WO2002042480A2 - Modified vaccinia ankara virus variant - Google Patents
Modified vaccinia ankara virus variant Download PDFInfo
- Publication number
- WO2002042480A2 WO2002042480A2 PCT/EP2001/013628 EP0113628W WO0242480A2 WO 2002042480 A2 WO2002042480 A2 WO 2002042480A2 EP 0113628 W EP0113628 W EP 0113628W WO 0242480 A2 WO0242480 A2 WO 0242480A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- virus
- mva
- vaccine
- anyone
- human
- Prior art date
Links
- 241001183012 Modified Vaccinia Ankara virus Species 0.000 title abstract description 7
- 241000700605 Viruses Species 0.000 claims abstract description 210
- 229960005486 vaccine Drugs 0.000 claims abstract description 74
- 230000028993 immune response Effects 0.000 claims abstract description 52
- 210000005260 human cell Anatomy 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 30
- 230000036039 immunity Effects 0.000 claims abstract description 25
- 206010061598 Immunodeficiency Diseases 0.000 claims abstract description 19
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 12
- 230000001939 inductive effect Effects 0.000 claims abstract description 11
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 210000004027 cell Anatomy 0.000 claims description 127
- 241000700618 Vaccinia virus Species 0.000 claims description 79
- 241001465754 Metazoa Species 0.000 claims description 50
- 208000015181 infectious disease Diseases 0.000 claims description 43
- 230000010076 replication Effects 0.000 claims description 43
- 238000002649 immunization Methods 0.000 claims description 40
- 238000011081 inoculation Methods 0.000 claims description 31
- 230000003053 immunization Effects 0.000 claims description 29
- 238000001727 in vivo Methods 0.000 claims description 22
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- 230000006698 induction Effects 0.000 claims description 18
- 150000007523 nucleic acids Chemical group 0.000 claims description 17
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 17
- 239000002671 adjuvant Substances 0.000 claims description 16
- 210000003292 kidney cell Anatomy 0.000 claims description 15
- 102000004169 proteins and genes Human genes 0.000 claims description 15
- 230000001850 reproductive effect Effects 0.000 claims description 15
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 14
- 210000001161 mammalian embryo Anatomy 0.000 claims description 14
- 231100000518 lethal Toxicity 0.000 claims description 13
- 230000001665 lethal effect Effects 0.000 claims description 13
- 230000000890 antigenic effect Effects 0.000 claims description 12
- 239000000427 antigen Substances 0.000 claims description 11
- 108091007433 antigens Proteins 0.000 claims description 11
- 102000036639 antigens Human genes 0.000 claims description 11
- 210000002950 fibroblast Anatomy 0.000 claims description 11
- 238000011225 antiretroviral therapy Methods 0.000 claims description 10
- 230000005847 immunogenicity Effects 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 241000287828 Gallus gallus Species 0.000 claims description 8
- 238000004113 cell culture Methods 0.000 claims description 8
- 241000699800 Cricetinae Species 0.000 claims description 7
- 210000002510 keratinocyte Anatomy 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000037452 priming Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000003362 replicative effect Effects 0.000 claims description 6
- 210000001519 tissue Anatomy 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 230000004071 biological effect Effects 0.000 claims description 5
- 201000008873 bone osteosarcoma Diseases 0.000 claims description 5
- 230000002458 infectious effect Effects 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 201000006662 cervical adenocarcinoma Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 241000932156 Proteinus Species 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000002708 enhancing effect Effects 0.000 claims description 2
- 238000001890 transfection Methods 0.000 claims description 2
- 230000002238 attenuated effect Effects 0.000 abstract description 16
- 206010072219 Mevalonic aciduria Diseases 0.000 description 51
- 238000002255 vaccination Methods 0.000 description 48
- 241000699670 Mus sp. Species 0.000 description 44
- 241000282693 Cercopithecidae Species 0.000 description 34
- 230000003321 amplification Effects 0.000 description 26
- 238000003199 nucleic acid amplification method Methods 0.000 description 26
- 238000003556 assay Methods 0.000 description 25
- 206010046865 Vaccinia virus infection Diseases 0.000 description 23
- 208000007089 vaccinia Diseases 0.000 description 23
- 230000004044 response Effects 0.000 description 22
- 108020004414 DNA Proteins 0.000 description 21
- 230000003612 virological effect Effects 0.000 description 17
- 210000000987 immune system Anatomy 0.000 description 13
- 241000282412 Homo Species 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 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 11
- 210000001672 ovary Anatomy 0.000 description 11
- 239000002953 phosphate buffered saline Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 9
- 244000005700 microbiome Species 0.000 description 9
- 241001529936 Murinae Species 0.000 description 8
- 241000700647 Variola virus Species 0.000 description 8
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000005875 antibody response Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000012678 infectious agent Substances 0.000 description 7
- 206010022000 influenza Diseases 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000282560 Macaca mulatta Species 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- 238000011510 Elispot assay Methods 0.000 description 4
- 241000224017 Plasmodium berghei Species 0.000 description 4
- 206010058874 Viraemia Diseases 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 210000003519 mature b lymphocyte Anatomy 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000000644 propagated effect Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 210000003501 vero cell Anatomy 0.000 description 4
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 3
- 238000011725 BALB/c mouse Methods 0.000 description 3
- 241000282552 Chlorocebus aethiops Species 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 108010008038 Synthetic Vaccines Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000001010 compromised effect Effects 0.000 description 3
- 230000000120 cytopathologic effect Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 229940124551 recombinant vaccine Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 102100039358 3-hydroxyacyl-CoA dehydrogenase type-2 Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001035740 Homo sapiens 3-hydroxyacyl-CoA dehydrogenase type-2 Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 241000726306 Irus Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000003679 cervix uteri Anatomy 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000008029 eradication Effects 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 108010027225 gag-pol Fusion Proteins Proteins 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000008348 humoral response Effects 0.000 description 2
- 230000006054 immunological memory Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 210000004988 splenocyte Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000012192 staining solution Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- JRBJSXQPQWSCCF-UHFFFAOYSA-N 3,3'-Dimethoxybenzidine Chemical compound C1=C(N)C(OC)=CC(C=2C=C(OC)C(N)=CC=2)=C1 JRBJSXQPQWSCCF-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229940033330 HIV vaccine Drugs 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001115401 Marburgvirus Species 0.000 description 1
- 241000701029 Murid betaherpesvirus 1 Species 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 241000700629 Orthopoxvirus Species 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 241000700625 Poxviridae Species 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 101150049512 ald gene Proteins 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000002516 postimmunization Effects 0.000 description 1
- 229940024231 poxvirus vaccine Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000003314 quadriceps muscle Anatomy 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/275—Poxviridae, e.g. avipoxvirus
-
- 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
- C12N7/04—Inactivation or attenuation; Producing viral sub-units
-
- 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
- A61K39/275—Poxviridae, e.g. avipoxvirus
- A61K39/285—Vaccinia virus or variola 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
-
- 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
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- 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
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
-
- 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
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
-
- 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
- A61K2039/5254—Virus avirulent or attenuated
-
- 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
- A61K2039/5256—Virus expressing foreign proteins
-
- 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
- A61K2039/53—DNA (RNA) vaccination
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/24011—Poxviridae
- C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
- C12N2710/24121—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/24011—Poxviridae
- C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
- C12N2710/24141—Use of virus, viral particle or viral elements as a vector
- C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
- C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Biotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Mycology (AREA)
- Biophysics (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Pulmonology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention provides an attenuated virus, which is derived from Modified Vaccinia Ankara virus and which is characterized by the loss of its capability to reproductively replicate in human cell lines. It further describes recombinant viruses derived from this virus and the use of the virus or its recombinants as medicament or vaccine. Additionally, a method for inducing an immune response even in immuno-compromised patients, patients with pre-existing immunity to the vaccine virus or patients undergoing antiviral therapies is provided.
Description
Modified Vaccinia Ankara Virus Variant
The present invention provides an attenuated virus, which is derived from Modified Vaccinia Ankara virus and which is characterized by the loss of its capability to reproductively replicate in human cell lines. It further describes recombinant viruses derived from this virus and the use of the virus or its recombinants as medicament or vaccine. Additionally, a method is provided for inducing an immune response even in immuno-compromised patients, patients with pre-existing immunity to the vaccine virus or patients undergoing antiviral therapy.
Background of the invention
Modified Vaccinia Ankara (MVA) virus is related to Vaccinia virus, a member of the genera Orthopoxvirus in the family of Poxviridae. MVA has been generated by 516 serial passages on chicken embryo fibroblasts of the A nkara strain of vaccinia v irus (CVA) (for review see Mayr, A ., et al. Infection 3, 6- 14 [1975]). As a consequence of these long-term passages the resulting MVA virus deleted about 31 kilobases of its genomic sequence and , therefore, was described as highly host cell restricted to avian cells (Meyer, H. et al., J. Gen. V irol. 72, 1031-1038 [1991]). It was shown, in a variety of animal models that the resulting MVA was significantly avirulent (Mayr, A . & Danner, K. [1978] Dev . Biol. Stand . 41 : 225-34). Add rtionally, this MVA strain has been tested in clinical trials as vaccine to immunize
against the human smallpox d isease (Mayr et al., Zbl. Bakt. Hyg. I , A bt. Org. B 167, 375-390 [1987], Stickl et al., Dtsch. med . Wschr. 99, 2386-2392 [1974]). These studies involved over 120,000 humans, including high risk patients, and proved that, compared to Vaccinia based vaccines, MVA had diminished virulence or infectiousness while it maintained good immunogenicity.
In the following decades MVA has been engineered to use it as viral vector for recombinant gene expression or as recombinant vaccine (Sutter, G. et al. [1994], Vaccine 12: 1032-40).
In this respect it is most astonishing that even though Mayr et al. demonstrated during the 1970s that MVA is highly attenuated and av irulent in humans and mammals, some recently reported observations (Blanchard et al., 1998, J Gen V irol 79, 1 159- 1 167;
Carroll & Moss, 1997, V irology 238, 198-21 1 ; A ltenberger, US Patent 5, 185, 146; A mbrosini et al., 1999, J Neurosci Res 55(5), 569) have shown that MVA is not fully attenuated in mammalian and human cell lines since residual replication might occur in these cells. It is assumed that the results reported in these publications have been obtained with various strains of MVA , since the used viruses essentially d iffer in their properties, particularly in their growth behavior in various cell lines.
Growth behavior is recognized as an ind icator for virus attenuation. Generally, a virus strain is regarded as attenuated if it has lost its capacity or only has reduced capacity to reproductively replicate in
host cells. The above-mentioned observation, that MVA is not completely rep lication incompetent in human and mammalian cells, brings into question the absolute safety of MVA as a human vaccine or a vector for recombinant vaccines.
Particularly, for a vaccine as well as for a recombinant vaccine the balance between the efficacy and the safety of the vaccine vector v irus is extremely important.
Object of the invention
Thus, it is an object of the invention to provide novel virus strains hav ing enhanced safety for the development of safer products such as vaccines or pharmaceuticals. Moreover, a further object is to provide means for improving an existing vaccination regimen.
Detailed description of the invention
To achieve the foregoing objects, according to a preferred embodiment of the present invention new vaccinia viruses are provided, which are capable of reproductive replication in non-human cells and cell lines, especially in chicken embryo fibroblasts (CEF) and in the Baby hamster kidney cell line BHK (ECACC 8501 1433), but not capable of reproductive replication in human cell lines.
The known vaccinia strains reproductively replicate in at least some human cell lines, in particular in the the human keratinocyte cell line HaCat_(Boukamp et al. 1988, J Cell Biol 106(3): 761-71). The replication in. the cell line HaCat is predictive for replication in vivo, in particular for in vivo replication in humans. Indeed, it is shown in the example section that all known vaccinia strains tested that show a residual productive replication in HaCat also replicate in vivo. Thus, the invention preferably relates to vaccinia viruses that do not reproductively replicate in the human cell line HaCat. Most preferably the invention concerns vaccinia virus strains that are not capable of reproductive replication in any of the following human cell lines: the human cervix adenocarcinoma cell line HeLa (ATCC No. CCL-2), the human embryo kidney cell line 293 (ECACC No. 85120602), the human bone osteosarcoma cell line 143B (ECACC No. 91112502) and the cell line HaCat.
The growth behavior or amplification/replication of a virus is normally expressed by the ratio of virus produced from an infected cell (Output) to the amount originally used to infect the cells in the first place (Input) ("amplification ratio"). A ratio of "1" between
Output and Input defines an amplification status wherein the amount of virus produced from the infected cells is the same as the amount initially used to infect the cells. This status hints to the fact, that the infected cells are permissive for virus infection and virus reproduction.
An amplification ratio of less than 1 , i.e. a decrease of the amplification below input level is an indicator for a lack of reproductive replication and, thus, an indicator for attenuation of the virus. Therefore, it- was of particular interest for the inventors to identify and finally to isolate a strain, which shows an amplification ratio of less than 1 in several human cell lines, in particular in all of the human cell lines 143B, HeLa, 293 and HaCat.
Thus, the term "not capable of reproductive replication" means that the virus according to the invention shows an amplification ratio of less than 1 in human cell lines, such as the cell lines 293 (ECACC No. 85120602), 143B (ECACC No. 91112502), HeLa (ATCC No. CCL- 2) and HaCat (Boukamp et al. 1988, J Cell Biol 106(3): 761-71), under the conditions as outlined in example 1 of the present specification for some specific MVA strains. Preferably, the amplification rate of the virus according to the invention is 0.8 or less in each of the above human cell lines HeLa, HaCat and 143B.
It is shown in detail in Example 1 and in table 1 that the viruses according to the present invention do not reproductively replicate in anyone of the cell lines 143B, HeLa and HaCat. The particular strain according to the present invention that has been used in the examples has been deposited at the European Collection of Cell Cultures under number V00083008. This strain is referred to as "MVA-BN" throughout the specification.
The known MVA strains show residual replication in at least one of the human cell lines tested (figure 1 , example 1). All known Vaccinia strains show at least some replication in the cell line HaCat, whereas the MVA strains according to the present invention, in particular MVA-BN, do not productively replicate in HaCat cells. I n more detai l
MVA-BN shows an amplification ratio of 0.05 to 0.2 in the Human embryo kidney cell line 293 (ECACC No. 85120602). In the Human bone osteosarcoma cell line 143B (ECACC No. 91 1 12502) the ratio is in the range of 0.0 to 0.6. For the Human cervix adeocarcinoma cell line HeLa (ATCC No. CCL-2) and the human keratinocyte cell line
HaCat (Boukamp et al. 1988, J Cell Biol -106(3): 761 -71) the amplification ratio is in the range of 0.04 to 0.8 and of 0.02 to 0.8, respectively. MVA-BN has an amplification ratio of 0.01 to 0.06 in African green monkey kidney cells (CV1 : ATCC No. CCL-70). Thus, MVA-BN which is a prototype strain according to the present invention does not productively replicate in anyone of the tested human cell lines.
The amplification ratio of MVA-BN is clearly above 1 in chicken embryo fibroblasts (CEF: primary cultures) or the baby hamster kidney cell l ine BHK (ATCC No. CRL- 1632). As outlined above, a ratio of more than " 1 " indicates reproductive replication, since the amount of virus produced from the infected cells is increased compared to the amount of virus, which was used to infect the cells. Therefore, the virus can be easily propagated and amplified in CEF primary cultures with a ratio of above 500 or in BHK cells with a ratio of above 50.
In a particular embodiment of the present invention the invention concerns derivatives of the virus as deposited under ECACC V0083008. "Derivatives" of the viruses as deposited under ECACC V00083008 refer to viruses showing essentially the same replication characteristics as the deposited strain but showing differences in one or more parts of its genome. Viruses having the same "replication characteristics" than the deposited virus are viruses that replicate with similar amplification ratios than the deposited strain in CEF cells and the cell lines BHK, HeLa, HaCat and 143B and that show a similar replication in vivo as determined in the AGR129 transgenic mouse model (see below).
In a preferred embodiment the vaccinia virus strains according to the present invention, in particular MVA-BN and its derivatives, are characterized by a failure to replicate in vivo. In the context of the present invention"failure to replicate in vivo" refers to viruses that do not replicate in humans and in the mice model explained below. The
"failure to replicate in vivo" can preferably determined in mice that are incapable of producing mature B and T cells. An example for such mice is the transgenic mouse model AGR 129 (obtained from Mark
Sutter, I nstitute of Virology, University of Zurich, Zurich, Switzerland).
This mouse strain has gene targeted disruptions in the IFN receptor type 1 (I FN- /β) and type I I (I FN-γ) genes and in RAG. Due to these disruptions the mice have no IFN system and are incapable of producing mature B and T cells and as such are severely immune
compromised and highly susceptable to a replicating virus. I nstead of the AGR129 mice any other mouse strain can be used that is incapable of producing mature B and T cells and as such is severely immune compromised and highly susceptable to a replicating virus. I n particular the viruses according to the present invention do not kill
AGR129 mice within a time period of at least 45 days, more preferably within at least 60 days, most preferably within 90 days after the infection of the mice with 107 pfu virus administered intra peritonealy. Preferably, the viruses that show "failure to replicate in vivo" are further charactericed in that no virus can be recoverd from organs or tissues of the AGR129 mice 45 days, preferably 60 days and most preferably 90 days after the infection of the mice with 107 pfu virus administered intra peritonealy. Detailed information regarding the infection assays with AGR129 mice and the assays that are used to determine whether virus can be recovered from organs and tissues of infected mice can be found in the example section.
I n a preferred embodiment the vaccinia virus strains according to the present invention, in particular MVA-BN and its derivatives, is characterized by a higher immunogenicity compared to the known strain MVA 575 as determined in a lethal chal lenge mouse model . The details of this experiment are outlined in example 2, shown below. Briefly, in such a model unvaccinated mice die after the infection with replication competent vaccinia strains such as the Western Reserve strain L929 TK+ or I HD-J. The infection with replication competent vaccinia viruses is referred to as "challenge" in
the context of description of the lethal challenge model. Four days after the challenge the mice are usually killed and the viral titer in the ovaries is determined by standard plaque assays using VERO cells (for more details see example section). The viral titer is determined for unvaccinated mice and for mice vaccinated with vaccina viruses according to the present invention. More specifically the viruses according to the present invention are characterized in that in this test after the vaccination with 102 TCIDso/ml virus according to the present invention the ovary virus titers are reduced by at least 70% , preferably by at least 80%, more preferably by at least 90% compared to unvaccinated mice.
In a preferred embodiment the vaccinia viruses according to the present invention, in particular MVA-BN and its derivatives, are useful for immunization with prime/boost administration of the vaccine. There have been numerous reports suggesting that prime/boost regimes using MVA as a delivery vector induce poor immune responses and are inferior to DNA-prime MVA-boost regimes (Schneider et al., 1998, Nat. Med. 4; 397-402). In all these studies MVA strains have been used that are different from the vaccinia viruses according to the present invention. To explain the poor immune response if MVA was used for prime and boost administration it has been hypothesized that antibodies generated to MVA during the prime-administration neutralize the MVA given in the second immunization, preventing an effective boost of the immune response. In contrast, DNA-prime/MVA-boost regimes are reported
to be superior at generating high avidity responses, because this regime combines the ability of DNA to effectively prime the immune response with the properties of MVA to boost this response in the absence of a pre-existing immunity to MVA. Clearly, if a pre-existing immunity to MVA and/or vaccinia prevents boosting of the immune response then the use of MVA as a vaccine or therapeutic would have limited efficacy, particularly in the individuals that have been vaccinated against smallpox. However, according to a further embodiment the vaccinia virus according the present invention, in particular MVA-BN and its derivatives as well as corresponding recombinant viruses harbouring heterologous sequences, can be used to efficiently first prime and then boost immune responses in native animals as well as in animals with a pre-existing immunity to poxviruses. Thus the vaccinia virus according to the present invention induces at least substantially the same level of immunity in vaccinia virus prime/ vaccinia virus boost regimes compared to DNA-prime/ vaccinia virus boost regimes.
A vaccinia virus is regarded as inducing at least substantially the same level of immunity in vaccinia virus prime/ vaccinia virus boost regimes when compared to DNA-prime/ vaccinia virus boost regimes if the CTL response as measured in one of the following two assays („assay 1 " and „assay 2"), preferably in both assays, is at least substantially the same in vaccinia virus prime/ vaccinia virus boost regimes when compared to DNA-prime/ vaccinia virus boost regimes. More preferably the CTL response after vaccinia virus
prime/vaccinia virus boost administration is higher in at least one of the assays, when compared to DNA-prime/vaccinia virus boost regimes. Most preferably the CTL response is higher in both of the following assays.
