CN112138151B - Foot-and-mouth disease vaccine composition and preparation method and application thereof - Google Patents
Foot-and-mouth disease vaccine composition and preparation method and application thereof Download PDFInfo
- Publication number
- CN112138151B CN112138151B CN201910580039.8A CN201910580039A CN112138151B CN 112138151 B CN112138151 B CN 112138151B CN 201910580039 A CN201910580039 A CN 201910580039A CN 112138151 B CN112138151 B CN 112138151B
- Authority
- CN
- China
- Prior art keywords
- head
- levamisole
- foot
- mouth disease
- adjuvant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 title claims abstract description 43
- 241000710198 Foot-and-mouth disease virus Species 0.000 title claims abstract description 43
- 229960005486 vaccine Drugs 0.000 title claims description 34
- 239000000203 mixture Substances 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229920002307 Dextran Polymers 0.000 claims abstract description 46
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 claims abstract description 44
- 239000002671 adjuvant Substances 0.000 claims abstract description 42
- 229960001614 levamisole Drugs 0.000 claims abstract description 42
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 claims abstract description 32
- 230000000091 immunopotentiator Effects 0.000 claims abstract description 31
- 229930006000 Sucrose Natural products 0.000 claims description 10
- 239000002480 mineral oil Substances 0.000 claims description 10
- 235000010446 mineral oil Nutrition 0.000 claims description 10
- 239000005720 sucrose Substances 0.000 claims description 10
- -1 sucrose ester Chemical class 0.000 claims description 10
- 230000002051 biphasic effect Effects 0.000 claims description 8
- 238000011260 co-administration Methods 0.000 claims 1
- 239000000427 antigen Substances 0.000 description 31
- 102000036639 antigens Human genes 0.000 description 31
- 108091007433 antigens Proteins 0.000 description 31
- 230000003053 immunization Effects 0.000 description 19
- 238000002649 immunization Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 8
- 230000036039 immunity Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000001681 protective effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 241000282887 Suidae Species 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 241001061264 Astragalus Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000006533 astragalus Nutrition 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000003308 immunostimulating effect Effects 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 210000004233 talus Anatomy 0.000 description 3
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940064004 antiseptic throat preparations Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940041984 dextran 1 Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002434 immunopotentiative effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- UFNDONGOJKNAES-UHFFFAOYSA-N Ginsenoside Rb1 Natural products CC(=CCCC(C)(OC1OC(COC2OC(CO)C(O)C(O)C2O)C(O)C(O)C1O)C3CCC4(C)C3C(O)CC5C6(C)CCC(OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C(C)(C)C6CC(O)C45C)C UFNDONGOJKNAES-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- LAZPBGZRMVRFKY-HNCPQSOCSA-N Levamisole hydrochloride Chemical compound Cl.C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 LAZPBGZRMVRFKY-HNCPQSOCSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241001493546 Suina Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229940089161 ginsenoside Drugs 0.000 description 1
- 229930182494 ginsenoside Natural products 0.000 description 1
- GZYPWOGIYAIIPV-JBDTYSNRSA-N ginsenoside Rb1 Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(CC[C@H]4C(C)(C)[C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GZYPWOGIYAIIPV-JBDTYSNRSA-N 0.000 description 1
- TXEWRVNOAJOINC-UHFFFAOYSA-N ginsenoside Rb2 Natural products CC(=CCCC(OC1OC(COC2OCC(O)C(O)C2O)C(O)C(O)C1O)C3CCC4(C)C3C(O)CC5C6(C)CCC(OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C(C)(C)C6CCC45C)C TXEWRVNOAJOINC-UHFFFAOYSA-N 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229940031551 inactivated vaccine Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 229960003734 levamisole hydrochloride Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5252—Virus inactivated (killed)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55583—Polysaccharides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
- C12N2770/32134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an immunopotentiator which is matched with a foot-and-mouth disease immune adjuvant for application, wherein the immunopotentiator comprises DEAE dextran and levamisole.
Description
Technical Field
The invention belongs to the field of medical preparations, and relates to an immunopotentiator composition, a preparation method and application thereof.
