CN1196956A - 流感疫苗 - Google Patents
流感疫苗 Download PDFInfo
- Publication number
- CN1196956A CN1196956A CN98108086A CN98108086A CN1196956A CN 1196956 A CN1196956 A CN 1196956A CN 98108086 A CN98108086 A CN 98108086A CN 98108086 A CN98108086 A CN 98108086A CN 1196956 A CN1196956 A CN 1196956A
- Authority
- CN
- China
- Prior art keywords
- influenza virus
- influenza
- cell culture
- described method
- dna
- 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.)
- Granted
Links
- 229960003971 influenza vaccine Drugs 0.000 title description 8
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 27
- 239000003599 detergent Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 210000004027 cell Anatomy 0.000 claims abstract description 19
- 102000036639 antigens Human genes 0.000 claims abstract description 16
- 108091007433 antigens Proteins 0.000 claims abstract description 16
- 241000700605 Viruses Species 0.000 claims abstract description 14
- 238000004113 cell culture Methods 0.000 claims abstract description 12
- 210000004102 animal cell Anatomy 0.000 claims abstract description 9
- 125000002091 cationic group Chemical group 0.000 claims abstract description 9
- 206010022000 influenza Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 238000009395 breeding Methods 0.000 claims description 6
- 230000001488 breeding effect Effects 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 5
- 102000038379 digestive enzymes Human genes 0.000 claims description 5
- 108091007734 digestive enzymes Proteins 0.000 claims description 5
- 229960000800 cetrimonium bromide Drugs 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000001450 anions Chemical group 0.000 claims description 2
- 239000012930 cell culture fluid Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 13
- 229960005486 vaccine Drugs 0.000 abstract description 13
- 239000000427 antigen Substances 0.000 abstract description 4
- 230000000644 propagated effect Effects 0.000 abstract 2
- 102000004190 Enzymes Human genes 0.000 abstract 1
- 108090000790 Enzymes Proteins 0.000 abstract 1
- 239000012530 fluid Substances 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000855 fermentation Methods 0.000 description 8
- 230000004151 fermentation Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 239000000463 material Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 238000000108 ultra-filtration Methods 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 102000002322 Egg Proteins Human genes 0.000 description 3
- 108010000912 Egg Proteins Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 239000000185 hemagglutinin Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- -1 myristyl leptodactyline Chemical compound 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229940031626 subunit vaccine Drugs 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 241000282465 Canis Species 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 101710154606 Hemagglutinin Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 2
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 2
- 101710176177 Protein A56 Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000004389 Ribonucleoproteins Human genes 0.000 description 2
- 108010081734 Ribonucleoproteins Proteins 0.000 description 2