Assay 1: For vaccinia virus prime/vaccinia virus boost administrations 6-8 week old BALB/c (H-2d) mice are prime- immunized by intravenous administration with 107 TCID50 vaccinia virus according to the present invention expessing the murine polytope as described in Thomson et al., 1988, J. Immunol. 160,
1717 and boost-immunized with the same amount of the same virus, administered in the same way three weeks later. To this end it is necessary to construct a recombinant vaccinia virus expressing said polytope. Methods to construct such recombinant viruses are known to the person skilled in the art and are described in more detail below. In DNA prime/vaccinia virus boost regimes the prime vaccination is done by intra muscular injection of the mice with 50 μg DNA expressing the same antigen than the vaccinia virus; the boost administration with the vaccinia virus is done in exactly the same way as for the vaccinia virus prime/vaccinia virus boost administration.
The DNA plasmid expressing the polytope is also described in the above referenced publication by Thomson et al. In both regimes the development of a CTL response against the epitopes SYI PSAEKI, RPQASGVYM and/or YPHFMPTNL is determined two weeks after the boost administration. The determination of the CTL response is preferably done by using the ELISPOT analysis as described by
Schneider et al., 1998, Nat. Med. 4, 397-402 and as outlined in the examples section below for one specific virus according to the present invention. The virus according to the present invention is characterized in this experiment in that the CTL immune response against the epitopes mentioned above which is induced by the vaccinia virus prime/vaccinia virus boost administration is substantially the same, preferably at least the same as induced by DNA prime/vaccinia virus boost administration as assessed by the number of IFN-γ producing cells/106 spleen cells (see also experimental section).
Assay 2: This assay basically corresponds to assay 1. However, instead of using 107 TCID50 vaccinia virus administered i.v. as in assay 1, in this assay 108 TCID50 vaccinia virus according to the present invention are administered subcutaneously for prime immunization and for boost immunization. The virus according to the present invention is characterized in this experiment in that the CTL immune response against the epitopes mentioned above which is induced by the vaccinia virus prime/vaccinia virus boost administration is substantially the same, preferably at least the same as induced by DNA prime/vaccinia virus boost administration as assessed by the number of I FN-γ producing cells/106 spleen cells (see also experimental section).
The strenght of a CTL response as measured in one of the assays shown above corresponds to the level of protection.
Thus, the viruses according to the present invention are particularly suitable for vaccination purposes.
In summary the vaccinia virus according to the present invention is characterized by having at least one of the folowing properties:
(i) capability of reproductive replication in chicken embryo fibroblasts (CEF) and in the cell line BHK, but no capability of reproductive replication in the human cell line HaCat,
(ii) failure to replicate in vivo,
(iii) induction of a higher immunogenicity compared to the known strain MVA 575 (ECACC V00120707) in a lethal challenge model and/or (iv) induction of at least substantially the same level of immunity in vaccinia virus prime/ vaccinia virus boost regimes when compared to DNA-prime/ vaccinia virus boost regimes.
Preferably the vaccinia virus according to the present invention has at least two of the above properties, more preferably at least three of the above properties. Most preferred are vaccinia viruses having all of the above properties.
In a further embodiment the invention concerns a kit for vaccination comprising a virus according to the present invention for
the first vaccination („priming") in a first vial/container and for a second vaccination („boosting") in a second vial/container. The virus may be a non-recombinant vaccinia virus, i.e. a vaccinia virus that does not contain heterologous nucleotide sequences. An example for such a vaccinia virus is MVA-BN and its derivatives. Alternatively the virus may be a recombinant vaccinia virus that contains additional nucleotide sequences which are heterologous to the vaccinia virus. As outlined in other sections of the description the heterologous sequences may code for epitopes that induce a response by the immune system. Thus, it is possible to use the recombinant vaccinia virus to vaccinate against the proteins or agents comprising said epitope. The viruses may be formulated as shown below in more detail. The amount of virus that may be used for each vaccination has been defined above.
It is known for a person skilled in the art, how he can obtain Vaccinia viruses having at least one the following properties:
- capability of reproductive replication in chicken embryo fibroblasts (CEF) and in the baby hamster kidney cell line BHK, but no capability of reproductive replication in the human keratinocyte cell line HaCat,
- failure to replicate in vivo,
- induction of a higher immunogenicity compared to the known strain MVA 575 in a lethal challenge model and/or
- induction of at least substantially the same level of immunity in vaccinia virus prime/ vaccinia virus boost regimes when compared to DNA-prime/ vaccinia virus boost regimes.
A process to obtain such a virus may comprise the following steps:
(i) introducing a known vaccinia virus strain, preferably MVA 574 or MVA 575 (ECACC V00120707) into non human cells in which the virus is able to reproductively replicate, wherein the non-human cells are preferably selected from
CEF cells and the cell line BHK, (ii) isolating/enriching virus particles from these cells and (iii) analysing whether the obtained virus has at least one of the desired biological properties as defined above, wherein the above steps can optionally be repeated until a virus with the desired replication characteristics is obtained. The invention further relates to the viruses obtained by this method according to the present invention. Methods how the desired biological properties can be determined are explained in other parts of this description.
In applying this method the inventors identified and isolated in several rounds of clone purification a strain according to the present invention starting from the MVA isolate passage 575 (MVA 575). This new strain corresponds to the strain with the accession number ECACC V0083008, mentioned above.
The growth behavior of the vaccinia viruses according to the present invention, in particular the growth behaviour of MVA-BN, indicates that the strains according to the present invention are far superior to any other so far characterized MVA isolate regarding attenuation in human cell lines and failure of in vivo replication. The strains according to the present invention are therefore ideal candidates for the development of safer products such as vaccines or pharmaceuticals as will be described below.
In one embodiment the virus according to the present invention, in particular MVA-BN and its derivatives, is used as a vaccine against human pox virus diseases such as smallpox. In a further embodiment the virus according to the present invention may be recombinant, i.e. may express heterologous genes as, e.g., antigens or epitopes heterologous to the virus and may thus be useful as a vaccine to induce an immune response against heterologous antigens or epitopes.
The term "immune response" means the reaction of the immune system, when a foreign substance or micro-organism enters the organism . Per definition, the immune response is divided into a specific and an unspecific reaction although both are closely cross linked. The unspecific immune response is the immediate defence against a wide variety of foreign substances and infectious agents. The specific immune response is the defence raised after a lag phase, when the organism is challenged with a substance for the first time.
The specific immune response is highly efficient and is responsible for the fact that an individual who recovers from a specific infection is protected against this specific infection. Thus, a second infection with the same or a very similar infectious agent causes much milder symptoms or no symptoms at all, since there is already a "preexisting immunity" to this agent. Such immunity and the immunological memory, respectively, persists for a long time, in some cases even lifelong. Accordingly, the induction of an immunological memory can be used for vaccination.
The "immune system" means a complex organ i nvolved in the defence of the organism against foreign substances and microorganisms. The immune system comprises a cellular part comprising several cell types, such as, e.g., lymphocytes and other cells derived from white blood cells, and a humoral part comprising small peptides and complement factors.
"Vaccination" means that an organism is chal lenged with an infectious agent, e.g., in an attenuated or inactivated form of said infectious agent, to induce a specific immunity. The term vaccination also covers the challenge of an organism with recombiant vaccinia viruses according to the present invention, in particular recombinant MVA-BN and its derivatives, expressing antigens or epitopes that are heterologous to the virus. Examples for such epitopes are given in other parts of the description and cover, e.g., epitopes from proteins derived from other viruses such as the Dengue virus, Hepatitis C
virus, HIV, or epitopes derived from proteins that are assoziated with the development of tumours and cancer. After the administration of the recombinant vaccinia virus into the body the epitopes are expressed and are presented to the immune system and a specific immune response against these epitope may be induced. The organism, thus, is immunized against the agent/protein containing the epitope that is encoded by the recombinant vaccinia virus.
"Immunity" means partial or complete protection of an organism against diseases caused by an infectious agent due to a successful elimination of a preceding infection with said infectious agent or a characteristic part thereof. Immunity is based on the existence, induction and activation of specialised cells of the immune system.
As pointed out above in one embodiment of the invention, the recombinant viruses according to the present invention, in particular recombinant MVA-BN and its derivatives, contain at least one heterologous nucleic acid sequence. The term "heterologous" is used hereinafter for any combination of nucleic acid sequences that is not normally found intimately associated with the virus in nature, such virus is also called "recombinant virus" .
According to a further embodiment of the present invention the heterologous sequences are preferably antigenic epitopes, which are selected from any non-vaccinia source. Most preferably, said
recombinant virus expresses one or more antigenic epitopes from Plasmodium falciparum, Mycobacteria, Influenza virus, from viruses selected of the family of Flaviviruses, Paramyxoviruses, Hepatitis viruses, Human immunodeficiency viruses or from viruses causing hemorrhagic fever such as Hantaviruses or Filoviruses, i.e., Ebola or
Marburg virus.
According to still a further embodiment, but also in addition to the above-mentioned selection of antigenic epitopes, the heterologous sequences can be selected from another poxviral or a vaccinia source. These viral sequences can be used to modify the host spectrum or the immunogenicity of the virus.
In a further embodiment the virus according to the present invention may code for a heterologous gene/nucleic acid expressing a therapeutic compound. A "therapeutic compound" encoded by the heterologous nucleic acid in the virus can be, e.g., a therapeutic nucleic acid such as an antisense nucleic acid or a peptide or protein with desired biological activity.
According to a further preferred embodiment the expression of heterologous nucleic acid sequence is preferably, but not exclusively, under the transcriptional control of a poxvirus promoter, more preferably of a vaccinia virus promoter.
According to still a further embodiment the insertion of heterologous nucleic acid sequence is preferably into a non-essential region of the virus genome. In another preferred embodiment of the invention, the heterologous nucleic acid sequence is inserted at a naturally occurring deletion site of the MVA genome (disclosed in
PCT/EP96/02926). Methods how to insert heterologous sequences into the poxviral genome are known to a person skilled in the art.
According to another further preferred embodiment the invention includes also the genome of the vi rus, its recombinants or functional parts thereof. Such viral sequences can be used to identify or isolate the virus or its recombinants, e.g., by using PCR, hybridization technologies or by establishing ELISA assays. Furthermore, such viral sequences can be expressed from an expression vector to produce the encoded protein or peptide which then may supplement deletion mutants of a virus that lacks the viral sequence contained in the expression vector.
"Functional part" of the viral genome means a part of the complete genomic sequence, which encodes a physical entity, such as a protein, protein domain, epitope of a protein. Functional part of the viral genome also describes parts of the complete genomic sequence, which code for regulatory elements or parts of such elements with ind ividualizable activity, such as promoter, enhancer, cis- or trans- acting elements.
The recombinant virus according to the present invention may be used for the introduction of the heterologous nucleic acid sequence into a target cell, said sequence being either homologous or heterologous to the target cell. The introduction of a heterologous nucleic acid sequence into a target cell may be used to produce in vitro heterologous peptides or polypeptides and/or complete viruses encoded by said sequence. This method comprises the infection of a host cell with the recombinant MVA, cultivation of the infected host cell under suitable conditions, and isolation and/or enrichment of the peptide, protein and/or virus produced by said host cell .
Furthermore, the method for introduction of a homologous or of a heterologous sequence to cells may be applied for in vitro and preferably in vivo therapy. For in vitro therapy, isolated cells that have been previously (ex vivo) infected with the virus are administered to the l iving animal body for inducing an immune response. For in vivo therapy, the virus or its recombinants are directly administered to the living animal body for inducing an immune response. In this case, the cells surrounding the site of inoculation are directly infected in vivo by the virus or its recombinants according to the invention.
Since the virus according to the invention is highly growth restricted in human and monkey cells and, thus, highly attenuated, it is ideal to treat a wide range of mammals including humans. Hence, the present invention also provides a pharmaceutical composition and a vaccine , e.g., for inducing an immune response in a living
animal body, including a human. The virus of the invention is further safe in any other gene therapy protocols.
The pharmaceutical composition may generally include one or more pharmaceutical acceptable and/or approved carriers, additives, antibiotics, preservatives, adjuvants, diluents and/or stabilizers. Such auxiliary substances can be water, saline, glycerol, ethanol, wetting or emulsifying agents, pH buffering substances, or the like. Suitable carriers are typically large, slowly metabolized molecules such as proteins, polysaccharides, polylactic acids, polyglycollic acids, polymeric amino acids, amino acid copolymers, lipid aggregates, or the like.
For the preparation of vaccines, the virus or its recombinants according to the invention is converted into a physiologically acceptable form. This can be done based on the experience in the preparation of poxvirus vaccines used for vaccination against smallpox (as described by Stickl, H. et al. [1974] Dtsch. med. Wschr. 99, 2386-2392). For example, the purified virus is stored at -80°C with a titre of 5xl08 TCIDso/ml formulated in about lOmM Tris, 140 mM o
NaCI pH 7.4. For the preparation of vaccine shots, e.g., 10 - 10 particles of the virus are lyophilized in 100 ml of phosphate-buffered saline (PBS) in the presence of 2% peptone and 1 % human albumin in an ampoule, preferably a glass ampoule. Alternatively, the vaccine shots can be produced by stepwise freeze-dryi ng of the virus in a formulation. This formulation can contain additional additives such as
mannitol, dextran, sugar, glycine, lactose or polyvinylpyrrol idone or other additives such as antioxidants or inert gas, stabilizers or recombinant proteins (e.g. human serum albumin) suitable for in vivo administration. The glass ampoule is then sealed and can be stored between 4°C and room temperature for several months. However, as long as no need exists the ampoule is stored preferably at temperatures below -20°C.
For vaccination or therapy the lyophilisate can be dissolved in 0.1 to 0.5 ml of an aqueous solution, preferably physiological saline or
Tris buffer, and administered either systemically or locally, i.e. by parenterally, intramuscularly or any other path of administration know to the skilled practitioner. The mode of administration, the dose and the number of administrations can be optimized by those skilled in the art in a known manner.
Additionally, according to a further embodiment the virus according the present invention is particularly useful to induce immune responses in immuno-compromised animals, e.g., monkeys (CD4 < 400/μl of blood) infected with SIV, or in immuno-compromised humans. The term "immuno-compromised" describes the status of the immune system of an individual, which shows only incomplete immune responses or has a reduced efficiency in the defence against infectious agents. Even more interesting and according to still a further embodiment the virus according the present invention can boost immune responses in immuno-compromised animals or humans,
even in the presence of a pre-existing immunity to poxvirus in these animals or humans. Particularly interesting was, that the virus according to the present invention can boost immune responses also in animals or humans undergoing an antiviral, e.g., antiretroviral therapy. "Antiviral therapy" includes therapeutic concepts in order to eliminate or suppress viral infection including , e.g., (i) the appl ication of nucleotide analogs, (ii) the application of inhibitors for viral enzymatic activity or viral assembling, or (iii) application of cytokins to influence immune responses of the host.
According to still a further embodiment the vaccine is especially, but not exclusively, applicable in the veterinary field, e.g. , for the immunization against animal pox infection. I n small animals the inoculation for immunization is preferably performed parenterally or nasaly, whereas in larger animals or humans a subcutaneous, intramuscular or oral inoculation is preferred.
It has been found by the inventors that already a vaccine shot containing an effective dose of only 102 TCID50 (tissue culture infectious dose) of the virus according the present invention is sufficient to induce complete immunity against a wild type vaccinia virus challenge in mice. This is particularly surprising since such high degree of attenuation of the virus according to the present invention would be expected to negatively influence and, thereby, reduce its immunogenicity. Such expectation is based on the believe that for induction of an immune response the antigenic epitopes need to be
presented to the immune system in sufficient quantity. A virus that is highly attenuated and, thus, not replicating can only present a very small amount of antigenic epitopes, that . is as much as itself incorporates. This amount of antigen, carried by the viral particles, was not considered sufficient for induction of a potent immune response. However, the virus according to the invention stimulates even with a very low effective dose of only 102 TCID50 a potent and protecting immune response in a mouse/vaccinia challenge model. The virus according to the present invention thus shows an unexpected and even increased immunogenicity compared to other so far characterized MVA strains. This high immunogenicity makes the virus according to the present invention and any vaccine derived thereof especially useful for application in immuno-compromised animals or humans.
According to still another embodiment of the invention, the virus is used as an adjuvant. An "adjuvant" in the context of the present desciption refers to an enhancer of the specific immune response in vaccines. "Using the virus as adjuvant" means including the virus in a pre-existing vaccine to additionally stimulate the immune system of the patient who receives the vaccine. The immunizing effect of an antigenic epitope in most vaccines is often enhanced by the addition of a so-called adjuvant. An adjuvant co-stimulates the immune system by causing a stronger specific immune reaction against an antigenic epitope of a vaccine. This stimulation can be regulated by factors of the unspecific immune system, such as interferon and interleukin.
Hence, in a further embodiment of the invention, the virus is used in mammals including humans to activate, support or suppress the immune system, and preferably to activate the immune response against any antigenic determinant. The virus may also be used to support the immune system in a situation of increased susceptibility against infections such as in the case of stress.
The virus used as an adjuvant may be a non-recombinant virus, i.e. a virus that does not contain heterologous DNA in its genome. An example for this type of virus is MVA-BN. Alternatively the virus that is used as an adjuvant is a recombinant virus containing in its genome heterologous DNA sequences that are not naturally present in the viral genome. For use as a adjuvant the recombinant viral DNA of the virus preferably contains and expresses genes that code for immune stimulatory peptides or proteins such as interleukines.
According to a further embodiment it is preferred that the virus is inactivated, when used as an adjuvant or added to another vaccine. The inactivation of the virus may be performed, e.g., by heat or chemicals, as known in the art. Preferably, the virus is inactivated by β-propriolacton. According to this embodiment of the invention, the inactivated virus may be added to vaccines against numerous infectious or proliferative diseases to increase the immune response of the patient to this disease.
Summary of the Invention
The invention inter alia comprises the following, alone or in combination:
Vaccinia virus having at least one of the following properties:
- capability of reproductive replication in chicken embryo fibroblasts (CEF) and in the baby hamster kidney cell line BHK, but no capability of reproductive replication in the human keratinocyte cell line HaCat, - failure to replicate in vivo,
- induction of a higher immunogenicity compared to the known strain MVA 575 in a lethal challenge model and/or
- induction of at least substantially the same level of immunity in vaccinia virus prime/ vaccinia virus boost regimes when compared to DNA-pri me/ vaccinia vi rus boost regimes.
The virus as above, wherein the virus is not capable of reproductively replicating in any of the following human cell lines: the human embryo kidney cell line 293, the human bone osteosarcoma cel l line 143B and the human cervix adenocarcinoma cell line HeLa.
The virus as above being deposited at the European Collection of Cell Cultures (ECACC), Salisbury (UK) under number V00083008 and derivatives thereof.
The virus as above comprising at least one heterologous nucleic acid sequence.
The virus as above, wherein said heterologous nucleic acid sequence being selected from a sequence coding for at least one antigen, antigenic epitope, and/or a therapeutic compound.
Genome or functional parts thereof derived from the virus as defined above.
Pharmaceutical composition comprising the virus as above and/or the genome and/or functional part thereof as defined above and a pharmaceutically acceptable carrier, diluent and/or additive.
Vaccine comprising the virus as above and/or the genome and/or functional part thereof as defined above.
The virus as above, the genome and/or functional part thereof as defined above, the composition as defined above or the vaccine as defined above as drug for affecting, preferably inducing, an immunological response in a living animal, including a human.
The virus as above, the pharmaceutical composition as defined above, the vaccine as defined above or the virus as defined above, wherein the virus, the composition or the vaccine is administered in
therapeutically effective amounts in a first inoculation ("priming inoculation") and in a second inoculation ("boosting inoculation").
Use of the virus as above, and/or the genome as defined above, for the preparation of a medicament or a vaccine.
Method for introducing homologous and/or heterologous nucleic acid sequences into target cells comprising the infection of the target cells with the virus comprising heterologous sequences as defined above or the transfection of the target cell with the genome as defined above.
Method for producing a peptide, protein and/or virus comprising
- infection of a host cell with the virus as above,
- cultivation of the infected host cell under suitable conditions, and - isolation and/or enrichment of the peptide and/or protein and/or viruses produced by said host cell.
Method for affecting, preferably inducing an immunological response in a living animal body including a human comprising administering the virus as above, the genome and/or functional part thereof as defined above, the composition as defined above or the vaccine as defined above to the animal or human to be treated.
The method as above comprising the administration of at least 102 TCI D50 (tissue culture infectious dose) of the virus.
The method as above, wherein the virus, the composition or the vaccine is administered in therapeutically effective amounts in a first inoculation ("priming inoculation") and in a second inoculation ("boosting inoculation").
The method as above, wherein the animal is immuno-compromised.
The method as above, wherein the animal has a pre-existing immunity to poxviruses.
The method as above, wherein the animal is undergoing an antiviral therapy.
The method wherein the animal is undergoing an antiviral therapy, characterized in that the antiviral therapy is an antiretroviral therapy
Use of the virus as above, the genome and/or functional part thereof as defined above as adjuvant.
A method for enhancing a specific immune response against an antigen and/or an antigenic epitope included in a vaccine comprising administration of the virus as above or the genome as defined above, as an adjuvant to a living animal body including a human to be treated with the vaccine.
