CZ20023642A3 - Geny virulence, proteiny a jejich použití - Google Patents
Geny virulence, proteiny a jejich použití Download PDFInfo
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- CZ20023642A3 CZ20023642A3 CZ20023642A CZ20023642A CZ20023642A3 CZ 20023642 A3 CZ20023642 A3 CZ 20023642A3 CZ 20023642 A CZ20023642 A CZ 20023642A CZ 20023642 A CZ20023642 A CZ 20023642A CZ 20023642 A3 CZ20023642 A3 CZ 20023642A3
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- 108090000623 proteins and genes Proteins 0.000 title claims abstract 7
- 102000004169 proteins and genes Human genes 0.000 title claims 2
- 230000001018 virulence Effects 0.000 title abstract 2
- 241000588650 Neisseria meningitidis Species 0.000 claims abstract 87
- 244000005700 microbiome Species 0.000 claims abstract 9
- 230000001225 therapeutic effect Effects 0.000 claims abstract 5
- 229960005486 vaccine Drugs 0.000 claims abstract 3
- 230000002238 attenuated effect Effects 0.000 claims abstract 2
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 241000282326 Felis catus Species 0.000 claims 132
- 108010050848 glycylleucine Proteins 0.000 claims 86
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 claims 69
- 108010047495 alanylglycine Proteins 0.000 claims 63
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 claims 62
- 108010005233 alanylglutamic acid Proteins 0.000 claims 57
- 108010034529 leucyl-lysine Proteins 0.000 claims 55
- 108020004414 DNA Proteins 0.000 claims 44
- 108010079364 N-glycylalanine Proteins 0.000 claims 44
- 108010025306 histidylleucine Proteins 0.000 claims 42
- 108010049041 glutamylalanine Proteins 0.000 claims 41
- 108010092854 aspartyllysine Proteins 0.000 claims 39
- 108010061238 threonyl-glycine Proteins 0.000 claims 39
- NSTPXGARCQOSAU-VIFPVBQESA-N N-formyl-L-phenylalanine Chemical compound O=CN[C@H](C(=O)O)CC1=CC=CC=C1 NSTPXGARCQOSAU-VIFPVBQESA-N 0.000 claims 36
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 claims 33
- 108010015792 glycyllysine Proteins 0.000 claims 32
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 claims 30
- ATIPDCIQTUXABX-UWVGGRQHSA-N Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN ATIPDCIQTUXABX-UWVGGRQHSA-N 0.000 claims 29
- 108010047857 aspartylglycine Proteins 0.000 claims 29
- 108010038633 aspartylglutamate Proteins 0.000 claims 27
- 108010089804 glycyl-threonine Proteins 0.000 claims 27
- 108010054155 lysyllysine Proteins 0.000 claims 27
- 241001122767 Theaceae Species 0.000 claims 26
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 claims 26
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 claims 25
- 108010002311 N-glycylglutamic acid Proteins 0.000 claims 25
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 claims 24
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 claims 23
- 108010013835 arginine glutamate Proteins 0.000 claims 23
- 108010051242 phenylalanylserine Proteins 0.000 claims 23
- 108010041407 alanylaspartic acid Proteins 0.000 claims 22
- 108010062796 arginyllysine Proteins 0.000 claims 22
- 108010081551 glycylphenylalanine Proteins 0.000 claims 22
- 108010064235 lysylglycine Proteins 0.000 claims 22
- 108010012581 phenylalanylglutamate Proteins 0.000 claims 22
- 108010005942 methionylglycine Proteins 0.000 claims 21
- 108010048818 seryl-histidine Proteins 0.000 claims 21
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 claims 20
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 claims 20
- 108010036413 histidylglycine Proteins 0.000 claims 20
- 108010003700 lysyl aspartic acid Proteins 0.000 claims 20
- 108010068265 aspartyltyrosine Proteins 0.000 claims 19
- 108010055341 glutamyl-glutamic acid Proteins 0.000 claims 19
- 108010073025 phenylalanylphenylalanine Proteins 0.000 claims 19
- CXISPYVYMQWFLE-VKHMYHEASA-N Ala-Gly Chemical compound C[C@H]([NH3+])C(=O)NCC([O-])=O CXISPYVYMQWFLE-VKHMYHEASA-N 0.000 claims 18
- 108010069205 aspartyl-phenylalanine Proteins 0.000 claims 17
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 claims 17
- RVLOMLVNNBWRSR-KNIFDHDWSA-N (2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O RVLOMLVNNBWRSR-KNIFDHDWSA-N 0.000 claims 16
- OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 claims 16
- YBAFDPFAUTYYRW-YUMQZZPRSA-N Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(O)=O YBAFDPFAUTYYRW-YUMQZZPRSA-N 0.000 claims 16
- UCGDDTHMMVWVMV-FSPLSTOPSA-N Ile-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(O)=O UCGDDTHMMVWVMV-FSPLSTOPSA-N 0.000 claims 16
- LRKCBIUDWAXNEG-CSMHCCOUSA-N Leu-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LRKCBIUDWAXNEG-CSMHCCOUSA-N 0.000 claims 16
- 108010079547 glutamylmethionine Proteins 0.000 claims 16
- 108010092114 histidylphenylalanine Proteins 0.000 claims 16
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 claims 16
- 108010009298 lysylglutamic acid Proteins 0.000 claims 16
- 108010056582 methionylglutamic acid Proteins 0.000 claims 16
- JZDHUJAFXGNDSB-WHFBIAKZSA-N Glu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O JZDHUJAFXGNDSB-WHFBIAKZSA-N 0.000 claims 15
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 claims 15
- 108010080629 tryptophan-leucine Proteins 0.000 claims 15
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 claims 14
- 108010011667 Ala-Phe-Ala Proteins 0.000 claims 14
- NKVZTQVGUNLLQW-JBDRJPRFSA-N Ile-Ala-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O)N NKVZTQVGUNLLQW-JBDRJPRFSA-N 0.000 claims 14
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 claims 14
- 108010070944 alanylhistidine Proteins 0.000 claims 14
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 claims 14
- 108010071207 serylmethionine Proteins 0.000 claims 14
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 claims 13
- LJHGALIOHLRRQN-DCAQKATOSA-N Leu-Ala-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LJHGALIOHLRRQN-DCAQKATOSA-N 0.000 claims 13
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 claims 13
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 claims 13
- 108010044374 isoleucyl-tyrosine Proteins 0.000 claims 13
- 108010003137 tyrosyltyrosine Proteins 0.000 claims 13
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 claims 12
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 claims 12
- HOBNTSHITVVNBN-ZPFDUUQYSA-N Asp-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N HOBNTSHITVVNBN-ZPFDUUQYSA-N 0.000 claims 12
- MMFKFJORZBJVNF-UWVGGRQHSA-N His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 MMFKFJORZBJVNF-UWVGGRQHSA-N 0.000 claims 12
- NFNVDJGXRFEYTK-YUMQZZPRSA-N Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O NFNVDJGXRFEYTK-YUMQZZPRSA-N 0.000 claims 12
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 claims 12
- 108010024078 alanyl-glycyl-serine Proteins 0.000 claims 12
- 108010086434 alanyl-seryl-glycine Proteins 0.000 claims 12
- 108010040443 aspartyl-aspartic acid Proteins 0.000 claims 12
- 108010018006 histidylserine Proteins 0.000 claims 12
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 claims 11
- ZVFVBBGVOILKPO-WHFBIAKZSA-N Ala-Gly-Ala Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O ZVFVBBGVOILKPO-WHFBIAKZSA-N 0.000 claims 11
- NBTGEURICRTMGL-WHFBIAKZSA-N Ala-Gly-Ser Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O NBTGEURICRTMGL-WHFBIAKZSA-N 0.000 claims 11
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 claims 11
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 claims 11
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 claims 11
- AIGROOHQXCACHL-WDSKDSINSA-N Glu-Gly-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O AIGROOHQXCACHL-WDSKDSINSA-N 0.000 claims 11
- VPZXBVLAVMBEQI-VKHMYHEASA-N Glycyl-alanine Chemical compound OC(=O)[C@H](C)NC(=O)CN VPZXBVLAVMBEQI-VKHMYHEASA-N 0.000 claims 11
- HGCNKOLVKRAVHD-UHFFFAOYSA-N L-Met-L-Phe Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 HGCNKOLVKRAVHD-UHFFFAOYSA-N 0.000 claims 11
- MLTRLIITQPXHBJ-BQBZGAKWSA-N Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O MLTRLIITQPXHBJ-BQBZGAKWSA-N 0.000 claims 11
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 claims 11
- OTXBNHIUIHNGAO-UWVGGRQHSA-N Leu-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN OTXBNHIUIHNGAO-UWVGGRQHSA-N 0.000 claims 11
- PTRKPHUGYULXPU-KKUMJFAQSA-N Leu-Phe-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O PTRKPHUGYULXPU-KKUMJFAQSA-N 0.000 claims 11
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 claims 11
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 claims 11
- OVAOHZIOUBEQCJ-IHRRRGAJSA-N Lys-Leu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OVAOHZIOUBEQCJ-IHRRRGAJSA-N 0.000 claims 11
- ZOKVLMBYDSIDKG-CSMHCCOUSA-N Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN ZOKVLMBYDSIDKG-CSMHCCOUSA-N 0.000 claims 11
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 claims 11
- LAFKUZYWNCHOHT-WHFBIAKZSA-N Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O LAFKUZYWNCHOHT-WHFBIAKZSA-N 0.000 claims 11
- 108010068380 arginylarginine Proteins 0.000 claims 11
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 claims 11
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 claims 11
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 claims 11
- 108010038320 lysylphenylalanine Proteins 0.000 claims 11
- 108010068488 methionylphenylalanine Proteins 0.000 claims 11
- YLTKNGYYPIWKHZ-ACZMJKKPSA-N Ala-Ala-Glu Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O YLTKNGYYPIWKHZ-ACZMJKKPSA-N 0.000 claims 10
- UTKUTMJSWKKHEM-WDSKDSINSA-N Glu-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O UTKUTMJSWKKHEM-WDSKDSINSA-N 0.000 claims 10
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 claims 10
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- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 claims 10
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 claims 10
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- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 claims 10
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 claims 10
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- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 claims 10
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 claims 10
- 108010020688 glycylhistidine Proteins 0.000 claims 10
- 108010087823 glycyltyrosine Proteins 0.000 claims 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims 10
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Classifications
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- 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
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/22—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Neisseriaceae (F)
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
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Description
Vynález se týká virulentních genů, proteinů a jejich použití. Přesněji, týká se genů a proteinů/peptidů získaných z Neisseria meningitidis a jejich použití při léčbě a screeningu léčiv.
Dosavadní stav techniky
Neisseria meningitidis je Gram-negativní bakteriální patogen, který se podílí na septickém šoku a bakteriální meningitidě. Tato bakterie je hlavní příčinou bakteriální meningitidy v rozvojových zemích a způsobuje rozsáhlou epidemii v Africe a Číně. V UK je Neisseria meningitidis hlavní příčinou smrti v dětství kromě dopravních nehod. Bakterie přirozeně inhibuje nosohltan pacienta a pak proniká do krevního oběhu a touto cestou způsobuje vážné septikemii nebo meningitidu. Ačkoli jsou současné antimikrobiální přípravky účinné při odstraňování bakterie z těla, úmrtnost na menigokokální septikemii je stále značná. Bylo by třeba poskytnout způsob léčby nebo prevence stavů vyvolaných Neisseria meningitidis, například imunizací.
Podstata vynálezu
Vynález vychází z objevu virulentních genů Neisseria meningitidis.
Podle prvního hlediska vynálezu je peptid podle vynálezu kódován operonem zahrnujícím kteroukoli nukleotidovou sekvenci zde uváděných jako SEQ ID NOS.
1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91,
93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125,
127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157,
159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189,
191, 193, 195, 197, 199, 201, 203, 205, 207 u N. meningitidis nebo podobné molekuly s alespoň 40% sekvenční podobností nebo shodou na úrovni peptidu nebo nukleotidu u Gram-negativní bakterie nebo jejího funkčního fragmentu pro terapeutické nebo diagnostické použití.
Peptidy mohou mít více léčebných použití pro léčbu infekcí Neisseria včetně použití jako očkovacích látek pro profílaktickou aplikaci.
Podle dalšího hlediska polynukleotid kódující peptid uvedený výše, může být též použitelný pro léčbu a diagnostiku.
Podle třetího hlediska mohou být geny, které kódují peptidy, použity k přípravě oslabených mikroorganismů. Oslabené mikroorganismy většinou obsahují mutaci, která přerušuje expresi jednoho nebo více genů zde uváděných za účelem přípravy kmene, který není virulentní. Tyto mikroorganismy je též možné použít k léčbě nebo diagnostice.
Podle čtvrtého hlediska mohou být peptidy, geny a oslabené mikroorganismy podle vynálezu použity pro léčbu nebo prevenci stavů spojených s infekcí Neisseria nebo Gram-negativními bakteriemi.
Vynález je založen na objevu genů kódujících peptidy, které se podílejí na virulenci. Peptidy a geny podle vynálezu jsou proto použitelné pro přípravu terapeutických látek pro léčbu infekce. Je třeba pochopit, že odkazy týkající se terapie zahrnují též prevenci, například očkování. Ačkoli produkty podle vynálezu jsou primárně určeny pro léčbu infekcí člověka, veterinární aplikace jsou též zahrnuty v rozsahu vynálezu.
Vynález je popsán s odkazem na Neisseria meningitidis. Avšak všechny kmeny Neisseria a mnoho dalších Gram-negativních bakteriálních kmenů pravděpodobně obsahují podobné peptidy nebo proteiny obsahující aminokyselinovou sekvenci shodnou nebo podobnou se sekvencí zde uváděnou. Podobné organismy obsahující peptid zahrnují, ale nejsou omezeny na rody Salmonella, Enterobacter, Klebsiella, Shigella a Yersinia.
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Provedené experimenty identifikují virulentní geny podle vynálezu využívající kmen Β N. meningitidis. Shody byly hledány v databázi kmene A, avšak výhodné jsou proteiny a geny kmene B.
Výhodně, peptidy, které jsou použitelné z různých hledisek podle vynálezu mají větší než 40% podobnost s peptidy zde uváděnými. Výhodněji, peptidy mají vyšší než 60% sekvenční podobnost. Nejlépe, peptidy mají vyšší než 80% sekvenční podobnost, například 95% podobnost. S ohledem na polynukleotidové sekvence zde uváděné, odvozené polynukleotidy, které mohou být použitelné z různých hledisek podle vynálezu, mají větší než 40% shodu s uváděnými sekvencemi. Výhodněji, polynukleotidové sekvence mají větší než 60% sekvenční shodu. Nejlépe, polynukleotidové sekvence mají vyšší než 80% sekvenční shodu, například 95% shodu.
Pojmy „podobnost“ a „shoda“ jsou známy v dosavadním stavu techniky. Použití pojmu „shoda“ se týká sekvenčního srovnání založeném na shodě mezi odpovídajícími shodnými pozicemi ve srovnávaných sekvencích. Pojem „podobnost“ se týká srovnám mezi aminokyselinovými sekvencemi a zahrnuje nejen shodné aminokyseliny v odpovídajících pozicích, ale též funkční podobnost aminokyselin v odpovídajících pozicích. Podobnost mezi polypeptidovými sekvencemi tak kromě sekvenční podobnosti vypovídá o funkční podobnosti.
Míra shody mezi genovou sekvencí a míra shody nebo podobnost mezi aminokyselinovými sekvencemi lze vypočítat pomocí známých metod. Vzhledem k vynálezu běžně dostupné počítačové metody pro stanovení shody a podobnosti zahrnují BLASTP, BLASTIN a FASTA (Atschul a kol., J. Molec. Biol., 1990; 215:403-410), pogram BLASTX dostupný z NCBI a program Gap od Genetic Computer Group, Madison WI. Míry podobnosti a shody takto stanovované se získaly za použití programu Gap s omezením 12 a Gap omezující délkou 4 pro stanovení srovnání aminokyselinové sekvence a Gap omezením 50 a Gap omezující délkou 3 pro srovnání polynukleotidové sekvence.
Získáním kmenové charakteristiky podle vynálezu je možné použít genovou sekvenci pro vyhledání odvozených genů nebo peptidů u jiných mikroorganismů. Toto je možné provést vyhledáváním v existujících databázích, například EMBL nebo GenBank.
