CN111437384A - 用于预防covid-19的蝙蝠源性冠状病毒疫苗 - Google Patents

Abstract

本发明公开了一种用于预防COVID‑19的蝙蝠源性冠状病毒疫苗，采用蝙蝠源性冠状病毒Bat/CovRaTG13来生产疫苗以控制和预防正在发生的COVID‑19大流行和未来的该疾病流行。Bat/CovRaTG13与2019新冠状病毒(SARS‑CoV‑2)的遗传指纹最接近。全氨基酸序列的同源性不仅决定了其亲缘关系，也决定了其生物学特性的相似性，其中抗原性是决定疫苗特异性和有效性的主要因素之一。其疫苗株来源为Bat/CovRaTG13家族成员，具有序列同源性。所述蝙蝠冠状病毒源性疫苗通过相对应构建和制造方法程序可制成三种类型疫苗：活疫苗、灭活疫苗和/或重组疫苗，以预防COVID‑19大流行。

Description

用于预防COVID-19的蝙蝠源性冠状病毒疫苗

技术领域

本发明为生物医药领域，涉及一种用于预防COVID-19的蝙蝠源性冠状病 毒疫苗。

背景技术

2019年冠状病毒病疾病(COVID-19)是由严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)引起的传染病。尽管大多数病例导致轻度症状，COVID-19可迅速 发展为急性呼吸窘迫综合征，引起呼吸衰竭、脓毒性休克或多器官衰竭。世界卫 生组织(世卫组织)于2020年1月30日宣布2019-2020年冠状病毒爆发为国际 关注的公共卫生紧急事件(PHEIC)，并于2020年3月11日宣布COVID-19大 流行。世卫组织所有六个区域的许多国家都发现了这种疾病在当地传播的证据。 迄今为止，冠状病毒大流行已导致多于100万人感染，4万多人死亡，并导致全 球经济衰退。

冠状病毒(CoV)是一种正链RNA病毒，在电子显微镜下，由于囊膜上有 棘突糖蛋白的存在，具有树冠状外观。冠状病毒科的正冠状病毒亚科(Nidovirales 目)分为四个属：α冠状病毒(alpha CoV)，Betacoronavirus(betaCoV)、 Deltacoronavirus(deltaCoV)和Gammacoronavirus(gammaCoV)。此外，betaCoV 属又分为5个亚属或谱系，基因组特征表明蝙蝠和啮齿动物可能是alphaCoVs 和betaCoV的基因来源。(Chan JF等,《物种间传播和新病毒的出现：蝙蝠和鸟 类的教训》,趋势微生物,2013年,21(10):544-55)。

总的来说，估计2％的人口是CoV的健康携带者，这些病毒对大约5％到10％ 的急性呼吸道感染负责(Chen Y等,新兴冠状病毒：基因组结构，复制和发病机制 [J],医学杂志,维罗尔,2020,92(4):418-423)。这包括常见的人类冠状病毒： HCoV-OC43和HCoV-HKU1(betaCoVs谱系)；HCoV-229E和HCoV-NL63 (alphaCoVs)。它们能引起普通感冒和免疫能力强的人的自限性上呼吸道感染。 在免疫功能低下的受试者和老年人中，可能会发生下呼吸道感染。其他人类冠状 病毒：SARS-CoV、SARS-CoV-2和MERS-CoV(分别属于B和C系的betaCoVs) 可引起具有呼吸和呼吸外表现的不同临床严重程度的流行病。SARS冠状病毒、MERS冠状病毒的死亡率分别可达10％和35％。

Chan等人已经证明，从一个非典型肺炎患者群中分离出的新人类冠状病毒 的基因组与蝙蝠类SARS-CoVZXC21的核苷酸同源性为89％，与人类SARS-CoV 的核苷酸同源性为82％(Chan JF，et al，一例非典型肺炎患者2019株新型人致 病性冠状病毒基因组特征分析[J],出现微生物感染,2020年,9(1):221-236)。迄今 为止发现的穿山甲冠状病毒最多只与SARS-CoV-2共享其全部基因组的92％， 这使得它们比另一种蝙蝠冠状病毒Bat/CovRaTG13的96％相似性更低。因此， 这种新病毒被称为SARS-CoV-2，分类属于BetaCoVs。

疫苗接种是最有效的公共卫生干预措施之一，在过去100年中，它在拯救生 命和大大改变许多传染病负担方面发挥了重要作用。疫苗可分为两大类：复制疫 苗(即活疫苗、减毒疫苗或重组疫苗)和非复制疫苗(如灭活疫苗或亚单位疫苗)。 已证实减毒活疫苗在抗病毒免疫应答质量、保护性免疫水平、保护性免疫持续时 间等方面均优于非复制疫苗。然而，安全性仍然是减毒活疫苗的主要问题，其中 一些疫苗最终被非复制或灭活疫苗所取代。例如，从1961年到1989年，美国口 服脊髓灰质炎活疫苗(OPV)的常规接种每年平均导致9例疫苗相关麻痹性脊髓 灰质炎(VAPP)。最近，尼日利亚的口服脊髓灰质炎疫苗接种也导致至少69例 VAPP病例。出于这些安全考虑，美国在2000年用灭活脊髓灰质炎疫苗(IPV) 完全取代了脊髓灰质炎活疫苗，这导致了VAPP的彻底消除。尽管减毒活疫苗比 灭活疫苗能在健康人群中产生更强的保护性免疫应答，但灭活(死亡疫苗仍然在 公共卫生中发挥着重要作用，特别是在没有活疫苗的情况下，在控制致命传染病 的流行方面。灭活疫苗不含任何活的病原体；它们不能引起它们所保护的疾病， 即使在免疫系统严重削弱的人身上也是如此。

由于可能导致人类感染的基因突变和COVID-19的发病机制尚不完全清楚， 因此迫切需要开发抗SARS-CoV-2疫苗，以控制正在进行的大流行并防止未来的 暴发。

发明内容

为解决上述技术问题，本发明公开了用于预防COVID-19的蝙蝠源性冠状 病毒疫苗，选用与COVID-19的蝙蝠源性冠状病毒具有生物同源性的原型或父本 株制备疫苗作为疫苗病毒株。

为实现以上发明目的，本发明提供以下技术方案：

一种用于预防COVID-19的蝙蝠源性冠状病毒疫苗，采用与SARS-CoV-2 病毒具有生物同源性的SARS-CoV-2的弱毒性原型或父本株制备疫苗。

进一步地，所述SARS-CoV-2的弱毒性原型或父本株与SARS-CoV-2病毒在RNA 序列上具有至少96％同源性、在蛋白氨基酸序列上具有至少97％同源性。

进一步地，所述SARS-CoV-2的弱毒性原型或父本株为蝙蝠冠状病毒 Bat/CovRaTG13株。

进一步地，所述SARS-CoV-2的弱毒性原型或父本株为与蝙蝠冠状病毒 Bat/CovRaTG13株具有同源序列性的任一亚属病毒株。

进一步地，所述疫苗为通过所述SARS-CoV-2的弱毒性原型或父本株制备的 活疫苗、灭活性疫苗或重组疫苗。

进一步地，所述活疫苗通过所述SARS-CoV-2的弱毒性原型或父本株经细胞 培养、纯化、制剂制备而成，不在体外进行基因修饰。

进一步地，所述灭活疫苗通过所述SARS-CoV-2的弱毒性原型或父本株经细 胞培养、纯化、灭活、制剂制备而成，不在体外进行基因修饰。

进一步地，所述灭活疫苗通过福尔马林对病毒灭活；所述灭活疫苗还包括铝 佐剂。

进一步地，所述重组疫苗为通过人工点突变和/或将基因片段插入 Bat/CovRaTG13的任一基因中而产生的基因修饰的可复制疫苗。

本发明通过采用与COVID-19的蝙蝠源性冠状病毒具有生物同源性的弱 毒性原型或父本株制备疫苗作为疫苗病毒株，其与COVID-19的蝙蝠源性冠状病 毒具有更好的同源性，在蛋白质序列和RNA序列上同源性更高，用该病毒株制 备的疫苗获得的抗体效果更好。