- 108010034546 Serratia marcescens nuclease Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 230000009849 deactivation Effects 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WSSDPLLBHSTNNM-UHFFFAOYSA-N C(CCCCCCCCCCCCCCC)[As] Chemical compound C(CCCCCCCCCCCCCCC)[As] WSSDPLLBHSTNNM-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229940124873 Influenza virus vaccine Drugs 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- QWZLBLDNRUUYQI-UHFFFAOYSA-M Methylbenzethonium chloride Chemical compound [Cl-].CC1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 QWZLBLDNRUUYQI-UHFFFAOYSA-M 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000725681 Swine influenza virus Species 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960003872 benzethonium Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- RLGQACBPNDBWTB-UHFFFAOYSA-N cetyltrimethylammonium ion Chemical group CCCCCCCCCCCCCCCC[N+](C)(C)C RLGQACBPNDBWTB-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 108010087236 cobra venom endonuclease Proteins 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 229950000405 decamethonium Drugs 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960002285 methylbenzethonium chloride Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- HLXQFVXURMXRPU-UHFFFAOYSA-L trimethyl-[10-(trimethylazaniumyl)decyl]azanium;dibromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCCCCCCC[N+](C)(C)C HLXQFVXURMXRPU-UHFFFAOYSA-L 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5252—Virus inactivated (killed)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16051—Methods of production or purification of viral material
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16211—Influenzavirus B, i.e. influenza B virus
- C12N2760/16234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及一种流感表面抗原疫苗,可由在动物细胞培养物上繁殖的流感病毒制得,其宿主细胞DNA含量等于或小于每剂25pg。本发明还涉及一种从在动物细胞培养物上繁殖的流感病毒制备表面抗原蛋白的方法,包括以下步骤:a.用DNA消化酶处理包含完整病毒的细胞培养液,和b.加入阳离子去污剂,然后分离表面抗原蛋白。
Description
本发明涉及由在动物细胞培养物上繁殖的流感病毒制得的流感表面抗原疫苗，和一种由在动物细胞培养物上繁殖的流感病毒制备表面抗原蛋白的方法。
流感病毒的体长大约125nm，含有一个与核蛋白有关的核糖核酸(RNA)的核心，此核心被一层具有脂质双层结构的病毒被膜围绕。病毒被膜的内层主要由基质蛋白质组成，外层含有大部分来源于宿主的类脂物质。
所谓的“表面蛋白质”，即神经氨酸酶(NA)和血细胞凝集素(HA)，表现为病毒体表的刺突。
大部分市售的失活流感疫苗是所谓的“断裂疫苗”或“亚单位疫苗”。
“断裂疫苗”是通过将整个流感病毒经可溶解浓度的去污剂处理，随后除去去污剂和大部分病毒的脂类物质制得。
抗流感“亚单位疫苗”与“断裂疫苗”不同，不含有全部的病毒蛋白质。“亚单位疫苗”富含在接种时可以诱发所需的中和(因此保护)抗体的病毒的表面蛋白。
大部分市售的流感疫苗由在鸡含胚卵上培育的流感病毒得到。然而一般认为，从卵来源制备的流感病毒作为疫苗有一些不利之处：
1.其制备过程由于卵的(微)生物学性质的不定性很易受破坏。
2.如果遇到突然增加的需求，即在感冒严重流行或大流行的情况下，其制备过程由于不能得到大量合格的鸡蛋而完全缺乏产量的适应性。
3.由此制备的疫苗对于已知对鸡和/或鸡蛋蛋白质过敏的人是禁忌的。
对于这些问题的一种解决办法可以求助于从组织培养物制备流感病毒。此制备方法被认为具有许多优点：
1.组织培育的细胞系可以在完全确定的，不含(微)生物污染物的细胞库体系中得到，因此批次间的一致性大大增加，从而得到高质量的产品。
2.在严重的流行病或传染病威胁的情况下，能得到充足疫苗的机会将增加。
3.所得的流感病毒物质将更适合于给药途径的选择(口服、经鼻给药、吸入)。
4.按WHO的观点，这项技术使每年一度的疫苗组合物的推荐可以被推迟(从二月中旬至三月中旬)，可以增进疫苗与流传菌株的匹配。
然而，流感病毒的组织培养也存在一个重要问题，因为从传代细胞系中得到的遗传物质可能仍存在于疫苗中。
这些问题形成一种危险，如不加以克服，将导致管理部门由于安全原因拒绝允许这些流感疫苗上市的请求。如美国食品药品管理局要求用于人体的生物技术产品每次服用剂量中含有的宿主细胞DNA不能超过100pg。
因此，本发明提供一种制备流感病毒表面抗原的方法，由此制得的疫苗是安全的，每次服用剂量中所含的有害遗传物质不超过可被接受的数量，以符合管理部门提出的要求。无论如何，此方法被认为是理想的和令人惊喜地可以制备每一服用剂量所含宿主DNA量大大低于100pg的流感疫苗。
相应地，本发明涉及一种从在动物细胞培养物上繁殖的流感病毒制得的流感表面抗原疫苗，其每次服用剂量中所含宿主细胞DNA等于或小于25pg。
具体地说，本发明提供一种制备表面抗原蛋白的方法，用于通过在动物细胞培养物上繁殖的流感病毒制备这种低DNA的流感疫苗，它包括以下步骤：
a.用一种DNA消化酶处理含有整个病毒的细胞培养液，和
b.加入阳离子去污剂，随后分离表面抗原蛋白。
本发明的方法适用于制备含多种流感病毒株的疫苗，如人流感病毒、猪流感病毒、马流感病毒、鸟流感病毒。
本发明的动物细胞培养物可以含有初级细胞如鸡胚成纤维细胞(CEF)或传代细胞系如犬肾细胞(Madin Darby Canine KidneyCells(MDCK))、中国仓鼠卵巢细胞(CHO)和Vero细胞。
可以直接在发酵罐中用DNA消化酶处理含完整病毒的发酵液，可以选择在细胞培养或病毒繁殖过程中进行。
适合的DNA消化酶是脱氧核糖核酸酶(如按照EC 3.1.21和EC3.1.22分类的)和核酸酶(按照EC3.1.30和3.1.31分类的)。
本发明所用适合的阳离子去污剂主要包括一种具有以下通式的化合物
其中R1、R2和R3是相同或不同的，各自代表烷基或芳基，
或R1和R2，与相连的氮原子一起形成5或6元结构的杂环，同时R3代表烷基或芳基，
或R1、R2和R3与相连的氮原子一起形成5或6元结构的杂环，在氮原子处不饱和，R4代表烷基或芳基，并且X代表阴离子。
阳离子去污剂的例子是十六烷基三甲基铵盐，如溴化十六烷基三甲基铵(C.T.A.B.)，和十四烷基三甲基铵盐。合适的去污剂也可以是lipofectine、lipofectamine、DOTMA。
阳离子去污剂可以补充以非离子去污剂，如吐温。
经去污剂处理后表面抗原蛋白的分离可以包括以下步骤：
1.用离心或超滤等方法从表面抗原蛋白中分离核糖核蛋白微粒(体)，和
2.通过去污剂与一种合适的树脂(如Amberlite XAD-4)的疏水性相互作用和/或通过超滤(透析)的方法，从表面抗原蛋白中除去去污剂。
本发明的方法令人惊喜地得到一种含有极低量的来源于动物细胞的DNA的产物。一次剂量中所含DNA低于25pg，在许多样品中甚至很易达到低于每剂10pg。
表面抗原蛋白可以被加工制成流感疫苗，如通过加入缓冲剂(如磷酸盐缓冲液)和/或与其它流感病毒血清型的抗原混合。
进一步制备疫苗过程中可以选择性地经过表面抗原的浓缩。实施例1A.病毒繁殖
1.在35℃条件下，将种子病毒和细胞在发酵罐中温育2天，使B/Yamagata型抗原的流感病毒在狗肾(Madin Darby CanineKidney(MDCK))细胞(ATCC CCL34)上繁殖。
2.随后加入稀NaOH将发酵液pH提高到8.0，并加入Benzon核酸酶至最终浓度为每升1000单位(1μg)。
3.在35℃条件下再进行4小时的温育。B.病毒分离