Peptidy nebo proteiny podle vynálezu mohou být přečištěné a izolované metodami známými v dosavadním stavu techniky. Přesněji, po identifikaci genové sekvence je možné použít rekombinantní techniky pro expresi genů ve vhodném hostiteli. Je možné odhalit aktivní fragmenty a odvozené molekuly, které mohou být použitelné pro léčbu. Například peptidy nebo jejich aktivní fragmenty mohou být použitelné jako antigenní determinanty v očkovací látce k vyvolání imunní reakce. Mohou být též použitelné při přípravě protilátek, pro pasivní imunizaci nebo diagnostické aplikace. Vhodné protilátky zahrnují monoklonální protilátky nebo jejich fragmenty včetně jednoduchého řetězce fragmentu Fv. Metody přípravy protilátek budou známé odborníkům v tomto oboru.
Aktivní fragmenty peptidů jsou takové, které zachovávají biologickou funkci peptidu. Například, pokud se použijí k vyvolání imunitní reakce, fragment musí mít dostatečnou velikost, aby protilátky vytvořené z fragmentu rozlišily mezi tímto a jinými peptidy bakteriálního mikroorganismu. Fragment má délku běžně alespoň 30 nukleotidů (10 aminokyselin), s výhodou 60 nukleotidů (20 aminokyselin) a nejlépe délku více než 90 nukleotidů (30 aminokyselin).
Je třeba si uvědomit, že kromě odvozených molekul jiných mikroorganismů vynález zahrnuje modifikace provedené u peptidů a polynukleotidů zde uvedených, které významně nemění biologickou funkci. Odborníkům v tomto oboru bude zřejmé, že degenerace genetického kódu může vést k polynukleotidů s minimálními změnami v bázích zde uváděných, které však přesto kódují shodný peptid. Komplementární polynukleotidy jsou též předmětem vynálezu. Konzervativní nahrazení na úrovni aminokyselin jsou též uvažována, to znamená různé kyselé nebo bazické aminokyseliny mohou být nahrazeny bez podstatné ztráty funkce.
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Příprava očkovacích látek založených na oslabených mikroorganismech je známá odborníkům v tomto oboru. Složení očkovací látky může být formulováno vhodnými nosiči nebo adjuvans, například kamencem, pokud je to nezbytné nebo žádané pro dosažení účinné imunizace proti infekci. Příprava formulace očkovací látky je známá odborníkům v tomto oboru. Oslabené mikroorganismy je možné připravit mutací, která porušuje expresi kteréhokoli uvedeného genu. Odborníkovi v tom to oboru jsou známy metody porušení exprese určitých genů. Techniky, které je možné použít, zahrnují inaktivaci inzercí nebo technikami genové delece. Oslabené mikroorganismy podle vynálezu mohou zahrnovat další mutace v jiných genech, například v druhém genu zde uvedeném nebo v samostatném genu důležitém pro růst mikroorganismu, například an aro mutace nebo s ohledem na Salmonelu, v genu umístěném v oblasti SP12 uváděné v WO-A-96/17951.
Oslabené mikroorganismy mohou být též použitelné jako nosné systémy pro přepravu heterologních antigenů, terapeutických proteinů nebo nukleových kyselin (DNA nebo RNA). V tomto provedení jsou oslabené mikroorganismy použitelné jako nosiče heterologního antigenů, proteinu nebo nukleové kyseliny na určité místo in vivo. Zavedením heterologního antigenů, peptidu nebo nukleové kyseliny do oslabeného mikroorganismu je možné provést známými technikami včetně použití rekombinantních konstruktů, například vektorů, které obsahují polynukleotidy, které exprimují heterologní antigen nebo terapeutický protein a obsahují též vhodné sekvence promotoru. Gen, který kóduje heterologní antigen nebo protein, může být případně včleněn do genomu mikroorganismu s endogenními promotory použitými ke kontrole exprese.
Obecněji, jak je známo odborníkům v tomto oboru, pro terapeutické použití je možné vybrat vhodné množství aktivní složky podle vynálezu, stejně jako vhodný nosič nebo excipient a způsob aplikace. Tyto faktory je možné vybrat nebo stanovit podle známých kritérií, jako například podstata/závažnost léčeného stavu, typ a/nebo zdravotní stav pacienta a podobně.
V jiném provedení mohou být produkty podle vynálezu použity pro testování identifikace potenciálního antimikrobiálního léčiva nebo pro detekci virulence. Rutinní testování jsou známá odborníkům v tomto oboru a je možné je upravit použitím produktů podle vynálezu vhodným způsobem. Například, produkty podle vynálezu mohou být cílem z hlediska použití jako potenciální léčiva se schopností inaktivovat nebo vázat cílovou částici charakterizující svoji potenciální antimikrobiální aktivitu.
Různé produkty podle vynálezu je též možné použít u veterinárních aplikací.
Následuje stručný přehled experimentálního postupu použitého pro identifikaci virulentního genu.
Příklady provedení vynálezu
K identifikaci genů u N. meningitidis, které jsou nezbytné pro septickou infekci byla použita značená (Signature-tagged) mutageneze (STM) (Hensel a kol., Science, 1995; 269; 400-403). Individuální mutanty jsou u značené mutageneze specifickými sekvenčními identifikátory, umožňujícími simultánní analýzu velkého počtu mutantů. Je však nezbytné konstruovat knihovny insertních mutantů až po studii N. meningitidis. Mutageneze byla úspěšně dokončena za použití postupu, kdy je DNA Neisseria modifikována in vitro za použití přečištěných komponentů transpozice Tn 10. Poněvadž N. meningitidis hojně využívá exogenní DNA, modifikované alely jsou pak zavedeny do N. meningitidis transformací. Mutanty pak mohu být sledovány na základě jejich schopnosti navozovat systémovou infekci.
Jako donor transpozonu pro mutagenezu in vitro byl použit vektor pSTMl 15 (Sun a kol. Nátuře Medicine, 2000: 6(11): 1269-1273). Do 96 oddělených transpozičních reakcí bylo zahrnuto 96 derivátů pSTMl 15, z nichž každý obsahoval specifickou sekvenční část. Modifikovaná genomová DNA byla opravena a vpravena do hostitele pomocí transformace. Ke zjištění, zda se inzerce Tn 10 objevuje na odlišných místech, bylo prověřeno 40 transformantů pomocí jediné transpoziční reakce analýzou Southern blot. Každá zahrnovala jedinou, odlišnou inzerci Tn 10. Pro stanovení, zda integrace Tn 10 byla stabilní během systémové infekce u mláďat krys, bylo provedeno srovnání hybridizačních vzorů šesti mutantů z krys. Byly získány identické hybridizační vzory před a po infekci.
Podmínky provedeného experimentu byly následující:
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Bakteriální kmen a růst
C311+je ET-5, serologická skupiny B izolátu N. meningitidis od pacienta s invazivní meningokokovou infekcí (Virji a kol., Mol. Microbiol., 1991; 5: 18311841). Kmen N. meningitidis byl pěstován na infuzním médiu pro mozek-srdce obsahující 5% Levinthalův doplněk. Kmeny E.coli byly namnoženy v médiu Luria Bertani. K pevnému médiu byl podle požadavků přidán kanamycin v koncentraci 75 a 50 pg/ml u N.meningitidis a respektive E.coli.
Transpozice in vitro a charakterizace inzerčního místa
K izolaci inzerčního místa pomocí markéru byl použit počátek pACYC184 replikace u pSTM115. Bylo provedeno nukleotidové sekvencování pomocí terminační metody za použití barviva (Perkin Elmer, Norwalk, Connecticut), primerů NG62 (5 '- TTGGTTAATTGGTTGTAACACTGG-3’) (SEQ ID NO. 209) nebo NG99 (5’- ATTCTCATGTTTGACAGCG-3’) (SEQ ID NO. 210). V proteinové databázi byl proveden průzkum homologie (http://www.ncbi.nim.nih.gov/) zahrnující serologické skupiny A a B N. meningitidis a genomové sekvence N. gonorhoeae (http://www.sanger.ac.uk/Projects/N_meningitidis a http://www.tigr.org a respektive http://dnal .chem.ou.edu/gono.html).
Tag amplifikace, klonování a analýza Southern blot
Hybridizace a příprava dot blot se prováděla podle popisu v Hansel a kol., supra, kromě toho, že koncové sekvence byly amplifikovány pomocí primerů NG13 (5’-ATCCTACAACCTCAAGCT-3’) (SEQ ID NO. 211) a NG14 (5’ATCCCATTCTAACCAAGC-3’) (SEQ ID NO. 212) a na membrány byly zafixovány spíše produkty PCR než plazmidová DNA. Oligonukleotidy SI (5’AAGAGATTACGCGCAGACC-3’) (SEQ ID NO. 213) a S2 (5’AATACGCAACCGCCTCTC-3’) (SEQ ID NO. 214) přiléhaly k sekvencím u pSTMl 15 vedle „signálních konců“ a byly použity k amplifikaci produktu o délce 367 párů bází u každého derivátu pSTMl 15. U Southern blot analýzy byla značena kazeta na kanamycinovou rezistanci za použití metody náhodných primerů (NEB) a byla použita jako sonda pro genomovou DNA štěpené C/al.
Zvířecí model:
Pro screening potenciálu pro značenou mutagenezi mutanty narůstaly individuálně 18 h na mikrotitračních destičkách. Bakterie se sklidily, pak rozsuspendovaly v PBS. Krysy Wistar (stáří 5 dnů) se inokulovaly intraperitoneálně 100 μΐ suspenze a pak se 48 hodin sledovaly. Ke stanovení kompetetivního indexu mutantu se množil divoký typ mutantní bakterie 18 h v pevném médiu a pak se sklidil do PBS a krysy se inokulovaly mutantem s buňkami divokého typu v poměru 1:1 v celkovém inokulu 5 χ 106 CFU. Poměr mutantu (kanamycin-rezistantní) a bakterie divokého typu (citlivý na kanamycin) se stanovil přenosem vzorků replikátu do média s přídavkem nebo bez přídavku antibiotika.
Výsledky sledování homologie jsou uvedeny v tabulce 1.
Tabulka 1
SEQ. ID NO. | PROTEIN | č. přístupu | ORGANISMUS |
3&4 | 3‘-dehydrochinát syntáza | NMB0647 | N.gonorrhoeae |
25 &26 | Glykozytransferáza | LS12 | N. gonorrhoeae |
35 & 36 | Polyribonucleotid- nucleotidyltransferáza | NMB0758 | N. meningitidis |
37 & 38 | Fosforibozylformylglycin amidsyntáza | PURL | E.coli |
43 & 44 | Sikimátdehydrogenáza | AROE | N. meningitidis |
47 & 48 | Hypotetický 21,7 kD protein | NMB0673 | N. meningitidis |
53 & 54 | Domnělý vazebný faktor buňky | NMB0345 | N. meningitidis |
57 & 58 | Hypotetický protein | HI0633 | H. influenzae |
61 & 62 | NaVí-Ř antiportér | NMRN0538 | N. meningitidis |
63 & 64 | Chorizmátsyntháza | AROC | V. angulliarum |
67 & 68 | Parachat-indukovatelný protein B | PQ15B | E.coli |
71 & 72 | 5 ‘ -methyltetrahydro- pteroylyltriglutamát- homocysteinmethyl- transferáza | NMB0944 | N. meningitidis |
79 &80 | α-1,2-N-acetylglukos- amintransferáza | RFAK | N. meningitidis |
83 & 84 | Domnělá RNA methyláza | NMB1348 | N. meningitidis |
89 &90 | L-laktátpermeáza | NMB0543 | N. meningitidis |
91 & 92 | ABC transportér | NMB1240 | N. meningitidis |
• · · · · ······ ··· ···· * · 9 • · 9 V · « · ·
103 & 104 | Pravděpodobný GTP- vazebný protein | HI0393 | H.influenzae |
109 & 110 | Kapsle polysacchande modifikaního proteinu | LIPB | N. meningitidis |
113 & 114 | Hypotetický 17,8 kD protein | NMB0734 | N. meningitidis |
115 & 116 | E. coli hypotetický protein | YIGC | S.typhimurium |
119 & 120 | Ribonukleáza III | NMB0686 | N. meningitidis |
121 & 122 | AMPD protein | NMB0686 | N. meningitidis |
123 &124 | 5-methyltetra- hydroylyltriglutamát- homocysteinmethyl- transferáza | NMB0944 | N. meningitidis |
133 &134 | Domnělá ATP dependentní RNA helikáza | NMB1422 | N. meningitidis |
137 & 138 | Domnělá RNA methyláza | NMB1348 | N. meningitidis |
141 &142 | Šikimátdehydrogenáza | AROE | N. meningitidis |
143 &144 | Domnělý vnější membránový protein | OMPU | N. meningitidis |
145 & 146 | TONB protein | TONB | N. meningitidis |
147 & 148 | Domnělý apolipoprotein N-acyltransferázy | NMB0713 | N. meningitidis |
149 & 150 | Transponáza | NMB0991 | N. meningitidis |
153 &154 | UTP-glukóza-1- fosfáturidylyltransferáza | NMB0638 | N. meningitidis |
157 & 158 | ADP heptóza.LPS | NMB1527 | N. meningitidis |
heptosyltransferáza II | |||
161 & 162 | Domnělá lytická mureintransglykozyláza B vážící se na membránu | NMB1279 | N. meningitidis |
171 &172 | Domnělý faktor vážící se na membránu | NMB0345 | N. meningitidis |
173 &174 | P-aminobenzoát- synthetáza | PABB | H.pylori J89 |
177 & 178 | 5 ‘ -methyltetrahydro- pteroylyltriglutamáthomo- cysteinmethyltransferáza | NMB0944 | N. meningitidis |
183 & 184 | Konzervativní hypotethický protein | NMB0183 | N. meningitidis |
185 & 186 | E. coli hypotetický protein | YIGC | S.typhi LT2 |
Pro zbývající sekvence zde nalezené nebyly získány žádné homologní výsledky.
K výrobě polyklonálních protilátek byly použity genové produkty, které byly testovány metodou Elisa u různých kmenů N. meningitidis ke zjištění možnosti jejich použití jako očkovacích látek. Byly použity tyto kmeny:
Neisseria meningitidis (B) Typ 1000
Neisseria meningitidis (B) Typ NGE31
Neisseria meningitidis (B) Typ NGH15
Neisseria meningitidis (B) Typ SW2 107
Neisseria meningitidis (B) Typ NHG38
Neisseria meningitidis (B) Typ NGE28
Neisseria meningitidis (B) Typ 2996
Z těchto údajů je zřejmé, kolik různých kmenů N. meningitidis je rozeznáváno těmito protilátkami.
Bakterie N. meningitidis rostla na čokoládově zbarveném Columbijském agaru s koňskou krví (Oxoid) po dobu 14 hodin při 37 °C v 5% CO2. Buňky se odstranily z agarových ploten a rozsuspendovaly ve 20 ml PBS v 50 ml zkumavce. Suspenze buněk se zahřívala 30 minut při 56 °C pro usmrcení bakterií.
μΐ vzorku bakterií usmrcených teplem N. meningitidis se navrstvilo na čokoládově zbarvený Columbii ský agar s koňskou krví a inkubovalo 18 hodin při 37 °C, 5% CO2. Tímto se usmrtily poslední buňky N. meningitidis. OD62o suspenze se upravilo na 0,1 OD jednotek oproti PBS.
Elisa stanovení s buňkami N. meningitidis usmrcenými teplem
Stanovení Elisa se provádělo za použití buněk N. meningitidis usmrcených teplem podle následujícího protokolu. Elisa destičky se přes noc pokryly buňkami usmrcenými teplem (50 μΐ usmrcených bakterií v PBS v každé jamce 96 jamkové destičky a inkubovaly se při 4 °C).
Postupovalo se podle standardního protokolu Elisa vždy s 1 h inkubací při 37 °C. Použil se PBS/3% blokující roztok BSA, promývací roztok PBS/Tween 0,1%, konjugát sekundární protilátky králičí AP (Sigma) a detekční činidlo Sigma Fast P nitrofenylfosfát (Sigma). Výsledky byly detekovány při 405nm za použití příslušného readeru na mikrodetičky. Použitá séra byla získána sedm dní po první propagaci vakcinace (35.den po první vakcinaci).
Byly testovány protilátky, které se vytvořily proti genovým produktům identifikovaným jako SEQ ID NOS. 8, 102, 140, 158 a 202. V každém případě výsledky ukazují, že antiséra rozlišovala několik různých kmenů N. meningitidis B.
Screening ex vivo/in vitro
Ochrana proti meningokokovým onemocněním u pacientů byla spojována s přítomností bakteriálních protilátek proti N. meningitidis (Goldscheider a kol. J Exp. Med., 1969; 129: 1307-1326). Je též zřejmé, že je dobré použít korelaci mezi detekovatelnou baktericidní aktivitou a ochranou v modelu in vivo (viz Martin, J. Bacteriol., 2000; 83: 27-31). Vytvořené antisérum bylo proto použito k vyhodnocení baktericidní aktivity vytvořených protilátek.
