CN101227919B - 基于肽的流感疫苗制剂 - Google Patents
基于肽的流感疫苗制剂 Download PDFInfo
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Abstract
本发明公开了针对A和B型流感的基于肽的抗流感制剂。所述肽来源于基于流感的表位。所述制剂是基于可以配制的肽混合物，从而在特定残基上存在变异性。所述制剂可用于制备预防人、禽、鼠或者马动物流感的疫苗。
Description
相关申请的交叉引用
本申请要求在2005年6月1日提交的美国临时专利申请No.60/686,041的优先权，其通过参考并入本文。
技术领域
本发明一般涉及抗病毒制剂，尤其涉及基于肽的流感疫苗制剂。
背景技术
流行性感冒是常见的呼吸系统传染病，其与正粘病毒(Orthomyxoviridae)科病毒有关。由于该病毒的高度变异性，通常需要每年用重新配制考虑毒株变异的疫苗进行疫苗接种。尽管进行重新配制，但疫苗不可能包括在特定季节中感染全世界人们的所有不同毒株。
尽管目前可以获得针对流感的有效疫苗，但由于病毒表面蛋白的抗原变异，所以必须每年对其进行重新配制。重新配制的一个障碍是需要相对长的时间才能配制和制备足够的疫苗剂量来应对流感感染的季节性增加。通常可能要耗费六个月以上的时间来制备疫苗；有时，一种新的或被忽略了的流感毒株在这六个月中开始盛行，从而导致流行病。
血凝素(HA)是流感病毒的主要表面糖蛋白，并且是病毒中和抗体所针对的有效免疫原。基于相对稳定的胞内核蛋白和包膜相关基质蛋白，流感病毒可分为A型和B型。病毒的亚型是基于病毒包膜中的两种蛋白(HA和神经氨酸酶(neuraminidase，NA))，它们不断进行抗原变化。对于流感A型病毒，识别了HA的十五种不同亚型和NA的9种亚型(De Jong，Rimmelzwaan，G.F.，Fouchier，R.A.M.和Osterhaus，A.D.M.E.Journal of Infection，2000；40：218-228)。突然出现的新亚型(抗原转变)引起了上个世纪的三次大流行：1918(西班牙流感，H1N1)、1957(亚洲流感，H2N2)和1968(香港流感，H3N2)。最近也已产生了对禽流感、马流感和人易感性的关注。
HA是流感病毒的主要包膜糖蛋白，介导病毒侵入宿主细胞(Wiley，D.C.等，Nature 1981；289(29)：373-377；Wilson，IA等，Nature 1981；289，366-373；Caton等，Cell 1982：417-427)。三种HA单体结合形成天然HA，所述HA单体作为病毒感染性的前提被酶切成氨基端HA1和羧基端HA2。基于HA1的三维结构，已经通过确定抗原变体的氨基酸变化对抗原位点进行了作图(Wiley，同上)。抗原变异在HA受体结合区的周围最常见，包括抗体难以进入的受体结合袋周围的残基。因此，期望阐明基于肽的方法来作为免疫疗法。然而，对基于肽的亚基疫苗的主要担心是线性肽诱导能识别构象性B细胞和T细胞表位的抗体的能力。针对这些抗原位点的单克隆抗体可在存在确切的该序列时中和流感病毒的感染性。T和B细胞表位均可见于这些位点上(Atassi等，Advances inExperimental Medicine and Biology，1989；251：49-635-6；Torres et al，Immunology Letters，1988；19(1)：49-53)。
在针对HA上抗原位点之一的单克隆抗体存在时，流感病毒的增殖导致对亲代病毒中极少数逃避变体(escape variants)的选择(Webster等，Virology 1983；126(2)：587-99；Webster等，Virology 1980；104(1)：139-48；Yewdell等，Nature 1979；279(5710)：246-8)。与这些体外数据一致，针对一种病毒株进行了免疫并用另一种进行感染的个体产生大量抗原变体。这些数据提示，针对这些表位的群体免疫性是选择流感病毒新毒株的驱动力。
美国每年开发的疫苗制剂由食品和药物管理局疫苗及相关生物制品顾问委员会( the Department of Food and Drug Administration Vaccinesand the Related Biologicals Advisory Commi
发明内容
本发明的一个目的是消除或减轻先前的流感疫苗制剂的至少一种缺点。
本发明提供基于肽的流感疫苗制剂，其源于流感HA的表位。与商品疫苗相比，本发明的疫苗制剂有利地改善了动物模型中的体液应答。由于所述制剂中的肽变体，本发明可针对不同的流感病毒株而提供广泛的保护。
意想不到的是，发现本发明基于肽的流感疫苗制剂(其代表流感病毒在保护性HA表位中的抗原多样性)引发保护性免疫，它比用商品疫苗(仅基于少数流感分离物)诱导的保护性免疫具有更广泛的反应性。
在第一个方面中，本发明提供基于肽的抗流感制剂，其包含选自SEQ ID NO：1-248中的至少一种肽。
在本发明的一个实施方案中提供了包含选自SEQ ID NO：1-248的至少4种肽序列的制剂。在另一实施方案中，所述制剂可以包含选自SEQID NO：1-64的至少两种肽和选自SEQ ID NO：133-180的至少两种肽。所述制剂还可以包含SEQ ID NO：1-64和SEQ ID NO：133-180。
本发明还提供包含选自SEQ ID NO：185-248的至少一种肽序列的制剂。在一个实施方案中，所述制剂可以包含以下至少两个组中来自每一个组的至少两种肽序列：SEQ ID NO：185-200；SEQ ID NO：201-216；SEQ ID NO：217-232或者SEQ ID NO：233-248。
本发明还提供包含选自SEQ ID NO：65-128的至少一种肽序列的制剂。在一个实施方案中，所述制剂可以包含以下至少两个组中来自每一个组的至少两种肽序列：SEQ ID NO：65-80；SEQ ID NO：81-96；SEQID NO：97-112或者SEQ ID NO：113-128。
本发明的制剂可用于制备疫苗。在所述疫苗的制备中可以应用佐剂，如明矾或者其它替代物。所述疫苗可用于治疗动物(如人、小鼠、马或者禽类)的流感。
本发明的制剂具有针对A和B型流感的广泛反应性。有利地，本发明的制剂可在仅为6周的时间内以合成方式制备。
参考下文对本发明具体实施方案的描述并结合附图之后，本发明的其它方面和特征对于本领域普通技术人员将是显而易见的。
附图说明
在此参考附图描述本发明的一些实施方案，其仅用于举例，其中：
图1显示对本发明的马流感discosite构建体(INFE-HA-1-V1至V4；A-D)的HPLC分析。
图2显示对本发明的人A型流感discosite构建体(INF-HA-1-V1至V4；A-D)的HPLC分析。
图3显示对本发明的人和禽流感discosite构建体(INF-HA-2-V1至V4；A-D)的HPLC分析。
图4显示对本发明的B型流感discosite构建体(INF-HB-1-V1至V4；A-D)的HPLC分析。
图5A-5D展示本发明的马流感discosite构建体(INFE-HA-1-V1至V4；图5A-5D)的质谱数据。
图6A-6D展示本发明的人A型流感discosite构建体(INF-HA-1-V1至V4；图6A-6D)的质谱数据。
图7A-7D展示本发明的人和禽流感discosite构建体(INF-HA-2-V1至V4；图7A-7D)的质谱数据。
图8A-8D展示本发明的人B型流感discosite构建体(INF-HB-1-V1至V4；图8A-8D)的质谱数据。
图9展示在免疫之后本发明疫苗对体液免疫的诱导。
图10显示接种了疫苗的小鼠对H3N2攻击的存活曲线。
图11显示用本发明的疫苗INF-01P(INF-HA-1-V1-V4)接种后受攻击小鼠的重量减轻百分比。
图12显示小鼠中由INFE-01P(INFE-HA-1-V1-V4)疫苗接种诱导的体液免疫，以HAI效价衡量。
图13展示了在鼠疫苗研究中进行的血细胞凝集测定的结果。
图14显示基于表22中数据的流感疫苗ELISA测试的结果。
发明详述
一般而言，本发明提供抗病毒制剂，更具体地，提供基于肽的抗流感制剂，其包含选自SEQ ID NO：1-248的至少一种肽。
本发明的制剂是包含一种或多种肽的混合物。所述制剂可以包含选自SEQ ID NO：1-248的至少四种肽序列。在一个实例中，所述制剂可以包含选自SEQ ID NO：1-64的至少两种肽以及选自SEQ ID NO：133-180的至少两种肽。一个具体实例包含SEQ ID NO：1-64和SEQ IDNO：133-180。在另一具体实例中，所述制剂包含SEQ ID NO：1-64。仍在另一具体实例中，所述制剂包含SEQ ID NO：185-248。
在另一实例中，所述制剂可以包含以下至少两个组中来自每一组的2n种肽序列：a)SEQ ID NO：1-16；b)SEQ ID NO：17-32；c)SEQ ID NO：33-48；或者d)SEQ ID NO：49-64，其中n为1-4。此外，所述制剂可包含来自a)-d)中至少两个组：a)来自SEQ ID NO：133-140的2m种肽序列；b)来自SEQ ID NO：141-156的2n种肽序列；c)来自SEQ ID NO：157-172的2n种肽序列；或者d)来自SEQ ID NO：173-180的2m种肽序列，其中m是1-3，n是1-4。本制剂可用于制备人的抗流感疫苗。
本文描述的人抗流感制剂可以单独使用或者组合使用。
在另一实施例中，本发明的制剂可包含选自SEQ ID NO：185-248的至少一种肽序列。在一个实施例中，所述制剂可包含以下至少两组中来自每一组的2n种肽序列：a)SEQ ID NO：185-200；b)SEQ ID NO：201-216；c)SEQ ID NO：217-232；或者d)SEQ ID NO：233-248，其中n是从1至4。本制剂可用于制备马抗流感疫苗。
在另一实施例中，本发明的制剂可包含选自SEQ ID NO：65-128的至少一种肽序列。在一个实施例，所述制剂可包含以下至少两组中来自每一组的2n种肽序列：a)SEQ ID NO：65-80；b)SEQ ID NO：81-96；c)SEQ ID NO：97-112；或者d)SEQ ID NO：113-128，其中n是从1至4。本制剂可用于制备禽抗流感疫苗。
在肽序列不代表变异性的制剂实施例中，该制剂可包含SEQ ID NO：129-132或者SEQ ID NO：181-184中的至少一种。在一个具体实施例中，所述制剂可以包含SEQ ID NO：129-132。在另一具体实施例中，所述制剂可以包含SEQ ID NO：181-184。
本发明还提供疫苗，其包含含有选自SEQ ID NO：1-248的至少一种肽的制剂以及可药用稀释剂或载体。所述疫苗还可以包含佐剂，例如可以是明矾。
所述制剂可用于制备预防或者治疗动物流感的疫苗。所述动物可以是人、鼠、马或者禽。
本发明涉及制剂在制备治疗人流感的疫苗中的用途，所述制剂包含选自SEQ ID NO：1-64的至少两种肽和选自SEQ ID NO：133-180的至少两种肽。
本发明还涉及制剂在制备治疗马流感的疫苗中的用途，所述制剂包含选自SEQ ID NO：185-248的至少一种肽序列。
本发明还涉及制剂在制备治疗禽流感的疫苗中的用途，所述制剂包含选自SEQ ID NO：65-128的至少一种肽序列。
根据本发明制备的疫苗可用于预防或者治疗流感。
基于对流感血凝素(HA)蛋白质晶体结构的分析来测定这些肽的序列，从而确定肽表位。血凝素是流感病毒的主要表面糖蛋白，并且是病毒中和抗体所针对的一种高效免疫原。混合物中的线性肽表位模拟HA蛋白表面上的非连续表位。应用分析来自数千个人流感隔离群的HA蛋白质抗原变异的生物信息学软件，可以基于这些表位制备简并性肽混合物，其代表这些表位中的HA的抗原变异。因此，本发明的流感疫苗制剂包含代表HA蛋白主要表位的肽的混合物。
可以制备代表或不代表各个肽中特定残基的变异的疫苗。在不代表变异时，所形成的肽在本文中可称为DiscotopeTM构建体。不连续表位(discotope)构建体是线性序列的合成构建体，它与组成非连续表位的一级序列节段的位置近似。在序列中构建各个节段，以引发识别原始完整蛋白质中非连续表位的免疫应答。
非连续表位由蛋白质一级序列的两个或多个区段组成，它们在正确折叠时聚在一起并与特异性抗体结合。它们在失去二级结构时不被抗体所识别，因此不能由连续的线性肽所代表。
当根据特定病原体的不同序列而已知具有不同氨基酸的特定残基位置上存在变异时，所述制剂包括多种肽，它们在本文中可整体称为DiscositeTM构建体。
为了制备肽混合物，有可能使用如Torres在美国专利申请No.10/072,084中指出的方法，其通过参考并入本文。
设计不连续表位/不连续位点(discosite)构建体
在本发明的疫苗制剂中，应用流感血凝素来设计代表4个非连续表位的线性序列。设计了模拟HA的四个抗原位点上的非连续B和T细胞表位的4种肽(不连续表位构建体)。应用固相肽合成方法合成各个不连续表位构建体。从GenbankTM和Swiss ProteinTM数据库获得200个以上人A型流感隔离群的序列，并进行比对以研究这些表位的组成。
流感疫苗制剂可以包含SEQ ID NO：129-132和/或SEQ ID NO：181-184的一种或多种不连续表位构建体。
设计疫苗制剂
在本发明的上下文中，疫苗制剂是用于制备流感疫苗的肽混合物。所述疫苗可以包含肽混合物以及本领域已知的其它可包括的替代物。这些替代物可包括但不仅限于佐剂、稀释剂和/或载体。
本发明的疫苗制剂尤其适用于制备治疗人、马和/或禽流感的疫苗。然而，应当理解，肽序列的任何组合或者包含这些肽序列的制剂也可用于其它流感表型。
可以用一种或多种肽序列的集合来制备肽疫苗，所述肽序列代表HA三维结构中包含的表位(SEQ ID NO：1-248)。所述疫苗包括一种或多种不连续表位构建体(含有非可变氨基酸残基的肽)或者一种或多种不连续位点构建体(含有可变氨基酸残基的肽)。本发明的不连续位点构建体源于这些表位之一。因此，不连续位点构建体制剂包含源于含有可变残基的表位的一种或多种肽序列。
基于x个可变残基，本发明的每种不连续位点构建体代表2x种可能的肽序列。例如，具有3或4个可变残基的不连续位点构建体分别代表23＝8或者24＝16种序列。因此，在本发明的上下文中，如本文所指的不连续位点构建体包括表位序列，该表位序列包含可变残基以及来源于该残基的一种或多种可能序列。
本发明的疫苗可包含来自给定dicosite构建体的至少两种肽序列，其源于疫苗中所含有的至少两种表位，在疫苗中有总共至少4种肽序列(来自SEQ ID NO：1-248)。在本发明的一些实施方案中，人流感疫苗制剂可以包含至少4种人流感-A(INF-HA-1-V1-V4)和/或4种人流感-BHA的不连续位点构建体序列(INF-HB-1-V1-V4)。这可以包含来自SEQ ID NO：1-64的至少两种肽和/或来自SEQ ID NO：133-180的至少两种肽。
或者，这可以包含以下至少两个组中来自每一组的至少两种肽序列：SEQ ID NO：1-16；SEQ ID NO：17-32；SEQ ID NO：33-48；或者SEQ IDNO：49-64；和/或以下至少两个组中来自每一组的至少两种肽序列：SEQID NO：133-140；SEQ ID NO：141-156；SEQ ID NO：157-172；和/或SEQ ID NO：173-180。
马流感疫苗的实施方案可以包含源于4种马不连续位点构建体(INFE-HA-1-V1-V4；SEQ ID NO：185-248)的至少一种肽序列。在一些实施方案中，所述马疫苗制剂可以包含以下至少两个组中来自每一组的至少两种肽序列：SEQ ID NO：185-200；SEQ ID NO：201-216；SEQID NO：217-232；和/或SEQ ID NO：233-248。
禽流感疫苗的实施方案可以包含4种禽不连续位点构建体(INF-HA-2-V1-V4；SEQ ID NO：65-128)的一种或多种肽序列。在一些实施方案中，所述禽疫苗制剂可以包含以下至少两个组中来自每一组的至少两种肽序列：SEQ ID NO：65-80；SEQ ID NO：81-96；SEQ ID NO：97-112；和/或SEQ ID NO：113-128。
本领域普通技术人员应当认识到，根据需要可以添加或可以不添加其他序列。用于本发明疫苗制剂的肽序列根据不连续位点(表1-16)或者不连续表位(表17-18)构建体来分组。
表1-4列出A型流感(人HA-1)表位序列的不连续位点构建体。
表5-8列出A型流感(禽HA-2)表位序列的不连续位点构建体。
表9-12列出B型流感(人HB-1)表位序列的不连续位点构建体。
表13-16列出马流感(马HA-1)表位序列的不连续位点构建体。
在所述表格列出的每个不连续位点构建体中，可变残基在下文显示为构建体中相应的残基。
表1：INF-HA-1-V1的不连续位点构建体
YACKRGGKSSGSSYPVLNVSY(SEQ ID NO：1)
----H------------S-TM
| 肽名称 | 序列 | MW |
| INF-HA-1-V1/1 | YACKRGGKSSGSSYPVLNVSY (SEQ ID NO：1) | 2223.47 |
| INF-HA-1-V1/2 | YACKRGGKSSGSSYPVLNVSM (SEQ ID NO：2) | 2191.49 |
| INF-HA-1-V1/3 | YACKRGGKSSGSSYPVLNVTY (SEQ ID NO：3) | 2237.5 |
| INF-HA-1-V1/4 | YACKRGGKSSGSSYPVLNVTM (SEQ ID NO：4) | 2205.52 |
| INF-HA-1-V1/5 | YACKRGGKSSGSSYPVLSVSY (SEQ ID NO：5) | 2196.44 |
| INF-HA-1-V1/6 | YACKRGGKSSGSSYPVLSVSM (SEQ ID NO：6) | 2164.47 |
| INF-HA-1-V2/7 | YACKRGGKSSGSSYPVLSVTY (SEQ ID NO：7) | 2210.47 |
| INF-HA-1-V1/8 | YACKRGGKSSGSSYPVLSVTM (SEQ ID NO：8) | 2178.49 |
| INF-HA-1-V1/9 | YACKHGGKSSGSSYPVLNVSY (SEQ ID NO：9) | 2204.42 |
| INF-HA-1-V1/10 | YACKHGGKSSGSSYPVLNVSM (SEQ ID NO：10) | 2172.45 |
| INF-HA-1-V1/11 | YACKHGGKSSGSSYPVLNVTY (SEQ ID NO：11) | 2218.45 |
| INF-HA-1-V1/12 | YACKHGGKSSGSSYPVLNVTM (SEQ ID NO：12) | 2186.47 |
| INF-HA-1-V1/13 | YACKHGGKSSGSSYPVLSVSY (SEQ ID NO：13) | 2177.4 |
| INF-HA-1-V1/14 | YACKHGGKSSGSSYPVLSVSM (SEQ ID NO：14) | 2145.42 |
| INF-HA-1-V1/15 | YACKHGGKSSGSSYPVLSVTY (SEQ ID NO：15) | 2191.42 |
