CN1391483A - Composition of octoxinol and polyvinyl chloride sorbitanate as accessory and uses in vaccins - Google Patents

Composition of octoxinol and polyvinyl chloride sorbitanate as accessory and uses in vaccins Download PDF

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CN1391483A
CN1391483A CN00816014A CN00816014A CN1391483A CN 1391483 A CN1391483 A CN 1391483A CN 00816014 A CN00816014 A CN 00816014A CN 00816014 A CN00816014 A CN 00816014A CN 1391483 A CN1391483 A CN 1391483A
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vaccine
virus
antigen
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influenza
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M·弗里德
P·赫尔曼德
V·亨德里克斯
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GlaxoSmithKline Biologicals SA
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SmithKline Beecham Biologicals SA
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Priority claimed from GB0016685A external-priority patent/GB0016685D0/en
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    • 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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
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    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

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Abstract

The invention relates to a novel adjuvant system comprising a polyoxyethylene sorbitan ester surfactant in combination with an octoxynol and vaccines comprising the adjuvant system together with an antigen. Further provided are methods of manufacturing the adjuvants and vaccines and the use of the adjuvants and vaccines in the prophylaxis or therapy of disease.

Description

Sorbitan ethoxylate and octoxinol combination and the application in vaccine thereof as adjuvant
The present invention relates to a kind of novel adjuvant system, described adjuvant system comprises and the bonded Sorbitan ethoxylate surfactant of octoxinol.The vaccine that the invention provides described novel adjuvant, comprises described adjuvant with and production method and it is formulated into method in the vaccine.The application aspect disease prevention or treatment of adjuvant of the present invention or vaccine also is provided.Described adjuvant especially can be used as mucosal adjuvants, but also is that system is effective.Described adjuvant especially can be used for influenza vaccines.
Except that avoiding the needs of the injection of misery with relevant because of the adverse effect that the patient is obedient to due to " syringe needle fear "; owing to shown that in animal through mucous membrane gives antigen and is that mucomembranous surface induces the efficient aspect the protective response bigger; and mucosa is the approach that many pathogen enter, so mucosal vaccination is attracting.Mucosal vaccination, for example intranasal vaccination in addition, are proposed, mucosa immunity-inducing in nasal mucosa not only, and in far-end mucosal sites also mucosa immunity-inducing (Mestecky, 1987 in the genitals mucosa for example, Joumal of ClinicalImmunology, 7,265-276; McGhee and Kiyono, Infectious Agents andDisease, 1993,2,55-73).Although many researchs are arranged in the art, be applicable to that human safe and effective adjuvant still has to be identified.The invention provides a kind of solution to this problem.
The medical applications of some non-ionic surface active agent is existing to be described.For example, having described intranasal gives Sorbitan ethoxylate, polyoxyethylene ether, bile salts and other penetration enhancers (Hirai etc. 1981 with the absorption that strengthens insulin in the nasal cavity, International Journal ofPharmaceutics, 9,165-172; Hirai etc. 1981, International Journal ofPharmaceutics, and 9,173-184).
Utilized other non-ionic surface active agent preparation.For example, comprise or the bacterin preparation of polyoxyethylene castor oil or caprylic/capric glyceride and polyethenoxy sorbitan one ester and antigenic mixture, can be behind the topical administration mucosa inducible system immunne response (WO94/17827).Present patent application discloses, non-ionic surface active agent TWEEN20 TM(polyethenoxy sorbitan one ester) and Imwitor742 TMThe combination or the TWEEN20 of (caprylic/capric glyceride) TMCan after the intranasal immunity, strengthen systemic immunity and reply with the combination of polyoxyethylene castor oil.This preparation has also been described in the literature for strengthening details (1996.Vaccine Research such as Gizurarson, 5, the 69-75 that gives the influence of antigenic immunne response at intranasal; Aggerbeck etc. 1997, Vaccine, 15,307-316; Tebbey etc., ViralImmunol 1999; 12 (1): 41-5).In the embodiment shown in the WO94/17827 (especially embodiment 4), strengthen the required TWEEN20 of described immunne response TMConcentration very high (36%), and even under the situation that caprylic/capric glyceride is arranged, the potentiation of immunne response does not take place under 28% concentration yet.
Also prepared non-ionic surface active agent in such a way, consequently formed the non-ionic surface active agent bubble and (be commonly referred to NISV; US5,679,355).The preparation of this non-ionic surface active agent is the formation double-layer of lipoid vesicle when cholesterol exists usually, described vesicle with antigen capture at inner aqueous phase or double-deck in itself.
WO96/36352 and US5,653,987 have described a kind of liquid preparation, and described medicament comprises at least two kinds of absorption enhancers and water, is mainly used in the oral delivery of insulin, and wherein the amount of every kind of absorption enhancer is the concentration of the 1-10%w/w of described total preparation.
Usually surfactant is used for the preparation of the oil emulsion adjuvant that Gong is administered systemically, plays the stabilize oil microdroplet.For example, Sorbitan ethoxylate (TWEEN TM) and fatty acid esters of sorbitan (SPAN TM) be used for the stabilized oil-in-water emulsion (EP0399843, WO95/17210).
In the past, the mixture that has utilized Triton X-100 or Tween and ether has prepared influenza virus vaccine with the influenza virus fracture.To this two kinds of fracture materials (split) systemic immunity originality clinical comparison shows that they be suitable (1981.J.Clin Microbiol 14 such as Gross, 534-8).Also studied other surfactant to the immunogenic influence of gained split vaccines.In the comparative study of parenteral, (1984 Vaccine 2 such as Mukhlis, 199-203) point out, totivirus has more immunogenicity than the virus of detergent fracture, but has produced the immunogenicity fracture material stronger than detergent empigen reluctantly between different detergent Triton X-100 and cetrimonium bromide (CTAB).
The applicant introduces a surprising discovery at this, and promptly Sorbitan ethoxylate and octoxinol are united as a kind of effective vaccine adjuvant.Advantageously, this compositions can system give, but through mucous membrane is enough to the inducible system immunne response when giving.The immunne response vaccine-induced by mucosal administration the present invention can be the same at least strong or suitable with it at least with observed immunne response behind system's injection traditional vaccine.
The invention provides safe and effective adjuvant, they are easy to produce, and can or give by mucosal route or by system approach.
Aspect first, the invention provides the adjuvant that comprises Sorbitan ethoxylate and octoxinol.
On the other hand, the invention provides and comprise according to adjuvant of the present invention and antigenic vaccine.
Especially preferably comprise according to adjuvant of the present invention and influenza antigen, be used to give mucomembranous surface, particularly give the vaccine combination of nasal mucosa.Yet, multiple alternative route of administration is arranged and, will describe these antigens hereinafter for other possible antigen of using according to vaccine of the present invention.
Octoxinol and Sorbitan ethoxylate are write at " Surfactant systems ": Attwood and Florence have description in (1983, Chapman and Hall).Merck IndexEntry 6858 (the 1162nd page, the 12nd edition, Merck ﹠amp; Co.Inc., Whitehouse Station, N.J., USA; ISBN 0911910-12-3) also describes octoxinol series in, comprised uncle's octylphenoxy polyethoxy ethanol (TRITON X-100 TM).Merck Index Entry 7742 (the 1308th page, the 12nd edition, Merck ﹠amp; Co.Inc., Whitehouse Station, N.J., USA; ISBN0911910-12-3) describe Sorbitan ethoxylate in, comprised polyethenoxy sorbitan monooleate (TWEEN80 TM).The two can be with the method production of wherein describing, perhaps from for example Sigma Inc purchase of commercial source.
The preferred octoxinol that confession is used according to adjuvant of the present invention comprises other non-ionic surface active agent from Triton series, for example Triton X-45,, Triton X-102, Triton X-114, Triton X-165, Triton X-205, Triton X-305, Triton N-57, Triton N-101 and Triton N-128, but special preferred tertiary octylphenoxy polyethoxy ethanol (Triton X-100).
Adjuvant of the present invention comprises a kind of Sorbitan ethoxylate and a kind of octoxinol.Described octoxinol is uncle's octylphenoxy polyethoxy ethanol (TRITON-X-100 preferably TM).Described Sorbitan ethoxylate is polyethenoxy sorbitan monooleate (TWEEN80 preferably TM).
Can also advantageously comprise a kind of bile salts or chlolic acid derivatives according to adjuvant of the present invention.
Therefore, described adjuvant can comprise for example polyethenoxy sorbitan monooleate (Tween 80), a kind of octoxinol for example NaTDC or sodium taurodeoxycholate of uncle's octylphenoxy polyethoxy ethanol (Triton X-100) and a kind of bile salts or chlolic acid derivatives for example of a kind of Sorbitan ethoxylate.In a preferred embodiment, the invention provides a kind of adjuvant formulation that comprises polyethenoxy sorbitan monooleate (Tween 80), uncle's octylphenoxy polyethoxy ethanol (Triton X-100) and NaTDC.
Preferably, the non-ionic surface active agent total concentration that exists in the described adjuvant formulation is lower than 40%, and more preferably about at the most 20%.Preferred range is between about 0.001-20%, more preferably 0.01-10%, most preferably about at the most 2% (w/v).
