CN101395176B - 肽序列和组合物 - Google Patents
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Abstract
本发明提供了一种具有不超过100个氨基酸的多肽,所述多肽含有与SEQ ID 1~6任一序列具有至少60%同源性的一条或者多条序列,或者含有两个或者更多个具有7个氨基酸或更多氨基酸的抗原决定簇,每个抗原决定簇与SEQ ID 1~6任一序列的和所述抗原决定簇长度相同的子序列具有至少60%的同源性:SEQ ID 1 DLEALMEWLKTRPILSPLTKGILGFVFTLTVP;SEQ ID 2 LLYCLMVMYLNPGNYSMQVKLGTLCALCEKQASHS;SEQ ID 3 DLIFLARSALILRGSVAHKSC;SEQ ID 4PGIADIEDLTLLARSMVV VRP;SEQ ID 5 LLIDGAASLSPGMMMGMFNMLSTVLGVSILNLGQ;SEQ ID 6 IIGILLLILWILDLLFFKCIYRLF;其中,所述多肽在表达主要组织相容性复合体(MHC)等位基因的脊椎动物中是免疫原性的,且其中所述多肽不是完整的流感病毒蛋白。
Description
技术领域
本发明涉及肽序列,含有这些肽序列的组合物,特别是含有这些序列和组合物的流感疫苗,以及这些序列的用途。具体的,本发明涉及疫苗,其能够防护抵抗多种流感病毒株,包括跨越不同物种的现有病毒(例如防护抵抗人类流感和禽流感)以及从现有病毒突变的未来病毒(例如容易在人与人之间传播的禽流感的未来突变形式,其可能引起大流行性流感)。
背景技术
对疾病的防御对于所有动物的生存而言是至关重要的,为该目的所采用的防御机制是动物的免疫系统。因此,对免疫系统的理解是开发用于人类和类似动物的新型和更完善治疗的关键。
免疫系统的运转机制已经被研究了许多年。该系统由许多细胞类型和多种分子构成,这使得该系统非常复杂。即使多年研究之后,免疫系统组分的整个范围以及它们相互之间的作用仍未被完全理解。
许多年之前,认识到从特定疾病恢复的人将来可能会获得某些防护抵抗该疾病,但不会抵抗他还未感染过的疾病。那时,免疫系统的这种基本方面被解释为一旦发生暴露给某些病原体,则免疫系统会获得某些针对这些病原体的一类“记忆”,该记忆对于某些疾病是特异的。
逐渐地,知道暴露到病原体的不大有害变异体会引起针对更有害变异体的防护(例如暴露到牛痘以防护抵抗天花,或者暴露到灭活的炭疽以保护抵抗活的炭疽)。因此,出现了接种疫苗抵抗疾病的观念。
目前已知免疫系统具有至少两个分支:先天性免疫和适应性免疫。在病原体进入免疫系统之前,先天性系统是具有完全功能的,而在病原体进入免疫系统之后,适应性系统才被打开。接着,其产生对病原体的 特异性攻击。先天性系统包括许多组分,包括吞噬细胞如巨噬细胞,其(如名字所暗示的)会“吃掉”或者吞掉外源物体如病原体。
通常,但不是排他的,本发明涉及适应性免疫系统,除非特别以其他方式说明,否则本文中的“免疫系统”是指适应性免疫系统。
为了更充分地理解免疫系统如何发挥功能,其每个个别组分的作用必须要被仔细考虑。关于适应性免疫系统,众所周知针对病原体的免疫性是由淋巴细胞的作用提供的,淋巴细胞构成了免疫系统中最常见的细胞类型。存在两种类型的淋巴细胞:B淋巴细胞和T淋巴细胞。通常分别被称作B细胞和T细胞。
B细胞具有发育成浆细胞的能力,所述浆细胞制造抗体。抗体是动物免疫系统非常重要的组分。它们是响应所入侵病原体的某些识别标志部分(病原体的抗原——抗原在这里被定义为免疫系统所识别的任何外源物质)而产生的,并且对于该病原体通常是特异性的。然而,如果两种病原体非常类似,或者至少含有相同的抗原,则针对一种病原体所产生的抗体仍然能够针对另一种病原体有效(它们可以“交叉反应”)。这解释了为什么接种牛痘能够防护抵抗天花。重要的是意识到抗体仅“识别”病原体的小部分抗原分子,而不是整个病原体。这些部分被称作抗原决定簇。
T细胞不具有抗体或者不产生抗体。而是,它们通过被称作TCR(T细胞受体)的特化受体来识别与主要组织相容性复合体(MHC)(或者对于人,是人白细胞抗原(HLA))形成复合物的外源抗原的片段(即抗原决定簇)。T细胞自身可以分成多种亚型,其可以具有调节功能或者效应功能。效应细胞参与“实现”清除外源物质。例如,细胞毒性T细胞(CTL)是效应细胞,其能够杀死被感染的细胞,以及其他多余的成分例如肿瘤细胞。另一方面,调节性T细胞在辅助效应T细胞和B细胞变得更有效方面发挥作用。由于该功能,这些调节性T细胞通常被命名为“辅助性”T细胞。另一种被命名为“阻抑性”T细胞的调节性T细胞被认为抑制免疫应答,但这些T细胞没有被充分了解。调节性T细胞也可以与先天性免疫系统的组分相互作用以加强它们的活性。
在正常的健康个体中,免疫系统的淋巴细胞直到免疫应答被触发前均保持无活性的“静息”状态。在需要免疫应答时,淋巴细胞变为被激活、增殖并开始发挥它们被指派的功能。例如,在表面上展示用于识别与MHC分子形成复合物的入侵病原体抗原决定簇的TCR的任何静息T细胞被激活、增殖(这被命名为克隆扩充),所得到的后代开始活跃地发挥它们预定的效应功能,所述功能是抗击入侵的生物体所需的。
当免疫应答结束时(即,病原体和/或被感染的细胞已经被清除),则淋巴细胞再次恢复到静息状态。然而,该静息状态不等同于开始的无活性静息状态。以后,响应相同或紧密相关病原体的感染,被激活过但静息的淋巴细胞,能够被快速地募集并诱导增殖。
在再次遇到入侵的病原体之后,被激活的静息淋巴细胞这种提供更快和更强应答的能力,有效地为免疫系统提供了“记忆”。免疫系统记忆的开发是所有长期免疫预防性药物(例如疫苗)的基础,并依然是非常长期免疫治疗性药物开发的目标。
为了使细胞在复杂的动物系统内发挥功能,细胞需要在其表面上具有“受体”。这些受体能够“识别”特异性的物质,所述特异性的物质控制各种基本过程,例如激活、增殖和附着到其他细胞或底物上。例如,在免疫系统的情况中,T细胞和B细胞上的受体使它们不仅识别抗原,而且相互作用,从而调节它们的活性。没有这些受体,这些细胞会缺乏基本的通讯手段,并可能无法有效协调地发挥作用,而这对于多细胞生物体的免疫系统是必要的。
为了能够特异性地识别和处理环境中存在的大量病原体,免疫系统在淋巴细胞上发展出两种类型的高度可变的抗原受体:B细胞中的抗体以及T细胞中的T细胞受体或TCR。
在身体中存在大量不同的可能抗原受体,以使免疫系统能够识别多种多样的入侵病原体。事实上,个体中存在大约1012种不同的B细胞和T细胞受体。每种单独的B细胞仅有一种类型的受体,以便处理特定的病原体,具有针对那种病原体的抗原的“最佳适合”受体的B细胞必须被选择。该过程被称作“克隆选择”。理论上,根据病原体所表现的抗原/抗 原决定簇的数目以及为这些抗原/抗原决定簇所选择的多种B细胞的特异性,可以仅一种克隆进行应答(单克隆应答)或者几个(寡克隆应答)或许多(多克隆应答)。
在能够被B细胞和T细胞识别的抗原类型之间存在重大的差别。根据目前已知,只有B淋巴细胞表面上的受体(即抗体)能够直接识别抗原如病毒和细菌上的蛋白质,或者溶解在体液中的外源分子。在B细胞被激活并发育成浆细胞时,B细胞也能够产生可溶形式的抗体。这些抗体也被命名为免疫球蛋白(缩写为Ig)。另一方面,T细胞受体仅识别身体细胞表面上的短肽,也被称作T细胞抗原决定簇。这些T细胞抗原决定簇是通过较大蛋白质的降解所产生的,所述蛋白质是自身的(即天然存在的体蛋白质)或非自身的(即来自感染身体的外源生物体)。只有来自外源蛋白质的那些,即抗原通常能够诱导体内的免疫应答。一旦产生,这些抗原决定簇会结合到特定类型的分子MHC(主要组织相容性复合体)上,接着所得到的复合物被呈递在细胞表面上用于结合T细胞受体。
需要理清楚的是,由于免疫应答的破坏性特征,该应答不得不仅针对外源病原体发挥作用,而不能针对身体自身细胞或蛋白质发挥作用。因此,免疫系统需要区分“自身”和“非自身”。已经提出,尽管产生针对自身反应的淋巴细胞克隆,但它们在能够发生任何反应之前就被除去了。该过程被命名为“克隆缺失”。还提出,任何自身反应的淋巴细胞可以被保留但仅处于“关闭”状态。这种机制被命名为“克隆无反应性”。无论考虑何种过程,仍不清楚精确的基本机制是什么,使得淋巴组织如胸腺从仅针对非自身反应的T淋巴细胞群中鉴定针对自身反应的个别T细胞克隆。目前本发明人已经更充分地研究了自身/非自身区分的机制,这导致了本发明的开发。目前,本发明人已经建立了一种预测物质如肽的免疫原性的方法,其能够在大的蛋白质内实现更快地鉴定免疫原性肽序列。
许多年来,已知主要组织相容性复合体(MHC)在动物的免疫系统中发挥了关键作用。正如上面已经讨论的,MHC分子使T细胞能够识别抗原。存在三种主要类型的MHC分子,I类、II类和III类。I类和II类MHC分子是存在于细胞表面上的糖蛋白,而III类则通常是细胞内存在的可溶分子。存在大量的不同类型的MHC分子。例如,在人类中(在人类中MHC被命名为HLA,人白细胞抗原),存在数百种不同的编码MHC分子的等位基因,这意味着在人群中,存在许多不同类型的HLA。通常,根据不同的惯例对不同物种的MHC进行命名,因此,小鼠的MHC被命名为H-2,大鼠是RT1,兔是RLA。个体中编码不同MHC分子的不同基因区通常被单独命名,例如在人类中为HLA-A、HLA-C等。
MHC分子是重要的免疫系统分子,这是因为是该分子将抗原的抗原决定簇呈递给免疫系统。例如,如果T细胞将对特定的病原体做出应答,则该病原体必须具有至少一个抗原(例如蛋白质),该抗原具有至少一个抗原决定簇(例如蛋白质的肽部分),该抗原决定簇能够与细胞表面上的MHC分子结合,并因此与能够结合MHC-肽复合物的T细胞相互作用。因此,该免疫应答依赖于MHC结合于抗原决定簇的能力。如果没有将与MHC结合的抗原决定簇,或者没有结合于MHC-肽复合物的T细胞,则不会出现免疫应答。
然而,关于“自身”蛋白质,许多抗原决定簇的一种可以能够结合MHC分子,并因此可能诱导免疫应答。在这些情况中,必须提供特异性的“信号”用于清除或“关闭”与自身反应的淋巴细胞克隆。
因此,如上所述,自身和外源(即,非自身)肽都能够结合MHC分子,各种肽与MHC分子的结合在免疫学领域中已经受到特别详细的研究。许多研究已经寻求算出或者预测某些MHC(特别是HLA和H-2)类型和肽序列之间结合的强度,以试图解释免疫应答或其缺失(即,区分自身和外源所必需的“信号”)。这些研究的例子包括以下:
Altuvia Y,Schueler O,Margalit H.1995.“Ranking potential bindingpeptides to MHC molecules by a computational threading approach(通过计算穿线法排列潜在的与MHC分子结合的肽)”.J.Mol.Biol.,249:244~250.
Altuvia Y,Sette A,Sidney J,Southwood S,Margalit H.1997.“Astructure-based algorithm to predict potential binding peptides to MHC moleculeswith hydrophobic binding pockets(用以预测具有与含疏水结合袋的MHC分子结合的潜力的肽的结构算法)”.Hum.Immunol.58:1~11.
G.E.Meister,C.G.P.Roberts,J.A.Berzofsky,A.S.De Groot,“Two novel Tcell epitope prediction algorithms based on MHC-binding motifs;comparison ofpredicted and published epitopes from Mycobacterium tuberculosis and HIV protein sequences(基于MHC结合基序的两种新型T细胞表位预测算法;来自结核丝杆菌的所预测并公开的表位和HIV蛋白序列的比较)”Vaccine,13:581~591,(1995).
Gulukota K,Sidney J,Sette A,DeLisi C.1997.“Two complementarymethods for predicting peptides binding major histocompatibilty complexmolecules(用于预测与主要组织相容性复合分子结合的肽的两种互补方法)”.J.Mol.Biol.267:1258~1267.
Pamer EG,Harty JT,Bevan MJ.“Precise prediction of a dominant class IMHC-restricted epitope of Listeria monocytogenes(单核细胞增生李斯特菌的显性I类MHC限制表位的精确预测)”.Nature 1991;353:852~855.
Parker KC,Bednarek MA,Coligan JE.1994.“Scheme for ranking potentialHLA-A2 binding peptides based on independent binding of individual peptideside-chains(基于各单独的肽侧链的独立结合来排列潜在的HLA-A2结合肽的方案)”.J.Immunol.152:163~175.
Rammensee HG,Friede T,Stevanoviic S.1995.“MHC ligands and peptidemotifs:First listing(MHC配体和肽基序:表1)”.Immunogenetics 41:178~228.
Ruppert J,Sidney J,Celis E,Kubo RT,Grey HM,Sette A.1993.“Prominentrole of secondary anchor residues in peptide binding to HLA-A2.1 molecules(在与HLA-A2.1分子结合的肽中的二级锚定残基的重要作用)”.Cell 74:929~937.
Schueler-Furman O,Elber R, Margalit H.1998.“Knowledge-basedstructure pr ediction of MHC class I bound peptides:A study of 23complexes(MHC I类结合肽的基于知识的结构预测:23个复合物的研究)”.Fold Des.3:549~564.
Sette A,Buus S,Appella E,Smith JA,Chesnut R,Miles C,Colon SM,GreyHM.1989.“Prediction of major histocompatibilty complex binding regions ofprotein antigens by sequence pattern analysis(通过序列模式分析来预测蛋白抗原的主要组织相容性区域)”.Proc.Natl.Acad.Sci.USA 86:3296~3300.
Sette A,Sidney J,del Guercio MF,Southwood S,Ruppert J,Dahlberg C,Grey HM,Kubo RT.1994a.“Peptide binding to the most frequent HLA-A class Ialleles measured by quantitative molecular binding assays(通过量化分子结合测定来测量与最常见的HLA-A I类等位基因结合的肽)”.Mol.Immunol.31:813~822.
Sette A,Vitiello A,Reherman B,Fowler P,Nayersina R,Kast WM,MeliefCJM,Oseroff C,Yuan L,Ruppert J,等.1994b.“The relationship between class Ibinding affimity and immunogenicity of potential cytotoxic T cell epitopes(潜在的细胞毒素T细胞表位的I类结合亲和性和免疫原性之间的关系)”.J.Immunol.153:5586~5592.
Stefan Stevanovic(2002):“Structural basis of immunogenicity(免疫原性的结构基础)”,Transplant Immunology 10:133~136.
Sturniolo T,Bono E,Ding J,Raddrizzani L,Tuereci O,Sahin U,Braxenthaler M,Gallazzi F,Protti MP,Sinigaglia F,Hammer J.1999.“Generationof tissue-specific and promiscuous HLA ligand databases using DNA microarraysand virtual HLA class II matrices(采用DNA微阵列和虚拟HLA II类矩阵来产生具有组织特异性的混杂的HLA配体数据库)”.Nat.Biotechnol.17:555~561.
T.Sudo,N.Kamikawaji,A.Kimura,Y.Date,C.J.Savoie,H.Nakashima,E.Furuichi,S.Kuhara,和T.Sasazuki,“Differences in MHC Class I self peptiderepertoires among HLA-A2 subtypes.(HLA-A2亚型中MHC I类自身肽集的差异)”J.Immunol.:155:4749~4756,(1995).
T.Tana,N.Kamikawaji,C.J.Savoie,T.Sudo,Y.Kinoshita,T.Sasazuki,“AHLA binding motif-aided peptide epitope library:A novel library design for thescreening of HLA-DR4-restricted antigenic peptides recognized by CD4+ Tcells(HLA结合基序辅助肽表位文库:设计用于筛查由CD4+T细胞识别的HLA-DR4限制抗原肽的新型文库).”J.Human Genet.,43:14~21(1998).K.Falk,等人.“Allele-specific motifs revealed by sequencing of selfpeptides eluted from MHC molecules(通过对由MHC分子洗提的自身肽进行测序所揭示的等位基因特异性基序)”,Nature,Vol.351,290~297(1991).
T Elliott等人.“Peptide-induced conformational change of the class I heavychain(I类重链的肽诱导构象变化)”,Nature,Vol.351,402~407,(1991).
P.Parham,“Deconstructing the MHC(MHC解构)”,Nature,Vol.360,300~301,(1992).
Hwai-Chen Guo等人.“Different length peptides bind to HLA-Aw68similarly at their ends but bulge out in the middle(与HLA-Aw68结合的不同长度肽具有相似的末端和不同的中部)”,Nature,Vol.360,364~367,(1992).
Y.Chen等人.“Naturally processed peptides longer than nine amino acidresidues bind to the class I MHC molecule HLA-A2.1 with high affinity and indifferent conformations(超过9个氨基酸残基长度的自然剪接肽以高亲和力和不同的构象与I类MHC分子HLA-A2.1结合)”,J.Immunol.,152,2874~2881,(1994).
D.F.Hunt等人.“Characterization of peptides bound to the class I MHCmolecule HLA-A2.1 by mass spectrometry(通过质谱法表征与I类MHC分子HLA-A2.1结合的肽)”,Science,Vol.255,1261~1263,(1992).