1.发酵液通过一种滤孔为0.5μm的深度滤器(depth filter)过滤除去细胞碎屑。
2.随后以截留分子量为300.000的滤膜超滤，将流感病毒浓缩和纯化。
3.在浓缩物中加入蔗糖至终浓度为30％(w/v)，然后加入甲醛至终浓度为0.015％(w/v)。此混合物在2-8℃搅拌72小时。
4.以磷酸盐缓冲盐水将病毒浓缩物稀释5倍，加到含有AmiconCellufine Sulphate的亲合柱上。以磷酸盐缓冲盐水洗涤除去杂质后，用1.5摩尔浓度氯化钠的磷酸盐缓冲盐水溶液洗脱病毒。洗脱物通过截留分子量为300.000的滤膜超滤而被浓缩并脱盐。C.亚单位分离
1.加入非离子去污剂吐温-80至终浓度为300μg/ml，加入溴化十六烷基三甲基铵至终浓度为750μg/ml。将此混合物在4℃搅拌3小时，然后离心以从表面抗原蛋白中分离核糖核蛋白颗粒。
2.上清液加入Amberlite XAD-4树脂在2-8℃搅拌过夜，除去去污剂。过滤除去Amberlite树脂，滤液随后通过0.22μm滤孔的滤器进行无菌过滤。
在以上步骤中，以有效的试验方法对样品中的宿主细胞DNA含量进行分析，此试验基于用一种32P标记的犬DNA探针进行的狭线印迹杂交。
各制备步骤后DNA的测定结果列于下表(此表中每剂量流感病毒疫苗中的DNA量表示为每50μg血细胞凝集素所含的微微克数(pg/50μgHA))。
表
实施例2
| 样品 | DNA含量 | 所经步骤 |
| 经过48小时温育的发酵液体 | 19.000.000 | A1 |
| 经核酸酶处理的发酵液 | 370.000 | A2 |
| 预过滤后的液体 | 10.000 | B1 |
| 超滤后的浓缩物 | 4350 | B2 |
| 灭活和经亲合层析后的液体 | 4200 | B4 |
| 吐温/C.T.A.B.处理并离心后的上清液 | ＜25 | C1 |
| 除去去污剂后的滤液 | ＜25 | C2 |
病毒的繁殖、纯化、灭活和裂解如实施例1所述。
在病毒繁殖的后几个小时(步骤A2 and A3)，在繁殖培养基的pH(步骤A1)条件下发酵液经Benzon核酸酶处理，对于除去DNA产生相似的结果。
脱氧核糖核酸酶I，虽然需要较高浓度，在去除宿主细胞DNA方面(步骤A1-A3)同样有效。采用其它核酸内切酶可以得到相似的结果。实施例3
制备过程如实施例1或实施例2所述，只是改用离心法去除细胞碎屑(步骤B1)。实施例4
制备过程如实施例1、实施例2或实施例3所述，只是改用离心法浓缩和纯化发酵液中的病毒(步骤B2)，使用连续液流离心机如在磷酸缓冲盐水中采用蔗糖梯度法的电核型离心机(RK型)。实施例5
制备过程如实施例1至实施例4所述，只是将在C1步骤中加入溴化十六烷基三甲基铵溶液改为加入溴化十六烷基砒啶、溴化十四烷基三甲基铵、氯化苯双胺、(benzetonium chloride)，氯化甲基苯双胺(methylbenzethonium chloride，)氯化十烷双胺或硬脂酰二甲基溴化苄铵，除去宿主细胞DNA的效果相似。实施例6
制备过程如实施例1所述，只是改为在经过亲合柱层析后加入蔗糖，加入甲醛达到最大浓度0.05％(w/v)，混合物搅拌120小时。实施例7
实施例1、2、3、4、和6的方法同样成功地适用于从流感病毒株B/Harbin、B/Panama、A/Texas(H1N1)、A/Taiwan(H1N1)、A/Johannesburg(H3N2)和A/Wuhan(H3N2)制备低DNA疫苗。
Claims (9)
1.流感表面抗原疫苗，由在动物细胞培养物上繁殖的流感病毒制得，其宿主细胞DNA含量等于或小于每剂25pg。
2.权利要求1所述的流感表面抗原疫苗，其宿主细胞DNA含量小于每剂10pg。
3.由在动物细胞培养物上繁殖的流感病毒制备表面抗原蛋白的方法，包括以下步骤：
a.用DNA消化酶处理包含完整病毒的细胞培养液，和
b.加入阳离子去污剂，
然后分离表面抗原蛋白。
4.权利要求3所述方法，其中在细胞培养物中流感病毒繁殖期进行DNA消化酶处理。
5.权利要求3所述方法，其中阳离子去污剂主要包括具有以下通式的化合物：
其中R1、R2、R3是相同或不同的，各自代表烷基或芳基，
或R1和R2与相连的氮原子一起形成5或6元结构的杂环，同时R3代表烷基或芳基，
或R1、R2和R3与相连的氮原子一起形成5或6元结构的杂环，在氮原子处不饱和，R4代表烷基或芳基，并且X代表阴离子。
6.权利要求3所述方法，其中阳离子去污剂主要包括溴化十六烷基三甲基铵。
7.权利要求3所述方法，其中阳离子去污剂可以补充以非离子去污剂。
8.权利要求3所述方法，其中流感病毒是在动物细胞系上繁殖的。
9.权利要求3所述方法，其中流感病毒是在MDCK细胞上繁殖的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97201007.8 | 1997-04-09 | ||
| EP97201007 | 1997-04-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1196956A true CN1196956A (zh) | 1998-10-28 |
| CN1138564C CN1138564C (zh) | 2004-02-18 |
Family
ID=8228174
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB981080863A Expired - Lifetime CN1138564C (zh) | 1997-04-09 | 1998-04-06 | 流感疫苗 |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US5948410A (zh) |
| EP (1) | EP0870508B1 (zh) |
| JP (1) | JP5258127B2 (zh) |
| KR (1) | KR100593235B1 (zh) |
| CN (1) | CN1138564C (zh) |
| AR (1) | AR011216A1 (zh) |
| AT (1) | ATE197406T1 (zh) |
| AU (1) | AU728939B2 (zh) |
| BR (1) | BR9801015A (zh) |
| CA (1) | CA2234208C (zh) |
| CZ (1) | CZ297492B6 (zh) |
| DE (2) | DE870508T1 (zh) |
| DK (1) | DK0870508T3 (zh) |
| DZ (1) | DZ2462A1 (zh) |
| ES (1) | ES2129386T3 (zh) |
| GR (2) | GR990300017T1 (zh) |
| HK (1) | HK1010833A1 (zh) |
| HR (1) | HRP980187B1 (zh) |
| HU (1) | HUP9800802A3 (zh) |
| ID (1) | ID20399A (zh) |
| IL (1) | IL123961A (zh) |
| NO (1) | NO323349B1 (zh) |
| NZ (1) | NZ330131A (zh) |
| PL (1) | PL187982B1 (zh) |
| PT (1) | PT870508E (zh) |
| RU (1) | RU2197264C2 (zh) |
| SI (1) | SI0870508T1 (zh) |
| SK (1) | SK282614B6 (zh) |
| TR (1) | TR199800613A1 (zh) |
| TW (1) | TW570803B (zh) |
| UA (1) | UA42089C2 (zh) |
| ZA (1) | ZA982915B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100415769C (zh) * | 2002-02-07 | 2008-09-03 | 中国科学院过程工程研究所 | 寡聚或多聚亚基蛋白质分离纯化的方法 |
Families Citing this family (98)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ517903A (en) * | 1999-09-24 | 2003-10-31 | Smithkline Beecham Biolog S | One dose intranasal influenza virus vaccine with split influenza viral antigens |
