CN1399539A - Adjuvant comprising polyxyethylene alkyl ether or ester and at least one nonionic surfactant - Google Patents
Adjuvant comprising polyxyethylene alkyl ether or ester and at least one nonionic surfactant Download PDFInfo
- Publication number
- CN1399539A CN1399539A CN00816263A CN00816263A CN1399539A CN 1399539 A CN1399539 A CN 1399539A CN 00816263 A CN00816263 A CN 00816263A CN 00816263 A CN00816263 A CN 00816263A CN 1399539 A CN1399539 A CN 1399539A
- Authority
- CN
- China
- Prior art keywords
- polyoxyethylene
- vaccine
- ether
- antigen
- adjunvant composition
- 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.)
- Pending
Links
- 239000002671 adjuvant Substances 0.000 title claims abstract description 55
- 150000005215 alkyl ethers Chemical class 0.000 title claims abstract description 33
- 150000002148 esters Chemical class 0.000 title claims abstract description 29
- 239000002736 nonionic surfactant Substances 0.000 title abstract description 5
- 229960005486 vaccine Drugs 0.000 claims abstract description 109
- 239000000203 mixture Substances 0.000 claims abstract description 80
- -1 polyoxyethylene Polymers 0.000 claims abstract description 62
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 40
- 239000004094 surface-active agent Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 20
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 239000000427 antigen Substances 0.000 claims description 77
- 108091007433 antigens Proteins 0.000 claims description 74
- 102000036639 antigens Human genes 0.000 claims description 74
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 24
- 206010022000 influenza Diseases 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 17
- 229920001282 polysaccharide Polymers 0.000 claims description 16
- 239000005017 polysaccharide Substances 0.000 claims description 16
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 claims description 15
- UYDLBVPAAFVANX-UHFFFAOYSA-N octylphenoxy polyethoxyethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCO)C=C1 UYDLBVPAAFVANX-UHFFFAOYSA-N 0.000 claims description 13
- 241000701806 Human papillomavirus Species 0.000 claims description 12
- 230000002949 hemolytic effect Effects 0.000 claims description 12
- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 12
- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 12
- 241000712461 unidentified influenza virus Species 0.000 claims description 12
- 241000700605 Viruses Species 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 8
- 230000001717 pathogenic effect Effects 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 7
- 239000003599 detergent Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004380 Cholic acid Substances 0.000 claims description 6
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 6
- 235000019416 cholic acid Nutrition 0.000 claims description 6
- 229960002471 cholic acid Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 241000224016 Plasmodium Species 0.000 claims description 4
- 238000012737 microarray-based gene expression Methods 0.000 claims description 4
- 238000012243 multiplex automated genomic engineering Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 241000589968 Borrelia Species 0.000 claims description 3
- 241000700199 Cavia porcellus Species 0.000 claims description 3
- 241000282414 Homo sapiens Species 0.000 claims description 3
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims description 3
- 208000016604 Lyme disease Diseases 0.000 claims description 3
- 241000607142 Salmonella Species 0.000 claims description 3
- 241000223996 Toxoplasma Species 0.000 claims description 3
- 125000005466 alkylenyl group Chemical group 0.000 claims description 3
- 238000002474 experimental method Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 102100035526 B melanoma antigen 1 Human genes 0.000 claims description 2
- 241000588807 Bordetella Species 0.000 claims description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims description 2
- 241000606069 Chlamydiaceae Species 0.000 claims description 2
- 206010011831 Cytomegalovirus infection Diseases 0.000 claims description 2
- 241000725619 Dengue virus Species 0.000 claims description 2
- 241000606790 Haemophilus Species 0.000 claims description 2
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 claims description 2
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 2
- 241000701074 Human alphaherpesvirus 2 Species 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 102100034256 Mucin-1 Human genes 0.000 claims description 2
- 108010008707 Mucin-1 Proteins 0.000 claims description 2
- 241000186359 Mycobacterium Species 0.000 claims description 2
- 241000588653 Neisseria Species 0.000 claims description 2
- 102000036673 PRAME Human genes 0.000 claims description 2
- 108060006580 PRAME Proteins 0.000 claims description 2
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 2
- 241000194017 Streptococcus Species 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 210000000601 blood cell Anatomy 0.000 claims 2
- 229960001438 immunostimulant agent Drugs 0.000 claims 2
- 239000003022 immunostimulating agent Substances 0.000 claims 2
- 230000003308 immunostimulating effect Effects 0.000 claims 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims 1
- 201000009906 Meningitis Diseases 0.000 claims 1
- 241000204031 Mycoplasma Species 0.000 claims 1
- 208000030852 Parasitic disease Diseases 0.000 claims 1
- 239000000443 aerosol Substances 0.000 claims 1
- 208000026935 allergic disease Diseases 0.000 claims 1
- 230000007815 allergy Effects 0.000 claims 1
- 201000010284 hepatitis E Diseases 0.000 claims 1
- 210000004400 mucous membrane Anatomy 0.000 claims 1
- 238000012797 qualification Methods 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 10
- 229920002113 octoxynol Polymers 0.000 abstract description 3
- 229940066429 octoxynol Drugs 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 210000002966 serum Anatomy 0.000 description 29
- 229920002884 Laureth 4 Polymers 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 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 17
- 229940062711 laureth-9 Drugs 0.000 description 17
- 239000002953 phosphate buffered saline Substances 0.000 description 17
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 17
- 229940124896 Fluarix Drugs 0.000 description 16
- 229920004890 Triton X-100 Polymers 0.000 description 15
- 241001597008 Nomeidae Species 0.000 description 14
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 14
- 229920000053 polysorbate 80 Polymers 0.000 description 14
- 239000013504 Triton X-100 Substances 0.000 description 11
- 229960003971 influenza vaccine Drugs 0.000 description 11
- 229920001213 Polysorbate 20 Polymers 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 108700006640 OspA Proteins 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 230000004927 fusion Effects 0.000 description 8
- 230000036039 immunity Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229960000814 tetanus toxoid Drugs 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000012459 cleaning agent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000005847 immunogenicity Effects 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 230000000890 antigenic effect Effects 0.000 description 6
- 210000002850 nasal mucosa Anatomy 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 238000002255 vaccination Methods 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- 241000283707 Capra Species 0.000 description 5
- 241000282693 Cercopithecidae Species 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 239000003833 bile salt Substances 0.000 description 5
- 229940093761 bile salts Drugs 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- 244000052769 pathogen Species 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 231100000765 toxin Toxicity 0.000 description 5
- 239000003053 toxin Substances 0.000 description 5
- 108700012359 toxins Proteins 0.000 description 5
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 4
- 102000002322 Egg Proteins Human genes 0.000 description 4
- 108010000912 Egg Proteins Proteins 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 108700023315 OspC Proteins 0.000 description 4
- 241000223960 Plasmodium falciparum Species 0.000 description 4
- 101100431670 Rattus norvegicus Ybx3 gene Proteins 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000009849 deactivation Effects 0.000 description 4
- 235000013861 fat-free Nutrition 0.000 description 4
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000004531 microgranule Substances 0.000 description 4
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 4
- 210000004681 ovum Anatomy 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000001593 sorbitan monooleate Substances 0.000 description 4
- 235000011069 sorbitan monooleate Nutrition 0.000 description 4
- 229940035049 sorbitan monooleate Drugs 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 241000589969 Borreliella burgdorferi Species 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000341655 Human papillomavirus type 16 Species 0.000 description 3
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 3
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 3
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 3
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 208000000292 ehrlichiosis Diseases 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 210000004392 genitalia Anatomy 0.000 description 3
- 230000035931 haemagglutination Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PMTMAFAPLCGXGK-JMTMCXQRSA-N (15Z)-12-oxophyto-10,15-dienoic acid Chemical compound CC\C=C/C[C@H]1[C@@H](CCCCCCCC(O)=O)C=CC1=O PMTMAFAPLCGXGK-JMTMCXQRSA-N 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 241000223836 Babesia Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 241000589876 Campylobacter Species 0.000 description 2
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 2
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 241000186216 Corynebacterium Species 0.000 description 2
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 108010003272 Hyaluronate lyase Proteins 0.000 description 2
- 102000001974 Hyaluronidases Human genes 0.000 description 2
- 241000222722 Leishmania <genus> Species 0.000 description 2
- 101710105759 Major outer membrane porin Proteins 0.000 description 2
- 101710164702 Major outer membrane protein Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000588655 Moraxella catarrhalis Species 0.000 description 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
- 241000588650 Neisseria meningitidis Species 0.000 description 2
- PMTMAFAPLCGXGK-UHFFFAOYSA-N OPDA Natural products CCC=CCC1C(CCCCCCCC(O)=O)C=CC1=O PMTMAFAPLCGXGK-UHFFFAOYSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 101100028078 Oryza sativa subsp. japonica OPR1 gene Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 101710132594 Protein E6 Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 101710137302 Surface antigen S Proteins 0.000 description 2
- 241000589886 Treponema Species 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 241000607734 Yersinia <bacteria> Species 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 201000008680 babesiosis Diseases 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 230000003067 hemagglutinative effect Effects 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 108010057760 hepatic sialoglycoprotein receptor Proteins 0.000 description 2
- 230000005745 host immune response Effects 0.000 description 2
- 229960002773 hyaluronidase Drugs 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000000415 inactivating effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229940124735 malaria vaccine Drugs 0.000 description 2
- 238000012067 mathematical method Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- IDOQDZANRZQBTP-UHFFFAOYSA-N 2-[2-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=CC=C1OCCO IDOQDZANRZQBTP-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 101100162403 Arabidopsis thaliana ALEU gene Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 241000539677 Berant virus Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000588779 Bordetella bronchiseptica Species 0.000 description 1
- 241000588780 Bordetella parapertussis Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000142472 Borreliella andersonii Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000589875 Campylobacter jejuni Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241001647372 Chlamydia pneumoniae Species 0.000 description 1
- 241001647378 Chlamydia psittaci Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 101710164918 Choline-binding protein Proteins 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 241000193155 Clostridium botulinum Species 0.000 description 1
- 241000193449 Clostridium tetani Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 1
- 102100031262 Deleted in malignant brain tumors 1 protein Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 241000224431 Entamoeba Species 0.000 description 1
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 101710154643 Filamentous hemagglutinin Proteins 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 241000605909 Fusobacterium Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 101000812705 Gallus gallus Endoplasmin Proteins 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- 241000224466 Giardia Species 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 101100406392 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) omp26 gene Proteins 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 101000844721 Homo sapiens Deleted in malignant brain tumors 1 protein Proteins 0.000 description 1
- 101001130441 Homo sapiens Ras-related protein Rap-2a Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241000701828 Human papillomavirus type 11 Species 0.000 description 1
- DGABKXLVXPYZII-UHFFFAOYSA-N Hyodeoxycholic acid Natural products C1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DGABKXLVXPYZII-UHFFFAOYSA-N 0.000 description 1
- 229940124915 Infanrix Drugs 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 102100032241 Lactotransferrin Human genes 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 241000589929 Leptospira interrogans Species 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241000186367 Mycobacterium avium Species 0.000 description 1
- 241000187482 Mycobacterium avium subsp. paratuberculosis Species 0.000 description 1
- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187480 Mycobacterium smegmatis Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- HCUVEUVIUAJXRB-UHFFFAOYSA-N OC1=C(C=C(CNC(CCCC=2SC=CC=2)=O)C=C1)OC Chemical compound OC1=C(C=C(CNC(CCCC=2SC=CC=2)=O)C=C1)OC HCUVEUVIUAJXRB-UHFFFAOYSA-N 0.000 description 1
- 101710116435 Outer membrane protein Proteins 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 101710099976 Photosystem I P700 chlorophyll a apoprotein A1 Proteins 0.000 description 1
- 101000983333 Plasmodium falciparum (isolate NF54) 25 kDa ookinete surface antigen Proteins 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 241000233872 Pneumocystis carinii Species 0.000 description 1
- 101710183389 Pneumolysin Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710188053 Protein D Proteins 0.000 description 1
- 101710132595 Protein E7 Proteins 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241001454523 Quillaja saponaria Species 0.000 description 1
- 235000009001 Quillaja saponaria Nutrition 0.000 description 1
- 102100022851 Rab5 GDP/GTP exchange factor Human genes 0.000 description 1
- 102100031420 Ras-related protein Rap-2a Human genes 0.000 description 1
- 101710203837 Replication-associated protein Proteins 0.000 description 1
- 101710132893 Resolvase Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000190932 Rhodopseudomonas Species 0.000 description 1
- 241000606695 Rickettsia rickettsii Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 101100338071 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) GTT3 gene Proteins 0.000 description 1
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 description 1
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000242678 Schistosoma Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- 241000217239 Schizotrypanum Species 0.000 description 1
- 108010079723 Shiga Toxin Proteins 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 101710084578 Short neurotoxin 1 Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000194019 Streptococcus mutans Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 108010011834 Streptolysins Proteins 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- 241000710771 Tick-borne encephalitis virus Species 0.000 description 1
- 101710182223 Toxin B Proteins 0.000 description 1
- 101710182532 Toxin a Proteins 0.000 description 1
- 101710134694 Transcriptional regulator ICP22 homolog Proteins 0.000 description 1
- 102000010912 Transferrin-Binding Proteins Human genes 0.000 description 1
- 241000589892 Treponema denticola Species 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- 229920004892 Triton X-102 Polymers 0.000 description 1
- 229920004929 Triton X-114 Polymers 0.000 description 1
- 229920004893 Triton X-165 Polymers 0.000 description 1
- 229920004894 Triton X-305 Polymers 0.000 description 1
- 229920004897 Triton X-45 Polymers 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 108010046334 Urease Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 206010047799 Vulvovaginitis trichomonal Diseases 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- 229940124832 acellular pertussis vaccine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000012387 aerosolization Methods 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 101150078331 ama-1 gene Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- IKRMZAOEXULJQX-UHFFFAOYSA-N calcium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound [Ca+2].O1B([O-])OB2OB([O-])OB1O2 IKRMZAOEXULJQX-UHFFFAOYSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 231100001102 clostridial toxin Toxicity 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940007078 entamoeba histolytica Drugs 0.000 description 1
- 230000000369 enteropathogenic effect Effects 0.000 description 1
- 230000000688 enterotoxigenic effect Effects 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- ZINJLDJMHCUBIP-UHFFFAOYSA-N ethametsulfuron-methyl Chemical compound CCOC1=NC(NC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CC=2)C(=O)OC)=N1 ZINJLDJMHCUBIP-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- DGABKXLVXPYZII-SIBKNCMHSA-N hyodeoxycholic acid Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DGABKXLVXPYZII-SIBKNCMHSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000003866 lung sarcoma Diseases 0.000 description 1
- 101710130522 mRNA export factor Proteins 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229940031346 monovalent vaccine Drugs 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000002353 niosome Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WVJVHUWVQNLPCR-UHFFFAOYSA-N octadecanoyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC WVJVHUWVQNLPCR-UHFFFAOYSA-N 0.000 description 1
- 229940125395 oral insulin Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 108010021711 pertactin Proteins 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940075118 rickettsia rickettsii Drugs 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 150000007949 saponins Chemical group 0.000 description 1
- 239000003229 sclerosing agent Substances 0.000 description 1
- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 description 1
- 229940118376 tetanus toxin Drugs 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
- 238000011200 topical administration Methods 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229940031418 trivalent vaccine Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 229940044959 vaginal cream Drugs 0.000 description 1
- 239000000522 vaginal cream Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000000277 virosome Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- 229940098232 yersinia enterocolitica Drugs 0.000 description 1
Images
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
- A61K39/39—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
- A61P31/10—Antimycotics
-
- 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
-
- 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
-
- 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
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a novel adjuvant system comprising a polyoxyethylene alkyl ether or ester surfactant in combination with at least one additional non-ionic surfactant. Preferably said additional non-ionic surfactant is an Octoxynol (the TRITON<TM> series). The present invention provides said novel adjuvants, vaccines comprising them, and methods of their manufacture and their formulation into vaccines. The use of the adjuvants or vaccines of the present invention in the prophylaxis or therapy of disease is also provided.