The virus as above or the genome as defined above, as adjuvant.
A cell, preferably a human cell, containing the virus as above or the genome or functional part thereof as defined above.
Method for obtaining the vaccinia virus as above comprising the following steps:
- introducing a commonly available vaccinia virus strain, preferably MVA 575 into non human cells in which the virus is able to reproductively replicate, wherein the non-human cells are preferably selected from CEF cells and the cell line BHK,
- isolating/enriching virus particles from these cells and
-analysing whether the obtained virus has at least one of the biological properties as defined above, wherein the above steps can optionally be repeated until a virus with the desired replication characteristics is obtained
Kit for prime/boost immunization comprising a virus as above, a vaccine as above or the virus as drug as defined above for a first inoculation ("priming inoculation") in a first vial/container and for a second inoculation ("boosting inoculation") in a second vial/container.
Use of the virus as above, the composition as defined above and/or of the vaccine as defined above for the preparation of a vaccine wherein the virus, the composition or the vaccine is administered in a prime
inoculation and wherein the same virus or vaccine is administered in a boost inoculation.
Short Description of the Figures
Figure 1: Growth kinetics of different strains of MVA in different cell lines. In part A) the results are grouped according to the MVA strains tested whereas in part B) the results are grouped according to the cell lines tested. B) The amount of virus recovered from a cell line after four days (D4) of culture was determined by plaque assay and expressed as the ratio of virus recovered after 4 days to the initial inoculum on day 1 (Dl)
Figure 2: Protection provided against a lethal challenge of vaccinia following vaccinations with either MVA-BN or MVA 575.
The protection is measured by the reduction in ovary titres determined 4 days post challenge by standard plaque assay.
Figure 3: Induction of CTL and protection provided against an influenza challenge using different prime-boost regimes.
3A: I nduction of CTL responses to 4 different H-2d restricted epitopes following vaccinations with different combinantions of DNA or MVA- BN vaccines encoding a murine polytope. BALB/c mice (5 per group) were vaccinated with either DNA (intramuscularly) or MVA-BN (subcutaneously) and received booster immunisations three weeks later. CTL responses to 4 different epitopes encoded by the vaccines (TYQRTRALV, infuenza; SYI PSAEKI , P. Berghei; YPHFMPTNL,
Cytomegalovirus; RPQASGVYM, LCV) were determined using an ELISPOT assay 2 weeks post the booster immunisations. 3B: . Induction of CTL responses to 4 different epitopes following vaccinations with different combinations of DNA or MVA-BN vaccines encoding a murine polytope. BALB/c mice (5 per group) were vaccinated with either DNA (intramuscularly) or MVA-BN (intraveneously) and received booster immunisations three weeks later. CTL responses to 4 different epitopes encoded by the vaccines (TYQRTRALV, infuenza; SYIPSAEKI, P. Berghei; YPHFMPTNL, Cytomegalovirus; RPQASGVYM, LCV) were determined using an
ELISPOT assay 2 weeks post the booster immunisations. 3C: Frequency of peptide and MVA specific T cells following homologous prime boost using an optimal dose (1 x 108 TCID50) of recombinant MVA-BN, given subcutaneously. Groups of 8 mice were vaccinated with two shots of the combinations as indicated in the figure. Two weeks post the final vaccination the number of peptide specific splenocytes were measured using an IFN-gamma ELISPOT assay. The bars represent the mean number of specific spots plus/minus the standard deviation from the mean.
Figure 4: SIV load of monkeys vaccinated with MVA-BN nef or MVA- BN.
Figure 5: Survival of vaccinated monkeys following infection with SIV.
Figure 6: Monkey serum antibody titres to MVA-BN. The antibody titres for each animal are shown as different shapes, while the mean titre is illustrated as a solid rectangle.
Figure 7: Levels of SIV in immuno-compromised monkeys (CD4 < 400 ml blood) following vaccinations with MVA-BN encoding tat. Monkeys had previously received three vaccinations with either MVA-BN or MVA-BN nef (week 0, 8, 16) and had been infected with a pathogenic isolate of SIV (week 22). At week 100, 102 and 106 (indicated by arrows) the monkeys were vaccinated with MVA-BN tat.
Figure 8: SIV levels in monkeys undergoing anti-retroviral therapy and therapeutic vaccinations using MVA-BN. Three groups of monkeys (n =6) were infected with SIV and treated daily with PMPA (indicated by black line). At week 10 and 16 animals were vaccinated (indicated by arrows) with either mixtures of recombinant MVA or saline.
Figure 9: Humoral response generated to SIV following infection and vaccinations with recombinant MVA. Three groups (n = 6) of monkeys were infected with a pathogenic isolate of SIV (week 0) and then treated with the anti-retroviral therapy (PMPA; indicated by bold line). Monkeys were vaccinated with mixtures of recombinant MVA or saline at week 10 and 16. Antibodies to SIV were determined using infected T cell lysates as antigen in a standard ELISA.
Figure 10: Humoral response generated to MVA in SIV infected monkeys undergoing anti-retroviral therapy. Three groups (n ~ 6) of monkeys were infected with a pathogenic isolate of SIV (week 0) and then treated with the anti-retroviral therapy (PMPA; indicated by bold line). Monkeys were vaccinated with mixtures of recombinant
MVA or saline at week 10 and 16. Antibodies to MVA were determined using a standard capture ELISA for MVA.
Figure 11: Induction of antibodies to MVA following vaccination of mice with different smallpox vaccines. The levels of antibodies generated to MVA following vaccinations with MVA-BN (week 0 and
4), was compared to conventional vaccinia strains, Elstree and Wyeth, given via tail scarification (week 0), MVA 572 (week 0 and 4) and
MVA-BN and MVA 572 given as a pre-Elstree vaccine. MVA 572 has ' been deposited at the European Collection of Animal Cell Cultures as
ECACC V94012707. The titres were determined using a capture
ELISA and calculated by linear regression using the linear part of the graph and defined as the dilution that resulted in an optical density of
0.3. * MVA-BN : MVA-BN is significantly (p > 0.05) different to M VA 572 : MVA 572.
Examples
The following examples will further illustrate the present invention. It will be well understood by a person skilled in the art that the provided examples in no way may be interpreted in a way that
limits the applicability of the technology provided by the present invention to this examples.
Example 1 Growth kinetics of a new strain of MVA in selected cell lines and replication in vivo
(i) Growth kinetics in cell lines:
To characterize a newly isolated strain according to the present invention (further referred to as MVA-BN) the growth kinetics of this new strain were compared to those of other MVA strains, which have already been characterized.
The experiment was done by comparing the growth kinetics of the following viruses in the subsequently listed primary cells and cell lines:
MVA-BN (Virus stock #23, 18. 02. 99 crude, titrated at 2,0 x lO^ TCIDso/ml);
MVA as characterized by Altenburger (US patent 5, 185, 146) and further referred to as MVA-HLR;
MVA (passage 575) as characterized by Anton Mayr (Mayr, A . , et al. [1975] Infection 3; 6- 14) and further referred to as M VA - 575 (ECACC V00120707); and
MVA-Vero as characterized in the International Patent
Application PCT/EP01/02703 (WO 01/68820)(Virus stock, passage 49, #20, 22.03.99 crude, titred at 4,2 x 10? TCIDso/ml).
The used primary cells and cell lines were:
CEF Chicken embryo fibroblasts (freshly prepared from
SPF eggs); HeLa Human cervix adeocarcinoma (epithelial), ATCC No.
CCL-2; 143B Human bone osteosarcoma TK-, ECACC No.
91112502; HaCaT Human keratinocyte cell line, Boukamp et al. 1988,
J Cell Biol 106(3): 761-771; BHK Baby hamster kidney, ECACC 85011433;
Vero African green monkey kidney fibroblasts, ECACC
85020299; CV1 African green monkey kidney fibroblasts, ECACC
87032605.
For infection the different cells were seeded into 6-well-plates at a concentration of 5 x 105 cells/well and incubated over night at 37°C, 5% C02 in DMEM (Gibco, Cat. No. 61965-026) plus 2% FCS. Cell culture medium was removed and cells were infected at approximately moi 0.05 for one hour at 37°C, 5% CO2 (for infection it is assumed that cell numbers doubled over night). The amount of
virus used for each infection of the different cell types was 5 X 104 TCID50 and this will be referred to as Input. Cells were then washed 3 times with DMEM and finally 1 ml DMEM, 2% FCS was added and the plates were left to incubate for 96 hours (4 days) at 37°C, 5 % CO2. These infections were stopped by freezing the plates at -80°C ready for titration analysis.
Titration analysis (immunostaining with a vaccinia virus specific antibody) For titration of amount of virus test cells (CEF) were seeded on
96-well-plates in RPM I (Gibco, Cat. No. 61870-010), 7% FCS, 1% Antibiotic/ Antimycotic (Gibco, Cat. No. 15240-062) at a concentration of 1 x 104 cells/well and incubated over night at 37°C, 5% CO2. The 6-well-plates containing the infection experiments were frozen/thawed 3 times and dilutions of 10 1 to 10-12 were prepared using RPM I growth medium. Virus dilutions were distributed onto test cells and incubated for five days at 37°C, 5% CO2 to allow CPE (cytopathic effect) development. Test cells were fixed (Aceton/Methanol 1 :1) for 10 min, washed with PBS and incubated with polyclonal vaccinia virus specific antibody (Quartett Berlin, Cat.
No. 9503-2057) at a 1 : 1000 dilution in incubation buffer for one hour at RT. After washing twice with PBS (Gibco, Cat. No. 20012-019) the HPR-coupled anti-rabbit antibody (Promega Mannheim, Cat. No. W4011) was added at a 1 :1000 dilution in incubation buffer (PBS containing 3% FCS) for one hour at RT. Cells were again washed twice with PBS and incubated with staining solution (10 ml PBS + 200 μl
saturated solution of o-dianisidine in 100% ethanol + 15 μl H2O2 freshly prepared) until brown spots were visible (two hours). Staining solution was removed and PBS was added to stop staining reaction. Every well showing a brown spot was marked as positive for CPE and titer was calculated using the formula of Kaerber (TCID50 based assay)
(Kaerber, G. 1931. Arch. Exp. Pathol . Pharmakol . 162, 480).
The viruses were used to infect duplicate sets of on the one hand CEF and BHK, which were expected to be permissive for MVA, and on the other hand CV- 1 , Vero, Hela, 143B and HaCat which were expected to be non-permissive for MVA, at a low multiplicity of infection, i.e., 0.05 infectious units per cell (5 x 104 TCID50). After this, the virus inoculum was removed and the cells washed three time to remove any remaining unabsorbed viruses. Infections were left for a total of 4 days where viral extracts were prepared and then titred on CEF cells. Table 1 and Figure 1 show the results of the titration assays where the values are given as total amount of virus produced after 4 days infection.
It was shown that all viruses amplified well in CEF cells (Chicken embryo fibroblasts) as expected since this is a permissive cell line for all MVAs. Additionally it was shown that all viruses amplified well in BHK (Hamster kidney cell line). MVA-Vero performed the best, since BHK is a permissive cell line.
Concerning replication in Vero cells (Monkey kidney cell line) MVA-Vero amplified well as expected namely 1000 fold above Input. MVA-HLR and also MVA-575 amplified well with 33 fold and 10 fold increase above Input, respectively. Only MVA-BN was found to not amplified as well in these cells as compared to the others, namely only 2 fold increase above Input.
Also concerning replication in CV1 cells (Monkey kidney cell line) it was found, that MVA-BN is highly attenuated in this cell line. It showed a 200 fold decrease below Input. Also MVA-575 did not amplify above the Input level also showed a slightly negative amplification, namely 16 fold decrease below Input. MVA-HLR amplified the best with 30 fold increase above Input, followed by MVA-Vero with 5 fold increase above Input.
Most interesting is to compare the growth kinetics of the various viruses in human cell lines. Regarding reproductive replication in 143B cells (human bone cancer cell line) it was shown that MVA- Vero was the only one to show amplification above I nput (3 fold increase). All other viruses did not amplify above I nput but there was a big difference between the MVA-HLR and both MVA-BN and MVA- 575. MVA-HLR was "borderline" (1 fold decrease below I nput), were as MVA-BN shows the greatest attenuation (300 fold decrease below I nput) followed by MVA-575 (59 fold decrease below Input). To summarize MVA-BN is superior regarding attenuation in human 143B cells.
Furthermore, concerning replication in HeLa cells (human cervix cancer cells) it was shown that MVA-HLR amplified well in this cell line, and even better than it did in the permissive BHK cells (Hela = 125 fold increase above Input; BHK = 88 fold increase above Input) MVA-Vero also amplified in this cell line (27 fold increase above Input). However, MVA-BN and also to a lesser extend MVA-575 were attenuated in these cell lines (MVA-BN = 29 fold decrease below Input and MVA-575 = 6 fold decrease below Input).
Concerning the replication in HaCat cells (human keratinocyte cell line) it was shown that MVA-HLR amplified well in this cell line (55 fold increase above Input). Both MVA-Vero adapted and MVA-575 showed amplification in this cell line (1.2 and 1.1 fold increase above Input respectively). However, MVA-BN was the only one to demonstrate attenuation (5 fold decrease below Input).
In conclusion it can be stated that MVA-BN is the most attenuated virus strain in this group of virus: MVA-BN demonstrates to be extremely attenuated in human cell lines by showing an amplification ratio of 0.05 to 0.2 in Human embryo kidney cells (293: ECACC No. 85120602)(data not incorporated in Table 1), it shows further an amplification ratio of about 0.0 in 143B cells; an amplification ratio of about 0.04 in HeLa cells; an amplification ratio of about 0.22 in HaCat cells. Additionally, MVA-BN is showing an amplification ratio of about 0.0 in CV1 cells. Only in Vero cells
amplification can be observed (ratio of 2.33), however, not to the same extent as it in the permissive cel l lines such as BHK and CEF (compare to Table 1). Thus, MVA-BN is the only known MVA strain showing an amplification ratio of less than 1 in all of the human cell lines 143B, Hela, HaCat and 293.
MVA-575 shows a similar profile as MVA-BN but is not as attenuated as MVA-BN .
MVA-HLR amplified wel l in all cell lines tested (except for 143B cells), it thus can be regarded as replication competent in al l cell lines tested with exception in 143B cells. In one case it even amplified better in a human cell line (HeLa) than in a permissive cell line (BHK).
MVA-Vero does show amplification in all cell lines but to a lesser extent than demonstrated by MVA-HLR (ignoring the 143B result). Nevertheless it cannot be considered as being in the same "class", with regards to attenuation, as MVA-BN or MVA-575.
2. Replication in vivo
Given that some MVA strains clearly replicate in w'tro the ability of different MVA strains was examined to replicate in vivo using a transgenic mouse model AGR129. This mouse strain has gene targeted disruptions in the I FN receptor type I (I FN- /β) and type I I
(I FN-γ) genes and in RAG. Due to these disruptions the mice have no
I FN system and are incapable of producing mature B and T cells and as such are severely immune compromised and highly susceptable to a replicating virus. Groups of six mice were immunised (i .p) with 107 pfu of either MVA-BN, MVA-HLR or MVA 572 (used in 120,000 people in Germany) and monitored daily for clinical signs. All mice vaccinated with MVA HLR or MVA 572 died within 28 and 60 days, respectively. At necropsy there were genera! signs of a severe viral infection in the majority of organs and by a standard plaque assay MVA (108 pfu) was recovered from the ovaries. In contrast, mice vaccinated with the same dose of MVA-BN (corresponding to the deposited strain ECACC V00083008) survived for more than 90 days and no MVA could be recovered from organs or tissues.
When taken together the data from the in vitro and in vivo studies clearly demonstrate that MVA-BN is more highly attenuated than the parental and commercial MVA-HLR strain.
Example 2
Immunological and in vivo Data
These experiments were set up to compare different dose and vaccination regimens of MVA-BN compared to other MVAs.
2.1. Different Strains of MVA Differ in their Ability to Stimulate the Immune Response.
Replication competent strains of vaccinia induce potent immune responses in mice and at high doses are lethal. Although MVA are highly attenuated and have a reduced ability to replicate on mammalian cells, there are differences in the attenuation between different strains of MVA. I ndeed, MVA BN appears to be more attenuated than other MVA strains, even the parental strain M VA 575. To determine whether this difference in attenuation affects the efficacy of MVA to induce protective immune responses, different doses of MVA BN and MVA 575 were compared in a lethal vaccinia challenge model. The levels of protection were measured by a reduction in ovary vaccinia titres determined 4 days post challenge, as this allowed a quantitative assessment of different doses and strains of MVA.
Lethal Chal lenge Model Specific pathogen-free 6-8-week-old female BALB/c (H-2d) mice
(n=5) were immunized (i.p.) with different doses (102, 104 or 106 TCIDso/ml) of either MVA BN or MVA 575. MVA-BN and MVA- 575 had been propagated on CEF cells, and had been sucrose purified and formulated in Tris pH 7.4. Three weeks later the mice received a boost of the same dose and strain of MVA, which was followed two weeks later by a lethal challenge (i.p.) with a replication competent strain of vaccinia. As replication competent vaccinia virus (abbreviated as "rVV") either the strain WR-L929 TK+ or the strain IHD-J were used. Control mice received a placebo vaccine. The protection was measured by the reduction in ovary titres determ i ned
4 days post challenge by standard plaque assay. For this the mice
were sacrificed on day 4 post the challenge and the ovaries were removed, homogenized in PBS (1ml) and viral titres determined by standard plaque assay using VERO cells (Thomson et a., 1998, J. Immunol. 160: 1717)..
Mice vaccinated with two immunizations of either 104 or 106 TCIDδo/ml of MVA-BN or MVA-575 were completely protected as judged by a 100% reduction in ovary rVV titres 4 days post challenge (Fig. 2). The challenge virus was cleared. However, differences in the levels of protection afforded by MVA-BN or MVA -
575 were observed at lower doses. Mice that received two immunizations of 102 TCI Dso/ml of MVA 575 failed to be protected as judged by the high ovary rVV titres (mean 3.7 xl O7 pfu +/- 2. 1 1 xlO7). I n contrast, mice vaccinated with the same dose of MVA-BN induced a significant reduction (96%) in ovary rVV titres (mean 0.21 xl O7 pfu +/-0.287 xl O7). The control mice that received a placebo vaccine had a mean viral titre of 5.1 1 xl O7 pfu (+/- 3.59 xlO7) (Fig. 2).
Both strains of MVA induce protective immune responses in mice against a lethal rVV challenge. Although both strains of MVA are equally efficient at higher doses, differences in their efficacy are clearly evident at sub-optimal doses. MVA-BN is more potent than its parent strain MVA-575 at inducing a protective immune response against a lethal rVV challenge, which may be related to the increased attenuation of MVA-BN compared to MVA-575. '
2.2. MVA-BN in Prime-Boost Vaccination Regimes
2.2.1. : Induction of antibodies to MVA following vaccination of mice with different smallpox vaccines The efficacy of MVA-BN was compared to other MVA and vaccinia strains previously used in the eradication of smallpox. These included single immunisations using the Elstree and Wyeth vaccinia strains produced in CEF cells and given via tail scarification and immunisations using MVA 572 that was previously used in the smallpox eradication program in Germany. In addition, both MVA-BN and MVA 572 were compared as a pre-vaccine followed by Elstree via scarification. For each group eight BALB/c mice were used and all MVA vaccinations (1 xlO7 TCID50) were given subcutaneously at week 0 and week 3. Two weeks following the boost immunisation the mice were challenged with vaccinia (IHD-J) and the titres in the ovaries was determined 4 days post challenge. All vaccines and regimes induced 100% protection.
The immune responses induced using these different vaccines or regimes were measured in animals prior to challenge. Assays to measure levels of neutralisating antibodies, T cell proliferation, cytokine production (I FN-γ vs I L-4) and I FN-γ production by T cells were used. The level of the T cell responses induced by MVA-BN, as measured by ELIspot, was generally equivalent to other MVA and vaccinia viruses demonstrating bio-equivalence. A weekly analysis of the antibody titres to MVA following the different vaccination regimes
revealed that - vaccinations with MVA-BN significantly enhanced the speed and_ magnitude of the antibody response compared to the other vaccination regimes (Fig. 11). Indeed the antibody titres to MVA were significantly higher (p>0.05) at weeks 2, 4 and 5 (1 week post boost at week 4) when vaccinated with MVA-BN compared to mice vaccinated with MVA 572. Following the boost vaccination at week 4 the antibody titres were also significantly higher in the MVA- BN group compared to the mice receiving a single vaccination of either the vaccinia strains Elstree or Wyeth. These results clearly demonstrate that 2 vaccinations with MVA-BN induced a superior antibody response compared to the classical single vaccination with traditional vaccinia strains (Elstree and Wyeth) and confirm the findings from section 1.5 that MVA-BN is more immunogenic than other MVA strains.