| GB9923176D0 (en) * | 1999-09-30 | 1999-12-01 | Smithkline Beecham Biolog | Novel composition |
| AU2003229159B2 (en) | 2002-04-30 | 2008-02-21 | Oncolytics Biotech Inc. | Improved viral purification methods |
| US20060110406A1 (en) | 2003-02-25 | 2006-05-25 | Medimmune Vaccines, Inc. | Refrigerator-temperature stable influenza vaccine compositions |
| EP1597400B8 (en) * | 2003-02-25 | 2013-10-09 | MedImmune, LLC | Methods of producing influenza vaccine compositions |
| DE602004028736D1 (de) * | 2003-06-20 | 2010-09-30 | Microbix Biosystems Inc | Verbesserungen bei der virusproduktion |
| US8506967B2 (en) | 2003-07-11 | 2013-08-13 | Novavax, Inc. | Functional influenza virus like particles (VLPs) |
| US8592197B2 (en) | 2003-07-11 | 2013-11-26 | Novavax, Inc. | Functional influenza virus-like particles (VLPs) |
| US8992939B2 (en) | 2003-07-11 | 2015-03-31 | Novavax, Inc. | Highly efficient influenza matrix (M1) proteins |
| US8080255B2 (en) | 2003-07-11 | 2011-12-20 | Novavax Inc. | Functional influenza virus like particles (VLPs) |
| AU2005214090B2 (en) | 2004-02-23 | 2008-09-11 | Crucell Holland B.V. | Virus purification methods |
| EP1722815A1 (en) | 2004-03-09 | 2006-11-22 | Chiron Corporation | Influenza virus vaccines |
| EP2471551B1 (en) | 2004-09-09 | 2017-02-01 | Novartis AG | Decreasing potential iatrogenic risks associated with influenza vaccines |
| US7901921B2 (en) | 2004-10-22 | 2011-03-08 | Oncolytics Biotech Inc. | Viral purification methods |
| US20090004222A1 (en) | 2004-11-03 | 2009-01-01 | O'hagan Derek | Influenza Vaccination |
| EP2368975B1 (en) | 2004-12-23 | 2014-09-17 | MedImmune, LLC | Non-tumorigenic MDCK cell line for propagating viruses |
| TW200700078A (en) | 2005-03-23 | 2007-01-01 | Glaxosmithkline Biolog Sa | Novel use |
| CA2602944C (en) * | 2005-04-11 | 2015-08-11 | Crucell Holland B.V. | Virus purification using ultrafiltration |
| ATE494906T1 (de) * | 2005-11-01 | 2011-01-15 | Novartis Vaccines & Diagnostic | Von zellen stammende virale impfstoffe mit geringen mengen an rest-zell-dna |
| 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 |
| AU2006310163B2 (en) | 2005-11-04 | 2011-09-15 | Seqirus UK Limited | Influenza vaccine with reduced amount of oil-in-water emulsion as adjuvant |
| PT1951299E (pt) | 2005-11-04 | 2012-02-28 | Novartis Vaccines & Diagnostic | Vacinas contra a gripe que incluem combinações de adjuvantes particulados e imuno-potenciadores |
| NZ568210A (en) * | 2005-11-04 | 2012-12-21 | Novartis Vaccines & Diagnostic | Emulsions with free aqueous-phase surfactant as adjuvants for split influenza vaccines |
| HUE051122T2 (hu) * | 2005-11-04 | 2021-03-01 | Seqirus Uk Ltd | Sejttenyészetben növesztett influenzavírusból elõállított nemvirion anti-géneket tartalmazó adjuvált vakcinák |
| CN102755645A (zh) | 2005-11-04 | 2012-10-31 | 诺华疫苗和诊断有限公司 | 佐剂配制的包含细胞因子诱导剂的流感疫苗 |
| EP1976559B3 (en) | 2006-01-27 | 2020-02-19 | Seqirus UK Limited | Influenza vaccines containing hemagglutinin and matrix proteins |
| WO2007110776A1 (en) | 2006-03-24 | 2007-10-04 | Novartis Vaccines And Diagnostics Gmbh & Co Kg | Storage of influenza vaccines without refrigeration |
| WO2007126810A2 (en) | 2006-03-31 | 2007-11-08 | Warf - Wisconsin Alumni Research Foundation | High titer recombinant influenza viruses for vaccines |
| PL2043682T3 (pl) | 2006-07-17 | 2014-09-30 | Glaxosmithkline Biologicals Sa | Szczepionka przeciw grypie |
| GB0614460D0 (en) * | 2006-07-20 | 2006-08-30 | Novartis Ag | Vaccines |
| WO2008032219A2 (en) | 2006-09-11 | 2008-03-20 | Novartis Ag | Making influenza virus vaccines without using eggs |
| AU2007347716B2 (en) | 2006-09-15 | 2013-06-20 | Medimmune, Llc | MDCK cell lines supporting viral growth to high titers and bioreactor process using the same |