Background
Foot-and-mouth disease (FMD) is a viral disease that is extremely infectious to artiodactyls including domestic animals (cattle, pigs, sheep, goats, etc.) and a variety of wild animals. Foot and mouth disease vaccines are currently commonly used in water-in-oil-in-water dosage forms, such as the 206 adjuvant of SEPPIC company or the biphasic adjuvant patent disclosed in CN 107596364. Biphasic adjuvants require secondary immunization to achieve the desired prophylactic effect.
In order to improve the immune effect of foot-and-mouth disease vaccine, an immunopotentiator is added in the prior art, and CN109395076A discloses an immunopotentiator which comprises astragalus polysaccharide, triphenyl phosphate, hyaluronic acid and muramyl dipeptide, but the well-known triphenyl phosphate is insoluble in water, and the technical scheme experience of the patent proves that the immunopotentiator is difficult to realize. CN 101554476B discloses an immune astragalus polysaccharide for foot-and-mouth disease vaccine, which consists of ginsenoside Rb1, atractylenolide and glycyrrhetinic acid, and is composed of traditional Chinese medicine monomers, and has higher cost and is not practical. CN 107158374A has monophosphoryl lipid A5-520 mug/mL, muramyl dipeptide 10-520 mug/mL, beta-glucan 1-520 mug/mL and astragalus polysaccharide 0.05-5.2 mg/mL, and is verified that the composition has no enhancement effect. CN 101185757 discloses that ginsenoside can be used as immunopotentiator of foot-and-mouth disease vaccine, but its immunopotentiating effect should be further improved.
CN107106674 discloses a foot-and-mouth disease adjuvant comprising an immunostimulatory oligonucleotide and DEAE dextran. It does not disclose the relationship between both the immunostimulatory oligonucleotide and the DEAE dextran, and there is another problem in that the safety of the immunostimulatory oligonucleotide has not been studied sufficiently. GB1256457 shows that DEAE-dextran can only be used as an adjuvant for foot-and-mouth disease at a dose of 50mg. The effect of its use with biphasic adjuvants is not disclosed.
Although the prior art discloses substances and compositions which can play a role in enhancing the immunity of foot and mouth diseases, the problems of excessive use amount or inaccurate effect of single components of the effect, such as levamisole which is a common immunopotentiator, are shown to have no immunopotentiating effect on the antibodies of foot and mouth diseases according to the feasibility application analysis of the immunopotentiator of foot and mouth disease inactivated vaccine such as Shi Chenghong [ J ]. Chinese preventive veterinary school report 2014 (1) 59-62.
Another problem with foot and mouth disease vaccines is that the uniformity of antibody titers after immunization is inadequate, and some pigs appear to have high antibody titers, but some pigs have very low antibody titers. For this reason, a higher antigen content is required for immunization, which in turn raises safety issues.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides an immunopotentiator which is matched with an immune adjuvant for foot-and-mouth disease, wherein the immunopotentiator comprises DEAE dextran and levamisole or derivatives thereof, the dosage of the DEAE dextran is 0.3-50 mg/head, and the dosage of the levamisole or derivatives thereof is 1-5 mg/head.
The immunopotentiator and the foot-and-mouth disease immune adjuvant are matched for application, so that the immunoprotection can be provided by one-time immunization; the uniformity of the antibody titer after immunization is ensured to be high when the content of foot-and-mouth disease antigen is low, and the antibody titer is effectively improved; at high antigen content, a single immunization can be achieved ensuring high antibody titres and protective efficacy for 4 months.
The term "adjuvant" refers to a compound that, when administered in conjunction with an antigen, enhances the immune response of a subject to that antigen. Adjuvant-mediated immune response enhancement can be assessed by any method known in the art, including (without limitation) one or more of the following: (i) The number of antibodies generated in response to the combined adjuvant/antigen immunization is increased compared to the number of antibodies generated in response to the antigen immunization alone; (ii) an increase in the number of T cells recognizing the antigen or adjuvant; (iii) increased levels of one or more type I cytokines; and (iv) protection in vivo (in vivo) following activation. In certain embodiments of the invention, an immune response is enhanced if any measurable parameter of antigen-specific immune response increases by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, or at least 1000%, as compared to a subject challenged with antigen alone, when the subject is challenged with the antigen and the adjuvant.