2.2.2. : MVA-prime and boost regimes generate the same level of protection as DNA-prime MVA-boost regimes in a influenza challenge model.
The efficacy of MVA prime-boost regimes to generate high avidity CTL responses was assessed and compared to D NA prime/MVA boost regimes that have been reported to be superior. The different regimes were assessed using a murine polytope construct encoded by either a DNA vector or MVA-BN and the levels of CTL induction were compared by ELISPOT, while the avidity of the response was measured as the degree of protected afforded following a challenge with influenza.
Constructs
The DNA plasmid encoding the murine polytope (10 CTL epitopes including influenza, ovalbumin) was described previously (Thomson et al., 1998, J. Immunol. 160: 1717). This murine polytope was inserted into deletion site II of MVA-BN, propagated on CEF cells, sucrose purified and formulated in Tris pH 7.4.
Vacci nation protocols In the current study specific pathogen free 6-8 week old female
BALB/c (H-2d) mice were used. Groups of 5 mice were used for ELISPOT analysis while 6 mice per group were used for the influenza challenge experiments. Mice were vaccinated with different pri me- boost regimes using MVA or DNA encoding the murine polytope as detai led in the results. For immunizations with DNA, mice were anesthetized and then given a single injection of 50 μg of endotoxin- free plasmid DNA (in 50 μl of PBS) in the quadriceps muscle under anaesthesia. Primary immunizations using MVA were done either by intravenous administration of 107 pfu MVA-BN per mouse or by subcutaneous administration of 107 pfu or 108 pfu MVA-BN per mouse. Boost immunizations were given three weeks post the primary immunizations. Boosting with plasmid DNA was done in the same way than the primary immunization with DNA (see above). I n order to establish CTL responses standard ELISPOT assays (Schneider et al., 1998, Nat. Med. 4; 397-402) were performed on splenocytes 2 weeks post the last booster immunization using the
influenza CTL epitope peptide (TYQRTRALV), the P.Berghei epitope peptide (SYIPSAEK1), the Cytomegalovirus peptide epitope (YPHFMPTNL) and/or the LCV peptide epitope (RPQASGVYM). For the challenge experiments mice were anesthetized and infected i.n. with a sub-lethal dose of the ressortant influenza virus, Mem71
(4.5 xlO5 pfu in 50ml PBS). At day 5 post infection, the lungs were removed and viral titres were determined in duplicate on Madin- Darby canine kidney cell line using a standard influenza plaque assay.
Results:
Using the DNA vaccine alone the induction of CTL to the 4 H-2d epitopes encoded by the murine polytope was poor and only weak responses could be detected to two of the epitopes for P.Berghei (SYIPSAEKI) and lymphocytic choriomeningitis virus (RPQASGVYM). In contrast, using a DNA prime MVA boost regime (107 pfu MVA-BN given subcutaneously) there were significantly more CTL induced to SLY (8-fold increase) and RPQ (3-fold increase) and responses were also observed to a third epitope for murine cytomegalovirus (YPHFMPTNL) (Fig. 3A). However, using 107 pfu MVA-BN given subcutaneously in a homologous prime boost regime induced the same level of responses as DNA followed by MVA-BN (Fig. 3A). Surprisingly, there was no significant difference in the numbers of CTLs induced to the three epitopes when one immunisation of MVA-BN (107 TCID50) was used, indicating that a secondary immunisation with MVA-BN did not significantly boost CTL responses.
The subcutaneous administration of 107 pfu MVA has previously been shown to be the most inefficient route and virus concentration for vaccination using other strains of MVA, particularly if compared to intravenous immunisations (Schneider et al 1998). In order to define optimal immunization regimes the above experiment was repeated by changing either the amount of virus or by changing the mode of administration. In one experiment 107 pfu MVA-BN vaccinations were given intravenously (Fig. 3B). In a further experiment 108 pfu MVA-BN were administered subcutaneously (Fig.3C). In these experiments MVA-BN prime-boost immunisations induced higher mean CTL numbers to all three CTL epitopes compared to DNA prime M VA boost regimes. Also unlike 107 pfu MVA-BN given subcutaneously the immunisation with 107 pfu MVA-BN given intraveneously and the immunization with 108 pfu given subcutaneously significantly boosted the CTL responses, clearly indicating that MVA-BN can be used to boost CTL responses in the presence of a pre-existing immunity to the vector.
2.2.3. : Efficacy of a MVA-BN nef Vaccine in SIV Infected Rhesus Monkeys.
To determine the efficacy of a MVA-BN nef vaccine by assessing the viral load and delay of disease following a challenge with a virulent primary isolate of SIV. Furthermore, the study will determine whether
MVA-BN can be used to safely boost immune responses in immuno- compromised monkeys with a pre-existing immunity to MVA.
Vaccination protocols
Two groups (n = 6) of rhesus monkeys (Macaca mulalta) were vaccinated with a bolus intramuscular injection with either MVA-BN alone or a recombinant MVA-BN nef at week 0, 8 and 16. On week 22 all monkeys were challenged with 50 MID50 of a pathogenic cell- associated SIV stock (IXC) from primary, uncultured rhesus monkey PBMC by the intravenous route. The clinical status of the animals was frequently monitored and regular blood samples were taken for the measurement of viremia, immune parameters, and a full range of hematology and blood clinical chemistry parameters. Animals were sacrificed that developed AlDs like disease and the surviving monkeys were monitored for 99 weeks post vaccination. At week 100 the surviving monkeys were all immunized i.m. with MVA-BN tat and received further immunizations with the same MVA-BN tat at weeks 102 and 106.
No adverse effects were observed following any of the vaccinations with either MVA-BN or MVA-BN nef. Following the infection of the monkeys with SIV the levels of viremia rose sharply and peaked two weeks post infection (Fig. 4). Due to the large standard deviations within the groups there was no significant difference in the mean levels of SIV between the groups vaccinated with MVA-BN nef or MVA-BN . However, there was a general 10 fold lower SIV load in the group vaccinated with the MVA-BN nef compared to the control (MVA-BN) group. Furthermore, after 35 weeks following infection (the initial observation period) only 1 out of
the six monkeys vaccinated with MVA-BN nef had to be euthanised due to the severity of the disease, compared to 4 out of the 6 animals in the control group (Fig. 5). The development of disease clearly correlated with a higher virus load and as such the animals were observed for an additional 29 weeks post infection. The M VA-
BN nef vaccine appeared to delay the progression of the disease, compared to the control group and even at week 46-post infection 5 out of the 6 MVA-BN nef animals survived (Fig. 5). However, by week 59-post infection two further animals in the nef vaccinated group were euthanised leaving five surviving animals (three from the MVA-BN nef group and two vaccinated with MVA-BN). An examination of the antibody titres generated to MVA-BN in these 12 monkeys clearly demonstrated that MVA-BN could boost the immune response even in the presence of a pre-existing immunity to MVA (Fig. 6). Following the primary immunization with either MVA-BN or MVA-BN nef all monkeys generated an antibody response to MVA with a mean titre of 1000. This antibody response was significantly boosted following the secondary immunization, clearly demonstrating that MVA can be used to prime-boost immune response in healthy monkeys. These antibody titres gradually declined, although by week 49 post immunization the titres plateaued, such that the mean titres to M VA at week 99 were 2000.
The five surviving monkeys were SIV infected and immuno- compromised with CD4 counts lower than 400/μl blood. To investigate the impact of using MVA-BN in immuno-compromised
monkeys the five animals were vaccination three times with MVA-BN tat at week 100, 102 and 106 post the initial vaccination. The first immunization with MVA-BN tat significantly boosted the antibody response to MVA in these immuno-compromised monkeys that was further boosted with the third immunization six weeks later (Fig. 6).
These results further demonstrate that MVA-BN can boost immune responses in the presence of a significant pre-existing immunity to MVA, even in immuno-compromised monkeys. Although the monkeys immune response was boosted following the immunizations with MVA- BN tat the levels of SIV remained stable, indicating that immunizations with MVA-BN are safe and do not affect SIV levels in immuno-compromised monkeys (Fig. 7).
This study has demonstrated that MVA-BN can prime-boost immune responses in immuno-compromised rhesus monkeys and that
MVA-BN immunizations are safe and do not affect the levels of viremia in SIV infected animals. The delay in the progression of AI DS like disease in the animals vaccinated with the MVA-BN nef vaccine, indicates that an immune response was successfully generated to nef.
2.2.4. : Therapeutic Vaccination of SIV-lnfected Monkeys Undergoing Anti-Retroviral Treatment
An MVA-BN based therapeutic HIV vaccine is likely to be used in individuals undergoing anti-retroviral therapy. Therefore this study investigated the safety (effect on SIV levels) and efficacy of
recombinant MVA's encoding a variety of SIV antigens (gag, pol, env, rev, tat, and nef) in SIV infected monkeys treated with PMPA. PMPA is a nucleoside analogue and is effective against HIV and SIV (Rosenwirth, B. et al., 2000, J Virol 74,1704-11).
Constructs
All the recombinant MVA constructs were propagated on CEF cells, sucrose purified and formulated in Tris pH 7.4.
Vaccination Protocol
Three groups (n = 6) of rhesus monkeys (Macaca mulatta) were infected with 50 M I Dso of a pathogenic primary SIV isolated (IXC) and then treated daily with PMPA (60 mg/kg given s.c.) for 19 weeks. A t week 10, animals were vaccinated with recombinant MVA-BN (i.m.), or saline and received identical vaccinations 6 weeks later. Group 1 received a mixture of MVA gag-pol and MVA-env, group 2 received MVA-tat, MVA-rev and MVA-nef, while group 3 received saline. The clinical status of the animals was frequently monitored and regular blood samples were taken for the measurement of viremia, immune parameters, and a full range of hematology and blood clinical chemistry parameters.
Al l animals established high SIV loads that peaked 2 weeks post infection (Fig. 8). Following daily treatment with PMPA the S I V levels decreased and stabilized to low levels by week 9. As in the previous study vaccinations with MVA- at week 10 and 16 had no
effect on the SIV levels, indicating that MVA-BN is a safe vaccine vector for immuno-compromised animals. Once the animals came off PMPA treatment (week 21) the SIV levels increased. Although three animals in group 1 had reduced levels of SIV compared to the control group 3, there was no significant difference in the mean SIV load between any of the groups following the end of PM PA treatment (Fig. 8). Using an ELISA to SIV infected T-cell lysates animals in all groups generated an antibody response to SIV by week 4 following infection (Fig. 9). The SIV antibody titre in the control group (saline) dropped during the PM PA treatment and increased rapidly when PM PA treatment stopped, reflecting the drop and subsequent increase in SIV levels during anti-retroviral therapy (Fig. 9). A similar pattern in SIV antibody titre was observed in group 2 that received MVA-tat, MVA-rev and MVA-nef, possibly reflecting the under-expression of these regulatory proteins in the SIV infected T cell lysates used in the
ELISA. I n contrast however, the anti-SIV antibody titres in group 1 increased following the vaccinations with MVA gag-pol and M VA-e nv at week 10, indicating that recombinant MVA-BN can boost the immune response to SIV in (SIV) infected animals undergoing anti- retroviral therapy. I mportantly, the anti-SIV antibody titres were boosted following the secondary immunization at week 16 again demonstrating that MVA can boost immune responses in immuno- compromised animals, even in the presence of a pre-existing immunity to MVA (Fig. 8). The anti-MVA antibody titres in group 1 also reflected this pattern with the generation of a antibody response
following the primary immunization and this was significantly boosted following the secondary vaccination (Fig. 10).
References
Schneider, J., Gilbert, SC, Blanchard, TJ., Hanke, T., Robson, KJ., Hannan, CM., Becker, M., Sinden, R., Smith, GL., and Hill, AVS. 1998. Enhanced immunogenicity for CD8+ T cell induction and complete efficacy of malaria DNA vaccination by boosting with modified vaccinia virus Ankara. Nat. Med. 4; 397-402.
Thomson, SA., Sherritt, MA., Medveczky, J., Elliott, SL., Moss, DJ., Fernando, GJP., Brown, LE., and Suhrbier, A. 1998. Delivery of multiple CD8 cytotoxic T cell epitopes by DNA vaccination. J. Immunol. 160: 1717.
Table 1:
Virus amplification above the input level after 4 days infection Amplification ratio = output TCID50 ■ input TCID50. Values are in TCID50.
Applicant s or agent s tile International apphcationNo refeiencenumber BN 35 PCT
INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule \2bιs)
A Theindicationsmadebelowrelatetothemicroorganismiefeπed to in the description
B. IDENTIFICATIONOFDEPOSrr Further deposits areidentif led on an additional sheet | |
Name of depositary institution ECACC
European Collection of Cell Cultures
Address of depositary institution (mclttdmg poital code and country)
Centre for Applied Microbiology & Research
Salisbury
Wiltshire SP4 OJG, United Kingdom
Dateof deposit AccessionNumber
August 30, 2000 00083008
C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet | |
In respect of all designated States to which such action is possible and to the extent that it is legally permissable under the law of the designated State, it is requested that a sample of the deposited microorganism be made available only by the issue thereof to an independent expert, in accordance with the relevant patent legislation, e g , EPC Rule 28 (4), UK Patent Rules 1995, Schedule 2, Paragraph 3 Australian Regulation 3 25(3), Danish Patents Act Sections 22 and 33(3) and generally similar provisions mutatis mutandis for any other designated State
D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the mduatm M are not for all designated Stata)
E. SETARA EFVSNISHIl IGOF' DICATION- S( vι.blaιιlιfιwt pplιcablc)
The indications listed below ill be submitted to the International Bmeau later (specify the general nature of 'the inώcatwm eg Accession Number of Deposit )
INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule ttbis)
A The indications made below relate to the microorganism referred torn the description on page 13 ,lme 13
B. IDENΠFICATIONOFDEPOSIT Further deposits are identified on an additional sheet V~\
Nameof depositary institution ECACC
European Collection of Cell Cultures
Address of depositary institution (including po tal code and country)
Centre for Applied Microbiology & Research
Salisbury
Wiltshire SP4 OJG, United Kingdom
Date of deposit Accession Number
December 7, 2000 00120707
C ADDITIONAL TNDICAΥIO'NS (leave blank if not applicable) Thisinformationiscontmuedonanadditionalsheet ]
In respect of all designated States to which such action is possible and to the extent that it is legally permissable under the law of the designated State, it is requested that a sample of the deposited microorganism be made available only by the issue thereof to an independent expert, in accordance with the relevant patent legislation, e.g , EPC Rule 28 (4), UK Patent Rules 1995, Schedule 2, Paragraph 3, Australian Regulation 325(3), Danish Patents Act Sections 22 and 33(3) and generally similar provisions mutatis mutandis for any other designated State
D DESIGNATED STATES FOR WHICH INDICATIONS ARE MADΕ(ιftlwmώtatιoιuarenotforalldcsιgnaledS tes)
E. SEPARATEFURNISHINGOFINDICATIONSrteareW ώifnnfαppkαite)
The indications listed below will be submitted to the International Bureau later (specify the geneial nature of the indications e._, , Accession Numbu of Deposit )
INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule Kbis)
A. The indications made below relate to the microorganism referred to in the description on page 35 ,lme 16
B. JDENTIFICATIONOFDEPOSIT Further deposits are identified on an additional sheet | |
Name of depositary institution PHLS Public Health Laboratory Service, Centre for Applied Microbiology and Research ECACC European Collection of Cell Cultures, CAMR
Address of depositary institution (including postal code and country)
ECACC European Collection of Cell Cultures, CAMR
Porton Down
Salisbury, SP4, OJG, UK
Date of deposit Accession Number
January 27, 1994 V94012707
C. ADDITIONAL INDICATIONS (leave blank if not applicable) This informationiscontinuedonanadditionalsheet Q
D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the indications are not for all designated Slates)
E. SEPARATE FURNISHING OF INDICATIONS (leave blank wtapplicable)
The indications listed below will be submitted to the International Bureau later (specify the general nature of tlie indications- e.g., "Accession Number of Deposit")
Claims
(1) Vaccinia virus having at least one of the following properties: (i) capability of reproductive replication in chicken embryo fibroblasts (CEF) and in the baby hamster kidney cell line BHK, but no capability of reproductive replication in the human keratinocyte cell line HaCat, (ii) failure to replicate in vivo, (iii) induction of a higher immunogenicity compared to the known strain MVA 575 in a lethal challenge model and/or
(iv) induction of at least substantially the same level of immunity in vaccinia virus prime/ vaccinia virus boost regimes when compared to DNA-prime/ vaccinia virus boost regimes.
(2 ) The virus according to claim 1 , wherein the virus is not capable of reproductively replicating in any of the following human cell lines: the human embryo kidney cell line 293, the human bone osteosarcoma cell line 143B and the human cervix adenocarcinoma cell line HeLa.
(3) The virus according to claim 1 or 2 being deposited at the European Collection of Cell Cultures (ECACC), Salisbury (UK) under number V00083008 and derivatives thereof.
(4) The virus according to anyone of the claims 1 to 3 comprising at least one heterologous nucleic acid sequence.
(5) The virus according to claim 4, wherein said heterologous nucleic acid sequence is selected from a sequence coding for at least one antigen, antigenic epitope, and/or a therapeutic compound.
(6) Genome or functional parts thereof derived from the virus according to anyone of the claims 1 to 5.
(7) Pharmaceutical composition comprising the virus according to anyone of the claims 1 to 5 and/or the genome and/or functional part thereof according to claim 6 and a pharmaceutically acceptable carrier, diluent and/or additive.
(8) Vaccine comprising the virus according to anyone of the claims 1 to 5 and/or the genome and/or functional part thereof according to claim 6.
(9) The virus according to anyone of the claims 1 to 5, the genome and/or functional part thereof according to claim 6, the composition according to claim 7 or the vaccine according to claim 8 as drug for affecting, preferably inducing, an immunological response in a living animal, including a human.
( 10 ) The virus according to anyone of claims 1 to 5, the pharmaceutical composition according to claim 7, the vaccine according to claim 8 or the virus according to claim 9, wherein the virus, the composition or the vaccine is administered in therapeutically effective amounts in a first
inoculation ("priming inoculation") and in a second inoculation ("boosting inoculation").
(11) Use of the virus according to anyone of the claims 1 to 5, and/or the genome according to claim 6, for the preparation of a medicament or a vaccine.
(12) Method for introducing a homologous and/or a heterologous nucleic acid sequence into target cells comprising the infection of the target cells with the virus according to claim 4 or 5 or the transfection of the target cell with the genome according to claim 6.
(13) Method for producing a peptide, protein and/or virus comprising
a) infection of a host cell with the virus according to claims 1 or 5, b) cultivation of the infected host cell under suitable conditions, and c) isolation and/or enrichment of the peptide and/or protein and/or viruses produced by said host cell.
(14 ) Method for affecting, preferably inducing an immunological response in a living animal body including a human comprising administering the virus according to anyone of the claims 1 to 5, the genome and/or functional part thereof according to claim 6, the composition according to claim 7 or.
the vaccine according to claim 8 to the animal or human to be treated.
(15) The method according to claim 14 comprising the administration of at least 102 TCID50 (tissue culture infectious dose) of the virus.
(16) Method according to claim 14 or 15, wherein the virus, the composition or the vaccine is administered in therapeutically effective amounts in a first inoculation ("priming inoculation") and in a second inoculation ("boosting inoculation").
(17 ) The method according to anyone of the claims 14 to 16, wherein the animal is immuno-compromised.
( 18 ) The method according to anyone of the claims 14 to 17, wherein the animal has a pre-existing immunity to poxviruses.
(19) The method according to anyone of the claims 14 to 18, wherein the animal is undergoing an antiviral therapy.
(20) The method according to claim 19, wherein the antiviral therapy is an antiretroviral therapy .
(21) Use of the virus according to anyone of the claims 1 to 5, the genome and/or functional part thereof according to claim 6 as adjuvant.
(22) A method for enhancing a specific immune response against an antigen and/or an antigenic epitope included in a vaccine comprising administration of the virus according to anyone of the claims 1 to 5 or the genome according to claim 6 as an adjuvant to a living animal body including a human to be treated with the vaccine.
(23) The virus according to anyone of claims 1 to 5 or the genome according to claim 6 as adjuvant.
(24) A cell, preferably a human cell, containing the virus according to any of claims 1 to 5 or the genome or functional part thereof of claim 6.
(25) Method for obtaining the vaccinia virus according to anyone of claims 1 to 3 comprising the following steps:
- introducing a commonly available vaccinia virus strain, preferably MVA 575 into non-human cells in which the virus is able to reproductively replicate, wherein the non-human cells are preferably selected from CEF cells and the cell line BHK,
- isolating/enriching virus particles from these cells and
- analysing whether the obtained virus has at least one of the biological properties as defined in claim
1 , wherein the above steps can optionally be repeated until a virus with the desired replication characteristics is obtained
(26) Kit for prime/boost immunization comprising a virus according to anyone of claims 1 to 5, a composition according to claim 7, a vaccine according to claim 8 or a virus according to claim 9 for a first inoculation ("priming inoculation") in a first vial/container and for a second inoculation ("boosting inoculation") in a second vial/container.