The preferred concentration of described various non-ionic surface active agent in final vaccine combination is as follows: octyl group or Nonylphenoxy polyethoxy ethanol be other detergent in Triton X-100 or the Triton series for example: 0.001%-20%, preferred 0.001-10%, more preferably 0.001-1%, most preferably 0.005-0.1% (w/v); Sorbitan ethoxylate is Tween 80:0.01-1% for example, most preferably from about 0.0% (w/v).
The particularly preferred scope of described non-ionic surface active agent concentration is: Tween 80 TM: 0.01-1%, most preferably from about 0.1% (v/v); Triton X-100 TM: 0.001-0.1%, most preferably 0.005-0.02% (w/v).
One aspect of the present invention is the bacterin preparation that comprises with the bonded Sorbitan ethoxylate surfactant of octoxinol, and wherein the antigen that exists in the vaccine is at large obtains in the bubble of non-ionic surface active agent.
For the influenza antigen used according to vaccine of the present invention can be any type of influenza antigen that is suitable for causing immunne response, comprises totivirus alive or inactivation, fracture virus or by the subunit antigen totivirus preparation or by recombinant methods.Being used for producing antigenic influenza virus can cultivate at embryonated egg with conventional method, or described virus can be cultivated in tissue culture.The suitable cellular matrix that is used for influenza virus tissue culture comprises: Madin-Darby canine kidney(cell line) for example, for example mdck cell, from a clone's of MDCK cell or MDCK like cell; Monkey-kidney cells, for example the AGMK cell comprises the Vero cell; Or be suitable for producing vaccine any other cell type with influenza virus.Suitable cellular matrix also comprises people's cell, for example the MRC-5 cell.Suitable cellular matrix is not limited to cell line, for example also comprises primary cell, for example chick embryo fibroblast.
The influenza antigen preparation that preferably comprises the fracture virus (split virus) that has experienced a series of purification steps.Therefore, described antigen preparation can adopt multiple different commercial suitable method production, the fracture influenza virus method of in No. 300 833, DD and 211 No. 444 patents of DD, describing for example, and described patent is attached to herein by reference.Commercially available fracture influenza vaccines comprise the Fluarix that is sold by SmithKline Beecham TM
Therefore, preferably comprise the influenza antigens (influenza antigen preferably ruptures) and Sorbitan ethoxylate and octoxinol in ovum or tissue culture source, randomly also comprise a kind of bile salts or chlolic acid derivatives according to bacterin preparation of the present invention.Most preferably this preparation comprises fracture influenza antigen, polyethenoxy sorbitan monooleate (Tween 80), uncle's octylphenoxy polyethoxy ethanol (Triton X-100) and NaTDC.
The multivalence influenza vaccines that preferably comprise two or more strains of influenza viruses according to influenza vaccines of the present invention.The trivalent vaccine that most preferably comprises three kinds of Strain.Traditional influenza vaccines comprise three kinds of strains of influenza viruses-two kind of A type Strain and a kind of Type B Strain.Yet the present invention does not get rid of the univalent vaccine that can be used under the pandemicity for example.The most most influenza antigens that contain from single A type Strain of the univalent vaccine of pandemic influenza.
Bacterin preparation of the present invention preferably is used for giving described vaccine by means of the through mucous membrane approach and protects or treat susceptibility to disease or ill mammal, and described mucosal route is for example oral/buccal/intestinal/vagina/rectum or nose approach.This give can microdroplet, spraying or dry powder form give.Spraying or aerial fog type bacterin preparation also constitute a part of the present invention.The suppository that enteric coated preparation for example is used for oral anti-gastric juice capsule and granule, be used for rectum or vagina administration also constitutes a part of the present invention.The present invention also can be used for strengthening the immunogenicity of antigens that is used for skin (transdermal delivery or percutaneous transmission).In addition, adjuvant of the present invention can parenteral transmission, for example intramuscular injection or subcutaneous injection.When for the intranasal vaccine time spent, with regard to character, vaccine of the present invention is hemolytic preferably.
According to route of administration, can use various dosers.For example, for preferred intranasal administration approach, can use sprayer unit, for example commercially available Accuspray TM(BectonDickinson).
The preferred spray devices that intranasal is used is the device that the performance of described device does not rely on the user applied pressure.These devices are called as pressure threshold device (pressure thresholddevice).Only when reaching threshold pressure, just discharge liquid from nozzle.These devices make and are easier to reach the consistent uniformly spraying of droplet size.Be applicable to that pressure threshold device of the present invention is known in the art, for example be described among WO91/13281, EP311863B and the EP516636B that described document is attached to herein by reference.This class device is at the commercial Pfeiffer GmbH that derives from.
Preferred intranasal device generation scope is the microdroplet (water is as liquid measure) of 1-200 μ m, preferred 10-120 μ m.Be lower than 10 μ m, the danger of suction is then arranged, therefore, the microdroplet that preferably is lower than 10 μ m is no more than about 5%.Not as less microdroplet, the microdroplet that therefore preferably surpasses 120 μ m is no more than about 5% greater than the propagation of the microdroplet of 120 μ m.
The dose double transmission is the preferred feature again for the intranasal transfer device that uses according to vaccine of the present invention.The dose double device contains two divided doses of a vaccine dose, gives a divided dose to each nostril.General described two divided doses are in a cell, and the structure of described device allows to transmit effectively a divided dose at every turn.
More on the one hand, the invention provides a kind of test kit, described test kit comprises a kind of intranasal administration device as herein described, and described device contains a kind of according to bacterin preparation of the present invention.In the preferred embodiment of the present invention aspect this, described intranasal administration device is equipped with influenza vaccines.
For some bacterin preparation, can in described preparation, comprise other vaccine component.Therefore, adjuvant formulation of the present invention also can comprise bile acid or derivatives thereof, especially salt form.These comprise the sodium salt or the chlolic acid derivatives of chlolic acid derivatives and salt thereof, particularly cholic acid.The example of bile acid and derivant thereof comprises cholic acid, deoxycholic acid, chenodeoxy cholic acid, lithocholic acid, ursodesoxycholic acid, hyodeoxycholic acid and derivant; for example the sweet ammonia of above-mentioned bile acid-, cattle sulphur, aminopropyl (amidopropyl)-1-propane sulfonic acid, aminopropyl-2-hydroxyl-1-propane sulfonic acid derivant or N, two (3D glucamide propyl group) the deoxidation gallbladder amide (deoxycholamide) of N-.A particularly preferred example is NaTDC (NaDOC), and it may reside in the final bacterin preparation.
Preferably, when preparation was the suspension of aqueous solution form or non-form of vesicles, adjuvant formulation of the present invention was favourable.This preparation is easy to and can repeatedly produces, also be easy to sterilization (by 450 or the 220nm pore membrane filter at the end eventually) and be easy to give nasal mucosa with Sprayable, and the complicated physical arrangement of described adjuvant can not be degraded.
In still another aspect of the invention, provide a kind of method for preparing vaccine, described method comprises and will mix with antigen according to adjuvant of the present invention.
More on the one hand, a kind of method of inducing or strengthening immunne response in curee's body is provided, described method comprises with described antigen with according to adjuvant of the present invention and mixing, and gives described curee with described mixture.
The approach that gives described curee more preferably passes through nasal mucosa preferably by mucomembranous surface.When described vaccine gave by nasal mucosa, described vaccine preferably gave as spray.Induce or a method for optimizing that enhance immunity is replied in, give described vaccine by per nasal, inducible system is replied.Therefore, according to mucosal vaccine of the present invention preferably when giving by mucosal route, can the inducible system immunne response.
The present invention also provides Sorbitan ethoxylate and octoxinol at adjuvant formulation, particularly in the application aspect the adjuvant formulation production that is used for patient's mucosa.The present invention also relates to Sorbitan ethoxylate, octoxinol and antigen at bacterin preparation, in particular for the application in the bacterin preparation production of mucosa.Described antigen is influenza antigen preferably.
Especially preferably give the adjuvant and the vaccine of nasal mucosa.
Preferably, bring out vaccine or potion reinforcement vaccine according to the potion that gives described vaccine comprising of vaccine of the present invention, the potion that for example comprises a kind of influenza vaccines of influenza antigens preparation brings out vaccine or potion reinforcement vaccine.
Can predict, compositions of the present invention will can be used to prepare and contain the antigenic vaccine that derives from various source.For example, antigen can comprise that the antigen in the antigen in nucleic acid, the antigen that derives from pathogen or antigenicity preparation, tumor source of people, antibacterial or virus or antigenicity preparation, host source comprises protein or peptide and the chimeric fusion protein that GnRH and IgE peptide, reorganization produce.