| INF-HA-1-V1/16 | YACKHGGKSSGSSYPVLSVTM (SEQ ID NO：16) | 2159.45 |
表2：INF-HA-1-V2的不连续位点构建体
KKGSVHHPSTITEQTSLYVNA (SEQ ID NO：17)
-S-------------T--QQ-
| 肽名称 | 序列 | MW |
| INF-HA-1-V2/1 | KKGSVHHPSTITEQTSLYVNA (SEQ ID NO：17) | 2297.53 |
| INF-HA-1-V2/2 | KKGSVHHPSTITEQTSLYVQA (SEQ ID NO：18) | 2311.55 |
| INF-HA-1-V2/3 | KKGSVHHPSTITEQTSLYQNA (SEQ ID NO：19) | 2326.53 |
| INF-HA-1-V2/4 | KKGSVHHPSTITEQTSLYQQA (SEQ ID NO：20) | 2340.55 |
| INF-HA-1-V2/5 | KKGSVHHPSTITEQTTLYVNA (SEQ ID NO：21) | 2311.55 |
| INF-HA-1-V2/6 | KKGSVHHPSTITEQTTLYVQA (SEQ ID NO：22) | 2325.58 |
| INF-HA-1-V2/7 | KKGSVHHPSTITEQTTLYQNA (SEQ ID NO：23) | 2340.55 |
| INF-HA-1-V2/8 | KKGSVHHPSTITEQTTLYQQA (SEQ ID NO：24) | 2354.58 |
| INF-HA-1-V2/9 | KSGSVHHPSTITEQTSLYVNA (SEQ ID NO：25) | 2256.43 |
| INF-HA-1-V2/10 | KSGSVHHPSTITEQTSLYVQA (SEQ ID NO：26) | 2270.46 |
| INF-HA-1-V2/11 | KSGSVHHPSTITEQTSLYQNA (SEQ ID NO：27) | 2285.43 |
| INF-HA-1-V2/12 | KSGSVHHPSTITEQTSLYQQA (SEQ ID NO：28) | 2299.46 |
| INF-HA-1-V2/13 | KSGSVHHPSTITEQTTLYVNA (SEQ ID NO：29) | 2270.46 |
| INF-HA-1-V2/14 | KSGSVHHPSTITEQTTLYVQA (SEQ ID NO：30) | 2284.48 |
| INF-HA-1-V2/15 | KSGSVHHPSTITEQTTLYQNA (SEQ ID NO：31) | 2299.46 |
| INF-HA-1-V2/16 | KSGSVHHPSTITEQTTLYQQA (SEQ ID NO：32) | 2313.48 |
表3：INF-HA-1-V3的不连续位点构建体
DVLFSVESPNNKNKDPIDTCD (SEQ ID NO：33)
------K-V-----ES-----
| 肽名称 | 序列 | MW |
| INF-HA-1-V3/1 | DVLFSVESPNNKNKDPIDTCD (SEQ ID NO：33) | 2350.52 |
| INF-HA-1-V3/2 | DVLFSVESPNNKNKDSIDTCD (SEQ ID NO：34) | 2340.48 |
| INF-HA-1-V3/3 | DVLFSVESPNNKNKEPIDTCD (SEQ ID NO：35) | 2364.55 |
| INF-HA-1-V3/4 | DVLFSVESPNNKNKESIDTCD (SEQ ID NO：36) | 2354.51 |
| INF-HA-1-V3/5 | DVLFSVESVNNKNKDPIDTCD (SEQ ID NO：37) | 2352.54 |
| INF-HA-1-V3/6 | DVLFSVESVNNKNKDSIDTCD (SEQ ID NO：38) | 2342.5 |
| INF-HA-1-V3/7 | DVLFSVESVNNKNKEPIDTCD (SEQ ID NO：39) | 2366.56 |
| INF-HA-1-V3/8 | DVLFSVESVNNKNKESIDTCD (SEQ ID NO：40) | 2356.52 |
| INF-HA-1-V3/9 | DVLFSVKSPNNKNKDPIDTCD (SEQ ID NO：41) | 2349.58 |
| INF-HA-1-V3/10 | DVLFSVKSPNNKNKDSIDTCD (SEQ ID NO：42) | 2339.54 |
| INF-HA-1-V3/11 | DVLFSVKSPNNKNKEPIDTCD (SEQ ID NO：43) | 2363.61 |
| INF-HA-1-V3/12 | DVLFSVKSPNNKNKESIDTCD (SEQ ID NO：44) | 2353.57 |
| INF-HA-1-V3/13 | DVLFSVKSVNNKNKDPIDTCD (SEQ ID NO：45) | 2351.6 |
| INF-HA-1-V3/14 | DVLFSVKSVNNKNKDSIDTCD (SEQ ID NO：46) | 2341.56 |
| INF-HA-1-V3/15 | DVLFSVKSVNNKNKEPIDTCD (SEQ ID NO：47) | 2365.62 |
| INF-HA-1-V3/16 | DVLFSVKSVNNKNKESIDTCD (SEQ ID NO：48) | 2355.58 |
表4：INF-HA-1-V4的不连续位点构建体
YVSVSTSRIASRPKVRGQSGR (SEQ ID NO：49)
--T--S---G---W-------
| 肽名称 | 序列 | MW |
| INF-HA-1-V4/1 | YVSVSTSRIASRPKVRGQSGR (SEQ ID NO：49) | 2291.57 |
| INF-HA-1-V4/2 | YVSVSTSRIASRPWVRGQSGR (SEQ ID NO：50) | 2349.61 |
| INF-HA-1-V4/3 | YVSVSTSRIGSRPKVRGQSGR (SEQ ID NO：51) | 2277.55 |
| INF-HA-1-V4/4 | YVSVSTSRIGSRPWVRGQSGR (SEQ ID NO：52) | 2335.58 |
| INF-HA-1-V4/5 | YVSVSSSRIASRPKVRGQSGR (SEQ ID NO：53) | 2277.55 |
| INF-HA-1-V4/6 | YVSVSSSRIASRPWVRGQSGR (SEQ ID NO：54) | 2335.58 |
| INF-HA-1-V4/7 | YVSVSSSRIGSRPKVRGQSGR (SEQ ID NO：55) | 2263.52 |
| INF-HA-1-V4/8 | YVSVSSSRIGSRPWVRGQSGR (SEQ ID NO：56) | 2321.56 |
| INF-HA-1-V4/9 | YVTVSTSRIASRPKVRGQSGR (SEQ ID NO：57) | 2305.6 |
| INF-HA-1-V4/10 | YVTVSTSRIASRPWVRGQSGR (SEQ ID NO：58) | 2363.64 |
| INF-HA-1-V4/11 | YVTVSTSRIGSRPKVRGQSGR (SEQ ID NO：59) | 2291.57 |
| INF-HA-1-V4/12 | YVTVSTSRIGSRPWVRGQSGR (SEQ ID NO：60) | 2349.61 |
| INF-HA-1-V4/13 | YVTVSSSRIASRPKVRGQSGR (SEQ ID NO：61) | 2291.57 |
| INF-HA-1-V4/14 | YVTVSSSRIASRPWVRGQSGR (SEQ ID NO：62) | 2349.61 |
| INF-HA-1-V4/15 | YVTVSSSRIGSRPKVRGQSGR (SEQ ID NO：63) | 2277.55 |
| INF-HA-1-V4/16 | YVTVSSSRIGSRPWVRGQSGR (SEQ ID NO：64) | 2335.58 |
表5：INF-HA-2-V1的A型禽流感不连续位点构建体
YACKRGGKSSGSSYPVLKVSY(SEQ ID NO：65)
----Y------------SRT-
| 肽名称 | 序列 | MW |
| INF-HA-2-V1/1 | YACKRGGKSSGSSYPVLKVSY (SEQ ID NO：65) | 2237.54 |
| INF-HA-2-V1/2 | YACKRGGKSSGSSYPVLKVTY (SEQ ID NO：66) | 2251.57 |
| INF-HA-2-V1/3 | YACKRGGKSSGSSYPVLKRSY (SEQ ID NO：67) | 2294.6 |
| INF-HA-2-V1/4 | YACKRGGKSSGSSYPVLKRTY (SEQ ID NO：68) | 2308.62 |
| INF-HA-2-V1/5 | YACKRGGKSSGSSYPVLSVSY (SEQ ID NO：69) | 2196.44 |
| INF-HA-2-V1/6 | YACKRGGKSSGSSYPVLSVTY (SEQ ID NO：70) | 2210.47 |
| INF-HA-2-V1/7 | YACKRGGKSSGSSYPVLSRSY (SEQ ID NO：71) | 2253.5 |
| INF-HA-2-V1/8 | YACKRGGKSSGSSYPVLSRTY (SEQ ID NO：72) | 2267.53 |
| INF-HA-2-V1/9 | YACKYGGKSSGSSYPVLKVSY (SEQ ID NO：73) | 2244.53 |
| INF-HA-2-V1/10 | YACKYGGKSSGSSYPVLKVTY (SEQ ID NO：74) | 2258.56 |
| INF-HA-2-V1/11 | YACKYGGKSSGSSYPVLKRSY (SEQ ID NO：75) | 2301.58 |
| INF-HA-2-V1/12 | YACKYGGKSSGSSYPVLKRTY (SEQ ID NO：76) | 2315.61 |
| INF-HA-2-V1/13 | YACKYGGKSSGSSYPVLSVSY (SEQ ID NO：77) | 2203.43 |
| INF-HA-2-V1/14 | YACKYGGKSSGSSYPVLSVTY (SEQ ID NO：78) | 2217.46 |
| INF-HA-2-V1/15 | YACKYGGKSSGSSYPVLSRSY (SEQ ID NO：79) | 2260.49 |
| INF-HA-2-V1/16 | YACKYGGKSSGSSYPVLSRTY (SEQ ID NO：80) | 2274.51 |
表6：INF-HA-2-V2的A型禽流感不连续位点构建体(不连续位点B2)
KKGSVHHPSTITEQTSLYVNA(SEQ ID NO：81)
-S-------------K--QQ-
| 肽名称 | 序列 | MW |
| INF-HA-2-V2/1 | KKGSVHHPSTITEQTSLYVNA (SEQ ID NO：81) | 2297.53 |
| INF-HA-2-V2/2 | KKGSVHHPSTITEQTSLYVQA (SEQ ID NO：82) | 2311.55 |
| INF-HA-2-V2/3 | KKGSVHHPSTITEQTSLYQNA (SEQ ID NO：83) | 2326.53 |
| INF-HA-2-V2/4 | KKGSVHHPSTITEQTSLYQQA (SEQ ID NO：84) | 2340.55 |
| INF-HA-2-V2/5 | KKGSVHHPSTITEQTKLYVNA (SEQ ID NO：85) | 2338.62 |
| INF-HA-2-V2/6 | KKGSVHHPSTITEQTKLYVQA (SEQ ID NO：86) | 2352.65 |
| INF-HA-2-V2/7 | KKGSVHHPSTITEQTKLYQNA (SEQ ID NO：87) | 2367.62 |
| INF-HA-2-V2/8 | KKGSVHHPSTITEQTKLYQQA (SEQ ID NO：88) | 2381.65 |
| INF-HA-2-V2/9 | KSGSVHHPSTITEQTSLYVNA (SEQ ID NO：89) | 2256.43 |
| INF-HA-2-V2/10 | KSGSVHHPSTITEQTSLYVQA (SEQ ID NO：90) | 2270.46 |
| INF-HA-2-V2/11 | KSGSVHHPSTITEQTSLYQNA (SEQ ID NO：91) | 2285.43 |
| INF-HA-2-V2/12 | KSGSVHHPSTITEQTSLYQQA (SEQ ID NO：92) | 2299.46 |
| INF-HA-2-V2/13 | KSGSVHHPSTITEQTKLYVNA (SEQ ID NO：93) | 2297.53 |
| INF-HA-2-V2/14 | KSGSVHHPSTITEQTKLYVQA (SEQ ID NO：94) | 2311.55 |
| INF-HA-2-V2/15 | KSGSVHHPSTITEQTKLYQNA (SEQ ID NO：95) | 2326.53 |
| INF-HA-2-V2/16 | KSGSVHHPSTITEQTKLYQQA (SEQ ID NO：96) | 2340.55 |
表7：INF-HA-2-V3的A型禽流感不连续位点构建体
DVLFSVESPNNKNKDPIDTCD(SEQ ID NO：97)
------P-N-----EE-----
| 肽名称 | 序列 | MW |
| INF-HA-2-V3/1 | DVLFSVESPNNKNKDPIDTCD (SEQ ID NO：97) | 2350.52 |
| INF-HA-2-V3/2 | DVLFSVESPNNKNKDEIDTCD (SEQ ID NO：98) | 2382.52 |
| INF-HA-2-V3/3 | DVLFSVESPNNKNKEPIDTCD (SEQ ID NO：99) | 2364.55 |
| INF-HA-2-V3/4 | DVLFSVESPNNKNKEEIDTCD (SEQ ID NO：100) | 2396.55 |
| INF-HA-2-V3/5 | DVLFSVESNNNKNKDPIDTCD (SEQ ID NO：101) | 2367.51 |
| INF-HA-2-V3/6 | DVLFSVESNNNKNKDEIDTCD (SEQ ID NO：102) | 2399.51 |
| INF-HA-2-V3/7 | DVLFSVESNNNKNKEPIDTCD (SEQ ID NO：103) | 2381.53 |
| INF-HA-2-V3/8 | DVLFSVESNNNKNKEEIDTCD (SEQ ID NO：104) | 2413.53 |
| INF-HA-2-V3/9 | DVLFSVPSPNNKNKDPIDTCD (SEQ ID NO：105) | 2318.52 |
| INF-HA-2-V3/10 | DVLFSVPSPNNKNKDEIDTCD (SEQ ID NO：106) | 2350.52 |
| INF-HA-2-V3/11 | DVLFSVPSPNNKNKEPIDTCD (SEQ ID NO：107) | 2332.55 |
| INF-HA-2-V3/12 | DVLFSVPSPNNKNKEEIDTCD (SEQ ID NO：108) | 2364.55 |
| INF-HA-2-V3/13 | DVLFSVPSNNNKNKDPIDTCD (SEQ ID NO：109) | 2335.51 |
| INF-HA-2-V3/14 | DVLFSVPSNNNKNKDEIDTCD (SEQ ID NO：110) | 2367.51 |
| INF-HA-2-V3/15 | DVLFSVPSNNNKNKEPIDTCD (SEQ ID NO：111) | 2349.54 |
| INF-HA-2-V3/16 | DVLFSVPSNNNKNKEEIDTCD (SEQ ID NO：112) | 2381.53 |
表8：INF-HA-2-V4的A型禽流感不连续位点构建体
YVSVSTSRIASRPKVRGQSGR(SEQ ID NO：113)
--T--S---G---W-------
| 肽名称 | 序列 | MW |
| INF-HA-2-V4/1 | YVSVSTSRIASRPKVRGQSGR (SEQ ID NO：113) | 2291.57 |
| INF-HA-2-V4/2 | YVSVSTSRIASRPWVRGQSGR (SEQ ID NO：114) | 2349.61 |
| INF-HA-2-V4/3 | YVSVSTSRIGSRPKVRGQSGR (SEQ ID NO：115) | 2277.55 |
| INF-HA-2-V4/4 | YVSVSTSRIGSRPWVRGQSGR (SEQ ID NO：116) | 2335.58 |
| INF-HA-2-V4/5 | YVSVSSSRIASRPKVRGQSGR (SEQ ID NO：117) | 2277.55 |
| INF-HA-2-V4/6 | YVSVSSSRIASRPWVRGQSGR (SEQ ID NO：118) | 2335.58 |
| INF-HA-2-V4/7 | YVSVSSSRIGSRPKVRGQSGR (SEQ ID NO：119) | 2263.52 |
| INF-HA-2-V4/8 | YVSVSSSRIGSRPWVRGQSGR (SEQ ID NO：120) | 2321.56 |
| INF-HA-2-V4/9 | YVTVSTSRIASRPKVRGQSGR (SEQ ID NO：121) | 2305.6 |
| INF-HA-2-V4/10 | YVTVSTSRIASRPWVRGQSGR (SEQ ID NO：122) | 2363.64 |
| INF-HA-2-V4/11 | YVTVSTSRIGSRPKVRGQSGR (SEQ ID NO：123) | 2291.57 |
| INF-HA-2-V4/12 | YVTVSTSRIGSRPWVRGQSGR (SEQ ID NO：124) | 2349.61 |
| INF-HA-2-V4/13 | YVTVSSSRIASRPKVRGQSGR (SEQ ID NO：125) | 2291.57 |
| INF-HA-2-V4/14 | YVTVSSSRIASRPWVRGQSGR (SEQ ID NO：126) | 2349.61 |
| INF-HA-2-V4/15 | YVTVSSSRIGSRPKVRGQSGR (SEQ ID NO：127) | 2277.55 |
| INF-HA-2-V4/16 | YVTVSSSRIGSRPWVRGQSGR (SEQ ID NO：128) | 2335.58 |