本发明所公开的COVID-19的蝙蝠源性冠状病毒疫苗基于SARS-CoV-2与 Bat/CovRaTG13的亲本关系。Bat/CovRaTG13与SARS-CoV-2之间的亲本关系由 每个病毒蛋白中同源的氨基酸序列所证明。除了S蛋白97.4％的同源性，所有其 它蛋白有98.45％同源显著相似性，有力地证明了这两种病毒是通过共同祖先遗 传进化而来，其小于1.6％氨基酸序列的变异仍然显示其遗传相关性。多个氨基 酸序列的比对表明，除了S蛋白内RBD和furin信号的区域外，每个蛋白的所有 区域在此两株病毒间都是同源的。S蛋白的序列同源性显示了相似的生物学表型， 包括抗原性，而RBD和furine基序中的变异或突变可能暗示了非人类病原体向 人类感染的遗传转移。由于这些原因，Bat/CovRaTG13可以是SARS-CoV-2的(非 致病)减毒原型。

本发明公开了使用蝙蝠起源的CoV，Bat/CovRaTG13株，开发针对COVID-19 的活性和/或非活性疫苗。由此产生的疫苗有机体保持复制(生长)和诱导免疫 的能力，但通常不会引起疾病。到目前为止，该Bat/CoVRaTG13株被发现是唯一 与SARS-CoV-2有共同祖先的蝙蝠冠状病毒。因此，对人类没有致病性的 Bat/CovRaTG13可以用作针对COVID-19的活疫苗。

附图说明

图1是本发明中Bat/CovRaTG13 RNA序列与最相关冠状病毒的多重对比；

图2是本发明中Bat/CovRaTG13多聚蛋白氨基酸序列多重比对分析；

图3是本发明中Bat/CovRaTG13 S蛋白氨基酸序列多重比对分析；

图4是本发明中Bat/CovRaTG13序列S蛋白RBD区(框内)与自成对的同 源性对比；

图5是本发明中Bat/CovRaTG13序列S蛋白RBD区(框内)与同一蝙蝠亚 种的另一株冠状病毒的同源性对比；

图6是本发明中Bat/CovRaTG13序列S蛋白RBD区(框内)与ARS-CoV-2 的同源性对比；

图7是本发明中Bat/CovRaTG13序列S蛋白RBD区(框内)与SARS样冠 状病毒的同源性对比；

具体实施方式

下面结合附图，对本发明作详细的说明。

为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施 例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用 以解释本发明，并不用于限定本发明。

SARS-CoV-2的来源被认为是自然的，出自于动物。通过对病毒株自然贮存 库的研究，发现了许多类似SARS的蝙蝠冠状病毒，与SARS-CoV-2病毒的相似 性达80％。然而，几乎所有COVID-19患者样本的病毒核酸序列都与2013年从 云南省采集的一蝙蝠(Rhinolophusaffinis)冠状病毒Bat/CovRaTG13有96％的 相似性。SARS-CoV-2和Bat/CovRaTG13菌株具有1141个核苷酸变异(替换) (遗传距离0.04和48个INDELs)。而与来自其他的bat-SL-CoVZC45/2017病毒 和SARS人-BJ182-12/2008病毒具有88％和80％的序列同源性(距离0.23和0.46)， 3542和5879个核苷酸替换(137和535个INDELs)。

Simplot分析和比对或非比对分析表明，SARS-CoV-2在整个基因组中与 Bat/CovRaTG13高度相似，全基因组RNA序列同源性大于96.2％，而全部氨基 酸序列达到97.95％同源性。其中S蛋白同源性为97.41％；而其余87％总结构和 非结构蛋白质氨基酸的同源性为98.45％，如图1所示。系统遗传分析也证实， SARS-CoV-2是Bat/CovRaTG13的近亲，而与其他SARSr-CoV分别形成了不同 的谱系。

冠状病毒颗粒含有四种结构蛋白，包括棘突蛋白(S)、包膜蛋白、膜蛋白和 核衣壳蛋白。其中，S蛋白在病毒的黏附、融合和进入细胞中起着最重要的作用， 是抗体、抑制剂和疫苗开发的靶点。S蛋白介导病毒进入宿主细胞，首先通过 S1亚单位的受体结合域(RBD)与宿主受体结合，然后通过S2亚单位融合病毒 膜和宿主膜。与SARS-CoV相似，SARS-CoV-2s蛋白也识别ACE2为其宿主受 体。包含RBD序列的S蛋白基因与其他SARSr-Cov高度不同，与所有先前描述 的SARSr-Cov的核苷酸序列同源性小于75％，但与Bat/CovRaTG13的核苷酸同源性为93.1％。对S蛋白氨基酸组成的比对分析表明，在SARS-CoV-2和 Bat/CovRaTG13之间，N末端400个氨基酸(S1亚单位)有98％相同，高于所 有其他冠状病毒、SARS-CoV或类SARS-CoV，如图3所示。然而，SARS-CoV-2 和Bat/CovRaTG13S1蛋白中的其余C末端残基具有94.4％的相似性，其同源性 高于其它蝙蝠类冠状病毒、类SARS冠状病毒。SARS-CoV-2S蛋白内的大多数 氨基酸变异集中在RBD区域。SARS-CoV-2和Bat/CovRaTG13的RBD基序中五 个关键残基中的四个与其他冠状病毒不同。然而，RBD区域的变异似乎并不影 响SARS-CoV-2s蛋白与ACE2受体的结合。此外，还有四个氨基酸插入进了S 蛋白，而且它们只存在于SARS-CoV-2的S蛋白，不存在于其他冠状病毒中。插 入的四个氨基酸PRRA位于S1和S2亚基结合处，被认为是furin裂解信号。然 而，插入的PRRA氨基酸是否对寄主范围、感染性和增加的传染性有影响尚不 清楚如图4～7所示。

与Bat/CovRaTG13相比，SARS-CoV-2核苷酸的变异多为沉默(silence)突变。 全基因组中不到1％的点突变引起了氨基酸的改变。如图3所示，S蛋白17个氨 基酸的聚集变异主要集中在RBD区。总之，遗传证据表明SARS-CoV-2与 Bat/CovRaTG13密切相关。如图2所示，而Bat/CovRaTG13与57株已测序 SARS-CoV-2(除外S蛋白)的氨基酸比对为98.45％同源性。因此，它们序列同 源性证明，后者是SARS-CoV-2的父本或亲本株。Bat/CovRaTG13(GenBank: MN996532.1)最初于2013年从中国云南省的一种蝙蝠(Rhinolophus affinis)-分离 出来。目前流行的SARS-CoV-2的祖先可能在2013年至2019年期间经历了重大 的进化，导致从蝙蝠物种向人类传播的遗传转变，尽管尚未确定中间宿主。

如上述所言，虽然导致人类感染的基因突变和COVID-19的发病机制尚不完 全清楚，但由于SARS-CoV-2与Bat/CovRaTG13的遗传关系最为密切，其S蛋 白的同源性为97.4％，具有相同抗原性，因此亲本Bat/CovRaTG13作为 SARS-CoV-2的弱毒株是COVID-19疫苗的一个很好的候选。Bat/CovRaTG13的 亲本型作为蝙蝠-CoV的来源，对人类没有或较低的致病性，使其成为一种很好 的候选疫苗。由于这两种病毒的生物学同源性，包括抗原性，接种Bat/CovRaTG13 可诱导对SARS-CoV-2的特异性免疫反应，保护健康人群免受SARS-CoV-2感染。

为了有效地使用Bat/CovRaTG13作为预防疫苗，本发明提供了可选择的解 决方案，其中包括：以Bat/CovRaTG13骨袈可以用作制造预防COVID-19的活 疫苗、灭活疫苗或重组疫苗。由于它的对人类无(或低)致病性，Bat/CovRaTG13 疫苗可以在低水平安全设施中生产。