Baktericidní stanovení se prováděla s pre-imunním sérem a odpovídajícím králičím antisérem vytvořeným proti případným antigenům. Bylo použito komerčně dostupné králičí sérum jako zdroj komplementu po pre-screeningu pro eliminaci usmrcení způsobeného pouze komplementem. V případě potřeby se jako pufr použil roztok Dulbecco PBS (Gibco). Kmen MC58 N. meningitidis se množil při 37 °C (5% CO2) 14 hodin před použitím ve stanovení.
200-400 CFU MC58 v 50 μΐ se inkubovalo za přítomnosti komplementu (50 μΐ) se 100 μΐ postupně ředěných roztoků séra inaktivovaného teplem. Vzorky v čase nula se na vrstvily na čokoládově zbarvený Columbijský agar s koňskou krví (Oxoid). Po 60 minutové inkubaci se stanovilo množství přežitých bakterií navrstvením na čokoládově zbarvený Columbijský agar s koňskou krví (Oxoid). Bakteriální aktivita se vyjádřila v procentech bakterií přežívajících 60 minut. Všechny vzorky se testovaly dvakrát a vrstvily se třikrát. Použily se všechny příslušné pozitivní a negativní kontroly. U každého testovaného vzorku byla baktericidní aktivita výrazně vyšší než u pre-imunního séra.
Screening in vivo
Ke stanovení ochranného účinku potenciální vakcíny se dospělé myši imunizovaly rekombinantními proteiny zde označenými jako SEQ ID NOS. 102 a 108 a ochranný účinek se stanovil bakteriální životaschopností. U každé 15. potenciální vakcíny se myš stáří šesti týdnů (šestitýdenní myš Balb/C) naočkovala (podkožně) 25pg antigenu u dvou odlišných případů v intervalu tří týdnů.
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Týden po ukončnení imunizace byla skupina vystavena homolognímu bakteriálnímu kmeni MC58. Bakterie se inokulovaly intraperitoneálně v objemu 500 μΐ v médiu infuze pro mozek a srdce/0,5 % dextran s kovem v dávce 10 CFU. Předchozí výsledky ukázaly, že kov je nezbytný k vyvolání bakteriálního onemocnění u těchto zvířat. Model byl dříve použit ke zjištění ochranného účinku očkování (Lissoio a kol., Infect. Immujn., 1995; 63: 884-890).
Kontrolní skupiny zahrnovaly zvířata očkovaná pouze adjuvans (negativní kontrola) nebo adjuvans v kombinaci s přečištěným PorA (pozitivní kontrola). PorA je vnější membránový protein exprimovaný výhradně N. meningitidis a je hlavním cílem pro bakteriální protilátky aktivované očkovací látkou membránové dutiny. Monoklonální protilátky proti PorA též pasivně chrání zvířata u modelu krysích mláďat. PorA se však významně liší v závislosti na kmeni, a protože to vede k určité ochraně při aktivaci homologním kmenem, není ideální jako potenciální očkovací látka. Přežití bylo sledováno po aktivaci. Negativní kontroly nepřežily 48 hodin. U případů očkovaných PorA přežilo po 72 hodinách 6. Případy očkovány proteiny SEQ ID NOS. 102 a 108 vykazovaly 5 a 3 přežívající případy.
7/ MM -Šéfa
Claims (20)
1.
Peptid kódovaný operonem obsahujícím kteroukoli z nukleotidových sekvencí, zde uváděných jako SEQ ID NOS. 1, 3, 5, 7, 9, 11, 13, 15, 17,19,
21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99,
101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129,
131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159,
161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189,
191,193,195, 197, 199, 201, 203, 205, 207 u N. meningitidis nebo podobné molekuly s alespoň 40% sekvenční podobností nebo shodou na úrovni peptidu nebo nukleotidu u Gram-negativní bakterie nebo jejího funkčního fragmentu pro terapeutické nebo diagnostické použití.
2. Peptid podle nároku 1, kde sekvenční podobnost nebo identita je alespoň 60%.
3. Peptid podle nároku 1 nebo nároku 2, kde sekvenční podobnost nebo identita je alespoň 90%.
4. Peptid podle nároku 1, obsahující aminokyselinovou sekvenci zde uváděnou jako SEQ ID NOS. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66? 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108,
110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138,
140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168,
170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198,
200, 202, 204, 206 a 208.
5. Polynukleotid kódující peptid podle kteréhokoli z předcházejících nároků pro terapeutické nebo diagnostické použití.
6. Hostitelský organismus transformovaný k expresi peptidu podle kteréhokoli z nároků 1 až 4.
7. Oslabený mikroorganismus obsahující mutaci, která zabraňuje expresi kterékoli nukleotidové sekvence podle nároku 1.
8. Mikroorganimus podle nároku 7, kde mutace je inzerční inaktivací nebo genovou delecí.
9. Mikroorganimus podle nároku 7 nebo 8, kdy je mikroorganismem Neisseria meningitidis.
10. Mikroorganimus podle kteréhokoli z nároků 7 nebo 8 obsahující druhou mutaci v druhé nukleotidové sekvenci.
11. Mikroorganimus podle kteréhokoli z nároků 7 nebo 8 pro terapeutické a diagnostické použití.
12. Mikroorganimus podle nároků 7 až 11 obsahující heterologní antigen, terapeutický peptid nebo nukleovou kyselinu.
13. Očkovací látka obsahující peptid podle kteréhokoli z nároků 1 až 4 nebo prostředek pro její expresi.
14. Očkovací látka obsahující mikroorganismus podle kteréhokoli z nároků 7 až
12.
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15. Protilátka vytvořená proti peptidu podle kteréhokoli z nároků 1 až 4.
16. Použití produktu podle kteréhokoli z nároků 1 až 12 pro výrobu léčiva pro použití při léčbě nebo prevenci stavů spojených s infekcí Neisseria nebo Gramnegativní bakterií.
17. Použití podle nároku 16, kde se jedná o stav při meningitidě.
18. Použití podle nároku 16 nebo nároku 17 pro veterinární léčbu.
19. Použití produktu podle kteréhokoli z nároků 1 až 12 pro screening identifikace antimikrobiálního léčiva.
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35 40 45 ggg ctg atg atg ctc gcc gcc gcc aag ggt acg gtc atc gaa ctg gag 192
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20 25 30 atg aca cgc aaa atc ctc gtt acc tcc gcc ctg ccc tat gcc aac ggc 144
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WO 01/85772
PCT/GB01/02003
WO 01/85772 PCT/GBO1/02003
Gly Ala Val Arg Asp Val Ala Gin Ile Glu Arg 610 615 <210> 29 <211> 1725 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1725) <400 29
115 120 125 »· ·» · · • · · · · ·
PCT/GB01/02003 atc aat gag ttg gcg gaa acc att aaa aag gcg 432
Ile Asn Glu Leu Ala Glu Thr Ile Lys Lys Ala 135 140 age ggc ega ccg ggg ccc gtg gtg gtt gat gtc 480
WO 01/85772 ttc ctg gtt acg gac Phe Leu Val Thr Asp 130 ttc caa att gcc gca
Phe Gin Ile Ala Ala Ser Gly Arg Pro Gly Pro Val Val Val Asp Val 145 150 155 160
305 3io 315 320
WO 01/85772
PCT/GB01/02003
WO 01/85772
PCT/GBO1/02003
565 570 575 <210> 30 <211> 575 <212> PRT
to ·
WO 01/85772 PCT/GBO1/02003
565 570 575 <210> 31 <211> 651 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1) .. (651) <400> 31 atg ttt tcc gta ccg cgt tcc ttt ttg ccg ggc gtt ttc gta ctt gcc 48 ·· 44
WO 01/85772
PCT/GB01/02003
Pro Tyr Gly Ser Glu Pro Glu Thr 205 ctc 651
Leu <210> 32 <211> 217 <212> PRT <213> Neisseria meningitidis <400> 32
Met Phe Ser Val Pro Arg Ser Phe 1 5
Ala Leu Ala Ala Cys Lys Pro Gin 20
Ser Ser Ser Ala Ser Ala Ser Ala 35 40
Thr Arg Gly Thr Asp Met Arg Lys 50 55
Leu Thr Asp Gly Glu Gly Lys Pro 65 70
Lys Val Val Ile Leu Ser Phe Gly 85
Pro Thr Glu Leu Leu Thr Tyr Ser 100
Gin Ala Lys Asp Val Lys Val Val 115 120
Asp Thr Pro Glu Ile Ile Gly Lys 130 135
Phe Ile Gly Leu Thr Ala Thr Gly 145 150
Gin Gin Tyr Arg Val Val Ser Ala 165
Glu Asn Tyr Leu Val Asp His Ser
·· ·*··
180 185 190
WO 01/85772 • fc ·* • · « · fc' · fc 9 e β • •fcfc ···· ·· fc » 9 · fc
9 9 9
9 9 9
9 9»
9 9 99 9
9 9 · • · ·
9 9 9 • · · · »· fcfc
PCT/GB01/02003
<210> 33 <211> 330 <212> DNA <213> Neisseria meningitidis <22G>
<221> CDS <222> (1)..(330) <400> 33
144
192
240
288
330
WO 01/85772 PCT/GB01/02003 <210> 34 <211> 110 <212> PRT <213> Neisseria meningitidis <400> 34
100 105 110 <210> 35 <211> 2118 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(2118) <400> 35
i
WO 01/85772 PCT/GBO1/02003
WO 01/85772 PCT/GB01/02003 • ·
• · · ♦ · · • · · · · · · · · • · · · · · • · · · · ··· • · * · · · ···· ···· ·· ···
WO 01/85772 PCT/GB01/02003
Ala Glu 705 <210> 36 <211> 706 <212> PRT
• fc fcfc • · · · fc · • · β fc • fcfcfc fcfcfcfc • fcfcfc fc
WO 01/85772
65 70 75
PCT/GB01/02003
···· ♦
WO 01/85772 PCT/GB01/02003 ·♦ ♦* • « · · • · « · · β · ♦ ··♦··«·
325 330 335
• ·
<210> 37 <211> 3972 <212> DNA <213> Neisseria meningitidis <22 0>
<221> CDS <222> (1)..(3972) <400> 37 gtg age ega att atg tet gtc gtt ttg ccc ttg cgc ggc gtt acc gcc 48
Val Ser Arg Ile Met Ser-Val Val Leu Pro Leu Arg Gly Val Thr Ala
15 10 15 ctt tcc gat ttc cgt gtt gaa aaa ctc ttg caa aaa gcc gcc gca ctc 96
Leu Ser Asp Phe Arg Val Glu Lys Leu Leu Gin Lys Ala Ala Ala Leu
20 25 30 ggt ctg ccc gaa gtc aaa tta age age gaa ttt tgg tat ttc gtc ggc 144
Gly Leu Pro Glu Val Lys Leu Ser Ser Glu Phe Trp Tyr Phe Val Gly
*· ·· · · · · ·· ·
WO 01/85772 PCT/GB01/02003 ·· ·· · ·· ···· ···· · · 9 4 4 4 9
4 4 4 9 9 · 9 · • 9 9 44 · · « 4 · • ' 9 9 4 9 ····
WO 01/85772 PCT/GB01/02003 • to · to · · to · toto · • · · to to · · · • · · · » · · to · · • · ··· · · · · ···· ···· ·· ··· ·· ··
• « 0 00 0
WO 01/85772 PCT/GBO1/02003
0« 00 00 0 ♦ 000 000 0 · · 0
0 0 000 0000
995 1000 1005
····
WO 01/85772 PCT/GBO1/02003
1315 1320 <210> 38 <211> 1324 <212> PRT <213> Neisseria meningitidis <400> 38
fcfc ·· fcfc · · fcfc fcfc • · · · fcfcfcfc · · • fc ♦ fc α fc · fc
WO 01/85772 PCT/GB01/02003
290 295 300
eo
WO 01/85772 PCT/GB01/02003
·· φφ · ·· ···· • φ · ·· · φ · • β φ φ φ ΦΦΦ φ · φ φ · φφφφ φ φ · φ φ φφφφ φφ φφφφ φφ ΦΦΦ φφ φφ
W0 01/85772 PCT/GB01/02003
1060 1065 1070
1300 1305 1310
Tyr Arg Leu Phe Ala Gly Ala Arg Lys Ala Leu Gly
WO 01/85772
1315 1320
PCT/GB01/02003 <210> 39 <211> 471 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(471) <400> 39
44 4444
WO 01/85772 PCT/GB01/02003
<210> 40 <211> 157 <212> PRT <213> Neisseria meningitidis <400> 40
145 150 155 <210> 41 <211> 504 <212> DNA ·· ····
WO 01/85772 PCT/GBO1/02003 <213> Neisseria meningitidis 4 <220>
<221> CDS <222> (1)..(504) <400> 41
WO 01/85772 PCT/GB01/02003
Leu Asp Glu Gly Leu Leu Asn Ala 165 <210> 42 <211> 168 <212> PRT <213> Neisseria meningitidis <400> 42
165 <210> 43 <211> 813 <212> DNA ·· ·· 49 ·
4 9 9 9 9 9 99
9 9 9 9 9
9 9 9 9 · 9
9 4 -4 4 9
9994 4994 44 444
49 944 9
4 9 9
4 9 9
9 4 · • β 9 9
44 49
WO 01/85772 PCT/GBO1/02003 <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(813) <400> 43
·· ·*·· ·· ·· ·· · • · « ♦. · · ·· • · · · · • » · · · · • · · β e ···· ···· «· ··· • · · • · · • · · β e * β «· ··
<210> 44 <211> 271 <212> PRT <213> Neisseria meningitidis <400> 44
Met Thr Met His Ala Leu Pro Arg Tyr Ala Val Phe Gly Asn Pro Val 1 5 10 15
Ala His Ser Lys Ser Pro Gin Ile His Gin Gin Phe Ala Leu Gin Glu 20 25 30
Gly Val Asp Ile Glu Tyr'Glu Arg Ile Cys Ala Asp Ile Gly Gly Phe 35 40 45
Ala Gin Ala Val Ser Thr Phe Phe Glu Thr Gly Gly Cys Gly Ala Asn 50 55 60
Val Thr Val Pro Phe Lys Gin Glu Ala Phe His Leu Ala Asp Glu His 65 70 75 80 • · • · · · · 9 · · • 4 β 4 · ···· • · · · · · · · ' 4 4 · · 4 · · · 4 4 · · · · · 4 9
<210> 45 <211> 546 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(546) • <5
180 • · · ·
0 · «Β 0 · © · · · ········ ·· »·Ό ·· ··
WO 01/85772 PCT/GB01/02003 <210> 46 <211> 182 <212> PRT <213> Neisseria meningitidis <400> 46
<210> 47 <211> 585
180 «
WO 01/85772 PCT/GBO1/02003 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(585) <400> 47
ί
WO 01/85772
PCT/GB01/02003
585 <210> 48 <211> 195 <212> PRT
WO 01/85772 PCT/GB01/02003
His Leu Pro Glu Phe Thr Glu Glu Leu Arg Arg Ile Ile Cys Gly Gly
165 170 ' 175
Lys Asn Pro Asp Ala Gly Cys Lys Gin Ala Gly Gin Val Gly Lys Arg
180 185 190
His Gin Lys 195 <210> 49 <211> 462 <212> DNA <213> Neisseria meningitidis <220> .