As used herein, the term "DEAE dextran" refers to dextran modified ethylenediamine ethyl modification having a molecular weight of 50000 to 5X 10 6 . Preferably, the DEAE-dextran has a molecular weight of 500000-1.5X10 6 . The dosage is 0.3mg per dose to 50mg per dose.
The DEAE-dextran in the immunopotentiator may be selected from 0.3 mg/head, 0.4 mg/head, 0.5 mg/head, 0.6 mg/head, 0.7 mg/head, 0.8 mg/head, 0.9 mg/head, 1.0 mg/head, 1.1 mg/head, 1.2 mg/head, 1.3 mg/head, 1.4 mg/head, 1.5 mg/head, 1.6 mg/head, 1.7 mg/head, 1.8 mg/head, 1.9 mg/head, 2.0 mg/head, 2.5 mg/head, 3.0 mg/head, 3.5 mg/head, 4.0 mg/head, 4.5 mg/head, 5.5 mg/head, 6.0 mg/head, 6.5 mg/head, 7.0 mg/head, 7.8 mg/head, 1.9 mg/head, 2.0 mg/head, 2.5 mg/head, 4.5 mg/head, 5 mg/head, 5.5 mg/head, 6.5 mg/head, 5 mg/head, 5.5 mg/head, 15 mg/head, 16.5 mg/head, 15 mg/head, 15.5 mg/head, 16 mg/head, 5 mg/head, 15.5 mg/head, 5 mg/head, 15.9 mg/head, head.
The term levamisole is a compound of the formula C11H12N2S, and the derivative of levamisole refers to the levamisole derivative which is the hydrochloride or the phosphate thereof, and the levamisole is used in an amount of 1mg to 5mg per dose according to the molecular weight of the levamisole.
Levamisole or a derivative thereof in the immunopotentiator may be selected from 1 mg/head, 1.1 mg/head, 1.2 mg/head, 1.3 mg/head, 1.4 mg/head, 1.5 mg/head, 1.6 mg/head, 1.7 mg/head, 1.8 mg/head, 1.9 mg/head, 2.0 mg/head, 2.1 mg/head, 2.2 mg/head, 2.3 mg/head, 2.4 mg/head, 2.5 mg/head, 2.6 mg/head, 2.7 mg/head, 2.8 mg/head, 2.9 mg/head, 3 mg/head, 3.5 mg/head, 4 mg/head, 4.5 mg/head, 5 mg/head.
As one embodiment of the invention, the foot-and-mouth disease immune adjuvant for the matched application is 206 adjuvant or is a biphasic adjuvant prepared from sucrose ester, AEO-5 and mineral oil, wherein the proportion of the sucrose ester, the AEO-5 and the mineral oil is 4g, 4g and 92g, and the sucrose ester, the AEO-5 and the mineral oil are uniformly mixed.
In one embodiment of the present invention, the immunopotentiator of the present invention comprises 0.3 to 1mg of DEAE-dextran per unit of head and 1 to 2mg of levamisole or its derivative.
DEAE dextran is in the content range of 0.3-1 mg/head, levamisole or its derivative is in the content range of 1-2 mg/head, and can produce better immune effect than single-component DEAE dextran 50 mg/head, single-component levamisole or its derivative 5 mg/head, namely in the low content range: when DEAE dextran is 0.3-1 mg/head part and levamisole or 1-2 mg/head part of derivative thereof, the DEAE dextran and the levamisole have synergistic effect.
As a preferred embodiment of the invention, in the immunopotentiator of the invention, the foot-and-mouth disease immunopotentiator for matched administration is 206 adjuvant, the DEAE dextran is used in an amount of 0.3-50 mg/head, and the levamisole or the derivative thereof is used in an amount of 1-5 mg/head.