其疫苗的具体制备方法如下：

所述活疫苗通过所述SARS-CoV-2的弱毒性原型或父本株经细胞培养、纯化、 制剂制备而成，不在体外进行基因修饰。由此产生的疫苗有机体保持复制(生长) 和诱导免疫的能力，但通常不会引起疾病。其具体包括以下步骤：细胞培养以扩 增Bat/CovRaTG13病毒；从培养液中收集病毒颗粒；通过培养液过滤、色谱或超 离心等方法纯化和浓缩病毒颗粒；无菌超滤、前它生产获得活疫苗。

所述灭活疫苗通过所述SARS-CoV-2的弱毒性原型或父本株经细胞培养、纯 化、灭活、制剂制备而成，不在体外进行基因修饰。其具体为：通过化学物质的 灭活或“杀死”过程制成灭活疫苗。灭活疫苗由全病毒(分子)组成，但丧失了 复制能力。但灭活疫苗是安全的，可与佐剂一起使用以增强免疫原性。所述化学 物质可以为福尔马林，所述佐剂可以为铝佐剂。

包括以下步骤：细胞培养以扩增Bat/CovRaTG13病毒；从培养液中收集病毒 颗粒；通过培养液过滤、色谱或超离心等方法纯化和浓缩病毒颗粒；使用福尔马 林“杀死”病毒颗粒；过滤并与佐剂混合；最后，将产品配制成带有缓冲液或保 护性试剂和预先确定剂量的产品疫苗，然后包装。

所述重组疫苗为通过人工点突变和/或将基因片段插入Bat/CovRaTG13的任 一基因中而产生的基因修饰的可复制疫苗。其具体为：通过在分子基础上，在 Bat/CovRaTG13 S蛋白中人工氨基酸突变或重组，而不改变S蛋白抗原性和不引 起COVID-19的相关疾病来制备。

本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披 露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的 组合。

序列表

<110> 四川骋誉生物制品有限公司

<120> 用于预防COVID-19的蝙蝠源性冠状病毒疫苗

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Glu Thr Pro Val Val Tyr Arg Lys Val Leu Leu Arg Lys Asn Gly Asn