Bacterin preparation of the present invention preferably contains the antigen or the antigenic composition that can cause at the immunne response of human pathogen, and described antigen or antigenic composition derive from: HIV-1 (for example tat, nef, gp120 or gp160); The herpes virus hominis, for example the gD or derivatives thereof or immediately early protein for example derive from the ICP27 of HSV1 or HSV2; Cytomegalovirus ((especially Human virus) (for example gB or derivatives thereof); Rotavirus (Rotavirus) (comprising attenuated live virus); Epstein-Barr virus (for example gp350 or derivatives thereof); Varicella zoster virus (for example gpI, II and IE63); Or hepatitis virus, for example hepatitis B virus (for example hbs antigen or derivatives thereof), hepatitis A virus, hepatitis C virus and hepatitis E virus; Perhaps described antigen or antigenic composition derive from other viral pathogen, paramyxovirus for example: respiratory syncytial virus (for example F albumen and G albumen or derivatives thereof), parainfluenza virus, Measles virus, mumps virus, human papillomavirus (HPV6 for example, 11,16,18, ...), banzi virus (yellow fever virus for example, dengue virus, Ticks passes meningitis virus, Japan's meningitis virus) or influenza virus (full live virus or inactivation of viruses, the fracture influenza virus, at ovum or mdck cell, or cultivate in Vero cell or the full influenza virus body (as R.G1uck, Vaccine, 1992,10, described in the 915-920); Or the protein of its purification or recombinant protein, for example HA, NP, NA or M albumen or its combination); Perhaps described antigenic composition derives from bacterial pathogens, for example: Neisseria gonorrhoeae (Neisseria spp.) comprises Diplococcus gonorrhoeae (N.gonorrhea) and Neisseria meningitidis (N.meningitidis) (for example pressing from both sides film polysaccharide and conjugate thereof, transferrin bindin, lactoferrin binding protein, PilC, adhesin); Streptococcus pyogenes (S.pyogenes) (for example M albumen or its fragment, C5A protease, lipoteichoic acid), streptococcus agalactiae (S.agalactiae), Streptococcus mutans (S.mutans); Ducrey bacillus (H.ducreyi); Catarrhalis (Moraxella spp.) comprises morazella catarrhalis (M.cararrhalis), is also referred to as mucositis branhamella (Branhamella catarrhalis) (for example high molecular and low-molecular-weight adhesin and invasin); Bordetella (Bordetella spp.) comprises Bordetella pertussis (B.pertussis) (for example pertactin, pertussis toxin, PT or derivatives thereof, filamentous hemagglutinin, adenyl cyclase, pilus), Bordetella parapertussis (B.parapertussis) and bronchus deteriorated blood Bordetella (B.bronchiseptica); Mycobacteria (Mycobacerium spp.) comprises mycobacterium tuberculosis (M.tuberculosis) (for example ESAT6, antigen 85A, 85B or 85C), Mycobacterium bovis (M.bovis), Mycobacterium leprae (M.leprae), black mycobacteria (N.avium), mycobacterium paratuberculosis (M.paratuberculosis), mycobacterium smegmatis (M.smegmatis); Legionella (Legionellaspp.) comprises legionella pneumophilia (L.pneumophila); Escherichia (Escherichia spp.) comprises enterotoxigenic Escherichia coli (for example colonizing factor, heat-labile toxin or derivatives thereof, thermally-stabilised toxicity or derivatives thereof), enterohemorrhagic Escherichia coli, enteropathogenic E.Coli (for example shiga toxin sample toxin or derivatives thereof); Vibrio (Vibrio spp.) comprises vibrio cholera (V.cholera) (for example cholera toxin or derivatives thereof); Shigella (Shigella spp.) comprises Shigella sonnei (S.sonnei), shigella dysenteriae (S.dysenteriae), shigella flexneri (S.flexnerii); Yersinia (Yersinia spp.) comprises yersinia enterocolitica (Y.enterocolitica) (for example Ypo albumen), Yersinia pestis (Y.pestis), artificial tuberculosis yersinia genus (Y.pseudotuberculosis); Campylobacter (Campylobacter spp) comprises campylobacter jejuni (C.jejuni) (for example toxin, adhesin and invasin) and large intestine Campylobacter (C.coli); Salmonella (Salmonella spp.) comprises salmonella typhi (S.typhi), salmonella paratyphi (S.paratyphi), Salmonella choleraesuls (S.choleaesuis), Salmonella enteritidis (S.entertidis); Listeria spp (Listeria spp.) comprises monocyte hyperplasia listeria spp (L.monocytogenes); Helicobacter pylori (Helicobacter spp) comprises helicobacter pylori (H.pylori) (for example urase, catalase, VacA (vacuolating toxin)); Pseudomonas (Pseudomonas spp.) comprises Pseudomonas aeruginosa (P.aeruginosa); Streptococcus (Staphylococcus spp.), golden yellow streptococcus (S.aureus), epidermis streptococcus (S.epidermidis); Enterococcus (Enterococcus spp.) comprises enterococcus faecalis (E.faecalis), enterococcus faecalis (E.faecium); Clostridium (Clostridium spp.) comprises clostridium tetani (C.tetani) (for example tetanus toxin and derivant thereof), bacillus botulinus (C.botulinum) (for example Botulinum toxin and derivant thereof), clostridium difficile (C.difficile) (for example clostridial toxin A or B and derivant thereof); Bacillus cereus (Baccillus spp.) comprises Bacillus anthracis (B.anthracis) (for example Botulinum toxin and derivant thereof); Rod bacillus (Corynebacterium spp.) comprises corynebacterium diphtheriae (C.diphtheriae) (for example diphtheria toxin, diphtherotoxin and derivant thereof); Burgdorferi (Borrelia spp.) comprises B. burgdorferi (B.burgdorferri) (for example OspA, OspC, DbpA, DbpB), lattice borrelia burgdorferi (B.garinii) (for example OspA, OspC, DbpA, DbpB), Ah's borrelia burgdorferi (B.afzelii) (for example OspA, OspC, DbpA, DbpB), B.andersonii (for example OspA, OspC, DbpA, DbpB), borrelia hermsii (B.hermsii); Ehrlichiosis body (Ehrlichia spp.) comprises the pathogen of horse ehrlichiosis body (R.equi) and human granular leukocyte ehrlichioses; Rickettsia (Rickettsia spp.) comprises Rickettsia rickettsii (R.rickettsii); Chlamydia (Chlamydia spp.) comprises sand holes chlamydia (C.trachomatis) (for example MOMP, hepatic binding protein (HBP)), Chlamydia pneumoniae (C.pneumoniae) (for example MOMP, hepatic binding protein (HBP)), chlamydia psittaci (C.psittaci); Leptospira (Leptospira spp.) comprises leptospira interrogans (L.interrogans); Treponema (Treponema spp.) comprises Treponoma palladium (T.pallidum) (for example rare outer membrane protein), treponema denticola (T.hyodusenteriae), swine dysentery treponema (T.hyodysenteriae); Perhaps described antigen or antigenic composition derive from parasite, and for example: plasmodium (Plasmodium spp.) comprises Plasmodium falciparum (P.falciparum); Toxoplasma (Toxoplasma spp.) comprises Mus toxoplasma (T.gondii) (for example SAG2, SAG3, Tg34); Entamoeba (Entamoeba spp.) comprises Entamoeba histolytica (E.histolytica); Babesia (Babesia spp.) comprises vole babesia (B.microti); Trypanosomicide (Trypanosomaspp.) comprises Crewe Si Shi trypanosomicide (T.cruzi); Giardia lamblia stiles (Giardia spp.) comprises giardia lamblia (G.lamblia); Leshmania spp. comprises L.major; Lung sac worm (Pneumocystis spp.) comprises Pneumocystis carinii (P.carinii); Trichomonacide (Trichomonasspp.) comprises trichomonal vaginitis (T.vaginalis); Schistosomicide (Schisostoma spp.) comprises Schistosoma mansoni (S.mensoni); Perhaps described antigen or antigen composition derive from yeast, and for example: candidiasis (Candida spp.) comprises Candida albicans (C.albicans); Cryptococcus (Cryptococcus spp.) comprises Cryptococcus histolyticus (C.neoformans).
Preferred bacterial vaccine comprises and derives from antigen and proteantigen pneumolysin (the Biochem Biophys Acta that streptococcus (Streptococcus spp.) comprises streptococcus pneumoniae (S.pneumoniae) (for example pressing from both sides film polysaccharide and conjugate thereof, PsaA, PspA, streptolysin, choline binding protein), 1989,67,1007; Rubins etc., MicrobialPathogenesis, 25,337-342) and saltant detoxification derivant (WO90/06951; WO99/03884).Other preferred bacterial vaccine comprise derive from that haemophilus (Haemophilus spp.) comprises Type B Haemophilus influenzae (H.influenzae type B) (for example PRP and conjugate thereof), the antigen of the Haemophilus influenzae (non typeable H.influenzae) that can not finalize the design for example OMP26, high molecular adhesin, P5, P6, protein D and lipoprotein D and fimbrin and fimbrin derived peptide (US5,843,464) or its multicopy variant (varient) or fusion rotein.Other preferred bacterial vaccine comprises antigen (comprising its adventitia vesicle (outmembrane vesicle) and OMP106 (WO97/41731)) that derives from morazella catarrhalis and antigen (comprising its adventitia vesicle) and the NspA (WO96/29412) that derives from Neisseria meningitidis B.
The derivant of hbs antigen is well-known in the art, especially is included in description is illustrated among European patent application EP-A-414374, EP-A-0304578 and the EP198-474 those PreS1, PreS2 S antigen.One preferred aspect, bacterin preparation of the present invention comprises HIV-1 antigen, gp120, especially when expressing in Chinese hamster ovary celI.In an embodiment again, bacterin preparation of the present invention comprises the gD2t of above qualification.