As a further preferred embodiment of the present invention, in the immunopotentiator of the present invention, DEAE-dextran is used in an amount of 0.3 mg/head and levamisole or its derivative is used in an amount of 1 mg/head; or DEAE dextran 1 mg/head, levamisole or its derivative 2 mg/head; or DEAE dextran 50 mg/head, levamisole or its derivative 5 mg/head.
As a preferred embodiment of the invention, in the immunopotentiator of the invention, the foot-and-mouth disease immune adjuvant which is cooperatively applied is a biphasic adjuvant prepared from sucrose ester, AEO-5 and mineral oil, the DEAE-dextran dosage is 0.3-50 mg/head, and the levamisole or the derivative thereof is 1-5 mg/head.
As a further preferred embodiment of the present invention, in the immunopotentiator of the present invention, DEAE-dextran is used in an amount of 0.3 to 1 mg/part, and levamisole or its derivative is used in an amount of 1 to 2 mg/part.
As a still further preferred embodiment of the present invention, in the immunopotentiator of the present invention, DEAE-dextran is used in an amount of 0.3 mg/head and levamisole or its derivative is used in an amount of 1 mg/head; or DEAE dextran 1 mg/head, levamisole or its derivative 2 mg/head.
The invention also provides a vaccine composition, wherein the vaccine composition comprises the foot-and-mouth disease immunopotentiator, a foot-and-mouth disease immune adjuvant, a foot-and-mouth disease antigen and a pharmaceutically acceptable carrier.
As one embodiment of the invention, in the vaccine composition, the foot-and-mouth disease antigen is O-type foot-and-mouth disease inactivated antigen, the antigen dosage is more than or equal to 6 mug/head, and the volume ratio of the adjuvant to the antigen is 1:1.
As a preferred embodiment of the present invention, the amount of the antigen used in the vaccine composition of the present invention is 6 to 25. Mu.g/head.
The immunopotentiator and the foot-and-mouth disease immune adjuvant are combined for administration, so that the immunity can be protected by one-time immunization; when the antigen content is low, the uniformity of the antibody titer after immunization can be ensured, the antibody titer is effectively improved, and the safety problem caused by higher antigen content is indirectly avoided; when high antigen content is selected, then a single immunization can be achieved ensuring high antibody titers and protective efficacy for 4 months.
The term "vaccine composition" is a composition that can be used to elicit protective immunity in a recipient. Thus, after a subject has been vaccinated with an antigen, a vaccine may prevent, delay, or reduce the severity of disease progression in a subject exposed to the same or a related antigen (relative to a non-vaccinated subject). The protective immunity provided by the vaccine may be humoral (antibody-mediated) immunity or cellular immunity, or both.
The term "pharmaceutically acceptable carrier" includes any solvent, isotonic agent, dispersion medium, stabilizer, diluent, preservative used. Such as diluents including but not limited to water, phosphate buffered saline, ethanol, glycerol, isotonic agents including but not limited to sodium chloride, dextran, dextrose; the stabilizer comprises protein or disodium ethylenediamine tetraacetate, and has stabilizing effect because the protein can bind with protease. The compositions may also contain antibiotics or antiseptics, including, for example: gentamicin, thimerosal, or chlorocresol; it is well known to those skilled in the art that different classes of antibiotics or antiseptics may be used.
Advantageous effects of the invention
The inventor unexpectedly found that DEAE dextran is used as an immunopotentiator, and after the DEAE dextran is matched with levamisole or a derivative thereof, a large dosage is not needed, and the two components of the immunopotentiator have obvious synergistic effect;
after the foot-and-mouth disease vaccine is added with the immunity enhancing agent, the immunity uniformity is improved; one immunization can be achieved.
Detailed Description
The advantages and features of the present invention will become more apparent from the following description of the embodiments. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
The chemical reagents used in the examples of the invention are all analytically pure and purchased from the national drug group. The experimental methods provided by the invention are conventional methods unless specified; the biological material, unless otherwise specified, is commercially available.
EXAMPLE 1 DEAE dextran solution
DEAE dextran (molecular weight 5×10) was weighed 5 ) 5.0g of DEAE-dextran was dissolved completely by adding 100ml of water for injection and autoclaved at a concentration of 5% w/v with stirring.