115 120 125

Lys Gly Ala Gly Gly His Ser Tyr Gly Ala Asp Leu Lys Ser Phe Asp

130 135 140

Leu Gly Asp Glu Leu Gly Thr Asp Pro Tyr Glu Asp Phe Gln Glu Asn

145 150 155 160

Trp Asn Thr Lys His Ser Ser Gly Val Thr Arg Asp Leu Met Arg Glu

165 170 175

Leu Asn Gly Gly Ala Tyr Thr Arg Tyr Val Asp Asn Asn Phe Cys Gly

180 185 190

Pro Asp Gly Tyr Pro Leu Glu Cys Ile Lys Asp Leu Leu Ala Arg Ala

195 200 205

Gly Lys Ala Ser Cys Thr Leu Ser Glu Gln Leu Asp Phe Ile Asp Thr

210 215 220

Lys Arg Gly Val Tyr Cys Cys Arg Glu His Glu His Glu Ile Ala Trp

225 230 235 240

Tyr Thr Glu Arg Ser Glu Lys Ser Tyr Glu Leu Gln Thr Pro Phe Glu

245 250 255

Ile Lys Leu Ala Lys Lys Phe Asp Thr Phe Asn Gly Glu Cys Pro Asn

260 265 270

Phe Val Phe Pro Leu Asn Ser Thr Ile Lys Thr Ile Gln Pro Arg Val

275 280 285

Glu Lys Lys Lys Leu Asp Gly Phe Met Gly Arg Ile Arg Ser Val Tyr

290 295 300

Pro Val Ala Ser Pro Asn Glu Cys Asn Gln Met Cys Leu Ser Thr Leu

305 310 315 320

Met Lys Cys Asp His Cys Gly Glu Thr Ser Trp Gln Thr Gly Asp Phe

325 330 335

Val Lys Ala Thr Cys Glu Phe Cys Gly Thr Glu Asn Leu Thr Lys Glu

340 345 350

Gly Ala Thr Thr Cys Gly Tyr Leu Pro Gln Asn Ala Val Val Lys Ile

355 360 365

Tyr Cys Pro Ala Cys His Asn Pro Glu Val Gly Pro Glu His Ser Leu

370 375 380

Ala Glu Tyr His Asn Glu Ser Gly Leu Lys Pro Ile Leu Arg Lys Gly

385 390 395 400

Gly Arg Thr Ile Ala Phe Gly Gly Cys Val Phe Ser Tyr Val Gly Cys

405 410 415

Tyr Asn Lys Cys Ala Tyr Trp Ile Pro Arg Ala Ser Ala Asn Ile Gly

420 425 430

Cys Asn His Thr Gly Val Val Gly Glu Gly Ser Glu Gly Leu Asn Asp

435 440 445

Asn Leu Leu Glu Ile Leu Gln Lys Glu Lys Val Asn Ile Asn Ile Val

450 455 460

Gly Asp Phe Lys Leu Asn Glu Glu Ile Ala Ile Ile Leu Ala Ser Phe

465 470 475 480

Ser Ala Ser Thr Ser Ala Phe Val Glu Thr Val Lys Gly Leu Asp Tyr

485 490 495

Lys Thr Phe Lys Gln Ile Val Glu Ser Cys Gly Asn Phe Lys Val Thr

500 505 510

Lys Gly Lys Ala Lys Lys Gly Ala Trp Asn Ile Gly Glu Gln Lys Ser

515 520 525

Ile Leu Ser Pro Leu Tyr Ala Phe Ala Ser Glu Ala Ala Arg Val Val

530 535 540

Arg Ser Ile Phe Ser Arg Thr Leu Glu Thr Ala Gln Asn Ser Val Arg

545 550 555 560

Ala Leu Gln Lys Ala Ala Ile Thr Ile Leu Asp Gly Ile Ser Gln Tyr

565 570 575

Ser Leu Arg Leu Ile Asp Ala Met Met Phe Thr Ser Asp Leu Val Thr

580 585 590

Asn Asn Leu Val Val Met Ala Tyr Ile Thr Gly Gly Val Val Gln Leu

595 600 605

Thr Ser Gln Trp Leu Thr Asn Ile Phe Gly Thr Val Tyr Glu Gln Leu

610 615 620

Lys Pro Val Leu Asp Trp Leu Glu Glu Lys Phe Lys Glu Gly Val Glu

625 630 635 640

Phe Leu Arg Asp Gly Trp Glu Ile Val Lys Phe Ile Ser Thr Cys Ala

645 650 655

Cys Glu Ile Val Gly Gly Gln Ile Val Thr Cys Ala Lys Glu Ile Lys

660 665 670

Glu Ser Val Gln Thr Phe Phe Lys Leu Val Asn Lys Phe Leu Ala Leu

675 680 685

Cys Ala Asp Ser Ile Ile Ile Gly Gly Ala Lys Leu Lys Ala Leu Asn

690 695 700

Leu Gly Glu Thr Phe Val Thr His Ser Lys Gly Leu Tyr Arg Lys Cys

705 710 715 720

Val Lys Pro Lys Glu Glu Thr Gly Leu Leu Met Pro Leu Lys Ala Pro

725 730 735

Lys Glu Ile Ile Phe Leu Glu Gly Glu Thr Leu Pro Thr Glu Val Leu

740 745 750

Thr Glu Glu Val Val Leu Lys Thr Gly Asp Leu Gln Pro Leu Glu Gln

755 760 765

Pro Thr Ser Glu Ala Val Glu Ala Pro Leu Val Gly Thr Pro Val Cys

770 775 780

Ile Asn Gly Leu Met Leu Leu Glu Ile Lys Asp Thr Glu Lys Tyr Cys

785 790 795 800

Ala Leu Ala Pro Asn Met Met Val Thr Asn Asn Thr Phe Thr Leu Lys

805 810 815

Gly Gly Ala Pro Thr Lys Val Thr Phe Gly Asp Asp Thr Val Ile Glu

820 825 830

Val Gln Gly Tyr Lys Ser Val Asn Ile Thr Phe Glu Leu Asp Glu Arg

835 840 845

Ile Asp Lys Val Leu Asn Glu Lys Cys Ser Thr Tyr Thr Val Glu Leu

850 855 860

Gly Thr Glu Val Asn Glu Phe Ala Cys Val Val Ala Asp Ala Val Ile

865 870 875 880

Lys Thr Leu Gln Pro Val Ser Glu Leu Leu Ile Pro Leu Gly Ile Asp

885 890 895

Leu Asp Glu Trp Gly Met Ala Thr Tyr Tyr Leu Phe Asp Glu Ser Gly

900 905 910

Glu Phe Lys Leu Ala Ser His Met Tyr Cys Ser Phe Tyr Pro Pro Asp

915 920 925

Glu Asp Glu Glu Glu Gly Asp Cys Glu Glu Glu Asp Phe Glu Pro Pro

930 935 940

Thr Gln Tyr Glu Tyr Gly Thr Glu Asp Asp Tyr Gln Gly Lys Ser Leu

945 950 955 960

Glu Phe Gly Ala Thr Ser Val Thr Pro Gln Pro Glu Glu Glu Leu Glu

965 970 975

Glu Asp Trp Leu Asp Asp Asp Ser Gln Gln Thr Val Val Gln Glu Asp

980 985 990

Asp Ser Glu Val Asn Gln Thr Thr Ile Thr Gln Ser Ile Ala Glu Val

995 1000 1005

Gln Pro Gln Leu Glu Met Glu Pro Thr Pro Val Val Gln Thr Glu Val

1010 1015 1020

Asn Ser Phe Ser Gly Tyr Leu Lys Leu Thr Asp Asn Val Tyr Ile Lys

1025 1030 1035 1040

Asn Ala Asp Ile Val Glu Glu Ala Lys Lys Val Lys Pro Thr Ile Val

1045 1050 1055

Val Asn Ala Ala Asn Val Tyr Leu Lys His Gly Gly Gly Val Ala Gly

1060 1065 1070

Ala Leu Asn Lys Ala Thr Asn Asn Ala Met Gln Val Glu Ser Asp His

1075 1080 1085

Tyr Ile Ala Thr Asn Gly Pro Leu Lys Val Gly Gly Gly Cys Val Leu

1090 1095 1100

Ser Gly His Asn Leu Ala Lys Asn Cys Leu His Val Val Gly Pro Asn

1105 1110 1115 1120

Val Asn Arg Gly Glu Asp Ile Gln Leu Leu Lys Ser Ala Tyr Glu Asn

1125 1130 1135

Phe Asn Gln His Asp Val Leu Leu Ala Pro Leu Leu Ser Ala Gly Ile

1140 1145 1150

Phe Gly Ala Asp Pro Val His Ser Leu Arg Val Cys Val Asp Thr Val

1155 1160 1165

Arg Thr Asn Val Tyr Leu Ala Val Phe Asp Lys Asn Leu Tyr Asp Lys

1170 1175 1180

