WO2024081774A1 - Adjuvants à base de saponine dmlt et utilisations associées - Google Patents

Adjuvants à base de saponine dmlt et utilisations associées Download PDF

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WO2024081774A1
WO2024081774A1 PCT/US2023/076673 US2023076673W WO2024081774A1 WO 2024081774 A1 WO2024081774 A1 WO 2024081774A1 US 2023076673 W US2023076673 W US 2023076673W WO 2024081774 A1 WO2024081774 A1 WO 2024081774A1
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virus
vaccine
dmlt
saponin
adjuvant
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PCT/US2023/076673
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English (en)
Inventor
Elizabeth Norton
Doug KLAIBER
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Q-Vant Biosciences, Inc.
The Administrators Of The Tulane Educational Fund
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Publication of WO2024081774A1 publication Critical patent/WO2024081774A1/fr

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    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/08—Clostridium, e.g. Clostridium tetani
    • 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
    • A61K2039/55544—Bacterial toxins
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants

Definitions

  • the present disclosure relates to an immune adjuvant system for vaccines containing a saponin component and a dmLT component, their methods of use for prophylactic use or therapeutic treatment.
  • exemplary adjuvant compositions include a double-mutant heat-labile toxin adjuvant derived from an Escherichia coli enterotoxin and a saponin, optionally with an additional vaccine component (e.g., an antigen), particularly when used in a vaccine.
  • the adjuvant dmLT is an 84-kDa polymeric protein with an AB5 structure composed of an enzymatically active A subunit (28 kDa) noncovalently associated with a pentameric B subunit (consisting of five 11.5-kDa monomers).
  • dmLT is distinguished from its parent molecule heat-labile enterotoxin (LT) by the substitution of two residues in the A subunit, a glycine for an arginine at amino acid 192 (R192G) and an alanine for a leucine at amino acid 211 (L211A).
  • dmLT The ribbon diagram of dmLT can be extrapolated from the crystal structure of the partially cleaved LT toxin (ref 1, 2), although there may be as-yet- unresolved changes in three-dimensional (3D) structure due to the amino acid substitutions in the A subunit.
  • dmLT is an adjuvant that enhances vaccine-specific systemic and mucosal immune responses following mucosal or parenteral delivery. Studies indicate four main features that define dmLT compared with other adjuvant systems. [0004] ( 1 ) dmLT promotes immunity to antigens that are codelivered after simply admixing dmLT and the antigen in aqueous buffer. Thus, unlike many depot-type adjuvants, such as aluminum hydroxide, no advanced preparation or absorption is required to formulate the antigen/ adj uvant vaccine. dmLT can be formulated with the antigen at either the point of manufacture or the point of delivery.
  • dmLT induces strong interleukm-17 (IL- 17) recall cytokine secretion and antigen-specific Th17 responses after parenteral or mucosal immunization (7-15), This is a newly appreciated arm of the adaptive immune response that is critical in protection from pathogens, particularly in preventing infections in mucosal tissue and control of bacterial infections (16).
  • IL-17 secretion enhances the availability of mucosal antibodies by upregulating polymeric Ig receptor levels in epithelial cells., increasing transport of secretory IgA (slgA) into the lumen of mucosal tissue, and promoting T- independent B-cell differentiation into IgA-secreting cells (17-20).
  • secretory IgA secretory IgA
  • Quillaja saponaria Molina found that Quil A stimulated both humoral and cellular immunity, as well as induced differential antibody isotypes. Since then, the Quil A® has been commercialized and has gained widespread use in veterinary vaccines and pre-clinical studies. Additional studies showed its effects when co-formulated with aluminum salts, liposomes and oil-in-water emulsions. and with amphipathic proteins and lipids forming detergent/' lipid/saponin complexes termed immune-stimulating complexes (ISCOMs)
  • Quil A is a heterogeneous product, consisting of up to 23 different saponin peaks detectable by HPLC and its toxicity when injected parentally precluded its use in human vaccines. Due to foe fact that Quil A is a mixture, a further study was performed by Kensil et al. in 1991 , in which 10 of RP-HPLC fractions from aqueous extract of Q. saponaria bark treated by ultrafiltration were tested and found the fractions QS-7, QS-17, QS-18 and QS-21 to be particularly potent. However, their toxicity when administered parentally (injected) varies considerably. QS-18, the major component of Q saponaria, was found to be highly toxic in mice, while QS-7 and QS- 21 shows far less toxicity.