EXAMPLE 2 levamisole solution
Levamisole hydrochloride was dissolved in deionized water, adjusted to pH 7.0 with sodium hydroxide solution to prepare a stock solution of 100 mg/ml, and filtered through a 0.2 μm filter.
EXAMPLE 3 immunization efficacy test of foot-and-mouth disease vaccine formulated with adjuvant of the invention
Vaccine compositions were prepared according to Table 1, in which antigen was inactivated with whole virus type O antigen MYA98 strain (derived from Zhongpu organism), DEAE dextran solution prepared in example 1 and levamisole solution prepared in example 2 were added to antigen solution in the amounts shown in Table 1, the volumes were supplemented with PBS solution having a pH of 7.4, and vaccine preparation was carried out using 206 adjuvant of SEPPIC in an adjuvant/antigen weight ratio of 1:1, at 31℃and 350 rpm for 5 minutes, to prepare foot-and-mouth disease vaccine.
Table 1 206 different formulations of adjuvant foot and mouth disease vaccine compositions
30 piglets negative for 28-day-old antibodies were selected and divided into 6 groups, 5 piglets per group, and according to the table, 2 ml/head were assayed for antibody titers by liquid phase blocking ELISA (liquid phase blocking ELISA kit, animal doctor institute in Lanzhou, antibody titer greater than 1:180, positive) at day 21 and day 28 after injection, and the detailed results are shown in Table 2.
TABLE 2 antibody detection effect of immunization with foot-and-mouth disease vaccine
The test results show that: the foot-and-mouth disease vaccine prepared by the 206 adjuvant in the comparative example 1 is immunized once, the uniformity of the antibody titer is poor, the titer of individual pig antibodies cannot be increased, the antibody titer is not obviously improved by the DEAE dextran or levamisole in the comparative example 2 and the comparative example 3, and the vaccines in the test examples A to C are all improved; the immunopotentiator disclosed by the invention can improve the immune uniformity and the antibody titer when the dosage of antigen is low, and the DEAE-dextran and levamisole have obvious synergistic enhancement effects, and the DEAE-dextran is in the content range of 0.3-1 mg/head, and the levamisole or the derivative thereof is in the content range of 1-2 mg/head, so that the immunopotentiator can generate better immune effects than 50 mg/head of single-component DEAE-dextran and 5 mg/head of single-component levamisole or the derivative thereof, thus the immunopotentiator can be seen in the low content range: when DEAE dextran is 0.3-1 mg/head part and levamisole or 1-2 mg/head part of derivative thereof, the DEAE dextran and the levamisole have synergistic effect.
EXAMPLE 4 Effect experiment of the immunopotentiator of the present invention in foot-and-mouth disease vaccine compositions containing different types of adjuvants
Vaccine compositions were formulated as in table 3, the antigen was inactivated with whole virus type O antigen MYA98 strain (derived from a mesogen) by adding DEAE dextran solution prepared in example 1 and levamisole solution prepared in example 2 in the amounts of table 3 to the antigen solution, supplementing the volumes with PBS solution having PH of 7.4, and the adjuvant was prepared using SEPPIC 206 adjuvant, or CN107596364a biphasic adjuvant prepared in example 1 (sucrose ester, AEO-5, biphasic adjuvant prepared with mineral oil in a ratio of 4g, 92g, sucrose ester, AEO-5, mineral oil, and heated to 30 c) and emulsified at 31 c for 5 minutes at 350 rpm to prepare the foot-and-mouth vaccine.
TABLE 3 formulation of the components of foot and mouth disease vaccine compositions with different adjuvant types
15 piglets negative for 28-day-old type O foot-and-mouth disease antibodies were selected, divided into 3 groups of 5 piglets, immunized with the vaccine composition prepared in accordance with Table 3, and the antibody titers were determined by liquid phase blocking ELISA (liquid phase blocking ELISA kit, animal doctor's institute, lanzhou, antibody titer was judged positive at more than 1:180) on day 21, day 28, 3 months after immunization and 4 months after immunization, respectively, at 2 ml/ad, with detailed results shown in Table 4 (average value of 5 pigs).