表9：INF-HB-1-V1的B型人流感不连续位点构建体
GSCPNATNRNGDNNKTAINPLTVEVPY(SEQ ID NO：133)
-------S-S-------T---------
| 肽名称 | 序列 | MW |
| INF-HB-1-V1/1 | GSCPNATNRNGDNNKTAINPLTVEVPY (SEQ ID NO：133) | 2860.08 |
| INF-HB-1-V1/2 | GSCPNATNRNGDNNKTATNPLTVEVPY (SEQ ID NO：134) | 2848.03 |
| INF-HB-1-V1/3 | GSCPNATNRSGDNNKTAINPLTVEVPY (SEQ ID NO：135) | 2833.06 |
| INF-HB-1-V1/4 | GSCPNATNRSGDNNKTATNPLTVEVPY (SEQ ID NO：136) | 2821 |
| INF-HB-1-V1/5 | GSCPNATSRNGDNNKTAINPLTVEVPY (SEQ ID NO：137) | 2833.06 |
| INF-HB-1-V1/6 | GSCPNATSRNGDNNKTATNPLTVEVPY (SEQ ID NO：138) | 2821 |
| INF-HB-1-V1/7 | GSCPNATSRSGDNNKTAINPLTVEVPY (SEQ ID NO：139) | 2806.03 |
| INF-HB-1-V1/8 | GSCPNATSRSGDNNKTATNPLTVEVPY (SEQ ID NO：140) | 2793.98 |
表10：INF-HB-1-V2的B型人流感不连续位点构建体
PKDNFHSDNKTQMERLYGDSN(SEQ ID NO：141)
RN-----------KN------
| 肽名称 | 序列 | MW |
| INF-HB-1-V2/1 | PKDNFHSDNKTQMERLYGDSN (SEQ ID NO：141) | 2496.63 |
| INF-HB-1-V2/2 | PKDNFHSDNKTQMENLYGDSN (SEQ ID NO：142) | 2454.55 |
| INF-HB-1-V2/3 | PKDNFHSDNKTQMKRLYGDSN (SEQ ID NO：143) | 2495.69 |
| INF-HB-1-V2/4 | PKDNFHSDNKTQMKNLYGDSN (SEQ ID NO：144) | 2453.61 |
| INF-HB-1-V2/5 | PNDNFHSDNKTQMERLYGDSN (SEQ ID NO：145) | 2482.56 |
| INF-HB-1-V2/6 | PNDNFHSDNKTQMENLYGDSN (SEQ ID NO：146) | 2440.48 |
| INF-HB-1-V2/7 | PNDNFHSDNKTQMKRLYGDSN (SEQ ID NO：147) | 2481.62 |
| INF-HB-1-V2/8 | PNDNFHSDNKTQMKNLYGDSN (SEQ ID NO：148) | 2439.54 |
| INF-HB-1-V2/9 | RKDNFHSDNKTQMERLYGDSN (SEQ ID NO：149) | 2555.7 |
| INF-HB-1-V2/10 | RKDNFHSDNKTQMENLYGDSN (SEQ ID NO：150) | 2513.62 |
| INF-HB-1-V2/11 | RKDNFHSDNKTQMKRLYGDSN (SEQ ID NO：151) | 2554.76 |
| INF-HB-1-V2/12 | RKDNFHSDNKTQMKNLYGDSN (SEQ ID NO：152) | 2512.68 |
| INF-HB-1-V2/13 | RNDNFHSDNKTQMERLYGDSN (SEQ ID NO：153) | 2541.63 |
| INF-HB-1-V2/14 | RNDNFHSDNKTQMENLYGDSN (SEQ ID NO：154) | 2499.55 |
| INF-HB-1-V2/15 | RNDNFHSDNKTQMKRLYGDSN (SEQ ID NO：155) | 2540.69 |
| INF-HB-1-V2/16 | RNDNFHSDNKTQMKNLYGDSN (SEQ ID NO：156) | 2498.61 |
表11：INF-HB-1-V3的B型人流感不连续位点构建体
RGKLCPNCFNCTDIICSEGEDLPLIGE(SEQ ID NO：157)
--------L----L--TK---------
| 肽名称 | 序列 | MW |
| INF-HB-1-V3/1 | RGKLCPNCFNCTDIICSEGEDLPLIGE (SEQ ID NO：157) | 2940 |
| INF-HB-1-V3/2 | RGKLCPNCFNCTDIICSKGEDLPLIGE (SEQ ID NO：158) | 2939 |
| INF-HB-1-V3/3 | RGKLCPNCFNCTDIICTEGEDLPLIGE (SEQ ID NO：159) | 2954 |
| INF-HB-1-V3/4 | RGKLCPNCFNCTDIICTKGEDLPLIGE (SEQ ID NO：160) | 2953 |
| INF-HB-1-V3/5 | RGKLCPNCFNCTDLICSEGEDLPLIGE (SEQ ID NO：161) | 2940 |
| INF-HB-1-V3/6 | RGKLCPNCFNCTDLICSKGEDLPLIGE (SEQ ID NO：162) | 2939 |
| INF-HB-1-V3/7 | RGKLCPNCFNCTDLICTEGEDLPLIGE (SEQ ID NO：163) | 2954 |
| INF-HB-1-V3/8 | RGKLCPNCFNCTDLICTKGEDLPLIGE (SEQ ID NO：164) | 2953 |
| INF-HB-1-V3/9 | RGKLCPNCLNCTDIICSEGEDLPLIGE (SEQ ID NO：165) | 2906 |
| INF-HB-1-V3/10 | RGKLCPNCLNCTDIICSKGEDLPLIGE (SEQ ID NO：166) | 2905 |
| INF-HB-1-V3/11 | RGKLCPNCLNCTDIICTEGEDLPLIGE (SEQ ID NO：167) | 2920 |
| INF-HB-1-V3/12 | RGKLCPNCLNCTDIICTKGEDLPLIGE (SEQ ID NO：168) | 2919 |
| INF-HB-1-V3/13 | RGKLCPNCLNCTDLICSEGEDLPLIGE (SEQ ID NO：169) | 2906 |
| INF-HB-1-V3/14 | RGKLCPNCLNCTDLICSKGEDLPLIGE (SEQ ID NO：170) | 2905 |
| INF-HB-1-V3/15 | RGKLCPNCLNCTDLICTEGEDLPLIGE (SEQ ID NO：171) | 2920 |
| INF-HB-1-V3/16 | RGKLCPNCLNCTDLICTKGEDLPLIGE (SEQ ID NO：172) | 2919 |
表12：INF-HB-1-V4的B型人流感不连续位点构建体
KFTSSANGIGGFPNQTEDEGLKQSGR (SEQ ID NO：173)
-------------D----G--P----
| 肽名称 | 序列 | MW |
| INF-HB-1-V4/1 | KFTSSANGIGGFPNQTEDEGLKQSGR (SEQ ID NO：173) | 2725.88 |
| INF-HB-1-V4/2 | KFTSSANGIGGFPNQTEDEGLPQSGR (SEQ ID NO：174) | 2694.82 |
| INF-HB-1-V4/3 | KFTSSANGIGGFPNQTEDGGLKQSGR (SEQ ID NO：175) | 2653.82 |
| INF-HB-1-V4/4 | KFTSSANGIGGFPNQTEDGGLPQSGR (SEQ ID NO：176) | 2622.76 |
| INF-HB-1-V4/5 | KFTSSANGIGGFPDQTEDEGLKQSGR (SEQ ID NO：177) | 2726.87 |
| INF-HB-1-V4/6 | KFTSSANGIGGFPDQTEDEGLPQSGR (SEQ ID NO：178) | 2695.81 |
| INF-HB-1-V4/7 | KFTSSANGIGGFPDQTEDGGLKQSGR (SEQ ID NO：179) | 2654.8 |
| INF-HB-1-V4/8 | KFTSSANGIGGFPDQTEDGGLPQSGR (SEQ ID NO：180) | 2623.75 |
表13：INFE-HA-1-V1的马流感不连续位点构建体
SACKRRSASSNAAFPQMNKTM(SEQ ID NO：185)
-------------Y---T-SY
| 肽名称 | 序列 | MW |
| INFE-HA-1-V1/1 | SACKRRSASSNAAFPQMNKTM (SEQ ID NO：185) | 2286.62 |
| INFE-HA-1-V1/2 | SACKRRSASSNAAFPQMNKTY (SEQ ID NO：186) | 2318.6 |
| INFE-HA-1-V1/3 | SACKRRSASSNAAFPQMNKSM (SEQ ID NO：187) | 2272.6 |
| INFE-HA-1-V1/4 | SACKRRSASSNAAFPQMNKSY (SEQ ID NO：188) | 2304.57 |
| INFE-HA-1-V1/5 | SACKRRSASSNAAFPQMTKTM (SEQ ID NO：189) | 2273.62 |
| INFE-HA-1-V1/6 | SACKRRSASSNAAFPQMTKTY (SEQ ID NO：190) | 2305.6 |
| INFE-HA-1-V1/7 | SACKRRSASSNAAFPQMTKSM (SEQ ID NO：191) | 2259.6 |
| INFE-HA-1-V1/8 | SACKRRSASSNAAFPQMTKSY (SEQ ID NO：192) | 2291.57 |
| INFE-HA-1-V1/9 | SACKRRSASSNAAYPQMNKTM (SEQ ID NO：193) | 2302.62 |
| INFE-HA-1-V1/10 | SACKRRSASSNAAYPQMNKTY (SEQ ID NO：194) | 2334.6 |
| INFE-HA-1-V1/11 | SACKRRSASSNAAYPQMNKSM (SEQ ID NO：195) | 2288.6 |
| INFE-HA-1-V1/12 | SACKRRSASSNAAYPQMNKSY (SEQ ID NO：196) | 2320.57 |
| INFE-HA-1-V1/13 | SACKRRSASSNAAYPQMTKTM (SEQ ID NO：197) | 2289.62 |
| INFE-HA-1-V1/14 | SACKRRSASSNAAYPQMTKTY (SEQ ID NO：198) | 2321.6 |
| INFE-HA-1-V1/15 | SACKRRSASSNAAYPQMTKSM (SEQ ID NO：199) | 2275.6 |
| INFE-HA-1-V1/16 | SACKRRSASSNAAYPQMTKSY (SEQ ID NO：200) | 2307.57 |
表14：INFE-HA-1-V2的马流感不连续位点构建体
SSTDNAIHHSSSNQEQTKLYVQE(SEQ ID NO：201)
-N-------P---T-------S-
| 肽名称 | 序列 | MW |
| INFE-HA-1-V2/1 | SSTDNAIHHSSSNQEQTKLYVQE (SEQ ID NO：201) | 2603.67 |
| INFE-HA-1-V2/2 | SSTDNAIHHSSSNQEQTKLYVSE (SEQ ID NO：202) | 2562.62 |
| INFE-HA-1-V2/3 | SSTDNAIHHSSSNTEQTKLYVQE (SEQ ID NO：203) | 2576.64 |
| INFE-HA-1-V2/4 | SSTDNAIHHSSSNTEQTKLYVSE (SEQ ID NO：204) | 2535.59 |
| INFE-HA-1-V2/5 | SSTDNAIHHPSSNQEQTKLYVQE (SEQ ID NO：205) | 2613.71 |
| INFE-HA-1-V2/6 | SSTDNAIHHPSSNQEQTKLYVSE (SEQ ID NO：206) | 2572.66 |
| INFE-HA-1-V2/7 | SSTDNAIHHPSSNTEQTKLYVQE (SEQ ID NO：207) | 2586.68 |
| INFE-HA-1-V2/8 | SSTDNAIHHPSSNTEQTKLYVSE (SEQ ID NO：208) | 2545.63 |
| INFE-HA-1-V2/9 | SNTDNAIHHSSSNQEQTKLYVQE (SEQ ID NO：209) | 2630.69 |
| INFE-HA-1-V2/10 | SNTDNAIHHSSSNQEQTKLYVSE (SEQ ID NO：210) | 2589.64 |
| INFE-HA-1-V2/11 | SNTDNAIHHSSSNTEQTKLYVQE (SEQ ID NO：211) | 2603.67 |
| INFE-HA-1-V2/12 | SNTDNAIHHSSSNTEQTKLYVSE (SEQ ID NO：212) | 2562.62 |
| INFE-HA-1-V2/13 | SNTDNAIHHPSSNQEQTKLYVQE (SEQ ID NO：213) | 2640.73 |
| INFE-HA-1-V2/14 | SNTDNAIHHPSSNQEQTKLYVSE (SEQ ID NO：214) | 2599.68 |
| INFE-HA-1-V2/15 | SNTDNAIHHPSSNTEQTKLYVQE (SEQ ID NO：215) | 2613.71 |
| INFE-HA-1-V2/16 | SNTDNAIHHPSSNTEQTKLYVSE (SEQ ID NO：216) | 2572.66 |
表15：INFE-HA-1-V3的马流感不连续位点构建体
DQFQEESPNNRNFDPDDNCE(SEQ ID NO：217)
---L-F---T---P------
| 肽名称 | 序列 | MW |
| INFE-HA-1-V3/1 | DQFQEESPNNRNFDPDDNCE (SEQ ID NO：217) | 2413.36 |
| INFE-HA-1-V3/2 | DQFQEESPNNRNFPPDDNCE (SEQ ID NO：218) | 2395.39 |
| INFE-HA-1-V3/3 | DQFQEESPNTRNFDPDDNCE (SEQ ID NO：219) | 2400.36 |
| INFE-HA-1-V3/4 | DQFQEESPNTRNFPPDDNCE (SEQ ID NO：220) | 2382.39 |
| INFE-HA-1-V3/5 | DQFQEFSPNNRNFDPDDNCE (SEQ ID NO：221) | 2431.42 |
| INFE-HA-1-V3/6 | DQFQEFSPNNRNFPPDDNCE (SEQ ID NO：222) | 2413.45 |
| INFE-HA-1-V3/7 | DQFQEFSPNTRNFDPDDNCE (SEQ ID NO：223) | 2418.42 |
| INFE-HA-1-V3/8 | DQFQEFSPNTRNFPPDDNCE (SEQ ID NO：224) | 2400.45 |
| INFE-HA-1-V3/9 | DQFLEESPNNRNFDPDDNCE (SEQ ID NO：225) | 2398.39 |
| INFE-HA-1-V3/10 | DQFLEESPNNRNFPPDDNCE (SEQ ID NO：226) | 2380.42 |
| INFE-HA-1-V3/11 | DQFLEESPNTRNFDPDDNCE (SEQ ID NO：227) | 2385.39 |
| INFE-HA-1-V3/12 | DQFLEESPNTRNFPPDDNCE (SEQ ID NO：228) | 2367.42 |
| INFE-HA-1-V3/13 | DQFLEFSPNNRNFDPDDNCE (SEQ ID NO：229) | 2416.45 |
| INFE-HA-1-V3/14 | DQFLEFSPNNRNFPPDDNCE (SEQ ID NO：230) | 2398.48 |
| INFE-HA-1-V3/15 | DQFLEFSPNTRNFDPDDNCE (SEQ ID NO：231) | 2403.45 |
| INFE-HA-1-V3/16 | DQFLEFSPNTRNFPPDDNCE (SEQ ID NO：232) | 2385.48 |
表16：INFE-HA-1-V4的马流感不连续位点构建体
RITVSTSRPGARPWVRGQSGR(SEQ ID NO：233)
-----S----S--Q-N-----
| 肽名称 | 序列 | MW |
| INFE-HA-1-V4/1 | RITVSTSRPGARPWVRGQSGR (SEQ ID NO：233) | 2324.61 |
| INFE-HA-1-V4/2 | RITVSTSRPGARPWVNGQSGR (SEQ ID NO：234) | 2282.52 |
| INFE-HA-1-V4/3 | RITVSTSRPGARPQVRGQSGR (SEQ ID NO：235) | 2266.53 |
| INFE-HA-1-V4/4 | RITVSTSRPGARPQVNGQSGR (SEQ ID NO：236) | 2224.44 |
| INFE-HA-1-V4/5 | RITVSTSRPGSRPWVRGQSGR (SEQ ID NO：237) | 2340.61 |
| INFE-HA-1-V4/6 | RITVSTSRPGSRPWVNGQSGR (SEQ ID NO：238) | 2298.52 |
| INFE-HA-1-V4/7 | RITVSTSRPGSRPQVRGQSGR (SEQ ID NO：239) | 2282.52 |
| INFE-HA-1-V4/8 | RITVSTSRPGSRPQVNGQSGR (SEQ ID NO：240) | 2240.44 |
| INFE-HA-1-V4/9 | RITVSSSRPGARPWVRGQSGR (SEQ ID NO：241) | 2310.58 |
| INFE-HA-1-V4/10 | RITVSSSRPGARPWVNGQSGR (SEQ ID NO：242) | 2268.5 |
| INFE-HA-1-V4/11 | RITVSSSRPGARPQVRGQSGR (SEQ ID NO：243) | 2252.5 |
| INFE-HA-1-V4/12 | RITVSSSRPGARPQVNGQSGR (SEQ ID NO：244) | 2210.42 |
| INFE-HA-1-V4/13 | RITVSSSRPGSRPWVRGQSGR (SEQ ID NO：245) | 2326.58 |
| INFE-HA-1-V4/14 | RITVSSSRPGSRPWVNGQSGR (SEQ ID NO：246) | 2284.5 |
| INFE-HA-1-V4/15 | RITVSSSRPGSRPQVRGQSGR (SEQ ID NO：247) | 2268.5 |
| INFE-HA-1-V4/16 | RITVSSSRPGSRPQVNGQSGR (SEQ ID NO：248) | 222 6.42 |
表17和18列举了不连续表位构建体(分别为A型和B型流感)，可用于制备本发明的疫苗。
表17：A型流感的不连续表位构建体
| 肽名称 | 序列 | MW |
| INF-HA-1-M1 | YACKRGGKSSGSSYPVLNVSY (SEQ ID NO：129) | 2223.47 |
| INF-HA-1-M2 | KKGSVHHPSTITEQTSLYVNA (SEQ ID NO：130) | 2297.53 |
| INF-HA-1-M3 | DVLFSVESPNNKNKDPIDTCD (SEQ ID NO：131) | 2350.52 |
| INF-HA-1-M4 | YVSVSTSRIASRPKVRGQSGR (SEQ ID NO：132) | 2291.57 |
表18：B型流感的不连续表位构建体
| 肽名称 | 序列 | MW |
| INF-HB-1-M1 | GSCPNVANGNGDNNKTAINPVTVEVPY (SEQ ID NO：181) | 2744.95 |
| INF-HB-1-M2 | PKDNFHSDDKTQMERLYGDSN (SEQ ID NO：182) | 2497.61 |
| INF-HB-1-M3 | RGKLCPNCFNCTDIICSEGEDLPLIGE (SEQ ID NO：183) | 2940.36 |
| INF-HB-1-M4 | KFTSSANGIGGFPNQTEDEGLKQSGR (SEQ ID NO：184) | 2725.88 |
肽合成
应用标准固相肽化学方法合成肽。应用9-芴甲氧羰基(Fmoc)化学方法，在PioneerTM自动肽合成仪上应用固相肽合成(SPPS)来合成所述肽，其中如所述使用预装的由Fmoc保护的NovaSynTM TGT树脂(NovaBiochem)。期望在给定位置存在变异性时，将两种氨基酸的混合物置于该位置上。在合成期间，在任何位置期望存在变异性时即重复进行该操作。在合成期间，用二甲基甲酰胺(DMF)中2-(1H-苯并三唑-1-基)-1，1，3，3-四甲基脲四氟硼酸酯(TBTU)和N-羟基苯并三唑(HOBt)的1 M溶液和DMF中二异丙基乙胺(DIPEA)的1M溶液来偶联氨基酸，而用DMF中20％的哌啶来去封闭氨基酸。
使偶联在室温下进行1小时。在最后一个氨基酸被偶联后，从合成仪中取出树脂，并在烧结玻璃漏斗中用DMF、用2-丙醇和用二氯亚甲基(dichloromethylene，DCM)清洗几次，并在高度真空下干燥。通过加入含有TFA/水/苯酚/苯甲硫醚/EDT/TIS[82∶5∶5∶5∶2∶1]的溶液来对肽混合物进行切割和去保护。树脂在室温下孵育4小时。随后在减压条件下，将切割混合物过滤至含有10倍体积冷醚的瓶中。树脂也用TFA清洗两次至同样的醚溶液中。
在冰箱中孵育30分钟以进一步促进沉淀之后，样品以1,000×g离心5分钟，并去除醚。该萃取过程重复3次。在最后一次醚萃取之后，在氮气中蒸发残余的有机溶剂，将肽混合物重新溶解在水中，并使用高效液相层析(HPLC)进行纯化。应用旋转蒸发器去除过剩的溶剂，最后经冻干成为干粉。对所有的不连续表位构建体进行质谱(MS)和氨基酸分析，以确保区具有正确的肽内含物。
图1-4展示了来自本发明不连续位点构建体的示例性HPLC数据。每条HPLC曲线对应于特定的不连续位点构建体制剂，其含有各个不连续位点构建体中的肽混合物。图1A-1D分别对应于不连续位点构建体INFE-HA-1-V1至V4(SEQ ID NO：185-248)。图2A-2D分别对应于不连续位点构建体INF-HA-1-V1至V4(SEQ ID NO：1-64)。图3A-3D分别对应于不连续位点构建体INF-HA-2-V1至V4(SEQ ID NO：65-128)。图4A-4D分别对应于不连续位点构建体INF-HB-1-V1至V4(SEQ IDNO：133-180)。
图5-8展示了来自本发明不连续位点构建体的MS数据。与HPLC曲线一样，每条MS曲线对应于特定的不连续位点构建体制剂，其含有各个不连续位点构建体中的肽混合物。图5A-5D分别对应于不连续位点构建体INFE-HA-1-V1至V4(SEQ ID NO：185-248)。图6A-6D分别对应于不连续位点构建体INF-HA-1-V1至V4(SEQ ID NO：1-64)。图7A-7D分别对应于不连续位点构建体INF-HA-2-V1至V4(SEQ ID NO：65-128)。图8A-8D分别对应于不连续位点构建体INF-HB-1-V1至V4(SEQ ID NO：133-180)。
实施例
根据本发明制备了两种示例性疫苗INF-01P(INF-HA-1-V1-V4)和INFE-01P(INFE-HA-V1-V4)。基于包含源于A型流感表位并如表1-4(SEQ ID NO：1-64)和表13-16(SEQ ID NO：185-248)中所列的肽序列的制剂来制备疫苗，总结于下文表19和20。应用鼠模型测试所述疫苗：a)以确定添加佐剂是否增强针对攻击的免疫性；b)以在鼠模型中与商品疫苗相比测定由候选疫苗诱导的体液应答；和c)以评估所述疫苗针对使用不同流感病毒株的流感攻击所引发的保护范围。
疫苗接种方案：在尾巴的根部对小鼠组进行皮下接种；接受商品疫苗的小鼠进行肌内免疫(如推荐)。相似地以三周的间隔对小鼠加强免疫两次。在最后一次免疫之后两周，用致死剂量的H3N2攻击小鼠。在攻击后，每日监测小鼠的体重和感染体征。
佐剂：以下佐剂与疫苗组合使用以加强免疫应答：Ribi(Cedarlane，1∶1的Ribi：疫苗)、明矾(Sigma，等体积的500ng/ml和疫苗)和Montanide(Seppic，1∶1比例的montanide：疫苗)。在本实施例中，应用明矾作为佐剂，然而可以应用任何适合的佐剂。
实施例1
在本实施例中，用INF-01P疫苗加明矾、Ribi或Montanide，或者用商品疫苗(2004-2005季)免疫B6小鼠。在病毒攻击之前一天获取接种过疫苗的小鼠的血清。用致病性A/HK/1/68-MA20c病毒攻击小鼠，并在随后实施三周的后续攻击。
INF-01P疫苗是基于如表19中所示的4种人流感序列不连续位点构建体制剂。
表19：INF-01P流感疫苗制剂
| INF-HA-1-V1(SEQ ID NO：1)YACKRGGKSSGSSYPVLNVSY(SEQ ID NO：1-16)---H------------S-TM |
| INF-HA-1-V2(SEQ ID NO：17)KKGSVHHPSTITEQTSLYVNA(SEQ ID NO：17-32)-S-------------T--QQ- |
| INF-HA-1-V3(SEQ ID NO：33)DVLFSVESPNNKNKDPIDTCD(SEQ ID NO：33-48)------K-V-----ES----- |
| INF-HA-1-V4(SEQ ID NO：49)YVSVSTSRIASRPKVRGQSGR(SEQ ID NO：49-64)--T--S---G---W-------- |
图9显示由INF-01P疫苗接种所诱导的体液免疫，通过HAI效价来衡量。如本实施例所示，与用INF-01P加Ribi或者INF-01P加Montanide免疫的小鼠相比，以及与当前的流感疫苗相比，用INF-01P加明矾的疫苗免疫的小鼠具有提高的体液免疫。
图10显示经INF-01P疫苗接种的小鼠针对H3N2攻击的存活曲线。在此实施例中，与INF-01P加Ribi或者INF-01P加Montanide相比，用INF-01P加明矾的疫苗免疫的小鼠受到更好的保护并且针对攻击有更好的存活率。
图11展示了用INF-01P免疫的小鼠经攻击后的体重减轻百分比。在本实施例所中，用INF-01P加明矾免疫的小鼠与用INF-01P加Ribi或者INF-01P加Montanide免疫的小鼠相比，前者在抗体重减轻方面受到更多的保护。
实施例2
用INFE-01P(马流感)疫苗加明矾或者商品疫苗(2004-2005季)免疫B6小鼠。测试小鼠血清针对几种流感毒株(H3N2 A/香港/1/68g、H1 N1 A/FM/1/47、H5N1 A/香港/213/2003、B/Mass/3/66和H1 N1 A/NewCaledonia/20/1999)的HAI活性。在第一次疫苗接种后获取血清。
INFE-01P疫苗是基于如表20所示的4种马流感序列不连续位点构建体制剂：
表20：INFE-01P马流感疫苗制剂
| INFE-HA-1-V1(SEQ ID NO：185)SACKRRSASSNAAFPQMNKTM(SEQ ID NO：185-200)-------------Y---T-SY |
| INFE-HA-1-V2(SEQ ID NO：201)SSTDNAIHHSSSNQEQTKLYVQE(SEQ ID NO：201-216)-N-------P---T-------S- |
| INFE-HA-1-V3(SEQ ID NO：217)DQFQEESPNNRNFDPDDNCE(SEQ ID NO：217-232)---L-F---T---P------ |
| INFE-HA-1-V4(SEQ ID NO：233)RITVSTSRPGARPWVRGQSGR(SEQ ID NO：233-248)-----S----S--Q-N----- |
图12展示了用INFE-01P免疫的小鼠中的体液免疫，通过HAI效价来衡量。如图示，与用商品疫苗或者仅用佐剂(对照)接种的小鼠相比，在用此示例性马疫苗制剂免疫的小鼠中诱导出了针对几种流感病毒毒株的体液免疫。
实施例3
血细胞凝集反应(HAI)测定
在小鼠中评价个体或者组合的不连续表位构建体的免疫原性。用四种不连续表位构建体一起免疫的小鼠发育出能够抑制病毒的血细胞凝集反应活性的抗体。基于流感的不连续表位构建体显示出成功地模拟了非连续表位，因为引发了抑制由流感病毒引起的血细胞凝集的抗体。
应用标准的HAI测定来测量对针对HA的功能性相关抗体的诱导。应用多种不同的流感毒株测试候选疫苗物诱导的HAI效价，从而确定该疫苗制剂诱导的免疫范围。
图13展示了鼠疫苗研究中进行的血细胞凝集测定的结果。每组疫苗接受不同的疫苗制剂或者磷酸缓冲盐水(阴性对照)。与病毒(H3亚型流感)一起孵育时，血将发生血细胞凝集(云雾状)；当凝集被保护或抑制时，RBC保留在沉淀中(暗圆)。
这些结果显示了VBI候选疫苗显示的血细胞凝集抑制强度(与已许可的商品流感疫苗相比)。注意每种VBI候选疫苗与佐剂的组合均显示与商品疫苗相同或更高的血细胞凝集抑制(HI)(可高至1/40-1/80)。含明矾佐剂的disocosite构建体免疫原(第12行)甚至在最高为1/320的稀释度时也显示可检测的HI。
表21：不同处理的倒数效价
| 免疫原 | 效价倒数 |
| 未接种疫苗的对照商品疫苗不连续位点免疫原+Montanide不连续表位免疫原+Ribi不连续位点免疫原+明矾 | 108080160320 |
图14显示流感疫苗ELISA测试的结果。这是基于表22中所示数据。
表22：流感疫苗ELISA测试结果
| 1/50 | 1/100 | 1/300 | 1/900 | 1/2700 | 1/8100 | |
| G1G2G3G4G5G6 | 1.5381.9651.5591.4271.2581.298 | 1.2951.3191.3211.241.130.926 | 0.9210.8180.7710.8540.6670.623 | 0.6650.5950.5830.5640.4560.45 | 0.3580.4550.3670.4460.3350.329 | 0.1340.1450.1210.1490.1410.13 |
| G7G8G9G10G11G12G13 | 1.4161.41.6861.212.822.9590.694 | 0.9121.1771.3550.952.292.9440.547 | 0.5710.7530.7950.6131.4672.6990.343 | 0.4210.4530.4770.4750.772.1740.289 | 0.2510.2710.2910.2960.4551.1460.253 | 0.1350.160.1930.1760.2360.5590.16 |
G1＝不连续位点构建体IFN-1(SEQ ID NO：1-16)+Ribi；G2＝不连续位点构建体IFN-2(SEQ ID NO：17-32)+Ribi；G3＝不连续位点构建体IFN-3(SEQ ID NO：33-48)+Ribi；G4＝不连续位点构建体IFN-4(SEQ ID NO：49-64)+Ribi；G5＝不连续表位构建体1(SEQ ID NO：129)+Ribi；G6＝不连续表位构建体2(SEQ ID NO：130)+Ribi；G7＝不连续表位构建体3(SEQID NO：131)+Ribi；G8＝不连续表位构建体4(SEQ ID NO：132)+Ribi；G9＝对照(仅有Ribi)；G10＝不连续位点构建体IFN-1-4+Ribi；G11＝不连续表位构建体1-4+Ribi；G12＝不连续位点构建体IFN-1-4+Montanide；和G13＝商品疫苗。
综上所述，这些数据提示了从根本上新颖的开发流感疫苗的方法，这可引起比当前疫苗更快的疫苗生产和更广泛的保护。该方法对开发流行性流感疫苗可能非常有价值。
本发明上述的实施方案旨在仅用于举例。本领域的技术人员可以对具体的实施方案作出改变、改良和变化，而不背离本发明的范围，本发明的范围仅由所附的权利要求进行限定。
所有参考文献均通过参考并入本文。
序列表
<110>变异生物技术公司
<120>基于肽的流感疫苗制剂
<130>PAT 2849w-90
<160>248
<170>PatentIn version 3.0
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<400>15
Tyr Ala Cys Lys His Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Val Thr Tyr
20
<210>16
<211>21
<212>PRT
<213>流感嗜血菌
<400>16
Tyr Ala Cys Lys His Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Val Thr Met
20
<210>17
<211>21
<212>PRT
<213>流感嗜血菌
<400>17
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>18
<211>21
<212>PRT
<213>流感嗜血菌
<400>18
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>19
<211>21
<212>PRT
<213>流感嗜血菌
<400>19
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>20
<211>21
<212>PRT
<213>流感嗜血菌
<400>20
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>21
<211>21
<212>PRT
<213>流感嗜血菌
<400>21
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>22
<211>21
<212>PRT
<213>流感嗜血菌
<400>22
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>23
<211>21
<212>PRT
<213>流感嗜血菌
<400>23
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>24
<211>21
<212>PRT
<213>流感嗜血菌
<400>24
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>25
<211>21
<212>PRT
<213>流感嗜血菌
<400>25
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>26
<211>21
<212>PRT
<213>流感嗜血菌
<400>26
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>27
<211>21
<212>PRT
<213>流感嗜血菌
<400>27
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>28
<211>21
<212>PRT
<213>流感嗜血菌
<400>28
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>29
<211>21
<212>PRT
<213>流感嗜血菌
<400>29
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>30
<211>21
<212>PRT
<213>流感嗜血菌
<400>30
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>31
<211>21
<212>PRT
<213>流感嗜血菌
<400>31
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>32
<211>21
<212>PRT
<213>流感嗜血菌
<400>32
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Thr
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>33
<211>21
<212>PRT
<213>流感嗜血菌
<400>33
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>34
<211>21
<212>PRT
<213>流感嗜血菌
<400>34
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Asp Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>35
<211>21
<212>PRT
<213>流感嗜血菌
<400>35
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>36
<211>21
<212>PRT