Leu Val Ser Ser Phe Leu Glu Met Lys Ser Glu Lys Gln Val Glu Gln

1185 1190 1195 1200

Lys Thr Ala Glu Ile Pro Lys Glu Glu Val Lys Ser Ser Ile Thr Glu

1205 1210 1215

Ser Lys Leu Ser Val Glu Gln Arg Gln Gln Val Asp Lys Lys Ile Lys

1220 1225 1230

Ala Cys Val Glu Glu Val Thr Thr Thr Leu Glu Glu Thr Lys Phe Leu

1235 1240 1245

Thr Glu Asn Leu Leu Leu Tyr Ile Asp Ile Asn Gly Asn Leu His Pro

1250 1255 1260

Asp Ser Ala Thr Leu Val Asn Asp Ile Asp Ile Thr Phe Leu Lys Lys

1265 1270 1275 1280

Asp Ala Pro Tyr Ile Val Gly Asp Val Val Gln Glu Gly Val Leu Thr

1285 1290 1295

Ala Val Val Ile Pro Thr Lys Lys Ala Gly Gly Thr Thr Glu Met Leu

1300 1305 1310

Thr Lys Ala Leu Arg Lys Val Pro Thr Asp Asn Tyr Ile Thr Thr Tyr

1315 1320 1325

Pro Gly Gln Gly Leu Asn Gly Tyr Thr Val Glu Glu Ala Arg Thr Val

1330 1335 1340

Leu Lys Lys Cys Lys Ser Ala Phe Tyr Ile Leu Pro Ser Ile Ile Ser

1345 1350 1355 1360

Asn Glu Lys Gln Glu Ile Leu Gly Thr Val Ser Trp Asn Leu Arg Glu

1365 1370 1375

Met Leu Ala His Ala Glu Glu Thr Arg Lys Leu Met Pro Val Cys Met

1380 1385 1390

Glu Thr Lys Ala Ile Val Ser Thr Ile Gln Arg Lys Tyr Lys Gly Ile

1395 1400 1405

Lys Ile Gln Glu Gly Val Val Asp Tyr Gly Ala Arg Phe Tyr Phe Tyr

1410 1415 1420

Thr Ser Lys Thr Thr Val Ala Ser Leu Ile Asn Thr Leu Asn Asp Leu

1425 1430 1435 1440

Asn Glu Thr Leu Val Thr Met Pro Leu Gly Tyr Val Thr His Gly Leu

1445 1450 1455

Asn Leu Glu Glu Ala Ala Arg Tyr Met Arg Ser Leu Lys Val Pro Ala

1460 1465 1470

Thr Val Ser Val Ser Ser Pro Asp Ala Val Thr Ala Tyr Asn Gly Tyr

1475 1480 1485

Leu Thr Ser Ser Ser Lys Thr Pro Glu Glu His Phe Ile Glu Thr Ile

1490 1495 1500

Ser Leu Ala Gly Ser Tyr Lys Asp Trp Ser Tyr Ser Gly Gln Ser Thr

1505 1510 1515 1520

Gln Leu Gly Ile Glu Phe Leu Lys Arg Gly Asp Lys Ser Val Tyr Tyr

1525 1530 1535

Thr Ser Asn Pro Ile Thr Phe His Leu Asp Gly Glu Val Ile Thr Phe

1540 1545 1550

Asp Asn Leu Lys Ile Leu Leu Ser Leu Lys Glu Val Arg Thr Ile Lys

1555 1560 1565

Val Phe Thr Thr Val Asp Asn Ile Asn Leu His Thr Gln Val Val Asp

1570 1575 1580

Met Ser Met Thr Tyr Gly Gln Gln Phe Gly Pro Thr Tyr Leu Asp Gly

1585 1590 1595 1600

Ala Asp Val Thr Lys Ile Lys Pro His Asn Ser His Glu Gly Lys Thr

1605 1610 1615

Phe Tyr Val Leu Pro Asn Asp Asp Thr Leu Arg Ala Glu Ala Phe Glu

1620 1625 1630

Tyr Tyr His Thr Thr Asp Pro Ser Phe Leu Gly Arg Tyr Met Ser Ala

1635 1640 1645

Leu Asn His Thr Lys Lys Trp Lys Tyr Pro Gln Val Asn Gly Leu Thr

1650 1655 1660

Ser Ile Lys Trp Ala Asp Asn Asn Cys Tyr Leu Ala Thr Ala Leu Leu

1665 1670 1675 1680

Thr Leu Gln Gln Ile Glu Leu Lys Phe Asn Pro Pro Ala Leu Gln Asp

1685 1690 1695

Ala Tyr Tyr Arg Ala Arg Ala Gly Glu Ala Ala Asn Phe Cys Ala Leu

1700 1705 1710

Ile Leu Ala Tyr Cys Asn Lys Thr Val Gly Glu Leu Gly Asp Val Arg

1715 1720 1725

Glu Thr Met Asn Tyr Leu Phe Gln His Ala Asn Leu Asp Ser Cys Lys

1730 1735 1740

Arg Val Leu Asn Val Val Cys Lys Thr Cys Gly Gln Gln Gln Thr Thr

1745 1750 1755 1760

Leu Lys Gly Val Glu Ala Val Met Tyr Met Gly Thr Leu Ser Tyr Glu

1765 1770 1775

Gln Leu Lys Lys Gly Val Gln Ile Pro Cys Thr Cys Gly Lys Gln Ala

1780 1785 1790

Thr Gln Tyr Leu Val Gln Gln Glu Ser Pro Phe Val Met Met Ser Ala

1795 1800 1805

Pro Pro Ala Gln Tyr Glu Leu Lys His Gly Thr Phe Ile Cys Ala Ser

1810 1815 1820

Glu Tyr Thr Gly Asn Tyr Gln Cys Gly His Tyr Lys His Ile Thr Ser

1825 1830 1835 1840

Lys Glu Thr Leu Tyr Cys Ile Asp Gly Ala Leu Leu Thr Lys Ser Ser

1845 1850 1855

Glu Tyr Lys Gly Pro Ile Thr Asp Ile Phe Tyr Lys Glu Asn Ser Tyr

1860 1865 1870

Ile Thr Thr Ile Lys Pro Val Ile Tyr Lys Leu Asp Gly Val Val Cys

1875 1880 1885

Thr Glu Ile Asp Pro Lys Leu Asp Asn Tyr Tyr Lys Lys Asp Asn Ser

1890 1895 1900

Tyr Phe Thr Glu Gln Pro Ile Asp Leu Val Pro Asn Gln Pro Tyr Pro

1905 1910 1915 1920

Asn Ala Ser Phe Asp Asn Phe Lys Phe Val Cys Asp Asn Ile Lys Leu

1925 1930 1935

Ala Asp Asp Leu Asn Gln Leu Thr Gly Tyr Lys Lys Pro Ala Ser Arg

1940 1945 1950

Glu Phe Lys Val Thr Phe Phe Pro Asp Leu Asn Gly Asp Val Val Ala

1955 1960 1965

Ile Asp Tyr Lys His Tyr Thr Pro Ser Phe Lys Lys Gly Ala Lys Leu

1970 1975 1980

Leu His Lys Pro Ile Val Trp His Val Asn Asn Ala Thr Asn Lys Ala

1985 1990 1995 2000

Thr Tyr Lys Pro Asn Thr Trp Cys Ile Arg Cys Leu Trp Asn Thr Lys

2005 2010 2015

Pro Val Glu Thr Ser Asn Ser Phe Asp Val Leu Lys Ser Glu Asp Thr

2020 2025 2030

Gln Gly Met Asp Asn Leu Ala Cys Glu Asp Leu Lys Pro Val Ser Glu

2035 2040 2045

Glu Val Val Glu Asn Pro Thr Ile Gln Lys Asp Ile Leu Glu Cys Asn

2050 2055 2060

Val Lys Thr Thr Glu Val Val Gly Asp Ile Ile Leu Lys Pro Ala Asn

2065 2070 2075 2080

Asp Gly Leu Lys Ile Thr Glu Glu Val Gly His Thr Asp Leu Met Ala

2085 2090 2095

Ala Tyr Val Asp Asn Ser Ser Leu Thr Ile Lys Lys Pro Asn Glu Leu

2100 2105 2110

Ser Arg Val Leu Gly Leu Lys Thr Leu Val Thr His Gly Leu Ala Ala

2115 2120 2125

Val Asn Ser Val Pro Trp Asp Thr Ile Ala Asn Tyr Ala Lys Pro Phe

2130 2135 2140

Leu Asn Lys Val Val Ser Thr Thr Thr Asn Ile Val Thr Arg Cys Leu

2145 2150 2155 2160

Asn Arg Val Cys Thr Asn Tyr Met Pro Tyr Phe Phe Thr Leu Leu Leu

2165 2170 2175

Gln Leu Cys Thr Phe Thr Arg Ser Thr Asn Ser Arg Ile Lys Ala Ser

2180 2185 2190

Met Pro Thr Thr Ile Ala Lys Asn Thr Val Lys Ser Val Gly Lys Phe

2195 2200 2205