Description
The present invention relates to a kind of new adjuvant system, comprise and at least a other non-ionic surface active agent and the polyoxyethylene alkyl ether or the polyxyethylated ester surfactant of usefulness.Preferred described other non-ionic surface active agent is a hot benzene polysaccharide (Octoxynol).The invention provides described new adjuvant, comprise they vaccine, and preparation method thereof and it is made into the method for vaccine.Adjuvant of the present invention or the vaccine purposes in prevention or treatment disease also is provided.A kind of method that strengthens the host immune response that uses adjuvant of the present invention and vaccine also is provided.This adjuvant is effective especially as mucosal adjuvants, but also effective to whole body.
Except having avoided because " fearing pin " and injection pain and the patient is produced the influence of related side effects; the mucosal vaccination vaccine is attractive; because shown for animal; mucosal administration antigen more high efficiency impels mucomembranous surface to produce protective response, and mucomembranous surface is the admission passage of many pathogen.In addition, shown the mucosal vaccination vaccine, for example intranasal vaccination not only can be at nasal mucosa, and mucosal sites causes mucosal immunity a long way off, as genitals mucosa (Mestecky, 1987, " clinical immunology magazine " (Journal of ClinicalImmunology), 7,265-276; McGhee and Kiyono, " infectiousness medicament and disease " (Infectious Agents and Disease), 1993,2,55-73).Although many researchs have been carried out in this field, the safety and the effective mucosal adjuvants that are fit to the people is used still have to be determined.The invention provides a solution to this problem.
The medical application of some non-ionic surface active agent has been described.For example, having described intranasal gives polyoxyethylene ether and polyoxyethylene ester (Hirai etc. 1981, " international journal of Practical Pharmacy " (International Journal of Pharmaceutics), 9,165-172 to strengthen the nasal absorption insulin; Hirai etc. 1981, " international journal of Practical Pharmacy " (International Journal ofPharmaceutics), and 9,173-184).
(JP 05 201877 as the description of the composition of fat liquor or acrylate copolymer adjuvant for existing polyoxyethylene alkyl ether; US 3,919, and 411).
Other non-ionic surface active agent has been used to vaccine mixture.For example, comprise polyoxyethylene castor oil or sad/certain herbaceous plants with big flowers acid glyceride, with the bacterin preparation of polyethenoxy sorbitan monoesters and antigenic mixture, after the mucosa topical administration, can cause systemic immune response (WO94/17827).This patent application discloses non-ionic surface active agent TWEEN20
TM(polyethenoxy sorbitan monoesters) and Imwitor742
TM(sad/the certain herbaceous plants with big flowers acid glyceride) associating, or TWEEN20
TMUnite use with polyoxyethylene castor oil and after the intranasal immunity inoculation, can strengthen systemic immune response.At document (Gizurarson etc. 1996 " vaccine research " (Vaccine Research), 5,69-75; Aggerbeck etc. 1997, " vaccine " (Vaccine), 15,307-316; Tebbey etc., Viral Immunol 1999; 12 (1): described this preparaton gives antigenic immunoreation potentiation at intranasal details 41-5).
Non-ionic surface active agent has formed nonionic surfactant vesicle (known NISV, US 5,679,355) in one way.The preparaton of this non-ionic surface active agent usually in the presence of cholesterol, forms two lipoid layer vesicle, and it is remaining antigen in internal layer aqueous phase or two lipoid layer itself.
(US 5 for International Patent Application WO 96/36352,653,987) described a kind of liquid pharmaceutical formulation, it comprises at least two kinds of absorption enhancers and water, be mainly the transmission of oral insulin, the amount of wherein each absorption enhancer is that the concentration with the 1-10%w/w of total preparaton exists.
The preparaton whole body that surfactant usually is used for the oil emulsion adjuvant gives, and plays the stabilize oil drop.For example, Sorbitan ethoxylate (TWEEN
TM) and fatty acid esters of sorbitan (SPAN
TM) be used for the stabilize water latex oil (EP 0 399 843 B, WO95/17210).
The applicant provides surprising discovery here, and polyoxyethylene alkyl ether or polyxyethylated ester with at least a other non-ionic surface active agent and usefulness, play a role as effective vaccine adjuvant together.Advantageously, but the said composition whole body give, but when vaccine combination adopts mucosal administration, also can effectively induce systemic immune response.The vaccine-induced immunoreation of mucosal administration of the present invention may be the same high with observed immunoreation behind the traditional vaccine systemic injection at least.
The invention provides safe and potent adjuvants, it is easy to produce, and comprises at least a polyoxyethylene alkyl ether or polyxyethylated ester and at least a other non-ionic surface active agent.The surfactant that uses among the present invention can be the suspension that aqueous solution maybe can form grain structure, as vesicle or micelle (micelle).Preferred this surfactant is aqueous solution or micellar form.
Can be allocated into the polyoxyethylene ether of vaccine of the present invention and adjuvant or the molecule that ester comprises general formula (I):
HO (CH
2CH
2O)
n-A-R wherein, n is 1-50, A be key or-C (O)-, R is C
1-50Alkyl or phenyl C
1-50Alkyl.
Thereby a scheme of the present invention comprises a kind of vaccine mixture, and this preparaton comprises the polyoxyethylene alkyl ether of general formula (I), and wherein n is 1 to 50, preferred 4-24, more preferably 6-12, most preferably 9; Composition R is C
1-50, preferred C
4-C
20Alkyl, more preferably C
12Alkyl.Polyoxyethylene ether concentration should be in the scope of 0.1-20%, preferred 0.1-10%, the more preferably scope of 0.1-1%.Suitable polyoxyethylene ether is selected from down group: polyoxyethylene-9-lauryl ether, polyoxyethylene-9-stearoyl ether, polyoxyethylene-8-stearoyl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether and polyoxyethylene-23-lauryl ether.
More preferably, described polyoxyethylene alkyl ether is polyoxyethylene-9-lauryl ether (laureth 9).The replacement term of polyoxyethylene lauryl ether or title are open in the CAS registration.The CAS number of registration of polyoxyethylene-9-lauryl ether is: 9002-92-0.Polyoxyethylene ether, as polyoxyethylene lauryl ether " Merck index " (the 12nd edition: clauses and subclauses 7717, Merck﹠amp; Co.Inc., Whitehouse Station, New Jersey, the U.S.; ISBN 0911910-12-3) open in, described therapeutic use comprises: local anesthesia; Antipruritic; With the sclerosing agent activity.As a class, this class polyoxyethylene ether or polyoxyethylene ester are non-ionic surface active agents.Oxirane and dodecanol reaction can form Laureth 9, and 9 ethylene oxide unit(s)s are on average arranged.In one embodiment, use the surfactant mixtures of such general formula (I), meant the average of the ethylene oxide unit(s) that exists in all surface activating agent in the n=mixture in the article of the present invention.
The length of polyoxyethylene part and the ratio of alkyl chain length (are n: the ratio of alkyl chain length), influence the dissolubility of this class cleaning agent (detergent) in aqueous medium in the surfactant.Thereby adjuvant of the present invention can be that solution maybe can form micrograined texture, as capsule or vesicle.As solution, adjuvant safety of the present invention for example adopts and is easy to sterilization by one deck 0.22 μ m film, and it is simple to give (administer), and can be by the plain mode manufacturing, and need not GMP relevant and QC permission (issue) with the formation of homogeneous micrograined texture.Some polyoxyethylene ether as laureth 9, can form no vesicle solution.Yet, polyoxyethylene-8 palmityl ether (C
18E
8) can form vesicle.Thereby, expect that especially the vesicle of polyoxyethylene-8 palmityl ether and at least a other non-ionic surface active agent unite use, to form adjuvant of the present invention.
Preferably, the polyoxyethylene alkyl ether composition that exists in the adjuvant compound of the present invention has hemolytic activity.But the hemolytic activity external test of polyoxyethylene alkyl ether with reference to following method, is represented with the maximum concentration that does not cause haemoclastic cleaning agent (detergent):
1. the Cavia porcellus fresh blood washs 3 times in desk centrifuge with phosphate buffered saline (PBS) (PBS).Again make suspension to initial volume, further dilute 10 times with PBS.
2. 50 these blood suspension of μ l being joined 800 μ l contains among the PBS of the cleaning agent of diluting 2 times.
3.8 after hour, naked eyes or by measuring the optical density assessment haemolysis of supernatant.Red supernatant occurs, show in the 570nm absorbing light to have haemolysis.
4. the result represents with the concentration that hemolytic first time of detergent dilution no longer takes place.
In the inherent experiment transmutability of this biological method, the surfactant of polyoxyethylene alkyl ether of the present invention or general formula (I), preferably has hemolytic activity, between about 0.5-0.0001%, more preferably between the 0.05-0.0001%, even more preferably between the 0.005-0.0001%, and most preferably between the 0.003-0.0004%.Ideally, described polyoxyethylene ether or polyoxyethylene ester should similar to the hemolytic activity of polyoxyethylene-9 lauryl ether or polyoxyethylene-8 stearoyl ether (promptly in 10 times of differences).