In a specific embodiments of the present invention, the vaccine that contains claimed adjuvant comprises antigen (HPV6 or HPV11 and other antigen) that derives from the human papillomavirus (HPV) who is considered to cause genital wart and the HPV virus (HPV16, HPV18 and other antigen) that causes cervical cancer.
Preventative or the therapeutic vaccine of the genital wart of special preferred form comprises L1 particle or capsomere and comprises one or more antigenic fusion rotein among albumen E6, E7, L1 and the L2 that is selected from HPV6 and HPV11.
The fusion rotein of most preferred form is: disclosed protein D (1/3)-E7 among disclosed L2E7 and the GB9717953.5 (PCT/EP98/05285) among the WO96/26277.
The HPV cervix uteri infects or a kind of preferred preventative or therapeutic vaccine compositions of cervical cancer, can comprise the antigen of HPV16 or 18.For example, L1 or L2 antigen monomer or the L1 that presents together as virus like particle (VLP) or L2 antigen or the independent L1 that in VLP or capsomere structure, presents separately.This class antigen, virus like particle and capsomere are known originally.Referring to for example WO94/00152, WO94/20137, WO94/05792 and WO93/02184.
Other early protein can comprise separately or for example comprise preferably E7, E2 or E5 with fusion rotein; Especially preferred embodiment comprises the VLP that contains L1E7 fusion rotein (WO96/11272).
Particularly preferred HPV16 antigen comprises getting up early albumen E6 or E7 or its combination of merging the HPV16 that forms protein D-E6 or E7 fusant with the protein D carrier; The perhaps combination of E6 or E7 and L2 (WO96/26277).
Perhaps, HPV16 or 18 early protein E6 and E7 may reside in the molecule, preferably protein D-E6/E7 fusant.This vaccine can randomly contain any one or two kinds of among the E6 of HPV18 and the E7, the preferably form of protein D-E6 or protein D-E7 fusion rotein or protein D E6/E7 fusion rotein.
Vaccine of the present invention can comprise in addition derive from other HPV strain, preferably from strain HPV6,11,31,33 or 45 antigen.
Vaccine of the present invention can comprise and derives from the parasitic antigen that causes malaria.For example, the preferred antigens that derives from Plasmodium falciparum comprises RTS, S and TRAP.RTS is a kind of hybrid albumen, comprises four proteic whole basically C-terminal parts of Plasmodium falciparum ring spore (CS) that aminoacid is connected with surface (S) antigen of hepatitis B virus by hbs antigen preS2 part.Its complete structure is disclosed in International Patent Application PCT/EP92/02591 number, and the publication No. of this patent application is WO93/10152, requires the priority of No. 9124390.7, UK Patent Application.When expressing in yeast, RTS produces as the lipoprotein particle, and when the S antigen coexpression of it and HBV, it produces a kind of RTS that is called, the stuff and other stuff of S.TRAP antigen is described in International Patent Application PCT/GB89/00895 number, and the latter's publication No. is WO90/01496.A preferred embodiment of the present invention is a malaria vaccine, and wherein said antigenicity preparation comprises RTS, the antigenic combination of S and TRAP.Other plasmodium antigens that may become multistage (multistage) malaria vaccine component candidate is its analog in MSP1, AMA1, MSP3, EBA, GLURP, RAP1, RAP2, sequestrin, PfEMP1, Pf332, LSA1, LSA3, STARP, SALSA, PfEXP1, Pfs25, Pfs28, PFS27/25, Pfs16, Pfs48/45, Pfs230 and the Plasmodium species of Plasmodium falciparum.
Perhaps, described preparation can contain a kind of tumor-resistant antigen, and can be used for the immunotherapeutical treatment of cancer.For example, described adjuvant formulation can be used together with tumor rejection antigen, and described tumor rejection antigen is carcinoma of prostate, breast carcinoma, colorectal carcinoma, pulmonary carcinoma, cancer of pancreas, renal carcinoma or melanomatous tumor rejection antigen for example.Exemplary antigen comprises and is used for the treatment of melanomatous MAGE 1 and MAGE 3 antigens or other MAGE antigen, PRAME, BAGE or GAGE (Robbins and Kawakami, 1996, Current Opinions in Immunology 8, the 628-636 pages or leaves; Van den Eynde etc., International Journal of Clinical ﹠amp; Laboratory Research (1997 submit to); 89, the 293 pages of Correale etc. (1997) Journal of theNational Cancer Institute).In fact, these antigens are expressed in various tumor types, for example express in melanoma, pulmonary carcinoma, sarcoma and bladder cancer.Other tumor specific antigen is suitable for using with adjuvant of the present invention, and described antigen includes but not limited to prostate specific antigen (PSA) or Her-2/neu, KSA (GA733), MUC-1 and carcinoembryonic antigen (CEA).Therefore, in one aspect of the invention, provide a kind of vaccine that comprises according to adjunvant composition of the present invention and a kind of tumor rejection antigen.
In addition, in many treatment for cancer or in immunocastration, described antigen can be the self peptide parahormone, for example the peptide of 10 of a kind of weak point amino acid longs-total length gonadotropin-releasing hormone (GnRH, WO95/20600).
Can predict, compositions of the present invention can be used for the antigenic vaccine that preparation contains the burgdorferi source.For example, antigen can comprise the antigen or the antigenicity preparation in nucleic acid, pathogen source, albumen or the peptide and the chimeric fusion protein of the generation of recombinating.Particularly, described antigen is OspA.OspA can be complete maturation protein that is called (Lipo-OspA) or the non-lipid derivant that is lipidization (lipidated) state by means of host cell (escherichia coli).The non-lipid derivant of this class comprises non-lipid NS1-OspA fusion rotein, it has preceding 81 aminoacid and the complete OspA albumen of the N-terminal of influenza virus non-structural protein (NS1), and another kind-MDP-OspA is the OspA that carries 3 amino acid whose non-lipid forms of extra N-terminal.
Vaccine of the present invention can be used for prevention or treatment allergy.This class vaccine will comprise allergen specific antigen (for example Der p1) and allergen heterogenetic antigen (for example derive from the peptide of people IgE, include but not limited to stanworth decapeptide (EP0477231B1)).
Proteinic amount in every vaccinating agent is chosen to be induction of immunity protective response in typical vaccine and do not have the amount of remarkable adverse side effect.According to using which kind of concrete immunogen and how it being presented, then this amount is with different.Generally speaking, every dose of expection will comprise 1-1000 μ g protein, preferred 1-500 μ g, preferred 1-100 μ g, 1-50 μ g most preferably.By relating to the research on standard of the intravital suitable immunne response of observation curee, can determine the optimal dose of concrete vaccine.Behind primary vaccination, the curee can accept once or the booster immunization of appropriate intervals for several times.
Vaccine of the present invention also can by oral route give.In this case, described pharmaceutically acceptable excipient also can comprise antiacid buffer agent or enteric coated capsule or microgranule.Vaccine of the present invention also can give by vaginal approach.In this case, described pharmaceutically acceptable excipient also can comprise for example CARBOPOL of emulsifying agent, polymer And the stabilizing agent of other known vaginal cream and suppository.Vaccine of the present invention also can give by the rectum approach.In this case, described excipient also can comprise wax and the polymer that is used to form rectal suppository known in the art.
Preparation of the present invention both can be used to prevent purpose, can be used for the treatment of purpose again.Therefore, the invention provides and a kind ofly treat easy trouble or suffer from infectious disease or the mammiferous method of cancer or allergy or autoimmune disease.In one side more of the present invention, provide a kind of adjuvant combination and a kind of vaccine that is used for medicine as herein described.New Trends and Developments inVaccines, Voller etc. write, University Park Press, Baltimore, Maryland, U.S.A.1978 have described bacterin preparation all sidedly.
In an alternate related embodiment of the present invention; adjuvant of the present invention can also be united with other adjuvant; described other adjuvant comprises cholera toxin and B subunit thereof; monophosphoryl lipid A and non-toxic derivant 3-deoxidation-acidylate monophosphoryl lipid A thereof (are described in British patent GB2; 220; No. 211); immunologic competence saponin part for example derives from the Quil A of bark of South America Quillaia saponaria QuillajaSaponaria Molina and derivant thereof (QS21 for example; U.S. Patent number 5; 057,540) and oligonucleotide adjuvant system CpG (being described in WO 96/02555); especially 5 ' TCG TCG TTT TGT CGT TTT GTC GTT3 ' (SEQ ID NO.1).