(27 ) Use of the virus according to anyone of claims 1 to 5, the composition according to claim 7, the vaccine according to claim 8 or the virus according to claim 9 for the preparation of a vaccine wherein the virus, the composition or the vaccine is administered in therapeutically effective amounts in a first inoculation and in a second inoculation.
Priority Applications (51)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE60116371.0T DE60116371T3 (en) | 2000-11-23 | 2001-11-22 | VARIANT OF THE MODIFIED VACCINIA ANKARA VIRUS |
| NZ524661A NZ524661A (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| MXPA03002513A MXPA03002513A (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant. |
| IL15471201A IL154712A0 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| PL361459A PL212047B1 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| SI200130512T SI1335987T2 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| UA2003054618A UA76731C2 (en) | 2000-11-23 | 2001-11-22 | Mva-bn strain of modified vaccinia ankara virus, pharmaceutical composition, vaccine, use of mva-bn strain for vaccine preparation, method for transfer of homologous and/or heterologous nucleic acid sequence into the target cells in vitro, method for preparing peptide or protein, method for obtaining mva-bn strain, host cell, set for primary/buster immunization |
| EP01991753.3A EP1335987B2 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| AU2002231639A AU2002231639B2 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| AT01991753T ATE314483T2 (en) | 2000-11-23 | 2001-11-22 | VARIANT OF MODIFIED VACCINIA ANKARA VIRUS |
| ES01991753.3T ES2256323T5 (en) | 2000-11-23 | 2001-11-22 | Variant of the Modified Vaccinia Ankara virus |
| KR1020037006970A KR100830295B1 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| EEP200300173A EE05680B1 (en) | 2000-11-23 | 2001-11-22 | Modified vaccine virus, its preparation and use, pharmaceutical composition containing it and vaccine |
| BRPI0115533A BRPI0115533B8 (en) | 2000-11-23 | 2001-11-22 | Variation of the modified vaccinia ankara virus |
| JP2002545184A JP4421188B2 (en) | 2000-11-23 | 2001-11-22 | Denatured vaccinia Ankara virus mutant |
| CA2421151A CA2421151C (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| AU3163902A AU3163902A (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| HU0400685A HU230198B1 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
| IL154712A IL154712A (en) | 2000-11-23 | 2003-03-03 | Modified vaccinia ankara virus variant |
| US10/418,854 US7097842B2 (en) | 2000-11-23 | 2003-04-18 | Modified vaccinia virus ankara for the vaccination of neonates |
| US10/440,073 US7189536B2 (en) | 2000-11-23 | 2003-05-16 | Modified vaccinia ankara virus variant |
| US10/439,953 US6761893B2 (en) | 2000-11-23 | 2003-05-16 | Modified vaccinia ankara virus variant |
| US10/439,439 US6913752B2 (en) | 2000-11-23 | 2003-05-16 | Modified Vaccinia Ankara virus variant |
| NO20032309A NO337867B1 (en) | 2000-11-23 | 2003-05-21 | Modified Vaccinia Ankara virus strain MVA-BN and derivatives thereof, methods for introducing nucleic acid sequence into target cells, preparation of peptide or protein and preparation of variant of MVA, cell containing the variant, immunization set and use of the variant. |
| HK04102348.1A HK1059453A1 (en) | 2000-11-23 | 2004-03-31 | Modified vaccinia ankara virus variant |
| US11/071,741 US7445924B2 (en) | 2000-11-23 | 2005-03-03 | Modified Vaccinia Ankara virus variant and cultivation method |
| US11/112,438 US7628980B2 (en) | 2000-11-23 | 2005-04-22 | Modified vaccinia virus ankara for the vaccination of neonates |
| US11/198,557 US7384644B2 (en) | 2000-11-23 | 2005-08-05 | Modified Vaccinia Ankara virus variant |
| US11/341,955 US20060127984A1 (en) | 2000-11-23 | 2006-01-27 | Modified Vaccinia virus Ankara for the vaccination of neonates |
| CY20061100421T CY1105594T1 (en) | 2000-11-23 | 2006-03-27 | VARIANT OF MODIFIED VACCINIA ANKARA VIRUS |
| US11/508,797 US7335364B2 (en) | 2000-11-23 | 2006-08-23 | Modified Vaccinia Ankara virus variant |
| US11/977,808 US7923017B2 (en) | 2000-11-23 | 2007-10-26 | Modified Vaccinia Ankara virus variant |
| US11/999,127 US7459270B2 (en) | 2000-11-23 | 2007-12-04 | Modified Vaccinia Ankara virus variant |
| US12/118,841 US7897156B2 (en) | 2001-11-22 | 2008-05-12 | Modified vaccinia virus ankara for the vaccination of neonates |
| US12/200,176 US7964395B2 (en) | 2000-11-23 | 2008-08-28 | Modified vaccinia ankara virus variant and cultivation method |
| US12/200,295 US7964396B2 (en) | 2000-11-23 | 2008-08-28 | Modified vaccinia ankara virus variant and cultivation method |
| US12/471,144 US7939086B2 (en) | 2000-11-23 | 2009-05-22 | Modified Vaccinia Ankara virus variant |
| US12/607,585 US7892533B2 (en) | 2000-11-23 | 2009-10-28 | Modified vaccinia virus ankara for the vaccination of neonates |
| US12/836,324 US7964398B2 (en) | 2000-11-23 | 2010-07-14 | Modified vaccinia ankara virus variant and cultivation method |
| US13/006,824 US8372622B2 (en) | 2000-11-23 | 2011-01-14 | Modified vaccinia virus ankara for the vaccination of neonates |
| US13/009,636 US8163293B2 (en) | 2000-11-23 | 2011-01-19 | Modified Vaccinia Virus Ankara for the vaccination of neonates |
| US13/053,450 US8268329B2 (en) | 2000-11-23 | 2011-03-22 | Modified Vaccinia ankara virus variant |
| US13/053,361 US8268325B2 (en) | 2000-11-23 | 2011-03-22 | Modified Vaccinia Ankara virus variant |
| US13/106,176 US8236560B2 (en) | 2000-11-23 | 2011-05-12 | Modified Vaccinia Ankara virus variant and cultivation method |
| US13/422,028 US20120183574A1 (en) | 2000-11-23 | 2012-03-16 | Modified vaccinia virus ankara for the vaccnation of neonates |
| US13/544,201 US8470598B2 (en) | 2000-11-23 | 2012-07-09 | Modified Vaccinia Ankara virus variant and cultivation method |
| US13/588,217 US20120328650A1 (en) | 2000-11-23 | 2012-08-17 | Modified vaccinia ankara virus variant |
| BE2013C065C BE2013C065I2 (en) | 2000-11-23 | 2013-11-21 | |
| FR13C0070C FR13C0070I2 (en) | 2000-11-23 | 2013-12-13 | MODIFIED VARIANT OF ANKARA VACCINE VIRUS |
| CY2013048C CY2013048I2 (en) | 2000-11-23 | 2013-12-23 | VARIANT OF MODIFIED VACCINIA ANKARA VIRUS |
| HUS1600010C HUS1600010I1 (en) | 2000-11-23 | 2016-02-29 | Modified vaccinia ankara virus variant |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200001764 | 2000-11-23 | ||
| DKPA200001764 | 2000-11-23 |
Related Child Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/418,854 Continuation-In-Part US7097842B2 (en) | 2000-11-23 | 2003-04-18 | Modified vaccinia virus ankara for the vaccination of neonates |
| US10/439,953 Continuation US6761893B2 (en) | 2000-11-23 | 2003-05-16 | Modified vaccinia ankara virus variant |
| US10/439,439 Continuation US6913752B2 (en) | 2000-11-23 | 2003-05-16 | Modified Vaccinia Ankara virus variant |
| US10/440,073 Continuation US7189536B2 (en) | 2000-11-23 | 2003-05-16 | Modified vaccinia ankara virus variant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002042480A2 true WO2002042480A2 (en) | 2002-05-30 |
| WO2002042480A3 WO2002042480A3 (en) | 2002-08-01 |
Family
ID=8159864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2001/013628 WO2002042480A2 (en) | 2000-11-23 | 2001-11-22 | Modified vaccinia ankara virus variant |
Country Status (30)
| Country | Link |
|---|---|
| US (11) | US6913752B2 (en) |
| EP (4) | EP2202315A1 (en) |
| JP (1) | JP4421188B2 (en) |
| KR (3) | KR100910297B1 (en) |
| CN (2) | CN100537773C (en) |
| AT (1) | ATE314483T2 (en) |
| AU (2) | AU2002231639B2 (en) |
| BE (1) | BE2013C065I2 (en) |
| BR (1) | BRPI0115533B8 (en) |
| CA (1) | CA2421151C (en) |
| CY (2) | CY1105594T1 (en) |
| CZ (1) | CZ295808B6 (en) |
| DE (2) | DE60116371T3 (en) |
| DK (1) | DK1335987T4 (en) |
| EE (1) | EE05680B1 (en) |
| ES (1) | ES2256323T5 (en) |
| FR (1) | FR13C0070I2 (en) |
| HK (1) | HK1059453A1 (en) |
| HU (2) | HU230198B1 (en) |
| IL (2) | IL154712A0 (en) |
| LU (1) | LU92311I2 (en) |
| MX (1) | MXPA03002513A (en) |
| NO (1) | NO337867B1 (en) |
| NZ (1) | NZ524661A (en) |
| PL (1) | PL212047B1 (en) |
| PT (1) | PT1335987E (en) |
| RU (1) | RU2290438C2 (en) |
| SI (1) | SI1335987T2 (en) |
| UA (1) | UA76731C2 (en) |
| WO (1) | WO2002042480A2 (en) |
Cited By (92)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003048184A2 (en) * | 2001-12-04 | 2003-06-12 | Bavarian Nordic A/S | Flavivirus ns1 subunit vaccine |
| WO2003088994A2 (en) * | 2002-04-19 | 2003-10-30 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| WO2003097846A1 (en) | 2002-05-16 | 2003-11-27 | Bavarian Nordic A/S | Recombinant poxvirus expressing homologous genes inserted into the poxviral genome |
| EP1536015A1 (en) * | 2003-11-24 | 2005-06-01 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus ankara |
| US7097842B2 (en) | 2000-11-23 | 2006-08-29 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7189536B2 (en) | 2000-11-23 | 2007-03-13 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant |
| EP1835031A1 (en) | 2006-03-14 | 2007-09-19 | Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe | Use of a recombinant modified vaccinia virus Ankara (MVA) for the treatment of type I hypersensitivity in a living animal including humans |
| WO2008028665A1 (en) * | 2006-09-08 | 2008-03-13 | Bavarian Nordic A/S | Phenotypic and genotypic differences of mva strains |
| US7445924B2 (en) | 2000-11-23 | 2008-11-04 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant and cultivation method |
| WO2008131927A1 (en) * | 2007-04-27 | 2008-11-06 | Bavarian Nordic A/S | Immediate protection against pathogens via mva |
| AU2003240243B2 (en) * | 2002-05-16 | 2009-01-22 | Bavarian Nordic A/S | Expression of genes in modified vaccinia virus Ankara by using the cowpox ATI promoter |
| US7501127B2 (en) | 2002-05-16 | 2009-03-10 | Bavarian Nordic A/S | Intergenic regions as novel sites for insertion of HIV DNA sequences in the genome of Modified Vaccinia virus Ankara |
| US7628980B2 (en) | 2000-11-23 | 2009-12-08 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| WO2009152969A1 (en) * | 2008-06-20 | 2009-12-23 | Bavarian Nordic A/S | Recombinant modified vaccinia virus measles vaccine |
| US7695939B2 (en) | 2002-09-05 | 2010-04-13 | Bavarian Nordic A/S | Method for the cultivation of primary cells and for the amplification of viruses under serum free conditions |
| WO2010102822A1 (en) | 2009-03-13 | 2010-09-16 | Bavarian Nordic A/S | Optimized early-late promoter combined with repeated vaccination favors cytotoxic t cell response against antigens in replication deficient recombinant virus vaccines |
| WO2011042180A1 (en) | 2009-10-08 | 2011-04-14 | Bavarian Nordic A/S | Generation of a broad t-cell response in humans against hiv |
| WO2011092029A1 (en) | 2010-01-28 | 2011-08-04 | Bavarian Nordic A/S | Vaccinia virus mutants containing the major genomic deletions of mva |
| WO2012010280A1 (en) | 2010-07-20 | 2012-01-26 | Bavarian Nordic A/S | Method for harvesting expression products |
| WO2012048817A2 (en) | 2010-10-15 | 2012-04-19 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara influenza vaccine |
| WO2013083254A1 (en) | 2011-12-09 | 2013-06-13 | Bavarian Nordic A/S | Poxvirus vector for the expression of bacterial antigens linked to tetanus toxin fragment c |
| EP2620446A1 (en) | 2012-01-27 | 2013-07-31 | Laboratorios Del Dr. Esteve, S.A. | Immunogens for HIV vaccination |
| US8613936B2 (en) | 2009-03-13 | 2013-12-24 | Bavarian Nordic A/S | Replication deficient recombinant viruses expressing antigens regulated by transcriptional control elements comprising multiple elements |
| WO2013189611A1 (en) | 2012-06-22 | 2013-12-27 | Bavarian Nordic A/S | Poxviral vectors for low antibody response after a first priming immunization |
| WO2014009438A2 (en) | 2012-07-10 | 2014-01-16 | Transgene Sa | Mycobacterial antigen vaccine |
| WO2014009433A1 (en) | 2012-07-10 | 2014-01-16 | Transgene Sa | Mycobacterium resuscitation promoting factor for use as adjuvant |
| WO2014019718A1 (en) | 2012-08-01 | 2014-02-06 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) respiratory syncytial virus (rsv) vaccine |
| WO2014037124A1 (en) | 2012-09-04 | 2014-03-13 | Bavarian Nordic A/S | Methods and compositions for enhancing vaccine immune responses |
| WO2015061416A2 (en) | 2013-10-23 | 2015-04-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hla-a24 agonist epitopes of muc1-c oncoprotein and compositions and methods of use |
| WO2015078856A1 (en) | 2013-11-28 | 2015-06-04 | Bavarian Nordic A/S | Compositions and methods vectors for inducing an enhanced immune response using poxvirus vectors |
| WO2015104380A1 (en) | 2014-01-09 | 2015-07-16 | Transgene Sa | Fusion of heterooligomeric mycobacterial antigens |
| WO2015175340A1 (en) | 2014-05-13 | 2015-11-19 | Bavarian Nordic, Inc. | Combination therapy for treating cancer with a poxvirus expressing a tumor antigen and a monoclonal antibody against tim-3 |
| WO2016049287A1 (en) | 2014-09-26 | 2016-03-31 | Beth Israel Deaconess Medical Center, Inc. | Methods and compositions for inducing protective immunity against human immunodeficiency virus infection |
| WO2016202828A1 (en) * | 2015-06-15 | 2016-12-22 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) foot and mouth disease virus (fmdv) vaccine |
| WO2017060650A1 (en) | 2015-10-08 | 2017-04-13 | Jean-Marc Limacher | Anti-tumoral composition |
| WO2017129765A1 (en) | 2016-01-29 | 2017-08-03 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) equine encephalitis virus vaccine |
| WO2017192418A1 (en) | 2016-05-02 | 2017-11-09 | Janssen Vaccine & Prevention B.V. | Therapeutic hpv vaccine combinations |
| WO2018011768A1 (en) | 2016-07-15 | 2018-01-18 | Janssen Vaccines And Prevention B.V. | Methods and compositions for inducing protective immunity against a marburg virus infection |
| WO2018045267A1 (en) | 2016-09-02 | 2018-03-08 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| WO2018060368A2 (en) | 2016-09-28 | 2018-04-05 | Bavarian Nordic A/S | Compositions and methods for enhancing the stability of transgenes in poxviruses |
| WO2018085751A1 (en) | 2016-11-07 | 2018-05-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Development of agonist epitopes of the human papillomavirus |
| WO2018185732A1 (en) | 2017-04-06 | 2018-10-11 | Janssen Vaccines & Prevention B.V. | Mva-bn and ad26.zebov or ad26.filo prime-boost regimen |
| WO2018210804A1 (en) | 2017-05-15 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
| WO2018211419A1 (en) | 2017-05-15 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
| WO2018229711A1 (en) | 2017-06-15 | 2018-12-20 | Janssen Vaccines & Prevention B.V. | Poxvirus vectors encoding hiv antigens, and methods of use thereof |
| WO2019018724A1 (en) | 2017-07-21 | 2019-01-24 | Janssen Vaccines & Prevention B.V. | Methods for safe induction of cross-clade immunity against human immunodeficiency virus infection in human |
| WO2019038388A1 (en) | 2017-08-24 | 2019-02-28 | Bavarian Nordic A/S | Combination therapy for treating cancer with an intravenous administration of a recombinant mva and an antibody |
| WO2019055888A1 (en) | 2017-09-18 | 2019-03-21 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| US10273268B2 (en) | 2016-06-16 | 2019-04-30 | Janssen Vaccines & Prevention B.V. | HIV vaccine formulation |
| WO2019123169A1 (en) | 2017-12-20 | 2019-06-27 | Glaxosmithkline Biologicals Sa | Epstein-barr virus antigen constructs |
| WO2019123250A1 (en) | 2017-12-19 | 2019-06-27 | Janssen Sciences Ireland Unlimited Company | Methods and compositions for inducing an immune response against hepatitis b virus (hbv) |
| US10369214B2 (en) | 2015-12-15 | 2019-08-06 | Janssen Vaccines & Prevention B.V. | Synthetic human immunodeficiency virus (HIV) envelope antigen, vectors, and compositions thereof |
| US10561722B2 (en) | 2014-09-03 | 2020-02-18 | Bavarian Nordic A/S | Methods and compositions for enhancing immune responses |
| US10561721B2 (en) | 2014-09-03 | 2020-02-18 | Bavarian Nordic A/S | Methods and compositions for inducing protective immunity against filovirus infection |
| WO2020049151A1 (en) | 2018-09-06 | 2020-03-12 | Bavarian Nordic A/S | Storage improved poxvirus compositions |
| WO2020070303A1 (en) | 2018-10-05 | 2020-04-09 | Bavarian Nordic A/S | Combination therapy for treating cancer with an intravenous administration of a recombinant mva and an immune checkpoint antagonist or agonist |
| WO2020102404A1 (en) | 2018-11-14 | 2020-05-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tp5, a peptide inhibitor of aberrant and hyperactive cdk5/p25 as treatment for cancer |
| WO2020104531A1 (en) | 2018-11-20 | 2020-05-28 | Bavarian Nordic A/S | Therapy for treating cancer with an intratumoral and/or intravenous administration of a recombinant mva encoding 4-1bbl (cd137l) and/or cd40l |
| US10793607B2 (en) | 2016-09-15 | 2020-10-06 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| WO2020237052A1 (en) | 2019-05-22 | 2020-11-26 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| EP3778904A1 (en) | 2012-10-28 | 2021-02-17 | Bavarian Nordic A/S | Pr13.5 promoter for robust t-cell and antibody responses |
| US10968254B2 (en) | 2017-07-19 | 2021-04-06 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| WO2021099586A1 (en) | 2019-11-20 | 2021-05-27 | Bavarian Nordic A/S | Recombinant mva viruses for intratumoral and/or intravenous administration for treating cancer |
| WO2021099572A1 (en) | 2019-11-20 | 2021-05-27 | Bavarian Nordic A/S | Medical uses of 4-1bbl adjuvanted recombinant modified vaccinia virus ankara (mva) |
| US11021692B2 (en) | 2017-12-19 | 2021-06-01 | Janssen Sciences Ireland Unlimited Company | Hepatitis B virus (HBV) vaccines and uses thereof |
| US11020476B2 (en) | 2017-12-19 | 2021-06-01 | Janssen Sciences Ireland Unlimited Company | Methods and compositions for inducing an immune response against Hepatitis B Virus (HBV) |
| US11040096B2 (en) | 2014-11-04 | 2021-06-22 | Janssen Vaccines & Prevention B.V. | Therapeutic HPV16 vaccines |
| WO2021150713A2 (en) | 2020-01-21 | 2021-07-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human immunogenic epitopes of h, k, and e human endogenous retroviruses (hervs) |
| WO2021150694A1 (en) | 2020-01-21 | 2021-07-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human immunogenic epitopes of hemo and hhla2 human endogenous retroviruses (hervs) |
| US11083786B2 (en) | 2018-01-19 | 2021-08-10 | Janssen Pharmaceuticals, Inc. | Induce and enhance immune responses using recombinant replicon systems |