通常,现有技术试图通过计算肽和特定MHC分子的已知结合环境之间的结合强度来预测特定肽的免疫原性。结合环境包括MHC分子中的“袋”,其适合接受一定长度的肽(例如7~15个氨基酸)。通过之前的X-射线晶体学研究已经可以知道所述“袋”的结构。使用原子和分子相互作用的适当运算法则可以在数学上计算这种强度。作为选择,现有技术试图根据肽中所存在的基序对肽的结合强度进行“评分”,例如与特定的已知HLA分子结合的在一定长度的肽的特定位置存在的特定氨基酸,例如在八氨基酸肽中位置3上存在的脯氨酸。通常,这些方法已经获得了有限的成功。
本发明人相信他们已经对上述理论进行了改进,其由于更充分地理解了与诸如自身蛋白质等自身物质反应的T细胞如何在它们的消除(克隆缺失)或沉默(克隆无反应性)之前被鉴定出来。因此,发明人已经能够鉴定特异性的免疫原性肽序列,其可提供针对特异性病原体的防护,并且使用所鉴定的序列已经开发出了针对这些病原体的疫苗。对于本发明,发明人已经开发出了用于引起T细胞应答的流感疫苗的肽。
之前,通过鉴定现有的流感病毒株并接着生产对该病毒具有特异性的疫苗,已经开发了流感疫苗。通常,这些疫苗已经基于B细胞(抗体)应答,所述抗体与特异性流感病毒株的表面抗原(即血凝素和神经氨酸苷酶)具有反应性,针对该流感病毒株已经开发了抗体。典型的是,含有抗原的表面蛋白在流感病毒株之间是可以变化的,这是因为产生新病毒的病毒突变倾向于出现在表面蛋白中。其结果是,传统的流感疫苗通常仅防护抵抗一种特定的病毒株,并且不会防护抵抗由突变导致的新病毒株。因此,需要新的疫苗防护抵抗出现的病毒株。这种方法的明确问题是在新病毒株的出现以及疫苗的开发之间存在一段时间,在这段时间中,针对该病毒没有可以利用的防护。如果病毒特别有害,则这能够引 起数百万人死亡,例如在上世纪出现的重大流行性流感。
知道细胞毒性T淋巴细胞可以提供对流感病毒株的免疫应答已经有一段时间了。最近的研究已显示人类中的CTL应答可以指向多个抗原决定簇。已经暗示,针对HLA-A2限定的M-158-66抗原决定簇存在显著的应答。这些研究包括A.C.Boon等人,J.Virol,2002年1月,582~90;S.Tamura等人,Jpn.J.Infect.Dis.,2004年12月,236~47;G.Deliyannis等人,J.Virol.,2002年5月,4212~21;C.Gianfrani等人,Hum.Immunol.,2000年5月,438~52;和J.Jameson等人,J.Immunol.,1999年6月,7578~83。
最近还已经有针对特异性免疫原性肽的研究,所述免疫原性肽可能对开发引起T细胞应答的流感疫苗有用。通常,这些工作已经涉及到研究CTL应答以测试例如在转基因小鼠中的流感肽。所测试的肽倾向于是可以与一种MHC(或HLA)类型反应的短序列,并且从特异性测试流感病毒株中获得。例如,在Vaccine,2005,5231~44中,N.Hu等人公开了在表达HLA-A2、HLA-B7或HLA-B27的HLA Tg小鼠中测试野生型M158-66肽。这些结果显示该肽是由表达HLA-A2的转基因小鼠所识别的流感抗原决定簇。在Clin.Exp.Immunol.,2005年10月,45~52中,A.C.Boon等人公开了M158-66和NP44-52流感A肽作为在HLA-A*0101和HLA-A*0201个体中所识别的抗原决定簇。在Cell Immunol.,2005年4月,110~123中,E.Cheuk等人公开NP383-391流感A肽作为HLA-B27/H2I类缺陷小鼠中所识别的抗原决定簇。使用抗原决定簇预测程序,作者鉴定了另外三种B27限制性流感A抗原决定簇BP-2702-710、PB-1571-579和PB-2368-376。在J.Immunol.,2004年2月,2453~60中,A.C.Boon等人公开了对NP418-426中HLA B*3501限制性抗原决定簇的天然变种特异的人CTL克隆。在J.Immunother.,2003年1月~2月,41~6中,A.Trojan等人公开了HLA-A3限制性九肽RLEDVFAGK,其能够诱导特异性的CTL反应性。还公开了HLA-A2限制性流感病毒A基质肽GILGFVFTL。在J.Gen.Virol.,2001年7月,1749~55中,S.Tourdot等人鉴定了来自于流感病毒株A/PR/8/34聚合酶蛋白PB-1的鼠D(k)限制性 抗原决定簇,其对应于氨基酸残基349~357(ARLGKGYMF)。在J.Immunol.中,2001年4月,4627~33,G.T.Belz等人从流感聚合酶蛋白PB-1鉴定了一种对应于氨基酸残基703~711的免疫原性肽(SSYRRPVGI)和来自PB-2聚合酶的模拟表位(ISPLMVAYM)。PCT/US2005/002954公开了含有NP265-273的CTL抗原决定簇,其具有序列ILRGSVAHK,还公开了含有NP305-313的抗原决定簇。最后,US6,740325公开了两种CTL抗原决定簇:NP335-350和NP380-393。
进一步研究已经显示来自转基因小鼠的数据提供了可靠的模型以用于研究人类中CTL应答。在Int.Immunol.,1995年4月,597-605中,S.Man等人已经显示来自HLA-A2.1转基因小鼠的HLA-A2.1限制性细胞毒性T淋巴细胞所识别的主要流感A抗原决定簇是基质蛋白1(M-1)肽抗原决定簇,其在人CTL应答中是免疫显性的。E.J.Bernhard等人(J.Exp.Med.,1998年9月,1157~62)和E.Cheuk等人(J.Immunol.,2002年11月,5571~80)已经进行了该领域的进一步研究。
然而,尽管已经广泛地研究了已知的抗原决定簇,但对于形成能够防护抵抗多于一种流感病毒株的流感疫苗的基础还没有令人满意的。而且,根据这些单个抗原决定簇的疫苗,即使它们提供了某些保护,但仍将对特定的HLA是特异性的,这使得它们在大比例人群中是无效的。
因此,无论依赖B细胞还是T细胞应答,已知疫苗的显著问题是它们仅防护抵抗现有的病毒株,而不提供针对未来可能发展出来的病毒株的防护。随着禽类中高度危险的H5N1株的出现,在基于H5N1株后续突变的人类大流行病之前变得越来越迫切需要疫苗。而且,根据引起T细胞应答的已知肽的疫苗可能在大部分人群中不会有效。
发明内容
因此,本发明的一个目的是解决与已知的上述现有技术相关的问题。本发明进一步的目的是提供一种多肽,该多肽能够在脊椎动物中针对多种流感株和/或在表达不同MHC(HLA)的多种个体中引起CTL免疫应答。本发明进一步的目的是提供一种使用本发明的多肽的流感疫苗。优 选的是,该疫苗能够防护抵抗多种流感株和/或在表达不同MHC(HLA)的多种个体中有效。
因此,本发明提供了一种具有不超过100个氨基酸的多肽,该多肽含有与SEQ ID 1~6任一序列具有至少60%同源性的一条或者多条序列,或者含有两个或者更多个具有7个氨基酸或更多氨基酸的抗原决定簇,每个抗原决定簇与SEQ ID 1~6任一序列的和所述抗原决定簇长度相同的子序列具有至少60%的同源性:
SEQ ID 1 DLEALMEWLKTRPILSPLTKGILGFVFTLTVP
SEQ ID 2 LLYCLMVMYLNPGNYSMQVKLGTLCALCEKQASHS
SEQ ID 3 DLIFLARSALILRGSVAHKSC
SEQ ID 4 PGIADIEDLTLLARSMVVVRP
SEQ ID 5 LLIDGTASLSPGMMMGMFNMLSTVLGVSILNLGQ
SEQ ID 6 IIGILHLILWILDRLFFKCIYRLF
其中,所述多肽在表达主要组织相容性复合体(MHC)等位基因的脊椎动物中是免疫原性的,且其中所述多肽不是完整的流感病毒蛋白。
因此,所述多肽是一种可以含有完整的上述序列中任一条序列(或者可以含有上述序列中任一条序列的至少两种七残基或者更多残基部分),但总体不能具有超过100个氨基酸残基。所述多肽在表达MHC(人类中为HLA)等位基因的脊椎动物中也必需是免疫原性的。免疫原性多肽在本文中被理解为一种多肽,其在脊椎动物中引发免疫应答,例如通过与脊椎动物MHC结合,并使MHC与细胞毒性T细胞淋巴细胞反应。在下面的实验1中提出了一种用于确定多肽是否具有免疫原性的方法。然而,本发明不限于这些方法,并且本领域技术人员可以根据需要选择任何已知的方法用于确定免疫原性。
如上所提到的,所述多肽可以是一种含有两种七残基或更多残基的抗原决定簇的多肽,所述抗原决定簇与一个或者多个MHC反应,这样引起广泛的CTL应答。该应答可以在一种个体中,或者可以在至少两种不同的个体中(并且所述个体可以是相同的物种或不同的物种)。因此,所述多肽可以含有至少两种不同的七残基或更多残基的抗原决定簇,其中 每个抗原决定簇独立地提供了对不同目标的应答。在本发明上下文中抗原决定簇是多肽的一部分,其能够结合于脊椎动物中的脊椎动物MHC,优选引发免疫应答,例如通过使MHC-抗原决定簇复合物与CTL反应。在下面的实验1中提出了一种用于确定多肽是否是抗原决定簇或者含有抗原决定簇的方法。然而,本发明不限于这些方法,并且本领域的技术人员可以根据需要选择任何已知的方法用于确定多肽是否是抗原决定簇或含有抗原决定簇。
本发明的发明人已经发现上述序列含有多种CTL抗原决定簇,其可以对群体中多种多样脊椎动物提供针对流感的防护。另外,发明人已经分析了跨所有物种的所有已知流感病毒株序列,并且已经发现所指定的序列在所有已知的流感病毒株中是非常保守的。同样地,这些序列在由现有株突变所产生的新株中也不太可能是显著变化的。因此,这些序列中提供防护作用的抗原决定簇在新株中很可能以未改变的形式存在,这是因为通常突变不会出现这些区域。因此,这些抗原决定簇提供了非常好的机会,不仅用于提供针对现有流感株(例如“鸟流感”的H5N1株)的防护,而且提供针对还未知的病毒株(例如H5N1的突变形式,其能够容易在人之间传播,并形成大流行病的基础)的防护。
如上所讨论的,在对跨所有物种的所有已知流感病毒株序列进行分析之后,已经鉴定了这些序列。因此,这些序列是从上述分析所得到的共有序列。尽管是共有序列,但在某些情况中,这些序列与某些已知流感病毒株中的天然序列精确对应。由于所有物种中所有病毒间的序列中的显著保守性,这些共有序列,即使在与实际序列有区别时,也仅在少量残基中有不同,并因此含有许多较小的抗原决定簇(八氨基酸、九氨基酸、十氨基酸等),因此与天然序列没有区别。因此,上述共有序列作为整体含有许多与天然的抗原决定簇相同的有效抗原决定簇,以及与天然抗原决定簇仅稍有不同的有效抗原决定簇。对于本领域技术人员显而易见的是,本发明不仅扩展到共有序列和它们的抗原决定簇,还扩展到任何流感病毒株中相应的实际序列。因此,与这些共有序列具有某些同源性的序列也在本发明的范围内。例如,这类同源性允许最高3个氨基 酸的取代存在于八氨基酸抗原决定簇中(62.5%同源性)或九氨基酸、十氨基酸或十一氨基酸抗原决定簇中。优选在对应SEQ ID 1~6全长序列的本发明序列中可以鉴定不超过10个这些取代(对于全长三十个氨基酸是66.6%的同源性)。优选的是,这些取代是符合已知取代方案的保守取代。
考虑到本发明从这些共有序列扩展到对应的天然序列,因此本发明还提供了一种不超过100个氨基酸的多肽,该多肽含有由流感病毒蛋白的下列氨基酸残基所限定的一条或者多条序列,或者含有两个或者更多个抗原决定簇,所述抗原决定簇具有来自由流感病毒蛋白的下列氨基酸残基所限定的序列的7个氨基酸或更多个氨基酸:
M1蛋白的残基36~75(优选来自流感A株)
M1蛋白的残基124~158(优选来自流感B株)
NP蛋白的残基255~275(优选来自流感A株)
NP蛋白的残基306~326(优选来自流感B株)
PB1蛋白的残基395~428
M2蛋白的残基32~55
其中,所述多肽在表达主要组织相容性复合体(MHC)等位基因的脊椎动物中是免疫原性的,且其中所述多肽不是完整的流感病毒蛋白。
对本发明中提及的序列的编号是根据公认的原则所确定的。因此,编号是从公认翻译起始密码子(ATG)的1位开始的。对于编码感兴趣蛋白的流感基因组的区段,这对应于甲硫氨酸(M)。换句话说,正如由已列出序列的数据库(即GenBank,SwissProt等)所使用和限定的,其开始于1位,相对于显示为感兴趣的蛋白质序列中的第一个氨基酸的甲硫氨酸。
附图说明
参考后面的附图仅以实施例的方式对本发明进行更充分地描述,其中:
图1A~1F显示根据下面实施例1所描述的方案,FLU-v和NRP疫苗接种的小鼠的原代脾细胞培养物所产生的IFN-γ,所述原代脾细胞培养 物被下列所刺激:Con A(10μg/ml)、可溶性溶菌酶(5μg/ml)、纯化的可溶性多肽(P1(图1A)、P2(图1B)、P3(图1C)、P4(图1D)、P5(图1E)和P6(图1F);5μg/ml)和被溶菌酶P1、P2、P3、P4、P5或P6所转染的HLA-匹配的T1(T1)和不匹配的JURKAT(Ju)人细胞(脾细胞与转染细胞的比例是10:1)。IFN-γ的产生被表示为响应所考虑抗原的产生水平减去响应可溶性溶菌酶或转染溶菌酶的相应细胞所产生的IFN-γ之间的差异。溶菌酶介导的IFN-γ的产生的背景水平对于可溶性抗原是25±10pg/ml,对于T1中的抗原是316±43pg/ml,对于Jurkat中的抗原是19±6pg/ml;
图2显示根据下面实施例1所描述的方案,FLU-v和NRP疫苗接种的小鼠的原代脾细胞培养物所产生的IFN-γ,所述原代脾细胞培养物被被下列所刺激:Con A(10μg/ml)、可溶性溶菌酶(5μg/ml)、纯化的可溶性FLU-v多肽制备物(P1、P2、P3、P4、P5和P6,全部为5μg/ml)和HLA匹配的T1(T1)和不匹配的JURKAT(Ju)人细胞,所述人细胞被感染流感病毒株A/New_Caledonia/20/99、A/NYMC/X-147或B/Johannesburg/5/99,或转染溶菌酶(脾细胞:感染/转染细胞的比例为10:1);IFN-γ的产生被表示为响应所考虑抗原的产生水平减去响应可溶性溶菌酶或转染溶菌酶的相应细胞所产生的IFN-γ之间的差异;溶菌酶介导的IFN-γ的产生的背景水平对于可溶性抗原是25±10pg/ml,对于T1中的抗原是316±43pg/ml,对于Jurkat中的抗原是19±6pg/ml;以及
图3A和3B显示在使用流感A/PR/8/34进行致死攻击之后,动物的存活率;在第1和15天,动物被皮下免疫FLU-v或NRP-v,第20天,在麻醉下,用45μl病毒(每剂量为5×107pfu)对所有的动物进行鼻内攻击;在第19和22天,将图3A中的动物腹腔内接种100μg的大鼠抗小鼠CD8血清;在第19和22天,将图3B中的动物腹腔内接种无关大鼠血清;箭头表示鼻内攻击的日期;而菱形表示动物接种抗CD8血清的日期。
具体实施方式
上面所描述的多肽通常含有一个或者多个(优选2个或者更多个) 抗原决定簇。优选的是,这些抗原决定簇是T细胞抗原决定簇,例如细胞毒性T淋巴细胞(CTL)抗原决定簇。通常,所述多肽对于流感病毒株是免疫原性的,并优选对于多种流感病毒株是免疫原性的。在本文中,对流感病毒株是免疫原性的多肽被理解为意味着所述多肽作为流感病毒蛋白一部分,并能够引起免疫系统应答,例如通过在结合MHC时表现CTL反应性。下面的实验1中提出了一种用于确定多肽是否具有这类免疫原性的方法。然而,本发明并不限于这些方法,本领域技术人员可以根据需要选择任何已知的方法用于确定免疫原性。
在本发明中,所述多肽含有上述的两条或者更多条序列。通常,如果需要,在多肽中可以存在两条、三条、四条、五条或者更多条这样的序列。所存在的这类抗原决定簇越多,则在具有不同HLA或MHC的人和/或动物个体群体中提供的保护幅度就越大。
如果需要,根据本发明的多肽还可以包含一条或者多条不是抗原决定簇的其他序列。通常,所述其他序列来自于一个或者多个流感病毒蛋白。这些序列可以位于上述两条或者更多条序列(抗原决定簇)之间,或者可以位于多肽的一个或者两个末端。这些其它序列的存在不应该影响所述多肽的功能,倘若所述多肽作为整体不会变得太大,干扰脊椎动物的免疫系统中抗原决定簇的呈递。在本发明的具体实施方式中,当所述多肽与SEQ ID 1同源时,则优选所述其他序列是来自流感M1蛋白(优选来自流感A株)的一条或者多条序列;当所述多肽与SEQ ID 2同源时,则优选所述其他序列是来自流感M1蛋白(优选来自流感B株)的一条或者多条序列;当所述多肽与SEQ ID 3同源时,则优选所述其他序列是来自流感NP蛋白(优选来自流感A株)的一条或者多条序列;当所述多肽与SEQ ID 4同源时,则优选所述其他序列是来自流感NP蛋白(优选来自流感B株)的一条或者多条序列;当所述多肽与SEQ ID 5同源时,则优选所述其他序列是来自流感PB1蛋白的一条或者多条序列;当所述多肽与SEQ ID 6同源时,则优选所述其他序列是来自流感M2蛋白的一条或者多条序列。
在最优选的实施方式中,来自上述蛋白质的所述其他序列是下列共 有序列内的序列,或者与下列共有序列内的序列具有至少60%的同源性的序列:
M1流感A共有序列-SEQ ID 7
MSLLTEVETYVLSIVPSGPLKAEIAQRLEDVFAGKNTDLEALMEWLKTRPILSPLTKGILGFVFTLTVPSERGLQRRRFVQNALNGNGDPNNMDKAVKLYRKLKREITFHGAKEIALSYSAGALASCMGLIYNRMGAVTTEVAFGLVCATCEQIADSQHRSHRQMVATTNPLIKHENRMVLASTTAKAMEQMAGSSEQAAEAMEIASQARQMVQAMRTVGTHPSSSTGLRDDLLENLQTYQKRMGVQMQRFK
M1流感B共有序列-SEQ ID 8
MSLFGDTIAYLLSLTEDGEGKAELAEKLHCWFGGKEFDLDSALEWIKNKRCLTDIQKALIGASICFLKPKDQERKRRFITEPLSGMGTTATKKKGLILAERKMRRCVSFHEAFEIAEGHESSALLYCLMVMYLNPGNYSMQVKLGTLCALCEKQASHSHRAHSRAARSSVPGVRREMQMVSAMNTAKTMNGMGKGEDVQKLAEELQSNIGVLRSLGASQKNGEGIAKDVMEVLKQSSMGNSALVKKYL
NP流感A共有序列-SEQ ID 9
MASQGTKRSYEQMETDGDRQNATEIRASVGKMIDGIGRFYIQMCTELKLSDYEGRLIQNSLTIEKMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRVDGKWMRELVLYDKEEIRRIWRQANNGEDATAGLTHMMIWHSNLNDATYQRTRALVRTGMDPRMCSLMQGSTLPRRSGAAGAAVKGIGTMVMELIRMIKRGINDRNFWRGENGRKTRSAYERMCNILKGKFQTAAQRAMVDQVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGPAVSSGYDFEKEGYSLVGIDPFKLLQNSQVYSLIRPNENPAHKSQLVWMACHSAAFEDLRLLSFIRGTKVSPRGKLSTRGVQIASNENMDNMGSSTLELRSGYWAIRTRSGGNTNQQRASAGQISVQPTFSVQRNLPFEKSTVMAAFTGNTEGRTSDMRAEIIRMMEGAKPEEVSFRGRGVFELSDEKATNPIVPSFDMSNEGSYFFGDNAEEYDN
NP流感B共有序列-SEQ ID 10
MSNMDIDGINTGTIDKTPEEITSGTSGTTRPIIRPATLAPPSNKRTRNPSPERATTSSEADVGRKTQKKQTPTEIKKSVYNMVVKLGEFYNQMMVKAGLNDDMERNLIQNAHAVERILLAATDDKKTEFQKKKNARDVKEGKEEIDHNKTGGTFYKMVRDDKTIYFSPIRITFLKEEVKTMYKTTMGSDGFSGLNHIMIGHSQMNDVCFQRSKALKRVGLDPSLISTFAGSTLPRRSGATGVAIKGGGTLVAEAIRFIGRAMADRGLLRDIKAKTAYEKILLNLKNKCSAPQQKALVDQVIGSRNPGIADIEDLTLLARSMVVVRPSVASKVVLPISIYAKIPQLGFNVEEYSMVGYEAMALYNMATPVSILRMGDDAKDKSQLFFMSCFGAAYEDLRVLSALTGTEFKPRSALKCKGFHVPAKEQVEGMGAALMSIKLQFWAPMTRSGGNEVGGDGGSGQISCSPVFAVERPIALSKQAVRRMLSMNIEGRDADVKGNLLKMMNDSMAKKTNGNAFIGKKMFQISDKNKTNPVEIPIKQTIPNFFFGRDTAEDYDDLDY
PB1流感共有序列-SEQ ID 11
MDVNPTLLFLKVPAQNAISTTFPYTGDPPYSHGTGTGYTMDTVNRTHQYSEKGKWTTNTETGAPQLNPIDGPLPEDNEPSGYAQTDCVLEAMAFLEESHPGIFENSCLETMEVVQQTRVDKLTQGRQTYDWTLNRNQPAATALANTIEVFRSNGLTANESGRLIDFLKDVMESMDKEEMEITTHFQRKRRVRDNMTKKMVTQRTIGKKKQRVNKRGYLIRALTLNTMTKDAERGKLKRRAIATPGMQIRGFVYFVETLARSICEKLEQSGLPVGGNEKKAKLANVVRKMMTNSQDTELSFTITGDNTKWNENQNPRMFLAMITYITKNQPEWFRNILSIAPIMFSNKMARLGKGYMFESKRMKLRTQIPAEMLASIDLKYFNESTRKKIEKIRPLLIDGTASLSPGMMMGMFNMLSTVLGVSILNLGQKKYTKTTYWWDGLQSSDDFALIVNAPNHEGIQAGVDRFYRTCKLVGINMSKKKSYINKTGTFEFTSFFYRYGFVANFSMELPSFGVSGINESADMSIGVTVIKNNMINNDLGPATAQMALQLFIKDYRYTYRCHRGDTQIQTRRSFELKKLWDQTQSKAGLLVSDGGPNLYNIRNLHIPEVCLKWELMDEDYRGRLCNPLNPFVSHKEIESVNNAVVMPAHGPAKSMEYDAVATTHSWIPKRNRSILNTSQRGILEDEQMYQKCCNLFEKFFPSSSYRRPVGISSMVEAMVSRARIDARIDFESGRIKKEEFSEIMKICSTIEELRRQKK