TABLE 4 immunization efficacy of foot and mouth disease vaccine
The test results show that the vaccine of the test example I, the vaccine of the test example II and the vaccine of the test example III can be immunized for 4 months for positive antibodies at one time, and the foot-and-mouth disease can realize high antibody titer and protective efficacy for 4 months after one immunization under high antigen content, while the vaccine of the comparative example 4 can not realize immune protection after one immunization (the antibody titer is more than or equal to 1:180).
The present invention is not limited to the above-mentioned embodiments, but is capable of modification and variation in all embodiments without departing from the spirit and scope of the present invention.
Claims (7)
1. The application of an immunopotentiator and a foot-and-mouth disease immune adjuvant in the combined preparation of a foot-and-mouth disease vaccine composition, wherein the immunopotentiator comprises a combination of DEAE dextran and levamisole, the DEAE dextran dosage is 0.3-50 mg/head, and the levamisole dosage is 1-5 mg/head;
the foot-and-mouth disease immune adjuvant for matched application is 206 adjuvant or is a biphase adjuvant prepared from sucrose ester, AEO-5 and mineral oil, wherein the proportion of the sucrose ester, the AEO-5 and the mineral oil is 4g, 4g and 92g, and the sucrose ester, the AEO-5 and the mineral oil are uniformly mixed.
2. The use according to claim 1, wherein DEAE dextran is 0.3-1 mg per head and levamisole is 1-2 mg per head.
3. The use according to claim 1, wherein the foot-and-mouth disease immune adjuvant for co-administration is 206 adjuvant, the amount of DEAE dextran is 0.3-50 mg/head, and the amount of levamisole is 1-5 mg/head.
4. The use according to claim 3, wherein DEAE dextran is used in an amount of 0.3 mg/head and levamisole is used in an amount of 1 mg/head; or (b)
The DEAE dextran dosage is 1 mg/head, and the levamisole dosage is 2 mg/head; or (b)
The DEAE-dextran amount was 50 mg/head and levamisole amount was 5 mg/head.
5. The use according to claim 1, wherein the foot-and-mouth disease immune adjuvant for the matched application is a biphasic adjuvant prepared from sucrose ester, AEO-5 and mineral oil, the DEAE dextran dosage is 0.3-50 mg/head, and the levamisole dosage is 1-5 mg/head.
6. The use according to claim 5, wherein the DEAE-dextran is used in an amount of 0.3-1 mg/head and levamisole is used in an amount of 1-2 mg/head.
7. The use according to claim 6, wherein DEAE dextran is used in an amount of 0.3 mg/head and levamisole is used in an amount of 1 mg/head; or (b)
The DEAE dextran amount was 1 mg/head and levamisole amount was 2 mg/head.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910580039.8A CN112138151B (en) | 2019-06-28 | 2019-06-28 | Foot-and-mouth disease vaccine composition and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910580039.8A CN112138151B (en) | 2019-06-28 | 2019-06-28 | Foot-and-mouth disease vaccine composition and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112138151A CN112138151A (en) | 2020-12-29 |
| CN112138151B true CN112138151B (en) | 2024-04-12 |
Family
ID=73891588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910580039.8A Active CN112138151B (en) | 2019-06-28 | 2019-06-28 | Foot-and-mouth disease vaccine composition and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112138151B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102361646A (en) * | 2009-03-23 | 2012-02-22 | 沃尔特及伊莱萨霍尔医学研究院 | Compounds and methods for modulating immune response |
| CN104248760A (en) * | 2013-12-16 | 2014-12-31 | 普莱柯生物工程股份有限公司 | Vaccine composition, preparation method and application thereof |
| CN104548083A (en) * | 2013-10-22 | 2015-04-29 | 普莱柯生物工程股份有限公司 | Vaccine composition as well as preparation method and application thereof |