| EP2532362A1 (en) | 2006-12-06 | 2012-12-12 | Novartis AG | Vaccines including antigen from four strains of influenza virus |
| US8697154B2 (en) * | 2007-03-05 | 2014-04-15 | Om Pharma Sa | Bacterial extract for respiratory disorders and process for its preparation |
| CA2680600A1 (en) | 2007-03-12 | 2008-09-18 | Antigen Express, Inc. | Li-rnai involved li suppression in cancer immunotherapy |
| AR066405A1 (es) | 2007-04-20 | 2009-08-19 | Glaxosmithkline Biolog Sa | Vacuna |
| US9474798B2 (en) | 2007-06-18 | 2016-10-25 | Wisconsin Alumni Research Foundation | Influenza M2 protein mutant viruses as live influenza attenuated vaccines |
| PT2185191E (pt) | 2007-06-27 | 2012-11-27 | Novartis Ag | Vacinas contra a gripe com baixo teor de aditivos |
| CA2697373C (en) * | 2007-08-27 | 2019-05-21 | Longhorn Vaccines & Diagnostics, Llc | Immunogenic compositions and methods |
| GB0810305D0 (en) | 2008-06-05 | 2008-07-09 | Novartis Ag | Influenza vaccination |
| CA2718430A1 (en) | 2008-03-18 | 2009-09-24 | Novartis Ag | Improvements in preparation of influenza virus vaccine antigens |
| WO2010036760A1 (en) * | 2008-09-24 | 2010-04-01 | Medimmune, Llc | Methods for cultivating cells, propagating and purifying viruses |
| WO2010052214A2 (en) | 2008-11-05 | 2010-05-14 | Glaxosmithkline Biologicals S.A. | Novel method |
| EA201171032A1 (ru) | 2009-02-10 | 2012-02-28 | Новартис Аг | Схемы лечения с помощью вакцины против гриппа, связанного с пандемическими штаммами |
| CA2752041A1 (en) | 2009-02-10 | 2010-08-19 | Novartis Ag | Influenza vaccines with increased amounts of h3 antigen |
| EP2396032B1 (en) | 2009-02-10 | 2016-09-28 | Seqirus UK Limited | Influenza vaccines with reduced amounts of squalene |
| CN102548577A (zh) | 2009-04-27 | 2012-07-04 | 诺华有限公司 | 用于抵抗流感的佐剂疫苗 |
| AU2010250832B2 (en) | 2009-05-21 | 2013-10-03 | Seqirus UK Limited | Reverse genetics using non-endogenous pol I promoters |
| WO2010144797A2 (en) | 2009-06-12 | 2010-12-16 | Vaccine Technologies, Incorporated | Influenza vaccines with enhanced immunogenicity and uses thereof |
| CA2803282C (en) | 2009-07-06 | 2018-05-01 | David E. Anderson | Methods for preparing vesicles and formulations produced therefrom |
| CN102482666B (zh) | 2009-07-06 | 2017-02-08 | 变异生物技术公司 | 制备囊泡的方法和由其产生的制剂 |
| CA2769673A1 (en) | 2009-07-31 | 2011-02-03 | Novartis Ag | Reverse genetics systems |
| WO2011030218A1 (en) | 2009-09-10 | 2011-03-17 | Novartis Ag | Combination vaccines against respiratory tract diseases |
| CN102741399A (zh) | 2009-10-20 | 2012-10-17 | 诺华有限公司 | 用于病毒拯救的改良反向遗传方法 |
| EP2493912B1 (en) | 2009-10-26 | 2020-07-29 | Wisconsin Alumni Research Foundation | High titer recombinant influenza viruses with enhanced replication in vero cells |
| US10130697B2 (en) | 2010-03-23 | 2018-11-20 | Wisconsin Alumni Research Foundation (Warf) | Vaccines comprising mutant attenuated influenza viruses |
| AU2011254204B2 (en) | 2010-05-21 | 2015-08-20 | Seqirus UK Limited | Influenza virus reassortment method |
| CN103096921A (zh) | 2010-06-01 | 2013-05-08 | 诺华有限公司 | 不用冻干疫苗抗原浓缩 |
| JP5976639B2 (ja) | 2010-06-01 | 2016-08-23 | ノバルティス アーゲー | インフルエンザワクチン抗原の濃縮および凍結乾燥 |
| US9610248B2 (en) | 2010-07-06 | 2017-04-04 | Variation Biotechnologies, Inc. | Compositions and methods for treating influenza |
| CA2808965C (en) | 2010-08-20 | 2020-01-07 | Novartis Ag | Soluble needle arrays for delivery of influenza vaccines |
| CA2862871C (en) | 2011-01-13 | 2020-09-22 | Variation Biotechnologies Inc. | Methods for preparing vesicles and formulations produced therefrom |
| EP2663327A4 (en) | 2011-01-13 | 2015-12-02 | Variation Biotechnologies Inc | COMPOSITIONS AND METHOD FOR THE TREATMENT OF VIRUS INFECTIONS |
| US20140248320A1 (en) | 2011-10-20 | 2014-09-04 | Novartis Ag | Adjuvanted influenza b virus vaccines for pediatric priming |