M2流感共有序列-SEQ ID 12
MSLLTEVETPIRNEWGCRCNDSSDPLVVAASIIGILHLILWILDRLFFKCIYRLFKHGLKRGPSTEGVPESMREEYRKEQQNAVDADDSHFVSIELE
关于这些序列与上面的同源性优选为75%、85%、95%或基本上为100%。
在本发明中,流感株不受到特别限制,所述多肽可以对任何已知的流感株是免疫原性的,和/或来自任何已知的流感株。然而,优选的是,相关的株是流感A株或流感B株。已从任何现有株突变得到的未来流感株也可以是以下流感株:所述多肽针对该流感株为免疫原性的,或者所述多肽来自该流感株。
定义本发明多肽的序列所位于其中的蛋白质选自任何流感病毒株(特别是A株和B株)的M1、NP、PB和M2蛋白(如上所述,其为所有分析序列的共有序列,或者作为选择,其位置位于所述蛋白质内)。发明人对下列特异性的蛋白进行了分析,优选本发明中所提到的流感病毒蛋白选自这些特定蛋白,或者来自这些蛋白的突变体。因此,上面所描述的与SEQ ID 1~6同源的特定序列优选是在下列蛋白内适当位置上的。类似的,由任何流感株的蛋白内残基位置所限定的本发明的序列,即M1蛋白的残基36~75(特别是流感A M1),M1蛋白的残基124~158(特别是在流感B M1中),NP蛋白的残基255~275(特别是在流感A NP中),NP蛋白的残基306~326(特别是在流感B NP中),PB1蛋白的残基395~428和M2蛋白的残基32~55优选是位于下列特定蛋白质中的序列。该列表是以|版本号(gi号)|数据库识别码(例如对于GenBank是gb)|NCBI索取号|可选择的其他信息(例如,产生蛋白序列的核苷酸序列的索取号)的形式。这些序列和产生它们的对应流感株可以全部在公共NCBI蛋白质数据库中发现,其可以通过以下URL地址在线进入:http://www.ncbi.nlm.nih.gov/entrez/query/static/help/helpdoc.htm1#Protein.该蛋白质数据库含有来自GenBank、EMBL和DDBJ中DNA序列经过翻译的编码区的序列数据,以及提交到蛋白质信息资源(Protein Information Resource,PIR)、SWISS-PROT、蛋白质研究基金会(PRF)和蛋白质数据银行(Protein Data Bank,PDB)(来自经解释的结构的序列)的蛋白质序列的序列数据。
M1蛋白
|27530653|dbj|BAC54009.1|;|27530634|dbj|BAC53998.1|; |53829719|gb|AAU94746.1|;|53829716|gb|AAU94744.1|; |53829713|gb|AAU94742.1|; |53829710|gb|AAU94740.1|;|53829707|gb|AAU94738.1|; |53829704|gb|AAU94736.1|; |53829701|gb|AAU94734.1|;|53829698|gb|AAU94732.1|; |53829695|gb|AAU94730.1|; |53829692|gb|AAU94728.1|;|53829689|gb|AAU94726.1|; |53829686|gb|AAU94724.1|; |53829683|gb|AAU94722.1|;|8486160|ref|NP_056664.1|;|30466242|ref|NP_848689.1|;|30349250|gb|AAP22121.1|;|30466211|ref|NP_848672.1|; |30349219|gb|AAP22104.1|;|4761025|gb|AAD29208.1|AF100392_1|; |4761022|gb|AAD29206.1|AF100391_1|;|4761019|gb|AAD29204.1|AF100390_1|; |4761016|gb|AAD29202.1|AF100389_1|;|4761013|gb|AAD29200.1|AF100388_1|; |4761010|gb|AAD29198.1|AF100387_1|;|4761007|gb|AAD29196.1|AF100386_1|; |4761004|gb|AAD29194.1|AF100385_1|;|4761001|gb|AAD29192.1|AF100384_1|; |4760998|gb|AAD29190.1|AF100383_1|;|4760995|gb|AAD29188.1|AF100382_1|; |4760992|gb|AAD29186.1|AF100381_1|;|4760989|gb|AAD29184.1|AF100380_1|; |4760986|gb|AAD29182.1|AF100379_1|;|4760983|gb|AAD29180.1|AF100378_1|; 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M2蛋白
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|62198925|gb|AAX76705.1|;|62198799|gb|AAX76635.1|; |62198781|gb|AAX76625.1|; |61620944|gb|AAX47527.1|;|62199015|gb|AAX76755.1|; |60683806|gb|AAX34063.1|; |59940442|gb|AAX12763.1|;|438084|emb|CAA81472.1|; |438081|emb|CAA81470.1|; |438078|emb|CAA81468.1|;|438075|emb|CAA81466.1|; |438071|emb|CAA81463.1|; |22859489|emb|CAD30543.1|;|22859487|emb|CAD30541.1|;|22859484|emb|CAD30539.1|;|22859481|emb|CAD30537.1|;|22859478|emb|CAD30535.1|;|20068130|emb|CAC87411.1|;|20068121|emb|CAC87405.1|;|20068109|emb|CAC87397.1|;|20068106|emb|CAC87395.1|;|20068100|emb|CAC87391.1|;|20068094|emb|CAC87387.1|;|14275728|emb|CAC40056.1|;|14275701|emb|CAC40042.1|;|12038901|emb|CAC19701.1|; |9857031|emb|CAC04080.1|; |62198997|gb|AAX76745.1|;|62198961|gb|AAX76725.1|; |62198943|gb|AAX76715.1|; |62198907|gb|AAX76695.1|;|62198889|gb|AAX76685.1|; |62198853|gb|AAX76665.1|; |62198835|gb|AAX76655.1|;|61970939|gb|AAX57946.1|; |61970885|gb|AAX57916.1|; |61970867|gb|AAX57906.1|;|61970849|gb|AAX57896.1|; |61970831|gb|AAX57886.1|; 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|50234735|gb|AAT70590.1|; |50234732|gb|AAT70588.1|;|50234723|gb|AAT70582.1|; |50234720|gb|AAT70580.1|; |50234717|gb|AAT70578.1|;|50234714|gb|AAT70576.1|; |50234711|gb|AAT70574.1|; |50234708|gb|AAT70572.1|;|50234705|gb|AAT70570.1|; |50234702|gb|AAT70568.1|; |50234699|gb|AAT70566.1|;|50234696|gb|AAT70564.1|; |50234687|gb|AAT70558.1|; |50234684|gb|AAT70556.1|;|50234681|gb|AAT70554.1|; |50234678|gb|AAT70552.1|; |50234672|gb|AAT70548.1|;|50234669|gb|AAT70546.1|; |50234666|gb|AAT70544.1|; |50234663|gb|AAT70542.1|;|50234660|gb|AAT70540.1|; |50234657|gb|AAT70538.1|; |50234654|gb|AAT70536.1|;|50234648|gb|AAT70532.1|; |50234645|gb|AAT70530.1|; |50234642|gb|AAT70528.1|;|50234639|gb|AAT70526.1|; |50234636|gb|AAT70524.1|; |50234633|gb|AAT70522.1|;|50234630|gb|AAT70520.1|; |50234627|gb|AAT70518.1|; |50234624|gb|AAT70516.1|;|50234621|gb|AAT70514.1|; |50234618|gb|AAT70512.1|; |50234615|gb|AAT70510.1|;|50234612|gb|AAT70508.1|; |50234609|gb|AAT70506.1|; |50234606|gb|AAT70504.1|;|50234603|gb|AAT70502.1|; |50234601|gb|AAT70501.1|; |34597771|gb|AAQ77443.1|;|34597768|gb|AAQ77441.1|; |34597765|gb|AAQ77439.1|; |34597759|gb|AAQ77435.1|;|34597756|gb|AAQ77433.1|; |21359673|gb|AAM49562.1|AF468843_2|;|21326690|gb|AAL75850.1|; |15193277|gb|AAK91757.1|; |9994775|emb|CAC07367.1|;|9863928|gb|AAG01223.1|AF216735_2|; |9863910|gb|AAG01213.1|AF216727_2|;|9863891|gb|AAG01203.1|AF216719_2|; |7861793|gb|AAF70407.1|AF203788_2|;|468300|gb|AAA62337.1|; |468295|gb|AAA62334.1|; |324336|gb|AAA43303.1|;|413855|gb|AAA43249.1|。
NP蛋白
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|37785190|gb|AAO46433.1|; |37785188|gb|AAO46432.1|;|37785186|gb|AAO46431.1|; |37785184|gb|AAO46430.1|; |37785182|gb|AAO46429.1|;|37785180|gb|AAO46428.1|; |37785178|gb|AAO46427.1|; |37785176|gb|AAO46426.1|;|37785174|gb|AAO46425.1|; |37785172|gb|AAO46424.1|; |37785170|gb|AAO46423.1|;|37785168|gb|AAO46422.1|; |13925172|gb|AAK49279.1|AF255753_1|;|13274625|gb|AAK18006.1|AF255749_1|; |13274623|gb|AAK18005.1|AF255748_1|;|31339496|gb|AAP49080.1|; |31339492|gb|AAP49078.1|; |66775627|gb|AAY56368.1|;|42661500|emb|CAF31360.1|; |54126502|gb|AAV30830.1|; |50234808|gb|AAT70633.1|;|18092172|gb|AAL59145.1|AF398420_1|; |18092170|gb|AAL59144.1|AF398419_1|;|8307799|gb|AAF74328.1|AF084278_1|; |8307797|gb|AAF74327.1|AF084277_1|;|8307795|gb|AAF74326.1|AF084276_1|; |2833664|gb|AAC34267.1|;|54126537|gb|AAV30838.1|;|73852953|ref|YP_308667.1|;|32140159|ref|NP_859032.1|;|30025978|gb|AAP04508.1|; |71013502|dbj|BAE07202.1|; |62466165|gb|AAX83408.1|;|62466157|gb|AAX83404.1|; |54610028|gb|AAV35112.1|; |54299852|gb|AAV32650.1|;|54299838|gb|AAV32642.1|; |52078184|gb|AAU25867.1|; |52078171|gb|AAU25860.1|;|52078148|gb|AAU25847.1|; |47834203|gb|AAT38823.1|; |49357240|gb|AAT65380.1|;|49357234|gb|AAT65377.1|; |49357232|gb|AAT65376.1|; |49357224|gb|AAT65372.1|;|49357216|gb|AAT65368.1|; |49357212|gb|AAT65366.1|;|49357208|gb|AAT65364.1|;|49357196|gb|AAT65358.1|; |49357186|gb|AAT65353.1|;|49357184|gb|AAT65352.1|;|13925169|gb|AAK49278.1|AF255752_1|; |13925167|gb|AAK49277.1|AF255751_1|;|13925164|gb|AK49276.1|AF255750_1|; |13925161|gb|AAK49275.1|AF255747_1|;|13925159|gb|AAK49274.1|AF255746_1|; |13925156|gb|AAK49273.1|AF255745_1|;|13925153|gb|AAK49272.1|AF255744_1|; |13925151|gb|AAK49271.1|AF255743_1|;|13925148|gb|AAK49270.1|AF255742_1|; |38154862|gb|AAR12367.1|;|38154860|gb|AAR12366.1|; |38154858|gb|AAR12365.1|; |38154856|gb|AAR12364.1|;|38154854|gb|AAR12363.1|; |38154852|gb|AAR12362.1|; |38154850|gb|AAR12361.1|;|38154848|gb|AAR12360.1|; |38154846|gb|AAR12359.1|; |38154844|gb|AAR12358.1|;|38154842|gb|AAR12357.1|; |38154840|gb|AAR12356.1|; |38154838|gb|AAR12355.1|;|38154836|gb|AAR12354.1|; |38154834|gb|AAR12353.1|; |38154832|gb|AAR12352.1|;|38154830|gb|AAR12351.1|; |38154828|gb|AAR12350.1|; |47156435|gb|AAT12105.1|; |47156433|gb|AAT12104.1|; |47156431|gb|AAT12103.1|; |47156429|gb|AAT12102.1|;|47156427|gb|AAT12101.1|; |47156425|gb|AAT12100.1|; |47156423|gb|AAT12099.1|;|47156421|gb|AAT12098.1|; |47156419|gb|AAT12097.1|; |47156417|gb|AAT12096.1|;|47156415|gb|AAT12095.1|; |47156413|gb|AAT12094.1|; |47156411|gb|AAT12093.1|;|47156409|gb|AAT12092.1|; |47156407|gb|AAT12091.1|; |47156405|gb|AAT12090.1|;|47156403|gb|AAT12089.1|; |47156401|gb|AAT12088.1|; |47156399|gb|AAT12087.1|;|47156397|gb|AAT12086.1|; |47156395|gb|AAT12085.1|; |30522970|gb|AAO65613.1|;|28849563|gb|AAO52964.1|AF509121_1|; |19422133|gb|AAL87893.1|AF455703_1|;|19422127|gb|AAL87890.1|AF455700_1|; |19422125|gb|AAL87889.1|AF455699_1|;|290762|gb|AAA51501.1|; |9802278|gb|AAF99666.1|AF258516_1|;|5732297|gb|AAD49024.1|AF156414_1|; |5732293|gb|AAD49022.1|AF156412_1|;|5732291|gb|AAD49021.1|AF156411_1|; |6048944|gb|AAF02408.1|AF098628_1|;|6048940|gb|AAF02406.1|AF098626_1|; |5805283|gb|AAD51925.1|AF144303_1|;|76800632|gb|ABA55723.1|; |59803332|gb|AAX07774.1|; |57916081|gb|AAW59409.1|;|57916035|gb|AAW59399.1|; |57915988|gb|AAW59391.1|; |47716775|gb|AAT37564.1|;|42661498|emb|CAF31359.1|; |60823|emb|CAA36505.1|; |60821|emb|CAA36234.1|;|58531177|dbj|BAD89346.1|;|58531159|dbj|BAD89336.1|; |58531141|dbj|BAD89326.1|;|58531123|dbj|BAD89316.1|;|58531091|dbj|3AD89306.1|; |50956630|gb|AAT90833.1|;|50234860|gb|AAT70659.1|; |50234830|gb|AAT70644.1|; |50234828|gb|AAT70643.1|;|50234826|gb|AAT70642.1|; |50234824|gb|AAT70641.1|; |50234822|gb|AAT70640.1|;|50234820|gb|AAT70639.1|; |50234818|gb|AAT70638.1|; |50234816|gb|AAT70637.1|;|50234814|gb|AAT70636.1|; |50234812|gb|AAT70635.1|; |50234810|gb|AAT70634.1|;|50234806|gb|AAT70632.1|; |50234804|gb|AAT70631.1|; |50234802|gb|AAT70630.1|;|50234800|gb|AAT70629.1|; |50234798|gb|AAT70628.1|; |50234796|gb|AAT70627.1|;|50234794|gb|AAT70626.1|; |50234792|gb|AAT70625.1|; |50234790|gb|AT70624.1|;|50234778|gb|AAT70618.1|; |50234776|gb|AAT70617.1|; |50234774|gb|AAT70616.1|;|42521292|gb|AAS18236.1|; |38524558|dbj|BAD02358.1|; |38524540|dbj|BAD02348.1|;|6177890|dbj|BAA86069.1|; |6177888|dbj|BAA86068.1|; |6177886|dbj|BAA86067.1|;|6177884|dbj|BAA86066.1|; |28194391|gb|AAO33540.1|AF474070_1|;|28194387|gb|AAO33539.1|AF474069_1|; |24286070|gb|AAN46830.1|;|14579581|gb|AAK69308.1|AF385293_1|; |18140826|gb|AAL60436.1|AF398867_1|;|18074925|emb|CAC84253.1|;|18074923|emb|CAC84252.1|;|18074921|emb|CAC84251.1|;|18074919|emb|CAC84250.1|;|18074917|emb|CAC84249.1|;|18074915|emb|CAC84248.1|;|18074913|emb|CAC84247.1|;|18074911|emb|CAC84246.1|;|18074909|emb|CAC84245.1|;|8452830|gb|AAF75110.1|AF115285_1|; |8452828|gb|AAF75109