By the following examples explanation the present invention, but the invention is not restricted to following embodiment.In following examples, we use the virus of that shell egg is cultivated, as to use formalin-inactivated influenza virus or the fragmentation of TWEEN-ether or the egg of NaDOC fragmentation to cultivate and additional virus with Triton X-100.The concentration of Tween-80 and Triton X-100 is shown among the embodiment. Embodiment 1, be used for measuring the method that antibody in the serum (Ab) is replied Be used to measure the ELISA of influenza specific serum Ig Ab:
(by SSD GmBH manufacturer-supplied, Dresden's HA of the influenza virus of dull and stereotyped 1 μ g/ml β-propanoic acid lactone (BPL) deactivation of diluting in PBS with 50 μ l/ holes of Maxisorp Nunc immunity Germany) is spent the night in 4 ℃ of bags.The PBS sealing (1 hour, 37 ℃) of 1%BSA, 0.1% polyethenoxy sorbitan, one lauric acid ester (TWEEN 20) is promptly contained in free site on the described flat board with saturated buffer.Then, the control serum that will add by standard curve (has the serum that the mid point represented with ELISA unit/ml is tired, place the A capable) and 2 times of serial dilutions of blood serum sample (start from 1/100 dilution factor, place B-H capable) in 37 ℃ of incubations 1 hour 30 minutes.Use lavation buffer solution (PBS, 0.1% polyethenoxy sorbitan, one lauric acid ester (TWEEN 20)) washing (* 3) flat board then.Then, will be with saturated buffer with the anti-people Ig of biotinylated goat (Amersham) (50 μ l/ hole) of 1/3000 dilution in 37 ℃ of incubations 1 hour 30 minutes.After 3 washing and adding Succ-PEG-DSPE-horseradish peroxidase conjugate (Amersham) subsequently, with flat board washing 5 times, and under room temperature with colour developing buffer (OPDA 0.4mg/ml (Sigma) and H dull and stereotyped and 50 μ l/ holes 2O 20.03%, in the citrate buffer solution of 50mM pH 4.5) be incubated 20 minutes together.Add 50 μ l/ hole 2N sulphuric acid and color development stopping.Read optical density with Biorad 3550 immune readout meters in 492nm and 630nm.Use SoftMaxPro software, according to tiring of 4 parameter mathematical method calculating antibody. The blood clotting of influenza specific serum Ab suppresses (HAI) activity in the mice
The Kaolin of at first using 100 μ l0.5M borate buffer solutions (pH9) and 125 μ l Dade Behring to buy was handled serum (25 μ l) 20 minutes down in room temperature (RT).After centrifugal (30 minutes, 3000RPM or 860g), get 100 μ l supernatant (1/10 diluent that is equivalent to serum), and itself and 0.5% chicken red blood cell one are arised from 4 ℃ hatched 1 hour.After centrifugal 10 minutes, collect supernatant with 3200RPM (970g).Carry out these two operations to eliminate the natural blood clotting factor that contains in the serum.Then, the treated serum of 25 μ l dilutes (2 times of serial dilutions start from 1/20) with 25 μ l PBS in 96 hole Greiner plates.Totivirus (25 μ l/ hole) with 4 HAUs (promptly causing 1/4th dilution factor of the greatest dilution of red cell agglutination) BPL deactivation under agitation reaches 30 minutes in room temperature.At last flat board is kept down spending the night in 4 ℃, read then.The tire inverse of minimum serum dilution of the blood clotting that is equivalent to suppress virus induction of HAI. Embodiment 2, TWEEN80 and Triton in the mice body to the immunogenic influence of intranasal of the complete influenza virus of deactivation
In the past, mainly in without the animal body of attacking, carry out estimating before other influenza vaccines (vaccine that for example adds the parenteral vaccine of adjuvant, transmits based on vaccine or the mucosa of DNA) clinical.Generally speaking, the promising result who obtains from these researchs is not confirmed in human body.This may be because such fact: with different without the animal of attacking, the great majority adult before inoculation and on immunology " contacted antigen " by natural infection.Therefore, the best mode of evaluation intranasal influenza vaccine may be to test it to strengthen the ability of the immunne response of foundation in advance in the contacted antigenic animal body of per nasal in animal model.We have estimated TWEEN-80 and Triton X-100 in the present embodiment to such influence of replying.
At the 0th day, the HA by with the A/Beijing/262/95 influenza virus of pipettor (under anesthesia) the 2.5 μ g BPL deactivations that give to contain among the 10 μ l PBS in each nostril carried out the antigen contact in female Balb/c mice (8 age in week).After 28 days, carry out intranasal for mice (6 animal/groups) with 20 μ l solution (each nostril 10 μ l, with pipettor with the droplet form transmission) and strengthen (under anaesthetizing), described solution be or A:PBS; Perhaps B:TWEEN80 (0.11%) adds the solution of the HA that contains 5 μ g BPL deactivation A/Beijing/262/95 influenza virus among the Triton X-100 (0.074%); Perhaps pass through C: the influenza vaccines of intramuscular injection 1.5 μ g HA, strengthen.Antigen is by SSD GmBH manufacturer (Dresden, Germany) supply.As described in example 1 above, the HAI Ab that measures in the serum replys.As shown in Figure 1, when with TWEEN80 and Triton preparation, the inactivating influenza virus of intranasal transmission can be replied with the system HAI Ab that traditional parenteral influenza vaccines are strengthened setting up in advance equally effectively.Yet, under the situation that lacks TWEEN80 and Triton, the identical antigen that intranasal gives, its immunogenicity is significantly lower. Embodiment 3: fracture influenza virus intranasal vaccine and traditional parenteral vaccine (Fluarix with TWEEN80 and TRITON X-100 through ratifying TM) in the intravital immunogenic comparison of healthy adult curee. The preparation that is used for the research
Two kinds of preparations (A, B) of the fracture influenza antigens in egg source have been estimated.A is a kind of intranasal preparation, and the Fluarix that B is an intramuscular to be given TM/ α-Rix Described preparation contains three kinds of deactivation fracture virion antigens by the Strain preparation in 1998/1999 season of WHO suggestion.
The device that is used for the intranasal transmission is the Accuspray of Becton Dickinson TMThe nasal injection device.Spray 100 μ l A preparations in each nostril. The composition of described preparation
Intranasal preparation (A) contains following deactivation fracture virion:
1.?30μg?HA?A/Beijing/262/95(H1N1)
2.?30μg?HA?A/Sydney/5/97(H3N2)
3. the HA of 30 μ g B/Harbin/7/94 and phosphate buffered saline(PBS) pH 7.4 ± 0.1, Tween 80 0.1%, Triton X-100 0.015%, NaTDC 0.0045% and be lower than the thimerosal of 35 μ g/ml.
The volume of potion is 200 μ l (divided doses of each nostril 100 μ l).
Comparison Fluarix TM/ α-Rix Be the commercially available inactivated trivalent fracture influenza vaccines of SmithKline Beecham Biologicals.Intramuscular gives the dosage of 500 μ l.
This dosage contains:
The phosphate buffered saline(PBS) of NaTDC, 100 μ g/ml thimerosal and the pH 6.8-7.5 of Triton X-100, the highest 100 μ g/ml of the HA of the above-mentioned three kinds of Strain of 15 μ g, the Tween 80 of 500-1000 μ g/ml (0.05%-0.1%), 50-170 μ g/ml (0.005%-0.017%). Immunogenicity research
One open, contrast and research are at random arranged, estimating fracture influenza intranasal vaccine and the traditional parenteral vaccine prepared with Tween 80 and TritonX-100 (is Fluarix TM) immunogenicity compared.The adult subjects of 20 health (age is 18-40 year) is accepted potion Fluarix TM, 10 curees accept the potion intranasal influenza vaccine.Described intranasal preparation (200 μ l) contains following inactivation of viruses body: 30 μ g hemagglutinin A/Beijing/262/95 (H1N1), 30 μ g hemagglutinin A/Sydney/5/97 (H3N2), 30 μ g hemagglutinin B/Harbin/7/94 and phosphate buffered saline(PBS) (pH 7.4 ± 0.1), Tween 80 (0.1%), Triton X-100 (0.015%), NaTDC (0.0045%) and thimerosal (＜35 μ g/ml).
For part of bringing out and general symptom 8 days follow-up period is arranged, these two kinds of vaccines can both tolerated aspect safety and the reactionogenicity well.Do not report the serious adverse events relevant with inoculation.
Tire to determine that serological conversion rate (is defined as: compared with the 0th day by estimating serum blood clotting inhibition (HI); in the time of the 21st day with regard to every kind of vaccine strain the tire percentage ratio of the vaccine that improves 3 times at least of serum HI); transformation ratio is defined as: compared with the 0th day; in the time of the 21st day with regard to every kind of vaccine strain the increase multiple of serum HI geometric mean titer (GMT)) and the serum protective rate (be defined as: inoculation back serum HI tires 〉=percentage ratio of the vaccine of 40 (for every kind of vaccine strains); serum HI tires 〉=and 40 be recognized as the indication protective effect), check the immunogenicity of described vaccine.Generally speaking, influenza vaccines are for every kind of Strain, and necessary serological conversion rate is more than or equal to 40%, and the serum protective rate is more than or equal to 70%, and transformation ratio is more than or equal to 2.5, so that satisfy the requirement of international regulatory.This is applicable to the 18-60 adult in year; The old people is suitable for different standards.
In addition, estimate replying of mucosa IgA antibody by enzyme-linked immunosorbent assay (ELISA).