<221> CDS <222> (1)..(462) <400> 49
WO 01/85772
PCT/GB01/02003
<210> 50 <211> 154 <212> PRT
WO 01/85772 φ ' φ φ φ · e φ · ΰ ·
9 Φ φ φ φ · φ φ · · · I » φ « <
• φ « * φ « Φ
PCT/GBO1/02003
Ala Lys Pro Val Leu Pro Ala Asp Lys Lys
145 150 <210> 51 <211> 969 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(969) <400> 51
WO 01/85772
PCT/GB01/02003
969
WO 01/85772
PCT/GBO1/O2OO3
Ser Thr Met <210> 52 <211> 323 <212> PRT <213> Neisseria meningitidis <400> 52
195 200 205 • · · · » · * · · • · ·
Ser Thr Met <210> 53 <211> 864 <212> DNA <213> Neisseria meningitidis <220>
WO 01/85772 ·· «·
PCT/GB01/02003
100 ® 4
101
WO 01/85772
PCT/GBO1/02003
Leu Thr Asp Lys Glu Glu Asn Ala Lys Lys Ala Val Ala Asp Leu Lys 165 170 175
Ala Lys Lys Gly Phe Asp Ala Val Leu Lys Gin Tyr Ser Leu Asn Asp 180 185 190
Arg Thr Lys Gin Thr Gly Ala Pro Val Gly Tyr Val Pro Leu Lys Asp 195 200 205
Leu Glu Gin Gly Val Pro Pro Leu Tyr Gin Ala Xle Lys Asp Leu Lys 210 215 220
Lys Gly Glu Phe Thr Ala Thr Pro Leu Lys Asn Gly Asp Phe Tyr Gly
225 230 235 240
Val Tyr Tyr Val Asn Asp Ser Arg Glu val Lys Val Pro Ser Phe Asp
245 250 255
Glu Met Lys Gly Gin Ile Ala Gly Asn Leu Gin Ala Glu Arg Ile Asp 260 265 270
Arg Ala Val Gly Ala Leu Leu Gly Lys Ala Asn Ile tys pro ai = rys 275 280 285 <210> 55 <211> 1257 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1257) <400> 55
102
WO 01/85772 PCT/GB01/02003 • to · to · to to ······ • to · · · · to · · · to * '· . · · * · · · to · · · i ' «i · * to • to toto · · ·· · · ··· <· < to
103
PCT/GBO1/02003 » ·« · · ··
1257
104 ·· 4444
WO 01/85772 PCT/GB01/02Q03
4 4 ·· ·4 • · 4 4 4 4
4 «44
4 4 · · 4
4 4 4 ·
44444444 44 <210> 56 <211> 419 <212> PRT <213> Neisseria meningitidis <400> 56
105 ·· 9999 • 9
WO 01/85772 PCT/GB01/02003 ·· ·· 99
9 9 9 9 9 9 9
9 9 · ·
9 9 9··
9 9 9 9 • 999 9999 99 9
405 410 415
Pro Thr Thr <210> 57 <211> 1407 <212> DNA <213> Neisseria meningitidis <220>
106 ·« ···· ·· ·· ·· • · · · · · · · φ · ·
9 · · · · · · «
4 949 4 944 9 4
4 4 4 4 4 9 4 4 9
4994 4444 ·· 444 44 ··
WO 01/85772 PCT/GB01/02003 <221> CDS <222> (1)..(1407) <400> 57
107 ·· ··«* * · ·
WO 01/85772
365
108
WO 01/85772 PCT/GBO1/02003 ·· ·· fl· • fl · · flfl fl fl · · • · · · · • · · fl • flflfl ···· ·· • fl ·*·· • · · • flfl flfl* · • · · · flfl flfl
450 455 460 atg ccg tet gaa aat 1407
Met Pro Ser Glu Asn
465 <210> 58 <211> 469 <212> PRT <213> Neisseria meningitidis <400> 58
109 ·· ·· «· · • · · · » c ·· • · · · · • · · * · t o · · · · ···· ···· ·· ··· ···· ·· • · · • · · • · · • · · · ·· ··
Ile
Thr
Phe
Val
140
Lys
Ala
Gly
Trp
Val
220
Val
Gly
Ala
Leu
Tyr
300
Leu
Leu
PCT/GB01/02003
Pro Gin Val Ile 95
Arg Leu Ile Arg 110
Leu Gly Met Leu 125
Gin Val Gly Ala
His Gly Leu Ala 160
Gly Ala Ala Gly 175
Val Ile Phe Ala 190
Glu Arg Gin Ile 205
Ala Ile Gin Gly
Leu Glu His Ile 240
Ala Ala Gly Gly 255
Phe Ala Pro Arg 270
Leu Ala Ala Leu 285
Gin Gly Lys Thr
His Gly Ile Tyr 320
Ala Thr Val Phe
110 . 4. Jkř,
455
460
450
Met Pro Ser Glu Asn 465 <210> 59 <211> 423 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(423) <400> 59
111
WO 01/85772 PCT/GB01/02003
<210> 60 <211> 141 <212> PRT <213> Neisseria meningitidis <400> 60
Met Thr Gin Glu Thr Ala Leu Gly Ala Ala Leu Lys Ser Ala Val Gin 15 10 15
Thr Met Ser Lys Lys Lys Gin Thr Glu Met Ile Ala Asp His Ile Tyr 20 25 30
Gly Lys Tyr Asp Val Phe Lys Arg Phe Lys Pro Leu Ala Leu Gly Ile 35 40 45
Asp Gin Asp Leu Ile Ala Ala Leu Pro Gin Tyr Asp Ala Ala Leu Ile 50 55 60
112 ··· 0 0 0 0 0 0 ·
0 000· 000 • · · · · 0 0 0 0 ·
0 0 ·* · .· *··
WO 01/85772
Ala Arg Val Leu Ala Asn His Cys Arg Arg Pro Arg 65 70 75
Leu Ala Arg Gly Gly Lys Arg Phe Asp Leu Asn Asn 85 90
Glu Val Thr Pro Glu Glu Gin Ala Ile Ala Gin Asn 100 105
Gin Gin Ala Leu Gin Gin Gin Ser Ala Gin Ala Val 115 120
Ser Val Glu Ala Glu Ala Ala Glu Ser Ser Thr Thr 130 135 140
PCT/GBO1/02003
Tyr Leu Lys Ala 80
Arg Phe Lys Gly 95
His Pro Phe Val 110
Ala Glu Thr Pro 125
Glu <210> 61 <211> 1377 <212> DNA <213> Neisseria meningitidis <22 0>
<221> CDS <222> (1)..(1377) <400> 61
113 • · · ·
WO 01/85772 PCT/GBO1/02003
114
WO 01/85772 PCT/GB01/02003 ···· β · · · « β · • · · · · ··· • · · · · · · · · · • « · β β β β · β
115 • · · ·
210 215 220
116
WO 01/85772
PCT/GB01/02003
450 455 <210> 63
117 ·· ·· ·· · ·· ···· ········ · · ·
WO 01/85772 PCT/GB01/02003 <211> 1098 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1098, <400> 63
118
WO 01/85772
PCT/GB01/02003
119
WO 01/85772 PCT/GB01/02003
<210> 64 <211> 366 <212> PRT <213> Neisseria meningitidis <400> 64
180 185 190
120 • · ··· ·
WO 01/85772 PCT/GB01/02003
<210> 65 <211> 461 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(459) <400> 65 atg caa age ggt ttt aac gct att ttc agg aat gac acc atg cag gtt 48
Met Gin Ser Gly Phe Asn Ala Ile Phe Arg Asn Asp Thr Met Gin Val
1 5 10 15
121
WO 01/85772 PCT/GB01/02003
<210> 66 <211> 153 <212> PRT <213> Neisseria meningitidis <400> 66
Met Gin Ser Gly Phe Asn Ala Xle Phe Arg Asn Asp Thr Met Gin Val 1 5 10 15
Thr Ser Lys Trp Ile Asp Gly Met Cys Phe Val Gly Thr Thr Glu Gly
122
WO 01/85772 PCT/GB01/02003
20 25 30
<210> 67 <211> 1659 <212> DNA <213> Nelsseria meningitidis <220>
<221> CDS <222> (1,..(1659, <400> 67 atg act gac aac agc cct cct cca aac gga cac gcc caa gca cgc gtc 48
Met Thr Asp Asn Ser Pro, Pro Pro. Asn Gly His Ala Gin Ala Arg Val
15 10 15 cgc aaa aac aac acc ttc ctc tet gcc gtc tgg ctg gtt ccg ctg atc 96
Arg Lys Asn Asn Thr Phe Leu Ser Ala Val Trp Leu Val Pro Leu Ile
20 25 30 gcg ctg att gcc ggc ggc tgg ctt tgg gtt aag gaa atc cgc aac agg 144
Ala Leu ile Ala Gly Gly Trp Leu Trp Val Lys Glu Ile Arg Asn Arg
123 φφ ·· ·· φ φ φ φφφ φ • φ φ * φ · φφ φφ φ φ φφφφ φφφ φ φφφφ φφφφ φ φ φ φφφ φφφφ φφφφ φφ·· φφ φφφ φφ φφ
W0 01/85772 PCT/GB01/02003
124 ·* ····
WO 01/85772 PCT/GBO1/02003 •« · · ·« • · · · · · • · * · • · · ♦ · • · · · ··· · · · ·· ··
125 ·· ·* * ·· ··«· • · · · · · ·« « · · « · · · · · « β « ··'·· · · · Λ φ • · * · · · · · · ···*···« ·« ··· ·· ··
WO 01/85772 PCT/GB01/02003
545 550 <210> 68 <211> 553 <212> PRT
126 ·· ·· ·· · • · · · ·' · »« Λ » « • · · · · ··· « ··«· ···· »· ·»·· ···· ···· ·· ··· ·« «·
WO 01/85772
PCT/GBO1/02003
Gly Pro Val Val Thr Leu Leu Met Asp Ser Ala Glu Gly Ile Glu Val 50 55 60
Asn Asn Thr Val Ile Lys Val Leu Ser Ile Asp Val Gly Arg Val Thr
65 70 75 80
Arg Ile Lys Leu Arg Asp Asp Gin Lys Gly Val Glu Val Thr Ala Gin
85 90 95
Leu Asn Ala Asp Val Ser Gly Leu Ile Arg Ser Asp Thr Gin Phe Trp 100 105 110
Val Val Lys Pro Arg Ile Asp Gin Ser Gly Val Thr Gly Leu Gly Thr 115 120 125
Leu Leu Ser Gly Ser Tyr Ile Ala Phe Thr Pro Gly Lys Ser Asp Glu 130 135 140
Ala Lys Asp Val Phe Gin Val Gin Asp Ile Pro Pro Val Thr Ala Ile
145 150 155 160
Gly Gin Ser Gly Leu Arg Leu Asn Leu Ile Gly Lys Asn Asp Arg Ile
165 170 175
Leu Asn Val Asn Ser Pro Val Leu Tyr Glu Asn Phe Met Val Gly Gin 180 185 190
Val Glu Ser Ala His Phe Asp Pro Ser Asp Gin Ser Val His Tyr Thr 195 200 205
Ile Phe Ile Gin Ser Pro Asn Asp Lys Leu Ile His Ser Ala Ser Arg 210 215 220
Phe Trp Leu Glu Ser Gly Ile Asn Ile Glu Thr Thr Gly Ser Gly Ile
225 230 235 240
Lys Leu Asn Ser Ala Pro Leu Pro Ala Leu Leu Ser Gly Ala Ile Ser
245 , 250 255
Phe Asp Ser Pro Lys Thr Lys Asn Ser Lys Asn Val Lys Ser Glu Asp 260 265 270
Ser Phe Thr Leu Tyr Asp ser Arg Ser Glu Val Ala Asn Leu Pro Asp 275 280 285
Asp Arg Ser Leu Tyr Tyr Thr Ala Phe Phe Lys Gin Ser Val Arg Gly
127
Ά-.·. ·. Λ·.
WO 01/85772
PCT/GB01/02003
128 • ·
WO 01/85772 PCT/GB01/02003
545 550 <210> 69 <211> 330 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(330) <400> 69
<210> 70 <211> 110 <212> PRT <213> Neisseria meningitidis
129
WO 01/85772
PCT/GB01/02003
<210> 71 <211> 2274 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(2274) <400> 71 atg aca aca tta cat ttc tea ggc ttc ccg cgt gtc ggt gcc ttc cgc 48
Met Thr Thr Leu His Phe Ser Gly Phe Pro Arg Val Gly Ala Phe Arg
15 10 15 gaa ttg aaa ttc gca caa gaa aaa tac tgg cgc aaa gaa atc age gag 96
Glu Leu Lys Phe Ala Gin'Glu Lys Tyr Trp Arg Lys Glu Ile Ser Glu
20 25 30 caa gaa ttg ctg get gtt get aaa gac ttg cgc gag aaa aac tgg aaa 144
Gin Glu Leu Leu Ala Val Ala Lys Asp Leu Arg Glu Lys Asn Trp Lys
35 40 45 cac cag gcc get gcc aac gcc gat tac gtt gcc gta ggc gat ttc act 192
His Gin Ala Ala Ala Asn Ala Asp Tyr Val Ala Val Gly Asp Phe Thr
130
WO 01/85772 PCT/GBO1/02003
131
132 • · · · · · ···· ···· 9 9 β « 9 9 9 9 9 9 9 • « · · · · · · · « 0 · ··· · · 9 ·
9999 9999 99 999 99 99
WO 01/85772 PCT/GBO1/02003
435 440 445
133
WO 01/85772 PCT/GBO1/02003
755 <210> 72 <211> 758 <212> PRT
134
WO 01/85772
V ·
44·«···» «fc · · 4 ·
4« 4
4 · 44 4
4 · 4 * · ·
4 4 · · · · 4
9 9 9 9 9 9 9
99 ·9 9 99 9 9
PCT/GBO1/02003
135 ·«·« • •flfl flflfl· fl fl
136 • ·· · · · · ·
WO 01/85772 PCT/GB01/02003
545 550 555 560
Arg Ala Glu Leu Ala Lys 755 <210> 73 <211> 2118 <212> DNA <213> Neisseria meningitidis
137
.. .............