For at least a other non-ionic surface active agent that adds in polyoxyethylene alkyl ether or the polyxyethylated ester, can be any cleaning agent with suitable surface activity ability.Suitable cleaning agent is described among Ed:Attwood and the Florence (1983, Chapman and Hall) at " surfactant system ".
Preferred nonionic surfactants is not to fall into those of general formula (I), as hot benzene polysaccharide (octoxynol) and Sorbitan ethoxylate.Especially preferred hot benzene polysaccharide comprises Triton X-45, uncle's octylphenoxy polyethoxy ethanol (Triton X-100), Triton X-102, Triton X-114, Triton X-165, Triton X-205, Triton X-305, Triton N-57, Triton N-101, Triton N-128.Preferred especially Triton X-100.Hot benzene polysaccharide series comprises uncle's octylphenoxy polyethoxy ethanol (TRITONX100
TM) the clauses and subclauses 6858 of " Merck index " (1162 pages, the 12nd edition, Merck﹠amp; Co.Inc., Whitehouse Station, New Jersey, the U.S.; ISBN 0911910-12-3) describes in.
Other preferred nonionic surfactants is a Sorbitan ethoxylate, and these esters comprise polyethenoxy sorbitan monooleate (TWEEN80
TM), the clauses and subclauses 7742 of " Merck index " (1308 pages, the 12nd edition, Merck﹠amp; Co.Inc., Whitehouse Station, New Jersey, the U.S.; ISBN 0911910-12-3) in description is arranged.Hot benzene polysaccharide and Sorbitan ethoxylate all can be bought from Sigma Inc..Preferred Sorbitan ethoxylate is polyethenoxy sorbitan monooleate (TWEEN80
TM).
The most preferred adjuvant of the present invention comprises polyoxyethylene alkyl ether and hot benzene polysaccharide, as uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM).Optional described mixture can further comprise Sorbitan ethoxylate, as polyethenoxy sorbitan monooleate (TWEEN80
TM).Most preferably, described polyoxyethylene alkyl ether is that polyoxyethylene-9-lauryl ether and described hot benzene polysaccharide are uncle's octylphenoxy polyethoxy ethanol (TRITONX100
TM).In these preparatons, can add the ion-type cleaning agent, as the derivant of bile salts or cholic acid.
Thereby adjuvant formulations can comprise polyoxyethylene alkyl ether or polyxyethylated ester (general formula I), and hot benzene polysaccharide randomly comprises Sorbitan ethoxylate and randomly comprises bile salts or chlolic acid derivatives.The preferred version of this preparaton comprises polyoxyethylene-9 lauryl ether, uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM), polyethenoxy sorbitan monooleate and NaTDC.
Polyoxyethylene alkyl ether or ester, as polyoxyethylene-9 lauryl ether, the typical concentration in adjuvant of the present invention will be in the scope of 0.001-20%, preferred 0.001-10% and more preferably 0.001-1% and most preferably 0.001-0.8% or about 0.5% (w/v).The other non-ionic surface active agent that adds wherein is not polyoxyethylene ether or polyoxyethylene ester.Each other non-ionic surface active agent typically will the concentration with 0.001-20% exist in final vaccine mixture, and more preferably 0.01-10% is most preferably up to about 2% (w/v).If there are two kinds of described other non-ionic surface active agents, preferably they exist up to about 2% concentration with every kind in final preparaton, typically exist up to about 0.6% concentration with every kind.If have 3 kinds or how other non-ionic surface active agent, they exist up to about 1% concentration with every kind usually, and typically every kind of trace is to up to about 0.2% or 0.1%.Any mixture of surfactant can be present in according in the vaccine mixture of the present invention.Non-ionic surface active agent, those surfactants as discussed above preferred concentration in final vaccine combination is as follows: hot-or the ninth of the ten Heavenly Stems-phenoxy group polyoxy ethanol (octyl-or nonylphenoxy polyoxyethanols), as Triton X-100
TMOr other cleaning agent in the Triton series: from 0.001%-20%, preferred 0.001%-10%, more preferably 0.001-1%, most preferably 0.005-0.1% (w/v); With if there is Sorbitan ethoxylate, as Tween 80
TM: 0.01-1%, more preferably from about 0.1% (w/v).
Total concentration of detergent in vaccine of the present invention or the adjuvant formulations, comprise polyoxyethylene ether or polyoxyethylene ester and one or more other non-ionic surface active agents, typical scope is 0.001-40%, preferably between 0.001 to 20%, more preferably between 0.001 to 10%, still more preferably between 0.001 to 1%, most preferably between 0.001 to 0.7% (w/v).
Give bacterin preparation of the present invention by mucosal route,, can be used for protecting or treat easily ill or ill mammal as oral cavity/cheek/intestinal/vagina/rectum or nasal mucosa approach.This administering mode can be droplet, spraying or dry powder form.The vaccine mixture of atomizing or aerosolization also constitutes a part of the present invention.The suppository of the intestinal preparation of oral administration such as anti-capsule for treating gastropathy (gastroresistant capsule) and granule, 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 applied to skin (percutaneous or subcutaneous transmission).In addition, adjuvant of the present invention can give through parenteral route, for example intramuscular or subcutaneous administration.When being used for intranasal vaccination, the character of preferred vaccine of the present invention is hemolytic.
According to route of administration, can use multiple doser.For example, the sprayer unit that intranasal administration uses is as the Accuspray that can use the merchant to sell
TM(Becton Dickinson).
The sprayer unit of preferred intranasal administration is the device that its performance does not rely on the user applied pressure.Known these devices are devices that pressure limit is arranged.Have only when reaching pressure limit, liquid just flows out from nozzle.These devices are easier to form the regular spraying of droplet liquid measure.The device that pressure limit is arranged that the present invention is suitable for is that prior art is known, for example states in WO91/13281 and EP311 863B.This device can buy from Pfeiffer GmbH.
Droplet (water is cooked liquid and the measured) scope that preferred intranasal device produces is at 1 to 200 μ m, preferred 10 to 120 μ m.Less than 10 μ m the danger that is inhaled into is arranged, therefore the droplet less than 10 μ m preferably is no more than about 5%.The above droplet of 120 μ m can not spread well as less droplet, and the droplet that therefore surpasses 120 μ m preferably is no more than about 5%.
Dose double transmission (bi-dose delivery) is the further preferred feature that is used for the intranasal transmitting device of vaccine of the present invention.The dose double device contains two sub-doses (subdose) of a vaccine dose, and a sub-doses gives a nostril.
The present invention further provides a test kit (kit), comprised the intranasal administration device that contains vaccine mixture of the present invention described herein.
For some vaccine mixture, can comprise other vaccine composition.Same adjuvant formulations of the present invention also can comprise the derivant of bile acid and cholic acid.Preferred chlolic acid derivatives is its salt, is more preferably its sodium salt.The example of bile acid and derivant thereof comprises cholic acid itself; the glycerol of deoxycholic acid, tauroursodeoxycholic acid (salt), chenodeoxy cholic acid, lithocholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid and aforementioned bile acid-, cattle sulphur-, aminopropyl-1-third sulphur-, aminopropyl-2-hydroxyl-1-third sulphur-derivant; or N, two (3D gluconic acid aminopropyl) the deoxidation cholamine of N-.Particularly preferred example is the NaTDC (NaDOC) that can be present in the final bacterin preparation.
Preferably, when adjuvant formulations of the present invention is the form of suspension of aqueous solution form or still (non-vesicular), has superiority.This preparaton is easy to repeat make, also be easy to sterilization (by have 450 or the film end-filtration in 220nm aperture) and be easy to Sprayable through nasal mucosa medicine administration, the complicated physical arrangement of adjuvant is not degraded simultaneously.Polyoxyethylene-9 lauryl ether and TRITON-X 100
TMCoupling is made into aqueous solution (also can have little micelle).
A scheme of the present invention provides a kind of bringing out (inducing) or has strengthened the method for host immune response, comprises antigen is mixed with adjuvant of the present invention, and use described mixture to the host.Preferably, described host's route of administration is by mucomembranous surface, more preferably passes through nasal mucosa.When giving mixture by nasal mucosa, preferred mixture gives with Sprayable.Preferably bring out in the immunoreactive method at one, give vaccine of the present invention by intranasal and induce systemic immune response.The method of preferred enhance immunity reaction can be used the initial dose or the booster dose of vaccine, and preferably this vaccine comprises influenza antigens or antigen preparation (antigenic preparation).In these methods, the preferred adjuvant preparaton of nasal mucosa medicine administration is that polyoxyethylene alkyl ether and hot benzene polysaccharide are united use, for example preferred polyoxyethylene-9 lauryl ether and uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM) associating, (monooleate for example, TWEEN 80 additionally to comprise Sorbitan ethoxylate in the optional described adjuvant associating agent
TM) and/or bile salts or chlolic acid derivatives, as NaTDC.
Predict compositions of the present invention and can be used for preparing the antigenic vaccine that contains multiple extensive source.For example, antigen can comprise people, antibacterial or viral nucleic acid, the deutero-antigen of pathogen or antigen preparation, the deutero-antigen of tumor or antigen preparation, comprises albumen or peptide and chimeric fusion protein that GnRH and IgE peptide, reorganization produce.
Preferred vaccine mixture of the present invention contains a kind of immunoreactive antigen or antigen composition that can cause anti-human pathogen (humanpathogen), this antigen or antigen composition are derived from HIV-1, (as tat, nef, gp120 or gp160), the herpes virus hominis, as the gD or derivatives thereof or immediately early protein as ICP27 from HSV1 or HSV2, cytomegalovirus ((especially human cytomegalic inclusion disease virus) (as gB or derivatives thereof), rotavirus (comprising active attenuated virus), Epstein-Barr virus (as the gp350 or derivatives thereof), varicella zoster virus (Varicella Zoster Virus) is (as gpI, II and IE63), or from hepatitis virus such as hepatitis B virus (for example hbs antigen or derivatives thereof), hepatitis A virus, hepatitis C virus and hepatitis E virus, or from other viral pathogen, as paramyxovirus: respiratory syncytial virus (as F and G albumen or derivatives thereof), parainfluenza virus, Measles virus, mumps virus, human papillomavirus (HPV6 for example, 11,16,18, ..), Flavivirus is (as yellow fever virus, dengue virus, tick borne encephalitis virus, Japanese encephalitis virus) or be grown in influenza virus in ovum or the mdck cell (active complete (whole) or inactivation of viruses, division influenza virus (split influenza virus), or Vero cell or complete (whole) influenza virus particles (whole flu virosomes) are (as R.Gluck, " vaccine " (Vaccine), 1992,10, describe among the 915-920) or purification or its recombiant protein, as HA, NP, NA, or M albumen, or their mixture (combination)), or, comprise Diplococcus gonorrhoeae and Neisseria meningitidis (for example capsule polysaccharide and conjugate thereof (conjugate) from bacterial pathogens such as neisseria, transferrin binding protein, lactoferrin binding protein, PilC, adhesin); Streptococcus pyogenes (for example M albumen or its fragment, C5A protease, lipoteichoic acid), streptococcus agalactiae, Streptococcus mutans; Haemophilus ducreyi; Moraxella comprises moraxella catarrhalis, also comprises known mucositis branhamella (for example high and low-molecular-weight adhesin and hyaluronidase); Bordetella comprises Bordetella pertussis (for example pertactin, pertussis toxin, PT or derivatives thereof, filamentous hemagglutinin, adenyl cyclase, pili), Bordetella parapertussis and bordetella bronchiseptica; Mycobacterium comprises mycobacterium tuberculosis (for example ESAT6, Antigen 85A ,-B or-C antigen), Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium, mycobacterium paratuberculosis, mycobacterium smegmatis; Legionnella comprises legionella pneumophilia; Escherichia comprises and produces enterotoxigenic Escherichia coli (for example colonizing factor, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof), enterohemorrhagic Escherichia coli, enteropathogenic E.Coli (for example shiga toxin sample toxin or derivatives thereof); Vibrio comprises vibrio cholera (for example cholera toxin or derivatives thereof); Shigella comprises bacillus ceylonensis A, shigella dysenteriae, shigella flexneri; Yersinia comprises yersinia enterocolitica (for example Yop albumen), Yersinia pestis, artificial tuberculosis yersinia genus; Campylobacter comprises campylobacter jejuni (for example toxin, adhesin and hyaluronidase) and large intestine Campylobacter; Salmonella comprises salmonella typhi, salmonella paratyphi, Salmonella choleraesuls, Salmonella enteritidis; Growth comprises the monocyte hyperplasia Listeria; Helicobacterium comprises helicobacter pylori (for example urease, catalase, VacA); Rhodopseudomonas comprises Pseudomonas aeruginosa; Staphylococcus comprises staphylococcus aureus, staphylococcus epidermidis; Enterococcus comprises enterococcus faecalis, enterococcus faecalis; Fusobacterium comprises clostridium tetani (for example tetanus toxin and derivant thereof), bacillus botulinus (for example creotoxin and derivant thereof), clostridium difficile (for example clostridial toxin A or B and derivant thereof); Bacillus comprises Bacillus anthracis (for example Botulinum toxin (botulinum toxin) and its derivant); Corynebacterium comprises diphtheria corynebacterium (for example diphtheria toxin, diphtherotoxin and its derivant); Borrelia comprises B. burgdorferi (OspA for example, OspC, DbpA, DbpB), loud, high-pitched sound borrelia burgdorferi (OspA for example, OspC, DbpA, DbpB), Ah's borrelia burgdorferi (OspA for example, OspC, DbpA, DbpB), B.andersonii (OspA for example, OspC, DbpA, DbpB), He Shi Ticks burgdorferi; The ehrlichiosis body belongs to, and comprises the pathogen of horse ehrlichiosis body and people's granular cell ehrlichiosis disease; Rickettsiae comprises rickettsia rickettsii; Chlamydiaceae comprises sand holes chlamydia (for example MOMP, heparin is conjugated protein), Chlamydia pneumoniae (for example MOMP, hepatic binding protein (HBP)), chlamydia psittaci; Leptospira comprises leptospira interrogans; Treponema comprises Treponoma palladium (for example rare outer membrane protein, treponema denticola, swine dysentery treponema; Or from parasite, for example Plasmodium comprises Plasmodium falciparum; Toxoplasma, comprise the Mus toxoplasma (SAG2 for example, SAG3, Tg34); Entamoeba comprises Entamoeba histolytica; Babesia comprises the vole babesia; Trypanosoma comprises schizotrypanum cruzi; Giardia comprises Giardia lamblia; Leishmania comprises large-scale Leishmania; Pneumocystis comprises Pneumocystis carinii; Trichomonas comprises trichomonal vaginitis; Schistosoma comprises Schistosoma mansoni; Or from yeast, for example Candida comprises Candida albicans; Cryptococcus comprises Cryptococcus histolyticus (C.neoformans).