In table 1, can see and give potion Fluarix TMOr 21 days HI seroprevalence, serological conversion rate and serum protective rate behind the described intranasal preparation. Table 1: HI seroprevalence, serological conversion rate and serum protective rate when giving after 1 dose 21 days
Strain Group Time ??N Seropositivity n % Serum protection n % Seropositive conversion n %
??A/Beijing The intranasal vaccine adds Tween 80 and Trinton X100 The 0th day the 21st day ??20 ??20 ??4??????20.0 ??17?????85.0 ??0?????0.0 ??15????75.0 ??15?????75.0
?????Fluarix TM The 0th day the 21st day ??19 ??19 ??4??????21.1 ??19?????100.0 ??3?????15.8 ??18????94.7 ??19?????100.0
??A/Sydney The intranasal vaccine adds Tween 80 and Trinton X100 The 0th day the 21st day ??20 ??20 ??13?????65.0 ??20?????100.0 ??3?????15.0 ??19????95.0 ??15?????75.0
?????Fluarix TM The 0th day the 21st day ??19 ??19 ??14?????73.7 ??19?????100.0 ??1?????5.3 ??18????94.7 ??16?????84.2
??B/Harbin The intranasal vaccine adds Tween 80 and Trinton X100 The 0th day the 21st day ??20 ??20 ??10?????50.0 ??20?????100.0 ??7?????35.0 ??18????90.0 ??14?????70.0
?????Fluarix TM The 0th day the 21st day ??19 ??19 ??17?????89.5 ??19?????100.0 ??11????57.9 ??19????100.0 ??15?????78.9
Seropositivity (n, %): tire 〉=10 curee's number and percentage rate
Serum protection (n, %): tire 〉=40 curee's number and percentage rate
Seropositive conversion (n, %): the curee's that increases at least 4 times of tiring from the 0th day to the 21st day number and percentage rate
In all cases, greater than 2.5, this is the successful desired level of influenza vaccines to transformation ratio (multiple that inoculation back serum HI GMT increases).
The ratio that can see specificity mucosa IgA antibody between the 21st day and the 0th day/total mucosa IgA antibody in table 2 increases the curee's of 1 times or 3 times percentage rate (potion). Table 2: The ratio of specificity IgA antibody between the 21st day and the 0th day/total IgA antibody increases by 1 times or 3 Curee's doubly percentage rate (potion).
Strain Group ????N Increase by 1 times (%) Increase by 3 times (%)
??A/Beijing Tween 80 and Trinton Fluarix TM ????20 ????19 ????55.0 ????52.6 ????30.0 ????26.3
??A/Sydney Tween 80 and Trinton Fluarix TM ????20 ????19 ????65.0 ????47.4 ????45.0 ????5.3
??B/Harbin Tween 80 and Trinton Fluarix TM ????20 ????19 ????40.0 ????26.3 ????30.0 ????5.3
Sum up
More than the immunogenicity result that shows of tabulation shows, behind potion 21 days the time, the level of the seropositivity that described intranasal preparation causes, seropositive conversion and serum protection with by traditional parenteral vaccine (Fluarix TM) caused similar.Behind potion, the mucosa IgA that described intranasal preparation causes replys than traditional parenteral vaccine (Fluarix TM) caused will getting well.

Claims (18)

1. the purposes of the combination of Sorbitan ethoxylate and octoxinol is used for the adjuvant of production application in patient's mucomembranous surface.
2. the purposes of claim 1, wherein said Sorbitan ethoxylate is polyethenoxy sorbitan monooleate (TWEEN80 TM).
3. the purposes of claim 1 or claim 2, wherein said octoxinol is uncle's octylphenoxy polyethoxy ethanol (TRITON X-100 TM).
4. each purposes among the claim 1-3 also comprises a kind of bile salts or chlolic acid derivatives.
5. the purposes of each adjuvant among the claim 1-4, described adjuvant and antigen one are used from the vaccine of producing for mucosa delivery.
6. the purposes of claim 5, wherein said antigen is selected from: the human immunodeficiency virus, varicella zoster virus, herpes simplex types 1 virus, herpes simplex types 2 virus, human cytomegalic inclusion disease virus, dengue virus, hepatitis A virus, hepatitis B virus, hepatitis C virus or hepatitis E virus, respiratory syncytial virus, the human papillomavirus, influenza virus, Hib, meningitis virus, Salmonella (Salmonella), eisseria (Neisseria), Borrelia (Borrelia), chlamydiaceae (Chlamydia), Bordetella (Bordetella), Streptococcus (Streptococcus), Mycoplasma (Mycoplasma), Mycobacterium (Mycobacteria), Haemophilus spp (Haemophilus), Plasmodium (Plasmodium) or toxoplasma (Toxoplasma), the stanworth decapeptide; Or tumor associated antigen (TMA), MAGE, BAGE, GAGE, MUC-1, Her-2 neu, LnRH, CEA, PSA, KSA or PRAME.
7. the purposes of claim 6, wherein said antigen is antigen or the antigenicity preparation that derives from influenza virus.
8. the purposes of claim 7, wherein said antigenicity preparation are fracture influenza virus preparations.
9. the purposes of claim 7 or claim 8 is used to produce the vaccine of flu-prevention.
10. each purposes among the claim 5-9 is used to produce the vaccine for pharmaceutical.
11. a method of producing vaccine, described method comprises: with (a) a kind of Sorbitan ethoxylate, (b) a kind of octoxinol and (c) a kind of antigen mix, and provide vaccine for a vaccine dose of mucosa delivery.
12. the method for claim 11, wherein said vaccine provides in intranasal aerosol or spray device.
13. spray or aerosol device, dose double device more particularly, described device is equipped with and comprises a kind of Sorbitan ethoxylate, a kind of octoxinol and a kind of antigenic vaccine.
14. the spray of claim 13 or aerosol device, wherein said antigen are influenza antigens or antigenicity preparation.
15. the spray of claim 14 or aerosol device, wherein said antigenicity preparation are fracture influenza virus preparations.
16. a treatment suffers from or easy ill pathogen infection or cancer or allergic mammiferous method, described method comprises and gives described mammiferous mucosa safety and the vaccine combination of effective dose that described vaccine combination comprises a kind of Sorbitan ethoxylate, a kind of octoxinol and a kind of antigen.
17. the method for claim 16, wherein said vaccine gives through intranasal.
18. the method for claim 16 or claim 17, wherein said vaccine is an influenza virus vaccine, and described influenza virus vaccine comprises a kind of influenza antigens or antigenicity preparation, for example a kind of fracture influenza virus preparation.
CN00816014A 1999-09-24 2000-09-22 Composition of octoxinol and polyvinyl chloride sorbitanate as accessory and uses in vaccins Pending CN1391483A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI750929B (en) * 2020-12-02 2021-12-21 林建宏 Temperature-sensitive adjuvant for aerosol immunity and its preparation method

Families Citing this family (154)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025429A1 (en) 1996-01-04 1997-07-17 Rican Limited Helicobacter pylori bacterioferritin
SG165981A1 (en) 2000-10-27 2010-11-29 Chiron Srl Nucleic acids and proteins from streptococcus groups a & b
EP2339035A1 (en) 2000-12-07 2011-06-29 Novartis Vaccines and Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
TWI228420B (en) * 2001-05-30 2005-03-01 Smithkline Beecham Pharma Gmbh Novel vaccine composition
GB0115176D0 (en) 2001-06-20 2001-08-15 Chiron Spa Capular polysaccharide solubilisation and combination vaccines
US8481043B2 (en) 2001-06-22 2013-07-09 Cpex Pharmaceuticals, Inc. Nasal immunization
GB0118249D0 (en) 2001-07-26 2001-09-19 Chiron Spa Histidine vaccines
GB0121591D0 (en) 2001-09-06 2001-10-24 Chiron Spa Hybrid and tandem expression of neisserial proteins
AR045702A1 (en) 2001-10-03 2005-11-09 Chiron Corp COMPOSITIONS OF ASSISTANTS.