  • Saponin fractions such as QS-21 , are currently being utilized in the GSK S.hingrix® shingle vaccine and the Mosquirix® malaria vaccine and saponin Fractions A and C are currently being used in the Matrix-M® adjuvant in the Novavax Covid- 19 vaccine in humans. Saponin-based adjuvants are also being investigated in numerous other human indications (i.e., IB, RS V, cancer, etc.).
  • Purified saponins have proven to be safe and effective when injected and have significantly enhanced the efficacy of some oral vaccines under clinical investigation.
  • the toxicity of the food- grade saponin (FGS) extract from Quillaja saponaria has limited its use as a parenteral adjuvant; however, this toxicity is abated when delivered orally.
  • FGS extract is commonly used within the global food and beverage industries and is Generally Recognized As Safe (GRAS) by FDA and in Europe by EFSA’s Panel on Food Additives and Nutrient Sources (ANS). FGS has no documented toxicity in humans at the present levels of consumption in both adults and in infants of 1.5 mg/kg/day or approximately 100 mg of pure saponins in adults and 12 mg in infants.
  • GRAS Generally Recognized As Safe
  • EFSA Panel on Food Additives and Nutrient Sources
  • compositions and methods of using compositions for the treatment of a disease or disorder, or illness or condition may include one or more or all of a saponin, and a heat-labile toxin including, for example, dmLT, and their use and methods for prophylactic use or therapeutic treatment.
  • exemplary adjuvant compositions include a double-mutant heat-labile toxin adjuvant derived from an Escherichia coll enterotoxin and a saponin, optionally with a vaccine or vaccine component (e.g., an antigen).
  • the composition may include (i) a polymeric protein containing at least a portion of dmLT, and (ii) a saponin compound derived from Quillaja Saponaria.
  • a polymeric protein containing at least a portion of dmLT
  • a saponin compound derived from Quillaja Saponaria derived from Quillaja Saponaria.
  • the polymeric protein is a detoxified enterotoxin derived from Escherichia coll with at least 80% identity to the amino acid sequence of dmLT, wherein the detoxified enterotoxin is an adjuvant that retains the immunological activities of dmLT.
  • the present disclosure provides a vaccine adjuvant system comprising (i) a composition comprising an dmLT, (ii) a composition comprising a saponin, and optionally (iii) a vaccine component.
  • the vaccine adjuvant system may include the composition above which includes an effective dose of the saponin compound derived from Quillaja saponaria and an effective dose of at least a portion of dmLT .
  • the present disclosure provides a vaccine containing the synergistic vaccine adjuvant system as above, wherein said system comprises an effective dose of a Quillaja saponaria composition and an effective dose of a dmLT.
  • a vaccine would further include the vaccine adjuvant system above that comprises or encodes at least one antigen.
  • the vaccine may further comprise a polypeptide, a nucleic acid, a polysaccharide, a polysaccharide-polypeptide conjugate, a live-atenuated or inactivated bacterium, a toxoid, a live- attenuated or inactivated virus, a virus-like particle, a viral vector, and/or combinations thereof.
  • Some embodiments of the vaccine may also comprise or encode a bacterial, viral or fungal antigen.
  • kits comprising any of the vaccine adjuvant systems or vaccines above may be provided.
  • a method of generating an immune response in a subject comprising administering to the subject the vaccine adjuvant system or a vaccine as above.
  • the step of administering is by an oral route or a sublingual route.
  • the immune response is a B cell response.
  • the immune response is the generation of CD4+ T cells.
  • the immune response is the generation of CDS + T cells.
  • the present disclosure provides a method of treating of an illness, disease, or a condition, comprising administering a vaccine containing a vaccine adjuvant system comprising an effective dose of a saponin compound derived from Quillaja Saponaria; an effective dose of at least a portion of dmLT; and, optionally, an effective dose of one or more vaccine components associated with the illness, disease, or condition.
  • a vaccine containing a vaccine adjuvant system comprising an effective dose of a saponin compound derived from Quillaja Saponaria; an effective dose of at least a portion of dmLT; and, optionally, an effective dose of one or more vaccine components associated with the illness, disease, or condition.
  • the present invention provides for use of the composition of in a vaccine.
  • the present invention provides for the use the vaccine adjuvant system in a vaccine.
  • the present invention provides use of the vaccine to treat an illness, disease, or condition.
  • FIG. 1 shows an oral immunization with combined dmLT and saponin adjuvant improves immunity to tetanus toxoid (TT) antigen. Analysis of anti-TT IgG by
  • composition such as, for example, a synergistic vaccine adjuvant system, comprising a saponin compound derived from Quillaja Saponaria and dmLT for use in vaccines and the like.