Cys Leu Glu Ala Ser Phe Asn Tyr Leu Lys Ser Pro Asn Phe Phe Thr

2210 2215 2220

Leu Ile Asn Ile Ile Ile Trp Phe Leu Leu Leu Ser Val Cys Leu Gly

2225 2230 2235 2240

Ser Leu Ile Tyr Ser Thr Ala Ala Leu Gly Val Leu Met Ser Asn Leu

2245 2250 2255

Gly Met Pro Ser Tyr Cys Thr Gly Tyr Arg Glu Gly Tyr Leu Asn Ser

2260 2265 2270

Thr Asn Val Thr Thr Ala Ile Tyr Cys Thr Gly Ser Ile Pro Cys Gly

2275 2280 2285

Val Cys Leu Ser Gly Leu Asp Ser Leu Asp Thr Tyr Pro Ser Leu Glu

2290 2295 2300

Thr Ile Gln Ile Thr Ile Ser Ser Phe Lys Trp Asp Leu Thr Ala Phe

2305 2310 2315 2320

Gly Leu Val Ala Glu Trp Phe Leu Ala Tyr Ile Leu Phe Thr Arg Phe

2325 2330 2335

Phe Tyr Val Leu Gly Leu Ala Ala Ile Met Gln Leu Phe Phe Ser Tyr

2340 2345 2350

Phe Ala Val His Phe Ile Ser Asn Ser Trp Leu Met Trp Leu Ile Ile

2355 2360 2365

Asn Leu Val Gln Met Ala Pro Ile Ser Ala Met Val Arg Met Tyr Ile

2370 2375 2380

Phe Phe Ala Ser Phe Tyr Tyr Val Trp Lys Ser Tyr Val His Val Val

2385 2390 2395 2400

Asp Gly Cys Thr Ser Ser Thr Cys Met Met Cys Tyr Lys Arg Asn Arg

2405 2410 2415

Ala Thr Arg Val Glu Cys Thr Thr Ile Val Asn Gly Val Arg Arg Ser

2420 2425 2430

Phe Tyr Val Tyr Ala Asn Gly Gly Lys Gly Phe Cys Lys Leu His Asn

2435 2440 2445

Trp Asn Cys Val Asn Cys Asp Thr Phe Cys Ala Gly Ser Thr Phe Ile

2450 2455 2460

Ser Asp Glu Val Ala Arg Asp Leu Ser Leu Gln Phe Lys Arg Pro Ile

2465 2470 2475 2480

Asn Pro Thr Asp Gln Ser Ser Tyr Ile Val Asp Ser Val Thr Val Lys

2485 2490 2495

Asn Gly Ser Ile His Leu Tyr Phe Asp Lys Ala Gly Gln Lys Thr Tyr

2500 2505 2510

Glu Arg His Ser Leu Ser His Phe Val Asn Leu Asp Asn Leu Arg Ala

2515 2520 2525

Ser Asn Thr Lys Gly Ser Leu Pro Ile Asn Val Ile Val Phe Asp Gly

2530 2535 2540

Lys Ser Lys Cys Glu Glu Ser Ser Ala Lys Ser Ala Ser Val Tyr Tyr

2545 2550 2555 2560

Ser Gln Leu Met Cys Gln Pro Ile Leu Leu Leu Asp Gln Ala Leu Val

2565 2570 2575

Ser Asp Val Gly Asp Ser Thr Glu Val Ala Val Lys Met Phe Asp Ala

2580 2585 2590

Tyr Val Asn Thr Phe Ser Ser Thr Phe Asn Val Pro Met Glu Lys Leu

2595 2600 2605

Lys Thr Leu Val Ala Thr Ala Glu Ala Glu Leu Ala Lys Asn Val Ser

2610 2615 2620

Leu Asp Asn Val Leu Ser Thr Phe Ile Ser Ala Ala Arg Gln Gly Phe

2625 2630 2635 2640

Val Asp Ser Asp Val Glu Thr Lys Asp Val Val Glu Cys Leu Lys Leu

2645 2650 2655

Ser His Gln Ser Asp Ile Glu Val Thr Gly Asp Ser Cys Asn Asn Tyr

2660 2665 2670

Met Leu Thr Tyr Asn Lys Val Glu Asn Met Thr Pro Arg Asp Leu Gly

2675 2680 2685

Ala Cys Ile Asp Cys Ser Ala Arg His Ile Asn Ala Gln Val Ala Lys

2690 2695 2700

Ser His Asn Ile Ala Leu Ile Trp Asn Val Lys Asp Phe Met Ser Leu

2705 2710 2715 2720

Ser Glu Gln Leu Arg Lys Gln Ile Arg Ser Ala Ala Lys Lys Asn Asn

2725 2730 2735

Leu Pro Phe Lys Leu Thr Cys Ala Thr Thr Arg Gln Val Val Asn Val

2740 2745 2750

Val Thr Thr Lys Ile Ala Leu Lys Gly Gly Lys Ile Val Asn Asn Trp

2755 2760 2765

Leu Lys Gln Leu Ile Lys Val Thr Leu Val Phe Leu Phe Val Ala Ala

2770 2775 2780

Ile Phe Tyr Leu Ile Thr Pro Val His Val Met Ser Lys His Thr Asp

2785 2790 2795 2800

Phe Ser Ser Glu Ile Ile Gly Tyr Lys Ala Ile Asp Gly Gly Val Thr

2805 2810 2815

Arg Asp Ile Ala Ser Thr Asp Thr Cys Phe Ala Asn Lys His Ala Asp

2820 2825 2830

Phe Asp Thr Trp Phe Ser Gln Arg Gly Gly Ser Tyr Thr Asn Asp Lys

2835 2840 2845

Ala Cys Pro Leu Ile Ala Ala Val Ile Thr Arg Glu Val Gly Phe Val

2850 2855 2860

Val Pro Gly Leu Pro Gly Thr Ile Leu Arg Thr Thr Asn Gly Asp Phe

2865 2870 2875 2880

Leu His Phe Leu Pro Arg Val Phe Ser Ala Val Gly Asn Ile Cys Tyr

2885 2890 2895

Thr Pro Ser Lys Leu Ile Glu Tyr Thr Asp Phe Ala Thr Ser Ala Cys

2900 2905 2910

Val Leu Ala Ala Glu Cys Thr Ile Phe Lys Asp Ala Ser Gly Lys Pro

2915 2920 2925

Val Pro Tyr Cys Tyr Asp Thr Asn Val Leu Glu Gly Ser Val Ala Tyr

2930 2935 2940

Glu Ser Leu Arg Pro Asp Thr Arg Tyr Val Leu Met Asp Gly Ser Ile

2945 2950 2955 2960

Ile Gln Phe Pro Asn Thr Tyr Leu Glu Gly Ser Val Arg Val Val Thr

2965 2970 2975

Thr Phe Asp Ser Glu Tyr Cys Arg His Gly Thr Cys Glu Arg Ser Glu

2980 2985 2990

Ala Gly Val Cys Val Ser Thr Ser Gly Arg Trp Val Leu Asn Asn Asp

2995 3000 3005

Tyr Tyr Arg Ser Leu Pro Gly Val Phe Cys Gly Val Asp Ala Val Asn

3010 3015 3020

Leu Leu Thr Asn Met Phe Thr Pro Leu Ile Gln Pro Ile Gly Ala Leu

3025 3030 3035 3040

Asp Ile Ser Ala Ser Ile Val Ala Gly Gly Ile Val Ala Ile Val Val

3045 3050 3055

Thr Cys Leu Ala Tyr Tyr Phe Met Arg Phe Arg Arg Ala Phe Gly Glu

3060 3065 3070

Tyr Ser His Val Val Ala Phe Asn Thr Leu Leu Phe Leu Met Ser Phe

3075 3080 3085

Thr Val Leu Cys Leu Thr Pro Val Tyr Ser Phe Leu Pro Gly Val Tyr

3090 3095 3100

Ser Val Ile Tyr Leu Tyr Leu Thr Phe Tyr Leu Thr Asn Asp Val Ser

3105 3110 3115 3120

Phe Leu Ala His Ile Gln Trp Met Val Met Phe Thr Pro Leu Val Pro

3125 3130 3135

Phe Trp Ile Thr Ile Val Tyr Val Ile Cys Ile Ser Thr Lys His Phe

3140 3145 3150

Tyr Trp Phe Phe Ser Asn Tyr Leu Lys Arg Arg Val Val Phe Asn Gly

3155 3160 3165

Val Ser Phe Ser Thr Phe Glu Glu Ala Ala Leu Cys Thr Phe Leu Leu

3170 3175 3180

Asn Lys Glu Met Tyr Leu Lys Leu Arg Ser Asp Val Leu Leu Pro Leu

3185 3190 3195 3200

Thr Gln Tyr Asn Arg Tyr Leu Ala Leu Tyr Asn Lys Tyr Lys Tyr Phe

3205 3210 3215

Ser Gly Ala Met Asp Thr Thr Ser Tyr Arg Glu Ala Ala Cys Cys His

3220 3225 3230