| CN107541533A (en) * | 2017-06-13 | 2018-01-05 | 湖南民康生物技术研究所 | A kind of preparation method of medicine food hypha polysaccharide polypeptide immunopotentiator |
| CN107596364A (en) * | 2017-09-19 | 2018-01-19 | 洛阳赛威生物科技有限公司 | A kind of w/o/w adjunvant compositions, the vaccine combination prepared and preparation method thereof |
-
2019
- 2019-06-28 CN CN201910580039.8A patent/CN112138151B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102361646A (en) * | 2009-03-23 | 2012-02-22 | 沃尔特及伊莱萨霍尔医学研究院 | Compounds and methods for modulating immune response |
| CN104548083A (en) * | 2013-10-22 | 2015-04-29 | 普莱柯生物工程股份有限公司 | Vaccine composition as well as preparation method and application thereof |
| CN104248760A (en) * | 2013-12-16 | 2014-12-31 | 普莱柯生物工程股份有限公司 | Vaccine composition, preparation method and application thereof |
| CN107541533A (en) * | 2017-06-13 | 2018-01-05 | 湖南民康生物技术研究所 | A kind of preparation method of medicine food hypha polysaccharide polypeptide immunopotentiator |
| CN107596364A (en) * | 2017-09-19 | 2018-01-19 | 洛阳赛威生物科技有限公司 | A kind of w/o/w adjunvant compositions, the vaccine combination prepared and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112138151A (en) | 2020-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5679356A (en) | Use of GM-CSF as a vaccine adjuvant | |
| US8303965B2 (en) | Polyinosinic acid-polycytidylic acid-based adjuvant | |
| Tamayo et al. | Poly (anhydride) nanoparticles act as active Th1 adjuvants through Toll-like receptor exploitation | |
| JP2018518457A (en) | PRIME-BOOST REGIMENS comprising administration of at least one mRNA construct | |
| JPH10500113A (en) | Improved modified live BRSV vaccine | |
| JP2011057692A (en) | West nile vaccine | |
| NZ537014A (en) | Combine vaccine against mycoplasma hyopneumoniae and porcine viruses | |
| BRPI0116249B1 (en) | vaccine composition for immunization of an animal against mycoplasma hyopneumoniae infection and vaccine | |
| CN113144186B (en) | Varicella-zoster vaccine composition and preparation method and application thereof | |
| US7767197B2 (en) | Delivery vehicle composition and methods for delivering antigens and other drugs | |
| CN104623654A (en) | Application of chitosan oligosaccharide and vaccine containing chitosan oligosaccharide | |
| Kornuta et al. | A plasmid encoding the extracellular domain of CD40 ligand and Montanide™ GEL01 as adjuvants enhance the immunogenicity and the protection induced by a DNA vaccine against BoHV-1 | |
| US20220047699A1 (en) | Immunological adjuvant composition, preparation method and application thereof | |
| US9700615B2 (en) | Adjuvant formulations and methods | |
| CN112138151B (en) | Foot-and-mouth disease vaccine composition and preparation method and application thereof | |
| WO2024066288A1 (en) | Vaccine adjuvant, vaccine composition, and use thereof | |
| CN106267183B (en) | Live vaccine composition containing adjuvant and preparation method and application thereof | |
| EP3392291A1 (en) | Vaccine adjuvant composition based on amphiphilic polyamino acid polymer, containing squalene | |
| CN110507819B (en) | Application of artesunate as immunologic adjuvant in preparation of rabies vaccine | |
| Rehmani et al. | The influence of adjuvants on oral vaccination of chickens against Newcastle disease | |
| CN111789943B (en) | Oil-in-water adjuvant composition and preparation method and application thereof | |
| JPWO2019021957A1 (en) | Nasal dry powder pharmaceutical composition | |
| US20240207394A1 (en) | Toll-like receptor agonist-nanoparticle vaccine adjuvant | |
| Hongtu et al. | Immunogenicity of rabies virus G mRNA formulated with lipid nanoparticles and nucleic acid immunostimulators in mice | |
| Shawky et al. | Immunological effect of levamisole as immunostimulant in vaccination with bivalent oil adjuvant foot and mouth disease vaccine in sheep |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |