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WO1994020070A1 - Polymeric mucoadhesives in the delivery of immunogens at mucosal surfaces - Google Patents

Polymeric mucoadhesives in the delivery of immunogens at mucosal surfaces Download PDF

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Publication number
WO1994020070A1
WO1994020070A1 PCT/US1994/002454 US9402454W WO9420070A1 WO 1994020070 A1 WO1994020070 A1 WO 1994020070A1 US 9402454 W US9402454 W US 9402454W WO 9420070 A1 WO9420070 A1 WO 9420070A1
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WO
WIPO (PCT)
Prior art keywords
antigen
mucoadhesive
composition
immunization
animal
Prior art date
Application number
PCT/US1994/002454
Other languages
English (en)
French (fr)
Inventor
Jacqueline D. Duncan
Dennis P. Schafer
Original Assignee
Secretech, 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 Secretech, Inc. filed Critical Secretech, Inc.
Priority to EP94910872A priority Critical patent/EP0688205A1/en
Priority to JP6520245A priority patent/JPH08508247A/ja
Priority to AU63616/94A priority patent/AU692440B2/en
Priority to BR9405996A priority patent/BR9405996A/pt
Publication of WO1994020070A1 publication Critical patent/WO1994020070A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K2039/525—Virus
    • A61K2039/5252—Virus inactivated (killed)
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/5555—Muramyl dipeptides
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55583—Polysaccharides
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55588—Adjuvants of undefined constitution
    • A61K2039/55594—Adjuvants of undefined constitution from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • Oral administration of immunogens is cost effective, safe and encourages compliance. It is now well established that stimulation of immunocompetent tissues and cells of the small intestine results in stimulation of protective immune responses at other mucosal surfaces through the common mucosal immune system. In some cases, such stimulation also results in serum responses.
  • oral vaccination is currently limited in medical practice to a small number of vaccines.
  • oral immunization requires significantly higher dosages of immunogen for the elicitation of a protective immune response, and some vaccines fail to elicit a response when delivered orally.
  • attempts to increase the safety of the vaccines by attenuation and the use of synthetic and subunit preparations usually result in antigen preparations which are less efficacious than the whole intact antigen.
  • adjuvants including mura yl dipeptide and fluoride
  • An alternative approach to adjuvants is to "package" the antigens in a particulate form and thus to present the antigen in a form that is readily taken up by the cells of the immune system.
  • antigens incorporated into, or attached to, polymeric microparticles, nanoparticles, or liposomes are frequently more immunogenic than soluble antigens.
  • These particulate antigens may be more effective because they become trapped in the mucus or because they are selectively scavenged by the M cells of the gut mucosa.
  • the immune response after oral immunization can also be increased by using immunogens that selectively bind to epithelial cells (e.g., the hemagglutinin of influenza, Vibria cholerae) or by coupling immunogens to compounds that selectively bind to these cells (e.g., the adhesins of enteric bacteria such as Shigella or Pseudomonas; toxoids such as cholera or pertussis toxoid; or pollen grains).
  • immunogens that selectively bind to epithelial cells e.g., the hemagglutinin of influenza, Vibria cholerae
  • the adhesins of enteric bacteria such as Shigella or Pseudomonas
  • toxoids such as cholera or pertussis toxoid
  • pollen grains e.g., the adhesins of enteric bacteria such as Shigella or Pseudomonas
  • toxoids such as
  • the object of the present invention is to enhance immune responses to immunogens administered at mucosal surfaces.
  • the immune response after immunization by oral and other mucosal routes is induced or increased by associating the immunogen with polymeric mucoadhesives.
  • the theoretical and practical value of mucoadhesives and other bioadhesives in drug delivery (particularly by transdermal and buccal devices) is well known in the art, but the use of an immunogen with a mucoadhesive to enhance an immune response was heretofore unknown.
  • the immune response after immunization by oral and other mucosal routes is induced or increased by including an adjuvant with the immunogen and polymeric mucoadhesive.
  • an adjuvant with the immunogen and polymeric mucoadhesive was previously unknown.
  • immunization compositions containing any of the conventional immunogens known for human or veterinary use to stimulate immune response in a host.
  • immunogen means a substance that when introduced into the body stimulates humoral, mucosal, or cell-mediated immunity.
  • immunogen and “antigen” are used interchangeably herein.
  • immune response means the development of specifically altered reactivity to foreign antigens following exposure to an immunogen, as indicated by an increase in mucosal or serum antibodies against the immunogen, or by a measure of cell-mediated immunity such as cytokine activity or proliferation.
  • the immune response produced by this invention is conveniently determined by measuring change in mucosal immunity, such as a change in salivary IgA measured by ELISA, or by determining change in systemic immunity, such as a change in antibody levels by ELISA, or by determining change in cellular immunity, such as by measuring T-cell proliferative responses.