<213>流感嗜血菌
<400>36
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Glu Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>37
<211>21
<212>PRT
<213>流感嗜血菌
<400>37
Asp Val Leu Phe Ser Val Glu Ser Val Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>38
<211>21
<212>PRT
<213>流感嗜血菌
<400>38
Asp Val Leu Phe Ser Val Glu Ser Val Asn Asn Lys Asn Lys Asp Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>39
<211>21
<212>PRT
<213>流感嗜血菌
<400>39
Asp Val Leu Phe Ser Val Glu Ser Val Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>40
<211>21
<212>PRT
<213>流感嗜血菌
<400>40
Asp Val Leu Phe Ser Val Glu Ser Val Asn Asn Lys Asn Lys Glu Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>41
<211>21
<212>PRT
<213>流感嗜血菌
<400>41
Asp Val Leu Phe Ser Val Lys Ser Pro Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>42
<211>21
<212>PRT
<213>流感嗜血菌
<400>42
Asp Val Leu Phe Ser Val Lys Ser Pro Asn Asn Lys Asn Lys Asp Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>43
<211>21
<212>PRT
<213>流感嗜血菌
<400>43
Asp Val Leu Phe Ser Val Lys Ser Pro Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>44
<211>21
<212>PRT
<213>流感嗜血菌
<400>44
Asp Val Leu Phe Ser Val Lys Ser Pro Asn Asn Lys Asn Lys Glu Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>45
<211>21
<212>PRT
<213>流感嗜血菌
<400>45
Asp Val Leu Phe Ser Val Lys Ser Val Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>46
<211>21
<212>PRT
<213>流感嗜血菌
<400>46
Asp Val Leu Phe Ser Val Lys Ser Val Asn Asn Lys Asn Lys Asp Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>47
<211>21
<212>PRT
<213>流感嗜血菌
<400>47
Asp Val Leu Phe Ser Val Lys Ser Val Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>48
<211>21
<212>PRT
<213>流感嗜血菌
<400>48
Asp Val Leu Phe Ser Val Lys Ser Val Asn Asn Lys Asn Lys Glu Ser
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>49
<211>21
<212>PRT
<213>流感嗜血菌
<400>49
Tyr Val Ser Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>50
<211>21
<212>PRT
<213>流感嗜血菌
<400>50
Tyr Val Ser Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>51
<211>21
<212>PRT
<213>流感嗜血菌
<400>51
Tyr Val Ser Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>52
<211>21
<212>PRT
<213>流感嗜血菌
<400>52
Tyr Val Ser Val Ser Thr Ser Arg Ile Gly Ser Arg ProTrp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>53
<211>21
<212>PRT
<213>流感嗜血菌
<400>53
Tyr Val Ser Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>54
<211>21
<212>PRT
<213>流感嗜血菌
<400>54
Tyr Val Ser Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>55
<211>21
<212>PRT
<213>流感嗜血菌
<400>55
Tyr Val Ser Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>56
<211>21
<212>PRT
<213>流感嗜血菌
<400>56
Tyr Val Ser Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>57
<211>21
<212>PRT
<213>流感嗜血菌
<400>57
Tyr Val Thr Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>58
<211>21
<212>PRT
<213>流感嗜血菌
<400>58
Tyr Val Thr Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>59
<211>21
<212>PRT
<213>流感嗜血菌
<400>59
Tyr Val Thr Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>60
<211>21
<212>PRT
<213>流感嗜血菌
<400>60
Tyr Val Thr Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>61
<211>21
<212>PRT
<213>流感嗜血菌
<400>61
Tyr Val Thr Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>62
<211>21
<212>PRT
<213>流感嗜血菌
<400>62
Tyr Val Thr Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>63
<211>21
<212>PRT
<213>流感嗜血菌
<400>63
Tyr Val Thr Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>64
<211>21
<212>PRT
<213>流感嗜血菌
<400>64
Tyr Val Thr Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>65
<211>21
<212>PRT
<213>流感嗜血菌
<400>65
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Val Ser Tyr
20
<210>66
<211>21
<212>PRT
<213>流感嗜血菌
<400>66
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Val Thr Tyr
20
<210>67
<211>21
<212>PRT
<213>流感嗜血菌
<400>67
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Arg Ser Tyr
20
<210>68
<211>21
<212>PRT
<213>流感嗜血菌
<400>68
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Arg Thr Tyr
20
<210>69
<211>21
<212>PRT
<213>流感嗜血菌
<400>69
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Val Ser Tyr
20
<210>70
<211>21
<212>PRT
<213>流感嗜血菌
<400>70
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Val Thr Tyr
20
<210>71
<211>21
<212>PRT
<213>流感嗜血菌
<400>71
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Arg Ser Tyr
20
<210>72
<211>21
<212>PRT
<213>流感嗜血菌
<400>72
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Arg Thr Tyr
20
<210>73
<211>21
<212>PRT
<213>流感嗜血菌
<400>73
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Val Ser Tyr
20
<210>74
<211>21
<212>PRT
<213>流感嗜血菌
<400>74
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Val Thr Tyr
20
<210>75
<211>21
<212>PRT
<213>流感嗜血菌
<400>75
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Arg Ser Tyr
20
<210>76
<211>21
<212>PRT
<213>流感嗜血菌
<400>76
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Lys Arg Thr Tyr
20
<210>77
<211>21
<212>PRT
<213>流感嗜血菌
<400>77
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Val Ser Tyr
20
<210>78
<211>21
<212>PRT
<213>流感嗜血菌
<400>78
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Val Thr Tyr
20
<210>79
<211>21
<212>PRT
<213>流感嗜血菌
<400>79
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Arg Ser Tyr
20
<210>80
<211>21
<212>PRT
<213>流感嗜血菌
<400>80
Tyr Ala Cys Lys Tyr Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Ser Arg Thr Tyr
20
<210>81
<211>21
<212>PRT
<213>流感嗜血菌
<400>81
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>82
<211>21
<212>PRT
<213>流感嗜血菌
<400>82
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>83
<211>21
<212>PRT
<213>流感嗜血菌
<400>83
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>84
<211>21
<212>PRT
<213>流感嗜血菌
<400>84
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>85
<211>21
<212>PRT
<213>流感嗜血菌
<400>85
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>86
<211>21
<212>PRT
<213>流感嗜血菌
<400>86
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>87
<211>21
<212>PRT
<213>流感嗜血菌
<400>87
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>88
<211>21
<212>PRT
<213>流感嗜血菌
<400>88
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>89
<211>21
<212>PRT
<213>流感嗜血菌
<400>89
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>90
<211>21
<212>PRT
<213>流感嗜血菌
<400>90
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>91
<211>21
<212>PRT
<213>流感嗜血菌
<400>91
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>92
<211>21
<212>PRT
<213>流感嗜血菌
<400>92
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>93
<211>21
<212>PRT
<213>流感嗜血菌
<400>93
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>94
<211>21
<212>PRT
<213>流感嗜血菌
<400>94
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Val Gln Ala
20
<210>95
<211>21
<212>PRT
<213>流感嗜血菌
<400>95
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Gln Asn Ala
20
<210>96
<211>21
<212>PRT
<213>流感嗜血菌
<400>96
Lys Ser Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Lys
1 5 10 15
Leu Tyr Gln Gln Ala
20
<210>97
<211>21
<212>PRT
<213>流感嗜血菌
<400>97
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>98
<211>21
<212>PRT
<213>流感嗜血菌
<400>98
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Asp Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>99
<211>21
<212>PRT
<213>流感嗜血菌
<400>99
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>100
<211>21
<212>PRT
<213>流感嗜血菌
<400>100
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Glu Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>101
<211>21
<212>PRT
<213>流感嗜血菌
<400>101
Asp Val Leu Phe Ser Val Glu Ser Asn Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>102
<211>21
<212>PRT
<213>流感嗜血菌
<400>102
Asp Val Leu Phe Ser Val Glu Ser Asn Asn Asn Lys Asn Lys Asp Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>103
<211>21
<212>PRT
<213>流感嗜血菌
<400>103
Asp Val Leu Phe Ser Val Glu Ser Asn Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>104
<211>21
<212>PRT
<213>流感嗜血菌
<400>104
Asp Val Leu Phe Ser Val Glu Ser Asn Asn Asn Lys Asn Lys Glu Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>105
<211>21
<212>PRT
<213>流感嗜血菌
<400>105
Asp Val Leu Phe Ser Val Pro Ser Pro Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>106
<211>21
<212>PRT
<213>流感嗜血菌
<400>106
Asp Val Leu Phe Ser Val Pro Ser Pro Asn Asn Lys Asn Lys Asp Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>107
<211>21
<212>PRT
<213>流感嗜血菌
<400>107
Asp Val Leu Phe Ser Val Pro Ser Pro Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>108
<211>21