The preferred bacterium vaccine comprises from Streptococcus, comprises streptococcus pneumoniae (for example capsule polysaccharide and its conjugate, PsaA, PspA, streptolysin, choline binding protein) and pneumolysin proteantigen (Biochem Biophys Acta, 1989,67,1007; Rubins etc., " microorganism pathology " (Microbial Pathogenesis), 25,337-342) and its sudden change detoxifcation derivant (WO 90/06951; WO 99/03884).Other preferred bacterium vaccine comprises from Haemophilus spp, comprise Type B type sepecies Haemophilus influenzae (for example PRP and couplings thereof), non-molding (nontypeable) Haemophilus influenzae, for example (US 5 for the antigen of OMP26, high molecular adhesin (adhesins), P5, P6, D albumen and lipoprotein D and actin and actin derived peptide, 843,464) or its multicopy variant or fusion rotein.Other preferred bacterium vaccine comprises from moraxella catarrhalis (comprise its outer membrane vesicles, and OMP106 (WO 97/41731)) with from the antigen of Type B Neisseria meningitidis (comprise its outer membrane vesicles, and NspA (WO96/29412)).
The hbs antigen derivant is to know in the prior art, and comprise other at European patent application EP-A-414 374; Those PreSl that propose among EP-A-0304 578 and the EP 198-474, PreS2 S antigen.In a preferred version, vaccine mixture of the present invention comprises HIV-1 antigen, gp120, especially when they are expressed in Chinese hamster ovary celI.In further scheme, vaccine mixture of the present invention comprises the gD2t of definition as mentioned.
In a preferred version of the present invention, vaccine contains the adjuvant of claim, comprise antigen from the human papillomavirus (HPV) of the reason that is considered to cause the genitals tumor, (HPV6 or HPV 11 and other), with HPV virus be the reason that forms cervical cancer (HPV16, HPV 18 and other).
Particularly preferred genitals tumor prevention or treatment vaccine form comprise L1 microgranule or capsomere, and the preferred fusion protein form, and it comprises that one or more are selected from the antigen of HPV6 and HPV11 albumen E6, E7, L1 and L2.
Most preferred fusion rotein form is: disclosed D (1/3)-E7 albumen among disclosed L2E7 and the GB9717953.5 (PCT/EP98/05285) among the WO96/26277.
Preferably be used to prevent or treat the vaccine of HPV cervical infection or HPV cervical cancer, its component can comprise HPV16 or 18 antigens.For example, L1 or L2 antigen monomer or L1 or L2 antigen occur simultaneously as a kind of viral sample microgranule (VLP), or L1 albumen occurs separately in VLP or capsomere structure separately.This antigen, viral sample microgranule and capsomere itself are known.For example referring to WO94/00152, WO94/20137, WO94/05792 and WO93/02184.
Other early protein, for example preferred E7, E2 or E5 can be comprised separately or as fusion rotein; Special preferred version comprises the VLP (WO96/11272) that includes the L1E7 fusion rotein.
Particularly preferred HPV 16 antigens comprise the early protein E6 that merges with the D protein carrier or E7 forming protein D-E6 or the E7 fusion rotein from HPV16, or their mixture (combination); Or the mixture of E6 or E7 and L2 (WO 96/26277).
Perhaps, HPV 16 or 18 early protein E6 and E7 can be present in the individual molecule, and optimization protein D-E6/E7 merges.This vaccine can randomly comprise from the E6 of HPV 18 or E7 albumen the two one or both of the form of optimization protein D-E6 or protein D-E7 fusion rotein or protein D E6/E7 fusion rotein is all arranged.
Vaccine of the present invention also can comprise the antigen from other HPV strain, preferably from HPV6, and 11,31,33 or the antigen of 45 strains.
Vaccine of the present invention further comprises from the parasite antigen that can cause malaria.For example, preferred antigens comprises RTS from Plasmodium falciparum, S and TRAP.RTS is a kind of hybridization albumen, comprises proteic all C-end portion basically of ring-type zygoblast (CS) of Plasmodium falciparum, and it is connected with surface (S) antigen of hepatitis B virus by four aminoacid of the PreS2 part of hbs antigen.Its entire infrastructure is disclosed in International Patent Application PCT/EP92/02591, publication number WO93/10152, the claim priority is UK Patent Application No.9124390.7.When it is expressed in yeast, produce hdl particle RTS, when the S antigen coordinate expression of it and HBV, produce known hybrid fine particles RTS, S.TRAP antigen has description in international patent application No.PCT/GB89/00895, its publication number is WO90/01496.A preferred version of the present invention is a malaria vaccine, and wherein antigen preparation comprises RTS, the antigenic mixture of S and TRAP.May be Plasmodium falciparum MSP1 as other plasmodium antigens of each stage malaria vaccine candidate composition, AMA1, MSP3, EBA, GLURP, RAP1, RAP2, sequestrin, PfEMP1, Pf332, LSA1, LSA3, STARP, SALSA, PfEXPl, Pfs25, Pfs28, PFS27/25, Pfs16, Pfs48/45, the analog of Pfs230 and Plasmodium thereof.
This preparaton also can contain a kind of tumor-resistant antigen, and can be used for immunization therapy ruling by law treatment cancer.For example, the discovery adjuvant formulations can be share with tumor rejection antigen, as the rejection antigen of prostate, chest, colorectum, lung, pancreas, kidney or melanoma cancer.Example antigen comprises and is used for the treatment of melanomatous MAGE 1 and MAGE 3 or other MAGE antigen, PRAME, BAGE or GAGE (Robbins and Kawakami, 1996, " the up-to-date opinion in the immunology " (Current Opinions in Immunology) 8, the 628-636 page or leaf; People such as Van denEynde, the international magazine of laboratory research " clinical and " (International Journalof Clinical﹠amp; Laboratory Research) (is published in 1997); People such as Correale (1997), " national cancer association magazine " (Journal of the National CancerInstitute) 89,293 pages.In fact, in the tumor type of wide scope, can both express these antigens, for example melanoma, pulmonary carcinoma, sarcoma and bladder cancer.Other tumor specific antigen is suitable for together using with adjuvant of the present invention, includes but not limited to prostate specific antigen (PSA) or Her-2/neu, KSA (GA733), MUC-1 and carcinoembryonic antigen (CEA).According to a scheme of the present invention, a kind of vaccine is provided, comprise a kind of according to adjunvant composition of the present invention and a kind of tumor rejection antigen.
Described antigen in addition can also be the self peptide hormone, and as total length gonadotropin releasing hormone (GnRH, WO 95/20600), it is that length is 10 amino acid whose small peptides, can be used for treating many cancers, or is applied to the immunity excision.
Can precognition compositions of the present invention can be used for preparing the antigenic vaccine that contains from Borrelia.For example, antigen can comprise albumen or peptide and the chimeric fusion protein that nucleic acid, the deutero-antigen of pathogen or antigen preparation, reorganization produce.This antigen is OspA especially.OspA can be the fat form (Lipo-OspA) or the non-fat derivant of the complete maturation protein (full matureprotein) of host cell (escherichia coli (E.Coli)) definition.This non-fat derivant comprises non-fat NS1-OspA fusion rotein, and it has preceding 81 the N terminal amino acids and the complete OspA albumen of the non-structural protein (NS1) of influenza virus; And another kind of, MDP-OspA is the non-fat form of OspA, has 3 other N terminal amino acids.
Vaccine of the present invention can be used for prevention hypersensitive or treatment.This vaccine can comprise allergen specificity antigen (for example Der p1) and anaphylactogen heterogenetic antigen (for example from the peptide of people IgE, including but not limited to stanworth decapeptide (EP 0 477 231 B1)).
The most preferred vaccine of the present invention and bring out immunoreactive method comprises influenza antigen.The inactivating influenza virus preparation can be obtained by conventional embryonated egg method, maybe can obtain for method (new generation method) by any new biography of viral growth that makes with tissue culture.Be used to make the suitable cell substrate of viral growth to comprise, such as Madin-Darby canine kidney(cell line) (MDCK), as MDCK or from the clone's of MDCK cell, MDCK like cell, monkey-kidney cells, as the AGMK cell, comprise any cell type that is suitable for producing the influenza virus that is used to prepare the vaccine purpose of African green monkey kidney cell or other.Suitable cell substrate comprises people's cell, as the MRC-5 cell.Suitable cell substrate is not limited to cell line; For example primary cell also can be included such as chick embryo fibroblast.Any obtaining in the processing method that the influenza antigen preparation can be sold by a large amount of merchants is as the division influenza antigens processing method of describing among the patent DD 300 833.Can buy the Fluarix that the division influenza that obtains comprises that SmithKline Beecham sells
TM, same Fluarix and adjuvant of the present invention are united use and are constituted the preferred vaccine of the present invention.
The preferred a kind of multivalence influenza vaccines of influenza vaccines according to the present invention comprise two or more influenza strains.More preferably it is a kind of trivalent vaccine that comprises 3 strains.The conventional flow influenza vaccine generally includes three kinds of strains of influenza, two A strains and a B strain.Yet, the present invention do not repel for example may be useful to popularity univalent vaccine.A kind of unit price pandemic influenza vaccine will contain the influenza antigens from single A strain probably.
Therefore, a kind of preferred vaccine mixture comprises ovum or tissue culture's influenza antigens, preferably divides influenza antigens, and a kind of polyoxyethylene alkyl ether and at least a other non-ionic surface active agent can optionally comprise the derivant of bile salts or cholic acid.The preferred version of this vaccine comprises division influenza antigen, polyoxyethylene-9 lauryl ether and TRITON-X 100
TMRandomly, this most preferred vaccine can further comprise a kind of Sorbitan ethoxylate, as TWEEN80
TMAnd/or NaTDC.
Protein content in every kind of vaccine dose is chosen to be can the induce protective immunity reaction and do not produce the dosage of tangible adverse side effect in typical vaccine.How this dosage can and produce (presented) and change along with the specific immunogens that uses.In general, expect that each dosage comprises 1-1000 μ g albumen, preferred 1-500 μ g, preferred 1-100 μ g, most preferably 1-50 μ g.The optimal dose of a specific vaccine can be determined by research on standard, comprises and observes the immunoreation that the experimenter matches.After the first vaccination, the experimenter can accept one and several abundant isolated booster immunization inoculation.
A preferred version of the present invention is can work in coordination with the adjuvant effect that strengthens polyoxyethylene alkyl ether by other non-ionic surface active agent.In this, the immunoreation degree that produces from the blended adjuvant formulations of coupling is higher than the immunoreation sum that is produced separately when each composition uses separately, promptly can be observed synergism.Another situation, when the polyoxyethylene ether and the other non-ionic surface active agent of low dosage produces tangible immunoreation, and even when being used alone or each composition all can not produce obviously or can detected immunoreation the time, also can be observed synergism.
A scheme of the present invention is adjuvant and vaccine mixture, and it comprises polyoxyethylene alkyl ether or polyxyethylated ester and at least a other non-ionic surface active agent, and wherein the antigen that exists in the vaccine does not wrap and is loaded within the non-ionic surface active agent vesicle.
But vaccine of the present invention also by oral route gives.In this case, pharmaceutically acceptable excipient also can comprise alkaline buffer or enteric bag quilt or microgranule.Vaccine of the present invention also can give by vaginal approach.In this case, pharmaceutically acceptable excipient also can comprise emulsifying agent, polymer such as the CARBOPOL of vaginal cream and suppository
_And other known stabilizing agent.Vaccine of the present invention also can give by the rectum approach.In this case, pharmaceutically acceptable excipient also can comprise wax and the polymer that is used to form rectal suppository well known in the prior art.
Preparaton of the present invention can be used for prevention and therapeutic purposes.Therefore, the invention provides a kind of method for the treatment of mammalian infections disease or cancer or irritated or autoimmune disease, or treat the method for the susceptibility of these diseases.Further scheme of the present invention provides a kind of adjuvant mixture (adjuvant combination) and the vaccine that is used for medicine described herein.The preparation of vaccine is usually at " new trend of vaccine and progress " (New Trends and Developments inVaccines), volumes such as Voller, and University Park publishes, Baltimore, the Maryland State, the U.S. states in 1978.
A scheme of the present invention relates to non-ionic surface active agent for example polyoxyethylene alkyl ether or the polyxyethylated ester and the application of hot benzene polysaccharide in the preparation adjuvant formulations of general formula (I).The present invention also relates to the polyoxyethylene alkyl ether or the application in the preparation vaccine mixture of polyxyethylated ester, hot benzene polysaccharide and antigen of general formula (I).The described adjuvant and the vaccine of method preparation can optionally further comprise Sorbitan ethoxylate as described.In all these schemes of the present invention, preferred polyoxyethylene alkyl ether is polyoxyethylene-9 lauryl ether, and preferred hot benzene polysaccharide is uncle's octylphenoxy polyethoxy ethanol (Triton X-100
TM).
In selectable relevant programme of the present invention, adjuvant of the present invention can further be united use with other adjuvant, comprises choiera toxin and B subunit thereof, the heat-labile enterotoxin LT of escherichia coli and B subunit LTB and their detoxifcation type such as mLT; Monophosphoryl lipid A (Monophosphoryl Lipid A) and its non-toxic derivative 3-O-deacylated tRNA monophosphoryl lipid A (3D-MPL, at British patent GB 2,220, description is arranged in 211), immunologic competence saponin fragment, as from the Quil A of the bark of South America Quillaja Saponaria Molina tree and derivant thereof (QS21 for example, US patent 5,057,540), and oligonucleotide (oligonucleotide) adjuvant system CpG (as describing among the WO 96/02555), especially 5 ' TCG TCG TTT TGT CGTTTT GTC GTT3 ' (SEQ ID NO.1).
In the technical program, preferred especially polyoxyethylene alkyl ether (as polyoxyethylene-9 lauryl ether), other non-ionic surface active agent are (as uncle's octylphenoxy polyethoxy ethanol (Triton X-100
TM) and the adjuvant mixture of 3-O-deacylated tRNA monophosphoryl lipid A (3D-MPL).This preferred version can further comprise Sorbitan ethoxylate such as TWEEN80 optionally
TM, and/or bile salts or chlolic acid derivatives such as NaTDC.Preferably include this adjuvant formulations and influenza antigens especially, especially divide the vaccine of influenza antigens.
The following example is used for explaining but does not limit the present invention.
Embodiment
Embodiment 1, be used for detecting the method that serum (sera) antibody (Ab) reacts
ELISA (enzyme disimmunity determining adsorption) measures monkey influenza-specific serum Ig Abs
Dilute β-propanoic acid lactone (BPL) inactivating influenza virus (by SSD GmBH producer, Dresden, Germany provides) 1 μ g/ml HA with PBS, wrap by MaxisorpNunc immunity dull and stereotyped (immunoplate) in 50 μ l/ holes (μ l/well), spends the night under 4 ℃.Room in the flat board select use saturated buffer: PBS to contain 1%BSA, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20) is filled out envelope (1 hour, 37 ℃).Then, successive 2 times of diluents of the reference serum that adds as standard curve are (in saturated buffer, 50 μ l/ holes) (serum with mid point titer (titer) is represented with ELISA unit/ml, it is capable to be put into A) and serum sample (since 1/100 dilution factor and to be put into B capable to H), cultivated 1 hour 30 minutes for 37 ℃.Then with lavation buffer solution (PBS, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20)) washing (* 3) flat board.Then, at saturated buffer biotinylated goat Anti-Human Ig (goat anti-human Ig) (Amersham) is diluted to 1/3000,37 ℃ of cultivation (50 μ l/ hole) 1 hour 30 minutes.Wash 3 times, add streptavidin-horseradish peroxidase conjugate (Amersham) subsequently, dull and stereotyped 5 times and with indication buffer (revelation buffer) (the OPDA 0.4mg/ml (Sigma) and the H in 50 μ l/ holes of washing
2O
20.03% in 50mM pH 4.5 citrate buffers) at room temperature cultivated 20 minutes.Add 50 μ l/ hole H
2SO
42N stops indication.With Biorad 3550 immune readers (immunoreader) 492 and 630nm obtain the optical density (OD) reading.4 parameter mathematical method calculating antibody titer with SoftMaxPro software.
The hemagglutination of monkey influenza-specific serum Abs suppresses (HAI) activity
In order to eliminate the hemagglutinative non-specific inhibitory action in the primate serum, these (25 μ l) 37 ℃ of overnight incubation, the every ml VCN of described mixed solution (BoerhingerMannheim) contains 400 receptor destroying enzyme units with 100 μ l chlorination (chlorure) calcium/Calcium pyroborate/sodium borate mixed solutions.After adding 2.5% sodium citrate solution, 75 μ l, heated serum 30 minutes at 56 ℃.Add 50 μ l PBS solution serum is diluted to 1/10 at last
ThThen, the serum of on 96 hole Greiner flat boards, handling with 25 μ l PBS (since 1/10, continuous 2 times of dilutions) dilution, 25 μ l.Added BPL deactivation intact virus (25 μ l/ hole) with 30 minutes with 4 hemagglutinating-unit concentration (promptly than the last low 4 times dilution factor that excites red cell agglutination) in room temperature (RT) with under stirring.Follow under RT with 1 hour adding chicken red blood cell (25 μ l/ hole).The last dull and stereotyped reading again that spends the night of under 4 ℃, preserving.HAI titer is equivalent to suppress the inverse of the hemagglutinative final serum dilution of virus induction.
ELISA measures mice tetanus toxoid (TT) specific serum IgG
The 50 μ l/ holes that are used in the 1 μ g/ml antigen (TT that Behring provides) of (B to H at flat board is capable) dilution among the PBS are wrapped by Maxisorp Nunc immunity dull and stereotyped, or the goat that is used in 5 μ g/ml purification among the PBS (A is capable) anti--the 50 μ l bag of mice (goat anti-mouse) Ig (Boerhinger) spent the night under 4 ℃ by dull and stereotyped.Room in the flat board is selected and is used saturated buffer: PBS (containing 1%BSA, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20) and 4% standard calf serum (NBS)) to fill out envelope (1 hour, 37 ℃).Then, adding as continuous 2 times of diluents of IgG homotype (isotype) mixture of a standard curve (in saturated buffer, 50 μ l/ holes) (use mouse monoclonal antibody IgG1, the IgG2a of Sigma and the mixture of IgG2b, begin and to be put into A capable from 200ng/ml) and serum sample (since 1/100 dilution factor and to be put into B capable to H), cultivated 1 hour 30 minutes at 37 ℃.Then with lavation buffer solution (PBS, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20)) washing (* 3) flat board.Then, the biotinylated goat that is diluted in saturated buffer in 1/5000 resisted-mice IgG (Amersham), 37 ℃ of cultivations (50 μ l/ hole) 1 hour 30 minutes.Wash 3 times, add streptavidin-horseradish peroxidase conjugate (Amersham) subsequently, dull and stereotyped 5 times and with indication buffer (OPDA 0.4 mg/ml (Sigma) and the H in 50 μ l/ holes of washing
2O
20.03% in 50mM pH 4.5 citrate buffers) at room temperature cultivated 20 minutes.Add 50 μ l/ hole H
2SO
42N stops indication.With Biorad 3550 immune readers 492 and the 630nm place obtain optical density readings.4 parameter mathematical method calculating antibody titer with SoftMaxPro software.
Embodiment 2, and common immunogenic influence to primed Rhesus Macacus intranasal influenza vaccine is used in uniting of laureth9 and TWEEN80 and TritonX100
Be contained in A/ Beijing/262/95 and B/ Harbin/7/94 influenza virus, the 25 μ gHA of the every strain β-propanoic acid lactone deactivation among the 100 μ l PBS for each nostril perfusion of Rhesus Macacus with sprayer unit (anesthesia down).After 28 days, give monkey (4 or 5/group) intranasal (anesthesia down) booster dose with 200 μ l solution (each nostril 100 μ l carries with sprayer unit), solution is at A: in polyoxyethylene-9-lauryl ether 0.5% (L9); Or at B: contain 30 μ g HA/BPL-deactivation A/ Beijing/262/95 and B/ Harbin/7/94 strains of influenza viruses among polyoxyethylene-9-lauryl ether 0.5%+TWEEN80 (0.11%)+triton-X-100 (0.074%); Or pass through C: intramuscular injection 15 μ gHA/ influenza vaccines strains, vaccine strain contains the strain identical with A and B.Virus antigen is grown in the ovum of the seed bank that is provided by manufacturer (SSD GmBH, Dresden, Germany).As HAI and IgAb reaction in the mensuration serum as described in the embodiment 1.The result improves the shared percentage of animal of 4 times of Ab after with booster immunization and recently represents.
Experience with 0.5% polyoxyethylene-9-lauryl ether showed that this preparaton was to inducing the influenza systemic immune response effective in the past.Yet, as shown in table 1, can significantly improve adjuvant complementary (adjuvanticity) level by adding other non-ionic surface active agent.When replenishing polyoxyethylene-9-lauryl ether with TWEEN80 and triton-X-100, this preparaton can strengthen the general IgAb that has set up in advance effectively as classical parenteral route influenza vaccines and react like this.
Also measure hemagglutination and suppress (HAI) reaction (table 2), again, best intranasal preparaton remains the polyoxyethylene-9-lauryl ether that has replenished TWEEN80 and triton-X-100.This preparaton is identical with the immunogenicity of traditional parenteral route vaccine.
Table 1, monkey serum Ig reaction
IgELISA antibody | Ab raises 4 times of seroconversion (%) extremely: | |
Group | A/ Beijing/262/95 | B/ Harbin/7/94 |
????A | ????0 | ????0 |
????B | ????100 | ????100 |
????C | ????75 | ????75 |
Table 2, monkey serum HAI titer
HAI antibody | Ab raises 4 times of seroconversion (%) extremely: | |
Group | A/ Beijing/262/95 | B/ Harbin/7/94 |
????A | ????0 | ????0 |
????B | ????20 | ????0 |
????C | ????25 | ????0 |
Embodiment 3: relatively add the intranasal that TWEEN80 and triton-X-100 be mixed with laureth9 and divide influenza vaccines and the traditional parenteral route vaccine (Fluarix that has gone through to use
TM) to healthy adult experimenter's immunogenicity.
Assess the intranasal preparaton that adds the ovum source division influenza antigens of TWEEN80 and triton-X-100 (A) preparation with laureth 9, and and Fluarix
TM/ α-Rix
_(B) compare.The preparaton that contains three kinds of deactivation division virus antigens is recommended the strain preparation by 1998/1999 season WHO.The device that is used to grant vaccine is the Accuspray from Becton Dickinson
TMThe nasal injection device, this device is similar with the conventional syringe operation principle, but has a special needle point that contains spirality channel, and when exerting pressure to piston, it can produce spraying.Each nostril is sprayed into 100 μ l preparatons.
The composition of preparaton
Intranasal preparaton (A) contains following deactivation division virion:
1.30 μ g HA A/ Beijing/262/95 (HlNl)
2.30 μ g HA A/ Sydney/5/97 (H3N2)
3.30 μ g HA B/ Harbin/7/94 and phosphate buffered saline pH7.4 ± 0.1,0.1%TWEEN80,0.015%Triton-X-100,0.0045% NaTDC and be lower than the thiomersalate of 35 μ g/ml.
The volume of a preparation is 200 μ l (each nostril 100 μ l sub-doses).
Assist in the formulation H into adjuvant laureth 9 so that final concentration reaches 0.5% (w/v).
Comparison Fluarix
TM/ α-Rix
_(B) be that the merchant of SmithKlineBeecham Biologicals sells inactivated trivalent division influenza vaccines, intramuscular administration, dosage is 500 μ l.
Immunogenicity research
Estimate the immunogenicities of intranasal division influenza vaccines with opening, contrast and randomised study, this vaccine is formulated by the laureth 9 that has replenished TWEEN80 and triton-X-100, and with traditional parenteral route vaccine (be Fluarix
TM) compare.20 healthy adult experimenters (age 18-40 year) accept the Fluarix of a dosage
TM, 10 experimenters accept the intranasal influenza vaccine an of dosage (two sub-doses, the sub-doses in each nostril).
About safety and reactionogenicity, two kinds of vaccines can both be stood by fine in the hope of producing part and General Symptoms in continuous 8 days.There is not the report serious side effects relevant with vaccination.
The immunogenicity determining of vaccine is: suppress (HI) titer by assessment serum hemagglutination and determine that seroconversion rate is (for each vaccine strain; its definition is to compare with the 0th day; serum HI titer was increased to 4 times the shared percentage ratio of vaccine at least in the 21st day); transform factor (for each vaccine strain; its definition is to compare with the 0th day; the 21st day serum HI geometric mean titer (GMT) is increased to multiple) and the serum protective rate (its definition is; the shared percentage ratio of vaccine of (for each vaccine strain) serum HI titer 〉=40 after the immunity inoculation is accepted its indication as protection).In addition, measure mucosa IgA antibody response with enzyme-linked immunosorbent assay (ELISA).
The Fluarix of a dosage of inoculation
TMOr behind the intranasal preparaton 21 days, HI seropositivity, seroconversion and serum protective rate can see Table 3.
Table 3: inoculate 21 days HI seropositivities, seroconversion and serum protective rates behind the dosage:
Strain | Group | Time | ??N | Seropositivity n % | Serum protection n % | Seroconversion n % |
A/ Beijing | The intranasal vaccine is added with Laureth 9 | It is 0 day 21 | ??20 ??20 | ??5????25.0 ?19????95.0 | ??1????5.0 ?10????50.0 | ?15????75.0 |
??Fluarix TM | It is 0 day 21 | ??19 ??19 | ??4????21.1 ?19????100.0 | ??3????15.8 ??18???94.7 | ?19????100.0 | |
A/ Sydney | The intranasal vaccine is added with Laureth-9 | It is 0 day 21 | ??20 ??20 | ?16????80.0 ?20????100.0 | ??4????20.0 ?19????95.0 | ?15????75.0 |
??Fluarix TM | It is 0 day 21 | ??19 ??19 | ?14????73.7 ?19????100.0 | ??1????5.3 ?18????94.7 | ?16????84.2 | |
B/ Harbin | The intranasal vaccine is added with Laureth-9 | It is 0 day 21 | ??20 ??20 | ?18????90.0 ?20????100.0 | ?11????55.0 ?19????95.0 | ?12????60.0 |
??Fluarix TM | It is 0 day 21 | ??19 ??19 | ?17????89.5 ?19????100.0 | ?11????57.9 ?19????100.0 | ?15????78.9 |
Seropositivity (n, %): the experimenter's quantity and the percentage ratio of titer 〉=10
The serum protection (n, %): the experimenter's quantity and the percentage ratio of titer 〉=40
(n, %): titer was increased at least 4 times experimenter's quantity and percentage ratio in from 0 to 21 day in seroconversion
Table 4 as seen, between 21 days and 0 day (1 dosage), specificity/total mucosa IgA antibody ratio is increased to the shared percentage ratio of experimenter of 2 times or 4 times.
Table 4: between 21 days and 0 day (1 dosage), specificity/total IgA ratio is increased to 2
Doubly or 4 times the shared percentage ratio of experimenter
Sum up
Strain | Group | ??N | Be increased to 2 times (%) | Be increased to 4 times (%) |
A/ Beijing | ????Laureth-9 ????Fluarix TM | ??20 ??19 | ????50.0 ????52.6 | ????20.0 ????26.3 |
A/ Sydney | ????Laureth-9 ????Fluarix TM | ??20 ??19 | ????55.0 ????47.4 | ????25.0 ????5.3 |
B/ Harbin | ????Laureth-9 ????Fluarix TM | ??20 ??19 | ????15.0 ????26.3 | ????10.0 ????5.3 |
Immunogenicity result in the tabulation shows intranasal preparaton and the traditional parenteral route vaccine (Fluarix that gives a dosage above
TM) back 21 days, the seropositivity of generation, seroconversion and serum protect level similar.After the dosage, the intranasal preparaton is usually than traditional parenteral route vaccine (Fluarix
TM) the mucosa IgA reaction that produces is better.Embodiment 4, and laureth 9 and Triton X100 share the immunogenic influence to primed mice intranasal tetanus toxoid vaccine
In the present embodiment, after we have estimated to low dosage and add Triton X100 in inferior to the Laureth-9 of optimal dose, intranasal is strengthened the effect of tetanus toxoid (TT)-specific serum antibody.The merchant that female balb/c mice intramuscular gives 20% (2 * 50 μ l) human dosage sells DTPa vaccine (Diptheria, tetanus, acellular pertussis vaccine: INFANRIX
TMSmithKline Beecham, Belgium).After one month, with the A:PBS that contains 5 μ gTT; B:0.5% polyoxyethylene-9 lauryl ether; C:0.1% polyoxyethylene-9 lauryl ether; D:0.1% polyoxyethylene-9 lauryl ethers+0.02%Triton X100 gives mice intranasal booster dose (under the anesthesia, each nostril 5 μ l), or uses E: by intramuscular booster injection DTPa vaccine (2 * 50 μ l).Strengthen two weeks of back, the TT-specific IgG of serum analysis.
As shown in Figure 1, opposite with 0.5% dosage, low dosage Laureth-9 (0.1%) can not effectively strengthen the reinforcement reaction to TT.Yet, by replenishing the adjuvanticity that Triton X100 (p<0.0001) can improve this preparaton greatly.The antibody response that causes is sold the vaccine-induced reacting phase of DTPa seemingly with the merchant.
Claims (36)
1. adjunvant composition, it comprises the polyoxyethylene alkyl ether or the polyxyethylated ester of (a) general formula (I):
HO (CH
2CH
2O)
n-A-R wherein, n is 1-50, A be key or-C (O)-, R is C
1-50Alkyl or phenyl C
1-50Alkyl; (b) at least a other non-ionic surface active agent.
2. adjunvant composition according to claim 1, wherein said other non-ionic surface active agent is hot benzene polysaccharide.
3. adjunvant composition according to claim 2, wherein said hot benzene polysaccharide is uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM).
4. one kind according to each adjunvant composition of claim 1 to 3, also comprises Sorbitan ethoxylate or cholic acid or derivatives thereof in addition or has both comprised in addition also that Sorbitan ethoxylate also comprised the cholic acid or derivatives thereof.
5. one kind according to each adjunvant composition of claim 1 to 4, it is characterized in that the polyoxyethylene alkyl ether of general formula (I) or polyxyethylated ester are hemolytic.
6. the adjunvant composition according to claim 5 is characterized in that measuring the hemolytic activity degree of polyoxyethylene alkyl ether or polyxyethylated ester in the scope of 0.05-0.0001% with guinea pig blood cell hemolytic experiment.
7. adjunvant composition according to claim 5 or 6 is wherein measured the difference of hemolytic activity of the hemolytic activity of the polyoxyethylene alkyl ether of general formula (I) or polyxyethylated ester and polyoxyethylene-9 lauryl ether or polyoxyethylene-8-stearoyl ether within 10 times with guinea pig blood cell hemolytic experiment.
8. one kind according to each adjunvant composition of claim 1 to 7, comprises the polyoxyethylene alkyl ether or the polyxyethylated ester of general formula (I), and wherein n is 4-24.
9. adjunvant composition according to Claim 8, wherein n is 9.
10. one kind according to each adjunvant composition of claim 1 to 7, comprises the polyoxyethylene alkyl ether or the polyxyethylated ester of general formula (I), and wherein R is C
8-20Alkyl or phenyl C
8-20Alkyl.
11. the adjunvant composition according to claim 10, wherein R is C
12Alkyl.
12. one kind according to each adjunvant composition of claim 1 to 11, comprises the polyoxyethylene alkyl ether or the polyxyethylated ester of general formula (I), wherein A is a key, thereby forms ether.
13. one kind according to each adjunvant composition of claim 1 to 12, comprises the polyoxyethylene alkyl ether or the polyxyethylated ester of general formula (I), wherein A be-C (O)-, thereby form ester.
14. one kind according to each adjunvant composition of claim 1 to 13, the polyoxyethylene ether or the polyoxyethylene ester of its formula of (I) are selected from: polyoxyethylene-9-lauryl ether, polyoxyethylene-9-Lauryl Ester, polyoxyethylene-9-stearoyl ether, polyoxyethylene-8-stearoyl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether, polyoxyethylene-23-lauryl ether.
15. an adjuvant mixture comprises polyoxyethylene-9-lauryl ether and uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM).
16. one kind according to each adjunvant composition of claim 1 to 15, wherein the total concentration of detergent of Cun Zaiing is 0.001-10%.
17. the adjunvant composition according to claim 16, wherein total concentration of detergent is 0.001-1%.
18. the adjunvant composition according to claim 17, wherein total concentration of detergent is 0.001-0.7%.
19. an adjuvant mixture comprises the adjuvant of uniting in the claim 1 to 17 of use each with at least a other immunostimulant.
20. the adjuvant mixture according to claim 19, wherein at least a other immunostimulant is selected from: LT, CT, 3D-MPL, CpG and QS21.
21. the adjunvant composition according to claim 20, wherein the CpG adjuvant is: TCCATG ACG TTC CTG ACG TT (SEQ ID NO.1).
22. one kind comprises polyoxyethylene-9 lauryl ether, uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM) and the adjuvant mixture of 3D-MPL.
23. one kind comprises each the vaccine of adjuvant of claim 1 to 22, it also comprises antigen.
24. the vaccine according to claim 23, wherein said antigen is selected from: human immunodeficiency virus, varicella zoster virus, herpes simplex virus type 1, herpes simplex virus type 2, human cytomegalic inclusion disease virus, dengue virus, first type, B-mode, third type or hepatitis E, respiratory syncytial virus, human papillomavirus, influenza virus, Hib, meningitis virus; Salmonella, neisseria, Borrelia, chlamydiaceae, Bordetella, Streptococcus, Mycoplasma, Mycobacterium, Haemophilus spp, Plasmodium or toxoplasma, stanworth decapeptide; Or tumor associated antigen (TMA), MAGE, BAGE, GAGE, MUC-1, Her-2 neu, LnRH, CEA, PSA, KSA or PRAME.
25. the vaccine according to claim 24, wherein said antigen are antigen or the antigen preparations from influenza virus.
26. a vaccine combination comprises polyoxyethylene-9 lauryl ether, uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM) and influenza antigen.
27. one kind according to each vaccine of claim 23 to 26, wherein vaccine is aerosol or Sprayable.
28. one kind according to each vaccine of claim 23 to 27, is used for medicine.
29. each adjunvant composition of claim 1 to 22 is applied to application in the medicine on patient's mucomembranous surface or the skin in preparation.
30. polyoxyethylene-9 lauryl ether and uncle's octylphenoxy polyethoxy ethanol (TRITON X100
TM) mixture be applied to application in the vaccine on patient's mucomembranous surface in preparation.
31. a sprayer unit, a kind of more specifically dose double sprayer unit wherein is equipped with each vaccine of claim 23 to 27.
32. the vaccine combination of each qualification of claim 23 to 27 is used for the treatment of application in the vaccine of virus, antibacterial, parasitic infection, allergy or cancer in preparation.
33. treat mammal pathogenic infection or cancer or irritated or for one kind, comprise each the vaccine combination of claim 23 to 27 of granting a kind of safe and effective amount to mammal to the method for the susceptibility of these diseases.
34. treat mammal pathogenic infection or cancer or irritated or for one kind, comprise each the vaccine combination of claim 23 to 27 of granting a kind of safe and effective amount to the mammal through mucous membrane to the method for the susceptibility of these diseases.
35. treat mammal pathogenic infection or cancer or irritated or for one kind, comprise each the vaccine combination of claim 23 to 27 of granting a kind of safe and effective amount to mammal through intranasal to the method for the susceptibility of these diseases.
36. one kind prepares each the method for vaccine combination of claim 23 to 27, comprises each adjunvant composition of (a) claim 1 to 22, (b) pharmaceutically acceptable excipient and (c) a kind of antigen or antigen composition mix.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9922700.1A GB9922700D0 (en) | 1999-09-24 | 1999-09-24 | Vaccine |
GB9922700.1 | 1999-09-24 | ||
GB0016647.0 | 2000-07-06 | ||
GB0016647A GB0016647D0 (en) | 2000-07-06 | 2000-07-06 | Novel compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1399539A true CN1399539A (en) | 2003-02-26 |
Family
ID=26244608
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN00816263A Pending CN1399539A (en) | 1999-09-24 | 2000-09-22 | Adjuvant comprising polyxyethylene alkyl ether or ester and at least one nonionic surfactant |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1214053A1 (en) |
JP (1) | JP2003509452A (en) |
KR (1) | KR20020048942A (en) |
CN (1) | CN1399539A (en) |
AR (1) | AR025749A1 (en) |
AU (1) | AU766635B2 (en) |
BR (1) | BR0014285A (en) |
CA (1) | CA2383110A1 (en) |
CO (1) | CO5200838A1 (en) |
CZ (1) | CZ20021045A3 (en) |
HK (1) | HK1046861A1 (en) |
HU (1) | HUP0203817A3 (en) |
IL (1) | IL148671A0 (en) |
MX (1) | MXPA02003068A (en) |
NO (1) | NO20021432L (en) |
NZ (1) | NZ517901A (en) |
PL (1) | PL355232A1 (en) |
TR (1) | TR200200777T2 (en) |
WO (1) | WO2001021152A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100438964C (en) * | 2003-05-15 | 2008-12-03 | 广州市白云化工实业有限公司 | Non-ionic active silicon surface activator and its preparation method |
US8562943B2 (en) | 2006-11-08 | 2013-10-22 | Novartis Ag | Quality control methods for oil-in-water emulsions containing squalene |
CN105792843A (en) * | 2013-11-29 | 2016-07-20 | 泰尔茂株式会社 | Adjuvant composition, vaccine composition comprising same, and method for producing same |
Families Citing this family (151)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1463097A (en) | 1996-01-04 | 1997-08-01 | Rican Limited | Helicobacter pylori bacterioferritin |
NZ560966A (en) | 2000-10-27 | 2010-06-25 | Novartis Vaccines & Diagnostic | Nucleic acids and proteins from streptococcus groups A & B |
JP2004535765A (en) | 2000-12-07 | 2004-12-02 | カイロン コーポレイション | Endogenous retrovirus up-regulated in prostate cancer |
EP2269639B1 (en) * | 2001-02-23 | 2018-11-28 | GlaxoSmithKline Biologicals s.a. | Influenza vaccine formulations for intradermal delivery |
DE10125731A1 (en) * | 2001-05-17 | 2003-03-06 | A I D Autoimmun Diagnostika Gm | Dosage form of immunological agents |
MY134424A (en) * | 2001-05-30 | 2007-12-31 | Saechsisches Serumwerk | Stable influenza virus preparations with low or no amount of thiomersal |
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. |
EP2572707A3 (en) | 2002-02-20 | 2013-11-06 | Novartis Vaccines and Diagnostics, Inc. | Microparticles with adsorbed polypeptide-containing molecules |
US8518694B2 (en) | 2002-06-13 | 2013-08-27 | Novartis Vaccines And Diagnostics, Inc. | Nucleic acid vector comprising a promoter and a sequence encoding a polypeptide from the endogenous retrovirus PCAV |
GB0220194D0 (en) | 2002-08-30 | 2002-10-09 | Chiron Spa | Improved vesicles |
SI1549338T1 (en) | 2002-10-11 | 2011-04-29 | Novartis Vaccines & Diagnostic | Polypeptide-vaccines for broad protection against hypervirulent meningococcal lineages |
DK2279746T3 (en) | 2002-11-15 | 2013-11-25 | Novartis Vaccines & Diagnostic | SURFACE PROTEINS IN NEISSERIA MENINGITIDIS |
GB0227346D0 (en) | 2002-11-22 | 2002-12-31 | Chiron Spa | 741 |
US8034378B2 (en) | 2002-12-27 | 2011-10-11 | Novartis Vaccines And Diagnostics, Inc | Immunogenic compositions containing phospholipid |
ES2411080T3 (en) | 2003-01-30 | 2013-07-04 | Novartis Ag | Injectable vaccines against multiple serogroups of meningococci |
US7893096B2 (en) | 2003-03-28 | 2011-02-22 | Novartis Vaccines And Diagnostics, Inc. | Use of small molecule compounds for immunopotentiation |
GB0308198D0 (en) | 2003-04-09 | 2003-05-14 | Chiron Srl | ADP-ribosylating bacterial toxin |
NZ543467A (en) | 2003-04-10 | 2008-07-31 | Novartis Vaccines & Diagnostic | The severe acute respiratory syndrome coronavirus |
JP5557415B2 (en) | 2003-06-02 | 2014-07-23 | ノバルティス バクシンズ アンド ダイアグノスティックス,インコーポレーテッド | Immunogenic compositions based on microparticles containing adsorbed toxoid and polysaccharide-containing antigens |
US20060035242A1 (en) | 2004-08-13 | 2006-02-16 | Michelitsch Melissa D | Prion-specific peptide reagents |
PL1961426T3 (en) | 2003-10-02 | 2012-03-30 | Gsk Vaccines S R L | Combined meningitis vaccines |
GB0323103D0 (en) | 2003-10-02 | 2003-11-05 | Chiron Srl | De-acetylated saccharides |
US20080254065A1 (en) | 2004-03-09 | 2008-10-16 | Chiron Corporation | Influenza Virus Vaccines |
SI1740217T1 (en) | 2004-04-30 | 2011-10-28 | Novartis Ag | Meningococcal conjugate vaccination |
GB0500787D0 (en) | 2005-01-14 | 2005-02-23 | Chiron Srl | Integration of meningococcal conjugate vaccination |
GB0409745D0 (en) | 2004-04-30 | 2004-06-09 | Chiron Srl | Compositions including unconjugated carrier proteins |
GB0410866D0 (en) | 2004-05-14 | 2004-06-16 | Chiron Srl | Haemophilius influenzae |
EP2848692B1 (en) | 2004-05-21 | 2017-08-16 | 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 |
US20060165716A1 (en) | 2004-07-29 | 2006-07-27 | Telford John L | 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 |
NZ555937A (en) | 2005-01-27 | 2009-05-31 | Childrens Hosp & Res Ct Oak | 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 |
LT2351772T (en) | 2005-02-18 | 2016-10-10 | 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 |
EP2357000A1 (en) | 2005-10-18 | 2011-08-17 | 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 |
US10842867B2 (en) | 2005-11-04 | 2020-11-24 | Seqirus UK Limited | Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture |
ES2514316T3 (en) | 2005-11-22 | 2014-10-28 | Novartis Vaccines And Diagnostics, Inc. | Norovirus and Sapovirus virus-like particles (VLPs) |
GB0524066D0 (en) | 2005-11-25 | 2006-01-04 | Chiron Srl | 741 ii |
EP1976559B3 (en) | 2006-01-27 | 2020-02-19 | Seqirus UK Limited | 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 |
ATE539079T1 (en) | 2006-03-23 | 2012-01-15 | Novartis Ag | IMIDAZOCHINOXALINE COMPOUNDS AS IMMUNE MODULATORS |
JP2009534303A (en) | 2006-03-24 | 2009-09-24 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス ゲーエムベーハー アンド カンパニー カーゲー | Preserving influenza vaccines that are not refrigerated |
WO2007126825A2 (en) | 2006-03-31 | 2007-11-08 | Novartis Ag | Combined mucosal and parenteral immunization against hiv |
EP2035035A2 (en) | 2006-06-09 | 2009-03-18 | Novartis AG | Immunogenic compositions for streptococcus agalactiae |
GB0614460D0 (en) | 2006-07-20 | 2006-08-30 | Novartis Ag | Vaccines |
JP2010500399A (en) | 2006-08-16 | 2010-01-07 | ノバルティス アーゲー | Immunogen from Urinary Pathogenic Escherichia coli |
CA3016948A1 (en) | 2006-09-11 | 2008-03-20 | Seqirus UK Limited | Making influenza virus vaccines without using eggs |
EA200900784A1 (en) | 2006-12-06 | 2009-12-30 | Новартис Аг | VACCINES INCLUDING ANTIGENS FROM FOUR STRAINS OF THE INFLUENZA VIRUS |
GB0700562D0 (en) | 2007-01-11 | 2007-02-21 | Novartis Vaccines & Diagnostic | Modified Saccharides |
EP2185191B1 (en) | 2007-06-27 | 2012-09-12 | Novartis AG | Low-additive influenza vaccines |
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 |
EP2537857B1 (en) | 2007-12-21 | 2017-01-18 | GlaxoSmithKline Biologicals SA | Mutant forms of streptolysin O |
CN102356089B (en) | 2008-02-21 | 2014-02-19 | 诺华股份有限公司 | Meningococcal fhbp polypeptides |
WO2009114485A2 (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 |
PE20142330A1 (en) | 2008-12-09 | 2015-01-14 | Pfizer Vaccines Llc | IGE CH3 PEPTIDE VACCINE |
CN103897045A (en) | 2009-01-12 | 2014-07-02 | 诺华股份有限公司 | Cna_b domain antigens in vaccines against gram positive bacteria |
ES2608841T3 (en) | 2009-02-10 | 2017-04-17 | Seqirus UK Limited | Flu shots with reduced amounts of squalene |
ES2733084T3 (en) | 2009-03-06 | 2019-11-27 | Glaxosmithkline Biologicals Sa | Chlamydia antigens |
BRPI1013780B8 (en) | 2009-04-14 | 2022-10-04 | Novartis Ag | IMMUNOGENIC COMPOSITION USEFUL FOR IMMUNIZATION AGAINST STAPHYLOCOCCUS AUREUS, ITS PREPARATION METHOD AND PHARMACEUTICAL COMPOSITION |
EP2944320A1 (en) | 2009-06-15 | 2015-11-18 | National University of Singapore | Influenza vaccine, composition, and methods of use |
CA2767536A1 (en) | 2009-07-07 | 2011-01-13 | Novartis Ag | Conserved escherichia coli immunogens |
EP4218799A1 (en) | 2009-07-15 | 2023-08-02 | GlaxoSmithKline Biologicals S.A. | Rsv f protein compositions and methods for making same |
CA2768343A1 (en) | 2009-07-16 | 2011-01-20 | Novartis Ag | Detoxified escherichia coli immunogens |
WO2011013034A1 (en) | 2009-07-30 | 2011-02-03 | Pfizer Vaccines Llc | Antigenic tau peptides and uses thereof |
CA2772104A1 (en) | 2009-08-27 | 2011-03-03 | Novartis Ag | Hybrid polypeptides including meningococcal fhbp sequences |
CN104548089B (en) | 2009-09-03 | 2017-09-26 | 辉瑞疫苗有限责任公司 | PCSK9 vaccines |
JP2013506651A (en) | 2009-09-30 | 2013-02-28 | ノバルティス アーゲー | Staphylococcus. aureus type 5 and type 8 capsular polysaccharide conjugates |
GB0918392D0 (en) | 2009-10-20 | 2009-12-02 | Novartis Ag | Diagnostic and therapeutic methods |
BR112012010531A2 (en) | 2009-10-27 | 2019-09-24 | Novartis Ag | "fhbp meningococcal modification polypeptides" |