  • a synergistic vaccine adjuvant system for use in vaccines is described, wherein said vaccine adjuvant system .comprises an effective dose of a Quillaja saponaria compound and an effective dose of a dmLT for use as an immune adj uvant system for vaccines.
  • the use of a vaccine adjuvant system is described, wherein the Quillaja saponaria compound and dmLT within the adjuvant system arc used as an immune adjuvant system for vaccines.
  • a therapeutic treatment method comprises administering a vaccine which includes an effective dose of a Quillaja saponaria compound, an effective dose of dmLT, and an active ingredient or vaccine component, such as a sterol, a phospholipid, and/or an antigen, for the prevention or treatment of an illness. disease, or a condition.
  • a vaccine which includes an effective dose of a Quillaja saponaria compound, an effective dose of dmLT, and an active ingredient or vaccine component, such as a sterol, a phospholipid, and/or an antigen, for the prevention or treatment of an illness. disease, or a condition.
  • the adjuvant system for vaccines described herein can be administered in any of a number of ways, including but not limited to the following routes: oral, sublingual. subcutaneous, parenterally, rectally, otic pathway, nasal route, cutaneous route, transdermal route. or combinations thereof.
  • Saponin compounds are raw materials and may be obtained from the bark or, in some cases, the whole biomass of the tree Quillaja saponaria Molina.
  • the term “saponin” as used herein includes glycosidic triterpenoid compounds (also known as triterpene glycoside compounds) which produce foam in aqueous solution, have hemolytic activity in most cases, and possess immune adjuvant activity.
  • the term “saponin” also encompasses biologically active fragments of the above compounds. It will be appreciated that the term “QS” refers to Quillaja saponin.
  • Quillaja saponins are structurally distinct from the saponins derived from other plant species. Two structural features that distinguish Quillaja saponaria saponins from those of other plant species are a fatty acid domain and a triterpene aldehyde at carbon 4 of the triterpene.
  • the Quillaja saponaria compounds can be selected form, but not necessarily limited to; Crude saponin extracts, Type 1 Extract, Type 2 Extract, QS-7, QS-8, QS- 17, QS-18, QS-21, QS-21 Fraction A, QS-21 Fraction C, or combinations thereof.
  • the four most predominant identified and purified Quillaja saponins are QS-7, QS-17, QS-18, and QS-21.
  • these adjuvant saponins have been identified and purified from an aqueous extract of the bark of the South American tree, Quillaja saponaria Molina, and have generally been purified by HPLC and low-pressure silica chromatography and were found to be adjuvant active, although differing in biological activities such as hemolysis and toxicity. More recently, the obtention of these saponins from the entire biomass of the Quillaja saponaria Molina tree has provided for significant increases in the available raw material, triggering an increase in production capacities, reducing costs and making the product sustainable, since the extraction of biomass does not cause the death of the tree or stress over the native Chilean forest.
  • the other component of the adjuvant compositions provided herein is a detoxified enterotoxin adjuvant derived from Escherichia coli referred to in the literature as dmLT.
  • the detoxified enterotoxin adjuvant exemplified herein was originally described in U.S. Patent No. 6,033,673. Referred to as " LT(R192G/L211 A)” in that patent and referred to as “dmLT” herein, the detoxified enterotoxin adjuvant is a genetically distinct mutant of the E.
  • dmLT can be produced by methods standard in the art.
  • plasmid pECD403 described in Example 6.1 of U.S. Patent No. 6, 033,673, can be utilized to produce substantially pure LT(R192G/L211 A) (dmLT) in E coli.
  • dmLT can be isolated by agarose affinity chromatography from bacteria expressing an dniLT-encoding plasmid. Alternate methods of purification standard in the art can be used to purify dmLT.
  • compositions arid preferably adjuvant compositions, provided herein comprise a detoxified bacterial endotoxin adjuvant and saponin compound adjuvant.
  • the adjuvant compositions can comprise a dmLT adjuvant and/or a Quillaja Saponaria compound including, but not limited to. Crude saponin extracts. Type 1 Extract, Type 2 Extract, QS-7, QS-8, QS-17, QS-18, QS-21, QS-21 Fraction A, QS-21 Fraction C, or combinations thereof [0032]
  • the adjuvant compositions, including the adjuvant systems described herein, may be administered as separate compositions with or without a vaccine composition. In other embodiments, the adjuvant compositions may be administered in the same/one composition, or optionally, separate from an optional one or more vaccine component.