.1|AF115284_1|;|77917343|gb|ABB05220.1|; |77917324|gb|ABB05209.1|; |77917305|gb|ABB05198.1|;|77869495|gb|ABB05187.1|; |77863498|gb|ABB05009.1|; |77863479|gb|ABB04998.1|;|77863460|gb|ABB04987.1|; |77863441|gb|ABB04976.1|; |77863422|gb|ABB04965.1|;|77863403|gb|ABB04954.1|; |77863384|gb|ABB04943.1|; |77863365|gb|ABB04932.1|;|77863346|gb|ABB04921.1|; |77863327|gb|ABB04910.1|; |77861874|gb|ABB04375.1|;|77861855|gb|ABB04364.1|; |77861836|gb|ABB04353.1|; |77861817|gb|ABB04342.1|;|77861798|gb|ABB04331.1|; |77861779|gb|ABB04320.1|; |77861760|gb|ABB04309.1|;|77861741|gb|ABB04298.1|; |77861722|gb|ABB04287.1|; |77747467|gb|ABB03149.1|;|77747448|gb|ABB03138.1|; |77747429|gb|ABB03127.1|; |77747409|gb|ABB03116.1|;|77747390|gb|ABB03105.1|; |77747371|gb|ABB03094.1|; |77747352|gb|ABB03083.1|;|77747333|gb|ABB03072.1|; |77747312|gb|ABB03061.1|; |77747293|gb|ABB03050.1|;|77747274|gb|ABB03039.1|; |77747255|gb|ABB03028.1|; |77747236|gb|ABB03017.1|;|77747217|gb|ABB03006.1|; |77747198|gb|ABB02995.1|; |77747179|gb|ABB02984.1|;|77747158|gb|ABB02973.1|; |77747139|gb|ABB02962.1|; |77747120|gb|ABB02951.1|; |77747101|gb|ABB02940.1|; |77747080|gb|ABB02928.1|; |77747061|gb|ABB02917.1|;|77747042|gb|ABB02906.1|; |77746996|gb|ABB02895.1|; |77746977|gb|ABB02884.1|;|77746958|gb|ABB02873.1|; |77746939|gb|ABB02862.1|; |77746920|gb|ABB02851.1|;|77746899|gb|ABB02840.1|; |77746880|gb|ABB02829.1|; |77746861|gb|ABB02818.1|;|77746842|gb|ABB02807.1|; |77746823|gb|ABB02796.1|; |77746804|gb|ABB02785.1|;|77543690|gb|ABA87257.1|; |77543670|gb|ABA87246.1|; |77543650|gb|ABA87235.1|;|77543368|gb|ABA87095.1|; |77543349|gb|ABA87084.1|; |77543305|gb|ABA87061.1|;|77543249|gb|ABA87049.1|; |76464403|gb|ABA43340.1|; |76454181|gb|ABA43204.1|;|76446827|gb|ABA43193.1|; |76446806|gb|ABA43182.1|; |76446435|gb|ABA43171.1|;|76446410|gb|ABA42993.1|; |76446391|gb|ABA42982.1|; |76446319|gb|ABA42943.1|;|76446300|gb|ABA42932.1|; |76443534|gb|ABA42579.1|; |76443515|gb|ABA42568.1|;|76443496|gb|ABA42557.1|; |76443477|gb|ABA42546.1|; |76443458|gb|ABA42535.1|;|76443439|gb|ABA42524.1|; |76443420|gb|ABA42513.1|; |76443401|gb|ABA42502.1|;|76443382|gb|ABA42491.1|; |76443363|gb|ABA42480.1|; |76443344|gb|ABA42469.1|;|76443325|gb|ABA42458.1|; |76443276|gb|ABA42447.1|; |76443257|gb|ABA42416.1|;|76443238|gb|ABA42405.1|; |76443219|gb|ABA42394.1|; |76443200|gb|ABA42383.1|;|76443181|gb|ABA42372.1|; |76440953|gb|ABA42361.1|; |76426705|gb|ABA42350.1|;|76418682|gb|ABA42339.1|; |76411109|gb|ABA42328.1|; |76410460|gb|ABA42317.1|;|76403227|gb|ABA42306.1|; |76381543|gb|ABA42295.1|; |76374097|gb|ABA42284.1|;|76366076|gb|ABA42273.1|; |76366057|gb|ABA42262.1|; |76366038|gb|ABA42251.1|;|76366019|gb|ABA42240.1|; |75750352|gb|ABA26803.1|; |75750333|gb|ABA26792.1|;|75750314|gb|ABA26781.1|; |58429773|gb|AAW78291.1|; |58429761|gb|AAW78285.1|;|58429759|gb|AAW78284.1|; |50542643|gb|AAT78586.1|; |50083045|gb|AAT70174.1|;|50059188|gb|AAT69352.1|; |55273941|gb|AAV48837.1|; |55233233|gb|AAV48549.1|;|53765727|gb|AAU93405.1|; |51094113|gb|AAS89187.2|; |51859870|gb|AAU11219.1|;|51859868|gb|AAU11218.1|; |51859866|gb|AAU11217.1|; |51859864|gb|AAU11216.1|;|51859862|gb|AAU11215.1|; |51859860|gb|AAU11214.1|; |51859858|gb|AAU11213.1|;|51859856|gb|AAU11212.1|; |51859854|gb|AAU11211.1|; |51859852|gb|AAU11210.1|;|51859850|gb|AAU11209.1|; |51859848|gb|AAU11208.1|; |51859846|gb|AAU11207.1|;|51859844|gb|AAU11206.1|; |51859842|gb|AAU11205.1|; |51859840|gb|AAU11204.1|;|50365720|gb|AAT76161.1|; |47834948|gb|AAT39109.1|; |47834946|gb|AAT39108.1|;|47834944|gb|AAT39107.1|; |47834934|gb|AAT39102.1|; |47834932|gb|AAT39101.1|;|33867359|gb|AAQ55062.1|; |45124766|emb|CAF33022.1|; |45124750|emb|CAF33013.1|;|45124746|emb|CAF33011.1|; |33318065|gb|AAQ04906.1|AF508617_1|;|33318063|gb|AAQ04905.1|AF508616_1|; |33318059|gb|AAQ04903.1|AF508614_1|;|33318055|gb|AAQ04901.1|AF508612_1|; |33318053|gb|AAQ04900.1|AF508611_1|;|33318049|gb|AAQ04898.1|AF508609_1|; |33318045|gb|AAQ04896.1|AF508607_1|;|33318043|gb|AAQ04895.1|AF508606_1|; |33318041|gb|AAQ04894.1|AF508605_1|;|41207477|gb|AAR99630.1|;|40732903|emb|CAF04486.1|;|14275699|emb|CAC40041.1|;|21902318|gb|AAM78513.1|AF483604_1|; |13383285|dbj|BAB39514.1|;|13383283|dbj|BAB39513.1|; |5531266|emb|CAB50887.1|;|30043924|gb|AAG01753.2|AF251399_1|; |28849599|gb|AAO52982.1|AF509139_1|;|28849561|gb|AAO52963.1|AF509120_1|; |28849559|gb|AAO52962.1|AF509119_1|;|28849557|gb|AAO52961.1|AF509118_1|; |28849555|gb|AAO52960.1|AF509117_1|;|28820286|gb|AAO46832.1|; |28820284|gb|AAO46831.1|; |28820282|gb|AAO46830.1|;|28820280|gb|AAO46829.1|; |28820278|gb|AAO46828.1|; |28820276|gb|AAO46827.1|;|28820047|gb|AAO46826.1|; |28819610|gb|AAO46825.1|; |28818981|gb|AAO46824.1|;|18496110|emb|CAD20329.1|; |27462153|gb|AAO15349.1|AF225537_1|;|27462151|gb|AAO15348.1|AF225536_1|; |27462149|gb|AAO15347.1|AF2255351|; |27462147|gb|AAO15346.1|AF2255341|; |22859439|emb|CAD30201.1|;|22859437|emb|CAD30200.1|; |21359670|gb|AAM49560.1|AF468842_1|;|20068061|emb|CAC85241.1|;|20068055|emb|CAC85238.1|;|20068051|emb|CAC85236.1|;|20068049|emb|CAC85235.1|;|20068037|emb|CAC85229.1|;|19913216|emb|CAD20330.1|;|19913210|emb|CAD20324.1|; |19697806|gb|AAL31404.1|;|19697804|gb|AAL31403.1|;|19697802|gb|AAL31402.1|; |19697800|gb|AAL31401.1|; |19697798|gb|AAL31400.1|;|19697796|gb|AAL31399.1|; |19697794|gb|AAL31398.1|;|19422139|gb|AAL87896.1|AF455706_1|; |19422137|gb|AAL87895.1|AF455705_1|;|19422135|gb|AAL87894.1|AF455704_1|; |19422131|gb|AAL87892.1|AF455702_1|;|19422129|gb|AAL87891.1|AF455701_1|;|16076709|gb|AAL14085.1|AF222815_1|。
PB1蛋白
|53829905|gb|AAU94857.1|; |53829903|gb|AAU94856.1|; |53829901|gb|AAU94855.1|;|53829899|gb|AAU94854.1|; |53829897|gb|AAU94853.1|; |53829895|gb|AAU94852.1|;|53829893|gb|AAU94851.1|; |53829891|gb|AAU94850.1|; |53829889|gb|AAU94849.1|;|53829887|gb|AAU94848.1|; |53829885|gb|AAU94847.1|; |53829883|gb|AAU94846.1|;|53829881|gb|AAU94845.1|; |9622317|gb|AAF89734.1|AF170571_1|;|558512|dbj|BAA00002.1|; |8486165|ref|NP_056657.1|;|30466229|ref|NP_848682.1|;|30466214|ref|NP_848674.1|; |30349237|gb|AAP22114.1|;|30349222|gb|AAP22106.1|;|325276|gb|AAA43767.1|; |67090|pir|P1IVBL|; |50059427|gb|AAT69445.1|;|50059408|gb|AAT69434.1|; |50059389|gb|AAT69423.1|;|6318399|gb|AAF06876.1|AF102007_1|; |6318397|gb|AAF06875.1|AF102006_1|;|6318395|gb|AAF06874.1|AF102005_1|; |6318393|gb|AAF06873.1|AF102004_1|;|6318391|gb|AAF06872.1|AF102003_1|; |6318389|gb|AAF06871.1|AF102002_1|;|6318387|gb|AAF06870.1|AF102001_1|; |6318385|gb|AAF06869.1|AF102000_1|;|6318383|gb|AAF06868.1|AF101999_1|; |6318381|gb|AAF06867.1|AF101998_1|;|6318379|gb|AAF06866.1|AF101997_1|; 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|9887168|gb|AAG01778.1|AF251421_1|;|9887151|gb|AAG01769.1|AF251413_1|; |9887134|gb|AAG01760.1|AF251405_1|;|9887117|gb|AAG01751.1|AF251397_1|; |9887103|gb|AAG01744.1|AF251390_1|;|8894712|emb|CAB95865.1|;|8894710|emb|CAB95864.1|;|8894708|emb|CAB95863.1|;|8515437|gb|AAF76001.1|AF250130_1|; |5732317|gb|AAD49034.1|AF156424_1|;|5732327|gb|AAD49039.1|AF156429_1|; |5732319|gb|AAD49035.1|AF156425_1|;|5732315|gb|AAD49033.1|AF156423_1|; |5732313|gb|AAD49032.1|AF156422_1|;|5732311|gb|AAD49031.1|AF156421_1|; |5732309|gb|AAD49030.1|AF156420_1|;|5732307|gb|AAD49029.1|AF156419_1|; |5732305|gb|AAD49028.1|AF156418_1|;|5732301|gb|AAD49026.1|AF156416_1|; |3722129|gb|AAC63454.1|;|3722127|gb|AAC63453.1|; |3722125|gb|AAC63452.1|; |3722123|gb|AAC63451.1|;|3722121|gb|AAC63450.1|; |3722119|gb|AAC63449.1|; |3721950|gb|AAC63412.1|;|3721948|gb|AAC63411.1|; |3721946|gb|AAC63410.1|; |3721944|gb|AAC63409.1|;|324978|gb|AAA19212.1|; |324976|gb|AAA19211.1|; |324974|gb|AAA19210.1|;|58618430|gb|AAW80713.1|; |58618428|gb|AAW80712.1|;|21636441|gb|AAM69995.1|AF457706_1|; 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|77863410|gb|ABB04958.1|;|77863391|gb|ABB04947.1|; |77863372|gb|ABB04936.1|; |77863353|gb|ABB04925.1|;|77863334|gb|ABB04914.1|; |77861881|gb|ABB04379.1|; |77861862|gb|ABB04368.1|; |77861843|gb|ABB04357.1|; |77861824|gb|ABB04346.1|; |77861805|gb|ABB04335.1|;|77861786|gb|ABB04324.1|; |77861767|gb|ABB04313.1|; |77861748|gb|ABB04302.1|;|77861729|gb|ABB04291.1|; |77747474|gb|ABB03153.1|; |77747455|gb|ABB03142.1|;|77747436|gb|ABB03131.1|; |77747416|gb|ABB03120.1|; |77747397|gb|ABB03109.1|;|77747378|gb|ABB03098.1|; |77747359|gb|ABB03087.1|; |77747340|gb|ABB03076.1|;|77747319|gb|ABB03065.1|; |77747300|gb|ABB03054.1|; |77747281|gb|ABB03043.1|;|77747262|gb|ABB03032.1|; |77747243|gb|ABB03021.1|; |77747224|gb|ABB03010.1|;|77747205|gb|ABB02999.1|; |77747186|gb|ABB02988.1|; |77747165|gb|ABB02977.1|;|77747146|gb|ABB02966.1|; |77747127|gb|ABB02955.1|; |77747108|gb|ABB02944.1|;|77747087|gb|ABB02932.1|; |77747068|gb|ABB02921.1|; |77747049|gb|ABB02910.1|;|77747003|gb|ABB02899.1|; |77746984|gb|ABB02888.1|; |77746965|gb|ABB02877.1|;|77746946|gb|ABB02866.1|; |77746927|gb|ABB02855.1|; |77746906|gb|ABB02844.1|;|77746887|gb|ABB02833.1|; |77746868|gb|ABB02822.1|; |77746849|gb|ABB02811.1|;|77746830|gb|ABB02800.1|; |77746811|gb|ABB02789.1|; |66733937|gb|AAY52743.1|;|66733935|gb|AAY52742.1|; |66733933|gb|AAY52741.1|; |66733931|gb|AAY52740.1|;|66733929|gb|AAY52739.1|; |66733927|gb|AAY52738.1|; |66733925|gb|AAY52737.1|;|66733923|gb|AAY52736.1|; |66733921|gb|AAY52735.1|; |66733919|gb|AAY52734.1|;|66733917|gb|AAY52733.1|; |66733915|gb|AAY52732.1|; |66733913|gb|AAY52731.1|;;|66733911|gb|AAY52730.1|; |66733909|gb|AAY52729.1|; |66733907|gb|AAY52728.1|;|66733905|gb|AAY52727.1|; |66733903|gb|AAY52726.1|; |66733901|gb|AAY52725.1|;|66733899|gb|AAY52724.1|; |66733897|gb|AAY52723.1|; |66733895|gb|AAY52722.1|;|66733893|gb|AAY52721.1; |66733891|gb|AAY52720.1|; |66733889|gb|AAY52719.1|;|66733887|gb|AAY52718.1|; |66733885|gb|AAY52717.1|; |66733883|gb|AAY52716.1|;|13925401|gb|AAK49363.1|AF258827_1|; |13274640|gb|AAK18