WO 01/85772
PCT/GB01/02003 <220>
<221> CDS <222> (1)..(2118) <400> 73
138 • ·
WO 01/85772 PCT/GBO1/02003
139
WO 01/85772
PCT/GB01/02003
140
WO 01/85772 PCT/GB01/02003
tat gcg 2118
Tyr Ala
705 <210> 74 <211> 706 <212> PRT <213> Neisseria meningitidis <400 74
141
WO 01/85772
PCT/GB01/02003
245 250 255
142
WO 01/85772
PCT/GB01/02003
143
WO 01/85772 PCT/GB01/02003
690 695 700
Tyr Ala 705 <210> 75 <211> 1686 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS
144 • 9
WO 01/85772 PCT/GB01/02003 <222> (1)..(1686) <400> 75
145
WO 01/85772
PCT/GB01/02003
146
WO 01/85772
PCT/GBO1/02003
gta gca
1686
147 ·· ·· ·· · ·· ···· ··· · ···· · · · • · · · · · · ·
WO 01/85772 PCT/GBO ί/02003
Val Ala <210> 76 <211> 562 <212> PRT <213> Neisseria meningitidis <400> 76
148 • «
149 *· ···· « · · • · · • · · · • · · « ·· ·· ·· ·· • · · ·
Val Ala <210> 77 <211> 1773 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1).. (1773) <400> 77
50 55 60
150
49 4499
44 ·· ·· • · 4 » · · · • · · · • 9 4 · · • · * · 944 · · · · * *· · • « * • · ·
4 4 4 4
4 4 9 9
44 49
WO 01/85772
PCT/GB01/02003
245 250 255
151 ···· ····
WO 01/85772
PCT/GB01/02003
445
152 ········ · ·
WO 01/85772
PCT/GB01/02003
<210> 78 <211> 591 <212> PRT <213> Neisseria meningitidis <400> 78
Met Ser Ile Val Leu His Gly Val Ala Ala Gly Lys Gly Ile Ala Val
1 5 10 15
Gly Cys Ala His Leu Ile Ala Arg Gly Thr Glu Glu Val Pro Gin Tyr
153
WO 01/85772
PCT/GB01/02003
154
WO 01/85772
530
Ile Leu. His 545
Ile Arg cys
Asn Ser Val
PCT/GB01/02003
<210> 79 <211> 1062 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1062) <400> 79
156
WO 01/85772
PCT/GB01/02003
157 • · α · · ·
WO 01/85772
PCT/GB01/02003
960
1008
1056
1062 <210> 80 <211> 354 <212> PRT <213> Nelsseria meningitidis <400> 80
115 120 125
158
WO 01/85772
PCT/GB01/02003
Gin Lys Asn Thr Asp Arg Phe Ile Cys 130 135
Val Gin Thr Ala Asp Asn Pro Phe Lys 145 150
Asn Gly Ile Asp Thr Gly Arg Phe Pro 165
Ser Arg Phe Phe Thr Val Ala Tyr Ala 180 185
Gly Leu Glu Asn Leu Ile Glu Ala Cys 195 200
Pro Gin Ile Arg Leu Lys Leu Ala Gly 210 215
Cys Arg Leu Lys Arg Asp Val Ser Ala 225 230
Ser Phe Glu Gly Phe Thr Glu Lys Leu 245
Asp Val Val Val Leu Pro Ser Leu Val 260 265
Leu Cys Glu Ala Met Tyr Cys Arg Thr 275 280
Gly Ala Gin Lys Glu Ile Ile Glu His 290 295
Asp Arg Leu Thr Pro Glu Ser Leu Ala 305 310
Leu Asn Pro Glu Thr Lys Asn Ala Leu 325
Val Ala Asn Arg Phe Thr Ile Asn His 340 345
Ala Ile
Val Ser Arg Leu Val Tyr Asp 140
Glu Lys Tyr Arg Ile Val His 155 160
Pro Pro Gin Glu Lys Pro Asp 170 175
Gly Arg Ile Ser Pro Glu Lys 190 val Ile Leu His Arg Lys Tyr 205
Asp Gly His Pro Asp Tyr Met 220
Ser Gly Ala Glu Pro Phe Val 235 240
Ala Ser Phe Tyr Arg Gin Ser 250 255
Pro Glu Ala Phe Gly Leu Ser 270
Ala Val Ile Ser Asn Thr Leu 285
His Gin Ser Gly Ile Leu Leu 300
Asp Glu Ile Glu Arg Leu Val 315 320
Ala Thr Ala Gly His Gin Cys 330 335
Thr Ala Asp Lys Leu Leu Asp 350
159 ···· ····
WO 01/85772 PCT/GB01/02003 <210> 81 <211> 795 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(795) <400> 81
160 ·· ·« ·· • · · · · ·
WO 01/85772
PCT/GB01/02003
260 265 <210> 82 <211> 265 <212> PRT
50 55 60
161
<220>
162 • · 9 99 9
99 *9 9« • · f · · v · · * · · • »49» · « « • ···· 9*9» « • · · 9 9 · 9 9 ·
9999 9499 99 ··· 99 «·
WO 01/85772 PCT/GB01/02003 <221> CDS <222> (1)..(876) <400> 83
163 φφ φφ φφ '* φ φ · « « • · φ · φφφφ φ φ > φ φ φφφφ φφφφ φφ φφφφ φ φφ φφ « φ φ * φ φ » φφφφ φ • φ φ φ φ φφφ φφ φφ
W0 01/85772
285
164
290
155
WO 01/85772
PCT/GBO1/02003 <2l0> 85 <211> 1545 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1545) <400> 85
166
167
WO 01/85772
PCT/GB01/02003
cgc ega gcc 1545
Arg Arg Ala
515
168
WO 01/85772
PCT/GBO1/02003 <210> 86 <211> 515 <212> PRT <213> Neisseria meningitidis <400> 86
210 215 220
169
WO 01/85772
PCT/GBO1/02003
465
470
475
480
170
WO 01/85772 PCT/GB01/02003
Ala Val Ser Leu Leu Pro Asp Leu Asp Asn Phe Val Ala Asn Asn Ile 485 490 495
Ile Ser Gly Gly Asp Gly Trp Leu Asp Ala Lys Leu Met Cys Lys Glu 500 505 510
Arg Arg Ala 515 <210> 87 <211> 840 <212> DNA <213> Neisseria meningitidis ;
<220>
<221> CDS <222> (1)..(840) <400> 87
171
WO 01/85772
PCT/GB01/02003
100 105 110
<210> 88
172 ·♦ ·· ·· · ···
WO 01/85772 PCT/GB01/02003 <211> 280 <212> PRT <213> Neisseria meningitidis <400> 88
173
00 00 0«
0 · e 0 β · « • 000
0 0 0 0 0
0 0 0 0 00000000 0 0 0
00 0 00 0
0 0 0
0 0«
0 0 0
0 0 0 0
00 00
WO 01/85772
PCT/GB01/02003
275
280 <210> 89 <211> 1584 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1584, <400> 89 atg gca ctt ttc ctc age ata ttc ccc atc gtc ctg ctg att tgg ctg 48
Met Ala Leu Phe Leu Ser Ile Phe Pro Ile Val Leu Leu Ile Trp Leu
1 5 10 15 atg gtg aaa aaa aac agt atg ccc tcc tac gtc gcg ctg ccg att acc 96
Met Val Lys Lys Asn Ser Met Pro Ser Tyr Val Ala Leu Pro Ile Thr
20 25 30 gca gtg ctg att tac gcc atc aaa ctt ttc tac ttc gac gat gcg ggc 144
Ala Val Leu Ile Tyr Ala Ile Lys Leu Phe Tyr Phe Asp Asp Ala Gly
35 40 45 atg ctg ctc aac gcc acc gcc gct tcc ggc ctc gtc aaa acg ctc acg 192
Met Leu Leu Asn Ala Thr Ala Alá Ser Gly Leu Val Lys Thr Leu Thr
50 55 60 ccg att acc gtg att ttc'ggc gcg att atg ttc aac cgt atg atg gaa 240
Pro Ile Thr Val Ile Phe Gly Ala Ile Met Phe Asn Arg Met Met Glu
65 70 75 80 acc acg ggc tgc atc gat gtc atc cgc aaa tgg ctg gcg acc atc age 288
Thr Thr Gly Cys Ile Asp Val Ile Arg Lys Trp Leu Ala Thr Ile Ser
85 90 95 ccc aac ccc gta gcg caa ctg atg att atc ggc tgg gct ttt gcc ttt 336
174
WO 01/85772 PCT/GB01/02003
175
WO 01/85772 PCT/GBO1/02003 • · · · · ······ e β · to 0·«· ·· · • ·· ·· « · · • ··«· · · · · · β to · · to · to to to • to·· ···· ·· ··· ·· ··
176
WO 01/85772
PCT/GB01/02003
1536
1584 <210> 90 <211> 528 <212> PRT
177 ·,« ·· ·· · ·· ···· ···· · · · · · · · • · · · · ···
9 · · · · 4 · · » ···· ···· ·· ··· 94 *·
WO 01/85772 PCT/GB01/02003
178
WO 01/85772 PCT/GB01/02003
<210> 91 <211> 1686 <212> DNA <213> Neisseria meningitidis <22 0>
<221> CDS <222> (1) . . (1686) <400> 91 atg tta caa tcc gaa aat tcg aaa aat tta atc tet tgt tea ata aag 48
Met Leu Gin Ser Glu Asn Ser Lys Asn Leu Ile Ser Cys Ser Ile Lys
1 5 10 15 gct tta cca atc atg att tet acc aac ggc atc acc atg cag ttc ggc 96
Ala Leu Pro Ile Met Ile Ser Thr Asn Gly Ile Thr Met Gin Phe Gly
20 25 30 gcg aag ccg ctg ttt gaa aac gta tcc gtt aaa ttc ggc gaa ggc aac 144
Ala Lys Pro Leu Phe Glu Asn Val Ser Val Lys Phe Gly Glu Gly Asn
35 40 45 cgc tac ggt ttg atc ggc gcg aac ggc tea ggc aaa tcc acc ttc atg 192
Arg Tyr Gly Leu Ile Gly Ala Asn Gly Ser Gly Lys Ser Thr Phe Met
50 55 60
179
WO 01/85772
PCT/GB01/02003
180
WO 01/85772
PCT/GB01/02003
181
WO 01/85772 PCT/GB01/02003 ·'·
gta gca 1686
Val Ala <210> 92 <211> 562 <212> PRT <213> Neisseria meningitidis <400> 92
35 40 45
182
183
184 • ··· ···· • »·
WO 01/85772 PCT/GBO1/O2OO3
Val Ala <210> 93 <211> 1126 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1125) <400> 93
185 *1
-l·
186 • · 4 « ·«·· » • · · · 4 · ·
WO 01/85772 PCT/GB01/02003
<210> 94 <211> 375 <212> PRT <213> Neisseria meningitidis <400> 94
130 135 140
187 « · · • · · ··
188 • # · 9 9 9 ® ® < · • · · » · 9 9 9
WO 01/85772 PCT/GBO1/O20O3 <210> 95 <211> 1725· <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1725) <400> 95
189
WO 01/85772 PCT/GB01/02003
190 fcfc fcfc fcfc · fcfcfcfc e © ee β • fcfc·· · • fcfcfc fc fcfcfc • · fcfcfc fc • fc
191
WO 01/85772
PCT/GB01/02003
1725
570
575 <210> 96 <211> 575 <212> PRT <213> Neisseria meningitidis <400> 96
192
WO 01/85772 PCT/GB01/02003
193
<210> 97 <211> 570 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(570) <400> 97
194 •fl ·· ·· • · · · · · • · · · • · · · · · · · · ···· ···· ·· • · ·· ····
WO 01/85772 PCT/GB01/02003
<210> 98 <211> 190 <212> PRT <213> Neisseria meningitidis <400> 98
195
WO 01/85772 PCT/GBO1/02003
<210> 99 <211> 1515 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1515) <400> 99
196 • · · ·
WO 01/85772 PCT/GB01/02003 • · ··· ···· ··· ···· ·· ··· ·· ··
197 • · · · .·’'·! i
WO 01/85772
PCT/GBO1/02003
370
375
380
198 ·· · · ···· • ·
WO 01/85772 PCT/GB01/02003
<210> 100 <211> 505 <212> PRT <213> Neisseria meningitidis <400> 100
35 40 45
199
200 ·· ···» • » ·
500 505 <210> 101 <211> 1476 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS
201
WO 01/85772 PCT/GBO1/02003 <222> (1)..(1476) <400> 101
202
WO 01/85772
PCT/GB01/02003
203
WO 01/85772 PCT/GB01/02003
<210> 102 <211> 492 <212> PRT <213> Neisseria meningitidis <400> 102
204
WO 01/85772 PCT/GB01/02003
205
V /· .. „ * r :
· · • 4 9494 4444 ·« > ·« • · ·« «·
WO 01/85772 PCT/GB01/02003
305 310 315 320
485 490 <210> 103 <211> 1089 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1089) <400> 103 atg agt ttg aaa tgc ggc atc gtc ggt ttg ccc aac gtc ggc aaa tcc 48
206
WO 01/85772 • » • · ·· ·»·
PCT/GBO1/02003
207
260 265 270
<210> 104 <211> 363 <212> PRT <213> Neisseria meningitidis
208 ··
WO 01/85772
PCT/GBO1/02003 <400> 104
209
WO 01/85772
PCT/GB01/02003 • · ···· · ·
210 ·· ·«>··
WO 01/85772
PCT/GB01/02003
211 • i β β ·· ··
340 345 350
<210> 106 <211> 392 <212> PRT <213> Neisseria meningitidis <400> 106
Met Ala Lys Met Met Lys Trp Ala Ala Val Ala Ala Val Ala Ala Ala 15 10 15
212 fcfc • fc fcfcfc fcfc fcfc fc fcfc · fc · fc fcfc » · fc fc fcfcfc fc' fc · • · fcfcfc ··· • fcfcfc fcfcfcfc fcfc fcfcfc fcfc fcfc
213 •4 ·· ·· · ·· 4444
4 9 4 4 9 4 44 9 4 9
4 9 4 9 4 4 ·4
4 4 9 4 4 9 4 4 9 9
4 9 4 4 » 4 9 9 4
WO 01/85772
PCT/GBO1/02003
<210> 107 <211> 1185 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1185)
214
99 ···· ♦ · ·· ·· « • · · 9 9 9 99 ♦ 9 · · · • · · · ♦ · • « 9 9 9 •9999999 99 9 99
WO 01/85772
PCT/GBO1/02003
215 ·· ·· • · « e • · • · • · ···· ····
99 9999
9 9 9
9 9 9
9 9 9
9 9 9 9 ·· 99
WO 01/85772 PCT/GB01/02003 • β β· • · ·
9 9 9
9 9 9
99 999
385 390 ' 395 <210> 108 <211> 395 <212> PRT <213> Neisseria meningitidis <400> 108
216 ο β e e e β·· · · · • · ·· · · ? « • ··*· ···· · • · · · · · · · ·
WO 01/85772 PCT/GB01/02003
217 • · β β β 9 9 4 4 4 4 9
4 · 9 · 4 · '·♦ • · β 4 · 9 9
4 4 9 9 ' 9 ··· · ······· ·· 499 44 44
WO 01/85772 PCT/GB01/02003
<210> 109 <211> 1257 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1257) <400> 109 atg aaa cag acc gtc ctc -aaa aat aac ctg caa aac ctg ctt gaa age 48
Met Lys Gin Thr Val Leu Lys Asn Asn Leu Gin Asn Leu Leu Glu Ser
15 10 15 gca gaa aat atc ctg ctg ctt caa ggc cct gtc ggc gat ttt ttt ctg 96
Ala Glu Asn Ile Leu Leu Leu Gin Gly Pro Val Gly Asp Phe Phe Leu
20 25 30 cgc ctt gcc gac tgg ctg act gca aac ggc aaa acc gta cat aaa ttc 144
218 'i.
• ·
219 ·· * * • · β· · to · · ·
Íte · ·.-·♦ • · ·
WO 01/85772
PCT/GB01/02003
405
1257 cca aca acc
220
WO 01/85772 PCT/GB01/02003
Pro Thr Thr .· <210> 110 <211> 419 <212> PRT <213> Neisseria meningitidis <400> 110
195 200 205
221 »·
WO 01/85772 PCT/GBOV02003
Pro Thr Thr <210> 111 <211> 1674 <212> DNA <213> Neisseria meningitidis
222
WO 01/85772 PCT/GB01/02003 <220>
<221> CDS <222> (1)..(1674) <400> 111
223
WO 01/85772 PCT/GB01/02003
224
PCT/GBO1/02003
WO 01/85772
355 360 aaa aac gta ttc gga ctg ccc gtc gtc gtt gcg ctc Lys Asn Val Phe Gly Leu Pro Val Val Val Ala Leu 370 375 380 tcc gac tcc gat gcc gag ttg gcg atg att gaa aaa
Ser Asp Ser Asp Ala Glu Leu Ala Met Ile Glu Lys
385 390 395 cac ggc gtt gaa gtt tcc ctg acc gaa gtg tgg ggc
His Gly Val Glu Val Ser Leu Thr Glu Val Trp Gly Lys Gly Gly Ala
405 410 415
365 aac cgc ttc gtg 1152 Asn Arg Phe val gcc tgt gcc gaa 1200 Ala Cys Ala Glu 400 aaa ggt ggt gcg 1248
225 • ·· · • ···· ··· • · * ·._· *«_,*·-· · · • · · · · * »· · ···· ···· ·· «·· ·· ··
WO 01/85772 PCT/GB01/02003
545 550 555 <210> 112 <211> 558 <212> PRT <213> Neisseria meningitidis <400> 112
195 200 205
226 • 9 ·· ·9 · ·· ···· • 9 · 9 · · ·9 · 9 9 • 9999 9··
227 • a
WO 01/85772 PCT/GB01/02003
<210> 113 <211> 475 <212> DNA <213> Neisseria meningitidis' <220>
<221> CDS <222> (1)..(474) <400> 113 atg gaa cac cta ttt gag gaa tgg ttg ccc gac ctg ccc gcc gac gtt 48
Met Glu His Leu Phe Glu Glu Trp Leu Pro Asp Leu Pro Ala Asp Val
15 10 15 tca gac ggc atc ggc ctg ccg atg agc cgg tta ttg aaa gcc cgg tcg 96
Ser Asp Gly Xle Gly Leu Pro Met Ser Arg Leu Leu Lys Ala Arg Ser
20 25 30 ctg act gcc gca ttg cgc gcc ttg ccg cat ctg ttt tcg gta gaa ctg 144
Leu Thr Ala Ala Leu Arg Ala Leu Pro His Leu Phe Ser Val Glu Leu
35 40 45 ctg aaa ctg ggc gaa ttg gaa acg gaa tgc gga ggg cgg ctg gtg cgc 192
Leu Lys Leu Gly Glu Leu Glu Thr Glu Cys Gly Gly Arg Leu Val Arg
50 55 60 gaa gtt ttg ttg aag ctg gac ggt atc cct gtt gtc gcg gca agg agc 240
Glu Val Leu Leu Lys Leu Asp Gly Ile Pro Val Val Ala Ala Arg Ser
228 ·· ···· • 9 ·
9 9 9 · L
WO 01/85772 PCT/GB01/02003
65 70 75 80
145 150 155 <210> 114 <211> 158 <212> PRT <213> Neisseria meningitidis <400> 114
229
V «
WO 01/85772
105
Ala Val Phe Gly Glu Gly 120
Arg Phe Ser His His Gly 135 140
Pro Glu Leu Lys Arg Phe 155
PCT/GBO1/02003
110
Cys Gly Arg Tyr 125
Glu Glu Met Leu
Ile Gly <210> 115 <211> 1476 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1476) <400> 115
230
WO 01/85772
PCT/GB01/02003
231
OÁuť»r to 'j :
9 9
--.9
9 9
WO 01/85772 »9 99 ·· 9
9 99 9 9 999
9 9 · 9 *
9 9 9 9 « 9
9 9 9 9 9
9999 9999 99 999
PCT/GBO1/02003
232 ·· ·· ·♦ · ····♦· • · · * · ♦ ·· · · · • 4 · · » · 4 4
4 «··· » · · · * • 4 4 · ·' -« · · φ ···« ···· ·· ··· ·· 44
WO 01/85772 PCT/GB01/02003
Ala Lys Ile Asp Glu Ile Trp Glu Glu Leu Gly Leu 485 490 <210> 116 <211> 492 <212> PRT <213> Neisseria meningitidis <400> 116
195 200 205
233 ·· ·«·« ·· <*· • · « • · β « • · ··· ···«
WO 01/85772 *· · • · · · • · ·
9 · ,· • · ··*’ ·· ··· ·· <·
PCT/GB01/02003
450 455 460
234
WO 01/85772 : ’'··::ο-- *·· ’··—··.' '···:( i ·. >'·’.* ;.. ·- ,\. ·· fcfc fcfc · ·· ·«·»
..λ-·:.··/· ,0.:10-0^··· • · · r · · ·· · · · • fc · « · ··· • fcfc·· · Λ · fc · fc e · fc.
• fcfcfc fcfc·· ·· fcfcd
PCT/GB01/02003
Thr Asp Arg Glu Trp Gly Arg Val Ile Lys Lys Asp Pro Ala Val Thr 465 470 475 480
Ala Lys Ile Asp Glu Ile Trp Glu Glu Leu Gly Leu 485 490 <210> 117 <211> 1515 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1515) <400> 117
235 ·· ·· • · · « ·*» ·!»·«
Κ · · ···
WO 01/85772 PCT/GB01/02003 ·♦·· ·*··
236
WO 01/85772
PCT/GBO1/02003
237
WO 01/85772
PCT/GB01/02003
238 » · · · · • · · · · • 9 · ·
WO 01/85772
PCT/GBO1/02003
450
455
460
239
WO 01/85772
PCT/GB01/02003
500
505 <210> 119 <211> 756 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(756) <400> 119
240 • ·
WO 01/85772 PCT/GBO1/02003
245 250 <210> 120 , <211> 252 <212> PRT <213> Neisseria meningitidis <400> 120
Met Glu Thr His Ser Gly Cys Phe Leu Arg Lys Thr Val Met Lys Asp 15 10 15
241
245 250 <210> 121
242
WO 01/85772
PCT/GBO1/02003 <211> 570 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(570) <400> 121
243
WO 01/85772 PCT/GB01/02003
<210> 122 <211> 190 <212> PRT <213> Neisseria meningitidis <400> 122
244 ·· 44 44
44 ·44 4
WO 01/85772 PCT/GB01/02003
Arg Ile Arg Glu Lys Gly Phe Pro Val Asp Arg Asn Ala Val 180 185 190 <210> 123 <211> 2274 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1) . .(2274) <400> 123
245 ·· ·r· ·
94«· «··· · • ·«·· «·· • ·«·· ···· · • · ··· · · · · ··«· ···· *« ·«· Φ·
246
WO 01/85772
PCT/GB01/02003 i
247
WO 01/85772 PCT/GBO1/02003
248
WO 01/85772
740
750
<210> 124 <211> 758 <212> PRT <213> Neisseria meningitidis <400> 124
249
WO 01/85772
130
Ala Gin Ala 145
The Phe Leu
Leu Sec Leu
Ala Leu Val 195
Leu Thr Val 210
Tyr Ala Thr 225
Phe Gly Ser
Asp Gly Leu
Phe Ala Asp 275
Asn Ile Trp 290
Leu Gin Ala 305
Leu Leu His
Asn Lys Pro
Gin Glu Leu 355
Val Ala Glu 370
Asn Ser Ser
PCT/GB01/02003
250
9 9
251
WO 01/85772
PCT/GBO1/02003
<210> 125 <211> 1137 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1137) <400> 125
252 tax
WO 01/85772
PCT/GBO1/02003
253
WO 01/85772 PCT/GB01/02003
<210> 126 <211> 379 <212> PRT <213> Neisseria meningitidis <400> 126 Met Ser Arg Leu Trp Phe Phe Ala Ala Lys Asn Ile Ile Ile Arg Leu 15 10 15
Ile Tyr Leu Leu Pro Lys Glu Thr Gin Met Ala Leu Val Ser Met Arg 20 25 30
254
κ.
f • · · · ·
WO 01/85772
Gin Leu Leu Asp 35
Asn Val Asn Asn 50
Gin Val Asn Ala 65
Tyr Ala Gly Ala
PCT/GB01/02003
Glu Phe Pro His 100
Pro Asp Val Cys 115
Met Asp Gly Ser 130
Tyr Asn Val Asn 145
Gly Val Ser Val
Gly Glu Ala Gly 180
His Asp Gin Met 195
Asp Thr Gly Val 210
Ala Tyr Lys Phe 225
Arg Ile Lys Glu
His Gly Ser Ser 260
Tyr Gly Gly Asn 275
280 285
255 • ' • ·
WO 01/85772
Val Glu Gly Ile Lys His Gly Val Arg Lys Val Asn Ile 290 295 300
Leu Arg Leu Ala Ser Thr Gly Ala Val Arg Arg Tyr Leu 305 310 315
Pro Ser Asp Phe Asp Pro Arg Lys Tyr Leu Ser Lys Thr 325 330
Met Lys Gin Ile Cys Leu Asp Arg Tyr Leu Ala Phe Gly 340 345
Gin Ala Gly Lys Ile Lys Pro Val Ser Leu Glu Lys Met 355 360 365
Tyr Ala Lys Gly Glu Leu Asn Gin Ile Val Lys 370 375
PCT/GBO1/02003
Asp Thr Asp
Ala Glu Asn 320
Ile Glu Ala 335
Cys Glu Gly 350
Ala Asn Arg <210> 127 <211> 444 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(444) <400> 127
256
0 0
WO 01/85772 PCT/GB01/02003
145 <210> 128 <211> 148 <212> PRT
257 • ·
WO 01/85772
PCT/GB01/02003
100 105 110
<210> 129 <211> 1308 <212> DNA <213> Neisseria meningitidis <22 0>
<221> CDS <222> (1)..(1308) <400> 129 atg tac get aaa aaa ggc ggt ttg gga ctg gtt aaa age cgc cgt ttc 48
Met Tyr Ala Lys Lys Gly Gly Leu Gly Leu Val Lys Ser Arg Arg Phe
15 10 15 gca cct ctt ttc get acg cag ttt ctc ggc gcg ttc aac gac aat gtg 96
Ala Pro Leu Phe Ala Thr Gin Phe Leu Gly Ala Phe Asn Asp Asn Val
20 25 30 ttc aaa acc gcg ctg ttt gtg atg att ggg ttt tac ggt ttg ggg caa 144
Phe Lys Thr Ala Leu Phe Val Met Ile Gly Phe Tyr Gly Leu Gly Gin
35 40 45 aac ggc ttc ctg cct gcc gga cag atg ttg aac ttg ggc gcg ttg ctg 192
Asn Gly Phe Leu Pro Ala Gly Gin Met Leu Asn Leu Gly Ala Leu Leu
50 55 60 ttt att ttg ccg tat ttc 'ctg ttt tcc tcg ctg tcg ggg cag ttg ggt 240
Phe Ile Leu Pro Tyr Phe Leu Phe Ser Ser Leu Ser Gly Gin Leu Gly
65 70 75 80 aac aaa ttc gac aag gcc gtt ttg gcg cgt tgg gcc aag gtg ctg gaa 288
Asn Lys Phe Asp Lys Ala Val Leu Ala Arg Trp Ala Lys Val Leu Glu
85 90 95 atg atc att atg gcg gtg gcg gca tac ggg ttt tat atc cgg tet gcc 336
258 • ·
WO 01/85772 PCT/GB01/02003
259
WO 01/85772 PCT/GB01/02003
agg aaa aaa cct 1308
Arg Lys Lys Pro
435 <210> 130 <211> 436 <212> PRT <213> Neisseria meningitidis <400> 130
Met Tyr Ala Lys Lys Gly Gly Leu Gly Leu Val Lys Ser Arg Arg Phe 15 10 15
260 ·· ·· • » · ' · • · ·· • « · • « ·· »·ύ·
WO 01/85772 PCT/GB01/02003 ···· ····
251
9· ·· ·* • 4 · · · · • · · · β · · · · • · · · ·«·· ···· ··
4« ····
WO 01/85772 PCT/GBO1/02003
420 425 430
Arg Lys Lys Pro 435 <210> 131 <211> 876 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(876) <400> 131 atg aat tac gca aaa gaa atc aat gcg tta aat aac age ctt tcc gat 48
Met Asn Tyr Ala Lys Glu Ile Asn Ala Leu Asn Asn Ser Leu Ser Asp
262
WO 01/85772 PCT/GB0V02003
263
WO 01/85772
<210> 132 <211> 292 <212> PRT
264
WO 01/85772 PCT/GB01/02003
275 280 285
Gly Val Arg Pro 290 <210> 133 <211> 1371 <212> DNA <213> Neisseria meningitidis
265
WO 01/85772 PCT/GB01/02003 <220>
<221> CDS <222> (1) . .(1371) <400> 133
266
WO 01/85772
PCT/GB01/02003
gcc 576 Ala gcg 624 Ala gtc 672 Val ctc 720
Leu
240 tgc 768 Cys cgc 816 Arg cgg 864 Arg gtc 912 Val ttc 960
Phe
320 cgc 1008 Arg ctg 1056 Leu acc 1104 Thr
267
268 •······· • ·
269
WO 01/85772
PCT/GBO1/02003
<210> 135 <211> 1374 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1374) <400> 135 atg aaa cac atc cac att atc ggt atc ggc ggc acg ttt atg ggt ggg
Met Lys His Ile His Ile Ile Gly Ile Gly Gly Thr Phe Met Gly Gly
15 10 15 att gcc gcc att gcc aaa gaa gca ggg ttt gaa gtc agc ggt tgc gat
Ile Ala Ala Ile Ala Lys Glu Ala Gly Phe Glu Val Ser Gly Cys Asp
20 25 30 gcg aag atg tat ccg ccg atg agc acc cag ctc gaa gcc ttg ggc ata
Ala Lys Met Tyr Pro Pro Met Ser Thr Gin Leu Glu Ala Leu Gly Ile
35 40 45
144
270 • · ········ ·· ·
WO 01/85772
PCT/GB01/02003
271
WO 01/85772
PCT/GB01/02003
272 • 4
WO 01/85772
PCT/GBO1/02003 age aac ggc ggt ttc ggc gga 1344 Ser Asn Gly Gly Phe Gly Gly
445 aga 1374
Arg <210> 136 <211> 458 <212> PRT
273
WO 01/85772
PCT/GB01/02003
274
WO 01/85772 PCT/GB01/02003
Glu Ala Gly Asp His Ile Leu Val Met Ser Asn Gly Gly Phe Gly Gly 435 440 445
Ile His Thr Lys Leu Leu Asp Ala Leu Arg 450 455 <210> 137 <211> 876 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(876) <400> 137
275
00 ·· 00 0 ·· 0000 0 0 0 0 «··· 0 0 0 « 0 0 · · 000 0 0 0 00 0 0 0 · 0
0 0 0· 0 000.0
0000 0000 00 000 00 00
WO 01/85772 PCT/GB01/02003
cat aaa aaa gac 876
His Lys Lys Asp
290 <210> 138
276 ·· ··
I · · « • β ····
WO 01/85772 PCT/GB01/02003 <211> 292 <212> PRT <213> Neisseria meningitidis <400> 138
277 ·· ·«·· ·· ·· ·· • » « · · Λ · * · · • · · 0 · ♦ · · · ···· ·♦·· ·« « • V · • · ·
4 4 « • · · ·
0· ··
WO 01/85772 PCT/GB01/02003
290 <210> 139 <211> 708 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(708, <400> 139
278
WO 01/85772 PCT/GB»1/<I2OO3
210 215 220
<210> 140 <211> 236 <212> PRT <213> Neisseria meningitidis <400> 140
Leu Arg Gin Leu Gly Cys Leu Ile Gly Phe Phe Ser Val Gly Ile Ile 1 5 10 .15
279 • ·
WO 01/85772 PCT/GBO1/02003
<210> 141 <211> 812 <212> DNA <213> Neisseria meningitidis
280 i
WO 01/85772 PCT/GBO1/02003 <22 0>
<221> CDS <222> (1)..(810) <400> 141
281 • · · ·· · · · · • · · · · · • · · · · • ···· · · · · ·
WO 01/85772 PCT/GBO1/02003
<210> .142 <211> 270 <212> PRT <213> Neisseria meningitidis <400> 142
65 70 75 80
282
WO 01/85772
PCT/GBO1/02003
260 265 270 <210> 143 <211> 1515 <212> DNA ' <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1515) <400> 143
283
WO 01/85772
PCT/GBO1/02003
284
WO 01/85772
PCT/GB01/02003
370
375
380
285
WO 01/85772 PCT/GB01/02003
<210> 144 <211> 505 <212> PRT <213> Neisseria meningitidis <400> 144
35 40 45
286
287
500 505 <210> 145 <211> 840 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS
288 ·· ·»«· «« ·· * • · · · · β ·· • · · · · • · · · · · • · · · · ········ ·· ··Λ • · · · ·· ··
WO 01/85772 PCT/GB01/02003 <222> (1)..(840) <400> 145
289
WO 01/85772
PCT/GB01/02003
672
720
768
816
840
624 <210> 146 <211> 280 <212> PRT
290
WO 01/85772 PCT/GB01/02003
275 280 <210> 147 <211> 1572 <212> DNA <213> Neisseria meningitidis <220>
291
WO 01/85772 PCT/GB01/02003 <221> CDS <222> (1)..(1572) <400> 147
165 170 175
292 • · · · · · · · · ···· ···# ·> c·· »· ··
WO 01/85772 PCT/GB01/02003
340 345 350
293
WO 01/85772 PCT/GBO1/02003
<210> 148 <211> 524 <212> PRT <213> Neisseria meningitidis <400> 148
Met Phe Arg Arg Tyr Leu Pro Asn Arg Gin Met Asn Met Val Ser Lys
294
WO 01/85772
1 5
PCT/GB01/02003
10 15
295
WO 01/85772
PCT/GB01/02003
260 265 270
296
WO 01/85772 PCT/GB01/02003
515 520 <210> 149 <211> 558 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1),.(558) <400> 149
297 • · σ··* ··♦» • ι»
WO 01/85772
PCT/GB01/02003
480
528
558 <210> 150 <211> 186 <212> PRT
298 * y '9 9
9 9 * 9
I'· 9 ’* 9
99·* 9 9 9*
PCT/GB01/02003
Val
160
Ala . 9 · ·· 9 9
9 9 9 9 9 9
WO 01/85772
Arg Lys Phe Arg Tyr Ala Arg Ala Ala Tyr Phe Gly Leu Ile Lys 145 150 155
Ser Ala Gin Ser His Leu Lys Ala Met Cys Leu Asn Leu Leu Lys 165 170 175
Ala Asn Lys Leu Ser Ala Pro Ala Ala Ala 180 185 <210> 151 <211> 1332 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> {1)..(1332) <400> 151
299 • · · fc 9
9 ·'
WO 01/85772
PCT/GBO í/02003
300 • · · · · · ·· · · «
9 · · · · 9 · 9 • 9 9 9 (ί 9 » 9 9 «
9 9 9 9 .· '9 9 9 »
9999 9999 · » 99'9 · fc
WO 01/85772 PCT/GB01/02003
<210> 152 <211> 444 <212> PRT <213> Neisseria meningitidis <400> 152
Met Thr Asp Leu Asn Thr Leu Phe Ala Asn Leu Lys Gin Arg Asn Pro
1 5 10 15
Asn Gin Glu Pro Phe His Gin Ala Val Glu Glu Val Phe Met Ser Leu
301 • · · ♦ · * ·· · · « • · · · · « · · • .· · · '· · ·· · · ···· ···· ·.· ··· ·»
WO 01/85772 PCT/GB01/02003
302 • 9 ·· ·φ · ·· ···· • · · · « « ·Γ • · · 9 ** · · · · '
9 9. · 4
WOOV85772 PCT/GBO1/02003
275 280 285
<210> 153 <211> 867 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(867) <400> 153
303 ·· ·Φ Φφ 9 φΦ φφφφ
Φ Φ · · 9 9 99 φ · 9
9 9 9 '9 '9 9 · Φ ·' ΦΦΦ φ Φ * φ · φ
Φ Φ « Φ ·Φ Φ 'Φ Φ' φ
ΦΦΦΦ ΦΦΦΦ ΦΦ ΦΦΦ Φ» Φφ
WO 01/85772 PCT/GB01/02003
195 200 205
304 ·· ’· · ·· ♦ ·φ< φφφφ φ φ φ · φ · ·· φ φ · • φφφ · · *φ φ · · · φ · '« φ • φ '· · · ν· '· φ φφφφ ···'< φ.φ φφφ φφ
ΦΦ
W0 01/85772 PCT/GB01/02003
275 280 285 gaa 867
Glu <210> 154 <211> 289 <212> PRT
305
WO «1/85772 PCT/GB01/02003
275 280 285
Glu <210> 155 <211> 876 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS
306
WO 01/85772 PCT/GB01/02003 <222> (1)..(876) <400> 155
307 ·· ·· ·* • · ·, · » « • « · · • « ♦ · ·
cat aaa aaa gac His Lys Lys Asp
290
<210> 156 <211> 292 <212> PRT <213> Neisseria meningitidis <400> 156
308
290
309 ···· • ·
WO 01/85772
PCT/GB01/02003 <210> 157 <211> 1008 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1008) <400> 157
310 *· • · · · φ · * · ·.» · • · ···· · · • · · ·. '·· · ···· · · « · φ
WO 01/85772 PCT/GB01/02003
311 ·· ···· ·· ··»« ·*·«
WO 01/85772 PCT/GBO1/02003 <210> 158 <211> 336 <212> PRT <213> Neisseria meningitidis <400> 158
210 215 220
312 ·· ·· ·· * ·» ···· • · · · · · ·· ·· · • · · · · ··· • · · · · ···» · • · · · · · 0 e e ···· ··*· ·· «·· ·· ··
PCT/GBO1/02003
WO 01/85772
325
330
335 <210> 159 <211> 381 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(381, <400> 159
313
WO 01/85772
PCT/GB01/02003
115 120 125 <210> 160 <211> 127 <212> PRT
115 120 125
314
99 9999
9 9
9 · · 9 · • · · ·
WO 01/85772 PCT/GB01/02003 <210> 161 <211> 990 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(990) <400> 161