  • the adjuvants provided herein are present in a composition in an amount between the ranges of 0.1-1000 pg/dose for each individual adjuvant (dmLT and saponin). Doses may be adjusted depending upon the body mass, body area, weight, blood volume of the subject, or route of delivery. It will be evident to those skilled in the art that the number and frequency of administration will be dependent upon the response of the host. As described herein, the appropriate dose may also depend upon the subj ect's condition, that is, stage of the disease, general health status, as well as age, gender, and weight, and other factors familiar to a person skilled in the medical art. Thus, by the term “effective dose,” it is meant a dosage believed by one of ordinary skill having knowledge of the individual subject or host as being suitable and sufficient to have a positive effect on the individual in the treatment of the condition, illness or disease.
  • the adjuvant compositions may be in any form which allows for the composition to be administered to a subject.
  • the adjuvant composition may be in the form of a solid, liquid or gas (aerosol).
  • Tire pharmaceutical compositions may be administered by any route. Typical routes of administration include, without limitation, oral, sublingual, buccal, topical, parenteral (including intradermal, subcutaneous, percutaneous, intravenous, intramuscular, intrasternal, intracavemous, intrameatal, intratumoral, intracranial, intraspinal or intraurethral injection or infusion), rectal, vaginal, intranasal (e.g., as a spray) and intrapulmonary administration.
  • parenteral includes, but is not limited to, iontophoretic, sonophoretic, thermal, passive transdermal, and microneedle administration and also intradermal/subcutaneous injections, intravenous, intramuscular, intrasternal, intracavernous, intrathecal, intranodal, intrameatal, intraurethral, intratumoral injection or infusion techniques.
  • An adjuvant composition as provided herein can be administered intradermally by a technique selected from iontophoresis, microcavitation, sonophoresis or microneedles.
  • the adjuvant compositions may further comprise at least one physiologically (or pharmaceutically) acceptable or suitable excipient.
  • any physiologically or 'pharmaceutically suitable excipient or carrier i.e., a non-toxic material that does not interfere with the activity of the active ingredient
  • suitable excipients include diluents and carriers that maintain stability and integrity of proteins. Excipients for therapeutic use are well known.
  • “Pharmaceutically acceptable carriers” are also well known in the pharmaceutical art.
  • sterile saline and phosphate buffered saline at physiological pH may be used.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of p hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • “Pharmaceutically acceptable salts” refers to salts of a compounds derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts).
  • Tire adjuvant compositions provided herein may be used in either the free base or salt forms.
  • compositions that will be administered to a patient take the form: of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of one or more adjuvants in aerosol form may hold a plurality of dosage units.
  • a liquid adjuvant composition can be provided herein, whether in the form of a solution, suspension or other like form, and may include one or more of the following carriers or excipients: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as squalene, squalane, mineral oil, a mannide monooleate, cholesterol, and/or synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • An adjuvant composition provided herein can comprise a stable aqueous suspension of less than 0.2 ⁇ M and further comprises at least one component selected from the group consisting of phospholipids, fatty acids, surfactants, detergents, saponins, fiuorodated lipids, and the like.
  • a stable aqueous formulation may be a micellar formulation.
  • An adjuvant composition provided herein can be formulated in a manner which can be aerosolized, either as a powder or liquid formulation.
  • the adjuvant composition may also be desirable to include other components in the adjuvant composition, such as including but not limited to water-in-oil emulsions, biodegradable oil vehicles, oil-in-water emulsions, liposomes, micellar components, microparticles, biodegradable microcapsules, and liposomes.
  • other components in the adjuvant composition such as including but not limited to water-in-oil emulsions, biodegradable oil vehicles, oil-in-water emulsions, liposomes, micellar components, microparticles, biodegradable microcapsules, and liposomes.
  • Adjuvant compositions provided herein can comprise a stable oil-in-water emulsion and a metabolizable oil.
  • metabolizable oil is well known in the art. Metabolizable can be defined as "being capable of being transformed by metabolism".
  • the oil may be any plant oil, vegetable oil, fish oil, animal oil or synthetic oil, which is not toxic to the recipient and is capable of being transformed by metabolism. Nuts (such as peanut oil), seeds, and grains are common sources of vegetable oils. Synthetic oils may also be used.
  • Additional immunostimulatory substances may be included in the adjuvant compositions provided herein and may include N-acetylmuramyl-L-alanine-D-isoglutamine (MDP), glucan, IL- 12, GM CSF, interferon- ⁇ and IL- 12,
  • any suitable carrier known to those of ordinary skill in the art may be employed in the adjuvant compositions provided herein, the type of carrier will vary depending on the mode of administration and whether a sustained release is desired.