GB0919690D0 (en) | 2009-11-10 | 2009-12-23 | Guy S And St Thomas S Nhs Foun | compositions for immunising against staphylococcus aureus |
JP6007105B2 (en) | 2009-12-22 | 2016-10-12 | セルデックス・セラピューティクス・インコーポレイテッド | Vaccine composition |
GB201003333D0 (en) | 2010-02-26 | 2010-04-14 | Novartis Ag | Immunogenic proteins and compositions |
CA2790167C (en) | 2010-03-30 | 2021-02-09 | Children's Hospital & Research Center Oakland | Factor h 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 |
EP2556151A1 (en) | 2010-04-07 | 2013-02-13 | Novartis AG | Method for generating a parvovirus b19 virus-like particle |
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 |
WO2011154878A1 (en) | 2010-06-07 | 2011-12-15 | Pfizer Vaccines Llc | Ige ch3 peptide vaccine |
WO2011154863A1 (en) | 2010-06-07 | 2011-12-15 | Pfizer Inc. | Her-2 peptides and vaccines |
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 |
EP2680883B1 (en) | 2011-03-02 | 2018-09-05 | Pfizer Inc | Pcsk9 vaccine |
LT3275892T (en) | 2011-05-13 | 2020-04-10 | Glaxosmithkline Biologicals S.A. | Pre-fusion rsv f antigens |
JP2014520807A (en) | 2011-07-06 | 2014-08-25 | ノバルティス アーゲー | Immunogenic compositions and uses thereof |
US11896636B2 (en) | 2011-07-06 | 2024-02-13 | Glaxosmithkline Biologicals Sa | Immunogenic combination compositions and uses thereof |
WO2013016460A1 (en) | 2011-07-25 | 2013-01-31 | Novartis Ag | Compositions and methods for assessing functional immunogenicity of parvovirus vaccines |
WO2013108272A2 (en) | 2012-01-20 | 2013-07-25 | International Centre For Genetic Engineering And Biotechnology | Blood stage malaria vaccine |
EP2659907A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
EP2659908A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
EP2659906A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
CN107746852B (en) | 2012-05-04 | 2021-10-08 | 辉瑞公司 | Prostate-associated antigens and vaccine-based immunotherapeutic therapies |
JP2015518845A (en) | 2012-05-22 | 2015-07-06 | ノバルティス アーゲー | Neisseria meningitidis serogroup X conjugate |
EP2869842A1 (en) | 2012-07-06 | 2015-05-13 | Novartis AG | Immunogenic compositions and uses thereof |
CN105307684A (en) | 2012-10-02 | 2016-02-03 | 葛兰素史密丝克莱恩生物有限公司 | Nonlinear saccharide conjugates |
ES2848048T3 (en) | 2012-10-03 | 2021-08-05 | Glaxosmithkline Biologicals Sa | Immunogenic compositions |
RU2018137673A (en) | 2012-11-30 | 2019-03-22 | Глаксосмитклайн Байолоджикалс Са | ANTIGENS AND ANTIGEN COMBINATIONS PSEUDOMONAS |
JP2016520077A (en) | 2013-05-15 | 2016-07-11 | ザ ガバナーズ オブ ザ ユニバーシティ オブ アルバータ | E1E2HCV vaccine and method of use |
KR102390192B1 (en) * | 2013-10-03 | 2022-04-22 | 다우 글로벌 테크놀로지스 엘엘씨 | Microbicidal composition comprising a benzoate or sorbate salt |
NZ759686A (en) | 2014-01-21 | 2023-07-28 | Pfizer | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
US11160855B2 (en) | 2014-01-21 | 2021-11-02 | Pfizer Inc. | 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 |
BR112017001417B1 (en) | 2014-07-23 | 2023-11-07 | Children's Hospital & Research Center At Oakland | FACTOR H-BINDING PROTEIN (FHBP) VARIANTS, IMMUNOGENIC COMPOSITION AND USE OF A CROSS-REFERENCED FHBP VARIANT |
HUE062499T2 (en) | 2015-01-15 | 2023-11-28 | Pfizer | Immunogenic compositions for use in pneumococcal vaccines |
CA2986494A1 (en) | 2015-06-03 | 2016-12-08 | Affiris Ag | Il-23-p19 vaccines |
US20180186896A1 (en) | 2015-07-07 | 2018-07-05 | Affiris Ag | Vaccines for the treatment and prevention of ige mediated diseases |
RU2721128C2 (en) | 2015-07-21 | 2020-05-18 | Пфайзер Инк. | Immunogenic compositions containing conjugated antigens of the capsular saccharide, kits containing these compositions and use thereof |
WO2017085586A1 (en) | 2015-11-20 | 2017-05-26 | Pfizer Inc. | Immunogenic compositions for use in pneumococcal vaccines |
PT3405212T (en) | 2016-01-19 | 2020-08-25 | Pfizer | Cancer vaccines |
RU2762723C2 (en) | 2017-01-20 | 2021-12-22 | Пфайзер Инк. | 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 |
EP3893926A1 (en) | 2018-12-12 | 2021-10-20 | 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 |
WO2020208502A1 (en) | 2019-04-10 | 2020-10-15 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
CN114667343A (en) | 2019-11-01 | 2022-06-24 | 辉瑞大药厂 | Escherichia coli composition and method thereof |
NL2027383B1 (en) | 2020-01-24 | 2022-04-06 | Aim Immunotech Inc | Methods, compositions, and vaccines for treating a virus infection |
US20230085173A1 (en) | 2020-02-21 | 2023-03-16 | Pfizer Inc. | Purification of saccharides |
BR112022014555A2 (en) | 2020-02-23 | 2022-09-20 | Pfizer | COMPOSITIONS OF ESCHERICHIA COLI AND METHODS THEREOF. |
AU2021368151A1 (en) | 2020-10-27 | 2023-06-01 | Pfizer Inc. | Escherichia coli compositions 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 |
WO2022178196A1 (en) | 2021-02-19 | 2022-08-25 | Sanofi Pasteur Inc. | Meningococcal b recombinant vaccine |
EP4333868A1 (en) | 2021-05-04 | 2024-03-13 | King Abdullah University Of Science And Technology | Immuogenic compositions of mutant sars-cov-2 n protein and gene and methods of use thereof |
BR112023023671A2 (en) | 2021-05-28 | 2024-02-06 | Pfizer | IMMUNOGENIC COMPOSITIONS COMPRISING CONJUGATED CAPSULAR SACHARIDE ANTIGENS AND USES THEREOF |
US20220387576A1 (en) | 2021-05-28 | 2022-12-08 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
WO2023062170A2 (en) * | 2021-10-15 | 2023-04-20 | Glaxosmithkline Biologicals Sa | Adjuvants |
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 |
KR102631297B1 (en) * | 2021-11-09 | 2024-01-30 | 주식회사에이치엔비랩스 | Manufacturing method of nanosome with improved stability through surface treatment |
CA3237496A1 (en) | 2021-11-18 | 2023-05-25 | Matrivax, Inc. | Immunogenic fusion protein compositions and methods of use thereof |
WO2023135515A1 (en) | 2022-01-13 | 2023-07-20 | Pfizer Inc. | 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 |
WO2024082281A1 (en) * | 2022-10-21 | 2024-04-25 | Nanjing Haiwei Pharmaceutical Technologies Co., Ltd. | Novel formulations of epinephrine and uses thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA929945B (en) * | 1991-12-23 | 1993-08-02 | Hem Pharma Corp | Method of diagnosing combined cognitive/debilatory disorders. |
US5653987A (en) * | 1995-05-16 | 1997-08-05 | Modi; Pankaj | Liquid formulations for proteinic pharmaceuticals |
BR9909915A (en) * | 1998-04-09 | 2000-12-26 | Smithkline Beecham Biolog | Adjuvant compositions |
-
2000
- 2000-09-22 WO PCT/EP2000/009368 patent/WO2001021152A1/en not_active Application Discontinuation
- 2000-09-22 CO CO00072101A patent/CO5200838A1/en not_active Application Discontinuation
- 2000-09-22 CA CA002383110A patent/CA2383110A1/en not_active Abandoned
- 2000-09-22 AR ARP000104977A patent/AR025749A1/en unknown
- 2000-09-22 CN CN00816263A patent/CN1399539A/en active Pending
- 2000-09-22 BR BR0014285-9A patent/BR0014285A/en not_active Application Discontinuation
- 2000-09-22 EP EP00964232A patent/EP1214053A1/en not_active Withdrawn
- 2000-09-22 CZ CZ20021045A patent/CZ20021045A3/en unknown
- 2000-09-22 HU HU0203817A patent/HUP0203817A3/en unknown
- 2000-09-22 JP JP2001524578A patent/JP2003509452A/en active Pending
- 2000-09-22 NZ NZ517901A patent/NZ517901A/en unknown
- 2000-09-22 TR TR2002/00777T patent/TR200200777T2/en unknown
- 2000-09-22 MX MXPA02003068A patent/MXPA02003068A/en unknown
- 2000-09-22 IL IL14867100A patent/IL148671A0/en unknown
- 2000-09-22 PL PL00355232A patent/PL355232A1/en not_active Application Discontinuation
- 2000-09-22 KR KR1020027003856A patent/KR20020048942A/en not_active Application Discontinuation
- 2000-09-22 AU AU75226/00A patent/AU766635B2/en not_active Ceased
-
2002
- 2002-03-21 NO NO20021432A patent/NO20021432L/en not_active Application Discontinuation
- 2002-11-21 HK HK02108461.1A patent/HK1046861A1/en unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100438964C (en) * | 2003-05-15 | 2008-12-03 | 广州市白云化工实业有限公司 | Non-ionic active silicon surface activator and its preparation method |
US8562943B2 (en) | 2006-11-08 | 2013-10-22 | Novartis Ag | Quality control methods for oil-in-water emulsions containing squalene |
US9744231B2 (en) | 2006-11-08 | 2017-08-29 | Novartis Ag | Quality control methods for oil-in-water emulsions containing squalene |
CN105792843A (en) * | 2013-11-29 | 2016-07-20 | 泰尔茂株式会社 | Adjuvant composition, vaccine composition comprising same, and method for producing same |
US11000586B2 (en) | 2013-11-29 | 2021-05-11 | Terumo Kabushiki Kaisha | Adjuvant composition, vaccine composition containing the same, and method for producing both of them |
Also Published As
Publication number | Publication date |
---|---|
AU7522600A (en) | 2001-04-24 |
CA2383110A1 (en) | 2001-03-29 |
NZ517901A (en) | 2003-08-29 |
TR200200777T2 (en) | 2002-09-23 |
HK1046861A1 (en) | 2003-01-30 |
HUP0203817A2 (en) | 2003-03-28 |
AR025749A1 (en) | 2002-12-11 |
PL355232A1 (en) | 2004-04-05 |
EP1214053A1 (en) | 2002-06-19 |
IL148671A0 (en) | 2002-09-12 |
NO20021432D0 (en) | 2002-03-21 |
NO20021432L (en) | 2002-05-21 |
AU766635B2 (en) | 2003-10-23 |
CO5200838A1 (en) | 2002-09-27 |
HUP0203817A3 (en) | 2004-07-28 |
JP2003509452A (en) | 2003-03-11 |
BR0014285A (en) | 2002-05-21 |
MXPA02003068A (en) | 2002-09-30 |
CZ20021045A3 (en) | 2002-08-14 |
KR20020048942A (en) | 2002-06-24 |
WO2001021152A1 (en) | 2001-03-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1399539A (en) | Adjuvant comprising polyxyethylene alkyl ether or ester and at least one nonionic surfactant | |
AU765824B2 (en) | Vaccines | |
AU746163B2 (en) | Adjuvant compositions | |
ES2267189T3 (en) | ANTIGEN ADMINISTRATION SYSTEM THAT INCLUDES DERIVATIVES OF MONOGLICERIDO OR DIGLICERIDO AS ADJUVANTS. | |
JP2021006567A (en) | Nanoemulsion compositions for preventing, suppressing and eliminating allergic and inflammatory diseases | |
Isaka et al. | Induction of systemic and mucosal antibody responses in mice immunized intranasally with aluminium-non-adsorbed diphtheria toxoid together with recombinant cholera toxin B subunit as an adjuvant | |
US8481043B2 (en) | Nasal immunization | |
JP6122083B2 (en) | Nanoemulsion vaccine | |
CN1674867A (en) | Antigenic compositions | |
ZA200202268B (en) | Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one non-ionic surfactant. | |
ZA200202270B (en) | Use of combination of polyxyethylene sorbitan ester and octoxynol as adjuvant and its use in vaccines. | |
MXPA00009887A (en) | Adjuvant compositions | |
CZ20003732A3 (en) | Auxiliary preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |