JP4592284B2 - 髄膜炎菌付着因子 - Google Patents
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
Description
本発明は、生化学の分野に関し、より具体的には、Neisseria属の病原性細菌(例えば、N.meningitidisおよびN.gonorrhoeae)の生化学に関する。
「ORF40」は、WO99/36544の実施例1に開示される。血清群AおよびBのN.meningitidis由来の配列が、開示される(この中で、配列番号1〜6)。他の形態のタンパク質は、WO99/31132およびWO99/58683に開示され、GenBankにおいてもまた、見出され得る(gi登録番号:11352902、7228562、14578015、12958107、7228586、7228572、7228594、7228588、14578013、7228568、7228546、7228548、7228592、14578009、7228558、7228600、7228596、7228542、7228574、7228552、7228554、14578023、14578021、11354080、7228584および7228590を参照のこと)。
GSTまたはhisタグ融合パートナーを伴わずにE.coli中で発現される場合、Appは、約160kDaの前駆体として外膜に露出し、ここでAppは、プロセシングされ、培養物中に分泌されることが見出されている。
国際特許出願WO01/64922の実施例22は、NadAタンパク質を発現するE.coliが、ヒト上皮細胞に付着し得ることを開示する。この付着活性は、さらに研究されており、この付着活性は、AppおよびORF40についても見出されている。
本発明は、上皮細胞へのNeisseria細胞の付着を防止するための方法を提供し、ここで、上皮細胞に結合する1つ以上のApp、ORF40および/またはNadAの能力がブロックされる。
本発明は、上皮細胞に対するNeisseria細胞の付着を防止するための方法を提供し、ここで、1つ以上のApp、ORF40および/またはNadAからのタンパク質発現が阻害される。この阻害は、転写および/または翻訳のレベルであり得る。
本発明は、上皮細胞に対するNeisseria細胞の付着を防止するための方法を提供し、ここで、1つ以上のApp、ORF40および/またはNadAは、ノックアウトである。
本発明は、上皮細胞に対するNeisseria細胞の付着を防止するための方法を提供し、ここで、1つ以上のApp、ORF40および/またはNadAが、その活性を阻害する変異を有する。
例えば、変異は、酵素活性を阻害し得るか、またはタンパク質における結合部位を除去し得る。
本発明はまた、上皮細胞に対するNeisseria細胞の結合を阻害するもの(アンタゴニスト)を同定するために化合物をスクリーニングするための方法を提供する。
国際特許出願公報WO01/52885は、OMVワクチンに対するさらに規定された成分の添加が、それらの効力を有意に広げることを開示する。
(A) WO99/24578からの配列番号2〜892の偶数の配列番号;
(B) WO99/36544からの配列番号2〜80の偶数の配列番号;
(C) WO99/57280からの配列番号2〜3020の偶数の配列番号:
(D) WO99/57280からの配列番号3040〜3114の偶数の配列番号;
(E) WO99/57280からの配列番号3115〜3241;
(F) Tettelinら[前出]からの2160個のタンパク質(NMB0001〜NMB2160);
(G) (A)〜(F)の1つ以上のアミノ酸配列を含むタンパク質;
(H) (A)〜(F)の1つ以上のアミノ酸配列と配列同一性を共有するタンパク質;および
(I) (A)〜(F)の1つ以上のフラグメントを含むタンパク質。
WO99/24578の配列番号650のアミノ酸267(本明細書中の配列番号32)は、セリンである。Appは、セリンプロテアーゼであると考えられており、そしてこのセリンは、その活性部位での触媒残基であると考えられる。標準的な配列整列技術が、任意の他のApp配列についてこのSer−267に対応するアミノ酸(例えば、WO99/24578の配列番号652の中のSer−260、配列番号654の中のSer−267など)を示す。
本発明は、配列番号1〜14のうちの1つ以上のアミノ酸配列を含むタンパク質を提供する。
本発明は、(a)Neisseria NadAタンパク質および/または(b)NadAタンパク質をコードする核酸を含む免疫原性組成物を提供する。
本発明は、好ましくは、以下を排除する:(a)2002年7月26日より前、より好ましくは、2001年7月27日より前に、公的配列データベース(例えば、GenBankまたはGENESEQ)において利用可能であったアミノ酸配列および核酸配列;(b)2002年7月26日より前、より好ましくは、2001年7月27日より前の出願日、または適用可能な場合には優先日、を有する特許出願に開示されたアミノ酸配列および核酸配列。特に、以下の特許出願における配列番号の実体が排除され得る:WO99/24578;WO99/36544;WO99/57280;WO00/22430;WO00/66741;WO00/66791;WO00/71574;WO00/71725;WO01/04316;WO01/31019;WO01/37863;WO01/38350;WO01/52885;WO01/64920;WO01/64922。
用語「含む」は、「含有する」および「構成される」を意味し、例えば、Xを「含む」組成物は、排他的にXからなり得るか、またはさらなる何かを含み得る(例えば、X+Y)。
(NadA相同性)
NadAは、(a)ビルレンスに関与する非ピリ線毛関連付着因子である腸病原性YersiniaのYadA[Cornelis(1998)Microbiol.Mol.Biol.Rev.62:1315−1352]および(b)血清耐性に関与するタンパク質でありかつ防御抗原であるMoraxella catarrhalisのUspA2[Chenら(1999)Infect.Immun.67:1310−1316]に対して相同性を示す。配列類似性は、主に、カルボキシル末端領域に密集している(最後の70アミノ酸において56〜63%同一性)。この領域の外側では、同一性のレベルは23〜25%に低下する。