| US20140328876A1 (en) | 2011-11-18 | 2014-11-06 | Variation Biotechnologies Inc. | Synthetic derivatives of mpl and uses thereof |
| CN104302323A (zh) | 2012-01-12 | 2015-01-21 | 变异生物技术公司 | 用于治疗病毒感染的组合物和方法 |
| CA2894467A1 (en) | 2012-01-27 | 2013-08-01 | Variation Biotechnologies Inc. | Methods for preparing thermostable compositions comprising a lipid component and thermolabile therapeutic agents |
| AU2013205478B9 (en) | 2012-03-02 | 2014-11-20 | Seqirus UK Limited | Influenza virus reassortment |
| AU2013270793A1 (en) | 2012-06-04 | 2014-12-11 | Novartis Ag | Improved safety testing |
| GB201218195D0 (en) | 2012-10-10 | 2012-11-21 | Istituto Zooprofilattico Sperimentale Delle Venezie | Composition |
| EP2925356A2 (en) | 2012-12-03 | 2015-10-07 | Novartis AG | Reassortant influenza a viren |
| CA2905612A1 (en) | 2013-03-13 | 2014-09-18 | Novartis Ag | Influenza virus reassortment |
| CN105828835A (zh) | 2013-05-10 | 2016-08-03 | 诺华股份有限公司 | 避免流感疫苗中的发作性嗜睡病风险 |
| DE202013005100U1 (de) | 2013-06-05 | 2013-08-26 | Novartis Ag | Influenza Virus Reassortierung |
| DE202013005130U1 (de) | 2013-06-05 | 2013-09-10 | Novartis Ag | Influenza Virus Reassortierung |
| CA2914604A1 (en) | 2013-06-06 | 2014-12-11 | Novartis Ag | Influenza virus reassortment |
| WO2015009743A1 (en) | 2013-07-15 | 2015-01-22 | Wisconsin Alumni Research Foundation | High titer recombinant influenza viruses with enhanced replication in mdck or vero cells or eggs |
| RU2535153C1 (ru) * | 2013-09-04 | 2014-12-10 | Федеральное государственное унитарное предприятие "Санкт-Петербургский научно-исследовательский институт вакцин и сывороток и предприятие по производству бактерийных препаратов" Федерального медико-биологического агентства России (ФГУП СПбНИИВС ФМБА России) | Способ получения высокоочищенных вирионных концентратов |
| CN105745218B (zh) | 2013-11-15 | 2020-11-06 | 诺华股份有限公司 | 去除残留细胞培养杂质 |
| WO2015196150A2 (en) | 2014-06-20 | 2015-12-23 | Wisconsin Alumni Research Foundation (Warf) | Mutations that confer genetic stability to additional genes in influenza viruses |
| EP2966093A1 (en) | 2014-07-07 | 2016-01-13 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Process for the preparation of magnetic sulfated cellulose particles, magnetic sulfated cellulose particles and their use |
| US10633422B2 (en) | 2015-06-01 | 2020-04-28 | Wisconsin Alumni Research Foundation (Warf) | Influenza virus replication by inhibiting microRNA lec7C binding to influenza viral cRNA and mRNA |
| RU2614127C2 (ru) * | 2015-06-04 | 2017-03-22 | Общество с ограниченной ответственностью "НТфарма" | Способ получения концентрата рекомбинантных псевдоаденовирусных частиц, экспрессирующих ген гемагглютинина вируса гриппа A/California/07/2009(H1N1) |
| BR112017028011A2 (pt) | 2015-06-26 | 2018-08-28 | Seqirus Uk Ltd | vacinas de gripe correspondentes antigenicamente |
| WO2017007839A1 (en) | 2015-07-06 | 2017-01-12 | Wisconsin Alumni Research Foundation (Warf) | Improved influenza virus replication for vaccine development |
| BR112018000296A2 (pt) | 2015-07-07 | 2018-09-04 | Seqirus UK Limited | ensaios de potência de influenza |
| CN109477074B (zh) | 2016-02-19 | 2023-01-24 | 威斯康星旧生研究基金会 | 用于疫苗开发的改进的乙型流感病毒复制 |
| EP3601544A4 (en) | 2017-03-30 | 2021-01-27 | Merck Sharp & Dohme Corp. | ADDITION OF NUCLEASES DIRECTLY TO CELL CULTURE TO FACILITATE DIGESTION AND CLEARANCE OF NUCLEIC ACIDS FROM HOST CELLS |
| RU2670001C1 (ru) * | 2017-12-25 | 2018-10-17 | Федеральное государственное бюджетное учреждение науки Институт биохимии и физиологии растений и микроорганизмов Российской академии наук | Способ получения белков клеточной поверхности |
| AU2019207600A1 (en) | 2018-01-09 | 2020-07-09 | Theriva Biologics, Inc. | Alkaline phosphatase agents for treatment of neurodevelopmental disorders |