<212>PRT
<213>流感嗜血菌
<400>108
Asp Val Leu Phe Ser Val Pro Ser Pro Asn Asn Lys Asn Lys Glu Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>109
<211>21
<212>PRT
<213>流感嗜血菌
<400>109
Asp Val Leu Phe Ser Val Pro Ser Asn Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>110
<211>21
<212>PRT
<213>流感嗜血菌
<400>110
Asp Val Leu Phe Ser Val Pro Ser Asn Asn Asn Lys Asn Lys Asp Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>111
<211>21
<212>PRT
<213>流感嗜血菌
<400>111
Asp Val Leu Phe Ser Val Pro Ser Asn Asn Asn Lys Asn Lys Glu Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>112
<211>21
<212>PRT
<213>流感嗜血菌
<400>112
Asp Val Leu Phe Ser Val Pro Ser Asn Asn Asn Lys Asn Lys Glu Glu
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>113
<211>21
<212>PRT
<213>流感嗜血菌
<400>113
Tyr Val Ser Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>114
<211>21
<212>PRT
<213>流感嗜血菌
<400>114
Tyr Val Ser Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>115
<211>21
<212>PRT
<213>流感嗜血菌
<400>115
Tyr Val Ser Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>116
<211>21
<212>PRT
<213>流感嗜血菌
<400>116
Tyr Val Ser Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>117
<211>21
<212>PRT
<213>流感嗜血菌
<400>117
Tyr Val Ser Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>118
<211>21
<212>PRT
<213>流感嗜血菌
<400>118
Tyr Val Ser Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>119
<211>21
<212>PRT
<213>流感嗜血菌
<400>119
Tyr Val Ser Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>120
<211>21
<212>PRT
<213>流感嗜血菌
<400>120
Tyr Val Ser Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>121
<211>21
<212>PRT
<213>流感嗜血菌
<400>121
Tyr Val Thr Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>122
<211>21
<212>PRT
<213>流感嗜血菌
<400>122
Tyr Val Thr Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>123
<211>21
<212>PRT
<213>流感嗜血菌
<400>123
Tyr Val Thr Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>124
<211>21
<212>PRT
<213>流感嗜血菌
<400>124
Tyr Val Thr Val Ser Thr Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>125
<211>21
<212>PRT
<213>流感嗜血菌
<400>125
Tyr Val Thr Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>126
<211>21
<212>PRT
<213>流感嗜血菌
<400>126
Tyr Val Thr Val Ser Ser Ser Arg Ile Ala Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>127
<211>21
<212>PRT
<213>流感嗜血菌
<400>127
Tyr Val Thr Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>128
<211>21
<212>PRT
<213>流感嗜血菌
<400>128
Tyr Val Thr Val Ser Ser Ser Arg Ile Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>129
<211>21
<212>PRT
<213>流感嗜血菌
<400>129
Tyr Ala Cys Lys Arg Gly Gly Lys Ser Ser Gly Ser Ser Tyr Pro Val
1 5 10 15
Leu Asn Val Ser Tyr
20
<210>130
<211>21
<212>PRT
<213>流感嗜血菌
<400>130
Lys Lys Gly Ser Val His His Pro Ser Thr Ile Thr Glu Gln Thr Ser
1 5 10 15
Leu Tyr Val Asn Ala
20
<210>131
<211>21
<212>PRT
<213>流感嗜血菌
<400>131
Asp Val Leu Phe Ser Val Glu Ser Pro Asn Asn Lys Asn Lys Asp Pro
1 5 10 15
Ile Asp Thr Cys Asp
20
<210>132
<211>21
<212>PRT
<213>流感嗜血菌
<400>132
Tyr Val Ser Val Ser Thr Ser Arg Ile Ala Ser Arg Pro Lys Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>133
<211>27
<212>PRT
<213>流感嗜血菌
<400>133
Gly Ser Cys Pro Asn Ala Thr Asn Arg Asn Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Ile Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>134
<211>27
<212>PRT
<213>流感嗜血菌
<400>134
Gly Ser Cys Pro Asn Ala Thr Asn Arg Asn Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Thr Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>135
<211>27
<212>PRT
<213>流感嗜血菌
<400>135
Gly Ser Cys Pro Asn Ala Thr Asn Arg Ser Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Ile Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>136
<211>27
<212>PRT
<213>流感嗜血菌
<400>136
Gly Ser Cys Pro Asn Ala Thr Asn Arg Ser Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Thr Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>137
<211>27
<212>PRT
<213>流感嗜血菌
<400>137
Gly Ser Cys Pro Asn Ala Thr Ser Arg Asn Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Ile Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>138
<211>27
<212>PRT
<213>流感嗜血菌
<400>138
Gly Ser Cys Pro Asn Ala Thr Ser Arg Asn Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Thr Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>139
<211>27
<212>PRT
<213>流感嗜血菌
<400>139
Gly Ser Cys Pro Asn Ala Thr Ser Arg Ser Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Ile Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>140
<211>27
<212>PRT
<213>流感嗜血菌
<400>140
Gly Ser Cys Pro Asn Ala Thr Ser Arg Ser Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Thr Asn Pro Leu Thr Val Glu Val Pro Tyr
20 25
<210>141
<211>21
<212>PRT
<213>流感嗜血菌
<400>141
Pro Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>142
<211>21
<212>PRT
<213>流感嗜血菌
<400>142
Pro Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>143
<211>21
<212>PRT
<213>流感嗜血菌
<400>143
Pro Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>144
<211>21
<212>PRT
<213>流感嗜血菌
<400>144
Pro Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>145
<211>21
<212>PRT
<213>流感嗜血菌
<400>145
Pro Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>146
<211>21
<212>PRT
<213>流感嗜血菌
<400>146
Pro Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>147
<211>21
<212>PRT
<213>流感嗜血菌
<400>147
Pro Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>148
<211>21
<212>PRT
<213>流感嗜血菌
<400>148
Pro Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>149
<211>21
<212>PRT
<213>流感嗜血菌
<400>149
Arg Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>150
<211>21
<212>PRT
<213>流感嗜血菌
<400>150
Arg Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln MetGlu Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>151
<211>21
<212>PRT
<213>流感嗜血菌
<400>151
Arg Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>152
<211>21
<212>PRT
<213>流感嗜血菌
<400>152
Arg Lys Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>153
<211>21
<212>PRT
<213>流感嗜血菌
<400>153
Arg Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>154
<211>21
<212>PRT
<213>流感嗜血菌
<400>154
Arg Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Glu Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>155
<211>21
<212>PRT
<213>流感嗜血菌
<400>155
Arg Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>156
<211>21
<212>PRT
<213>流感嗜血菌
<400>156
Arg Asn Asp Asn Phe His Ser Asp Asn Lys Thr Gln Met Lys Asn Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>157
<211>27
<212>PRT
<213>流感嗜血菌
<400>157
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Ser Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>158
<211>27
<212>PRT
<213>流感嗜血菌
<400>158
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Ser Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>159
<211>27
<212>PRT
<213>流感嗜血菌
<400>159
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Thr Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>160
<211>27
<212>PRT
<213>流感嗜血菌
<400>160
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Thr Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>161
<211>27
<212>PRT
<213>流感嗜血菌
<400>161
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Ser Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>162
<211>27
<212>PRT
<213>流感嗜血菌
<400>162
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Ser Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>163
<211>27
<212>PRT
<213>流感嗜血菌
<400>163
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Thr Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>164
<211>27
<212>PRT
<213>流感嗜血菌
<400>164
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Thr Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>165
<211>27
<212>PRT
<213>流感嗜血菌
<400>165
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Ser Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>166
<211>27
<212>PRT
<213>流感嗜血菌
<400>166
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Ser Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>167
<211>27
<212>PRT
<213>流感嗜血菌
<400>167
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Thr Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>168
<211>27
<212>PRT
<213>流感嗜血菌
<400>168
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Thr Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>169
<211>27
<212>PRT
<213>流感嗜血菌
<400>169
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Ser Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>170
<211>27
<212>PRT
<213>流感嗜血菌
<400>170
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Ser Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>171
<211>27
<212>PRT
<213>流感嗜血菌
<400>171
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Thr Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>172
<211>27
<212>PRT
<213>流感嗜血菌
<400>172
Arg Gly Lys Leu Cys Pro Asn Cys Leu Asn Cys Thr Asp Leu Ile Cys
1 5 10 15
Thr Lys Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>173
<211>26
<212>PRT
<213>流感嗜血菌
<400>173
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asn Gln Thr
1 5 10 15
Glu Asp Glu Gly Leu Lys Gln Ser Gly Arg
20 25
<210>174
<211>26
<212>PRT
<213>流感嗜血菌
<400>174
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asn Gln Thr
1 5 10 15
Glu Asp Glu Gly Leu Pro Gln Ser Gly Arg
20 25
<210>175
<211>26
<212>PRT
<213>流感嗜血菌
<400>175
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asn Gln Thr
1 5 10 15
Glu Asp Gly Gly Leu Lys Gln Ser Gly Arg
20 25
<210>176
<211>26
<212>PRT
<213>流感嗜血菌
<400>176
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asn Gln Thr
1 5 10 15
Glu Asp Gly Gly Leu Pro Gln Ser Gly Arg
20 25
<210>177
<211>26
<212>PRT
<213>流感嗜血菌
<400>177
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asp Gln Thr
1 5 10 15
Glu Asp Glu Gly Leu Lys Gln Ser Gly Arg
20 25
<210>178
<211>26
<212>PRT
<213>流感嗜血菌
<400>178
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asp Gln Thr
1 5 10 15
Glu Asp Glu Gly Leu Pro Gln Ser Gly Arg
20 25
<210>179
<211>26
<212>PRT
<213>流感嗜血菌
<400>179
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asp Gln Thr
1 5 10 15
Glu Asp Gly Gly Leu Lys Gln Ser Gly Arg
20 25
<210>180
<211>26
<212>PRT
<213>流感嗜血菌
<400>180
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asp Gln Thr
1 5 10 15
Glu Asp Gly Gly Leu Pro Gln Ser Gly Arg
20 25
<210>181
<211>27
<212>PRT
<213>流感嗜血菌
<400>181
Gly Ser Cys Pro Asn Val Ala Asn Gly Asn Gly Asp Asn Asn Lys Thr
1 5 10 15
Ala Ile Asn Pro Val Thr Val Glu Val Pro Tyr
20 25
<210>182
<211>21
<212>PRT
<213>流感嗜血菌
<400>182
Pro Lys Asp Asn Phe His Ser Asp Asp Lys Thr Gln Met Glu Arg Leu
1 5 10 15
Tyr Gly Asp Ser Asn
20
<210>183
<211>27
<212>PRT
<213>流感嗜血菌
<400>183
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Ile Ile Cys
1 5 10 15
Ser Glu Gly Glu Asp Leu Pro Leu Ile Gly Glu
20 25
<210>184
<211>26
<212>PRT
<213>流感嗜血菌
<400>184
Lys Phe Thr Ser Ser Ala Asn Gly Ile Gly Gly Phe Pro Asn Gln Thr
1 5 10 15
Glu Asp Glu Gly Leu Lys Gln Ser Gly Arg
20 25
<210>185
<211>21
<212>PRT
<213>流感嗜血菌
<400>185
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Asn Lys Thr Met
20
<210>186
<211>21
<212>PRT
<213>流感嗜血菌
<400>186
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Asn Lys Thr Tyr
20
<210>187
<211>21
<212>PRT
<213>流感嗜血菌
<400>187
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Asn Lys Ser Met
20
<210>188
<211>21
<212>PRT
<213>流感嗜血菌
<400>188
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Asn Lys Ser Tyr
20
<210>189
<211>21
<212>PRT
<213>流感嗜血菌
<400>189
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Thr Lys Thr Met
20
<210>190
<211>21
<212>PRT
<213>流感嗜血菌
<400>190
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Thr Lys Thr Tyr
20
<210>191
<211>21
<212>PRT
<213>流感嗜血菌
<400>191
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Thr Lys Ser Met
20
<210>192
<211>21
<212>PRT
<213>流感嗜血菌
<400>192
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Phe Pro Gln
1 5 10 15
Met Thr Lys Ser Tyr
20
<210>193
<211>21
<212>PRT
<213>流感嗜血菌
<400>193
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Asn Lys Thr Met
20
<210>194
<211>21
<212>PRT
<213>流感嗜血菌
<400>194
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Asn Lys Thr Tyr
20
<210>195
<211>21
<212>PRT
<213>流感嗜血菌
<400>195
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Asn Lys Ser Met
20
<210>196
<211>21
<212>PRT
<213>流感嗜血菌
<400>196
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Asn Lys Ser Tyr
20
<210>197
<211>21
<212>PRT
<213>流感嗜血菌
<400>197
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Thr Lys Thr Met
20
<210>198
<211>21
<212>PRT
<213>流感嗜血菌
<400>198
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Thr Lys Thr Tyr
20
<210>199
<211>21
<212>PRT
<213>流感嗜血菌
<400>199
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Thr Lys Ser Met
20
<210>200
<211>21
<212>PRT
<213>流感嗜血菌
<400>200
Ser Ala Cys Lys Arg Arg Ser Ala Ser Ser Asn Ala Ala Tyr Pro Gln
1 5 10 15
Met Thr Lys Ser Tyr
20
<210>201
<211>23
<212>PRT
<213>流感嗜血菌
<400>201
Ser Ser Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>202
<211>23
<212>PRT
<213>流感嗜血菌
<400>202
Ser Ser Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>203
<211>23
<212>PRT
<213>流感嗜血菌
<400>203
Ser Ser Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>204
<211>23
<212>PRT
<213>流感嗜血菌
<400>204
Ser Ser Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>205
<211>23
<212>PRT
<213>流感嗜血菌
<400>205
Ser Ser Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>206
<211>23
<212>PRT
<213>流感嗜血菌
<400>206
Ser Ser Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>207
<211>23
<212>PRT
<213>流感嗜血菌
<400>207
Ser Ser Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>208
<211>23
<212>PRT
<213>流感嗜血菌
<400>208
Ser Ser Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>209
<211>23
<212>PRT
<213>流感嗜血菌
<400>209
Ser Asn Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>210
<211>23
<212>PRT
<213>流感嗜血菌
<400>210
Ser Asn Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>211
<211>23
<212>PRT
<213>流感嗜血菌
<400>211
Ser Asn Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>212
<211>23
<212>PRT
<213>流感嗜血菌
<400>212
Ser Asn Thr Asp Asn Ala Ile His His Ser Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>213
<211>23
<212>PRT
<213>流感嗜血菌
<400>213
Ser Asn Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>214
<211>23
<212>PRT
<213>流感嗜血菌
<400>214
Ser Asn Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Gln Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>215
<211>23
<212>PRT
<213>流感嗜血菌
<400>215
Ser Asn Thr Asp Asn Ala Ile His His Pro Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Gln Glu
20
<210>216
<211>23
<212>PRT
<213>流感嗜血菌
<400>216
Ser Asn Thr Asp Asn AlaIle His His Pro Ser Ser Asn Thr Glu Gln
1 5 10 15
Thr Lys Leu Tyr Val Ser Glu
20
<210>217
<211>20
<212>PRT
<213>流感嗜血菌
<400>217
Asp Gln Phe Gln Glu Glu Ser Pro Asn Asn Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>218
<211>20
<212>PRT
<213>流感嗜血菌
<400>218
Asp Gln Phe Gln Glu Glu Ser Pro Asn Asn Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>219
<211>20
<212>PRT
<213>流感嗜血菌
<400>219
Asp Gln Phe Gln Glu Glu Ser Pro Asn Thr Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>220
<211>20
<212>PRT
<213>流感嗜血菌
<400>220
Asp Gln Phe Gln Glu Glu Ser Pro Asn Thr Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>221
<211>20
<212>PRT
<213>流感嗜血菌
<400>221
Asp Gln Phe Gln Glu Phe Ser Pro Asn Asn Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>222
<211>20
<212>PRT
<213>流感嗜血菌
<400>222
Asp Gln Phe Gln Glu Phe Ser Pro Asn Asn Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>223
<211>20
<212>PRT
<213>流感嗜血菌
<400>223
Asp Gln Phe Gln Glu Phe Ser Pro Asn Thr Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>224
<211>20
<212>PRT
<213>流感嗜血菌
<400>224
Asp Gln Phe Gln Glu Phe Ser Pro Asn Thr Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>225
<211>20
<212>PRT
<213>流感嗜血菌
<400>225
Asp Gln Phe Leu Glu Glu Ser Pro Asn Asn Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>226
<211>20
<212>PRT
<213>流感嗜血菌
<400>226
Asp Gln Phe Leu Glu Glu Ser Pro Asn Asn Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>227
<211>20
<212>PRT
<213>流感嗜血菌
<400>227
Asp Gln Phe Leu Glu Glu Ser Pro Asn Thr Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>228
<211>20
<212>PRT
<213>流感嗜血菌
<400>228
Asp Gln Phe Leu Glu Glu Ser Pro Asn Thr Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>229
<211>20
<212>PRT
<213>流感嗜血菌
<400>229
Asp Gln Phe Leu Glu Phe Ser Pro Asn Asn Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>230
<211>20
<212>PRT
<213>流感嗜血菌
<400>230
Asp Gln Phe Leu Glu Phe Ser Pro Asn Asn Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>231
<211>20
<212>PRT
<213>流感嗜血菌
<400>231
Asp Gln Phe Leu Glu Phe Ser Pro Asn Thr Arg Asn Phe Asp Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>232
<211>20
<212>PRT
<213>流感嗜血菌
<400>232
Asp Gln Phe Leu Glu Phe Ser Pro Asn Thr Arg Asn Phe Pro Pro Asp
1 5 10 15
Asp Asn Cys Glu
20
<210>233
<211>21
<212>PRT
<213>流感嗜血菌
<400>233