US7501134B2 (en) 2002-02-20 2009-03-10 Novartis Vaccines And Diagnostics, Inc. Microparticles with adsorbed polypeptide-containing molecules
EP2302039A1 (en) 2002-06-13 2011-03-30 Novartis Vaccines and Diagnostics, Inc. Virus-like particles comprising HML-2 gag polypeptide
GB0220194D0 (en) 2002-08-30 2002-10-09 Chiron Spa Improved vesicles
HUE031886T2 (en) 2002-10-11 2017-08-28 Glaxosmithkline Biologicals Sa Polypeptide vaccines for broad protection against hypervirulent meningococcal lineages
ATE466875T1 (en) 2002-11-15 2010-05-15 Novartis Vaccines & Diagnostic UNEXPECTED SURFACE PROTEINS IN NEISSERIA MENINGITIDIS
GB0227346D0 (en) 2002-11-22 2002-12-31 Chiron Spa 741
EP1585542B1 (en) 2002-12-27 2012-06-13 Novartis Vaccines and Diagnostics, Inc. Immunogenic compositions containing phospholipid
CA2514328C (en) 2003-01-30 2020-01-14 Chiron Srl Injectable vaccines against multiple meningococcal serogroups
GB0308198D0 (en) 2003-04-09 2003-05-14 Chiron Srl ADP-ribosylating bacterial toxin
US20060257852A1 (en) 2003-04-10 2006-11-16 Chiron Corporation Severe acute respiratory syndrome coronavirus
US9107831B2 (en) 2003-06-02 2015-08-18 Novartis Vaccines And Diagonstics, Inc. Immunogenic compositions containing microparticles comprising adsorbed toxoid and polysaccharide-containing antigens
US20060035242A1 (en) 2004-08-13 2006-02-16 Michelitsch Melissa D Prion-specific peptide reagents
GB0323103D0 (en) 2003-10-02 2003-11-05 Chiron Srl De-acetylated saccharides
EP1670506B1 (en) 2003-10-02 2012-11-21 Novartis AG Liquid vaccines for multiple meningococcal serogroups
CA2559371C (en) 2004-03-09 2014-07-08 Chiron Corporation Influenza virus vaccines
GB0409745D0 (en) 2004-04-30 2004-06-09 Chiron Srl Compositions including unconjugated carrier proteins
EP1740217B1 (en) 2004-04-30 2011-06-15 Novartis Vaccines and Diagnostics S.r.l. Meningococcal conjugate vaccination
GB0410866D0 (en) 2004-05-14 2004-06-16 Chiron Srl Haemophilius influenzae
EP1766034B1 (en) 2004-05-21 2014-03-19 Novartis Vaccines and Diagnostics, Inc. Alphavirus vectors for influenza virus vaccines
EP2277595A3 (en) 2004-06-24 2011-09-28 Novartis Vaccines and Diagnostics, Inc. Compounds for immunopotentiation
US20090317420A1 (en) 2004-07-29 2009-12-24 Chiron Corporation Immunogenic compositions for gram positive bacteria such as streptococcus agalactiae
GB0424092D0 (en) 2004-10-29 2004-12-01 Chiron Srl Immunogenic bacterial vesicles with outer membrane proteins
AU2006208208B2 (en) 2005-01-27 2011-05-19 Children's Hospital & Research Center At Oakland GNA1870-based vesicle vaccines for broad spectrum protection against diseases caused by Neisseria meningitidis
GB0502095D0 (en) 2005-02-01 2005-03-09 Chiron Srl Conjugation of streptococcal capsular saccharides
EP1858920B1 (en) 2005-02-18 2016-02-03 GlaxoSmithKline Biologicals SA Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli
EP1858919B1 (en) 2005-02-18 2012-04-04 Novartis Vaccines and Diagnostics, Inc. Immunogens from uropathogenic escherichia coli
DE602006020738D1 (en) 2005-08-01 2011-04-28 Hisamitsu Pharmaceutical Co ADJUVANS OR PHARMACEUTICAL PREPARATION FOR TRANSDERMAL OR TRANSMUCOSAL ADMINISTRATION
WO2007047749A1 (en) 2005-10-18 2007-04-26 Novartis Vaccines And Diagnostics Inc. Mucosal and systemic immunizations with alphavirus replicon particles
US11707520B2 (en) 2005-11-03 2023-07-25 Seqirus UK Limited Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
EP2368572B1 (en) 2005-11-04 2020-03-04 Seqirus UK Limited Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
CA2628379A1 (en) * 2005-11-04 2007-05-10 Novartis Vaccines And Diagnostics S.R.L. Adminstration routes for priming/boosting with influenza vaccines
WO2007081447A2 (en) 2005-11-22 2007-07-19 Novartis Vaccines And Diagnostics, Inc. Norovirus and sapovirus antigens
GB0524066D0 (en) 2005-11-25 2006-01-04 Chiron Srl 741 ii
KR20110110853A (en) 2006-01-27 2011-10-07 노파르티스 파르마 아게 Influenza vaccines containing hemagglutinin and matrix proteins
US8535683B2 (en) 2006-03-22 2013-09-17 Abbott Biologicals B.V. Intranasal or inhalational administration of virosomes
EP2357184B1 (en) 2006-03-23 2015-02-25 Novartis AG Imidazoquinoxaline compounds as immunomodulators
US20100068223A1 (en) * 2006-03-24 2010-03-18 Hanno Scheffczik Storage of Influenza Vaccines Without Refrigeration
CA2647942A1 (en) 2006-03-31 2007-11-08 Novartis Ag Combined mucosal and parenteral immunization against hiv
EP2054431B1 (en) 2006-06-09 2011-08-31 Novartis AG Conformers of bacterial adhesins
GB0614460D0 (en) 2006-07-20 2006-08-30 Novartis Ag Vaccines
EP2586790A3 (en) 2006-08-16 2013-08-14 Novartis AG Immunogens from uropathogenic Escherichia coli
CA3016948A1 (en) 2006-09-11 2008-03-20 Seqirus UK Limited Making influenza virus vaccines without using eggs
PL2121011T3 (en) 2006-12-06 2014-10-31 Novartis Ag Vaccines including antigen from four strains of influenza virus
GB0700562D0 (en) 2007-01-11 2007-02-21 Novartis Vaccines & Diagnostic Modified Saccharides
EP2123296B1 (en) * 2007-01-31 2019-05-22 Hisamitsu Pharmaceutical Co., Inc. Adjuvant for transdermal or transmucosal administration and pharmaceutical preparation containing the same
EA201070066A1 (en) 2007-06-27 2010-06-30 Новартис Аг VACCINES AGAINST FLU WITH LOW CONTENT OF ADDITIVES
GB0713880D0 (en) 2007-07-17 2007-08-29 Novartis Ag Conjugate purification
GB0714963D0 (en) 2007-08-01 2007-09-12 Novartis Ag Compositions comprising antigens
GB0810305D0 (en) 2008-06-05 2008-07-09 Novartis Ag Influenza vaccination
EP3067048B1 (en) 2007-12-07 2018-02-14 GlaxoSmithKline Biologicals SA Compositions for inducing immune responses
GB0818453D0 (en) 2008-10-08 2008-11-12 Novartis Ag Fermentation processes for cultivating streptococci and purification processes for obtaining cps therefrom
BRPI0821240B8 (en) 2007-12-21 2022-10-04 Novartis Ag mutant forms of streptolysin o
AU2009215364B2 (en) 2008-02-21 2014-09-18 Glaxosmithkline Biologicals S.A. Meningococcal fHBP polypeptides
CA2717870A1 (en) 2008-03-10 2009-09-17 Children's Hospital & Research Center At Oakland Chimeric factor h binding proteins (fhbp) containing a heterologous b domain and methods of use
SG186611A1 (en) 2008-12-09 2013-01-30 Pfizer Vaccines Llc Ige ch3 peptide vaccine
AU2010204139A1 (en) 2009-01-12 2011-08-11 Novartis Ag Cna_B domain antigens in vaccines against gram positive bacteria
EA201500910A1 (en) 2009-02-10 2016-04-29 Новартис Аг VACCINES AGAINST FLU WITH REDUCED NUMBER OF SQUALES
JP2012519482A (en) 2009-03-06 2012-08-30 ノバルティス アーゲー Chlamydia antigen
US8679505B2 (en) 2009-04-14 2014-03-25 Novartis Ag Compositions for immunising against Staphylococcus aureus
CN102413838A (en) 2009-04-30 2012-04-11 科勒制药集团有限公司 Pneumococcal vaccine and uses thereof
CA2765364C (en) 2009-06-15 2015-05-26 National University Of Singapore Influenza vaccine, composition, and methods of use
MX2012000395A (en) 2009-07-07 2012-02-28 Novartis Ag Conserved escherichia coli immunogens.
ES2918381T3 (en) 2009-07-15 2022-07-15 Glaxosmithkline Biologicals Sa RSV F protein compositions and methods for producing the same
JP2012532626A (en) 2009-07-16 2012-12-20 ノバルティス アーゲー Detoxified Escherichia coli immunogen
MX2012001194A (en) 2009-07-30 2012-03-07 Pfizer Vaccines Llc Antigenic tau peptides and uses thereof.