| WO2021180943A1 (en) | 2020-03-12 | 2021-09-16 | Bavarian Nordic A/S | Compositions improving poxvirus stability |
| EP3888676A1 (en) | 2014-06-13 | 2021-10-06 | GlaxoSmithKline Biologicals S.A. | Immunogenic combinations |
| WO2021250219A1 (en) | 2020-06-10 | 2021-12-16 | Bavarian Nordic A/S | A recombinant modified vaccinia virus ankara (mva) vaccine against coronavirus disease |
| EP3928789A1 (en) | 2020-06-24 | 2021-12-29 | Consejo Superior de Investigaciones Científicas (CSIC) | Mva-based vaccine against covid-19 expressing sars-cov-2 antigens |
| WO2021260065A1 (en) | 2020-06-24 | 2021-12-30 | Consejo Superior De Investigaciones Científicas (Csic) | Mva-based vaccine against covid-19 expressing sars-cov-2 antigens |
| WO2022008613A1 (en) | 2020-07-08 | 2022-01-13 | Janssen Sciences Ireland Unlimited Company | Rna replicon vaccines against hbv |
| WO2022084333A1 (en) | 2020-10-20 | 2022-04-28 | Janssen Vaccines & Prevention B.V. | Hiv vaccine regimens |
| US11364310B2 (en) | 2016-10-17 | 2022-06-21 | Janssen Pharmaceuticals, Inc. | Recombinant virus replicon systems and uses thereof |
| US11389531B2 (en) | 2017-12-19 | 2022-07-19 | Janssen Sciences Ireland Unlimited Company | Methods and apparatus for the delivery of hepatitis B virus (HBV) vaccines |
| EP4108257A1 (en) | 2021-06-23 | 2022-12-28 | Consejo Superior De Investigaciones Científicas | Mva-based vaccine against covid-19 expressing a prefusion-stabilized sars-cov-2 s protein |
| WO2022269003A1 (en) | 2021-06-23 | 2022-12-29 | Consejo Superior De Investigaciones Cientificas | MVA-BASED VACCINE EXPRESSING A PREFUSION-STABILIZED SARS-CoV-2 S PROTEIN |
| US11555205B2 (en) | 2016-04-13 | 2023-01-17 | Janssen Pharmaceuticals, Inc. | Recombinant arterivirus replicon systems and uses thereof |
| WO2023031428A1 (en) | 2021-09-03 | 2023-03-09 | Bavarian Nordic A/S | Utilization of micro-rna for downregulation of cytotoxic transgene expression by modified vaccinia virus ankara (mva) |
| US11666651B2 (en) | 2019-11-14 | 2023-06-06 | Aelix Therapeutics, S.L. | Prime/boost immunization regimen against HIV-1 utilizing a multiepitope T cell immunogen comprising Gag, Pol, Vif, and Nef epitopes |
| WO2023118563A1 (en) | 2021-12-23 | 2023-06-29 | Bavarian Nordic A/S | Therapy for modulating immune response with recombinant mva encoding il-12 |
| WO2023118508A1 (en) | 2021-12-23 | 2023-06-29 | Bavarian Nordic A/S | Recombinant mva viruses for intraperitoneal administration for treating cancer |
| WO2023198815A1 (en) | 2022-04-14 | 2023-10-19 | Janssen Vaccines & Prevention B.V. | Sequential administration of adenoviruses |
| US11845939B2 (en) | 2016-12-05 | 2023-12-19 | Janssen Pharmaceuticals, Inc. | Compositions and methods for enhancing gene expression |
| WO2024003238A1 (en) | 2022-06-29 | 2024-01-04 | Bavarian Nordic A/S | Epstein-barr-virus vaccine |
| WO2024003346A1 (en) | 2022-06-30 | 2024-01-04 | Bavarian Nordic A/S | Mammalian cell line for the production of modified vaccinia virus ankara (mva) |
| WO2024003239A1 (en) | 2022-06-29 | 2024-01-04 | Bavarian Nordic A/S | RECOMBINANT MODIFIED saRNA (VRP) AND VACCINIA VIRUS ANKARA (MVA) PRIME-BOOST REGIMEN |
| EP4316514A1 (en) | 2022-08-03 | 2024-02-07 | Consejo Superior de Investigaciones Científicas (CSIC) | Mva-based vectors and their use as vaccine against sars-cov-2 |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA82466C2 (en) * | 2001-07-18 | 2008-04-25 | Бавариан Нордика А/С | Method for intensification of chordopoxvirus amplification |
| DK1757312T3 (en) * | 2004-06-14 | 2011-04-11 | Ishihara Sangyo Kaisha | Freeze-dried composition of inactivated virus envelope with membrane fusion activity |
| CN1295339C (en) * | 2005-01-11 | 2007-01-17 | 武汉大学 | Attenuated vaccinia virus Tiantan strain vector and its preparation and application |
| FI1855720T4 (en) * | 2005-02-23 | 2023-08-31 | Use of a modified proxvirus for the rapid induction of immunity against a poxvirus or other infectious agents | |
| US20090269365A1 (en) * | 2005-04-20 | 2009-10-29 | University Of Washington | Immunogenic vaccinia peptides and methods of using same |
| KR100717279B1 (en) * | 2005-08-08 | 2007-05-15 | 삼성전자주식회사 | Mask rom device and method of formimg the same |
| US7913477B2 (en) * | 2006-01-27 | 2011-03-29 | William Anthony Harper | Insert registration in packets |
| EP1826264A1 (en) * | 2006-02-24 | 2007-08-29 | Deutsches Primatenzentrum GmbH | Primate model for orthopox virus infections |
| DK2530161T3 (en) * | 2006-06-20 | 2018-06-06 | Transgene Sa | Process for the preparation of poxviruses and poxvirus compositions |
| EP2029169A2 (en) | 2006-06-20 | 2009-03-04 | Transgene S.A. | Recombinant viral vaccine |
| ES2500465T3 (en) * | 2006-10-06 | 2014-09-30 | Bavarian Nordic Inc. | Recombinant modified Ankara vaccinia virus encoding HER-2 antigen in combination with a taxane for use in cancer treatment |
| US8003364B2 (en) * | 2007-05-14 | 2011-08-23 | Bavarian Nordic A/S | Purification of vaccinia viruses using hydrophobic interaction chromatography |
| US8012738B2 (en) | 2007-05-14 | 2011-09-06 | Bavarian Nordic A/S | Purification of vaccinia virus- and recombinant vaccinia virus-based vaccines |
| EP2207564B1 (en) * | 2007-10-18 | 2016-10-05 | Bavarian Nordic A/S | Use of mva to treat prostate cancer |
| KR100970449B1 (en) * | 2007-12-21 | 2010-07-16 | (주)이지아이 | Safety rubber plate for children playground and construction method its |
| BRPI1006901A2 (en) | 2009-01-20 | 2016-02-16 | Transgène S A | ex vivo method and kit for testing if a patient will respond therapeutically to a treatment method, and use of sicam-1 levels in a blood sample |
| HUE026194T2 (en) | 2009-03-24 | 2016-05-30 | Transgene Sa | Biomarker for monitoring patients |
| RU2555340C2 (en) | 2009-04-17 | 2015-07-10 | Трансжене Са | Biomarker for patient monitoring |
| DK2452194T3 (en) | 2009-07-10 | 2015-11-30 | Transgene Sa | Biomarker PATIENT SELECTION AND RELATED PRACTICES |
| US9011874B2 (en) * | 2009-11-20 | 2015-04-21 | Takeda Vaccines, Inc. | Compositions, methods and uses for poxvirus elements in vaccine constructs |
| CA2793959C (en) | 2010-03-25 | 2019-06-04 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
| WO2012018856A2 (en) * | 2010-08-02 | 2012-02-09 | Virxsys Corporation | Hiv vaccine therapy with concomitant antiviral monotherapy |
| SI2691530T1 (en) | 2011-06-10 | 2018-08-31 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
| ES2813413T3 (en) | 2011-08-05 | 2021-03-23 | Sillajen Biotherapeutics Inc | Methods and compositions for the production of vaccina virus |
| US20130189754A1 (en) | 2011-09-12 | 2013-07-25 | International Aids Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing hiv-1 proteins by broadly neutralizing antibodies |
| EP2586461A1 (en) | 2011-10-27 | 2013-05-01 | Christopher L. Parks | Viral particles derived from an enveloped virus |
| ES2631608T3 (en) | 2012-06-27 | 2017-09-01 | International Aids Vaccine Initiative | Env-glycoprotein variant of HIV-1 |
| WO2014043535A1 (en) | 2012-09-14 | 2014-03-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compositions for the treatment of cancer |
| AU2013331328B2 (en) | 2012-10-19 | 2018-05-31 | Bavarian Nordic A/S | Methods and compositions for the treatment of cancer |
| SG10201707340XA (en) * | 2013-03-15 | 2017-10-30 | Bavarian Nordic As | Single high dose of mva induces a protective immune response in neonates and infants |
| EP2848937A1 (en) | 2013-09-05 | 2015-03-18 | International Aids Vaccine Initiative | Methods of identifying novel HIV-1 immunogens |
| US10058604B2 (en) | 2013-10-07 | 2018-08-28 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
| US10801070B2 (en) | 2013-11-25 | 2020-10-13 | The Broad Institute, Inc. | Compositions and methods for diagnosing, evaluating and treating cancer |
| WO2015085147A1 (en) | 2013-12-05 | 2015-06-11 | The Broad Institute Inc. | Polymorphic gene typing and somatic change detection using sequencing data |
| WO2015095811A2 (en) | 2013-12-20 | 2015-06-25 | The Board Institute Inc. | Combination therapy with neoantigen vaccine |
| KR101645642B1 (en) | 2014-10-16 | 2016-08-11 | 대한민국 | Kvac recombinant vaccinia virus derived from kvac strain |
| KR101623498B1 (en) | 2014-10-16 | 2016-05-24 | 대한민국 | Kvacattenuated vaccinia virus kvac strain |
| WO2016100975A1 (en) | 2014-12-19 | 2016-06-23 | Massachsetts Institute Ot Technology | Molecular biomarkers for cancer immunotherapy |
| WO2016100977A1 (en) | 2014-12-19 | 2016-06-23 | The Broad Institute Inc. | Methods for profiling the t-cel- receptor repertoire |
| EP3261669B1 (en) | 2015-02-25 | 2022-08-03 | Memorial Sloan Kettering Cancer Center | Use of inactivated nonreplicating modified vaccinia virus ankara (mva)as monoimmunotherapy or in combination with immune checkpoint blocking agents for solid tumors |
| US10174292B2 (en) | 2015-03-20 | 2019-01-08 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
| EP3072901A1 (en) | 2015-03-23 | 2016-09-28 | International Aids Vaccine Initiative | Soluble hiv-1 envelope glycoprotein trimers |
| KR20180006916A (en) | 2015-04-17 | 2018-01-19 | 메모리얼 슬로안-케터링 캔서 센터 | Use of MVA or MVA delta E3L as an immunotherapeutic agent for solid tumors |
| MX2017014700A (en) | 2015-05-20 | 2018-08-15 | Broad Inst Inc | Shared neoantigens. |
| TW202241500A (en) | 2015-06-09 | 2022-11-01 | 美商博德研究所有限公司 | Formulations for neoplasia vaccines and methods of preparing thereof |
| US9925258B2 (en) | 2015-10-02 | 2018-03-27 | International Aids Vaccine Initiative | Replication-competent VSV-HIV Env vaccines |
| CN106591361A (en) * | 2015-10-20 | 2017-04-26 | 钱文斌 | Recombinant pox oncolytic virus, and construction method and application thereof |
| AU2017222687B2 (en) | 2016-02-25 | 2022-02-24 | Memorial Sloan Kettering Cancer Center | Recombinant MVA or MVADELE3L expressing human Flt3L and use thereof as immuno-therapeutic agents against solid tumors |
| CN116440176A (en) | 2016-02-25 | 2023-07-18 | 纪念斯隆凯特琳癌症中心 | Replication-competent attenuated vaccinia virus with thymidine kinase deficiency and with or without human FLT3L or GM-CSF expression |
| WO2017184590A1 (en) | 2016-04-18 | 2017-10-26 | The Broad Institute Inc. | Improved hla epitope prediction |
| US11549149B2 (en) | 2017-01-24 | 2023-01-10 | The Broad Institute, Inc. | Compositions and methods for detecting a mutant variant of a polynucleotide |
| US11242509B2 (en) | 2017-05-12 | 2022-02-08 | Memorial Sloan Kettering Cancer Center | Vaccinia virus mutants useful for cancer immunotherapy |
| WO2020014658A1 (en) * | 2018-07-13 | 2020-01-16 | University Of Georgia Research Foundation | Broadly reactive immunogens of dengue virus, compositions, and methods of use thereof |
| WO2020072700A1 (en) | 2018-10-02 | 2020-04-09 | Dana-Farber Cancer Institute, Inc. | Hla single allele lines |
| WO2020131586A2 (en) | 2018-12-17 | 2020-06-25 | The Broad Institute, Inc. | Methods for identifying neoantigens |
| TW202043256A (en) | 2019-01-10 | 2020-12-01 | 美商健生生物科技公司 | Prostate neoantigens and their uses |
| US20220305120A1 (en) | 2019-06-11 | 2022-09-29 | Glaxosmithkline Biologicals Sa | Mucosal vaccine formulations |
| WO2024015892A1 (en) | 2022-07-13 | 2024-01-18 | The Broad Institute, Inc. | Hla-ii immunopeptidome methods and systems for antigen discovery |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1335987B1 (en) | 2000-11-23 | 2005-12-28 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant |
Family Cites Families (70)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072565A (en) * | 1974-11-04 | 1978-02-07 | The Dow Chemical Company | Production of viruses in tissue culture without use of serum |
| US3914408A (en) * | 1973-10-12 | 1975-10-21 | Univ Nebraska | Vaccine for neonatal calf diarrhea |
| DE2714665A1 (en) * | 1977-04-01 | 1978-10-05 | Mayr Anton | PREPARATION FOR TREATING HERPES ZOSTER AND OTHER HERPES INFECTIONS AND METHOD FOR THE PRODUCTION THEREOF |
| US5155020A (en) * | 1989-03-08 | 1992-10-13 | Health Research Inc. | Recombinant poxvirus host range selection system |
| US5338683A (en) | 1981-12-24 | 1994-08-16 | Health Research Incorporated | Vaccinia virus containing DNA sequences encoding herpesvirus glycoproteins |
| GB8322414D0 (en) * | 1983-08-19 | 1983-09-21 | Szelke M | Renin inhibitors |
| FR2603040B1 (en) | 1986-08-22 | 1990-01-26 | Transgene Sa | PROTEIN, DNA SEQUENCE, POXVIRUSES, CELLS AND THEIR CULTURE PROCESS, AS WELL AS THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, USEFUL IN THE PREVENTION OF SCHISTOSOMOSIS |
| AU613583B2 (en) | 1986-08-22 | 1991-08-08 | Transgene S.A. | Proteins and the method for preparing them, DNA sequences, antibodies and their application, poxviruses, transformed or infected cells, pharmaceutical compositions which are useful in the prevention of schistosomiasis and application by way of an agent possessing glutathione s-transferase activity |
| DE3743298A1 (en) | 1987-12-19 | 1989-06-29 | Wilkinson Sword Gmbh | SHAVING APPARATUS AND METHOD FOR PRODUCING A LAYER OF LOW FRICTION RESISTANCE ON A SHAVING APPARATUS |
| CA1341245C (en) | 1988-01-12 | 2001-06-05 | F. Hoffmann-La Roche Ag | Recombinant vaccinia virus mva |
| US6248333B1 (en) * | 1990-04-04 | 2001-06-19 | Health Research Inc. | Isolated nucleic acid sequence of equine herpesvirus type 1 glycoprotein D (EHV-1 gD) |
| JPH06500918A (en) | 1990-09-25 | 1994-01-27 | スミスクライン・ビーチャム・コーポレイション | Mammalian cell culture medium |
| US5843456A (en) * | 1991-03-07 | 1998-12-01 | Virogenetics Corporation | Alvac poxvirus-rabies compositions and combination compositions and uses |
| EP0575491B1 (en) * | 1991-03-07 | 2003-08-13 | Virogenetics Corporation | Genetically engineered vaccine strain |
| US5403582A (en) | 1993-01-21 | 1995-04-04 | Nippon Zeon Co., Ltd. | Vaccine comprising fowlpox virus recombinants expressing the envelope glycoprotein of an avian reticuloendotheliosis retrovirus |
| US5405772A (en) | 1993-06-18 | 1995-04-11 | Amgen Inc. | Medium for long-term proliferation and development of cells |
| US6015686A (en) * | 1993-09-15 | 2000-01-18 | Chiron Viagene, Inc. | Eukaryotic layered vector initiation systems |
| US5490794A (en) * | 1993-11-05 | 1996-02-13 | Sumitomo Wiring Systems, Ltd. | Branch joint box |
| US6190655B1 (en) | 1993-12-03 | 2001-02-20 | Immunex Corporation | Methods of using Flt-3 ligand for exogenous gene transfer |
| DE4405841C1 (en) † | 1994-02-23 | 1995-01-05 | Mayr Anton Prof Dr Med Vet Dr | Multipotent non-specific immunity inducers based on combinations of poxvirus components, processes for their preparation and their use as pharmaceuticals |
| WO1995030018A2 (en) * | 1994-04-29 | 1995-11-09 | Immuno Aktiengesellschaft | Recombinant poxviruses with foreign polynucleotides in essential regions |
| NZ290089A (en) * | 1994-07-27 | 1999-05-28 | Queensland Inst Med Res | Recombinant polyepitope cytotoxic t lymphocyte (ctl) vaccines |
| US5676950A (en) * | 1994-10-28 | 1997-10-14 | University Of Florida | Enterically administered recombinant poxvirus vaccines |
| US5756341A (en) | 1994-11-10 | 1998-05-26 | Immuno Ag | Method for controlling the infectivity of viruses |
| US5753489A (en) | 1994-11-10 | 1998-05-19 | Immuno Ag | Method for producing viruses and vaccines in serum-free culture |
| US5566011A (en) * | 1994-12-08 | 1996-10-15 | Luncent Technologies Inc. | Antiflector black matrix having successively a chromium oxide layer, a molybdenum layer and a second chromium oxide layer |
| UA68327C2 (en) * | 1995-07-04 | 2004-08-16 | Gsf Forschungszentrum Fur Unwe | A recombinant mva virus, an isolated eukaryotic cell, infected with recombinant mva virus, a method for production in vitro of polypeptides with use of said cell, a method for production in vitro of virus parts (variants), vaccine containing the recombinant mva virus, a method for immunization of animals |
| NZ331369A (en) | 1996-02-21 | 2001-04-27 | Franco Lori | Use of a genetic construct that directs virus expression in a lymphoid organ or a transduced cell thereof for genetic immunization |
| WO1998004680A1 (en) | 1996-07-26 | 1998-02-05 | University Of Manitoba | Serum-free medium for growth of anchorage-dependant mammalian cells |
| US6869793B2 (en) * | 1996-09-24 | 2005-03-22 | Bavarian Nordic Research Institute | Recombinant MVA virus expressing dengue virus antigens, and the use thereof in vaccines |
| WO1998017283A1 (en) | 1996-10-25 | 1998-04-30 | The Wistar Institute Of Anatomy & Biology | Method of vaccinating infants against infections |
| US6204250B1 (en) * | 1996-11-22 | 2001-03-20 | The Mount Sinai Medical Center Of The City Of New York | Immunization of infants |
| WO2000029428A2 (en) | 1998-11-18 | 2000-05-25 | Oxford Biomedica (Uk) Limited | 5t4 tumour-associated antigen for use in tumour immunotherapy |
| US20030138454A1 (en) * | 1997-06-09 | 2003-07-24 | Oxxon Pharmaccines, Ltd. | Vaccination method |
| GB0023203D0 (en) | 2000-09-21 | 2000-11-01 | Isis Innovation | Vaccination method |
| GB9711957D0 (en) * | 1997-06-09 | 1997-08-06 | Isis Innovation | Methods and reagents for vaccination |
| DE19729279A1 (en) † | 1997-07-09 | 1999-01-14 | Peter Hildebrandt | Urological implant, in particular vascular wall support for the urinal tract |
| AU3910097A (en) † | 1997-08-05 | 1999-03-01 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Live recombinant vaccine comprising inefficiently or non-replicating vir us |
| US6667176B1 (en) * | 2000-01-11 | 2003-12-23 | Geron Corporation | cDNA libraries reflecting gene expression during growth and differentiation of human pluripotent stem cells |
| AU776865B2 (en) | 1998-11-10 | 2004-09-23 | University Of Rochester | T cells specific for target antigens and methods and vaccines based thereon |
| GB2370573A (en) | 1998-11-18 | 2002-07-03 | Oxford Biomedica Ltd | Poxviral vectors |
| US6173813B1 (en) | 1998-12-23 | 2001-01-16 | Otis Elevator Company | Electronic control for an elevator braking system |
| US6497883B1 (en) | 1999-06-10 | 2002-12-24 | Merial | Porcine circovirus recombinant poxvirus vaccine |
| EP2388015A1 (en) * | 2000-03-02 | 2011-11-23 | Emory University | DNA expression vectors and methods of use |
| PL205922B1 (en) | 2000-03-14 | 2010-06-30 | Bavarian Nordic As | Altered strain of the modified vaccinia virus ankara (mva) |
| KR100341030B1 (en) | 2000-03-16 | 2002-06-20 | 유태욱 | method for replaying caption data and audio data and a display device using the same |
| CN1443076A (en) | 2000-05-24 | 2003-09-17 | 梅瑞尔公司 | Porcine reproductive and respiratory syndrome virus (PRRSV) recombinant avipoxvirus vaccine |