| WO2019183209A1 (en) | 2018-03-20 | 2019-09-26 | Synthetic Biologics, Inc. | Alkaline phosphatase agents for treatment of radiation disorders |
| WO2019183208A1 (en) | 2018-03-20 | 2019-09-26 | Synthetic Biologics, Inc. | Intestinal alkaline phosphatase formulations |
| WO2020167432A2 (en) | 2019-01-23 | 2020-08-20 | Yoshihiro Kawaoka | Mutations that confer genetic stability to additional genes in influenza viruses |
| EP3921413A1 (en) | 2019-02-08 | 2021-12-15 | Wisconsin Alumni Research Foundation (WARF) | Humanized cell line |
| WO2020223699A1 (en) | 2019-05-01 | 2020-11-05 | Wisconsin Alumni Research Foundation (Warf) | Improved influenza virus replication for vaccine development |
| US11807872B2 (en) | 2019-08-27 | 2023-11-07 | Wisconsin Alumni Research Foundation (Warf) | Recombinant influenza viruses with stabilized HA for replication in eggs |
| US20230000971A1 (en) | 2019-11-18 | 2023-01-05 | Seqirus Pty Ltd. | Method for producing reassortant influenza viruses |
| KR102444684B1 (ko) * | 2020-04-29 | 2022-09-16 | 에스케이바이오사이언스(주) | 일회용 배양 공정 시스템을 이용한 인플루엔자 바이러스 생산 방법 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH589453A5 (zh) * | 1974-01-14 | 1977-07-15 | Sandoz Ag | |
| US4500513A (en) * | 1979-05-15 | 1985-02-19 | Miles Laboratories, Inc. | Influenza vaccine production in liquid cell culture |
| US4317811A (en) * | 1980-09-11 | 1982-03-02 | Merck & Co., Inc. | Herpes simplex type 1 subunit vaccine |
| DE3237313A1 (de) * | 1982-10-08 | 1984-04-12 | Werner Heese | Verfahren zur gewinnung und reinigung antigenhaltiger loesungen, insbesondere fuer influenza-viren, aus antigenhaltiger allantoisfluessigkeit |
| US4783411A (en) * | 1984-10-22 | 1988-11-08 | Janis Gabliks | Influenza-A virus vaccine from fish cell cultures |
| US5173418A (en) * | 1985-05-10 | 1992-12-22 | Benzon Pharma, A/S | Production in Escherichia coli of extracellular Serratia spp. hydrolases |
| US5006472A (en) * | 1988-06-03 | 1991-04-09 | Miles Inc. | Enzymatic purification process |
| RU2080876C1 (ru) * | 1989-02-07 | 1997-06-10 | Био-Текнолоджи Дженерал Корп. | Способ получения очищенных частиц поверхностного антигена гепатита в, очищенная частица поверхностного антигена гепатита в человека и вакцина против гепатита в |
| ATE132160T1 (de) * | 1989-03-29 | 1996-01-15 | Univ New York State Res Found | Verfahren zur reinigung von aussenmembran-protein von haemophilus influenza |
| DZ1706A1 (fr) * | 1992-08-07 | 2002-02-17 | Merck & Co Inc | Vaccin contre le virus de l'hepatite a. |
| HRP950097A2 (en) * | 1994-03-08 | 1997-06-30 | Merck & Co Inc | Hepatitis a virus culture process |
| WO1996015231A2 (en) * | 1994-11-10 | 1996-05-23 | Immuno Aktiengesellschaft | Method for producing biologicals in protein-free culture |
| US5681746A (en) * | 1994-12-30 | 1997-10-28 | Chiron Viagene, Inc. | Retroviral delivery of full length factor VIII |
| WO1997004803A1 (fr) * | 1995-08-01 | 1997-02-13 | Pasteur Merieux Serums & Vaccins | Procede de production industrielle d'un vaccin contre l'encephalite japonaise et vaccin obtenu |
| WO1997011605A1 (en) * | 1995-09-28 | 1997-04-03 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Stimulation of cell-mediated immune responses by targeted particulate genetic immunization |
-
1998
- 1998-04-01 TW TW087104913A patent/TW570803B/zh not_active IP Right Cessation
- 1998-04-02 DK DK98201056T patent/DK0870508T3/da active
- 1998-04-02 ES ES98201056T patent/ES2129386T3/es not_active Expired - Lifetime
- 1998-04-02 PT PT98201056T patent/PT870508E/pt unknown
- 1998-04-02 SI SI9830010T patent/SI0870508T1/xx unknown
- 1998-04-02 DE DE0870508T patent/DE870508T1/de active Pending
- 1998-04-02 AT AT98201056T patent/ATE197406T1/de active