US20110076300A1 (en) 2009-08-27 2011-03-31 Mariagrazia Pizza Hybrid Polypeptides Including Meningococcal fHBP Sequences
EP2473605B1 (en) 2009-09-03 2018-04-11 Pfizer Vaccines LLC Pcsk9 vaccine
ES2812523T3 (en) 2009-09-30 2021-03-17 Glaxosmithkline Biologicals Sa Conjugation of Staphylococcus aureus type 5 and type 8 capsular polysaccharides
GB0918392D0 (en) 2009-10-20 2009-12-02 Novartis Ag Diagnostic and therapeutic methods
US20130022633A1 (en) 2009-10-27 2013-01-24 University Of Florence MENINGOCOCCAL fHBP POLYPEPTIDES
GB0919690D0 (en) 2009-11-10 2009-12-23 Guy S And St Thomas S Nhs Foun compositions for immunising against staphylococcus aureus
CN107412754A (en) 2009-12-22 2017-12-01 塞尔德克斯医疗公司 Vaccine combination
ES2707778T3 (en) 2009-12-30 2019-04-05 Glaxosmithkline Biologicals Sa Immunogens polysaccharides conjugated with carrier proteins of E. coli
GB201003333D0 (en) 2010-02-26 2010-04-14 Novartis Ag Immunogenic proteins and compositions
ES2661569T3 (en) 2010-03-30 2018-04-02 Children's Hospital & Research Center At Oakland H-factor binding proteins (fHbp) with altered properties and methods of use thereof
GB201005625D0 (en) 2010-04-01 2010-05-19 Novartis Ag Immunogenic proteins and compositions
US9597326B2 (en) 2010-04-13 2017-03-21 Glaxosmithkline Biologicals Sa Benzonapthyridine compositions and uses thereof
WO2011149564A1 (en) 2010-05-28 2011-12-01 Tetris Online, Inc. Interactive hybrid asynchronous computer game infrastructure
WO2011154863A1 (en) 2010-06-07 2011-12-15 Pfizer Inc. Her-2 peptides and vaccines
CA2800774A1 (en) 2010-06-07 2011-12-15 Pfizer Vaccines Llc Ige ch3 peptide vaccine
GB201009861D0 (en) 2010-06-11 2010-07-21 Novartis Ag OMV vaccines
EP3153578A1 (en) 2010-07-06 2017-04-12 Novartis Ag Norovirus derived immunogenic compositions and methods
US9192661B2 (en) 2010-07-06 2015-11-24 Novartis Ag Delivery of self-replicating RNA using biodegradable polymer particles
GB201101665D0 (en) 2011-01-31 2011-03-16 Novartis Ag Immunogenic compositions
WO2012072769A1 (en) 2010-12-01 2012-06-07 Novartis Ag Pneumococcal rrgb epitopes and clade combinations
WO2012085668A2 (en) 2010-12-24 2012-06-28 Novartis Ag Compounds
PT2667892T (en) 2011-01-26 2019-06-07 Glaxosmithkline Biologicals Sa Rsv immunization regimen
US20140004142A1 (en) 2011-03-02 2014-01-02 Pfizer Inc. Pcsk9 vaccine
JP2014519819A (en) 2011-05-13 2014-08-21 ノバルティス アーゲー RSVF antigen before fusion
EP3508219A1 (en) 2011-07-06 2019-07-10 GlaxoSmithKline Biologicals S.A. Self-replicating rna prime - protein boost vaccines
ES2656050T3 (en) 2011-07-06 2018-02-22 Glaxosmithkline Biologicals Sa Immunogenic combination compositions and uses thereof
US10030052B2 (en) 2011-07-25 2018-07-24 Glaxosmithkline Biologicals Sa Parvovirus Vp1 unique region polypeptides and compositions thereof
EP2659907A1 (en) 2012-05-01 2013-11-06 Affiris AG Compositions
EP2659906A1 (en) 2012-05-01 2013-11-06 Affiris AG Compositions
EP2659908A1 (en) 2012-05-01 2013-11-06 Affiris AG Compositions
CN105457021A (en) 2012-05-04 2016-04-06 辉瑞公司 Prostate-associated antigens and vaccine-based immunotherapy regimens
MX2014014067A (en) 2012-05-22 2015-02-04 Novartis Ag Meningococcus serogroup x conjugate.
EP2869842A1 (en) 2012-07-06 2015-05-13 Novartis AG Immunogenic compositions and uses thereof
MX2015004171A (en) 2012-10-02 2015-10-22 Glaxosmithkline Biolog Sa Nonlinear saccharide conjugates.
KR20150073943A (en) 2012-10-03 2015-07-01 글락소스미스클라인 바이오로지칼즈 에스.에이. Immunogenic composition
US9987344B2 (en) 2012-11-30 2018-06-05 Glaxosmithkline Biologicals Sa Pseudomonas antigens and antigen combinations
EP3689375A1 (en) 2013-05-15 2020-08-05 The Governors Of The University Of Alberta E1e2 hcv vaccines and methods of use
ES2744454T3 (en) 2013-10-31 2020-02-25 Hisamitsu Pharmaceutical Co Adjuvant composition
US11160855B2 (en) 2014-01-21 2021-11-02 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
KR102157200B1 (en) 2014-01-21 2020-09-21 화이자 인코포레이티드 Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
US10279019B2 (en) 2014-02-11 2019-05-07 Stc.Unm PCSK9 peptide vaccine conjugated to a Qbeta carrier and methods of using the same
CR20170020A (en) 2014-07-23 2017-08-10 Children´S Hospital & Res Center At Oakland VARIANTS OF PROTEIN UNIONS TO FACTOR H AND METHODS OF USE OF THESE
PL3244917T3 (en) 2015-01-15 2023-07-17 Pfizer Inc. Immunogenic compositions for use in pneumococcal vaccines
EP3302536A1 (en) 2015-06-03 2018-04-11 Affiris AG Il-23-p19 vaccines
EP3319988A1 (en) 2015-07-07 2018-05-16 Affiris AG Vaccines for the treatment and prevention of ige mediated diseases
KR102225282B1 (en) 2015-07-21 2021-03-10 화이자 인코포레이티드 Immunogenic composition comprising conjugated capsular saccharide antigen, kit comprising same, and use thereof
CA3005524C (en) 2015-11-20 2023-10-10 Pfizer Inc. Immunogenic compositions for use in pneumococcal vaccines
CN108778321A (en) 2016-01-19 2018-11-09 辉瑞公司 Cancer vaccine
KR102459629B1 (en) 2017-01-20 2022-10-28 화이자 인코포레이티드 Immunogenic compositions for use in pneumococcal vaccines
US11633471B2 (en) 2018-03-06 2023-04-25 Unm Rainforest Innovations Compositions and methods for reducing serum triglycerides
US11260119B2 (en) 2018-08-24 2022-03-01 Pfizer Inc. Escherichia coli compositions and methods thereof
CA3120922A1 (en) 2018-12-12 2020-06-18 Pfizer Inc. Immunogenic multiple hetero-antigen polysaccharide-protein conjugates and uses thereof
JP7239509B6 (en) 2019-02-22 2023-03-28 ファイザー・インク Method for purifying bacterial polysaccharides
US20220184199A1 (en) 2019-04-10 2022-06-16 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof
EP4051696A1 (en) 2019-11-01 2022-09-07 Pfizer Inc. Escherichia coli compositions and methods thereof
JP2021132644A (en) 2020-02-21 2021-09-13 ファイザー・インク Purification of saccharide
CA3173729A1 (en) 2020-02-23 2021-08-26 Pfizer Inc. Escherichia coli compositions and methods thereof
JP2023514825A (en) 2020-02-26 2023-04-11 ヴェルシテック リミテッド PD-1-based vaccine against coronavirus infection
PE20231934A1 (en) 2020-10-27 2023-12-01 Pfizer COMPOSITIONS OF ESCHERICHIA COLI AND METHODS THEREOF
CN116744965A (en) 2020-11-04 2023-09-12 辉瑞大药厂 Immunogenic compositions for pneumococcal vaccines
EP4243863A2 (en) 2020-11-10 2023-09-20 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
US20220202923A1 (en) 2020-12-23 2022-06-30 Pfizer Inc. E. coli fimh mutants and uses thereof
WO2022147373A1 (en) 2020-12-31 2022-07-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antibody-guided pcsk9-mimicking immunogens lacking 9-residue sequence overlap with human proteins
AU2022223712A1 (en) 2021-02-19 2023-10-05 Sanofi Pasteur Inc. Meningococcal b recombinant vaccine
US20240226280A1 (en) 2021-05-04 2024-07-11 King Abdullah University Of Science And Technology Immuogenic compositions of mutant sars-cov-2 n protein and gene and methods of use thereof
EP4346893A2 (en) 2021-05-28 2024-04-10 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
MX2023013434A (en) 2021-05-28 2023-12-12 Pfizer Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof.
WO2023079529A1 (en) 2021-11-05 2023-05-11 King Abdullah University Of Science And Technology Re-focusing protein booster immunization compositions and methods of use thereof
WO2023079528A1 (en) 2021-11-05 2023-05-11 King Abdullah University Of Science And Technology Compositions suitable for use in a method for eliciting cross-protective immunity against coronaviruses
IL312890A (en) 2021-11-18 2024-07-01 Matrivax Inc Immunogenic fusion protein compositions and methods of use thereof
CN118510548A (en) 2022-01-13 2024-08-16 辉瑞公司 Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
WO2023161817A1 (en) 2022-02-25 2023-08-31 Pfizer Inc. Methods for incorporating azido groups in bacterial capsular polysaccharides
WO2023218322A1 (en) 2022-05-11 2023-11-16 Pfizer Inc. Process for producing of vaccine formulations with preservatives
WO2024018061A1 (en) 2022-07-22 2024-01-25 Institut National de la Santé et de la Recherche Médicale Use of bordetella strains for the treatment of chronic obstructive pulmonary disease
WO2024110827A1 (en) 2022-11-21 2024-05-30 Pfizer Inc. Methods for preparing conjugated capsular saccharide antigens and uses thereof
WO2024110839A2 (en) 2022-11-22 2024-05-30 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
WO2024116096A1 (en) 2022-12-01 2024-06-06 Pfizer Inc. Pneumococcal conjugate vaccine formulations
WO2024130009A1 (en) 2022-12-14 2024-06-20 Yale University Compositions and methods of use thereof for the treatment of virally driven cancers
WO2024166008A1 (en) 2023-02-10 2024-08-15 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
WO2024201324A2 (en) 2023-03-30 2024-10-03 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4772466A (en) * 1983-08-22 1988-09-20 Syntex (U.S.A.) Inc. Vaccines comprising polyoxypropylene-polyoxyethylene block polymer based adjuvants
NL8403195A (en) * 1984-10-19 1986-05-16 Nederlanden Staat IMMUNOGENIC COMPLEXES AND VACCINES CONTAINING THESE.
CA1291036C (en) * 1986-04-23 1991-10-22 Edwin I. Stoltz Nasal administration of drugs
US5653987A (en) * 1995-05-16 1997-08-05 Modi; Pankaj Liquid formulations for proteinic pharmaceuticals

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI750929B (en) * 2020-12-02 2021-12-21 林建宏 Temperature-sensitive adjuvant for aerosol immunity and its preparation method

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