Leu Ala Lys Ala Leu Asn Asp Phe Ser Asn Ser Gly Ser Asp Val Leu

3235 3240 3245

Tyr Gln Pro Pro Gln Thr Ser Ile Thr Ser Ala Val Leu Gln Ser Gly

3250 3255 3260

Phe Arg Lys Met Ala Phe Pro Ser Gly Lys Val Glu Gly Cys Met Val

3265 3270 3275 3280

Gln Val Thr Cys Gly Thr Thr Thr Leu Asn Gly Leu Trp Leu Asp Asp

3285 3290 3295

Val Val Tyr Cys Pro Arg His Val Ile Cys Thr Ser Glu Asp Met Leu

3300 3305 3310

Asn Pro Asn Tyr Glu Asp Leu Leu Ile Arg Lys Ser Asn His Asn Phe

3315 3320 3325

Leu Val Gln Ala Gly Asn Val Gln Leu Arg Val Ile Gly His Ser Met

3330 3335 3340

Gln Asn Cys Val Leu Lys Leu Lys Val Asp Thr Ala Asn Thr Lys Thr

3345 3350 3355 3360

Pro Lys Tyr Lys Phe Val Arg Ile Gln Pro Gly Gln Thr Phe Ser Val

3365 3370 3375

Leu Ala Cys Tyr Asn Gly Ser Pro Ser Gly Val Tyr Gln Cys Ala Met

3380 3385 3390

Arg Pro Asn Phe Thr Ile Lys Gly Ser Phe Leu Asn Gly Ser Cys Gly

3395 3400 3405

Ser Val Gly Phe Asn Ile Asp Tyr Asp Cys Val Ser Phe Cys Tyr Met

3410 3415 3420

His His Met Glu Leu Pro Thr Gly Val His Ala Gly Thr Asp Leu Glu

3425 3430 3435 3440

Gly Thr Phe Tyr Gly Pro Phe Val Asp Arg Gln Thr Ala Gln Ala Ala

3445 3450 3455

Gly Thr Asp Thr Thr Ile Thr Val Asn Val Leu Ala Trp Leu Tyr Ala

3460 3465 3470

Ala Val Ile Asn Gly Asp Arg Trp Phe Leu Asn Arg Phe Thr Thr Thr

3475 3480 3485

Leu Asn Asp Phe Asn Leu Val Ala Met Lys Tyr Asn Tyr Glu Pro Leu

3490 3495 3500

Thr Gln Asp His Val Asp Ile Leu Gly Pro Leu Ser Ala Gln Thr Gly

3505 3510 3515 3520

Ile Ala Val Leu Asp Met Cys Ala Ser Leu Lys Glu Leu Leu Gln Asn

3525 3530 3535

Gly Met Asn Gly Arg Thr Ile Leu Gly Ser Ala Leu Leu Glu Asp Glu

3540 3545 3550

Phe Thr Pro Phe Asp Val Val Arg Gln Cys Ser Gly Val Thr Phe Gln

3555 3560 3565

Ser Ala Val Lys Arg Thr Ile Lys Gly Thr His His Trp Leu Leu Leu

3570 3575 3580

Thr Ile Leu Thr Ser Leu Leu Val Leu Val Gln Ser Thr Gln Trp Ser

3585 3590 3595 3600

Leu Phe Phe Phe Val Tyr Glu Asn Ala Phe Leu Pro Phe Ala Met Gly

3605 3610 3615

Ile Ile Ala Met Ser Ala Phe Ala Met Met Phe Val Lys His Lys His

3620 3625 3630

Ala Phe Leu Cys Leu Phe Leu Leu Pro Ser Leu Ala Thr Val Ala Tyr

3635 3640 3645

Phe Asn Met Val Tyr Met Pro Ala Ser Trp Val Met Arg Ile Met Thr

3650 3655 3660

Trp Leu Asp Met Val Asp Thr Ser Leu Ser Gly Phe Lys Leu Lys Asp

3665 3670 3675 3680

Cys Val Met Tyr Ala Ser Ala Val Val Leu Leu Ile Leu Met Thr Ala

3685 3690 3695

Arg Thr Val Tyr Asp Asp Gly Ala Arg Arg Val Trp Thr Leu Met Asn

3700 3705 3710

Val Leu Thr Leu Val Tyr Lys Val Tyr Tyr Gly Asn Ala Leu Asp Gln

3715 3720 3725

Ala Ile Ser Met Trp Ala Leu Ile Ile Ser Val Thr Ser Asn Tyr Ser

3730 3735 3740

Gly Val Val Thr Thr Val Met Phe Leu Ala Arg Gly Ile Val Phe Met

3745 3750 3755 3760

Cys Val Glu Tyr Cys Pro Ile Phe Phe Ile Thr Gly Asn Thr Leu Gln

3765 3770 3775

Cys Ile Met Leu Val Tyr Cys Phe Leu Gly Tyr Phe Cys Thr Cys Tyr

3780 3785 3790

Phe Gly Leu Phe Cys Leu Leu Asn Arg Tyr Phe Arg Leu Thr Leu Gly

3795 3800 3805

Val Tyr Asp Tyr Leu Val Ser Thr Gln Glu Phe Arg Tyr Met Asn Ser

3810 3815 3820

Gln Gly Leu Leu Pro Pro Lys Asn Ser Ile Asp Ala Phe Lys Leu Asn

3825 3830 3835 3840

Ile Lys Leu Leu Gly Val Gly Gly Lys Pro Cys Ile Lys Val Ala Thr

3845 3850 3855

Val Gln Ser Lys Met Ser Asp Val Lys Cys Thr Ser Val Val Leu Leu

3860 3865 3870

Ser Val Leu Gln Gln Leu Arg Val Glu Ser Ser Ser Lys Leu Trp Ala

3875 3880 3885

Gln Cys Val Gln Leu His Asn Asp Ile Leu Leu Ala Lys Asp Thr Thr

3890 3895 3900

Glu Ala Phe Glu Lys Met Val Ser Leu Leu Ser Val Leu Leu Ser Met

3905 3910 3915 3920

Gln Gly Ala Val Asp Ile Asn Lys Leu Cys Glu Glu Met Leu Asp Asn

3925 3930 3935

Arg Ala Thr Leu Gln Ala Ile Ala Ser Glu Phe Ser Ser Leu Pro Ser

3940 3945 3950

Tyr Ala Ala Phe Ala Thr Ala Gln Glu Ala Tyr Glu Gln Ala Val Ala

3955 3960 3965

Asn Gly Asp Ser Glu Val Val Leu Lys Lys Leu Lys Lys Ser Leu Asn

3970 3975 3980

Val Ala Lys Ser Glu Phe Asp Arg Asp Ala Ala Met Gln Arg Lys Leu

3985 3990 3995 4000

Glu Lys Met Ala Asp Gln Ala Met Thr Gln Met Tyr Lys Gln Ala Arg

4005 4010 4015

Ser Glu Asp Lys Arg Ala Lys Val Thr Ser Ala Met Gln Thr Met Leu

4020 4025 4030

Phe Thr Met Leu Arg Lys Leu Asp Asn Asp Ala Leu Asn Asn Ile Ile

4035 4040 4045

Asn Asn Ala Arg Asp Gly Cys Val Pro Leu Asn Ile Ile Pro Leu Thr

4050 4055 4060

Thr Ala Ala Lys Leu Met Val Val Ile Pro Asp Tyr Asn Thr Tyr Lys

4065 4070 4075 4080

Asn Thr Cys Asp Gly Thr Thr Phe Thr Tyr Ala Ser Ala Leu Trp Glu

4085 4090 4095

Ile Gln Gln Val Val Asp Ala Asp Ser Lys Ile Val Gln Leu Ser Glu

4100 4105 4110

Ile Ser Met Asp Asn Ser Pro Asn Leu Ala Trp Pro Leu Ile Val Thr

4115 4120 4125

Ala Leu Arg Ala Asn Ser Ala Val Lys Leu Gln Asn Asn Glu Leu Ser

4130 4135 4140

Pro Val Ala Leu Arg Gln Met Ser Cys Ala Ala Gly Thr Thr Gln Thr

4145 4150 4155 4160

Ala Cys Thr Asp Asp Asn Ala Leu Ala Tyr Tyr Asn Thr Thr Lys Gly

4165 4170 4175

Gly Arg Phe Val Leu Ala Leu Leu Ser Asp Leu Gln Asp Leu Lys Trp

4180 4185 4190

Ala Arg Phe Pro Lys Ser Asp Gly Thr Gly Thr Ile Tyr Thr Glu Leu

4195 4200 4205

Glu Pro Pro Cys Arg Phe Val Thr Asp Thr Pro Lys Gly Pro Lys Val

4210 4215 4220

Lys Tyr Leu Tyr Phe Ile Lys Gly Leu Asn Asn Leu Asn Arg Gly Met

4225 4230 4235 4240

Val Leu Gly Ser Leu Ala Ala Thr Val Arg Leu Gln Ala Gly Asn Ala

4245 4250 4255