| DE50109630D1 (en) * | 2000-07-11 | 2006-06-01 | Bayer Healthcare Ag | USE OF PARAPOXVIRUS OVIS STRAINS FOR THE MANUFACTURE OF ANTIVIRAL MEDICINAL PRODUCTS AND MEDICINAL PRODUCTS AGAINST CANCER |
| US6733993B2 (en) * | 2000-09-15 | 2004-05-11 | Merck & Co., Inc. | Enhanced first generation adenovirus vaccines expressing codon optimized HIV1-gag, pol, nef and modifications |
| US7445924B2 (en) * | 2000-11-23 | 2008-11-04 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant and cultivation method |
| US7097842B2 (en) * | 2000-11-23 | 2006-08-29 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7628980B2 (en) * | 2000-11-23 | 2009-12-08 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| UA82466C2 (en) * | 2001-07-18 | 2008-04-25 | Бавариан Нордика А/С | Method for intensification of chordopoxvirus amplification |
| EP2345665A3 (en) * | 2001-12-04 | 2012-02-15 | Bavarian Nordic A/S | Flavivirus NS1 subunit vaccine |
| HU227507B1 (en) | 2001-12-20 | 2011-07-28 | Bavarian Nordic As | Method for the recovery and purification of poxviruses from infected cells |
| WO2003078640A2 (en) | 2002-03-15 | 2003-09-25 | Baxter International Inc. | Recombinant drug-sensitive vaccinia virus as smallpox vaccine |
| EP1420822B2 (en) * | 2002-04-19 | 2017-07-05 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| NZ536502A (en) * | 2002-05-16 | 2005-10-28 | Bavarian Nordic As | Recombinant poxvirus expressing homologous genes inserted into the poxviral genome for inducing an immune response in a mammal |
| PL372091A1 (en) * | 2002-05-16 | 2005-07-11 | Bavarian Nordic A/S | Expression of genes in modified vaccinia virus ankara by using the cowpox ati promoter |
| PL215169B1 (en) * | 2002-09-05 | 2013-10-31 | Bavarian Nordic As | Method for the cultivation of primary cells and for the amplification of viruses under serum free conditions |
| ATE365220T1 (en) * | 2002-11-25 | 2007-07-15 | Bavarian Nordic As | RECOMBINANT SMALLPOX VIRUS CONTAINING AT LEAST TWO ATI PROMOTERS |
| US6976752B2 (en) * | 2003-10-28 | 2005-12-20 | Lexmark International, Inc. | Ink jet printer with resistance compensation circuit |
| ATE471383T1 (en) * | 2003-11-24 | 2010-07-15 | Bavarian Nordic As | PROMOTORS FOR EXPRESSION IN MODIFIED VACCINIA VIRUS ANKARA |
| EP1586330A1 (en) * | 2004-04-16 | 2005-10-19 | Georg-August-Universität Göttingen | Vaccination against malignant melanoma |
| WO2006044716A2 (en) * | 2004-10-15 | 2006-04-27 | Washington University In St.Louis | CELL PERMEABLE NANOCONJUGATES OF SHELL-CROSSLINKED KNEDEL (SCK) AND PEPTIDE NUCLEIC ACIDS ('PNAs') WITH UNIQUELY EXPRESSED OR OVER-EXPRESSED mRNA TARGETING SEQUENCES FOR EARLY DIAGNOSIS AND THERAPY OF CANCER |
| EP1835031A1 (en) | 2006-03-14 | 2007-09-19 | Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe | Use of a recombinant modified vaccinia virus Ankara (MVA) for the treatment of type I hypersensitivity in a living animal including humans |
| ES2500465T3 (en) * | 2006-10-06 | 2014-09-30 | Bavarian Nordic Inc. | Recombinant modified Ankara vaccinia virus encoding HER-2 antigen in combination with a taxane for use in cancer treatment |
| EP1925318A1 (en) | 2006-11-20 | 2008-05-28 | Paul-Ehrlich-Institut | Recombinant modified vaccinia virus Ankara (MVA)-based vaccine for the avian flu |
| US8268327B2 (en) * | 2007-04-27 | 2012-09-18 | Bavarian Nordic A/S | Immediate protection against pathogens via MVA |
| EP2207564B1 (en) * | 2007-10-18 | 2016-10-05 | Bavarian Nordic A/S | Use of mva to treat prostate cancer |
-
2001
- 2001-11-22 IL IL15471201A patent/IL154712A0/en unknown
- 2001-11-22 UA UA2003054618A patent/UA76731C2/en unknown
- 2001-11-22 KR KR1020087007423A patent/KR100910297B1/en active IP Right Grant
- 2001-11-22 CN CNB018194109A patent/CN100537773C/en not_active Expired - Lifetime
- 2001-11-22 EP EP10158051A patent/EP2202315A1/en not_active Withdrawn
- 2001-11-22 SI SI200130512T patent/SI1335987T2/en unknown
- 2001-11-22 KR KR1020037006970A patent/KR100830295B1/en active IP Right Grant
- 2001-11-22 AU AU2002231639A patent/AU2002231639B2/en not_active Expired
- 2001-11-22 NZ NZ524661A patent/NZ524661A/en not_active IP Right Cessation
- 2001-11-22 MX MXPA03002513A patent/MXPA03002513A/en active IP Right Grant
- 2001-11-22 DE DE60116371.0T patent/DE60116371T3/en not_active Expired - Lifetime
- 2001-11-22 DK DK01991753.3T patent/DK1335987T4/en active
- 2001-11-22 HU HU0400685A patent/HU230198B1/en active Protection Beyond IP Right Term
- 2001-11-22 RU RU2003118436/13A patent/RU2290438C2/en active
- 2001-11-22 EE EEP200300173A patent/EE05680B1/en unknown
- 2001-11-22 CA CA2421151A patent/CA2421151C/en not_active Expired - Lifetime
- 2001-11-22 CN CN200910151102A patent/CN101676389A/en active Pending
- 2001-11-22 AU AU3163902A patent/AU3163902A/en active Pending
- 2001-11-22 EP EP01991753.3A patent/EP1335987B2/en not_active Expired - Lifetime
- 2001-11-22 ES ES01991753.3T patent/ES2256323T5/en not_active Expired - Lifetime
- 2001-11-22 DE DE20122302U patent/DE20122302U1/en not_active Expired - Lifetime
- 2001-11-22 EP EP05017694A patent/EP1598425A1/en not_active Withdrawn
- 2001-11-22 CZ CZ20031366A patent/CZ295808B6/en not_active IP Right Cessation
- 2001-11-22 JP JP2002545184A patent/JP4421188B2/en not_active Expired - Lifetime
- 2001-11-22 KR KR1020097010451A patent/KR20090057335A/en not_active Application Discontinuation
- 2001-11-22 BR BRPI0115533A patent/BRPI0115533B8/en not_active IP Right Cessation
- 2001-11-22 WO PCT/EP2001/013628 patent/WO2002042480A2/en active Application Filing
- 2001-11-22 PL PL361459A patent/PL212047B1/en unknown
- 2001-11-22 EP EP10158053A patent/EP2204452A1/en not_active Withdrawn
- 2001-11-22 AT AT01991753T patent/ATE314483T2/en active
- 2001-11-22 PT PT01991753T patent/PT1335987E/en unknown
-
2003
- 2003-03-03 IL IL154712A patent/IL154712A/en active IP Right Grant
- 2003-05-16 US US10/439,439 patent/US6913752B2/en not_active Expired - Lifetime
- 2003-05-16 US US10/440,073 patent/US7189536B2/en not_active Expired - Lifetime
- 2003-05-16 US US10/439,953 patent/US6761893B2/en not_active Expired - Lifetime
- 2003-05-21 NO NO20032309A patent/NO337867B1/en not_active IP Right Cessation
-
2004
- 2004-03-31 HK HK04102348.1A patent/HK1059453A1/en not_active IP Right Cessation
-
2005
- 2005-08-05 US US11/198,557 patent/US7384644B2/en not_active Expired - Lifetime
-
2006
- 2006-03-27 CY CY20061100421T patent/CY1105594T1/en unknown
- 2006-08-23 US US11/508,797 patent/US7335364B2/en not_active Expired - Lifetime
-
2007
- 2007-10-26 US US11/977,808 patent/US7923017B2/en not_active Expired - Fee Related
- 2007-12-04 US US11/999,127 patent/US7459270B2/en not_active Expired - Lifetime
-
2009
- 2009-05-22 US US12/471,144 patent/US7939086B2/en not_active Expired - Lifetime
-
2011
- 2011-03-22 US US13/053,450 patent/US8268329B2/en not_active Expired - Lifetime
- 2011-03-22 US US13/053,361 patent/US8268325B2/en not_active Expired - Lifetime
-
2012
- 2012-08-17 US US13/588,217 patent/US20120328650A1/en not_active Abandoned
-
2013
- 2013-11-20 LU LU92311C patent/LU92311I2/en unknown
- 2013-11-21 BE BE2013C065C patent/BE2013C065I2/fr unknown
- 2013-12-13 FR FR13C0070C patent/FR13C0070I2/en active Active
- 2013-12-23 CY CY2013048C patent/CY2013048I2/en unknown
-
2016
- 2016-02-29 HU HUS1600010C patent/HUS1600010I1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1335987B1 (en) | 2000-11-23 | 2005-12-28 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant |
Non-Patent Citations (1)
| Title |
|---|
| SUTER, M.; C. MEISINGER-HENSCHEL; M. TZATZARIS; V. HULSEMANN; S. LUKASSEN; N. H. WULFF; J. HAUSMANN; P. HOWLEY; P. CHAPLIN: "Modified vaccinia Ankara strains with identical coding sequences actually represent complex mixtures of viruses that determine the biological properties of each strain", VACCINE, vol. 27, 2009, pages 7442 - 50 |
Cited By (180)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7445924B2 (en) | 2000-11-23 | 2008-11-04 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant and cultivation method |
| US7964395B2 (en) | 2000-11-23 | 2011-06-21 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant and cultivation method |
| US7628980B2 (en) | 2000-11-23 | 2009-12-08 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7892533B2 (en) | 2000-11-23 | 2011-02-22 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US8372622B2 (en) | 2000-11-23 | 2013-02-12 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7459270B2 (en) | 2000-11-23 | 2008-12-02 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant |
| US8236560B2 (en) | 2000-11-23 | 2012-08-07 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant and cultivation method |
| US7097842B2 (en) | 2000-11-23 | 2006-08-29 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7964398B2 (en) | 2000-11-23 | 2011-06-21 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant and cultivation method |
| US7189536B2 (en) | 2000-11-23 | 2007-03-13 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant |
| US8163293B2 (en) | 2000-11-23 | 2012-04-24 | Bavarian Nordic A/S | Modified Vaccinia Virus Ankara for the vaccination of neonates |
| US8470598B2 (en) | 2000-11-23 | 2013-06-25 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant and cultivation method |
| US7964396B2 (en) | 2000-11-23 | 2011-06-21 | Bavarian Nordic A/S | Modified vaccinia ankara virus variant and cultivation method |
| US7335364B2 (en) | 2000-11-23 | 2008-02-26 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant |
| US7897156B2 (en) | 2001-11-22 | 2011-03-01 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US8815501B2 (en) | 2001-12-04 | 2014-08-26 | Bavarian Nordic A/S | Flavivirus NS1 subunit vaccine |
| WO2003048184A3 (en) * | 2001-12-04 | 2004-01-29 | Bavarian Nordic As | Flavivirus ns1 subunit vaccine |
| WO2003048184A2 (en) * | 2001-12-04 | 2003-06-12 | Bavarian Nordic A/S | Flavivirus ns1 subunit vaccine |
| EP2345665A3 (en) * | 2001-12-04 | 2012-02-15 | Bavarian Nordic A/S | Flavivirus NS1 subunit vaccine |
| JP2005511042A (en) * | 2001-12-04 | 2005-04-28 | バヴァリアン・ノルディック・アクティーゼルスカブ | Flavivirus NS1 subunit vaccine |
| US7759116B2 (en) | 2001-12-04 | 2010-07-20 | Bavarian Nordic A/S | MVA virus vector expressing dengue NS1 protein |
| EP2345665A2 (en) | 2001-12-04 | 2011-07-20 | Bavarian Nordic A/S | Flavivirus NS1 subunit vaccine |
| EP1839672A3 (en) * | 2002-04-19 | 2007-11-21 | Bavarian Nordic A/S | Modified vaccinia virus Ankara for the vaccination of neonates |
| AU2003239805B2 (en) * | 2002-04-19 | 2009-09-10 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| EA011233B1 (en) * | 2002-04-19 | 2009-02-27 | Бавариан Нордик А/С | Use of modified vaccina virus ankara for the vaccination of neonates |
| WO2003088994A2 (en) * | 2002-04-19 | 2003-10-30 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| EP2204179A3 (en) * | 2002-04-19 | 2010-12-22 | Bavarian Nordic A/S | Modified Vaccinia Virus Ankara for the vaccination of neonates |
| EP2204180A3 (en) * | 2002-04-19 | 2010-12-22 | Bavarian Nordic A/S | Modified Vaccinia Virus Ankara for the vaccination of neonates |
| EP2204180A2 (en) | 2002-04-19 | 2010-07-07 | Bavarian Nordic A/S | Modified Vaccinia Virus Ankara for the vaccination of neonates |
| EP2204179A2 (en) | 2002-04-19 | 2010-07-07 | Bavarian Nordic A/S | Modified Vaccinia Virus Ankara for the vaccination of neonates |
| WO2003088994A3 (en) * | 2002-04-19 | 2004-02-19 | Bavarian Nordic As | Modified vaccinia virus ankara for the vaccination of neonates |
| US7501127B2 (en) | 2002-05-16 | 2009-03-10 | Bavarian Nordic A/S | Intergenic regions as novel sites for insertion of HIV DNA sequences in the genome of Modified Vaccinia virus Ankara |
| US8198088B2 (en) | 2002-05-16 | 2012-06-12 | Bavarian Nordic A/S | Method for introducing human immunodeficiency virus nucleotide sequences into a cell utilizing modified vaccinia virus Ankara (MVA) recombinants comprising HIV genes inserted into one or more intergenic regions (IGRs) |
| EP2253709A1 (en) | 2002-05-16 | 2010-11-24 | Bavarian Nordic A/S | Recombinant poxvirus expressing homologous genes inserted into the poxviral genome |
| US8197822B2 (en) | 2002-05-16 | 2012-06-12 | Bavarian Nordic A/S | Method for the production of human immunodeficiency virus (HIV) proteins utilizing modified vaccinia virus ankara (MVA) recombinants comprising HIV genes inserted into one or more intergenic regions (IGRs) |
| US8029800B2 (en) | 2002-05-16 | 2011-10-04 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (MVA) comprising human immunodeficiency virus (HIV) genes inserted into one or more intergenic regions (IGRs) |
| AU2003240243B2 (en) * | 2002-05-16 | 2009-01-22 | Bavarian Nordic A/S | Expression of genes in modified vaccinia virus Ankara by using the cowpox ATI promoter |
| US8309098B2 (en) | 2002-05-16 | 2012-11-13 | Bavarian Nordic A/S | Recombinant modified vaccinia ankara (MVA) virus containing heterologous DNA inserts encoding human immunodeficiency virus (HIV) antigens inserted into one or more intergenic regions (IGRs) |
| US8323661B2 (en) | 2002-05-16 | 2012-12-04 | Bavarian Nordic A/S | Method for generating a stable recombinant modified vaccinia virus ankara (MVA) comprising human immunodeficiency virus (HIV) genes inserted into one or more intergenic regions (IGRs) |
| WO2003097846A1 (en) | 2002-05-16 | 2003-11-27 | Bavarian Nordic A/S | Recombinant poxvirus expressing homologous genes inserted into the poxviral genome |
| US7695939B2 (en) | 2002-09-05 | 2010-04-13 | Bavarian Nordic A/S | Method for the cultivation of primary cells and for the amplification of viruses under serum free conditions |
| US8329466B2 (en) | 2002-09-05 | 2012-12-11 | Bavarian Nordic A/S | Method for the cultivation of primary cells and for the amplification of viruses under serum free conditions |
| US7964397B2 (en) | 2002-09-05 | 2011-06-21 | Bavarian Nordic A/S | Method for the cultivation of primary cells and for the amplification of viruses under serum free conditions |
| US8673318B2 (en) | 2002-09-05 | 2014-03-18 | Bavarian Nordic A/S | Method for the cultivation of primary cells and for the amplification of viruses under serum free conditions |
| EA012846B1 (en) * | 2003-11-24 | 2009-12-30 | Бавариан Нордик А/С | Promoter for expression of genes in vaccinia viruses and/or in vaccinia virus infected cells, and methods for use of the promoter |
| EP1956094A1 (en) * | 2003-11-24 | 2008-08-13 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus ankara |
| EP1536015A1 (en) * | 2003-11-24 | 2005-06-01 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus ankara |
| WO2005054484A1 (en) * | 2003-11-24 | 2005-06-16 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus ankara |
| US7816508B2 (en) | 2003-11-24 | 2010-10-19 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus Ankara |
| EP1845164A2 (en) * | 2003-11-24 | 2007-10-17 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus ankara |
| EP1845164A3 (en) * | 2003-11-24 | 2008-03-19 | Bavarian Nordic A/S | Promoters for expression in modified vaccinia virus ankara |
| EP1835031A1 (en) | 2006-03-14 | 2007-09-19 | Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe | Use of a recombinant modified vaccinia virus Ankara (MVA) for the treatment of type I hypersensitivity in a living animal including humans |
| WO2008028665A1 (en) * | 2006-09-08 | 2008-03-13 | Bavarian Nordic A/S | Phenotypic and genotypic differences of mva strains |
| US8961998B2 (en) | 2007-04-27 | 2015-02-24 | Bavarian Nordic A/S | Immediate protection against pathogens via MVA |
| US8268327B2 (en) | 2007-04-27 | 2012-09-18 | Bavarian Nordic A/S | Immediate protection against pathogens via MVA |
| WO2008131927A1 (en) * | 2007-04-27 | 2008-11-06 | Bavarian Nordic A/S | Immediate protection against pathogens via mva |
| US8268328B2 (en) | 2007-04-27 | 2012-09-18 | Bavarian Nordic A/S | Immediate protection against pathogens via MVA |
| WO2009152969A1 (en) * | 2008-06-20 | 2009-12-23 | Bavarian Nordic A/S | Recombinant modified vaccinia virus measles vaccine |
| WO2010102822A1 (en) | 2009-03-13 | 2010-09-16 | Bavarian Nordic A/S | Optimized early-late promoter combined with repeated vaccination favors cytotoxic t cell response against antigens in replication deficient recombinant virus vaccines |
| EP3456349A1 (en) | 2009-03-13 | 2019-03-20 | Bavarian Nordic A/S | Optimized early-late promoter combined with repeated vaccination favors cytotoxic t cell response against recombinant antigen in mva vaccines |
| US8394385B2 (en) | 2009-03-13 | 2013-03-12 | Bavarian Nordic A/S | Optimized early-late promoter combined with repeated vaccination favors cytotoxic T cell response against recombinant antigen in MVA vaccines |
| US8613936B2 (en) | 2009-03-13 | 2013-12-24 | Bavarian Nordic A/S | Replication deficient recombinant viruses expressing antigens regulated by transcriptional control elements comprising multiple elements |
| US9163237B2 (en) | 2009-03-13 | 2015-10-20 | Bavarian Nordic A/S | Replication deficient recombinant viruses expressing antigens regulated by transcriptional control elements comprising multiple elements |
| WO2011042180A1 (en) | 2009-10-08 | 2011-04-14 | Bavarian Nordic A/S | Generation of a broad t-cell response in humans against hiv |
| WO2011092029A1 (en) | 2010-01-28 | 2011-08-04 | Bavarian Nordic A/S | Vaccinia virus mutants containing the major genomic deletions of mva |
| WO2012010280A1 (en) | 2010-07-20 | 2012-01-26 | Bavarian Nordic A/S | Method for harvesting expression products |
| WO2012048817A2 (en) | 2010-10-15 | 2012-04-19 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara influenza vaccine |
| WO2012048817A3 (en) * | 2010-10-15 | 2012-09-13 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) influenza vaccine |
| AU2011316164B2 (en) * | 2010-10-15 | 2016-01-14 | Bavarian Nordic A/S | Recombinant modified vaccinia virus Ankara (MVA) influenza vaccine |
| US9173933B2 (en) | 2010-10-15 | 2015-11-03 | Bavarian Nordic A/S | Recombinant modified vaccinia virus Ankara influenza vaccine |
| WO2013083254A1 (en) | 2011-12-09 | 2013-06-13 | Bavarian Nordic A/S | Poxvirus vector for the expression of bacterial antigens linked to tetanus toxin fragment c |
| US9988425B2 (en) | 2012-01-27 | 2018-06-05 | Laboratories Del Dr. Esteve S.A. | Immunogens for HIV vaccination |
| EP2620446A1 (en) | 2012-01-27 | 2013-07-31 | Laboratorios Del Dr. Esteve, S.A. | Immunogens for HIV vaccination |