1086bpのnadAコード領域は、その3’末端にターミネーター配列が隣接し、5’末端には(図12A)、このコード領域は、ATG開始コドンの8塩基対および47塩基対上流に、それぞれ、推定リボソーム結合部位(RBS;5’−AAGG−3’)および推定プロモーター領域を示す。
血清型Aと血清型Bとの間のnadA配列の差異を考慮して、175個の異なるN.meningitidis株が分析のために選択された。150個の単離株が、5つの疾患関連血清群(A、B、C、YおよびW−135)を示し、25株が、健常キャリアから単離された。この分析はまた、N.gorrhoeae、N.cinereaおよびN.lactamicaの各々株1つを含んだ。
PCR産物が差次的にサイズ分類され(図13)、NadA+株のうちのほとんどは、3つの異なるサイズにグループ分けされ得たので、各サイズを示す36個の株について、遺伝子が配列決定された:26個がポジティブ株であり、4株が長いPCR産物を有し、6株がNadA−株であった。
血清群CのISS1024株は、残基229〜235に1つの7個組反復欠失を含む、対立遺伝子2の改変体を有する(配列番号7/8)。この配列は、ものもと第4の対立遺伝子として分類されたが、対立遺伝子2の改変体として再分類されている。従って、対立遺伝子2は、すべてのET−37株、クラスターA4の1つの株およびさらなる3つの非ET型血清群C株において見出される;
血清群CのISS759株および973−1720株の両方は、リーダーペプチド中に単一アミノ酸変異を含む対立遺伝子3の改変体を含み(配列番号9/10)、この単一アミノ酸変異は、単一ヌクレオチド変異から生じる。対立遺伝子3の株すべてのうち、973−1720のみが、過剰毒性株(クラスターA4)に属する;
血清群Bの株95330は、対立遺伝子1および対立遺伝子2の組換え体(キメラ)(配列番号11/12)を含み、nadAが、対立遺伝子2のN末端部分と対立遺伝子1のC末端セグメントとの間の融合物である。推定組換え部位は、このタンパク質の残基141と残基265との間にほぼ位置する。
WO01/64922は、NadAがオリゴマー構造を形成することを報告する。より詳細にNadAオリゴマーを研究するために、N.meningitidisの全細胞溶解物が、ウェスタンブロットによりプロービングされた。
ポリクローナル抗NadA血清を、補体源として使用されるプールされたウサギ新生児血清(CedarLane)を用いて、以前に記載されたように殺菌活性について試験した[Pizzaら(2000);Peetersら(1999) Vaccine 17:2702−2712]。血清殺菌力価を、反応混合物中の細菌の60分のインキュベーション後の1mlあたりのコロニー形成単位(CFU)において、0分の時点での1mlあたりのコントロールCFUと比較して50%の減少を生じる血清希釈として規定した。代表的には、補体の存在下でネガティブコントロール抗体と共にインキュベートされた細菌は、60分のインキュベーションの間、CFU/mlにおける150〜200%の増加を示した。
ORF40は、Hsfおよびその対立遺伝子改変体Hia(両方ともHaemophilus influenzaeの付着因子)に対して相同性を示す。Hia、HsfおよびORF40のサイズが異なることは、部分的に、Hsfにおける大きな繰り返しドメインの3つのコピーの存在により説明され、これは、Hiaに単一のコピーとして存在し、そしてORF40には部分的にしか存在しない(図7)。MenBにおいて、ORF40は、約200kDaのタンパク質(成熟タンパク質についての59kDaの推定分子量を参照のこと)として外膜に見出される。
Appは、H.influenzaeの付着および浸透タンパク質Hapに対して相同性を示し(図8)、これは、自己タンパク質分解切断および細胞外放出を受ける、セリンプロテアーゼ活性を有する付着因子である[Hendrixsonら(1997) Mol Microbiol 26:505−518]。切断されない表面結合Hapは、上皮細胞への付着を媒介し、そして細菌凝集および集落形成を促進する。
ORF40、AppおよびNadAの全長遺伝子を、pET21b+ベクター中にクローン化し、そしてこのプラスミドで、T7プロモーターの制御下でこれらの遺伝子を発現させるために、E.coli BL21(DE3)を形質転換した。
−ORF40は、モノマー形態で発現され、そしておそらくマルチマーも形成する(図1)。
−Appは、約160kDaの前駆体としてE.coli外膜に輸送され、プロセシングされて培養上清に分泌される(図2)。
−NadAは、約180kDaの単一の高分子量バンドとして外膜の画分に存在することが見出される。これは、おそらくこのタンパク質のオリゴマー形態に対応する。このようなバンドは、E.coli発現細胞内NadAには存在しない(図3)。
免疫応答の誘導に対するタンパク質コンホメーションの役割を評価するために、ORF40、AppまたはNadAを発現するE.coli由来の外膜小胞を単離し、これを使用してマウスを免役した。殺細菌活性について血清を試験し、結果を、融合タンパク質により得られた結果と比較した。殺細菌応答(株2996)は、そのタンパク質がOMV中でそれらの「ネイティブな」形態で生成される場合に、5〜10倍改善された:
E.coli pET−App形質転換体は、100kDa産物を培養上清に分泌し、160kDa表面産物を示す。分泌App産物が自己タンパク質分解性プロセスから得られるか否かを試験するために、推定触媒性残基のうちの1つ(Ser−267)を、Alaと置換した。
国際特許出願WO01/64922の実施例22は、E.coliにおけるNadA発現により、形質転換細菌がヒト上皮細胞に接着するようになることを開示する。この接着性の表現型は、NadAについて、AppおよびORF40についてもさらに研究された。
Appの結合領域を同定するために、Appβと命名されたキメラタンパク質を使用した。このタンパク質は、N.gonorrhoeaeのIgA1プロテアーゼのリーダーペプチドに融合されたAppのC末端ドメイン(アミノ酸1077〜1454)からなる。淋菌のリーダー配列は、よく特徴づけられており、E.coli中で機能するので、それを選択した。プラスミドpET−Appβは、配列番号26および27を使用してたPCRにより増幅された、1.1kbpDNAフラグメントを含む。