014.1|AF258823_1|;|13274638|gb|AAK18013.1|AF258822_1|; |50296446|gb|AAT73499.1|;|8307775|gb|AAF74316.1|AF084266_1|; |8307773|gb|AAF74315.1|AF084265_1|;|8307771|gb|AAF74314.1|AF084264_1|; |73852949|ref|YP_308665.1|;|71013490|dbj|BAE07199.1|;|54610035|gb|AAV35116.1|; |54299856|gb|AAV32652.1|;|54299842|gb|AAV32644.1|; |13925398|gb|AAK49362.1|AF258826_1|;|13925395|gb|AAK49361.1|AF258825_1|; |13925392|gb|AAK49360.1|AF258824_1|;|13925389|gb|AAK49359.1|AF258821_1|; |13925386|gb|AAK49358.1|AF258820_1|;|13925383|gb|AAK49357.1|AF258819_1|; |13925380|gb|AAK49356.1|AF258818_1|;|13925377|gb|AAK49355.1|AF258817_1|; |13925374|gb|AAK49354.1|AF258816_1|;|47156561|gb|AAT12168.1|;|47156559|gb|AAT12167.1|;|47156557|gb|AAT12166.1|;|47156555|gb|AAT12165.1|;|47156553|gb|AAT12164.1|;|47156551|gb|AAT12163.1|;|47156549|gb|AAT12162.1|;|47156547|gb|AAT12161.1|;|47156545|gb|AAT12160.1|;|47156543|gb|AAT12159.1|;|47156541|gb|AAT12158.1|;|47156539|gb|AAT12157.1|;|47156537|gb|AAT12156.1|;|47156535|gb|AAT12155.1|;|47156533|gb|AAT12154.1|;|47156531|gb|AAT12153.1|;|47156529|gb|AAT12152.1|; |47156527gb|AAT12151.1|;|47156525|gb|AAT12150.1|;|47156523|gb|AAT12149.1|;|47156521|gb|AAT12148.1|;|1430831|emb|CAA67498.1|; |19422189|gb|AAL87925.1|AF455727_1|;|19422183|gb|AAL87922.1|AF455724_1|; |19422181|gb|AAL87921.1|AF455723_1|;|14532423|gb|AAK64188.1|; |13661046|emb|CAC37002.1|; |5805279|gb|AAD51923.1|;|57916067|gb|AAW59406.1|;|57916013|gb|AAW59396.1|; |57915966|gb|AAW59388.1|;|47716769|gb|AAT37561.1|;|58531173|dbj|BAD89344.1|; |58531153|dbj|BAD89333.1|;|58531135|dbj|BAD89323.1|;|58531117|dbj|BAD89313.1|; |58531085|dbj|BAD89303.1|;|50956624|gb|AAT90830.1|; |50296498|gb|AAT73525.1|; |50296468|gb|AAT73510.1|;|50296462|gb|AAT73507.1|; |50296458|gb|AAT73505.1|; |50296456|gb|AAT73504.1|;|50296454|gb|AAT73503.1|; |50296452|gb|AAT73502.1|; |50296450|gb|AAT73501.1|; |50296448|gb|AAT73500.1|; |50296444|gb|AAT73498.1|; |50296440|gb|AAT73496.1|;|50296438|gb|AAT73495.1|; |50296436|gb|AAT73494.1|; |50296432|gb|AAT73492.1|;|50296430|gb|AAT73491.1|; |50296428|gb|AAT73490.1|; |50296416|gb|AAT73484.1|;|50296414|gb|AAT73483.1|; |50296412|gb|AAT73482.1|; |37963694|gb|AAR05984.1|;|37963692|gb|AAR05983.1|; |37963696|gb|AAR05985.1|; |38524562|dbj|BAD02360.1|;|38524542|dbj|BAD02349.1|; |24286097|gb|AAN46833.1|; |61612044|gb|AAX47280.1|;|61612038|gb|AAX47279.1|; |71000178|dbj|BAE07153.1|; |30025725|gb|AAP04506.1|;|70905275|gb|AAZ14161.1|; |70905273|gb|AAZ14160.1|; |70905271|gb|AAZ14159.1|;|70905269|gb|AAZ14158.1|; |70905267|gb|AAZ14157.1|; |70905265|gb|AAZ14156.1|;|70905263|gb|AAZ14155.1|; |70905261|gb|AAZ14154.1|; |70905259|gb|AAZ14153.1|;|70905257|gb|AAZ14152.1|; |70905255|gb|AAZ14151.1|; |70905253|gb|AAZ14150.1|;|3335435|gb|AAC32096.1|; |3335415|gb|AAC32085.1|; |56548870|gb|AAV97600.1|;|56548868|gb|AAV97599.1|; |56548866|gb|AAV97598.1|; |56548864|gb|AAV97597.1|;|56424948|gb|AAV91207.1|; |56424946|gb|AAV91206.1|; |56424942|gb|AAV91204.1|;|50542650|gb|AAT78590.1|; |50365727|gb|AAT76165.1|; |47834828|gb|AAT39049.1|;|47834824|gb|AAT39047.1|; |47834822|gb|AAT39046.1|; |47834814|gb|AAT39042.1|;|47834812|gb|AAT39041.1|; |40732896|emb|CAF04464.1|; |14275693|emb|CAC40038.1|;|13383273|dbj|BAB39508.1|; |13383271|dbj|BAB39507.1|; |13661044|emb|CAC37001.1|;|28823019|gb|AAO46859.1|; |28822828|gb|AAO46858.1|; |28822609|gb|AAO46857.1|;|28822076|gb|AAO46856.1|; |28821871|gb|AAO46855.1|; |28821644|gb|AAO46854.1|;|28821462|gb|AAO46853.1|; |28821280|gb|AAO46852.1|; |28821223|gb|AAO46851.1|;|27462113|gb|AAO15325.1|AF225521_1|; |27462111|gb|AAO15324.1|AF225520_1|;|27462109|gb|AAO15323.1|AF225519_1|; |27462107|gb|AAO15322.1|AF225518_1|;|21359664|gb|AAM49557.1|AF468839_1|; |20068025|emb|CAC84758.1|;|20068023|emb|CAC84686.1|;|20068021|emb|CAC84757.1|;|20068019|emb|CAC84756.1|;|20068017|emb|CAC84755.1|;|20068015|emb|CAC84754.1|;|20068007|emb|CAC84750.1|;|19697848|gb|AAL31425.1|;|19697846|gb|AAL31424.1|; |19697836|gb|AAL31419.1|;|19422195|gb|AAL87928.1|AF455730_1|; |19422193|gb|AAL87927.1|AF455729_1|;|19422191|gb|AAL87926.1|AF455728_1|; |19422187|gb|AAL87924.1|AF455726_1|;|19422185|gb|AAL87923.1|AF4557251|; |16076717|gb|AAL14089.1|AF222819_1|;|16076715|gb|AAL14088.1|AF222818_1|; |13661048|emb|CAC37003.1_|;|8452850|gb|AAF75122.1|AF115293_1|; |8452848|gb|AAF75121.1|AF115292_1|;|323669|gb|AAA42968.1|; |133517|sp|P16508|RRP1_IAMAN|;|133523|sp|P03430|RRP1_IAWIL|; |2506782|sp|P16506|RRP1_IAKOR|;|133527|sp|P16512|RRP1_IAZTF|; |133526|sp|P16510|RRP1_IAZON|;|133525|sp|P16509|RRP1_IAZH3|; |133524|sp|P16514|RRP1_IAWIS|;|133522|sp|P16513|RRP1_IATKM|; |133521|sp|P16511|RRP1_IASIN|;|133518|sp|P16507|RRP1_IAME8|; |133512|sp|P18882|RRP1_IAKIE|;|133511|sp|P16505|RRP1_IAHTE|; |133510|sp|P16504|RRP1_IAHLO|;|133509|sp|P16503|RRP1_IAGU2|; |133506|sp|P16502|RRP1_IABEI|;|6647779|sp|Q82571|RRP1_IAFOM|; |6647775|sp|O91741|RRP1_IAKIT|;|6647773|sp|O89749|RRP1_IACKH|; |133531|sp|P19703|RRP1_INCJJ|;|133520|sp|P03431|RRP1_IAPUE|; |133519|sp|P03432|RRP1_IANT6|;|133505|sp|P21426|RRP1_IAANN|; |401026|sp|P31341|RRP1_IAVI7|;|133516|sp|P26121|RRP1_IALE3|; |133515|sp|P26120|RRP1_IALE2|;|133514|sp|P26119|RRP1_IALE1|; |133508|sp|P26118|RRP1_IADUN|;|34733402|gb|AAQ81638.1|; |34733400|gb|AAQ81637.1|;|9863938|gb|AAG01228.1|AF216740_1|; |9863920|gb|AAG01218.1|AF216732_1|;|9863902|gb|AAG01208.1|AF216724_1|; |9863883|gb|AAG01198.1|AF216716_1|; |324980|gb|AAA43647.1|;|324970|gb|AAA43646.1。
在本发明中所引用的优选流感株是含有这些特定蛋白质的流感株,例如针对该流感株的本发明多肽需要是免疫原性的。上述的索取号除明确表明特定蛋白质序列外,还明确地表明病毒株的身份(identity)。
在某些优选实施方式中,根据本发明的多肽可以含有一条或者多条上述的序列,并且与已知人类和禽流感病毒株的共有序列具有至少60%的同源性(或与这样序列具有至少60%同源性的2个或更多个七氨基酸或者更多氨基酸的抗原决定簇)。在进一步优选的实施方式中,所述多肽可以含有一条或者多条上述的序列,并且与已知人类流感病毒株的共有序列具有至少60%的同源性(或与这样序列具有至少60%同源性的2个或更多个七氨基酸或者更多氨基酸的抗原决定簇)。
在本发明的上下文中所提及的第一多肽序列与第二多肽序列的同源性百分比被定义为将第二序列中与第一序列的氨基酸残基在位置和同一性上均匹配的氨基酸残基的数目除以第二多肽中氨基酸残基的总数(第一多肽和第二多肽必需具有相同的氨基酸残基数目)并乘以100。在本发明中,优选与所限定序列的多肽同源性是75%或更高,85%或更高,95%或更高或100%(或基本上为100%)。
在上述序列内的抗原决定簇不受到特别限定,只要它们含有7个氨基酸或更多。优选的是,这些抗原决定簇的长度适合用于具有特定MHC的特定脊椎动物物种中(例如人类中)的CTL抗原决定簇。通常,这些抗原决定簇含有8个、9个、10个或11个氨基酸残基,但如果需要可以含有更多个。通常,适当的抗原决定簇是脊椎动物如人类中的CTL抗原决定簇。
通常,所述多肽含有7~100个氨基酸,优选8~50个氨基酸。该尺寸不应该大到可使所用的抗原决定簇会遭受与免疫系统中非保护性的抗原决定簇的竞争(由于这个原因,不包括全长蛋白质),该尺寸也不能小到仅提供非常窄的保护范围。更优选的范围是8~40个氨基酸,15~40个氨基酸和15~35个氨基酸。最优选的长度是20~35个氨基酸残基。特别优选的是,所述多肽由以下序列构成(或基本上由其构成),该序列选自在上面所列出的蛋白质具体列表中如上限定的位置的序列。
除了长度不应该超过100个氨基酸残基的上述多肽外,本发明还提供了多抗原决定簇免疫原性多肽,其含有本发明的两个或者更多个多肽。这些多抗原决定簇多肽在尺寸上不受到限制。因此,它们不仅扩展到上面提出的具有7~100个氨基酸残基的多肽,还扩展到较大的多肽,只要这些较大的多肽含有两个或者更多个单元,每个单元都由本发明的多肽构成。因此,本发明包括一种多肽,其具有本发明的100个重复的七氨基酸单元,比方说作为一种多肽,其具有52个某八氨基酸抗原决定簇单元,23个另一种十氨基酸抗原决定簇单元。这种类型的多肽将不会遭受与含有一个或两个抗原决定簇的类似长度多肽相关的竞争问题。为了避免怀疑,所述多抗原决定簇多肽可以含有相同抗原决定簇的多个拷贝,或者许多不同抗原决定簇的单拷贝,或者两个或更多个抗原决定簇的多拷贝。
本发明还提供了一种多肽组合物,其含有两种或者更多种不同的上述多肽。因此,所述多肽组合物可以含有共同在相同混合物或制剂中的任何数目的本发明多肽。同时存在多种多肽是有用的,因为每一种都可以引发其自己的免疫应答,从而扩大了该组合物的保护效果。特别优选的是,该组合物含有所有的SEQ ID 1~6序列,可以每一种序列都在单独的肽中,也可以几种序列在较少数目的肽中(例如,三种序列组合在一条较大的肽中,另外三种序列组合在另一条较大的肽中等)。
本发明还提供了一种多肽构建体,该构建体含有载体和上述的多肽。可以通过将载体与上述的两个或者更多个抗原决定簇和/或多肽组合在一起形成该构建体。所述载体可以是分子,例如辅助剂(adjuvant)和/或赋形剂。在本文中,组合的意思是混合在一起或者结合在一起(例如通过共价键)。
本发明还提供了一种用于药物中的上述多肽。还提供了一种针对流感的药物或疫苗组合物,其含有上述的多肽,和一中或者多种适当的赋形剂和/或辅助剂,或者上述的多肽构建体,以及可选择地一个或者多个适当的赋形剂和/或辅助剂(如果所述构建体的载体部分自身是赋形剂或辅助剂,则可以不需要其他的赋形剂或辅助剂)。赋形剂或辅助剂不受到 特别的限制,可以采用在药物和疫苗中所使用的任何赋形剂或辅助剂。根据为本发明进行适当改造(例如通过将本发明的多肽与适当的赋形剂进行混合)的任何已知方法可以生产所述药物或疫苗组合物。
本发明还提供了一种生产上述多肽的方法。该方法不受特别的限制,并通常包括将两个或者更多个抗原决定簇连接以形成所述多肽。然而,所述多肽可以通过直接化学合成(例如每次引入一个氨基酸,直到形成全长的多肽)或者通过重组方法来合成。这些普通的方法对于本领域技术人员是公知的,并且如果需要还可以根据本发明进行改造。在某些情况中,本发明的多肽可以在一个末端或者两个末端含有额外的氨基酸序列,以辅助合成该多肽。优选的是,这些额外的序列长度为1~5个氨基酸。典型的是,包括3个氨基酸。例如,在一个优选的实施方式中,SEQID 6在所述序列的IIG部分之前紧接着包含氨基酸AAS。
本发明还提供了上述多肽或组合物在制备药物或疫苗中的应用,所述药物或疫苗能有效地治疗或预防流感。本发明还提供了一种治疗或预防流感的方法,该方法包括给脊椎动物施用上述的多肽、组合物、药物或疫苗。给药方法不受到特别限制,并可以包括皮下给药、肌内给药、静脉内给药、皮内给药或鼻内给药,或者可以口服给药(例如以药丸或液体制剂的形式),或者如果需要,可以以栓剂的形式给药。这些给药制剂的形式不受特别的限制,可以采用已知的进行过对本领域技术人员显而易见的适当改变的形式。剂量不受到特别的限制,可以在1μg~100g多肽/个体的范围内,这依赖于所涉及个体的尺寸、体重和物种。
本发明可以应用于任何脊椎动物,这是因为脊椎动物的免疫系统以相关的方式运行。本文中所提到的脊椎动物通常是哺乳动物、鸟类、爬行动物或鱼。特别优选的是所述脊椎动物是人、家畜(例如狗和猫)、养殖的动物(例如猪或马)、牛类动物(例如牛或奶牛)或家禽(例如家养的鸟、养殖的鸟类、猎鸟)。如果所述脊椎动物是鸟类,则优选是鸡、火鸡、鸭或鹅。
本发明可以采用的人MHC(HLA)的例子包括下列:
HLA-A
A*010101、A*010102、A*010103、A*0102、A*0103、A*0104N、A*0106、A*0107、 A*0108、A*0109、A*0110、A*02010101、A*02010102L、A*020102、A*020103、A*020104、A*020105、A*020106、A*020107、A*020108、A*020109、A*020110、A*020111、A*0202、A*020301、A*020302、A*0204、A*0205、A*020601、A*020602、A*020603、A*0207、A*0208、A*0209、A*0210、A*0211、A*0212、A*0213、A*0214、A*0215N、A*0216、A*021701、A*021702、A*0218、A*0219、A*022001、A*022002、A*0221、A*0222、A*0224、A*0225、A*0226、A*0227、A*0228、A*0229、A*0230、A*0231、A*0232N、A*0233、A*0234、A*023501、A*023502、A*0236、A*0237、A*0238、A*0239、A*0240、A*0241、A*0242、A*0243N、A*0244、A*0245、A*0246、A*0247、A*0248、A*0249、A*0250、A*0251、A*0252、A*0253N、A*0254、A*0255、A*0256、A*0257、A*0258、A*0259、A*0260、A*0261、A*0262、A*0263、A*0264、A*0265、A*0266、A*0267、A*0268、A*0269、A*0270、A*0271、A*0272、A*0273、A*03010101、A*03010102N、A*03010103、A*030102、A*030103、A*0302、A*0303N、A*0304、A*0305、A*0306、A*0307、A*0308、A*0309、A*0310、A*0311N、A*0312、A*0313、A*0314、A*110101、A*110102、A*1102、A*1103、A*1104、A*1105、A*1106、A*1107、A*1108、A*1109、A*1110、A*1111、A*1112、A*1113、A*1114、A*1115、A*1116、A*1117、A*1118、A*1119、A*2301、A*2302、A*2303、A*2304、A*2305、A*2306、A*2307N、A*2308N、A*2309、A*2310、A*2311N、A*2312、A*24020101、A*24020102L、A*240202、A*240203、A*240204、A*240205、A*240206、A*240301、A*240302、A*2404、A*2405、A*2406、A*2407、A*2408、A*2409N、A*2410、A*2411N、A*2413、A*2414、A*2415、A*2417、A*2418、A*2419、A*2420、A*2421、A*2422、A*2423、A*2424、A*2425、A*2426、A*2427、A*2428、A*2429、A*2430、A*2431、A*2432、A*2433、A*2434、A*2435、A*2436N、A*2437、A*2438、A*2439、A*2440N、A*2441、A*2442、A*2443、A*2444、A*2445N、A*2446、A*250101、A*250102、A*2502、A*2503、A*2504、A*2601、A*2602、A*2603、A*2604、A*2605、A*2606、A*260701、A*260702、A*2608、A*2609、A*2610、A*2611N、A*2612、A*2613、A*2614、A*2615、A*2616、A*2617、A*2618、A*2619、A*2620、A*2621、A*2622、A*2623、A*29010101、A*29010102N、A*290201、A*290202、A*290203、A*2903、A*2904、A*2905、A*2906、A*2907、A*2908N、A*2909、A*2910、A*2911、A*300101、A*300102、A*300201、A*300202、A*3003、A*3004、A*3006、A*3007、A*3008、A*3009、A*3010、A*3011、A*3012、A*310102、A*3102、A*3103、A*3104、A*3105、A*3106、A*3107、A*3108、A*3109、A*3110、A*3201、A*3202、A*3203、A*3204、A*3205、A*3206、A*3207、A*3208、A*3301、A*330301、A*330302、A*3304、A*3305、A*3306、A*3307、A*3401、A*3402、A*3403、A*3404、A*3405、A*3406、A*3601、A*3602、A*3603、A*3604、A*4301、A*6601、A*6602、A*6603、A*6604、A*680101、A*680102、A*680103、A*6802、A*680301、A*680302、A*6804、A*6805、A*6806、A*6807、A*6808、A*6809、A*6810、A*6811N、A*6812、A*6813、A*6814、A*6815、A*6816、A*6817、A*6818N、A*6819、A*6820、A*6821、A*6822、A*6823、A*6824、A*6825、A*6826、A*6827、A*6901、A*7401、A*7402、A*7403、A*7404、A*7405、A*7406、A*7407、A*7408、A*7409、A*7410、A*8001。
HLA-B
B*070201、B*070202、B*070203、B*070204、B*0703、B*0704、B*0705、B*0706、B*0707、B*0708、B*0709、B*0710、B*0711、B*0712、B*0713、B*0714、B*0715、B*0716、B*0717、B*0718、B*0719、B*0720、B*0721、B*0722、B*0723、B*0724、 B*0725、B*0726、B*0727、B*0728、B*0729、B*0730、B*0731、B*0732、B*0733、B*0734、B*0735、B*0736、B*0737、B*0738、B*0801、B*0802、B*0803、B*0804、B*0805、B*0806、B*0807、B*0808N、B*0809、B*0810、B*0811、B*0812、B*0813、B*0814、B*0815、B*0816、B*0817、B*0818、B*0819N、B*0820、B*0821、B*0822、B*1301、B*1302、B*1303、B*1304、B*1306、B*1307N、B*1308、B*1309、B*1310、B*1311、B*1312、B*1313、B*1401、B*1402、B*1403、B*1404、B*1405、B*140601、B*140602、B*15010101、B*15010102N、B*150102、B*150103、B*150104、B*150105、B*1502、B*1503、B*1504、B*1505、B*1506、B*1507、B*1508、B*1509、B*1510、B*151101、B*151102、B*1512、B*1513、B*1514、B*1515、B*1516、B*15170101、B*15170102、B*1518、B*1519、B*1520、B*1521、B*1523、B*1524、B*1525、B*1526N、B*1527、B*1528、B*1529、B*1530、B*1531、B*1532、B*1533、B*1534、B*1535、B*1536、B*1537、B*1538、B*1539、B*1540、B*1542、B*1543、B*1544、B*1545、B*1546、B*1547、B*1548、B*1549、B*1550、B*1551、B*1552、B*1553、B*1554、B*1555、B*1556、B*1557、B*1558、B*1560、B*1561、B*1562、B*1563、B*1564、B*1565、B*1566、B*1567、B*1568、B*1569、B*1570、B*1571、B*1572、B*1573、B*1574、B*1575、B*1576、B*1577、B*1578、B*1579N、B*1580、B*1581、B*1582、B*1583、B*1584、B*1585、B*1586、B*1587、B*1588、B*1589、B*1590、B*1591、B*1592、B*1593、B*1594N、B*180101、B*180102、B*1802、B*1803、B*1804、B*1805、B*1806、B*1807、B*1808、B*1809、B*1810、B*1811、B*1812、B*1813、B*1814、B*1815、B*1817N、B*1818、B*1819、B*1820、B*2701、B*2702、B*2703、B*2704、B*270502、B*270503、B*270504、B*270505、B*270506、B*270507、B*2706、B*2707、B*2708、B*2709、B*2710、B*2711、B*2712、B*2713、B*2714、B*2715、B*2716、B*2717、B*2718、B*2719、B*2720、B*2721、B*2723、B*2724、B*2725、B*2726、B*350101、B*350102、B*3502、B*3503、B*3504、B*3505、B*3506、B*3507、B*3508、B*350901、B*350902、B*3510、B*3511、B*3512、B*3513、B*351401、B*351402、B*3515、B*3516、B*3517、B*3518、B*3519、B*3520、B*3521、B*3522、B*3523、B*3524、B*3525、B*3526、B*3527、B*3528、B*3529、B*3530、B*3531、B*3532、B*3533、B*3534、B*3535、B*3536、B*3537、B*3538、B*3539、B*3540N、B*3541、B*3542、B*3543、B*3544、B*3545、B*3546、B*3547、B*3548、B*3549、B*3550、B*3551、B*3552、B*3553N、B*3701、B*3702、B*3703N、B*3704、B*3705、B*3706、B*3707、B*3801、B*380201、B*380202、B*3803、B*3804、B*3805、B*3806、B*3807、B*3808、B*3809、B*3810、B*390101、B*390103、B*390104、B*390201、B*390202、B*3903、B*3904、B*3905、B*390601、B*390602、B*3907、B*3908、B*3909、B*3910、B*3911、B*3912、B*3913、B*3914、B*3915、B*3916、B*3917、B*3918、B*3919、B*3920、B*3922、B*3923、B*3924、B*3925N、B*3926、B*3927、B*3928、B*3929、B*3930、B*3931、B*3932、B*400101、B*400102、B*400103、B*400104、B*400105、B*400201、B*400202、B*4003、B*4004、B*4005、B*40060101、B*40060102、B*4007、B*4008、B*4009、B*4010、B*4011、B*4012、B*4013、B*401401、B*401402、B*401403、B*4015、B*4016、B*4018、B*4019、B*4020、B*4021、B*4022N、B*4023、B*4024、B*4025、B*4026、B*4027、B*4028、B*4029、B*4030、B*4031、B*4032、B*4033、B*4034、B*4035、B*4036、B*4037、B*4038、B*4039、B*4040、B*4042、B*4043、B*4044、B*4045、B*4046、B*4047、B*4048、B*4049、B*4050、B*4051、B*4052、B*4053、B*4054、B*4055、B*4056、B*4057、B*4101、B*4102、B*4103、B*4104、B*4105、B*4106、B*4201、B*4202、B*4204、B*420501、B*420502、 B*4206、B*44020101、B*44020102S、B*440202、B*440203、B*440301、B*440302、B*4404、B*4405、B*4406、B*4407、B*4408、B*4409、B*4410、B*4411、B*4412、B*4413、B*4414、B*4415、B*4416、B*4417、B*4418、B*4419N、B*4420、B*4421、B*4422、B*4423N、B*4424、B*4425、B*4426、B*4427、B*4428、B*4429、B*4430、B*4431、B*4432、B*4433、B*4434、B*4435、B*4436、B*4437、B*4438、B*4439、B*4440、B*4501、B*4502、B*4503、B*4504、B*4505、B*4506、B*4507、B*4601、B*4602、B*4603、B*4604、B*47010101、B*47010102、B*4702、B*4703、B*4704、B*4705、B*4801、B*4802、B*4803、B*4804、B*4805、B*4806、B*4807、B*4808、B*4809、B*4810、B*4901、B*4902、B*4903、B*5001、B*5002、B*5004、B*510101、B*510102、B*510103、B*510104、B*510105、B*510201、B*510202、B*5103、B*5104、B*5105、B*5106、B*5107、B*5108、B*5109、B*5110、B*5111N、B*5112、B*511301、B*511302、B*5114、B*5115、B*5116、B*5117、B*5118、B*5119、B*5120、B*5121、B*5122、B*5123、B*5124、B*5126、B*5127N、B*5128、B*5129、B*5130、B*5131、B*5132、B*5133、B*5134、B*5135、B*5136、B*520101、B*520102、B*520103、B*520104、B*5202、B*5203、B*5204、B*5205、B*5206、B*530101、B*530102、B*5302、B*5303、B*5304、B*5305、B*5306、B*5307、B*5308、B*5309、B*5401、B*5402、B*5501、B*5502、B*5503、B*5504、B*5505、B*5507、B*5508、B*5509、B*5510、B*5511、B*5512、B*5513、B*5514、B*5515、B*5516、B*5601、B*5602、B*5603、B*5604、B*560501、B*560502、B*5606、B*5607、B*5608、B*5609、B*5610、B*5611、B*5612、B*5613、B*5614、B*570101、B*570102、B*5702、B*570301、B*570302、B*5704、B*5705、B*5706、B*5707、B*5708、B*5709、B*5801、B*5802、B*5804、B*5805、B*5806、B*5807、B*5808、B*5809、B*5810N、B*5901、B*670101、B*670102、B*6702、B*7301、B*7801、B*780201、B*780202、B*7803、B*7804、B*7805、B*8101、B*8102、B*8201、B*8202、B*8301。
HLA-C
Cw*010201、Cw*010202、Cw*0103、Cw*0104、Cw*0105、Cw*0106、Cw*0107、Cw*0108、Cw*0109、Cw*0110、Cw*020201、Cw*020202、Cw*020203、Cw*020204、Cw*020205、Cw*0203、Cw*0204、Cw*0205、Cw*0206、Cw*0207、Cw*0208、Cw*0209、Cw*030201、Cw*030202、Cw*030301、Cw*030302、Cw*030303、Cw*030304、Cw*030401、Cw*030402、Cw*030403、Cw*0305、Cw*0306、Cw*0307、Cw*0308、Cw*0309、Cw*0310、Cw*0311、Cw*0312、Cw*0313、Cw*0314、Cw*0315、Cw*0316、Cw*0317、Cw*0318、Cw*04010101、Cw*04010102、Cw*040102、Cw*0403、Cw*040401、Cw*040402、Cw*0405、Cw*0406、Cw*0407、Cw*0408、Cw*0409N、Cw*0410、Cw*0411、Cw*0412、Cw*0413、Cw*0414、Cw*0415、Cw*050101、Cw*050102、Cw*0502、Cw*0503、Cw*0504、Cw*0505、Cw*0506、Cw*0507N、Cw*0508、Cw*0509、Cw*0510、Cw*0602、Cw*0603、Cw*0604、Cw*0605、Cw*0606、Cw*0607、Cw*0608、Cw*0609、Cw*0610、Cw*0611、Cw*070101、Cw*070102、Cw*070103、Cw*07020101、Cw*07020102、Cw*07020103、Cw*0703、Cw*070401、Cw*070402、Cw*0705、Cw*0706、Cw*0707、Cw*0708、Cw*0709、Cw*0710、Cw*0711、Cw*0712、Cw*0713、Cw*0714、Cw*0715、Cw*0716、Cw*0717、Cw*0718、Cw*0719、Cw*0720、Cw*0721、Cw*0722、Cw*0723、Cw*0724、Cw*0725、Cw*0726、Cw*0727、Cw*0728、Cw*0729、Cw*080101、Cw*080102、Cw*0802、Cw*0803、Cw*0804、Cw*0805、Cw*0806、Cw*0807、Cw*0808、Cw*0809、Cw*0810、Cw*0811、Cw*0812、 Cw*120201、Cw*120202、Cw*120203、Cw*120301、Cw*120302、Cw*120303、Cw*120401、Cw*120402、Cw*1205、Cw*1206、Cw*1207、Cw*1208、Cw*1209、Cw*1210、Cw*1211、Cw*1212、Cw*1213、Cw*1214、Cw*1215、Cw*140201、Cw*140202、Cw*140203、Cw*1403、Cw*1404、Cw*1405、Cw*150201、Cw*150202、Cw*1503、Cw*1504、Cw*150501、Cw*150502、Cw*150503、Cw*150504、Cw*1506、Cw*1507、Cw*1508、Cw*1509、Cw*1510、Cw*1511、Cw*1512、Cw*1601、Cw*1602、Cw*160401、Cw*1606、Cw*1701、Cw*1702、Cw*1703、Cw*1801、Cw*1802。
HLA-E
E*0101、E*010301、E*010302、E*010303、E*0104。
HLA-F
F*010101、F*010102。
HLA-G
G*010101、G*010102、G*010103、G*010104、G*010105、G*010106、G*010107、G*010108、G*0102、G*0103、G*010401、G*010402、G*010403、G*0105N、G*0106。
HLA-DRA
DRA*0101、DRA*010201、DRA*010202。
HLA-DRB1
DRB1*010101、DRB1*010102、DRB1*010103、DRB1*010201、DRB1*010202、DRB1*010203、DRB1*010204、DRB1*0103、DRB1*0104、DRB1*0105、DRB1*0106、DRB1*0107、DRB1*0108、DRB1*0109、DRB1*0110、DRB1*0111、DRB1*030101、DRB1*030102、DRB1*030201、DRB1*030202、DRB1*0303、DRB1*0304、DRB1*030501、DRB1*030502、DRB1*0306、DRB1*0307、DRB1*0308、DRB1*0309、DRB1*0310、DRB1*0311、DRB1*0312、DRB1*0313、DRB1*0314、DRB1*0315、DRB1*0316、DRB1*0317、DRB1*0318、DRB1*0319、DRB1*0320、DRB1*0321、DRB1*0322、DRB1*0323、DRB1*0324、DRB1*0325、DRB1*0326、DRB1*0327、DRB1*0328、DRB1*040101、DRB1*040102、DRB1*0402、DRB1*040301、DRB1*040302、DRB1*0404、DRB1*040501、DRB1*040502、DRB1*040503、DRB1*040504、DRB1*0406、DRB1*040701、DRB1*040702、DRB1*040703、DRB1*0408、DRB1*0409、DRB1*0410、DRB1*0411、DRB1*0412、DRB1*0413、DRB1*0414、DRB1*0415、DRB1*0416、DRB1*0417、DRB1*0418、DRB1*0419、DRB1*0420、DRB1*0421、DRB1*0422、DRB1*0423、DRB1*0424、DRB1*0425、DRB1*0426、DRB1*0427、DRB1*0428、DRB1*0429、DRB1*0430、DRB1*0431、DRB1*0432、DRB1*0433、DRB1*0434、DRB1*0435、DRB1*0436、DRB1*0437、DRB1*0438、DRB1*0439、DRB1*0440、DRB1*0441、DRB1*0442、DRB1*0443、DRB1*0444、DRB1*0445、DRB1*0446、DRB1*0447、DRB1*0448、DRB1*0449、DRB1*0450、DRB1*070101、DRB1*070102、DRB1*0703、DRB1*0704、DRB1*0705、DRB1*0706、DRB1*0707、DRB1*0708、DRB1*080101、DRB1*080102、DRB1*080201、DRB1*080202、DRB1*080203、DRB1*080302、DRB1*080401、DRB1*080402、DRB1*080403、DRB1*080404、DRB1*0805、DRB1*0806、DRB1*0807、DRB1*0808、DRB1*0809、DRB1*0810、DRB1*0811、DRB1*0812、DRB1*0813、DRB1*0814、DRB1*0815、DRB1*0816、DRB1*0817、DRB1*0818、DRB1*0819、DRB1*0820、 DRB1*0821、DRB1*0822、DRB1*0823、DRB1*0824、DRB1*0825、DRB1*0826、DRB1*0827、DRB1*0828、DRB1*0829、DRB1*090102、DRB1*090103、DRB1*0902、DRB1*0903、DRB1*100101、DRB1*100102、DRB1*110101、DRB1*110102、DRB1*110103、DRB1*110104、DRB1*110105、DRB1*1102、DRB1*1103、DRB1*110401、DRB1*110402、DRB1*1105、DRB1*110601、DRB1*110602、DRB1*1107、DRB1*110801、DRB1*110802、DRB1*1109、DRB1*1110、DRB1*1111、DRB1*111201、DRB1*111202、DRB1*1113、DRB1*1114、DRB1*1115、DRB1*1116、DRB1*1117、DRB1*1118、DRB1*1119、DRB1*1120、DRB1*1121、DRB1*1122、DRB1*1123、DRB1*1124、DRB1*1125、DRB1*1126、DRB1*112701、DRB1*112702、DRB1*1128、DRB1*1129、DRB1*1130、DRB1*1131、DRB1*1132、DRB1*1133、DRB1*1134、DRB1*1135、DRB1*1136、DRB1*1137、DRB1*1138、DRB1*1139、DRB1*1140、DRB1*1141、DRB1*1142、DRB1*1143、DRB1*1144、DRB1*1145、DRB1*1146、DRB1*1147、DRB1*1148、DRB1*1149、DRB1*1150、DRB1*1151、DRB1*1152、DRB1*1153、DRB1*1154、DRB1*120101、DRB1*120102、DRB1*120201、DRB1*120202、DRB1*120302、DRB1*1204、DRB1*1205、DRB1*1206、DRB1*1207、DRB1*1208、DRB1*1209、DRB1*1210、DRB1*130101、DRB1*130102、DRB1*130103、DRB1*130201、DRB1*130202、DRB1*130301、DRB1*130302、DRB1*1304、DRB1*1305、DRB1*1306、DRB1*130701、DRB1*130702、DRB1*1308、DRB1*1309、DRB1*1310、DRB1*1311、DRB1*1312、DRB1*1313、DRB1*131401、DRB1*131402、DRB1*1315、DRB1*1316、DRB1*1317、DRB1*1318、DRB1*1319、DRB1*1320、DRB1*1321、DRB1*1322、DRB1*1323、DRB1*1324、DRB1*1325、DRB1*1326、DRB1*1327、DRB1*1328、DRB1*1329、DRB1*1330、DRB1*1331、DRB1*1332、DRB1*1333、DRB1*1334、DRB1*1335、DRB1*1336、DRB1*1337、DRB1*1338、DRB1*1339、DRB1*1340、DRB1*1341、DRB1*1342、DRB1*1343、DRB1*1344、DRB1*1345、DRB1*1346、DRB1*1347、DRB1*1348、DRB1*1349、DRB1*1350、DRB1*1351、DRB1*1352、DRB1*1353、DRB1*1354、DRB1*1355、DRB1*1356、DRB1*1357、DRB1*1358、DRB1*1359、DRB1*1360、DRB1*1361、DRB1*1362、DRB1*1363、DRB1*1364、DRB1*1365、DRB1*140101、DRB1*140102、DRB1*1402、DRB1*140301、DRB1*140302、DRB1*1404、DRB1*140501、DRB1*140502、DRB1*1406、DRB1*140701、DRB1*140702、DRB1*1408、DRB1*1409、DRB1*1410、DRB1*1411、DRB1*1412、DRB1*1413、DRB1*1414、DRB1*1415、DRB1*1416、DRB1*1417、DRB1*1418、DRB1*1419、DRB1*1420、DRB1*1421、DRB1*1422、DRB1*1423、DRB1*1424、DRB1*1425、DRB1*1426、DRB1*1427、DRB1*1428、DRB1*1429、DRB1*1430、DRB1*1431、DRB1*1432、DRB1*1433、DRB1*1434、DRB1*1435、DRB1*1436、DRB1*1437、DRB1*1438、DRB1*1439、DRB1*1440、DRB1*1441、DRB1*1442、DRB1*1443、DRB1*1444、DRB1*1445、DRB1*1446、DRB1*1447、DRB1*1448、DRB1*150101、DRB1*150102、DRB1*150103、DRB1*150104、DRB1*150105、DRB1*150201、DRB1*150202、DRB1*150203、DRB1*1503、DRB1*1504、DRB1*1505、DRB1*1506、DRB1*1507、DRB1*1508、DRB1*1509、DRB1*1510、DRB1*1511、DRB1*1512、DRB1*1513、DRB1*1514、DRB1*1515、DRB1*1516、DRB1*160101、DRB1*160102、DRB1*160201、DRB1*160202、DRB1*1603、DRB1*1604、DRB1*160501、DRB1*160502、DRB1*1607、DRB1*1608。
HLA-DRB2-9
DRB2*0101、DRB3*010101、DRB3*01010201、DRB3*01010202、DRB3*010103、DRB3*010104、DRB3*0102、DRB3*0103、DRB3*0104、DRB3*0105、DRB3*0106、DRB3*0107、DRB3*0108、DRB3*0109、DRB3*0110、DRB3*0111、DRB3*0201、DRB3*020201、DRB3*020202、DRB3*020203、DRB3*020204、DRB3*0203、DRB3*0204、DRB3*0205、DRB3*0206、DRB3*0207、DRB3*0208、DRB3*0209、DRB3*0210、DRB3*0211、DRB3*0212、DRB3*0213、DRB3*0214、DRB3*0215、DRB3*0216、DRB3*0217、DRB3*0218、DRB3*0219、DRB3*030101、DRB3*030102、DRB3*0302、DRB3*0303、DRB4*01010101、DRB4*0102、DRB4*01030101、DRB4*01030102N、DRB4*010302、DRB4*010303、DRB4*010304、DRB4*0104、DRB4*0105、DRB4*0106、DRB4*0107、DRB4*0201N、DRB4*0301N、DRB5*010101、DRB5*010102、DRB5*0102、DRB5*0103、DRB5*0104、DRB5*0105、DRB5*0106、DRB5*0107、DRB5*0108N、DRB5*0109、DRB5*0110N、DRB5*0111、DRB5*0112、DRB5*0113、DRB5*0202、DRB5*0203、DRB5*0204、DRB5*0205、DRB6*0101、DRB6*0201、DRB6*0202、DRB7*010101、DRB7*010102、DRB8*0101、DRB9*0101。
HLA-DQA1
DQA1*010101、DQA1*010102、DQA1*010201、DQA1*010202、DQA1*0103、DQA1*010401、DQA1*010402、DQA1*0105、DQA1*0106、DQA1*0107、DQA1*0201、DQA1*030101、DQA1*0302、DQA1*0303、DQA1*040101、DQA1*040102、DQA1*0402、DQA1*0403N、DQA1*0404、DQA1*050101、DQA1*050102、DQA1*0502、DQA1*0503、DQA1*0504、DQA1*0505、DQA1*060101、DQA1*060102、DQA1*0602。
HLA-DQB1
DQB1*020101、DQB1*020102、DQB1*0202、DQB1*0203、DQB1*030101、DQB1*030102、DQB1*030201、DQB1*030202、DQB1*030302、DQB1*030303、DQB1*0304、DQB1*030501、DQB1*030502、DQB1*030503、DQB1*0306、DQB1*0307、DQB1*0308、DQB1*0309、DQB1*0310、DQB1*0311、DQB1*0312、DQB1*0313、DQB1*0401、DQB1*0402、DQB1*050101、DQB1*050102、DQB1*050201、DQB1*050202、DQB1*050301、DQB1*050302、DQB1*0504、DQB1*060101、DQB1*060102、DQB1*060103、DQB1*0602、DQB1*0603、DQB1*060401、DQB1*060402、DQB1*060501、DQB1*060502、DQB1*0606、DQB1*0607、DQB1*0608、DQB1*0609、DQB1*0610、DQB1*061101、DQB1*061102、DQB1*0612、DQB1*0613、DQB1*0614、DQB1*0615、DQB1*0616、DQB1*0617、DQB1*0618、DQB1*0619、DQB1*0620、DQB1*0621、DQB1*0622、DQB1*0623。
HLA-DPA1
DPA1*010301、DPA1*010302、DPA1*010303、DPA1*0104、DPA1*0105、DPA1*0106、DPA1*0107、DPA1*0108、DPA1*020101、DPA1*020102、DPA1*020103、DPA1*020104、DPA1*020105、DPA1*020106、DPA1*020201、DPA1*020202、DPA1*020203、DPA1*0203、DPA1*0301、DPA1*0302、DPA1*0303、DPA1*0401。
HLA-DPB1
DPB1*010101、DPB1*010102、DPB1*010103、DPB1*0102、DPB1*020102、 DPB1*020103、DPB1*020104、DPB1*020105、DPB1*020106、DPB1*0202、DPB1*0203、DPB1*030101、DPB1*030102、DPB1*0302、DPB1*040101、DPB1*040102、DPB1*0402、DPB1*0501、DPB1*0601、DPB1*0801、DPB1*0901、DPB1*1001、DPB1*110101、DPB1*110102、DPB1*1301、DPB1*1401、DPB1*1501、DPB1*1601、DPB1*1701、DPB1*1801、DPB1*1901、DPB1*200101、DPB1*200102、DPB1*2101、DPB1*2201、DPB1*2301、DPB1*2401、DPB1*2501、DPB1*260101、DPB1*260102、DPB1*2701、DPB1*2801、DPB1*2901、DPB1*3001、DPB1*3101、DPB1*3201、DPB1*3301、DPB1*3401、DPB1*3501、DPB1*3601、DPB1*3701、DPB1*3801、DPB1*3901、DPB1*4001、DPB1*4101、DPB1*4401、DPB1*4501、DPB1*4601、DPB1*4701、DPB1*4801、DPB1*4901、DPB1*5001、DPB1*5101、DPB1*5201、DPB1*5301、DPB1*5401、DPB1*5501、DPB1*5601、DPB1*5701、DPB1*5801、DPB1*5901、DPB1*6001、DPB1*6101N、DPB1*6201、DPB1*6301、DPB1*6401N、DPB1*6501、DPB1*6601、DPB1*6701、DPB1*6801、DPB1*6901、DPB1*7001、DPB1*7101、DPB1*7201、DPB1*7301、DPB1*7401、DPB1*7501、DPB1*7601、DPB1*7701、DPB1*7801、DPB1*7901、DPB1*8001、DPB1*8101、DPB1*8201、DPB1*8301、DPB1*8401、DPB1*8501、DPB1*8601、DPB1*8701、DPB1*8801、DPB1*8901、DPB1*9001、DPB1*9101、DPB1*9201、DPB1*9301、DPB1*9401、DPB1*9501、DPB1*9601、DPB1*9701、DPB1*9801、DPB1*9901。
HLA-DMA
DMA*0101、DMA*0102、DMA*0103、DMA*0104。
HLA-DMB
DMB*0101、DMB*0102、DMB*0103、DMB*0104、DMB*0105、DMB*0106。
HLA-DOA
DOA*010101、DOA*01010201、DOA*01010202、DOA*01010203、DOA*010103、DOA*01010401、DOA*01010402、DOA*010105。
HLA-DOB
DOB*01010101、DOB*01010102、DOB*010102、DOB*010201、DOB*010202、DOB*0103、DOB*01040101、DOB*01040102。
MHCI类
H-2Db、H-2Dd、H-2Dk、H-2Dq、H-2Kb、H-2Kd、H-2Kk、H-2Ld、H-2M3、H-2Ad、H-2Ag7、H-2Ak、H2-Ab、H-2Ed、H-2Ek、H-2Bxk、H-2F、H-2I、H-2P、H-2R、H-2S、H-2Sxd、H-2T4、H-2U。
MHC II类
I-Ab、I-Ad、I-Ag7、I-Ak、I-Ap、I-Aq、I-Ar、I-As、I-Au、I-Av、I-Ea、I-Eb、I-Ed、I-Ek、I-Es、I-Eu、H-2Q、H-2Qa-2、H-2Qa-2a、Qa-1a、Qa-1b。
本发明不限于这些MHC和HLA分子,并且如果需要,可以仅仅通过建立诸如肽的物质与这些分子的反应性来适应于新发现的这类分子。这可以使用本领域中标准的已知技术而容易地完成。用于本发明的特别优选的HLA等位基因包括下列基因:
HLAI类
HLAA HLAB HLACw
A*6802 B*5801 Cw*1701
A*6801 B*5701 Cw*1601
A*6601 B*5501 Cw*1502
A*3303 B*5201 Cw*1402
A*3301 B*5101 Cw*1203
A*3201 B*5001 Cw*0802
A*310102 B*4901 Cw*0801
A*3002 B*4501 Cw*0704
A*3001 B*4403 Cw*0703
A*2902 B*4402 Cw*0702
A*2608 B*4101 Cw*0701
A*2601 B*4002 Cw*0602
A*2501 B*4001 Cw*0501
A*2402 B*3901 Cw*0401
A*2301 B*3801 Cw*0304
A*1101 B*3701 Cw*0303
A*0302 B*3503 Cw*0202
A*0301 B*3501 Cw*0102
A*0205 B*2705
A*0201 B*1801
A*0101 B*1501
B*1402
B*1401
B*1302
B*0801
B*0705
B*0702
HLAII类
HLADPB HLADQA HLADQB HLADRB
DPB1*1701 DQA1*0505 DQB1*0604 DRB1*1601
DPB1*1301 DQA1*0501 DQB1*0603 DRB1*1501
DPB1*1001 DQA1*0401 DQB1*0602 DRB1*1401
DPB1*0601 DQA1*0303 DQB1*0503 DRB1*1302
DPB1*0501 DQA1*0302 DQB1*0502 DRB1*1301
DPB1*0402 DQA1*0301 DQB1*0501 DRB1*1201
DPB1*0401 DQA1*0201 DQB1*0402 DRB1*1104
DPB1*0301 DQA1*0104 DQB1*0303 DRB1*1101
DPB1*0201 DQA1*0103 DQB1*0302 DRB1*0801
DPB1*0101 DQA1*0102 DQB1*0301 DRB1*0701
DQA1*0101 DQB1*0202 DRB1*0404
DQB1*0201 DRB1*0401
DRB1*0301
DRB1*0103
DRB1*0102
DRB1*0101
本发明最优选的等位基因是下列基因:
HLA-A*0201、HLA-A*0206、HLA-A*0301、HLA-A*1101、HLA-A*2402、HLA-A*3401、HLA-B*0702、HLA-B*0801、HLA-B*1301、HLA-B*27、HLA-B*4002、HLA-B*5101、HLA-Cw*03、HLA-cW*07
HLA-DRB1*0301、HLA-DRB1*0401、HLA-DRB1*0701、HLA-DRB1*1501、HLA-DRB1*1104、HLA-DRB1*1101、HLA-DRB4*0101
HLA-DQA1*01、HLA-DQA1*02、HLA-DQA1*05
HLA-DQB1*03、HLA-DQB1*04、HLA-DQB1*05、HLA-DQB1*06
HLA-DPA1*01、HLA-DPA1*02
HLA-DPB1*02、HLA-DPB1*04
将参考下面的具体实施方式仅以实施例的方式对本发明进行描述。
实施例
实验1-多肽针对流感抗原的反应性
本研究的目的是证明上述流感多肽的反应性和它们在人HLA(HLA-A*0201)的情况中诱导针对天然处理和呈递的流感蛋白的特异Th1型细胞因子应答的能力。
作为实验的背景,有用的是理解Th1和Th2应答是由它们中所涉及的辅助性T细胞所产生的细胞因子的模式所限定的。然而,这并不意味着这些特异性的应答中所涉及的其余淋巴细胞(T细胞和B细胞)也不产生细胞因子(所述细胞因子辅助驱动它们所参与的应答的特性模式)。这样,Th1类应答的特征在于产生IFN-γ和IL-2,其导致刺激CD8+CTL应答和相关的(在小鼠中)IgG2a抗体应答。IFN-γ应答可以由CD4+辅助性T细胞1以及由同样形成其一部分的CD8+T细胞产生。在这种情况中,对CD8+T细胞所产生的应答的IFN-γ组分进行了研究。那是因为,本实验主要是研究CD8+T细胞抗原决定簇,并且期望证明所观察到的应答是由这些细胞所引起的。由于CD8+T细胞仅与MHC I类分子上的抗原决定簇反应,因此使用与转基因小鼠仅共有一种MHC I类分子(即HLA-A*0201)的人类细胞。Th2类应答的特征在于产生IL-4和IL-10,这导致刺激IgGE、IgG1和(在小鼠中)IgG2b抗体应答。这些应答都是 与IFN-γ和IL-10具有拮抗性,从而下调各自的产生。
下面所描述的全部实验都进行两次。
材料和方法
肽和重组蛋白
在本研究中所使用的全部多肽(即,P1:M1A氨基酸(aa)36~75(SEQ ID 1);P2:M1B aa 124~158(SEQ ID 2);P3:NPA aa 255~275(SEQID 3);P4:NPB aa 306~326(SEQ ID 4);P5:PB1 aa 395~428(SEQ ID 5);P6:M2 aa 32~55(SEQ ID 6);以及NRP:对照用的无关多肽)都是由Fmoc化学合成的,并重新悬浮在PBS的10%DMSO中。
细胞系和病毒
T1和JURKAT细胞系是分别来自携带和未携带HLA-A*0201的个体的人淋巴样干细胞系。将T1维持在IMDM培养基(Invitrogen)中,而将JURKAT维持在含有10mM HEPES和1mM丙酮酸钠的RPMI-1640培养基(Sigma)中。两种培养基都补充有50IU/50mg/ml的青霉素/链霉素(Sigma)以及作为完全培养基加入10%胎牛血清(FCS)。在潮湿的5%CO2环境中将细胞培养物维持在37℃。
在潮湿的5%CO2环境中于37℃,将原代脾细胞维持在IMDM培养基(Invitrogen)中,所述IMDM培养基补充有0.02mM的β-巯基乙醇(Sigma)、50IU/50mg/ml的青霉素/链霉素(Sigma)以及10%的FCS(Sigma)。
流感A株New_Caledonia/20/99、NYMC/X-147以及流感B株Johannesburg/5/99都是从NIBSC获得的冻干储藏物,并用于感染同基因型(T1)和异基因型(JURKAT)人细胞系。
制备用于细胞因子分析的目标细胞
通过离心(250g,5分钟)收集指数期的细胞培养物,并以106个细胞/ml的密度重悬浮在无血清的培养基中。使用Lipofectin(Invitrogen)根据厂商说明书,用一系列浓度为5μg/106个细胞的多肽抗原转染等量份的细胞悬浮液,并在丝裂霉素C(MMC)处理之前在完全培养基中孵育8~10个小时。作为选择,用一系列的活流感病毒(MOI为5~10)感染 等量份的细胞悬浮液1小时,在无血清的培养基中洗两次,并在MMC处理之前在完全培养基中孵育24小时。
对于MMC处理,使用离心(250g,5分钟)收集细胞,并重悬浮在含有50μg/ml的丝裂霉素C(Sigma)的无血清IMDM培养基中。在37℃孵育45分钟后,将细胞悬浮液在无血清的IMDM培养基中清洗四次(250g,5分钟),最终重悬浮在IMDM完全培养基中。
免疫接种
为7~10周龄的C57BL/6-Tg(HLA-A2.1)1Enge/J小鼠(C57/BL6背景上的HLA-A*0201转基因小鼠,Jackson Labs)皮下免疫接种每只小鼠200μl剂量的抗原制备物。在测试组中,每剂量抗原制备物含有60nmol的所有六种肽的等摩尔混合物(每种肽为10nmol),所述肽根据厂商说明书制备在IFA(Sigma)中(FLU-v制备物)。在对照组中,每剂量抗原制备物含有等剂量的无关多肽,该多肽根据厂商说明书制备在IFA(Sigma)中(NRP制备物)。
在免疫接种后的第14天,所有的动物均接受加强免疫接种,其使用与最初所使用的相同的剂量和输送途径。最后,在第21天或第22天,将所有的动物挑出,并收集它们的脾。
免疫接种方案可以示意性地表示如下:
方案1、接种
统计分析
通过对样品的非参数Mann-Whitney分析,建立FLU-v和NRP接种的动物之间IFN-γ应答对不同抗原的统计学上的显著差异。如果p值低于0.05,则认为差异是统计学上显著的。
细胞因子ELISA
汇集属于相同实验组的小鼠脾,轻压通过细胞滤网,并通过使用红细胞裂解缓冲液(9份0.16M NH4Cl和1份0.17M Tris,pH7.2)的处理除去红细胞。将来自每个实验组的脾细胞悬浮液以4×106个细胞/孔的密度铺在24孔板中,所述孔中含有一系列多肽抗原(5μg/ml)或者作为选择,MMC处理的细胞系(脾细胞:该细胞(S:C)比例为10:1),所述MMC处理的细胞系被如上所述的多肽抗原转染或者用不同的活流感病毒感染。
在37℃孵育4天之后,收集上清,并根据厂商方案(Pharmingen)通过夹心型细胞因子ELISA分析IFN-γ和IL-4。该测定的检测下限对于IL-4是9.77pg/ml,对于IFN-γ是39.06pg/ml。
结果
在本专利申请中所描述的每种多肽的肽(包括在本实施例中所测试的P1、P2、P3、P4、P5和P6)已经被定义为含有在多种人HLA分子中发生反应的T细胞抗原决定簇,所述HLA分子中包括HLA-A*0201。因此,本研究的目的是评价上述多肽诱导特异性多抗原Th1类免疫应答(即IFN-γ介导的免疫应答)的能力,以及在携带人HLA-A*0201的被感染细胞的环境中,该应答特异性地与天然加工和呈递的流感抗原反应的能力,所述流感抗原来自多种对人类致病的无关株。
肽1的反应性
在通过转基因小鼠的抗原呈递细胞(APC)对多肽进行内部加工之后,所含有的CD8+T细胞特异性抗原决定簇将联合HLA-A*0201分子被呈递到APC的表面中,在该APC中,它们将被加工以激活幼稚CD8+T细胞并诱导P1特异性的Th1类免疫应答。
为了确认这一点,通过液体载体(Lipofectin,INVITROGEN)方式将携带HLA-A*0201的人细胞系(T1)和不携带HLA-A*0201的人细胞系(JURKAT)在细胞内加载P1。与来自NRP免疫动物的脾细胞相比,发现来自用流感多肽制备物(FLU-v)免疫的动物的脾细胞在与MMC处理的携带HLA-A*0201的转染有P1的人细胞(T1)共培养时,产生显著提高水平的INF-γ,但与以同样方式处理的不携带HLA-A*0201的人细胞(JURKAT)共培养时,并不如此(参见图1A,其数据提供在下面的表1中)。
表1
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽1(sol) | 119.3±7.1 | <39 |
T1-FLU肽1(pro) | 228.4±16.6 | 55.8±7 |
Ju-FLU肽1(pro) | <39 | 51.2±1.6 |
标注:
“Lys”的意思是基于其计算所有数值的阴性对照背景。“Sol”的意思是呈递到原代脾细胞群的可溶性肽。“Pro”的意思是在内部加工并将所得到的抗原决定簇装载到MHC分子上之后,与细胞的HLA分子形成复合物而被呈递的肽。数值表示为平均值±相对于Lys的ΔIFN-γ的标准误差(pg/ml)。
该实验可以可以示意性地表示如下:
方案2、T1和JURKAT的对照测试
方案3、 T1和JURKAT的FLU-v测试结果
因为在这些实验中所使用的转基因小鼠不携带任何其他人HLA,并且其CD8+T细胞在它们从未遇到过的其他人HLA的环境中,特异性地识别衍生自P1的抗原决定簇的能力低,因此这些结果清楚地显示所观察到的IFN-γ应答是特异性地由被致敏的CD8+T细胞所造成的,所述CD8+T细胞联合HLA-A*0201分子识别衍生自P1的抗原决定簇。
同样重要的是注意在FLU-v或NRP免疫的动物中,均没有检测到针对P1转染的细胞的IL-4应答(数据未显示)。由于IL-4的产生对于IFN-γ产生是拮抗的,因此对于抗原特异性CD8+T细胞应答的形成也是拮抗 的,因此在两种组中IL-4产生的缺乏明显地显示使用FLU-v的免疫能诱导针对制备物中P1组分的特异性Th1类应答。
当仅仅将可溶性P1抗原加入到脾细胞培养物(无T1或JURKAT细胞)中时,与NRP免疫组相比,在FLU-v中也观察到了IFN-γ水平的显著提高。然而,该IFN-γ应答的整体水平低于当抗原由通过携带HLA-A*0201的T1细胞所呈递时所观察到的水平。这种观察结果的解释是P1在以下基础上定义的,即,含有的抗原决定簇在人类HLA的环境中是主要反应性的,而在小鼠HLA的环境下并不如此。除了HLA-A*0201分子外,这里所使用的转基因小鼠还含有小鼠MHC分子的完整补体(fullcomplement),因此在原代脾细胞培养物中存在的APC群所捕获的可溶性P1也能够被加工进入小鼠MHCI类和II类途径(Peachman KK,Rao M,Alving CR,Palmer DR,Sun W,Rothwell SW.“Human dendritic cells andmacrophages exhibit different intracellular processing pathways for solubleand liposome-encapsulated antigens.”Immunobiology.2005;210(5):321~33),其分别介导H-2D限制性CD8+和CD4+T细胞应答。结果,如果P1含有多个鼠抗原决定簇,则将预期IFN-γ对可溶性P1的应答与人类细胞介导的呈递情况所观察到的相同或更高,因为多得多的CD4+和CD8+T细胞将能够对刺激做出反应。因为这个并未被观察到,并且体外免疫应答的水平主要由抗原的可利用度来确定,则其明确遵循在T1共培养实验中所检测到的P1特异性CD8+T淋巴细胞只是不能够以相同水平应答,这是因为在正确的HLA-A*0201环境中对其呈递的抗原的量降低。
肽2的反应性
与来自NRP免疫的动物的脾细胞相比,发现来自用FLU-v免疫的动物的脾细胞,在与MMC处理的携带HLA-A*0201的转染P2的人细胞(T1)共培养时,产生显著提高水平的INF-γ,但与以同样方式处理的不携带HLA-A*0201的人细胞(JURKAT)共培养时并不如此(参见图1B,其数据显示在下面的表2中)。与P1的情况一样,这些结果清楚地显示所观察到的IFN-γ应答是特异性地由CD8+T细胞造成的,所述CD8+T细胞联合HLA-A*0201分子识别衍生自P2的抗原决定簇。类似的,因为 IL-4的产生对IFN-γ的产生是拮抗的,因此对CD8+T细胞的发育是拮抗的,所以在FLU-v或NRP免疫的动物中针对P2转染细胞的IL-4应答的缺失(数据未显示)清楚地显示FLU-v免疫能诱导P2特异性的Th1类应答。
表2
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽2(sol) | 976.9±24.1 | 468.4±14.7 |
T1-FLU肽2(pro) | 372.9±6.4 | 154.5±10.7 |
Ju-FLU肽2(pro) | <39 | <39 |
标注:
“Lys”的意思是基于其计算所有数值的阴性对照背景。“Sol”的意思是呈递到原代脾细胞群的可溶性肽。“Pro”的意思是在内部加工并将所得到的抗原决定簇装载到MHC分子上之后,与细胞的HLA分子形成复合物而被呈递的肽。数值表示为平均值±相对于Lys的ΔIFN-γ的标准误差(pg/ml)。
在仅将P2加入到脾细胞培养物中时,与NRP免疫组相比,在FLU-v中也观察到了显著提高的IFN-γ产生。然而,与P1相反,针对可溶性抗原的IFN-γ应答的整体水平大于针对携带HLA-A*0201的细胞所呈递的抗原的IFN-γ应答的整体水平。这种观察将显示P2不仅具有强HLA-A*0201抗原决定簇,而且具有强小鼠(H-2D)抗原决定簇。
肽3、4和5的反应性
与肽2的情况相同,当仅仅将P3、P4和P5加入到培养物中,以及当它们通过HLA匹配的转染人细胞系(T1)进行呈递时,在FLU-v和NRP免疫组中可以观察到显著提高的IFN-γ产生,而当它们通过HLA非匹配的(JURKAT)人细胞系进行呈递时,却不如此(参见图1C、1D和1E,其数据显示下表3~5中)。在所有这三种情况中,当将脾细胞与转染的人细胞共培养时,而不是仅仅将可溶性抗原加入到培养基中时,则IFN-γ产生的增加较大。鉴于对P2情况所进行的阐述的相同论点,这些结果显示除了人抗原决定簇外,P3、P4和P5还含有许多强小鼠T细胞抗原决定簇。
表3
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽3(sol) | 1734.1±57.2 | 268.0±11.0 |
T1-FLU肽3(pro) | 587.5±14.9 | <39 |
Ju-FLU肽3(pro) | 148.5±3.0 | 146.5±17.6 |
表4
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽4(sol) | 1170.5±27.8 | 693.8±5.6 |
T1-FLU肽4(pro) | 229.9±35.2 | 84.6±11.6 |
Ju-FLU肽4(pro) | <39 | <39 |
表5
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽5(sol) | 1067.7±7.3 | 220.5±6.6 |
T1-FLU肽5(pro) | 405.6±11.8 | <39 |
Ju-FLU肽5(pro) | <39 | <39 |
标注:
“Lys”的意思是基于其计算所有数值的阴性对照背景。“Sol”的意思是呈递到原代脾细胞群的可溶性肽。“Pro”的意思是在内部加工并将所得到的抗原决定簇装载到MHC分子上之后,与细胞的HLA分子形成复合物而被呈递的肽。数值表示为平均值±相对于切s的ΔIFN-γ的标准误差(pg/ml)。
最后,由于所有三种肽都不能诱导产生IL-4(数据未显示),因此,清楚的是使用FLU-v制备物疫苗接种诱导的免疫应答能诱导针对这三种多肽中每一种的Th1类应答。
肽6的反应性
与P1的情况相同,当仅仅将P6加入到培养物中以及当其通过HLA匹配的转染人细胞系(T1)进行呈递时,在FLU-v和NRP免疫组中可以观察到显著提高的IFN-γ产生,而当其通过HLA非匹配的(JURKAT)人细胞系进行呈递时并不如此(参见图1F,其数据显示下表6中)。同样与P1相同,观察到针对可溶性抗原的应答更大,这说明P6不含有强的H-2D抗原决定簇。由于这些观察结果的原因已经在P1情况中进行了解 释,因此这里不再进行进一步展开阐述,人们可以参考前面的部分。
表6
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽6(sol) | 496.2±11.8 | 105.5±7.0 |
T1-FLU肽6(pro) | 1210.5±11.5 | 817.6±8.9 |
Ju-FLU肽6(pro) | <39 | <39 |
标注:
“Lys”的意思是基于其计算所有数值的阴性对照背景。“Sol”的意思是呈递到原代脾细胞群的可溶性肽。“Pro”的意思是在内部加工并将所得到的抗原决定簇装载到MHC分子上之后,与细胞的HLA分子形成复合物而被呈递的肽。数值表示为平均值±相对于Lys的ΔIFN-γ的标准误差(pg/ml)。
使用P6的刺激不能诱导任何IL-4产生(数据未显示),这清楚地说明FLU-v疫苗接种诱导的免疫应答能诱导针对P6的Th1类应答。
FLU-v对无关流感株的反应性
到目前这一点所描述的实验清楚地显示使用FLU-v进行的免疫诱导了针对六种组成型多肽中每一种的特异性CD8+T细胞IFN-γ应答。然而,由于这六种多肽被限定为含有反应性CD8+T细胞抗原决定簇,所述抗原决定簇在所分析的流感病毒群内具有低水平的序列变化,因此还期望建立FLU-v疫苗接种的小鼠是否能够识别在使用不同的无关流感株进行感染之后天然加工并呈递的T细胞抗原决定簇,进而诱导特异性的Th1类免疫应答。这类分析提供了明确指示,即借助靶向人和动物流感群间低序列可变性的T细胞抗原决定簇,FLU-v多肽混合物作为流感疫苗的潜在能力将提供针对所有目前的流感株以及可以在将来通过高致病性动物株与目前人株之间的自发重组而产生的流感株的保护。
对于该分析,将使用FLU-v或NRP免疫的转基因动物的原代脾细胞培养物与多种流感感染的携带HLA-A*0201(T1)和不携带HLA-A*0201(JURKAT)人细胞进行共培养。进行感染所使用的三种流感株(A/New_Caledonia/20/99,A/NYMC/X-147和B/Johannesburg/5/99)对于人都是致病性的,并且都是从总部位于NIBSC(UK)的流感WHO储藏 室(Influenza WHO repository)获得的。作为抗原特异性阳性对照,使用加入到原代脾细胞制备物中的等摩尔可溶性六种多肽的制备物。
与来自NRP免疫的动物的脾细胞相比,来自FLU-v免疫的动物的脾细胞在与MMC处理的流感感染的被转染携带HLA-A*0201的人细胞(T1)共培养时产生了显著较高的IFN-γ水平,而在与以相同方式处理的不携带HLA-A*0201的人细胞(JURKAT)共培养时并不如此(参见图2,其数据显示在下面的表7中)。在针对可溶性多肽抗原或流感感染的细胞进行疫苗免疫的任何小鼠中,没有检测到IL-4应答(数据未显示)。这些结果明确显示所观察到的IFN-γ应答是由致敏的CD8+T细胞所特异性引起的,所述致敏的CD8+T细胞识别在FLU-v制备物中所包含的抗原决定簇,并且所述抗原决定簇还联合流感感染的人细胞中的HLA-A*0201分子被天然加工和呈递。
表7
相对于Lys的ΔIFN-γ(pg/ml) | FLU-v | NRP |
Con A | 2395.6±45.9 | 2257.5±29.8 |
FLU肽混合物(sol) | 1440.2±44.9 | 678.3±29.2 |
T1-Flu A/NC/20/99 | 2146.4±23.7 | 1282.1±4.8 |
Ju-Flu A/NC/20/99 | 1246.9±48.8 | 1206.4±10.9 |
T1-Flu A/NYMC/X147 | 1949.4±37.9 | 1101±5.9 |
Ju-Flu A/NYMC/X147 | 1342.3±14.5 | 1248.6±8.3 |
T1-Flu B/Johannesburg/5/99 | 1769.0±33.6 | 1196.0±16.2 |
Ju-Flu B/Johannesburg/5/99 | 257.6±3.0 | 257.0±8.3 |
标注:
“Lys”的意思是基于其计算所有数值的阴性对照背景。“Sol”的意思是呈递到原代脾细胞群的可溶性肽。“Pro”的意思是在内部加工并将所得到的抗原决定簇装载到MHC分子上之后,与细胞的HLA分子形成复合物而被呈递的肽。T1是携带HLA-A*0201的人细胞系。“Ju”是指JURKAT,其是不携带HLA-A*0201 的人细胞系。 A/NC/20/99(即A/New_Caledonia/20/99)、A/NYMC/X147和B/Johannesburg/5/99分别是用于感染人细胞系的两种流感A株和一种流感B株。数值表示为平均值±相对于Lys的ΔIFN-γ的标准误差(pg/ml)。
有趣的是,对于所有流感感染组,IFN-γ的背景生产高于在使用纯化 的多肽抗原进行类似的分析时所观察到的。然而,这种观察结果最可能反映MMC处理不能完全灭活在细胞制备物中所存在的病毒。进而,这将导致在原代脾细胞培养物中存在多种可以感染易感小鼠细胞的有生存力的流感病毒,因此导致体外的初级应答。以下观测结果支持了这种解释,即观察到不依赖所考虑的受感染人细胞系和疫苗接种组,所使用的大部分流感病毒株诱导相同水平的背景IFN-γ应答。该规律的唯一例外是在感染B/Johannesburg/5/99的JURKAT细胞中观察到显著降低的背景IFN-γ产生。然而,因为,即使在该情况中,对于FLU-v和NRP疫苗接种的动物,IFN-γ产生都是等价的,因此似乎所观察到的差别更多是由JURKAT细胞对流感B/Johannesburg/5/99感染的易感性降低造成的,而不是由任何与不同疫苗接种方案相关的内在原因造成的。无论情况是怎样,该观察结果都不能减损以下明确事实,即在使用多种无关的感染性流感病毒株对人细胞进行感染之后,使用FLU-v进行疫苗接种会导致对联合HLA-A*0201分子而被呈递的天然加工的流感抗原决定簇的特异性识别。因此,FLU-v构成了有效的候选疫苗制备物,用于保护抵抗多种流感株,因此避免了对目前每年重新接种疫苗方案的需要。
实验2-多肽在小鼠中的保护效果
本研究的目的是证明使用所鉴定的流感保守性T细胞多抗原决定簇肽(FLU-v)的低剂量免疫能诱导CD8+T细胞介导针对流感病毒的致死攻击的保护。
材料和方法
肽,抗血清和病毒:
在该研究中所测试的候选疫苗制备物(FLU-v)是由多种肽构成的,所述肽(即:P1:M1A氨基酸(aa)36~75(SEQ ID 1);P2:M1B aa 124~158(SEQ ID 2);P3:NPA aa 255~275(SEQ ID 3);P4:NPB aa 306~326(SEQ ID 4);P5:PB1 aa 395~428(SEQ ID 5);P6:M2 aa 32~55(SEQ ID6))全部是由Fmoc化学法合成的,并重悬浮在PBS中的DMSO中(DMSO在最终制备物中的浓度低于5%)。使用通过煮沸变性的溶菌酶(Sigma)作为对照用的无关制备物(NRP-v)。
从AbD Serotec(UK)获得纯化的大鼠抗小鼠CD8 IgG2a(克隆YTS169.4),而从NIBSC获得作为冻干的标准储藏物的感染性病毒株流感A/PR/8/34。
免疫
在第1天,对7~10周龄的C57BL/6-Tg(HLA-A2.1)1Enge/J小鼠(C57/BL6背景基础上的HLA-A*0201转基因小鼠,Jackson Labs),用在IFA(Sigma)中乳化的200μl剂量的抗原制备物在尾部的基部进行皮下免疫。在测试组(n=14)中,每剂量抗原制备物含有60nmol的全部六种肽的等摩尔混合物(每种为10nmol),而在对照组(n=14)中,每剂量抗原制备物含有等剂量的无关多肽。
在第15天,所有的动物均接受加强免疫,其中使用与起始相同的剂量和输送途径。
在第16天,将测试组和对照组都分成两个相同的亚组(每个亚组的n=7,即对照-1,对照-2,测试-1和测试-2)。
在第19天,对照-1和测试-1组中的所有动物均接受200μl腹膜内注射大鼠抗小鼠CD8血清(100μg),而对照-2和测试-2组中的所有动物均接受等量注射的无关血清。
次日(第20天),麻醉下对所有组进行致死大剂量(大约1.5×107pfu)的流感A/PR/8/34的鼻内攻击。
在第22天,再次为动物腹膜内注射上述大鼠抗小鼠CD8或无关血清。
从第20天起,每日对所有动物监测流感征兆(例如打喷嚏和发热)以及体重损失。
在第27天将所有仍然存活的动物挑出处死,终止该研究。
结果
为了评价FLU-v制备物作为候选流感疫苗的效率,期望在NRP-v和FLU-v免疫的动物中使用流感A/PR/8/34株建立攻击研究。通常,在攻击之后第4或5天,大约1.5×107 pfu的鼻内剂量将杀死未免疫的C57BL/6-Tg(HLA-A2.1)1Enge/J小鼠(数据未显示)。
如图3A中所示,使用FLU-v或NRP-v肽制备物免疫,但进行CD8缺失的大部分动物,在鼻内攻击后7天内死于流感A/PR/8/34的感染(分别为71%与100%)。相反,如图3B所示,没有CD8的缺失时,使用FLU-v制备物免疫的动物与使用NRP-v制备物免疫的动物相比,显示死亡率的显著降低(p<0.05)(28%与100%)。
该研究的结果明确显示使用FLU-v肽制备物进行疫苗接种,即使在其每种构成活性肽为低水平剂量(10nmol)时,也会诱导显著水平的针对流感致死攻击的保护。如前所述,这些肽是最初通过它们在人HLAI类环境中的T细胞反应性在硅上(in silico)鉴定的。这些结果确认了以下事实,即通过使用FLU-v肽制备物进行疫苗接种而刺激的CD8+T细胞在提供针对流感感染的保护中发挥显著作用。
Claims (37)
1.一种多肽,所述多肽的序列为SEQ ID 1:DLEALMEWLKTRPILSPLTKGILGFVFTLTVP。
2.如权利要求1所述的多肽,其对流感病毒株是免疫原性的。
3.如权利要求2所述的多肽,其对多种流感病毒株是免疫原性的。
4.如权利要求1所述的多肽,所述多肽用于药物中。
5.如权利要求2所述的多肽,其中所述流感病毒株是流感A株。
6.如权利要求2所述的多肽,其中所述流感病毒株是流感B株。
7.一种多肽组合物,所述多肽组合物由序列分别为SEQ ID 1、3、4和6的多肽组成:
SEQ ID 1 DLEALMEWLKTRPILSPLTKGILGFVFTLTVP
SEQ ID 3 DLIFLARSALILRGSVAHKSC
SEQ ID 4 PGIADIEDLTLLARSMVVVRP
SEQ ID 6 IIGILHLILWILDRLFFKCIYRLF。
9.如权利要求7或8所述的多肽组合物,所述多肽组合物用于药物中。
10.一种多肽构建体,所述构建体包含载体和前述任一项权利要求所述的多肽。
11.如权利要求10所述的多肽构建体,其中所述载体是分子。
12.如权利要求10或11中所述的多肽构建体,其中所述载体包括辅助剂和/或赋形剂。
13.一种产生权利要求10所述的多肽构建体的方法,所述方法包括将所述多肽与所述载体组合。
14.如权利要求13所述的方法,其中所述载体是分子。
15.如权利要求13或14中所述的方法,其中所述载体包括辅助剂和/或赋形剂。
16.一种针对流感的药物,其包含权利要求1~9中任一项所述的多肽或多肽组合物,以及适当的赋形剂和/或辅助剂。
17.如权利要求16所述的药物,其中所述流感是流感A株。
18.如权利要求16所述的药物,其中所述流感是流感B株。
19.一种针对流感的疫苗组合物,其包含权利要求1~9中任一项所述的多肽或多肽组合物,以及适当的赋形剂和/或辅助剂。
20.如权利要求19所述的疫苗组合物,其中所述流感是流感A株。
21.如权利要求19所述的疫苗组合物,其中所述流感是流感B株。
22.一种针对流感的药物,其包含权利要求10、11或12所述的多肽构建体,并且任选包含适当的赋形剂和/或辅助剂。
23.如权利要求22所述的药物,其中所述流感是流感A株。
24.如权利要求22所述的药物,其中所述流感是流感B株。
25.一种针对流感的疫苗组合物,其包含权利要求10、11或12所述的多肽构建体,并且任选包含适当的赋形剂和/或辅助剂。
26.如权利要求25所述的疫苗组合物,其中所述流感是流感A株。
27.如权利要求25所述的疫苗组合物,其中所述流感是流感B株。
28.一种制备权利要求16所述的药物或权利要求19所述的疫苗组合物的方法,所述方法包括将权利要求1~9中任一项所述的多肽或多肽组合物与适当的赋形剂和/或辅助剂进行混合。
29.权利要求1~9、10~12和16~27中任一项所述的多肽、多肽组合物、多肽构建体或药物或疫苗组合物在制备有效治疗或预防流感的药物或疫苗中的应用。
30.如权利要求29所述的应用,其中所述流感是脊椎动物的流感。
31.如权利要求30所述的应用,其中所述脊椎动物选自哺乳动物、鸟、爬行动物和鱼。
32.如权利要求31所述的应用,其中所述脊椎动物是人或养殖的动物。
33.如权利要求31所述的应用,其中所述脊椎动物是家养的动物。
34.如权利要求31所述的应用,其中所述脊椎动物是牛类动物或家禽。
35.如权利要求31所述的应用,其中所述脊椎动物选自鸡、鸭、鹅、猪、马、牛、狗或猫。
36.如权利要求29所述的应用,其中所述流感是流感A株。
37.如权利要求29所述的应用,其中所述流感是流感B株。
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GB0613977D0 (en) * | 2006-02-07 | 2006-08-23 | Peptcell Ltd | Peptide sequences and compositions |
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