lnp compositions comprising rna and methods for preparing, storing and using the same
AU2021405281A1 (en) 2020-12-22 2023-07-06 Glaxosmithkline Biologicals Sa Rna vaccine against sars-cov-2 variants
CN112575008B (zh) * 2020-12-31 2023-03-24 四川大学华西医院 编码新型冠状病毒的结构蛋白的核酸分子以及新型冠状病毒疫苗
WO2022155524A1 (en) * 2021-01-15 2022-07-21 Modernatx, Inc. Variant strain-based coronavirus vaccines
CA3208303A1 (en) * 2021-01-15 2022-07-21 Modernatx, Inc. Variant strain-based coronavirus vaccines
US20220356212A1 (en) * 2021-03-26 2022-11-10 Nanogen Pharmaceutical Biotechnology JSC Modified spike protein and method of treatment
WO2022215036A1 (en) * 2021-04-08 2022-10-13 Vaxthera Sas Coronavirus vaccine comprising a mosaic protein
WO2022232648A1 (en) 2021-04-29 2022-11-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion-stabilized lassa virus glycoprotein complex and its use
WO2022235853A1 (en) 2021-05-04 2022-11-10 BioNTech SE Immunogen selection
CN115594742A (zh) * 2021-07-09 2023-01-13 复旦大学（Cn） 一种冠状病毒s蛋白变体及其应用
JP2024539512A (ja) 2021-10-22 2024-10-28 セイル バイオメディシンズ インコーポレイテッド Ｍｒｎａワクチン組成物
US20250000968A1 (en) 2021-11-12 2025-01-02 The United States of America, as represented by the Secretary,Department of Health and Human Service Sars-cov-2 spike fused to a hepatitis b surface antigen
US20250002941A1 (en) 2021-11-23 2025-01-02 Sail Biomedicines, Inc. A bacteria-derived lipid composition and use thereof
US12186387B2 (en) 2021-11-29 2025-01-07 BioNTech SE Coronavirus vaccine
EP4440613A2 (en) * 2021-11-30 2024-10-09 Novavax, Inc. Coronavirus vaccine formulations
CN117580587B (zh) * 2021-12-03 2024-10-15 苏州艾博生物科技有限公司 基于源自SARS-CoV-2奥密克戎毒株的序列的冠状病毒核酸疫苗
WO2023121264A1 (ko) * 2021-12-20 2023-06-29 아이진 주식회사 변이 sars-cov-2 백신 조성물 및 이의 용도
WO2023122080A1 (en) 2021-12-20 2023-06-29 Senda Biosciences, Inc. Compositions comprising mrna and lipid reconstructed plant messenger packs
US20250099574A1 (en) * 2021-12-22 2025-03-27 Hanmi Pharm Co., Ltd. Coronavirus vaccine
CN114031675B (zh) * 2022-01-10 2022-06-07 广州市锐博生物科技有限公司 基于SARS-CoV-2的S蛋白的疫苗和组合物
WO2023154818A1 (en) * 2022-02-09 2023-08-17 Modernatx, Inc. Mucosal administration methods and formulations
CN114404584B (zh) * 2022-04-01 2022-07-26 康希诺生物股份公司 一种新型冠状病毒mRNA疫苗及其制备方法和用途
WO2023196898A1 (en) 2022-04-07 2023-10-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Beta globin mimetic peptides and their use
WO2023213990A1 (en) 2022-05-05 2023-11-09 Etherna Immunotherapies Nv Multi-epitope construct
AU2023268543A1 (en) 2022-05-10 2024-11-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Vaccine for human t-lymphotropic virus-1
WO2023250111A1 (en) 2022-06-22 2023-12-28 Flagship Pioneering Innovations Vi, Llc Combination therapies for the treatment of viral infections
US11654121B1 (en) 2022-06-22 2023-05-23 Flagship Pioneering Innovations Vi, Llc Combination therapies for the treatment of viral infections
WO2024002985A1 (en) 2022-06-26 2024-01-04 BioNTech SE Coronavirus vaccine
WO2024014770A1 (ko) * 2022-07-14 2024-01-18 엠큐렉스 주식회사 mRNA 백신 및 치료제의 제조를 위한 변형된 RNA
US12186389B2 (en) 2022-10-28 2025-01-07 Glaxosmithkline Biologicals Sa Nucleic acid base vaccine against emerging SARS-CoV-2 variants
WO2024102434A1 (en) 2022-11-10 2024-05-16 Senda Biosciences, Inc. Rna compositions comprising lipid nanoparticles or lipid reconstructed natural messenger packs
WO2024159172A1 (en) 2023-01-27 2024-08-02 Senda Biosciences, Inc. A modified lipid composition and uses thereof
CN117886903A (zh) * 2023-03-03 2024-04-16 上海蓝鹊生物医药有限公司 一种抗新冠病毒的蛋白或mRNA疫苗及其制备方法和应用
WO2024220712A2 (en) 2023-04-19 2024-10-24 Sail Biomedicines, Inc. Vaccine compositions
WO2024249626A1 (en) 2023-05-30 2024-12-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv-1 envelope triple tandem trimers and their use

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10121252A1 (de) 2001-04-30 2002-11-07 Christos C Zouboulis Behandlung der Akne
ES2340499T3 (es) 2001-06-05 2010-06-04 Curevac Gmbh Arnm de antigeno tumoral estabilizado con un contenido de g/c aumentado.
US9012219B2 (en) 2005-08-23 2015-04-21 The Trustees Of The University Of Pennsylvania RNA preparations comprising purified modified RNA for reprogramming cells
DE102005046490A1 (de) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz Modifikationen von RNA, die zu einer erhöhten Transkriptstabilität und Translationseffizienz führen
AU2008271907A1 (en) 2007-06-29 2009-01-08 Commonwealth Scientific And Industrial Research Organisation Methods for degrading toxic compounds
KR101541935B1 (ko) 2007-09-26 2015-08-05 인트렉손 코포레이션 합성 5'ｕｔｒ, 발현 벡터, 및 전이유전자 발현의 증가방법
CA2904904A1 (en) 2007-12-11 2009-06-18 The Scripps Research Institute Compositions and methods related to mrna translational enhancer elements
DK2459231T3 (en) 2009-07-31 2016-09-05 Ethris Gmbh RNA with a combination of unmodified and modified nucleotides for protein expression
DK3586861T3 (da) 2011-06-08 2022-04-25 Translate Bio Inc Lipidnanopartikelsammensætninger og fremgangsmåder til mrna-indgivelse
EP3884949A1 (en) 2012-06-08 2021-09-29 Translate Bio, Inc. Pulmonary delivery of mrna to non-lung target cells
WO2014071963A1 (en) 2012-11-09 2014-05-15 Biontech Ag Method for cellular rna expression
JP6399560B2 (ja) 2013-03-14 2018-10-03 トランスレイト バイオ， インコーポレイテッド ｍＲＮＡによってコードされる抗体を送達するための方法及び組成物
LT2972360T (lt) 2013-03-15 2018-09-10 Translate Bio, Inc. Sinergistinis nukleorūgščių pristatymo padidinimas sumaišytų kompozicijų pagalba
EP3578663A1 (en) 2013-03-15 2019-12-11 ModernaTX, Inc. Manufacturing methods for production of rna transcripts
MX2016002152A (es) 2013-08-21 2017-01-05 Curevac Ag Metodo para aumentar la expresion de proteinas codificadas por arn.
ES2806575T3 (es) 2013-11-01 2021-02-18 Curevac Ag ARN modificado con propiedades inmunoestimuladoras disminuidas
JP6584414B2 (ja) 2013-12-30 2019-10-02 キュアバック アーゲー 人工核酸分子
CN111304231A (zh) 2013-12-30 2020-06-19 库瑞瓦格股份公司 人工核酸分子
KR101793271B1 (ko) 2015-07-09 2017-11-20 인텔렉추얼디스커버리 주식회사 공기압을 이용한 휴대용 살균수 스프레이건
HRP20220872T1 (hr) * 2015-10-22 2022-12-23 Modernatx, Inc. Cjepiva protiv respiratornih virusa
EP3405579A1 (en) 2016-01-22 2018-11-28 Modernatx, Inc. Messenger ribonucleic acids for the production of intracellular binding polypeptides and methods of use thereof
JP6983455B2 (ja) 2016-09-14 2021-12-17 モデルナティーエックス， インコーポレイテッド 高純度ｒｎａ組成物及びその調製のための方法
EP3558356A2 (en) * 2016-12-23 2019-10-30 CureVac AG Mers coronavirus vaccine
US20200030432A1 (en) 2017-03-17 2020-01-30 Modernatx, Inc. Zoonotic disease rna vaccines
ES2983060T3 (es) 2017-08-18 2024-10-21 Modernatx Inc Variantes de ARN polimerasa

Also Published As

Publication number Publication date
CO2022011685A2 (es) 2022-08-30
JP2023511633A (ja) 2023-03-20
MX2022009280A (es) 2022-08-16
TW202142556A (zh) 2021-11-16
WO2021154763A1 (en) 2021-08-05
BR112022014837A2 (pt) 2022-09-27
EP4096710A1 (en) 2022-12-07
CA3168902A1 (en) 2021-08-05
CN115175698A (zh) 2022-10-11
US20230108894A1 (en) 2023-04-06
AU2021213108A1 (en) 2022-08-18
IL295016A (en) 2022-09-01
DOP2022000152A (es) 2022-10-31
KR20220133224A (ko) 2022-10-04

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