Appに対する接着機能を示唆するE.coliでの研究の後、N.meningitidisの同系変異株を構築した。出発株はMC58であった。MC58のapp遺伝子を短縮し、そしてプラスミドpBSUDAppERM(これは、対立遺伝子交換のため、短縮app遺伝子およびermC遺伝子(エリスロマイシン耐性)を含む)を有する親株を形質転換することによって抗生物質カセットで置き換えた。簡潔に述べると、開始コドンを含む600bpの上流隣接領域および終始コドンを含む700bpの下流隣接領域を、配列番号28〜31のプライマーを使用してMC58から増幅した。フラグメントを、標準的な技術を使用して、pBluescriptへとクローン化し、そしてE.coli DH5へと形質転換した。全てのサブクローン化を完了すると、本質的にコンピテントなN.meningitidis MC58株を、GC寒天プレート上で一晩増殖したいくつかのコロニーを選択することによって形質転換し、そしてそれらを1μgのプラスミドDNAを含む20μlの10mM TrisHCl(pH8.5)と混合した。この混合物を、GC寒天プレート上にスポットし、5%CO2、37℃で6時間インキュベートし、次いでPBS中に希釈し、そして5μg/mlエリスロマイシンを含むGC寒天プレート上に広げた。MC58ゲノム中のapp遺伝子欠損をPCRによって確認した。App発現の欠損を、ウェスタンブロット分析によって確認した。
Claims (4)
- 上皮細胞へのNeisseria細胞の付着を予防するための組成物であって、
配列番号32によりコードされるペプチドの残基1077〜1176内のエピトープに対して特異的なポリクローナル抗体
を含み、
該上皮細胞は、結膜細胞、Chang上皮細胞、A−549上皮細胞、およびHeLa上皮細胞からなる群より選択される、組成物。 - Neisseria感染を予防することにおいて使用するための、請求項1に記載の組成物。
- 髄膜炎または菌血症の処置において使用するための、請求項1に記載の組成物。
- 前記Neisseria感染が、高ビルレント系統であるET−5、ET−37およびクラスターA4由来のN.meningitidisの感染である、請求項2に記載の組成物。
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GB0211025A GB0211025D0 (en) | 2002-05-14 | 2002-05-14 | Meningococcus adhesins |
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Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9808866D0 (en) * | 1998-04-24 | 1998-06-24 | Smithkline Beecham Biolog | Novel compounds |
EP2261343A3 (en) | 1998-05-01 | 2012-01-18 | Novartis Vaccines and Diagnostics, Inc. | Neisseria meningitidis antigens and compositions |
PT1228217E (pt) | 1999-04-30 | 2013-01-28 | Novartis Vaccines & Diagnostic | Antígenos de neisseria conservados |
CA2929348A1 (en) * | 1999-05-19 | 2000-11-30 | Novartis Vaccines And Diagnostics S.R.L. | Combination neisserial compositions |
GB9928196D0 (en) | 1999-11-29 | 2000-01-26 | Chiron Spa | Combinations of B, C and other antigens |
CN100339482C (zh) | 2000-02-28 | 2007-09-26 | 启龙股份公司 | 奈瑟球菌蛋白质的杂交表达 |
AU2001280883A1 (en) | 2000-07-27 | 2002-02-13 | The Children's Hospital & Research Center At Oakland | Vaccines for broad spectrum protection against diseases caused by neisseria meningitidis |
GB0118249D0 (en) | 2001-07-26 | 2001-09-19 | Chiron Spa | Histidine vaccines |
BR0211494A (pt) | 2001-07-27 | 2004-08-17 | Chiron Srl | Adesinas de meningococo nada, app e orf 40 |
GB0121591D0 (en) | 2001-09-06 | 2001-10-24 | Chiron Spa | Hybrid and tandem expression of neisserial proteins |
NZ574530A (en) * | 2002-08-02 | 2010-12-24 | Glaxosmithkline Biolog Sa | Vaccine compositions comprising L2 and/or L3 immunotype lipooligosaccharides from lgtB-neisseria minigitidis |
EP2351579B1 (en) | 2002-10-11 | 2016-09-21 | Novartis Vaccines and Diagnostics S.r.l. | Polypeptide vaccines for broad protection against hypervirulent meningococcal lineages |