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ala Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>234
<211>21
<212>PRT
<213>流感嗜血菌
<400>234
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ala Arg Pro Trp Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>235
<211>21
<212>PRT
<213>流感嗜血菌
<400>235
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ala Arg Pro Gln Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>236
<211>21
<212>PRT
<213>流感嗜血菌
<400>236
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ala Arg Pro Gln Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>237
<211>21
<212>PRT
<213>流感嗜血菌
<400>237
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>238
<211>21
<212>PRT
<213>流感嗜血菌
<400>238
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ser Arg Pro Trp Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>239
<211>21
<212>PRT
<213>流感嗜血菌
<400>239
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ser Arg Pro Gln Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>240
<211>21
<212>PRT
<213>流感嗜血菌
<400>240
Arg Ile Thr Val Ser Thr Ser Arg Pro Gly Ser Arg Pro Gln Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>241
<211>21
<212>PRT
<213>流感嗜血菌
<400>241
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ala Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>242
<211>21
<212>PRT
<213>流感嗜血菌
<400>242
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ala Arg Pro Trp Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>243
<211>21
<212>PRT
<213>流感嗜血菌
<400>243
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ala Arg Pro Gln Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>244
<211>21
<212>PRT
<213>流感嗜血菌
<400>244
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ala Arg Pro Gln Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>245
<211>21
<212>PRT
<213>流感嗜血菌
<400>245
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ser Arg Pro Trp Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>246
<211>21
<212>PRT
<213>流感嗜血菌
<400>246
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ser Arg Pro Trp Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>247
<211>21
<212>PRT
<213>流感嗜血菌
<400>247
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ser Arg Pro Gln Val Arg
1 5 10 15
Gly Gln Ser Gly Arg
20
<210>248
<211>21
<212>PRT
<213>流感嗜血菌
<400>248
Arg Ile Thr Val Ser Ser Ser Arg Pro Gly Ser Arg Pro Gln Val Asn
1 5 10 15
Gly Gln Ser Gly Arg
20
Claims (7)
1.基于肽的抗流感制剂，其包含序列包括所有SEQ ID NO：1-64的肽。
2.基于肽的抗流感制剂，其包含序列包括以下至少两组中来自每一组的所有16种序列的肽：
a)SEQ ID NO：1-16；
b)SEQ ID NO：17-32；
c)SEQ ID NO：33-48；或者
d)SEQ ID NO：49-64。
3.疫苗，其包含权利要求1或2的制剂以及可药用稀释剂或载体。
4.权利要求3的疫苗，还包含佐剂。
5.权利要求4的疫苗，其中所述佐剂为明矾。
6.用于治疗人流感的疫苗，其包含权利要求1或2的制剂。
7.权利要求1或2的制剂在制备用于预防或治疗流感之疫苗中的用途。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68604105P | 2005-06-01 | 2005-06-01 | |
| US60/686,041 | 2005-06-01 | ||
| PCT/CA2006/000891 WO2006128294A1 (en) | 2005-06-01 | 2006-06-01 | Peptide-based influenza vaccine formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101227919A CN101227919A (zh) | 2008-07-23 |
| CN101227919B true CN101227919B (zh) | 2011-10-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200680023950XA Expired - Fee Related CN101227919B (zh) | 2005-06-01 | 2006-06-01 | 基于肽的流感疫苗制剂 |
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| Country | Link |
|---|---|
| US (1) | US20090104216A1 (zh) |
| EP (1) | EP1906998A4 (zh) |
| JP (1) | JP4939531B2 (zh) |
| KR (1) | KR20080027777A (zh) |
| CN (1) | CN101227919B (zh) |
| CA (1) | CA2610667A1 (zh) |
| MX (1) | MX2007015105A (zh) |
| WO (1) | WO2006128294A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11865172B2 (en) | 2005-04-21 | 2024-01-09 | University Of Florida Research Foundation, Inc. | Materials and methods for respiratory disease control in canines |
| US7959929B2 (en) | 2005-04-21 | 2011-06-14 | University Of Florida Research Foundation, Inc. | Materials and methods for respiratory disease control in canines |
| WO2007120834A2 (en) | 2006-04-13 | 2007-10-25 | Peptimmune, Inc. | Methods for designing and synthesizing directed sequence polymer compositions via the directed expansion of epitope permeability |
| US20090036653A1 (en) * | 2006-04-13 | 2009-02-05 | Peptimmune, Inc. | Methods for the directed expansion of epitopes for use as antibody ligands |
| US20100068224A1 (en) * | 2006-04-24 | 2010-03-18 | Roberto Crea | Method for Producing Viral Vaccine and Therapeutic Peptide Antigens |
| FI20060946A0 (fi) * | 2006-10-26 | 2006-10-26 | Glykos Finland Oy | Influenssaviruksen nukleiinihappoja ja peptidejä |
| CA2670965C (en) * | 2006-11-30 | 2015-02-24 | Variation Biotechnologies Inc. | Influenza vaccine formulation |
| KR20100019487A (ko) * | 2007-05-07 | 2010-02-18 | 펩팀문, 인코포레이티드 | 항체 리간드로서 사용하기 위한 에피토프의 지시된 연장 방법 |
| GB0714963D0 (en) * | 2007-08-01 | 2007-09-12 | Novartis Ag | Compositions comprising antigens |
| CA2695399C (en) | 2007-08-02 | 2017-10-17 | Biondvax Pharmaceuticals Ltd. | Multimeric multiepitope influenza vaccines |
| WO2009051797A1 (en) * | 2007-10-16 | 2009-04-23 | Peptimmune, Inc. | Methods for designing and preparing vaccines comprising directed sequence polymer compositions via the directed expansion of epitopes |
| EP2296688A2 (en) * | 2007-10-26 | 2011-03-23 | Glykos Finland Oy | Peptide vaccine for influenza virus |
| EP2278998A1 (en) * | 2008-04-17 | 2011-02-02 | Declion Pharmaceuticals, Inc. | Design and synthesis of directed sequence polymer compositions and antibodies thereof for the treatment of protein conformational disorders |
| FI20080333A0 (fi) * | 2008-05-02 | 2008-05-02 | Glykos Finland Oy | Influenssaviruksen nukleiinihappoja ja peptidejä |
| BRPI0914224A2 (pt) | 2008-06-19 | 2019-09-24 | Variation Biotechnologies Inc | composições e métodos para tratar a gripe |
| JP6069212B2 (ja) | 2010-12-02 | 2017-02-01 | ビオノール イミュノ エーエスＢｉｏｎｏｒ Ｉｍｍｕｎｏ Ａｓ | ペプチド骨格設計 |
| WO2012114323A1 (en) | 2011-02-22 | 2012-08-30 | Biondvax Pharmaceuticals Ltd. | Multimeric multiepitope polypeptides in improved seasonal and pandemic influenza vaccines |
| MY184269A (en) | 2015-11-27 | 2021-03-30 | Viramatix Sdn Bhd | Broad-spectrum anti-influenza virus therapeutic peptides |
| JP7233737B2 (ja) | 2017-05-26 | 2023-03-07 | ビラマティクス スンディリアン ブルハド | ペプチドおよび抗ウイルス剤としてのその使用 |
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| WO2003066090A1 (en) * | 2002-02-08 | 2003-08-14 | Variation Biotechnologies Inc. | Immunogenic formulations of variable peptidic epitopes and process for preparation thereof |
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| CA2084180A1 (en) * | 1991-12-11 | 1993-06-12 | Paul P. Hung | Expression of specific immunogens using viral antigens |
| US7118874B2 (en) * | 1998-10-09 | 2006-10-10 | Variation Biotechnologies Inc. | Immunogenic formulation and process for preparation thereof |
| IL127331A0 (en) * | 1998-11-30 | 1999-09-22 | Yeda Res & Dev | Peptide-based vaccine for influenza |
| US20040223976A1 (en) * | 2003-03-07 | 2004-11-11 | Elisabetta Bianchi | Influenza virus vaccine |
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2006
- 2006-06-01 WO PCT/CA2006/000891 patent/WO2006128294A1/en active Application Filing
- 2006-06-01 MX MX2007015105A patent/MX2007015105A/es not_active Application Discontinuation
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- 2006-06-01 JP JP2008513881A patent/JP4939531B2/ja not_active Expired - Fee Related
- 2006-06-01 CN CN200680023950XA patent/CN101227919B/zh not_active Expired - Fee Related
- 2006-06-01 KR KR1020077029582A patent/KR20080027777A/ko not_active Application Discontinuation
- 2006-06-01 EP EP06741591A patent/EP1906998A4/en not_active Withdrawn
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| WO2003066090A1 (en) * | 2002-02-08 | 2003-08-14 | Variation Biotechnologies Inc. | Immunogenic formulations of variable peptidic epitopes and process for preparation thereof |
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| Publication number | Publication date |
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| MX2007015105A (es) | 2008-03-18 |
| US20090104216A1 (en) | 2009-04-23 |
| CN101227919A (zh) | 2008-07-23 |
| JP2008542309A (ja) | 2008-11-27 |
| WO2006128294A1 (en) | 2006-12-07 |
| CA2610667A1 (en) | 2006-12-07 |
| EP1906998A1 (en) | 2008-04-09 |
| EP1906998A4 (en) | 2010-02-17 |
| KR20080027777A (ko) | 2008-03-28 |
| JP4939531B2 (ja) | 2012-05-30 |
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