315
WO 01/85772
PCT/GBO1/02003
316 tta s · * «
WO 01/85772 PCT/GB01/02003 <210> 162 <211> 330 <212> PRT <213> Neisseria meningitidis <400> 162
210 215 220
317
WO 01/85772
PCT/GBO1/O2OO3
<210> 163 <211> 1773 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1773) <400> 163 atg agt atc gtg ctg cac ggc gtg gcg gcg ggc aaa ggc att gcc gtc
Met Ser Xle Val Leu His Gly Val Ala Ala Gly Lys Gly Xle Ala Val
15 10 15 ggt tgc gcc cac ctg att gcg cgc ggt acg gag gaa gtg ccg cag tat
Gly Cys Ala His Leu Ile .Ala Arg Gly Thr Glu Glu Val Pro Gin Tyr
20 ' 25 30 gat gtt gcg gag gcg gac acc gat gcc gaa gcc gaa cgt ttc gat gcc
Asp Val Ala Glu Ala Asp Thr Asp Ala Glu Ala Glu Arg Phe Asp Ala
35 40 45 gcc gtc aaa gcc acg cgc aaa gag ttg gaa cag ctc cgc agc gcg att
Ala Val Lys Ala Thr Arg Lys Glu Leu Glu Gin Leu Arg Ser Ala Ile
144
192
318 • · · · · ··· · · · • ···· ··· • · · · · · · · · · • · ··· ···· ··«· *··· ·· ··· ·· ··
319 β · e · · 9 φ e
320 ·· «« • · · · ·
WO 01/85772 PCT/GB01/02003
580 585 590 <210> 164 <211> 591 <212> PRT <213> Neisseria meningitidis <400> 164
Met Ser Ile Val Leu His Gly Val Ala Ala Gly Lys Gly Ile Ala Val 15 10 15
321
322 ·· ·· ·« • « · · · ·
323 fc· ·· ·· • · · fc 8 fc • · · * • fc fc · fc • · » · • fcfcfc ···· fcfc • fc ·*·· fc
WO 01/85772
Arg Arg Phe 530
Ile Leu His 545
Ile Arg Cys
Asn Ser Val
PCT/GB01/02003
Pro Val Lys Asn Ile 540
Asp Ile Val Lys Val 560
Leu Ile Lys Gin Met 575
Lys Gly Arg Lys 590 <210> 165 <211> 381 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(381) <400> 165 atg gaa cct tcc tcc tac gcg gca gaa aaa aaa gga aaa ggc ggc atc 48
Met Glu Pro Ser Ser Tyr Ala Ala Glu Lys Lys Gly Lys Gly Gly Ile
15 10 15 agg cgc gtc atc aac gca ttc ggc tat tcg ata gac ggc atc gcc gcc 96
Arg Arg Val Ile Asn Ala Phe Gly Tyr Ser Ile Asp Gly Ile Ala Ala
20 25 30 gcc tac cgt tac gaa gcg gca ttc cgt cag gtt ttg tgg ctg aac gcg 144
Ala Tyr Arg Tyr Glu Ala Ala Phe Arg Gin Val Leu Trp Leu Asn Ala
35 40 45 ctg ctg gtg tgc gcg gca ttt ttt tgg gtt tcc gaa aag tcc ctc cgc 192
Leu Leu Val cys Ala Ala Phe Phe Trp Val Ser Glu Lys Ser Leu Arg
50 55 60 ctg ccg ttg att atc gcg' tet ttt gtg tcg gtc att gtc gaa ctg ttc 240
Leu Pro Leu Ile Ile Ala Ser Phe Val Ser Val Ile Val Glu Leu Phe
65 70 75 80 aac act gcc gtc gaa gcc gcc gtc gat cat act tcg act gaa aaa cac 288
Asn Thr Ala Val Glu Ala Ala Val Asp His Thr Ser Thr Glu Lys His
85 90 95
324
WO 01/85772
PCT/GBO1/02003
115 120 125 <210> 166 <211> 127 <212> PRT
<210> 167 <211> 1257 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS
325 • · · · ·· · ···· • · · fc fc··· ·· • · · · · · ·
WO 01/85772 PCT/GB01/02003 <222> (1)..(1257, <400> 167
326
WO 01/85772 PCT/GBO1/O2OO3
:ý
327
WO 01/85772 PCT/GB01/02003
caa aag cat 1257
Gin Lys His <210> 168 <211> 419 <212> PRT <213> Neisseria meningitidis <400> 168
328
PCT/GBO1/02003
WO 01/85772
385
390
395
400
329
WO 01/85772 PCT/GB01/02003
Val Leu Leu Pro Asn Lys His Gin Asp Gly Phe Tyr Tyr Ala Leu Ile 405 410 415
Gin Lys His <210> 169 <211> 804 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1,..(804) <400> 169
330 • ·
WO 01/85772 PCT/GB01/02003
<210> 170 <211> 268 <212> PRT <213> Neisseria meningitidis <400> 170
Met Asn Met Lys Lys Trp Ile Ala Ala Ala Leu Ala Cys Ser Ala Leu 1 5 10 15
331
WO 01/85772 ·· ·· ·· • · · · · · ·
PCT/GB01/02003
260 265
332
WO 01/85772 PCT/GBO V02003 <210> 171 <211> 864 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(864) <400> 171
333
;ec « 0000
Sé··
WO 01/85772
PCT/GB01/02003
<210> 172 <211> 288 <212> PRT <213> Neisseria meningitidis <400> 172
Met Lys Ala Lys Ile Leu Thr Ser Val Ala Leu Leu Ala Cys Ser Gly 15 10 15
Ser Leu Phe Ala Gin Thr Leu Ala Thr Val Asn Gly Gin Lys Ile Asp 20 25 30
334 v,
335 a£*
• · ·· «· » · · φ
WO 01/85772
PCT/GB01/02003 <210> 173 <211> 1794 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1794) <400> 173
336 • 4 ·· · ·· ···· • * · · · > ·· · · « « ···· · · · • · · · · ···· · • 4 9 9 9 9 4 4 9
9444 4449 94 944 ·· ··
337
WO 01/85772 PCT/GBO1/02003
515 520 525
338 ·· 09 «· · ·* ···· • · · · · * ·· « · ·
4 Λ β 4 β — 4 · • *’«.»· » « · * · • .· 0 · · · · · · βίΐς S9SS 99 999 99 99
W0 01/85772 PCT/GB01/02003
595 <210> 174 <211> 598 <212> PRT <213> Neisseria meningitidis <400> 174
339 ·· ·· «« • · · · t » tt · · ·
9 9 · · · • · · · eeee eeee
WO 01/85772
9 «« «««· • · e * · » · · . · «99® 9 • · · · · eee se ee
PCT/GB01/02003
340 • ·
595
341 • ·
WO 01/85772 PCT/GBO1/O2OO3 <210> 175 <211> 279 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(279) <400> 175
<210> 176 <211> 93 <212> PRT <213> Neisseria meningitidis <400> 176
342 ·· ·· ·· · ·· ····
WO 01/85772
35 40
Ala Phe Ala Glu Met Gin Gin Leu Ser Gly Gin 50 55
Ile Phe Ile Gly Glu Thr His Val Gly Gly Phe 65 70 75
Leu Gin Gin Glu Gly Gly Leu Asp Gly Leu Leu 85 90
PCT/GB01/02003
Arg Ser Val Pro Gin 60
Thr Asp Leu Tyr Arg 80
Asn Pro <210> 177 <211> 2274 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(2274) <400> 177
343 scss íe?s ee eee ee ee
344 ses e e tese ssec st
PCT/GB01/02003
345
9999 «««s 99 999 99 99
WO 01/85772 PCT/GB01/02003
346 φφ • · · · φφ • · φφφφ φ φφφφ φφφφ φ φ φ φφφ φφφφ φφφφ φφφφ φφ φφφ φφ φφ
WO 01/85772
PCT/GBO1/02003
750
2274 <210> 178 <211> 758 <212> PRT <213> Neisseria meningitidis <400> 178
85 90 95
347 ·· ·· ·* • · ·*· · • ···· · · · e · • · ··· · · · · e;*e«s$e » * · t« ·« · ·
WO 01/85772 PCT/GB01/02003
348 • · • · ··· · · · · ··«···'·« · · toto* toto 9 9
WO 01/85772 PCT/GB01/02003
349
WO Ot/85772 PCT/GBO1/O2OO3
755 <210> 179 <211> 567 <212> DNA <213> Neisseria meningitidis <220>
350 • · 9 9 9 9 · β β β 9 9 9 9
9 · 9 99 · 9 ··
W0 01/85772
PCT/GBO1/02003
351 • ·
WO 01/85772
PCT/GBO1/02003
210
220
215
285 gaa 867
Glu <210> 180 <211> 289 <212> PRT
352
GlU <210> 181 <211> 603 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(603)
353 • · ·
WO 01/85772 <400> 181
PCT/GBO1/02003
190
354 ·*
WO 01/85772 PCT/GB01/02003 ccg cac aat aag aaa aat att tea aaa 603
Pro His Asn Lys Lys Asn Ile Ser Lys
195 200 <210> 182 <211> 201 <212> PRT <213> Neisseria meningitidis <400> 182
180 185 190
355 ssec β e c «
WO 01/85772 PCT/GB01/02003
Pro His Asn Lys Lys Asn Ile Ser Lys 195 200 <210> 183 <211> 1338 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1338) <400> 183
356
49 94 eceeeeee «β
WO 01/85772 PCT/GB01/02003
357
405 410 415
<210> 184 <211> 446 <212> PRT <213> Neisseria meningitidis <400> 184
358
--Μ.
·· ·* ·· · ·· · ···· · · ·· ·· • · β · « · ·
WO 01/85772 PCT/GB01/02003
359 • · ♦ · · β 9 ··· 99
335
WO 01/85772
305
310
PCT/GBOl/02003
320
315
415
400 <210> 185 <211> 1476 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1476) <400> 185
360
99 ·· 99 9 999999 ···· 9 9 9« 9 9 9
9 9 9 9 9 · 9 9 • · « 9 · 9999 9
9 9 99 9 9999
WO 01/85772
PCT/GBO1/02003
35 40 45
361 ·· « · w ·
WO 01/85772
PCT/GB01/02003
225
230 235 240
362 • · «fcfcfc • fc fc· fc « t · ·· • · · e fc fc······· • fc · fc * • · · · ···· · • · · · · • •e fcfc ·<
WO 01/85772 PCT/GB01/02003
<210> 186 <211> 492 <212> PRT <213> Neisseria meningitidis <400> 186
115 120 125
363 • · · · · · · ·· ···· ♦ · · · ·· · o · β β β β β · · ········ ·· ··· ·· ··
W0 01/85772 PCT/GBO1/O2OO3
370 375 380
364
WO 01/85772
PCT/GBO1/02003
<210> 187 <211> 1191 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1191) <400> 187
144
192
365
366
WO 01/85772 PCT/GB01/02003
<210> 188 <211> 397 <212> PRT <213> Neisseria meningitidis <400> 188
Met Phe Phe Lys His Ile Glu Ala Ala Pro Ala Asp Pro Ile Leu Gly 15 10 15
367
368
WO 01/85772
PCT/GBO1/02003
<210> 189 <211> 462 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1) .. (462) <400> 189 ttg ctt tgc ccg gaa aaa atg tcg ggg atg gcg gga cag tat ccg tac 48
Leu Leu Cys Pro Glu Lys Met Ser Gly Met Ala Gly Gin Tyr Pro Tyr
1 5 10 15 *
ggc gtc cgg tcg ggt ttg cgg agg aac ggc ttg aaa ctt tgg gat att 96
Gly Val Arg Ser Gly Leu Arg Arg Asn Gly Leu Lys Leu Trp Asp ile
20 25 30 cat ttt aga atg acc cgt ttt atc gtc gca aga tgc ggt tta ttg ttt 144
His Phe Arg Met Thr Arg Phe Ile Val Ala Arg Cys Gly Leu Leu Phe
35 40 45
369
WO 01/85772
PCT/GBO1/02003
140 aaa aaa . 462
Lys Lys <210> 190 <211> 154 <212> PRT
370 • 0 • 0 ··· ·
145 150 <210> 191 <211> 684 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(684) <400> 191
65 70 75 80
371 φφφφ φφφφ
WO 01/85772 PCT/GB01/02003
agc aaa caa taa 684
Ser Lys Gin
225 , <210> 192 <211> 227 <212> PRT <213> Neisseria meningitidis <4OO> 192
372 titi9Stt
WO 01/85772 PCT/GB01/02003
Ser Lys Gin 225 <210> 193
373 • fc fc* ·* · fc fcfc · » fc · · * fc · « » fc fcfcfcfc · ·· e © fc ···· ·«·· ·· ···
WO 01/85772 PCT/GB01/02003 <211> 1089 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(1089, <400> 193
374 • · · ·
WO 01/85772 e e ec s « s«
PCT/GB01/02003
340 345 350
375 • · · ·
WO 01/85772 PCT/GBO1/02003 agt ggt gta ttg ttg aaa aag aaa atc ctt tga 1089
Ser Gly Val Leu Leu Lys Lys Lys Ile Leu
355 360 <210> 194 <2U> 362 <212> PRT <213> Neisseria meningitidis <400> 194
180 185 Í90
376
0· ·« ·* · ·· ···· »··· ···· · · · • ο β β e © e e β ··· ···· ·· ··· ·· ··
355 360 <210> 195 <211> 2145 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(2145) <400> 195 atg aat acc cca ttg ttc cgt ctc age ctg ctc tcg ctt acc ctg gcg 48
Met Asn Thr Pro Leu Phe Arg Leu Ser Leu Leu Ser Leu Thr Leu Ala
&
• · • ···· · · · · · • · ··· · · · · »««· «*«« ** ··· ·· ··
WO 01/85772 PCT/GB01/02003
378 • · · ·
WO 01/85772
PCT/GBO1/02003
379 • · ···· • 0
PCT/GB01/02003
580 585
380
4 -*^λΜ5&
• · · eeβe ···« «β ee
WO 01/85772
PCT/GBO1/02003
705
710
715 <210> 196 <211> 714 <212> PRT <213> Neisseria meningitidis <400> 196
Met Asn Thr Pro Leu Phe 'Arg Leu Ser Leu Leu Ser Leu Thr Leu Ala 1 5 10 15
Ala Gly Phe Ala His Ala Ala Glu Asn Asn Ala Lys Val Val Leu Asp 20 25 30
Thr Val Thr Val Lys Gly Asp Arg Gin Gly Ser Lys Ile Arg Thr Asn 35 40 45
381
382 • « β e se a
WO 01/85772
PCT/GBO1/02003
383 eeeo esee
<210> 197 <211> 2625 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(2625) <400> 197 atg aaa acc tcc gaa ctg cgc caa aaa ttc cta aaa ttt ttt gaa acc 48
Met Lys Thr Ser Glu Leu Arg Gin Lys Phe Leu Lys Phe Phe Glu Thr
15 10 15 aaa ggc cac acc gtc gtc cgc tet tcc agc ctc gtg ccg cac gac gac 96
384
385
386
9* »··♦ e e r ·· ·· 9· • 99 9
A 9
9 9
9 9
9.9« ¢¢64
9 9 ·
9 9 > 9
9 9 9 9 9 • 9 9 9 9 eee e<* »9
387
1«·9 9 9 9 9 9
999
WO 01/85772
PCT/GBO1/02003
388
389
WO 01/85772
PCT/GB01/02003
340 345 350
390 ·· ϊ c e e e e« í frfr
PCT/GB01/02003
WO 01/85772
595 600 605
391 ·· eee β®
PCT/GBO1/02003
WO 01/85772
392
WO 01/85772 PCT/GBO1/02003
Val Lys Asp Trp Val Gly Ala Lys Leu Val
865 870 <210> 199 <211> 207 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(207) <400> 199
50 55 60 tac ttg cta ega taa 207
Tyr Leu Leu Arg <210> 200 <211> 68 <212> PRT <213> Neisseria meningitidis <400> 200
Val Gin Arg Gly Arg Leu Lys Gly Leu Val Cys Arg Arg Leu Gly Arg 15 10 15
Asp Pro Thr Asn Phe Val Lys Tyr Lys Asn Val Gly His Asp Pro Thr 20 25 30
393
WO 01/85772
Tyr Leu Pro Phe Cys Thr Lys Arg Leu Ser Glu Arg Pro Cys 35 40 45
Tyr Gly Gly Ser Arg Pro Ser Arg Phe Leu Leu Gly Tyr Asp 50 55 60
Tyr Leu Leu Arg 65
PCT/GB01/02003
Leu Pro
Pro Ser <210> 201 <211> 2277 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(2277) <400> 201
394
WO 01/85772 PCT/GB01/02003
290 295 300
395
4 '4 '9 c «c « · » ·· ϋ fc
4 ís β
WO 01/85772 PCT/GB01/02003
396 ·'· 99 ♦ <' « · · · · ·'· · 9 '9
9 9 « -9 * » « » ’*
99 99 9 99 9 *· ··-» ·» ·.·
WO 01/85772 PCT/GB01/02003
397
WO 01/85772 PCT/GB01/02003
755 <210> 202 <211> 758 <212> PRT
398
WO 01/85772
Glu Thr
Asp Thr 130
Leu Leu 145
Gly Lys
Gly Leu
Ile Asn.
Tyr Arg 210
Arg Leu 225
Ser Trp
Arg Asp
His Ala
Gin Leu 290
Pro Gly 305
Thr His
Leu Arg
Val His
PCT/GBO1/02003
355 360 365
399
0 ,0 0 · · 00« ··*«««· ·0 ·*0 00 «0
610 615 620
400 • · <· to to ’ to to to · e β to
WO 01/85772 ···· ···· • · « to toto « • to toto • to
PCT/GB01/02003
755 <210> 203 <211> 225 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(225) <400> 203
401 • · · · ·
WO 01/85772
PCT/GB01/02003
act tgg cat cat cat caa gat aca 144
Thr Trp His His His Gin Asp Thr ggc ttg cat cat gat acc ggc cat 192 Gly Leu His His Asp Thr Gly His gga agg taa 225
Gly Arg <210> 204 <211> 74 <212> PRT <213> Neisseria meningitidis <400> 204
65 70
402 · fcfc fcfc fcfc * ·· ···· fc · · · fcfc fcfc fcfc fc • fcfcfcfc · fc · • · · fc · fc · fc fc · • fc β e fc fc e · fc ···· ···· ·· ··· «fc ··
WO 01/85772 PCT/GB01/02003
1 5 10 15
403
ΦΦ «ο ·· ·· φ φφ ··· • •φφ φφφφ φφ φ φ φ φ φ φ φ φ φ φφφφ φφφφ φ φ φ φ β # φφφφ φφφφ φφφφ φφ φφφ φφ φφ
W0 01/85772 PCT/GB01/02003
404
405
385 390 <210> 207 <211> 342 <212> DNA <213> Neisseria meningitidis <220>
<221> CDS <222> (1)..(342) <400> 207
406 ·· ·· · • · · · « « · « · 4 * · · · · « · · • « · ♦ · · · · · · e # e ě i e & « « ···· ···· ·· ·*· ·· «·
WO 01/85772 PCT/GBO1/02003 ·· ·«··
gtc tgt .342
Val Cys <210> 208 <211> 114 <212> PRT <213> Neisseria meningitidis <400> 208
407 /
·· ·· • 4 4 · • · • · e β
44444444
44 4 44 4444
4 9 4 4 4 4 4
9 4 4 4 4 4
4 4 4 9 4 4 4
4 4 4 4 4 4 ®
94 944 · ··
WO 01/85772
50 55
Gin Val Arg Glu Ile Phe Glu Arg Phe 65 70
Thr Glu Tyr Arg Arg Phe Lys Ala Asp 85
Lys Ala Asn Ser Ile Phe Glu Tyr Leu 100 105
Val Cys
PCT/GBO1/02003
110 <210> 209 <211> 24 <212> DNA <2i3> syntetická sekvence <220>
<223> Popis syntetické sekvence: sekvence primeru <400> 209 ttggttaatt ggttgtaaca ctgg 24 <210> 210 <211> 19 <212> DNA <2i3> syntetická sekvence <220>
<223> Popis syntetické sekvence: sekvence primeru <400> 210 attctcatgt ttgacagcg 19 <210> 211 <211> 18 <212> DNA <2i3> syntetická sekvence <220>
<223> Popis syntetické sekvence: sekvence primeru
408 ě
···
WO 01/85772
PCT/GBO1/02003 ·« ·· • · · · β e ···· ···· ·· ···· • · « • · · • · · e e · · ·· ·· <400> 211 atcctacaac ctcaagct 18 <210> 212 <211> 18 <212> DNA <213> syntetická sekvence <22 0>
<223> Popis syntetické sekvence: sekvence primeru ;
<400> 212 atcccattct aaccaagc 18 <210> 213 <211> 19 <212> DNA <2i3> syntetická sekvence <220>
<223> Popis syntetické sekvence: sekvence primeru <400> 213 aagagattac gcgcagacc 19 <210> 214 <211> 18 <212> DNA <2i3> syntetická sekvence <220>
<223> Popis syntetické sekvence: sekvence primeru <400> 214 aatacgcaac cgcctctc 18
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0011108.8A GB0011108D0 (en) | 2000-05-08 | 2000-05-08 | Virulence gene and protein and their use |
Publications (1)
Publication Number | Publication Date |
---|---|
CZ20023642A3 true CZ20023642A3 (cs) | 2003-04-16 |
Family
ID=9891203
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CZ20023642A CZ20023642A3 (cs) | 2000-05-08 | 2001-05-08 | Geny virulence, proteiny a jejich použití |
Country Status (16)
Country | Link |
---|---|
US (2) | US20040087770A1 (cs) |
EP (2) | EP1908839A3 (cs) |
JP (1) | JP2003532404A (cs) |
KR (3) | KR20030032948A (cs) |
CN (2) | CN1840665A (cs) |
AT (1) | ATE382056T1 (cs) |
AU (1) | AU776508B2 (cs) |
CA (1) | CA2408738A1 (cs) |
CZ (1) | CZ20023642A3 (cs) |
DE (1) | DE60132084T2 (cs) |
GB (1) | GB0011108D0 (cs) |
HU (1) | HUP0302481A2 (cs) |
NO (1) | NO20025329L (cs) |
NZ (3) | NZ522277A (cs) |
RU (2) | RU2252224C2 (cs) |
WO (1) | WO2001085772A2 (cs) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1996017951A2 (en) | 1994-12-09 | 1996-06-13 | Rpms Technology Limited | Identification of genes responsible for in vivo survival of microorganisms |
DK1108034T3 (da) | 1998-09-04 | 2008-11-10 | Emergent Product Dev Uk Ltd | Svækkede salmonella SPI2-mutanter som antigenbærere |
EP1163343B1 (en) | 1999-03-12 | 2009-12-09 | GlaxoSmithKline Biologicals S.A. | Neisseria meningitidis antigenic polypeptides, corresponding polynucleotides and protective antibodies |
GB9910812D0 (en) | 1999-05-10 | 1999-07-07 | Microscience Ltd | Vaccine composition |
KR101239242B1 (ko) * | 2002-08-02 | 2013-03-11 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | 항원 조합물을 포함하는 나이세리아 백신 조성물 |
GB0330007D0 (en) * | 2003-12-23 | 2004-01-28 | Imp College Innovations Ltd | Vaccines |
US7709001B2 (en) | 2005-04-08 | 2010-05-04 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
CN102716480B (zh) | 2005-04-08 | 2023-03-21 | 惠氏有限责任公司 | 多价肺炎球菌多糖-蛋白质缀合物组合物 |
AU2008304231A1 (en) * | 2007-09-27 | 2009-04-02 | Albany Molecular Research, Inc. | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
EP2326344A4 (en) | 2008-06-16 | 2013-08-07 | Prokarium Ltd | VACCINES WITH SALMONELLA VECTOR AGAINST CHLAMYDIA AND METHOD OF ADMINISTRATION |
GB0816447D0 (en) * | 2008-09-08 | 2008-10-15 | Glaxosmithkline Biolog Sa | Vaccine |
CA2792691A1 (en) * | 2010-03-11 | 2011-09-15 | Glaxosmithkline Biologicals S.A. | Immunogenic composition or vaccine against gram-negative bacterial, for example, neisserial, infection or disease |
CN111118043B (zh) * | 2020-01-13 | 2022-07-05 | 吉林大学 | 一种苦豆子SaMET6基因克隆及其应用 |
CN116042562B (zh) * | 2022-03-11 | 2023-10-20 | 山东恒鲁生物科技有限公司 | 重组酵母菌及其应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2047043A1 (en) * | 1990-07-19 | 1992-01-20 | Allen I. Oliff | Class ii protein of the outer membrane of neisseria meningitidis having immune enhancement properties |
US5338664A (en) * | 1992-12-04 | 1994-08-16 | American Cyanamid Company | Assay for detection of bacterial iron transport inhibitors |
US6121037A (en) * | 1994-10-18 | 2000-09-19 | Stojiljkovic; Igor | Bacterial hemoglobin receptor genes |
WO1996017951A2 (en) * | 1994-12-09 | 1996-06-13 | Rpms Technology Limited | Identification of genes responsible for in vivo survival of microorganisms |
FR2751000B1 (fr) * | 1996-07-12 | 1998-10-30 | Inst Nat Sante Rech Med | Adn specifiques des bacteries de l'espece neisseria meningitidis, leurs procedes d'obtention et leurs applications biologiques |
US6472518B1 (en) * | 1996-10-24 | 2002-10-29 | Centers For Disease Control And Prevention, As Represented By The Secretary, Department Of Health And Human Services | Invasion associated genes from Neisseria meningitidis serogroup B |
GB9711964D0 (en) * | 1997-06-09 | 1997-08-06 | Medical Res Council | Live attenuated vaccines |
DE69836333T2 (de) * | 1997-08-15 | 2007-04-19 | Rijksuniversiteit Utrecht | Neisseria lactoferrin-bindendes protein |
CA2308606A1 (en) * | 1997-11-06 | 1999-05-20 | Chiron S.P.A. | Neisserial antigens |
AU3968599A (en) * | 1998-04-29 | 1999-11-16 | American Cyanamid Company | Vaccines containing recombinant pilin against Neisseria Gonorrhoeae or Neisseria Meningitidis |
GB9811260D0 (en) * | 1998-05-26 | 1998-07-22 | Smithkline Beecham Biolog | Novel compounds |
JP2004511201A (ja) * | 1998-10-09 | 2004-04-15 | カイロン コーポレイション | ナイセリアゲノム配列およびそれらの使用方法 |
US6610836B1 (en) * | 1999-01-29 | 2003-08-26 | Genome Therapeutics Corporation | Nucleic acid amino acid sequences relating to Klebsiella pneumoniae for diagnostics and therapeutics |
DK1185691T3 (da) * | 1999-04-30 | 2009-06-22 | Novartis Vaccines & Diagnostic | Genomiske neisseriasekvenser og fremgangmåder til anvendelse deraf |
-
2000
- 2000-05-08 GB GBGB0011108.8A patent/GB0011108D0/en not_active Ceased
-
2001
- 2001-05-08 CN CNA2005101362903A patent/CN1840665A/zh active Pending
- 2001-05-08 US US10/275,026 patent/US20040087770A1/en not_active Abandoned
- 2001-05-08 CZ CZ20023642A patent/CZ20023642A3/cs unknown
- 2001-05-08 CN CN01809191A patent/CN1427892A/zh active Pending
- 2001-05-08 AT AT01925742T patent/ATE382056T1/de not_active IP Right Cessation
- 2001-05-08 RU RU2002132891/13A patent/RU2252224C2/ru not_active IP Right Cessation
- 2001-05-08 NZ NZ522277A patent/NZ522277A/en unknown
- 2001-05-08 DE DE60132084T patent/DE60132084T2/de not_active Expired - Fee Related
- 2001-05-08 WO PCT/GB2001/002003 patent/WO2001085772A2/en active IP Right Grant
- 2001-05-08 AU AU52422/01A patent/AU776508B2/en not_active Ceased
- 2001-05-08 HU HU0302481A patent/HUP0302481A2/hu unknown
- 2001-05-08 JP JP2001582371A patent/JP2003532404A/ja active Pending
- 2001-05-08 NZ NZ549068A patent/NZ549068A/en unknown
- 2001-05-08 EP EP07114502A patent/EP1908839A3/en not_active Withdrawn
- 2001-05-08 EP EP01925742A patent/EP1287024B1/en not_active Expired - Lifetime
- 2001-05-08 CA CA002408738A patent/CA2408738A1/en not_active Abandoned
- 2001-05-08 KR KR1020027014876A patent/KR20030032948A/ko not_active Application Discontinuation
- 2001-05-08 NZ NZ532297A patent/NZ532297A/en unknown
-
2002
- 2002-11-06 NO NO20025329A patent/NO20025329L/no not_active Application Discontinuation
-
2005
- 2005-01-24 RU RU2005101623/13A patent/RU2005101623A/ru not_active Application Discontinuation
-
2007
- 2007-08-17 US US11/893,649 patent/US20080241151A1/en not_active Abandoned
- 2007-08-29 KR KR1020070087191A patent/KR20070102447A/ko not_active Application Discontinuation
-
2008
- 2008-07-10 KR KR1020080067099A patent/KR20080080069A/ko not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CA2408738A1 (en) | 2001-11-15 |
EP1287024B1 (en) | 2007-12-26 |
AU776508B2 (en) | 2004-09-09 |
RU2005101623A (ru) | 2006-07-10 |
NO20025329D0 (no) | 2002-11-06 |
NZ522277A (en) | 2004-05-28 |
KR20070102447A (ko) | 2007-10-18 |
WO2001085772A2 (en) | 2001-11-15 |
AU5242201A (en) | 2001-11-20 |
DE60132084D1 (de) | 2008-02-07 |
NZ532297A (en) | 2005-07-29 |
HUP0302481A2 (hu) | 2003-10-28 |
US20040087770A1 (en) | 2004-05-06 |
KR20030032948A (ko) | 2003-04-26 |
US20080241151A1 (en) | 2008-10-02 |
EP1908839A3 (en) | 2008-07-16 |
WO2001085772A3 (en) | 2002-03-28 |
CN1427892A (zh) | 2003-07-02 |
RU2252224C2 (ru) | 2005-05-20 |
EP1287024A2 (en) | 2003-03-05 |
KR20080080069A (ko) | 2008-09-02 |
EP1908839A2 (en) | 2008-04-09 |
CN1840665A (zh) | 2006-10-04 |
DE60132084T2 (de) | 2008-12-11 |
NO20025329L (no) | 2003-01-06 |
GB0011108D0 (en) | 2000-06-28 |
JP2003532404A (ja) | 2003-11-05 |
NZ549068A (en) | 2008-03-28 |
ATE382056T1 (de) | 2008-01-15 |
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