- 1998-04-02 EP EP98201056A patent/EP0870508B1/en not_active Revoked
- 1998-04-02 TR TR1998/00613A patent/TR199800613A1/xx unknown
- 1998-04-02 DE DE69800383T patent/DE69800383T2/de not_active Expired - Lifetime
- 1998-04-06 CA CA002234208A patent/CA2234208C/en not_active Expired - Lifetime
- 1998-04-06 DZ DZ980072A patent/DZ2462A1/xx active
- 1998-04-06 BR BR9801015-8A patent/BR9801015A/pt not_active Application Discontinuation
- 1998-04-06 HU HU9800802A patent/HUP9800802A3/hu not_active Application Discontinuation
- 1998-04-06 HR HR980187A patent/HRP980187B1/xx not_active IP Right Cessation
- 1998-04-06 NO NO981557A patent/NO323349B1/no not_active IP Right Cessation
- 1998-04-06 ID IDP980519A patent/ID20399A/id unknown
- 1998-04-06 KR KR1019980012018A patent/KR100593235B1/ko not_active IP Right Cessation
- 1998-04-06 IL IL12396198A patent/IL123961A/xx not_active IP Right Cessation
- 1998-04-06 CZ CZ0105098A patent/CZ297492B6/cs unknown
- 1998-04-06 AU AU60659/98A patent/AU728939B2/en not_active Expired
- 1998-04-06 US US09/055,321 patent/US5948410A/en not_active Expired - Lifetime
- 1998-04-06 SK SK445-98A patent/SK282614B6/sk not_active IP Right Cessation
- 1998-04-06 NZ NZ330131A patent/NZ330131A/en not_active IP Right Cessation
- 1998-04-06 CN CNB981080863A patent/CN1138564C/zh not_active Expired - Lifetime
- 1998-04-06 PL PL98325722A patent/PL187982B1/pl unknown
- 1998-04-06 RU RU98106860/13A patent/RU2197264C2/ru active
- 1998-04-06 ZA ZA982915A patent/ZA982915B/xx unknown
- 1998-04-07 JP JP11010198A patent/JP5258127B2/ja not_active Expired - Lifetime
- 1998-04-08 UA UA98041787A patent/UA42089C2/uk unknown
- 1998-04-08 AR ARP980101611A patent/AR011216A1/es not_active Application Discontinuation
- 1998-11-17 HK HK98112068A patent/HK1010833A1/xx not_active IP Right Cessation
-
1999
- 1999-01-01 GR GR990300017T patent/GR990300017T1/el unknown
-
2000
- 2000-11-09 GR GR20000402476T patent/GR3034798T3/el not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100415769C (zh) * | 2002-02-07 | 2008-09-03 | 中国科学院过程工程研究所 | 寡聚或多聚亚基蛋白质分离纯化的方法 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1138564C (zh) | 流感疫苗 | |
| EP2172543B1 (en) | Process for the replication of influenza viruses in cell culture, and the influenza viruses obtainable by the process | |
| US6656720B2 (en) | Animal cells and processes for the replication of influenza viruses | |
| CN104888212A (zh) | 一种流感病毒亚单位疫苗及其制备方法 | |
| Virelizier et al. | The role of humoral immunity in host defence against influenza A infection in mice | |
| EP3420076B1 (en) | Methods of producing and characterizing virus vaccine and virus vaccine composition | |
| CN101274097B (zh) | 喷雾流行性感冒疫苗组合物及其制备方法 | |
| CN102154418B (zh) | 一种动物干扰素的制备方法 | |
| MXPA98002766A (en) | Vaccine against influe | |
| CA2250714C (en) | Animal cells and processes for the replication of influenza viruses | |
| CN1544089A (zh) | 一种预防流感病毒dna疫苗 | |
| Cox | FluBlok, A High Dose Recombinant Hemagglutinin Influenza Vaccine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20090320 Address after: Holland Weesp Patentee after: Solvay Pharm BV Address before: Holland Westberg Patentee before: Duphar International Research B. V. |
|
| ASS | Succession or assignment of patent right |
Owner name: SOLVAN BIOLOGY CO., LTD. Free format text: FORMER OWNER: DUFEIER INTERNATIONAL DEVELOPMENT CO., LTD. Effective date: 20090320 |
|
| C56 | Change in the name or address of the patentee |
Owner name: ABBOTT BIOLOGY CO., LTD. Free format text: FORMER NAME: SOLVAY PHARM BV |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Holland Weesp Patentee after: Abbott Biologicals B.V. Address before: Holland Weesp Patentee before: Solvay Pharm BV |
|
| CX01 | Expiry of patent term |
Granted publication date: 20040218 |
|
| CX01 | Expiry of patent term |