  • change in mucosal immunity such as a change in salivary IgA measured by ELISA
  • systemic immunity such as a change in antibody levels by ELISA
  • determining change in cellular immunity such as by measuring T-cell proliferative responses.
  • HI serum hemagglutinin inhibition titer
  • this invention makes it possible to obtain an immune response in mice that is about equal in magnitude to the immune response obtained in about the same period of time after subcutaneous injection of the same materials in equivalent amounts when these analytical techniques are employed.
  • the classes of immunogens that can be used to stimulate the common mucosal immune system after oral or other mucosal route of immunization include without limitation: 1) any infectious disease antigens that are capable of inducing an immune response when administered to mucosal surfaces, including particularly the natural mucosal immunogens (for example, influenza virus and antigens of enteric bacteria such as Escherichla coll , Vibrio cholerae and Heliobacter) , which may bind to the mucosal epithelium through specific interactions between such antigens and ligands and receptors on the mucosal membrane; 2) live attenuated enteric pathogens (for example, polio virus or rotavirus); 3) synthetic particulate antigens (for example, antigen-containing microspheres and nanospheres) ; 4) allergens which bind to the mucosae (for example, ragweed pollen); and 5) autoantigens and tissue antigens (for example, myeiin basic protein, CD
  • the immunogen preparation which may be the entire immunogen, a modified immunogen, a synthetic immunogen or subunits of the above, can be derived from a virus (for example, influenza, HIV, rotavirus or hepatitis), a bacteria (for example, Shigella, Bordetella pertussis or Chlamydia ) , a eukaryotic parasitic organism (for example, Plasmodiu , the causative organism of malaria), a toxin (for example, cholera toxin or endotoxin), an allergen (for example, ragweed pollen) or a tissue marker (for example, melanoma, CD4, or myelin basic protein).
  • a virus for example, influenza, HIV, rotavirus or hepatitis
  • a bacteria for example, Shigella, Bordetella pertussis or Chlamydia
  • a eukaryotic parasitic organism for example, Plasmodiu , the causative organism of
  • the immunogen is derived from a virus.
  • This invention is applicable to a wide variety of viruses against which a vaccine is desired.
  • the invention is especially well suited for use against the common respiratory or enteric viruses.
  • influenza virus is described here.
  • the invention is not intended to be limited to the influenza virus, nor to the strain of influenza virus used in the embodiments described herein.
  • viruses against which the invention can be employed include, for example, parainfluenza virus, respiratory syncytial virus, rhinovirus, corona virus, and adenovirus.
  • influenza virus the choice of virus from which a vaccine is derived will depend in part on the strain or subtype of influenza against which protection is desired. In order to obtain a vaccine useful against a particular strain of influenza, it is preferable to use as the starting material of the vaccine a strain of influenza that possesses at least one antigenic determinant in common with the strain against which the vaccine is to be utilized.
  • influenza virus will typically be one that infects animals, such as chickens or,ducks, and pigs.
  • the invention is particularly suitable for use in primates, including humans.
  • the invention can be carried out with human influenza subtypes HON1, H3N8, H2N2 (pandemic Asian virus), H3N2 (pandemic Hong Kong virus), H1N1 (pandemic Russian virus), or other vial subtypes caused by antigenic shift, as well as subtypes resulting from antigenic drift.
  • influenza virus A/Udorn/307/72 H3N2
  • Dr. B. R. Murphy National Institutes of Health, Bethesda, MD
  • This subtype is a human influenza virus strain that also infects squirrel monkeys and mice.
  • the A/Udorn/307/72 subtype is well suited for use in experiments in animals, such as mouse infection models.
  • mucoadhesives are employed with the immunogen to increase the efficacy of delivery of the immunogen to the mucosal immune system.
  • Various mucoadhesives are currently used in the pharmaceutical industry for drug delivery, as film formers and as viscosity increasing agents, and in the food industry, and are generally considered to be safe by the Food and Drug Administration. Examples include: sodium carboxymethyl cellulose, carbopol, polycarbophil, sodium alginate, and hydroxypropyl methyl cellulose.
  • This association may increase the efficacy of the interaction of the associated compound with the mucosal membrane by: (1) removing the compound from the central lumen of the gut to the relatively immobile mucus layer associated with the mucosal epithelium, thus increasing the time span in which the compound has the potential of interacting with the immune cells of the mucosal membrane of the intestine and its immunocompetent cells; (2) increasing the effective concentration of the compound by separating it from the large volume of fluid and matter in the lumen into the relatively thin layer of mucin adjacent to the mucosal membrane; and (3) protecting the immunogen from denaturation by recovery into this mucin layer, where the molecules are protected from the pH changes and catabolic enzymes in the gut by the diffusion barrier of the polymeric mucin.
  • the interaction of the immunogens with the mucoadhesive polymers may protect the immunogen from the effects of phase changes and the detergent action of bile salts.
  • the hydrophilic properties of the mucoadhesives result in the dehydrated mucoadhesive removing water from its immediate environment. This dehydration of the mucosal epithelial layer may result in increased bioavailability of the immunogen.
  • association of the immunogen with the polymer may stabilize the immunogen. While these factors may explain the effectiveness of mucoadhesives, the inventors do not wish to be restricted by the accuracy of these explanations.
  • the known mucoadhesives are polymers which bind to the polymeric, negatively charged mucin through one or several mechanisms, including hydrophobic interactions, van der Waal forces, interaction of charged groups, polymer admixing and linear chain association, binding of specific residues and interaction of receptors and ligands. All known mucoadhesives are polymers, and it is taken for granted in the literature, but a monomeric mucoadhesive might be possible.
  • Mucoadhesives are generally not in themselves immunogenic and many are safe for human use. They are currently used as mucomimetic agents, as surgical glues, as wound healing adjuncts, in antidiarrheal and anti- constipation agents, and for the delivery of drugs. Mucoadhesives have been successfully applied to transdermal delivery systems for drugs, including peptide drugs, for nasal delivery of drugs (for example, diuretics and insulin) and for controlled and localized delivery of drugs in the buccal cavity (for example, steroids). Although mucoadhesives have been used as depot adjuvants in parenteral immunization and have been studied as potential controlled release systems for the delivery of peptide drugs, they have not been used previously for the mucosal delivery of vaccines. Examples of compounds that are considered to act as mucoadhesives include:
  • mucoadhesives can be employed in the composition and method of this invention.
  • the preferred mucoadhesives are sodium carboxymethyl cellulose and other cellulosics, polycarbophil, and carbopol.
  • Sodium carboxymethylcellulose is a particularly preferred mucoadhesive. It will be understood that mixtures of these mucoadhesives can also be employed.
  • the immunization composition of the invention can also include an adjuvant in an amount sufficient to enhance the magnitude or duration of the immune response in the host, or to enhance the qualitative response in the subject, such as by stimulating antibodies of different immunoglobulin classes than those stimulated by the immunogen.
  • the adjuvant should efficiently elicit cell-mediated and humoral immune responses to antigens without systemic or localized irritation of the host system.
  • the adjuvant has low pyrogenicity.
  • Well known adjuvant formulations for human or veterinary applications can be employed. Such adjuvants can be based on emulsions, with or without mycobacteria, or adjuvants based on adsorption of antigens to aluminum salts, especially aluminum hydroxide or aluminum phosphate.
  • oil adjuvants based on mineral, animal and vegetable oils. Oil based adjuvants are useful for increasing humoral responses of farm animals to the vaccine antigens, and certain oil-based adjuvants have been tested for human use. Typical adjuvants are Freund's complete adjuvant and Freund's incomplete adjuvant.
  • Suitable adjuvants that have been developed more recently, include liposomes, immune-stimulating complexes (ISCOMs) , and squalene or squalene emulsions.
  • Surface active agents having adjuvant activity can also be employed. These include saponin-like Quil A molecules in ISCOMs and Pluronic® block copolymers that are used to make stable squalene emulsions. Saponins are .surface-active agents widely distributed in plants.
  • MDP muramyl dipeptide
  • MTP muramyl tripeptide
  • LPS lipopolysaccharide
  • Another suitable peptide is the synthetic muramyl peptide MTP-PE (N- acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-[1,2- dipalmitoyl-sn-glycero-3-(hydroxyphosphoryloxy) ] ethylamide) .
  • a particularly suitable formulation is Syntex Adjuvant Formulation-1 or SAF-1, which combines the threonyl analog of MDP in a vehicle comprised of Pluronic L-121 triblogk polymer with squalene and a small proportion of Tween 80® as an emulsifying detergent.
  • the preferred adjuvants for use in humans are MDP and its analogs, with or without squalene, saponins, and the monophosphoryl derivative of lipid A.
  • adjuvants include ox bile, polycations, such as DEAE-4 dextran and polyarnithine, sodium dodecylbenzene sulphate, lipid-conjugated materials, streptomycin, vitamin A, and other agents that can influence the structural or functional integrity of the mucosal surface to which they are applied.
  • the mucoadhesive may facilitate presentation of the immunogen and adjuvant to responding cells to thereby enhance the effects of these substances in a synergistic manner.
  • Mucosal surfaces to which mucoadhesives may be used to administer antigen include the gastrointestinal mucosae (including stomach, small intestine, large intestine, colon and rectum); oral mucosae (including the buccal and esophagal membranes and tonsil surface); respiratory mucosae (including nasal, pharyngeal, tracheal and bronchial membranes); genital (including vaginal, cervical and urethral membranes); and ocular membranes.
  • Preferred routes of administering the composition of the invention to a host are oral, nasal, rectal, and swab on the tonsil.
  • Oral administration is the particularly preferred mode of administration because of its simplicity and because it is relatively non-invasive. It will be understood that any of the modes of administration can be combined. For example, the initial dosage can be given orally and a booster dosage given nasally, or vice versa.
  • the immunization composition of the invention can also be employed in a vaccine.
  • the vaccine can be a therapeutic material containing as the immunogen an antigen derived from one or more pathogenic organisms, which on administration to man or animal will stimulate active immunity and protect against or reduce the intensity of infection by these or related organisms.
  • the vaccine can be a live vaccine, an inactivated vaccine, an attenuated vaccine, or a subunit or mixed vaccine.
  • composition of the invention can be incorporated into any suitable delivery system.
  • the antigen, mucoadhesive and adjuvant can be combined with a pharmaceutically acceptable liquid vehicle, such as water, buffered saline or edible animal or vegetable oil.
  • a pharmaceutically acceptable liquid vehicle such as water, buffered saline or edible animal or vegetable oil.
  • the composition can be combined with one or more suitable pharmaceutically acceptable excipients or core materials, such as cellulose, cellulose derivatives, sucrose, gelatin, Starch 1500, NuTab, lactose, malto-dextrin, talc, Cabosil, magnesium stearate, alginate, Actisol, PEG 400, Myvacet, Triacetine, syrup, oil, sorbitol, mannitol, and Plasdone.
  • compositions of the invention can be formulated to include chemical agents that are capable of neutralizing stomach pH.
  • Suitable neutralizing agents include H2 antagonists, bicarbonate of soda, calcium carbonate, and aluminum hydroxide.
  • composition of the invention can be utilized in the form of elixirs, solutions, suspensions, syrups, aerosols, and the like.
  • the composition can also be prepared in dosage units suitable for oral administration, such as particles, granules, beads, tablets, hard gelatin capsules, and soft gelatin capsules.
  • each dosage unit such as a tablet or capsule
  • each dosage unit is coated-with an enteric coating using conventional methods, including but not limited to pan coating; fluidized bed coating, such as the Wurster method or top spraying; spray drying; and an emulsion or microencapsulation method.
  • a subcoating can be used, such as hydroxypropyl methyl cellulose, Opadry or Dryclean.
  • An enteric coating is applied to each dosage unit.
  • the enteric coating can be any pharmaceutically acceptable material that protects the antigen and permits release of the antigen in the intestine.
  • enteric coating is within the ordinary skill in the art, and will depend in part on the dosage form, e.g., tablet or capsule.
  • suitable enteric coatings are HPMCP 55 (hydroxypropyl methyl cellulose phthalate), CAP (cellulose acetate phthalate), Eudragit, Aquateric, Coateric, Surlease, shellac, and wax.
  • the immunogen, mucoadhesive, and adjuvant are employed in a combined amount to provide an immune response against an infectious agent. This can be determined by estimating seroconversion, that is, the levels of antibody before and after immunization. If the host has a preexisting antibody titer to the antigen, the success of immunization can be determined by the extent of increase in the level of specific antibody. In cases where there is no correlation between seroconversion and protection, cell-mediated immune response can be monitored.
  • a single dosage unit can contain the antigen in an amount of about lO ⁇ g to about 150 ⁇ g of hemagglutinin (HA), preferably about 5 ⁇ g to about 45 ⁇ g of HA; the mucoadhesive in an amount of about 10 ⁇ g to about lg, preferably about 1 mg to about 50mg; and the adjuvant in an amount of about l ⁇ g to about 2 ⁇ g, preferably about 10 ⁇ g to about 200 ⁇ g.
  • HA hemagglutinin
  • each dosage unit contains an amount of influenza antigen effective to protect the animal against disease following exposure to the virus.
  • the dose can be defined as the amount of immunogen necessary to raise an immune response in an individual.
  • the level of homologous neutralizing antibody in the serum is predictive of the susceptibility of an individual to infection by a homologous influenza strain.
  • a serum hemagglutination inhibition titer of about 1:32 or 1:40 or greater is considered to be protective against natural infection by homologous virus.
  • a preferred dose of the influenza antigen is one that will result in a serum hemagglutination titer of about 1:32 or 1:40 or higher, as determined by standard methods.
  • the protective effect of the immunogen can also be expressed in terms of the rise in the level of serum hemagglutinin inhibition or mucosal antibody titers that are found post-immunization.
  • a four-fold increase in the serum HI titer over a period of 7- 21 days after immunization is considered to be protective.
  • a four-fold increase in the mucosal antibody titer (e.g., IgA in saliva or nasal wash) over a period of 7-21 days is also considered by some to be protective against influenza.
  • a preferred dose of the immunization composition according to the invention raises the specific antibody levels in a human to these ranges. Immunization dosages can be adjusted until a detectable antibody titer, and preferably a neutralizing antibody titer is obtained.
  • this invention can be employed with immunogens against any parasitic, bacterial or virus type or subtype, as well as different strains of a given subtype.
  • the parasite, bacterium or virus will typically be one that infects animals, such as dogs, cats, poultry, pigs, horses, and cattle, and especially mammals, such as primates, including humans.
  • the immunogen can be administered before or after the mucoadhesive or adjuvant, but generally the immunogen, mucoadhesive, and adjuvant are simultaneously administered to the subject.
  • the immunogenic composition of the invention can be prepared by simply mixing the immunogen, mucoadhesive and adjuvant together without covalent bonding or otherwise coupling the ingredients together.
  • the composition thus has the added advantage of ease of preparation.
  • influenza virus A/Udorn/307/72(H3N2) , BK6, Egg3, clone 3A (7-25-89) was a gift from Dr. B. R. Murphy, (NIH,
  • the pellet was sonicated and again centrifuged.
  • the pooled supernatants containing the virus suspension were loaded on top of 10-60% continuous sucrose gradients in PBS and centrifuged for 2 hrs. at 1000,OOOg in a swing-out rotor.
  • the virus bands were collected, diluted 1:1 in PBS and the virus inactivated by incubation with formalin (1:4000 v/v) for 72 hrs. at 37°C.
  • the material was dialyzed overnight at 4°C against PBS, pelleted as above, resuspended in PBS or water to 5 mg protein ml " and stored at -80°C. Protein was measured by a Coomassie blue binding assay (Pierce, Rockford, IL, USA) for sodium hydroxide- disrupted virus.
  • CMC carboxy methyl cellulose
  • a CMC gel was prepared by making a 2% solution in H «0.
  • Carbopol and Polycarbophil acrylic polymers were purchased from B.F. Goodrich (Cleveland, Ohio). Gels were produced from these polymers by preparing a 0.25% suspension of Carbopol in H 2 0, and a 0.5% suspension of Polycarbophil in H 2 0. The pH of these solutions was raised from approximately 3 to approximately 4 by adding several drops of IN NaOH. The acrylic polymer suspension becomes a gel when the pH reaches 4.
  • Sodium alginate was purchased from Kelco, a division of Merck & Co., Inc. (San Diego, CA) .
  • a gel was produced by preparing a 2% solution in H ⁇ O.
  • Zilactin was purchased from Zila Pharmaceuticals, Inc. (Phoenix, AZ).
  • a 1:10 solution of Zilactin to H2O was prepared immediately before immunization.
  • Influenza vaccine solution 50 ⁇ g of virus protein/10 ⁇ l of phosphate buffered saline
  • mice Groups of five BALB/c mice (8 weeks old, female) obtained from Charles River or Jackson Laboratories were used.
  • the vaccine in mucoadhesive 500 ⁇ l was administered intragastrically with an animal feeding needle.
  • influenza vaccine in 0.1 M NaHCO ⁇ solution, was also delivered intragastrically with an animal feeding tube.
  • Blood was collected from the tail veins of mice before and at selected times after immunization. Blood was centrifuged and plasma was collected and frozen. Stimulated saliva was collected with capillary tubes after intraperitoneal injection of mice with carbamyl-choline chloride (1 ⁇ g/mouse). Amounts of 2 ⁇ g each of soybean trypsin inhibitor, phenylmethyl-sulphonyl fluoride, sodium azide and fetal calf serum were added before clarification and storage at -80°C.
  • ELISA was performed in 96-well polystyrene microtitre plates (Dynatech, Alexandria, VA, USA) coated with purified A/Udorn influenza virus at a concentration of 4 ⁇ g ml " .
  • Endpoint titres of serum and saliva were determined using horseradish peroxidase-labelled goat IgG against mouse Ig or IgA (Southern Biotechnology Associates, Birmingham, AL, USA) and substrate 2,2'-azino-bis-(3-ethylbenzthiazoline) sulphonic acid (Sigma, St. Louis, MO, USA). The colour developed was measured in a Vmax photometer (Molecular Devices, Palo Alto, CA, USA) at 414 nm.
  • Haemagglutination inhibition (HI) reaction was performed with mouse sera diluted 1:5 with PBSA and treated for removing non-specific inhibitors (heated by 56°C for 30 min; incubated with 15% acid-treated kaolin for 30 min; and incubated with 10% suspension of chicken red blood cells for 30 min). Twofold dilutions of sera were prepared in 96-well microtitre plates. Viral suspension (8 HA units in an equal volume) was added to each well and incubated at room temperature for 30 min. A 0.5% suspension of chicken erythrocytes was added to each well and incubated at room temperature for 45-60 min. The HI titers were expressed as the reciprocal of the highest dilution that completely inhibited haemagglutination of erythrocytes.
  • influenza virus A/Udorn/307/72(H3N2) , BK6, Egg3, clone 3A (7-25-89) was a gift from Dr. B.R. Murphy, (NIH,
  • the pooled supernatants containing the virus suspension were loaded on top of 10-60% continuous sucrose gradients in PBS and centrifuged for 2 hours at 100,000g in a swing-out rotor.
  • the virus bands were collected, diluted 1:1 in PBS and the virus inactivated by incubation with formalin (1:4000 v/v) for 72 hours at 37°C.
  • the material was dialyzed overnight at 4°C against PBS, pelleted as above, resuspended in PBS or water to 5 mg protein ml " and stored at -80°C. Protein was measured by a Coomassie Blue binding assay (Pierce, Rockford, IL, USA) for sodium hydroxide disrupted virus.
  • CMC carboxymethyl cellulose
  • a CMC gel was prepared by making a 2% solution in H 2 0.
  • Carbopol and Polycarbophil acrylic polymers were purchased from B.F. Goodrich (Cleveland, Ohio). Gels were produced from these polymers by preparing a 0.25% suspension of Carbopol in H-O, and a 0.5% suspension in Polycarbophil in H 2 0. The pH of these solutions was raised from approximately 3 to approximately 4 by adding several drops of IN NaOH. The acrylic polymer suspension becomes a gel when the pH reaches 4.
  • Sodium alginate was purchased from Kelco, a division of Merck & Co., Inc. (San Diego, CA) .
  • a gel was produced by preparing a 2% solution in H2O.
  • Zilactin was purchased from Zila Pharmaceuticals, Inc. (Phoenix, AZ).
  • a 1:10 solution of Zilactin to H 2 0 was prepared immediately before immunization.
  • Influenza vaccine solution 50 ⁇ g of virus protein/ 10 ⁇ l of phosphate buffered saline
  • the mucoadhesive gels at a 1:50 ratio of vaccine to gel (10 ⁇ l vaccine solution and 490 ⁇ l mucoadhesive per dose).
  • mixing was accomplished by simple agitation for approximately 1-2 minutes, until a homogeneous solution was achieved by visual inspection, and was done immediately before immunization.
  • mice Groups of five BALB/c mice (8 weeks old, female) obtained from Charles River or Jackson Laboratories were used.
  • the vaccine in mucoadhesive 500 ⁇ l was administered intragastrically with an animal feeding needle.
  • influenza vaccine in 0.1 M NaHCO., solution, was also delivered intragastrically with an animal feeding tube.
  • ELISA was performed in 96-we11 polystyrene microtiter plates (Dynatech, Alexandria, VA, USA) coated with purified A/Udorn influenza virus at a concentration of 4 ⁇ g ml " .
  • Endpoint titers of serum and saliva were determined using horseradish peroxidase-labelled goat IgG against mouse Ig or IgA (Southern Biotechnology Associates, Birmingham, AL, USA) and substrate 2,2-azino-bis-(3-ethylbenzthiazoline) sulphonic acid (Sigma, St. Louis, MO, USA). The color developed was measured in a Vmax photometer (Molecular Devices, Palo Alto, CA, USA) at 414 nm. Hema ⁇ qlutinin Inhibition (HI ⁇ Assays
  • HI assays were performed with mouse sera diluted 1:5 with PBS and treated for the removal of non-specific inhibitors (heated at 56°C for 30 minutes; incubated with 15% acid-treated kaolin for 30 minutes; and incubated with 10% suspension of chicken red blood cells for 30 minutes). Twofold dilutions of sera were prepared in 96-well microtiter plates. Viral suspension (8 HA units in an equal volume) was added to each well and incubated at room temperature for 30 minutes. A 0.5% suspension of chicken erythrocytes was added to each well and incubated at room temperature for 45-60 minutes. The HI titers were expressed as the reciprocal of the highest dilution that completely inhibited hemagglutination of erythrocytes. Result
  • mice were immunized by oral gavage with the virus was prepared in various concentrations of the mucoadhesive carboxymethyl cellulose (substitution type 7MF) .
  • substitution type 7MF the mucoadhesive carboxymethyl cellulose
  • two groups of mice were immunized by oral gavage with influenza A/Udorn virus prepared in substituted carboxymethyl celluloses, either type 9M31FPH or 12M31P.
  • mice comprised of five, female BALB/c mice per group were immunized with the mucoadhesive preparation containing formalinized influenza virus (A/Udorn) prepared as described in Example 2, except that the preservative, thimerosal, was added to the allantoic fluid at a concentration of 0.02% (w/v) on harvesting of the virus and was maintained at the same concentration in all the subsequent steps of viral preparation.
  • the mice were immunized, the serum collected and the hemagglutinin inhibition titers determined.
  • mice The effect of the contents of the stomach at the time of oral gavage on the outcome of the immunization was investigated by modifying the feeding regimen of the mice.
  • Four groups of mice comprised of five, female BALB/c mice per group, were placed on regimens in which they were deprived of food or water prior to immunization by oral gavage with a preparation containing 2% (w/v) carboxymethyl cellulose mucoadhesive and 50 ⁇ g of a preparation of formalinized influenza virus A/Udorn, prepared as described in Example 3. That is, the virus had been prepared in the presence of preservative (0.02% thimerosal).
  • the mice were immunized, bled and the hemagglutination titer of the serum determined as described in Example 2. No serum hemagglutinin inhibition titers were obtained at day 14 in any of these groups, including the control group that were offered food and water ad libitum. Salivary IgA and antibody levels by ELISA were not determined.
  • Example 2 indicates that oral immunization with influenza virus (A/Udorn) prepared according to the protocol described in Example 2 yielded positive serum hemagglutinin titers on immunization by oral gavage in the presence of mucoadhesives, including carboxymethyl cellulose.
  • Examples 3 and 4 indicate that influenza A/Udorn virus prepared according to Example 3 failed to yield positive serum hemagglutinin titers on oral immunization in the presence of carboxymethyl cellulose, but did yield positive serum hemagglutinin titers on subcutaneous immunization with the free virus.
  • influenza virus A/Udorn/307/72 H3N2
  • BK6 Egg3, clone 3A (7-25-89) containing Klebsiella planticola and Xanthomonas altophilia was deposited with the American Type Culture Collection, Rockville, Maryland.
  • mice were immunized, bled and the serum hemagglutinin inhibition titer and serum anti-influenza total immunoglobulin antibodies assayed by ELISA determined, all as described in Example 2.
  • the influenza virus stock that was prepared according to Example 2 in the absence of thimerosal and known to be contaminated with bacteria was effective in eliciting an immune response in the mice as assayed by ELISA or serum hemagglutinin inhibition when delivered either subcutaneously or orally.
  • the immune response elicited by oral immunization in the presence of the mucoadhesive and the bacterial contaminant was higher than that elicited by the immunogen containing the bacterial contaminant in the absence of the mucoadhesive, indicating that both the bacterial contaminant and the mucoadhesive were required for the effective elicitation of an immune response.
  • the virus stock prepared with thimerosal according to Example 3 that was known to be free of bacterial contamination was capable of eliciting an immune response on subcutaneous immunization, it was unable to elicit a significant immune response on oral immunization even in the presence of the mucoadhesive, carboxymethyl cellulose.
  • the results obtained in the ELISA assay for Groups 1, 2 and 4 are combined and the sum compared with the ELISA results for Group 5, it appears that synergism occurred between the immunogen, adjuvant, and mucoadhesive according to the invention.
  • mice/group assays performed on pooled sera
  • Example 6 viral preparations that were known to be contaminated with bacteria were capable of eliciting an immune response when delivered orally in the presence of the mucoadhesive, carboxymethyl cellulose. In contrast, viral preparations that were not contaminated with bacteria did not elicit an immune response when delivered orally in the presence of the mucoadhesive, carboxymethyl cellulose.
  • the possibility that the bacteria functioned as an adjuvant in Example 6 was tested by including other known adjuvants in the formulation. The effect of the adjuvants lipopolysaccharide and muramyl dipeptide in the presence of the mucoadhesive, carboxymethylcellulose, was therefore determined. Mice were immunized orally using 50 ⁇ g of an influenza virus preparation that was known to be free of bacteria with 500 ⁇ l of 2% carboxymethyl cellulose, either with or without the addition of LPS or MDP as an adjuvant. Results

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WO1999021579A1 (en) * 1997-10-27 1999-05-06 R.P. Scherer Corporation Solid dispersing vaccine composition for oral delivery
WO2000050078A1 (en) * 1999-02-26 2000-08-31 Chiron Corporation Use of bioadhesives and adjuvants for the mucosal delivery of antigens
WO2000056361A3 (en) * 1999-03-24 2001-03-01 Secr Defence Vaccine composition
EP1260213A3 (de) * 2001-05-17 2003-09-17 A.I.D. Autoimmun Diagnostika GmbH Darreichungsform von immunologischen Wirkstoffen
US6656481B1 (en) 1996-09-06 2003-12-02 Mitsubishi Chemical Corporation Vaccinal preparations
US6713068B1 (en) 1998-03-03 2004-03-30 Merial Live recombined vaccines injected with adjuvant
US7524509B2 (en) 2001-03-09 2009-04-28 Id Biomedical Corporation Of Quebec Proteosome-liposaccharide vaccine adjuvant
WO2010114169A1 (en) * 2009-03-31 2010-10-07 Japan As Represented By The Director-General Of National Institute Of Infectious Diseases Method for prophylaxis of influenza using vaccine for intranasal administration
US8012505B2 (en) 2003-02-28 2011-09-06 Alk-Abello A/S Dosage form having a saccharide matrix
WO2011151431A1 (en) * 2010-06-03 2011-12-08 Glaxosmithkline Biologicals S.A. Oral vaccine comprising an antigen and a toll-like receptor agonist
WO2012048333A1 (en) * 2010-10-08 2012-04-12 R.P. Scherer Technologies, Llc Oral vaccine fast-dissolving dosage form using starch
US8470331B2 (en) 2000-01-14 2013-06-25 Allergy Therapeutics (Uk) Limited Composition of antigen and glycolipid adjuvant for sublingual administration
EP2515661A4 (en) * 2009-12-23 2013-11-13 Vaxgene Corp IMMUNE PROTECTION THROUGH ORAL ADMINISTRATION OF MINI-CAPSULES WITH RECOMBINANT LACTOCOCCUS LACTIS
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US9943584B2 (en) 2008-09-17 2018-04-17 Hunter Immunology Limited Non-typeable haemophilus influenzae vaccines and their uses
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WO2003009868A1 (en) * 2001-07-26 2003-02-06 Otago Innovation Limited Antigenic compositions
EP1599185A1 (en) * 2003-02-28 2005-11-30 Alk-Abello A/S Dosage form having a saccharide matrix
JP2009209086A (ja) * 2008-03-04 2009-09-17 Masami Moriyama 粘膜投与型ワクチン
JP2011057605A (ja) * 2009-09-09 2011-03-24 Masami Moriyama 粘膜投与型ワクチン
CN104271155A (zh) * 2011-11-14 2015-01-07 诺华股份有限公司 聚阴离子卡波姆和Env多肽的免疫原性复合物及其制造方法和用途

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JP2001521007A (ja) * 1997-10-27 2001-11-06 アール、ピー、シャーラー コーポレイション 経口固体分散ワクチン組成物
WO1999021579A1 (en) * 1997-10-27 1999-05-06 R.P. Scherer Corporation Solid dispersing vaccine composition for oral delivery
US6713068B1 (en) 1998-03-03 2004-03-30 Merial Live recombined vaccines injected with adjuvant
US7507416B2 (en) 1998-03-03 2009-03-24 Merial Limited Live recombined vaccines injected with adjuvant
EP2275133A1 (en) * 1999-02-26 2011-01-19 Novartis Vaccines and Diagnostics, Inc. Use of bioadhesives and adjuvants for the mucosal delivery of antigens
WO2000050078A1 (en) * 1999-02-26 2000-08-31 Chiron Corporation Use of bioadhesives and adjuvants for the mucosal delivery of antigens
WO2000056361A3 (en) * 1999-03-24 2001-03-01 Secr Defence Vaccine composition
US8470331B2 (en) 2000-01-14 2013-06-25 Allergy Therapeutics (Uk) Limited Composition of antigen and glycolipid adjuvant for sublingual administration
US7524509B2 (en) 2001-03-09 2009-04-28 Id Biomedical Corporation Of Quebec Proteosome-liposaccharide vaccine adjuvant
EP1260213A3 (de) * 2001-05-17 2003-09-17 A.I.D. Autoimmun Diagnostika GmbH Darreichungsform von immunologischen Wirkstoffen
US8012505B2 (en) 2003-02-28 2011-09-06 Alk-Abello A/S Dosage form having a saccharide matrix
US9943584B2 (en) 2008-09-17 2018-04-17 Hunter Immunology Limited Non-typeable haemophilus influenzae vaccines and their uses
US9603919B2 (en) 2009-03-31 2017-03-28 Japan As Represented By The Director-General Of National Institute Of Infectious Diseases Method for prophylaxis of influenza using vaccine for intranasal administration
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US20130089570A1 (en) * 2010-06-03 2013-04-11 Glaxo Smith Kline Biologicals S.A. Oral vaccine compromising an antigen and a toll-like receptor agonist
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WO2011151431A1 (en) * 2010-06-03 2011-12-08 Glaxosmithkline Biologicals S.A. Oral vaccine comprising an antigen and a toll-like receptor agonist
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US11185579B2 (en) 2016-12-12 2021-11-30 Intervet Inc. Oral vaccine against ruminant respiratory disease comprising polyvinylpyrrolidone

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