GB0227346D0 (en) | 2002-11-22 | 2002-12-31 | Chiron Spa | 741 |
ATE552844T1 (de) | 2003-01-30 | 2012-04-15 | Novartis Ag | Injizierbarer impfstoff gegen multiple meningokokken-serogruppen |
GB0315022D0 (en) * | 2003-06-26 | 2003-07-30 | Chiron Srl | Virulence-associated adhesins |
BR122017002991B1 (pt) | 2003-10-02 | 2023-01-10 | Novartis Vaccines And Diagnostics S.R.L. | Composições imunogênicas aquosas para múltiplos sorogrupos meningocócicos |
GB0408977D0 (en) | 2004-04-22 | 2004-05-26 | Chiron Srl | Immunising against meningococcal serogroup Y using proteins |
GB0415160D0 (en) * | 2004-07-06 | 2004-08-11 | Chiron Srl | Inhibitors of bacterial infection |
CN101107007B (zh) | 2005-01-27 | 2011-08-17 | 奥克兰儿童医院及研究中心 | 对脑膜炎奈瑟球菌所致疾病具有广谱保护作用的gna1870囊泡疫苗 |
US20110008279A1 (en) * | 2005-12-06 | 2011-01-13 | Vega Masignani | Methods and Compositions Relating to Adhesins as Adjuvants |
AU2009298499A1 (en) * | 2008-09-30 | 2010-04-08 | Abbvie Inc. | Improved method of RNA display |
EP2443250B8 (en) | 2009-06-16 | 2016-09-21 | GlaxoSmithKline Biologicals SA | High-throughput complement-mediated antibody-dependent and opsonic bactericidal assays |
EP2613805B1 (en) | 2010-09-10 | 2019-10-23 | GlaxoSmithKline Biologicals SA | Meningococcus overexpressing nada and/or nhba and outer membrane vesicles derived therefrom |
RU2644340C2 (ru) * | 2012-06-14 | 2018-02-08 | Новартис Аг | Вакцины для менингококка серогруппы х |
WO2014016152A1 (en) | 2012-07-27 | 2014-01-30 | Institut National De La Sante Et De La Recherche Medicale | Cd147 as receptor for pilus-mediated adhesion of meningococci to vascular endothelia |
TW201620927A (zh) * | 2014-02-24 | 2016-06-16 | 葛蘭素史密斯克藍生物品公司 | Uspa2蛋白質構築體及其用途 |
EP3263695A1 (en) | 2016-06-29 | 2018-01-03 | GlaxoSmithKline Biologicals SA | Immunogenic compositions |
GB202115151D0 (en) | 2021-10-21 | 2021-12-08 | Glaxosmithkline Biologicals Sa | Methods |
WO2023187743A1 (en) * | 2022-03-31 | 2023-10-05 | The University Of Queensland | Improved chimeric polypeptides and uses thereof |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU545912B2 (en) | 1980-03-10 | 1985-08-08 | Cetus Corporation | Cloned heterologous jive products in bacillies |
ZA811368B (en) | 1980-03-24 | 1982-04-28 | Genentech Inc | Bacterial polypedtide expression employing tryptophan promoter-operator |
DK188582A (da) | 1981-04-29 | 1982-10-30 | Biogen Nv | Bacillus-kloningsvektorer rekombinations-dna-molekyler bacillus-vaerter transformeret dermed samt fremgangsmaader til ekspressionaf fremmede dna-sekvenser og fremstilling af polypeptideer som er kodede dermed |
US4551433A (en) | 1981-05-18 | 1985-11-05 | Genentech, Inc. | Microbial hybrid promoters |