  • Biodegradable microspheres e.g., polylactic galactide
  • Suitable biodegradable microspheres are known in the art. In this regard, it is preferable that the microsphere be larger than approximately 25 microns.
  • Adjuvant compositions provided herein may also contain diluents such as buffers, antioxidants such as ascorbic acid, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients. Neutral buffered saline or saline mixed with nonspecific serum albumin are exemplary appropriate diluents. Adjuvants may be formulated as a lyophilizate using appropriate excipient solutions sucrose) as diluents.
  • the adjuvant compositions may further be contained in a vaccine.
  • the vaccine may further comprise or encode an antigen.
  • the adjuvant compositions and methods provided herein are intended for use in a subject, including humans and other animals.
  • Vaccines contemplated for use with adjuvant compositions may comprise or encode an antigen.
  • the vaccines containing the adjuvant composition therein may also comprise or encode, for example, a bacterial, viral or fungal antigen.
  • Antigens contemplated by the disclosure include antigens from pathogenic strains of bacteria (including, but not limited to. Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria gonorrhoea, Neisseria meningitidis, Corynebacterhtm diphtheriae, Clostridium botulinum, Clostridium perfringens, Clostridium tetani, Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella ozaenae, Klebsiella rhinoscleromotis, Staphylococcus aureus, Bordetella pertussis , Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Campylobacter jejuni, Aeromonas hydrophila, Bacillus cereus, Edwardsiella tarda, Yers
  • Shigella sonnet Salmonella typhimurium, Salmonella typhi, Treponema pallidum, Treponema per pneumonia, Treponema car ateneum, Borrelia vincentii, Borrelia burgdorferi, Leptospira icterohemorrhagiae.
  • Mycobacterium tuberculosis Toxoplasma gondii, Pneumocystis carinii.
  • Francisella tularensis Brucella abortus, Brucella suis, Brucella melitensis.
  • Mycoplasma spp Rickettsia prowazeki, Rickettsia tsu-tsugumushi, Chlamydia spp., Helicobacter pylori); pathogenic fungi (Coccidioides immltis, Aspergillus fuminagatus Candida albicans, Blastomyces dermatitidis, Cryptocaccus neafarmans, Histoplasma capsulatum); protozoa (Entamoeba histolytica.
  • Plasmodium falciparum, Plasmodium malaria or Helminths (Enterobius verinicularis, Trichuris trichiura, Ascaris lumbricoides, Trichinella spiralis, Strongyloides stercoralis, Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium, and hookworms) either presented to the immune system in whole organism form or in part isolated from media cultures designed to grow said organisms which are well known in the art. or protective antigens from said organisms obtained by genetic engineering techniques or by chemical synthesis.
  • antigens contemplated include, for example, antigens from pathogenic viruses (e.g , Poxviridae, Herpesviridae, Herpes Simplex virus 1, Herpes Simplex virus 2, Adenoviridae, Papovaviridae, Enteroviridae, Picornaviridae, Parvoviridae, Reoviridae, Retroviridae, influenza viruses, parainfluenza viruses, mumps, measles, respiratory syncytial virus, rubella, Arboviridae,
  • pathogenic viruses e.g , Poxviridae, Herpesviridae, Herpes Simplex virus 1, Herpes Simplex virus 2, Adenoviridae, Papovaviridae, Enteroviridae, Picornaviridae, Parvoviridae, Reoviridae, Retroviridae, influenza viruses, parainfluenza viruses, mumps, measles, respiratory syncytial virus, rubella, Arb
  • Rhabdoviridae, Arenaviridae, Hepatitis A virus, Hepatitis B virus. Hepatitis C virus. Hepatitis E virus, Non-A/Non-B Hepatitis virus, Rhinoviridae, Coronaviridae, Rotoviridae, and Human Immunodeficiency Virus) e.g., rabies virus, herpesviruses, such as herpes simplex virus (HSV) type 2, HSV type 1, human cytomegalovirus, Epstein-Barr virus, and varicella zoster virus (VZV), human papillomavirus (HPV), Human T-cell lymphotropic virus type 1 , rotavirus, norovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, influenza virus, polio virus, Japanese encephalitis virus, measles virus, mumps virus, rubella virus, yellow fever virus, varicella virus, dengue virus, rota
  • Respiratory Syndrome Coronavirus, SARS coronavirus, SARS coronavirus 2, Crimean-Congo hemorrhagic fever virus, enteroviruses, and noroviruses either presented to the immune system in whole or in part isolated from media cultures designed to grow such viruses which are well known in the an, or antigens therefrom obtained by genetic engineering techniques or by chemical synthesis.