| US11325946B2 (en) | 2012-01-27 | 2022-05-10 | Laboratorios Del Dr. Esteve S.A. | Method of treating HIV-1 infection utilizing a multiepitope T cell immunogen comprising gag, pol, vif and nef epitopes |
| EP4163290A1 (en) | 2012-01-27 | 2023-04-12 | Esteve Pharmaceuticals, S.A. | Immunogens for hiv vaccination |
| WO2013110818A2 (en) | 2012-01-27 | 2013-08-01 | Laboratorios Del Dr. Esteve, S.A. | Immunogens for hiv vaccination |
| US10815278B2 (en) | 2012-01-27 | 2020-10-27 | Laboratorios Del Dr. Esteve S.A. | Immunogens for HIV vaccination |
| US11919926B2 (en) | 2012-01-27 | 2024-03-05 | Esteve Pharmaceuticals, S.A. | Method of treating HIV-1 infection utilizing a multiepitope T cell immunogen comprising Gag, Pol, Vif, and Nef epitopes |
| WO2013189611A1 (en) | 2012-06-22 | 2013-12-27 | Bavarian Nordic A/S | Poxviral vectors for low antibody response after a first priming immunization |
| WO2014009433A1 (en) | 2012-07-10 | 2014-01-16 | Transgene Sa | Mycobacterium resuscitation promoting factor for use as adjuvant |
| WO2014009438A2 (en) | 2012-07-10 | 2014-01-16 | Transgene Sa | Mycobacterial antigen vaccine |
| EP3656396A1 (en) | 2012-08-01 | 2020-05-27 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) respiratory syncytial virus (rsv) vaccine |
| WO2014019718A1 (en) | 2012-08-01 | 2014-02-06 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) respiratory syncytial virus (rsv) vaccine |
| WO2014037124A1 (en) | 2012-09-04 | 2014-03-13 | Bavarian Nordic A/S | Methods and compositions for enhancing vaccine immune responses |
| EP3639851A1 (en) | 2012-09-04 | 2020-04-22 | Bavarian Nordic A/S | Methods and compositions for enhancing vaccine immune responses |
| EP3778904A1 (en) | 2012-10-28 | 2021-02-17 | Bavarian Nordic A/S | Pr13.5 promoter for robust t-cell and antibody responses |
| EP3412304A2 (en) | 2013-10-23 | 2018-12-12 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Hla-a24 agonist epitopes of muc1-c oncoprotein and compositions and methods of use |
| WO2015061416A2 (en) | 2013-10-23 | 2015-04-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hla-a24 agonist epitopes of muc1-c oncoprotein and compositions and methods of use |
| EP3971298A2 (en) | 2013-11-28 | 2022-03-23 | Bavarian Nordic A/S | Compositions and methods for inducing an enhanced immune response using poxvirus vectors |
| WO2015078856A1 (en) | 2013-11-28 | 2015-06-04 | Bavarian Nordic A/S | Compositions and methods vectors for inducing an enhanced immune response using poxvirus vectors |
| WO2015104380A1 (en) | 2014-01-09 | 2015-07-16 | Transgene Sa | Fusion of heterooligomeric mycobacterial antigens |
| WO2015175340A1 (en) | 2014-05-13 | 2015-11-19 | Bavarian Nordic, Inc. | Combination therapy for treating cancer with a poxvirus expressing a tumor antigen and a monoclonal antibody against tim-3 |
| EP3888676A1 (en) | 2014-06-13 | 2021-10-06 | GlaxoSmithKline Biologicals S.A. | Immunogenic combinations |
| EP3656395A1 (en) | 2014-09-03 | 2020-05-27 | Bavarian Nordic A/S | Methods and compositions for inducing protective immunity against filovirus infection |
| US11918639B2 (en) | 2014-09-03 | 2024-03-05 | Bavarian Nordic A/S | Methods and compositions for inducing protective immunity against filovirus infection |
| US11173201B2 (en) | 2014-09-03 | 2021-11-16 | Bavarian Nordic A/S | Methods and compositions for inducing protective immunity against filovirus infection |
| US10561721B2 (en) | 2014-09-03 | 2020-02-18 | Bavarian Nordic A/S | Methods and compositions for inducing protective immunity against filovirus infection |
| US10561722B2 (en) | 2014-09-03 | 2020-02-18 | Bavarian Nordic A/S | Methods and compositions for enhancing immune responses |
| WO2016049287A1 (en) | 2014-09-26 | 2016-03-31 | Beth Israel Deaconess Medical Center, Inc. | Methods and compositions for inducing protective immunity against human immunodeficiency virus infection |
| US10137191B2 (en) | 2014-09-26 | 2018-11-27 | Janssen Vaccines & Prevention B.V. | Methods and compositions for inducing protective immunity against human immunodeficiency virus infection |
| EP3868398A1 (en) | 2014-09-26 | 2021-08-25 | Beth Israel Deaconess Medical Center, Inc. | Methods and compositions for inducing protective immunity against human immunodeficiency virus infection |
| US11207400B2 (en) | 2014-09-26 | 2021-12-28 | Janssen Vaccines & Prevention B.V. | Compositions and methods for inducing protective immunity against human immunodeficiency virus infection |
| US10471137B2 (en) | 2014-09-26 | 2019-11-12 | Janssen Vaccines & Prevention B.V. | Methods for inducing protective immunity against human immunodeficiency virus infection |
| US11040096B2 (en) | 2014-11-04 | 2021-06-22 | Janssen Vaccines & Prevention B.V. | Therapeutic HPV16 vaccines |
| US20180185466A1 (en) * | 2015-06-15 | 2018-07-05 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) foot and mouth disease virus (fmdv) vaccine |
| WO2016202828A1 (en) * | 2015-06-15 | 2016-12-22 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) foot and mouth disease virus (fmdv) vaccine |
| US11103570B2 (en) | 2015-06-15 | 2021-08-31 | Bavarian Nordic A/S | Recombinant modified vaccinia virus Ankara (MVA) foot and mouth disease virus (FMDV) vaccine |
| WO2017060650A1 (en) | 2015-10-08 | 2017-04-13 | Jean-Marc Limacher | Anti-tumoral composition |
| US10369214B2 (en) | 2015-12-15 | 2019-08-06 | Janssen Vaccines & Prevention B.V. | Synthetic human immunodeficiency virus (HIV) envelope antigen, vectors, and compositions thereof |
| US11896663B2 (en) | 2015-12-15 | 2024-02-13 | Janssen Vaccines & Prevention B.V. | Immunodeficiency virus type 1 (HIV-1) mutant envelope proteins |
| US10973907B2 (en) | 2015-12-15 | 2021-04-13 | Janssen Vaccines & Prevention B.V. | Recombinant adenoviruses encoding mosaic human immunodeficiency virus (HIV) Env, Gag, and Pol antigens |
| US10881725B2 (en) | 2016-01-29 | 2021-01-05 | Bavarian Nordic A/S | Recombinant modified vaccinia virus Ankara (MVA) equine encephalitis virus vaccine |
| WO2017129765A1 (en) | 2016-01-29 | 2017-08-03 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (mva) equine encephalitis virus vaccine |
| US11571471B2 (en) | 2016-01-29 | 2023-02-07 | Bavarian Nordic A/S | Recombinant modified vaccinia virus ankara (MVA) equine encephalitis virus vaccine |
| US11555205B2 (en) | 2016-04-13 | 2023-01-17 | Janssen Pharmaceuticals, Inc. | Recombinant arterivirus replicon systems and uses thereof |
| JP2019514943A (en) * | 2016-05-02 | 2019-06-06 | ヤンセン ファッシンズ アンド プリベンション ベーフェーＪａｎｓｓｅｎ Ｖａｃｃｉｎｅｓ ＆ Ｐｒｅｖｅｎｔｉｏｎ Ｂ．Ｖ． | Therapeutic HPV vaccine combination |
| WO2017192418A1 (en) | 2016-05-02 | 2017-11-09 | Janssen Vaccine & Prevention B.V. | Therapeutic hpv vaccine combinations |
| US11603389B2 (en) | 2016-06-16 | 2023-03-14 | Janssen Vaccines & Prevention B.V. | HIV vaccine formulation |
| US10273268B2 (en) | 2016-06-16 | 2019-04-30 | Janssen Vaccines & Prevention B.V. | HIV vaccine formulation |
| US10934328B2 (en) | 2016-06-16 | 2021-03-02 | Janssen Vaccines & Prevention B.V. | HIV vaccine formulation |
| US10925956B2 (en) | 2016-07-15 | 2021-02-23 | Janssen Vaccines & Prevention B.V. | Methods and compositions for inducing protective immunity against a marburg virus infection |
| WO2018011768A1 (en) | 2016-07-15 | 2018-01-18 | Janssen Vaccines And Prevention B.V. | Methods and compositions for inducing protective immunity against a marburg virus infection |
| US10525123B2 (en) | 2016-09-02 | 2020-01-07 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| WO2018045267A1 (en) | 2016-09-02 | 2018-03-08 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| US10307477B2 (en) | 2016-09-02 | 2019-06-04 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| US11820796B2 (en) | 2016-09-15 | 2023-11-21 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| US10793607B2 (en) | 2016-09-15 | 2020-10-06 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| US11365222B2 (en) | 2016-09-15 | 2022-06-21 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| WO2018060368A2 (en) | 2016-09-28 | 2018-04-05 | Bavarian Nordic A/S | Compositions and methods for enhancing the stability of transgenes in poxviruses |
| US11364310B2 (en) | 2016-10-17 | 2022-06-21 | Janssen Pharmaceuticals, Inc. | Recombinant virus replicon systems and uses thereof |
| WO2018085751A1 (en) | 2016-11-07 | 2018-05-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Development of agonist epitopes of the human papillomavirus |
| US11845939B2 (en) | 2016-12-05 | 2023-12-19 | Janssen Pharmaceuticals, Inc. | Compositions and methods for enhancing gene expression |
| WO2018185732A1 (en) | 2017-04-06 | 2018-10-11 | Janssen Vaccines & Prevention B.V. | Mva-bn and ad26.zebov or ad26.filo prime-boost regimen |
| US11173204B2 (en) | 2017-04-06 | 2021-11-16 | Janssen Vaccines & Prevention B.V. | MVA-BN and Ad26.ZEBOV or Ad26.filo prime-boost regimen |
| US11052147B2 (en) | 2017-05-15 | 2021-07-06 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
| WO2018210804A1 (en) | 2017-05-15 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
| US11306292B2 (en) | 2017-05-15 | 2022-04-19 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
| WO2018211419A1 (en) | 2017-05-15 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
| US11723970B2 (en) | 2017-06-15 | 2023-08-15 | Janssen Vaccines & Prevention B. V. | Poxvirus vectors encoding HIV antigens, and methods of use thereof |
| US11229693B2 (en) | 2017-06-15 | 2022-01-25 | Janssen Vaccines & Prevention B.V. | Poxvirus vectors encoding HIV antigens, and methods of use thereof |
| WO2018229711A1 (en) | 2017-06-15 | 2018-12-20 | Janssen Vaccines & Prevention B.V. | Poxvirus vectors encoding hiv antigens, and methods of use thereof |
| US10968254B2 (en) | 2017-07-19 | 2021-04-06 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| US11732010B2 (en) | 2017-07-19 | 2023-08-22 | Janssen Vaccines & Prevention B.V. | Trimer stabilizing HIV envelope protein mutations |
| WO2019018724A1 (en) | 2017-07-21 | 2019-01-24 | Janssen Vaccines & Prevention B.V. | Methods for safe induction of cross-clade immunity against human immunodeficiency virus infection in human |
| WO2019038388A1 (en) | 2017-08-24 | 2019-02-28 | Bavarian Nordic A/S | Combination therapy for treating cancer with an intravenous administration of a recombinant mva and an antibody |
| WO2019055888A1 (en) | 2017-09-18 | 2019-03-21 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| US11021692B2 (en) | 2017-12-19 | 2021-06-01 | Janssen Sciences Ireland Unlimited Company | Hepatitis B virus (HBV) vaccines and uses thereof |
| US11725194B2 (en) | 2017-12-19 | 2023-08-15 | Janssen Sciences Ireland Unlimited Company | Hepatitis B virus (HBV) vaccines and uses thereof |
| US11020476B2 (en) | 2017-12-19 | 2021-06-01 | Janssen Sciences Ireland Unlimited Company | Methods and compositions for inducing an immune response against Hepatitis B Virus (HBV) |
| WO2019123250A1 (en) | 2017-12-19 | 2019-06-27 | Janssen Sciences Ireland Unlimited Company | Methods and compositions for inducing an immune response against hepatitis b virus (hbv) |
| US11389531B2 (en) | 2017-12-19 | 2022-07-19 | Janssen Sciences Ireland Unlimited Company | Methods and apparatus for the delivery of hepatitis B virus (HBV) vaccines |
| WO2019123169A1 (en) | 2017-12-20 | 2019-06-27 | Glaxosmithkline Biologicals Sa | Epstein-barr virus antigen constructs |
| US11826416B2 (en) | 2018-01-19 | 2023-11-28 | Janssen Pharmaceuticals, Inc. | Induce and enhance immune responses using recombinant replicon systems |
| US11083786B2 (en) | 2018-01-19 | 2021-08-10 | Janssen Pharmaceuticals, Inc. | Induce and enhance immune responses using recombinant replicon systems |
| WO2020049151A1 (en) | 2018-09-06 | 2020-03-12 | Bavarian Nordic A/S | Storage improved poxvirus compositions |
| WO2020070303A1 (en) | 2018-10-05 | 2020-04-09 | Bavarian Nordic A/S | Combination therapy for treating cancer with an intravenous administration of a recombinant mva and an immune checkpoint antagonist or agonist |
| WO2020102404A1 (en) | 2018-11-14 | 2020-05-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tp5, a peptide inhibitor of aberrant and hyperactive cdk5/p25 as treatment for cancer |
| WO2020104531A1 (en) | 2018-11-20 | 2020-05-28 | Bavarian Nordic A/S | Therapy for treating cancer with an intratumoral and/or intravenous administration of a recombinant mva encoding 4-1bbl (cd137l) and/or cd40l |
| WO2020237052A1 (en) | 2019-05-22 | 2020-11-26 | Janssen Vaccines & Prevention B.V. | Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment |
| US11666651B2 (en) | 2019-11-14 | 2023-06-06 | Aelix Therapeutics, S.L. | Prime/boost immunization regimen against HIV-1 utilizing a multiepitope T cell immunogen comprising Gag, Pol, Vif, and Nef epitopes |
| WO2021099586A1 (en) | 2019-11-20 | 2021-05-27 | Bavarian Nordic A/S | Recombinant mva viruses for intratumoral and/or intravenous administration for treating cancer |
| WO2021099572A1 (en) | 2019-11-20 | 2021-05-27 | Bavarian Nordic A/S | Medical uses of 4-1bbl adjuvanted recombinant modified vaccinia virus ankara (mva) |
| WO2021150694A1 (en) | 2020-01-21 | 2021-07-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human immunogenic epitopes of hemo and hhla2 human endogenous retroviruses (hervs) |
| WO2021150713A2 (en) | 2020-01-21 | 2021-07-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human immunogenic epitopes of h, k, and e human endogenous retroviruses (hervs) |
| WO2021180943A1 (en) | 2020-03-12 | 2021-09-16 | Bavarian Nordic A/S | Compositions improving poxvirus stability |
| WO2021250219A1 (en) | 2020-06-10 | 2021-12-16 | Bavarian Nordic A/S | A recombinant modified vaccinia virus ankara (mva) vaccine against coronavirus disease |
| EP3928789A1 (en) | 2020-06-24 | 2021-12-29 | Consejo Superior de Investigaciones Científicas (CSIC) | Mva-based vaccine against covid-19 expressing sars-cov-2 antigens |
| WO2021260065A1 (en) | 2020-06-24 | 2021-12-30 | Consejo Superior De Investigaciones Científicas (Csic) | Mva-based vaccine against covid-19 expressing sars-cov-2 antigens |
| WO2022008613A1 (en) | 2020-07-08 | 2022-01-13 | Janssen Sciences Ireland Unlimited Company | Rna replicon vaccines against hbv |
| WO2022084333A1 (en) | 2020-10-20 | 2022-04-28 | Janssen Vaccines & Prevention B.V. | Hiv vaccine regimens |
| EP4108257A1 (en) | 2021-06-23 | 2022-12-28 | Consejo Superior De Investigaciones Científicas | Mva-based vaccine against covid-19 expressing a prefusion-stabilized sars-cov-2 s protein |
| WO2022269003A1 (en) | 2021-06-23 | 2022-12-29 | Consejo Superior De Investigaciones Cientificas | MVA-BASED VACCINE EXPRESSING A PREFUSION-STABILIZED SARS-CoV-2 S PROTEIN |
| WO2023031428A1 (en) | 2021-09-03 | 2023-03-09 | Bavarian Nordic A/S | Utilization of micro-rna for downregulation of cytotoxic transgene expression by modified vaccinia virus ankara (mva) |
| WO2023118508A1 (en) | 2021-12-23 | 2023-06-29 | Bavarian Nordic A/S | Recombinant mva viruses for intraperitoneal administration for treating cancer |
| WO2023118563A1 (en) | 2021-12-23 | 2023-06-29 | Bavarian Nordic A/S | Therapy for modulating immune response with recombinant mva encoding il-12 |
| WO2023198815A1 (en) | 2022-04-14 | 2023-10-19 | Janssen Vaccines & Prevention B.V. | Sequential administration of adenoviruses |
| WO2024003239A1 (en) | 2022-06-29 | 2024-01-04 | Bavarian Nordic A/S | RECOMBINANT MODIFIED saRNA (VRP) AND VACCINIA VIRUS ANKARA (MVA) PRIME-BOOST REGIMEN |
| WO2024003238A1 (en) | 2022-06-29 | 2024-01-04 | Bavarian Nordic A/S | Epstein-barr-virus vaccine |
| WO2024003346A1 (en) | 2022-06-30 | 2024-01-04 | Bavarian Nordic A/S | Mammalian cell line for the production of modified vaccinia virus ankara (mva) |
| EP4316514A1 (en) | 2022-08-03 | 2024-02-07 | Consejo Superior de Investigaciones Científicas (CSIC) | Mva-based vectors and their use as vaccine against sars-cov-2 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2421151C (en) | Modified vaccinia ankara virus variant | |
| AU2002231639A1 (en) | Modified vaccinia ankara virus variant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 2421151 Country of ref document: CA Ref document number: 154712 Country of ref document: IL |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2002231639 Country of ref document: AU |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1200300227 Country of ref document: VN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 291/MUMNP/2003 Country of ref document: IN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 524661 Country of ref document: NZ |
|
| WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/002513 Country of ref document: MX |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 10418854 Country of ref document: US |
|
| WWE | Wipo information: entry into national phase |
Ref document number: PV2003-1366 Country of ref document: CZ Ref document number: 10439953 Country of ref document: US Ref document number: 10440073 Country of ref document: US Ref document number: 10439439 Country of ref document: US |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2001991753 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2002545184 Country of ref document: JP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1020037006970 Country of ref document: KR Ref document number: 018194109 Country of ref document: CN |
|
| ENP | Entry into the national phase |
Ref document number: 2003118436 Country of ref document: RU Kind code of ref document: A Ref country code: RU Ref document number: RU A |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1-2003-500105 Country of ref document: PH |
|
| WWP | Wipo information: published in national office |
Ref document number: PV2003-1366 Country of ref document: CZ |
|
| WWP | Wipo information: published in national office |
Ref document number: 2001991753 Country of ref document: EP |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| WWP | Wipo information: published in national office |
Ref document number: 1020037006970 Country of ref document: KR |
|
| WWP | Wipo information: published in national office |
Ref document number: 524661 Country of ref document: NZ |
|
| WWG | Wipo information: grant in national office |
Ref document number: 524661 Country of ref document: NZ |
|
| WWG | Wipo information: grant in national office |
Ref document number: PV2003-1366 Country of ref document: CZ |
|
| WWG | Wipo information: grant in national office |
Ref document number: 2001991753 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 201642 Country of ref document: IL |