JPS59166086A (ja) | 1983-03-09 | 1984-09-19 | Teruhiko Beppu | 新規な発現型プラスミドとそれらを用いて仔牛プロキモシン遺伝子を大腸菌内で発現させる方法 |
JPS59205983A (ja) | 1983-04-28 | 1984-11-21 | ジエネツクス・コ−ポレイシヨン | 異種遺伝子を原核微生物で発現させる方法 |
US4663280A (en) | 1983-05-19 | 1987-05-05 | Public Health Research Institute Of The City Of New York | Expression and secretion vectors and method of constructing vectors |
US4689406A (en) | 1983-08-10 | 1987-08-25 | Amgen | Enhancement of microbial expression of polypeptides |
NZ209308A (en) | 1983-08-30 | 1991-08-27 | Genentech Inc | Vaccine against hsv involving a truncated membrane-free derivative of a membrane-bound protein |
JPS6054685A (ja) | 1983-09-02 | 1985-03-29 | Suntory Ltd | 改良発現ベクタ−およびその利用 |
EP0136907A3 (en) | 1983-10-03 | 1986-12-30 | Genentech, Inc. | A xenogeneic expression control system, a method of using it, expression vectors containing it, cells transformed thereby and heterologous proteins produced therefrom |
US4738921A (en) | 1984-09-27 | 1988-04-19 | Eli Lilly And Company | Derivative of the tryptophan operon for expression of fused gene products |
US4745056A (en) | 1984-10-23 | 1988-05-17 | Biotechnica International, Inc. | Streptomyces secretion vector |
US4865974A (en) | 1985-09-20 | 1989-09-12 | Cetus Corporation | Bacterial methionine N-terminal peptidase |
JPS63123383A (ja) | 1986-11-11 | 1988-05-27 | Mitsubishi Kasei Corp | ハイブリツドプロモ−タ−、発現調節dna配列および発現ベクタ− |
ATE246244T1 (de) | 1988-01-29 | 2003-08-15 | Aventis Pasteur | Rekombinante cmv-neutralisierungsproteine |
IT1253009B (it) | 1991-12-31 | 1995-07-10 | Sclavo Ricerca S R L | Mutanti immunogenici detossificati della tossina colerica e della tossina lt, loro preparazione ed uso per la preparazione di vaccini |
US6165747A (en) * | 1993-12-30 | 2000-12-26 | President & Fellows Of Harvard College | Nucleic acids encoding hedgehog proteins |
UA56132C2 (uk) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
US6610539B1 (en) | 1997-07-10 | 2003-08-26 | Genesense Technologies, Inc. | Antisense oligonucleotide sequences as inhibitors of microorganisms |
US6300318B1 (en) | 1997-09-16 | 2001-10-09 | Peter E. Nielsen | Antibacterial and antibiotic methods using peptide nucleic acids and pharmaceutical compositions therefor |
CA2308606A1 (en) | 1997-11-06 | 1999-05-20 | Chiron S.P.A. | Neisserial antigens |
GB9726398D0 (en) | 1997-12-12 | 1998-02-11 | Isis Innovation | Polypeptide and coding sequences |
PT1047784E (pt) | 1998-01-14 | 2009-12-21 | Novartis Vaccines & Diagnostic | Antigénios de neisseria meningitidis |
KR100627590B1 (ko) | 1998-01-30 | 2006-09-25 | 다이이치 아스비오파마 가부시키가이샤 | 보조 펩타이드를 사용하는 펩타이드의 제조방법 |
GB9808866D0 (en) | 1998-04-24 | 1998-06-24 | Smithkline Beecham Biolog | Novel compounds |
EP2261343A3 (en) | 1998-05-01 | 2012-01-18 | Novartis Vaccines and Diagnostics, Inc. | Neisseria meningitidis antigens and compositions |
GB9810276D0 (en) | 1998-05-13 | 1998-07-15 | Smithkline Beecham Biolog | Novel compounds |
EP2796148A3 (en) | 1998-05-29 | 2015-02-25 | Novartis Vaccines and Diagnostics, Inc. | Combination meningitidis B/C vaccines |
GB9818004D0 (en) | 1998-08-18 | 1998-10-14 | Smithkline Beecham Biolog | Novel compounds |
WO2000018434A1 (en) | 1998-09-30 | 2000-04-06 | American Cyanamid Company | Mutant cholera holotoxin as an adjuvant |
EP1559795A3 (en) | 1998-10-09 | 2005-11-09 | Chiron Corporation | Neisseria genomic sequences and methods of their use |
PT1228217E (pt) | 1999-04-30 | 2013-01-28 | Novartis Vaccines & Diagnostic | Antígenos de neisseria conservados |
CN1359426A (zh) | 1999-04-30 | 2002-07-17 | 希龙公司 | 奈瑟球菌基因组序列及其用法 |
CA2929348A1 (en) | 1999-05-19 | 2000-11-30 | Novartis Vaccines And Diagnostics S.R.L. | Combination neisserial compositions |
GB9911683D0 (en) | 1999-05-19 | 1999-07-21 | Chiron Spa | Antigenic peptides |
GB9916529D0 (en) | 1999-07-14 | 1999-09-15 | Chiron Spa | Antigenic peptides |
ES2564463T3 (es) | 1999-10-29 | 2016-03-22 | Glaxosmithkline Biologicals S.A. | Péptidos antigénicos de Neisseriales |
RU2002117308A (ru) | 1999-11-29 | 2004-03-10 | Чирон Спа (It) | 85 кДа АНТИГЕН NEISSERIA |
GB9928196D0 (en) | 1999-11-29 | 2000-01-26 | Chiron Spa | Combinations of B, C and other antigens |
BRPI0107679B8 (pt) * | 2000-01-17 | 2021-05-25 | Chiron Spa | composição compreendendo vesículas de membrana externa do grupo sérico b de neisseria meningitidis e um componente inorgânico e uso da mesma |
CN100339482C (zh) | 2000-02-28 | 2007-09-26 | 启龙股份公司 | 奈瑟球菌蛋白质的杂交表达 |
AU2002330681C1 (en) | 2001-07-26 | 2015-04-02 | Glaxosmithkline Biologicals S.A. | Vaccines comprising aluminium adjuvants and histidine |
GB0118249D0 (en) | 2001-07-26 | 2001-09-19 | Chiron Spa | Histidine vaccines |
GB0121591D0 (en) * | 2001-09-06 | 2001-10-24 | Chiron Spa | Hybrid and tandem expression of neisserial proteins |
BR0211494A (pt) | 2001-07-27 | 2004-08-17 | Chiron Srl | Adesinas de meningococo nada, app e orf 40 |
NZ574530A (en) | 2002-08-02 | 2010-12-24 | Glaxosmithkline Biolog Sa | Vaccine compositions comprising L2 and/or L3 immunotype lipooligosaccharides from lgtB-neisseria minigitidis |
EP2351579B1 (en) * | 2002-10-11 | 2016-09-21 | Novartis Vaccines and Diagnostics S.r.l. | Polypeptide vaccines for broad protection against hypervirulent meningococcal lineages |
ATE552844T1 (de) * | 2003-01-30 | 2012-04-15 | Novartis Ag | Injizierbarer impfstoff gegen multiple meningokokken-serogruppen |
BR122017002991B1 (pt) * | 2003-10-02 | 2023-01-10 | Novartis Vaccines And Diagnostics S.R.L. | Composições imunogênicas aquosas para múltiplos sorogrupos meningocócicos |
-
2002