  • vaccines contemplated include, but are not limited to, influenza vaccine, pertussis vaccine, diphtheria and tetanus toxoid combined with pertussis vaccine, hepatitis A vaccine, hepatitis B vaccine, hepatitis C vaccine, hepatitis E vaccine, Japanese encephalitis vaccine, herpes vaccine, measles vaccine, rubella vaccine, mumps vaccine, mixed vaccine of measles, mumps and rubella, papillomavirus vaccine, parvovirus vaccine, respiratory syncytial virus vaccine, Lyme disease vaccine, polio vaccine, varicella vaccine, gonorrhea vaccine, schistosomiasis vaccine, rotavirus vaccine, mycoplasma vaccine pneumococcal vaccine, meningococcal vaccine, Campylobacter vaccine, helicobacter vaccine, cholera vaccine, enterotoxigenic E.
  • coli vaccine enterohernmorgagic E. coli vaccine, shigella vaccine, salmonella vaccine and others. These are produced by known common processes. In general, such vaccines comprise either the entire organism or virus grown and isolated by techniques well known to the skilled artisan, or comprise relevant antigens of these organisms or viruses which are produced by genetic engineering techniques or chemical synthesis.
  • compositions as provided herein may be in a kit.
  • the components of the adjuvant composition can already be mixed together for administration, or the components can be separate in the kit and administered separately as directed.
  • LT (R192G/L211 A), or dml.T
  • dmLT has recently had success in Phase 1 and 2 clinical trials: for ETEC and polio virus, though success for oral delivery seems to be dependent upon the immunogenicity of the antigen.
  • Both adjuvants have been pursued independently for various vaccines and delivery routes but have not been pursued together in any context.
  • synergistic adjuvant activity unexpected ex when dmLT and saponins are co-administered by oral and sublingual vaccination.
  • SDA saponin dmLT adjuvant
  • Campylobacter vaccine targeting bacterial enteric infections and inactivated polio vaccine. Projects are also exploring formation preparations specific to gastrointestinal delivery and conduct IND -enabling studies such as GLP and cGMP manufacturing, toxicology, and stability testing. It is believed that the present invention will help to define the SDA adjuvant platform and formulation that provides potent systemic immunity and/or sustained mucosal immunity.
  • compositions and methods of using the compositions for the treatment of a disease or disorder, or illness or condition may include one or more of a Quillaia saponin, and a heat-labile toxin including, for example, dmLT, and their use and methods for prophylactic use or therapeutic treatment.
  • Serum was collected on day 21 for analysis of anti-TT IgG by ELISA.
  • Results as shown in Figure 1 show a synergistic and unexpected effect when the two adjuvants are combined versus no adjuvant and when compared to the individual adjuvants.

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Abstract

Composition, de préférence un système adjuvant immunitaire, pour des vaccins contenant un composant de saponine et un composant de dmLT. La combinaison du composant de saponine et du composant de dmLT présente un effet synergique dans le traitement de divers états et diverses maladies. Les procédés d'utilisation pour un emploi prophylactique ou un traitement thérapeutique sont divulgués. Des exemples de compositions d'adjuvant comprennent un adjuvant de toxine thermolabile à double mutant dérivé d'une entérotoxine Escherichia coli et d'une saponine, éventuellement avec un composant de vaccin supplémentaire (par exemple, un antigène), en particulier lorsqu'il est utilisé dans un vaccin.
PCT/US2023/076673 2022-10-13 2023-10-12 Adjuvants à base de saponine dmlt et utilisations associées WO2024081774A1 (fr)

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WO2022106703A1 (fr) * 2020-11-20 2022-05-27 Institut Pasteur Disaccharides protégés, leur procédé de préparation et leur utilisation dans la synthèse d'oligosaccharides zwittérioniques, et leurs conjugués

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US20200330580A1 (en) * 2013-03-08 2020-10-22 Research Institute At Nationwide Children's Hospital Transcutaneous Dosage Formulation
WO2022106703A1 (fr) * 2020-11-20 2022-05-27 Institut Pasteur Disaccharides protégés, leur procédé de préparation et leur utilisation dans la synthèse d'oligosaccharides zwittérioniques, et leurs conjugués

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