- 2002-07-26 BR BR0211494-1A patent/BR0211494A/pt not_active IP Right Cessation
- 2002-07-26 US US10/484,703 patent/US20050232936A1/en not_active Abandoned
- 2002-07-26 PT PT100056852T patent/PT2248822T/pt unknown
- 2002-07-26 EP EP02790218A patent/EP1412381B1/en not_active Expired - Lifetime
- 2002-07-26 WO PCT/IB2002/003396 patent/WO2003010194A2/en active Application Filing
- 2002-07-26 JP JP2003515553A patent/JP4592284B2/ja not_active Expired - Fee Related
- 2002-07-26 AT AT02790218T patent/ATE469915T1/de not_active IP Right Cessation
- 2002-07-26 EP EP10005685.2A patent/EP2248822B1/en not_active Expired - Lifetime
- 2002-07-26 AU AU2002355197A patent/AU2002355197A1/en not_active Abandoned
- 2002-07-26 DK DK10005685.2T patent/DK2248822T3/en active
- 2002-07-26 DE DE60236596T patent/DE60236596D1/de not_active Expired - Lifetime
- 2002-07-26 MX MXPA04000653A patent/MXPA04000653A/es active IP Right Grant
- 2002-07-26 ES ES10005685.2T patent/ES2615362T3/es not_active Expired - Lifetime
- 2002-07-26 CA CA2452836A patent/CA2452836C/en not_active Expired - Fee Related
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2009
- 2009-02-16 JP JP2009033304A patent/JP4902678B2/ja not_active Expired - Lifetime
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2010
- 2010-05-06 US US12/775,457 patent/US20100221256A1/en not_active Abandoned
- 2010-06-29 JP JP2010148240A patent/JP2010268801A/ja not_active Withdrawn
- 2010-08-20 CY CY20101100776T patent/CY1111715T1/el unknown
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2014
- 2014-03-24 US US14/224,031 patent/US9249197B2/en not_active Expired - Fee Related
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2017
- 2017-02-14 CY CY20171100197T patent/CY1118628T1/el unknown
Also Published As
Publication number | Publication date |
---|---|
CA2452836A1 (en) | 2003-02-06 |
EP2248822A2 (en) | 2010-11-10 |
BR0211494A (pt) | 2004-08-17 |
JP2005503785A (ja) | 2005-02-10 |
US20140294884A1 (en) | 2014-10-02 |
DK2248822T3 (en) | 2017-02-13 |
EP1412381A2 (en) | 2004-04-28 |
WO2003010194A3 (en) | 2003-10-02 |
JP2009148279A (ja) | 2009-07-09 |
ES2615362T3 (es) | 2017-06-06 |
JP4902678B2 (ja) | 2012-03-21 |
EP1412381B1 (en) | 2010-06-02 |
US9249197B2 (en) | 2016-02-02 |
CY1118628T1 (el) | 2017-07-12 |
AU2002355197A1 (en) | 2003-02-17 |
US20100221256A1 (en) | 2010-09-02 |
WO2003010194A2 (en) | 2003-02-06 |
PT2248822T (pt) | 2017-02-14 |
US20050232936A1 (en) | 2005-10-20 |
MXPA04000653A (es) | 2004-11-22 |
EP2248822B1 (en) | 2016-11-23 |
CY1111715T1 (el) | 2015-10-07 |
EP2248822A3 (en) | 2011-04-13 |
ATE469915T1 (de) | 2010-06-15 |
DE60236596D1 (de) | 2010-07-15 |
CA2452836C (en) | 2012-11-27 |
JP2010268801A (ja) | 2010-12-02 |
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