Thr Glu Val Pro Ala Asn Ser Thr Val Leu Ser Phe Cys Ala Phe Ala

4260 4265 4270

Val Asp Ala Ala Lys Ala Tyr Lys Asp Tyr Leu Ala Ser Gly Gly Gln

4275 4280 4285

Pro Ile Thr Asn Cys Val Lys Met Leu Cys Thr His Thr Gly Thr Gly

4290 4295 4300

Gln Ala Ile Thr Val Thr Pro Glu Ala Asn Met Asp Gln Glu Ser Phe

4305 4310 4315 4320

Gly Gly Ala Ser Cys Cys Leu Tyr Cys Arg Cys His Ile Asp His Pro

4325 4330 4335

Asn Pro Lys Gly Phe Cys Asp Leu Lys Gly Lys Tyr Val Gln Ile Pro

4340 4345 4350

Thr Thr Cys Ala Asn Asp Pro Val Gly Phe Thr Leu Lys Asn Thr Val

4355 4360 4365

Cys Thr Val Cys Gly Met Trp Lys Gly Tyr Gly Cys Ser Cys Asp Gln

4370 4375 4380

Leu Arg Glu Pro Met Leu Gln Ser Ala Asp Ala Gln Ser Phe Leu Asn

4385 4390 4395 4400

Arg Val Cys Gly Val Ser Ala Ala Arg Leu Thr Pro Cys Gly Thr Gly

4405 4410 4415

Thr Ser Thr Asp Val Val Tyr Arg Ala Phe Asp Ile Tyr Asn Asp Lys

4420 4425 4430

Val Ala Gly Phe Ala Lys Phe Leu Lys Thr Asn Cys Cys Arg Phe Gln

4435 4440 4445

Glu Lys Asp Glu Asp Asp Asn Leu Ile Asp Ser Tyr Phe Val Val Lys

4450 4455 4460

Arg His Thr Phe Ser Asn Tyr Gln His Glu Glu Thr Ile Tyr Asn Leu

4465 4470 4475 4480

Leu Lys Asp Cys Pro Ala Val Ala Lys His Asp Phe Phe Lys Phe Arg

4485 4490 4495

Ile Asp Gly Asp Met Val Pro His Ile Ser Arg Gln Arg Leu Thr Lys

4500 4505 4510

Tyr Thr Met Ala Asp Leu Val Tyr Ala Leu Arg His Phe Asp Glu Gly

4515 4520 4525

Asn Cys Asp Thr Leu Arg Glu Ile Leu Val Thr Tyr Asn Cys Cys Asp

4530 4535 4540

Asp Asp Tyr Phe Asn Lys Lys Asp Trp Tyr Asp Phe Val Glu Asn Pro

4545 4550 4555 4560

Asp Ile Leu Arg Val Tyr Ala Asn Leu Gly Glu Arg Val Arg Gln Ala

4565 4570 4575

Leu Leu Lys Thr Val Gln Phe Cys Asp Ala Met Arg Asp Ala Gly Ile

4580 4585 4590

Val Gly Val Leu Thr Leu Asp Asn Gln Asp Leu Asn Gly Asn Trp Tyr

4595 4600 4605

Asp Phe Gly Asp Phe Ile Gln Thr Thr Pro Gly Ser Gly Val Pro Ile

4610 4615 4620

Val Asp Ser Tyr Tyr Ser Leu Leu Met Pro Ile Leu Thr Leu Thr Arg

4625 4630 4635 4640

Ala Leu Thr Ala Glu Ser His Val Asp Thr Asp Leu Thr Lys Pro Tyr

4645 4650 4655

Ile Lys Trp Asp Leu Leu Lys Tyr Asp Phe Thr Glu Glu Arg Leu Lys

4660 4665 4670

Leu Phe Asp Arg Tyr Phe Lys Tyr Trp Asp Gln Thr Tyr His Pro Asn

4675 4680 4685

Cys Val Asn Cys Leu Asp Asp Arg Cys Ile Leu His Cys Ala Asn Phe

4690 4695 4700

Asn Val Leu Phe Ser Thr Val Phe Pro Pro Thr Ser Phe Gly Pro Leu

4705 4710 4715 4720

Val Arg Lys Ile Phe Val Asp Gly Val Pro Phe Val Val Ser Thr Gly

4725 4730 4735

Tyr His Phe Arg Glu Leu Gly Val Val His Asn Gln Asp Val Asn Leu

4740 4745 4750

His Ser Ser Arg Leu Ser Phe Lys Glu Leu Leu Val Tyr Ala Ala Asp

4755 4760 4765

Pro Ala Met His Ala Ala Ser Gly Asn Leu Leu Leu Asp Lys Arg Thr

4770 4775 4780

Thr Cys Phe Ser Val Ala Ala Leu Thr Asn Asn Val Ala Phe Gln Thr

4785 4790 4795 4800

Val Lys Pro Gly Asn Phe Asn Lys Asp Phe Tyr Asp Phe Ala Val Ser

4805 4810 4815

Lys Gly Phe Phe Lys Glu Gly Ser Ser Val Glu Leu Lys His Phe Phe

4820 4825 4830

Phe Ala Gln Asp Gly Asn Ala Ala Ile Ser Asp Tyr Asp Tyr Tyr Arg

4835 4840 4845

Tyr Asn Leu Pro Thr Met Cys Asp Ile Arg Gln Leu Leu Phe Val Val

4850 4855 4860

Glu Val Val Asp Lys Tyr Phe Asp Cys Tyr Asp Gly Gly Cys Ile Asn

4865 4870 4875 4880

Ala Asn Gln Val Ile Val Asn Asn Leu Asp Lys Ser Ala Gly Phe Pro

4885 4890 4895

Phe Asn Lys Trp Gly Lys Ala Arg Leu Tyr Tyr Asp Ser Met Ser Tyr

4900 4905 4910

Glu Asp Gln Asp Ala Leu Phe Ala Tyr Thr Lys Arg Asn Val Ile Pro

4915 4920 4925

Thr Ile Thr Gln Met Asn Leu Lys Tyr Ala Ile Ser Ala Lys Asn Arg

4930 4935 4940

Ala Arg Thr Val Ala Gly Val Ser Ile Cys Ser Thr Met Thr Asn Arg

4945 4950 4955 4960

Gln Phe His Gln Lys Leu Leu Lys Ser Ile Ala Ala Thr Arg Gly Ala

4965 4970 4975

Thr Val Val Ile Gly Thr Ser Lys Phe Tyr Gly Gly Trp His Asn Met

4980 4985 4990

Leu Lys Thr Val Tyr Ser Asp Val Glu Asn Pro His Leu Met Gly Trp

4995 5000 5005

Asp Tyr Pro Lys Cys Asp Arg Ala Met Pro Asn Met Leu Arg Ile Met

5010 5015 5020

Ala Ser Leu Val Leu Ala Arg Lys His Thr Thr Cys Cys Ser Leu Ser

5025 5030 5035 5040

His Arg Phe Tyr Arg Leu Ala Asn Glu Cys Ala Gln Val Leu Ser Glu

5045 5050 5055

Met Val Met Cys Gly Gly Ser Leu Tyr Val Lys Pro Gly Gly Thr Ser

5060 5065 5070

Ser Gly Asp Ala Thr Thr Ala Tyr Ala Asn Ser Val Phe Asn Ile Cys

5075 5080 5085

Gln Ala Val Thr Ala Asn Val Asn Ala Leu Leu Ser Thr Asp Gly Asn

5090 5095 5100

Lys Ile Ala Asp Lys His Val Arg Asn Leu Gln His Arg Leu Tyr Glu

5105 5110 5115 5120

Cys Leu Tyr Arg Asn Arg Asp Val Asp Thr Asp Phe Val Asn Glu Phe

5125 5130 5135

Tyr Ala Tyr Leu Arg Lys His Phe Ser Met Met Ile Leu Ser Asp Asp

5140 5145 5150

Ala Val Val Cys Phe Asn Ser Thr Tyr Ala Ser Gln Gly Leu Val Ala

5155 5160 5165

Ser Ile Lys Asn Phe Lys Ser Val Leu Tyr Tyr Gln Asn Asn Val Phe

5170 5175 5180

Met Ser Glu Ala Lys Cys Trp Thr Glu Thr Asp Leu Thr Lys Gly Pro

5185 5190 5195 5200

His Glu Phe Cys Ser Gln His Thr Met Leu Val Lys Gln Gly Asp Asp

5205 5210 5215

Tyr Val Tyr Leu Pro Tyr Pro Asp Pro Ser Arg Ile Leu Gly Ala Gly

5220 5225 5230

Cys Phe Val Asp Asp Ile Val Lys Thr Asp Gly Thr Leu Met Ile Glu

5235 5240 5245

Arg Phe Val Ser Leu Ala Ile Asp Ala Tyr Pro Leu Thr Lys His Pro

5250 5255 5260

Asn Gln Glu Tyr Ala Asp Val Phe His Leu Tyr Leu Gln Tyr Ile Arg

5265 5270 5275 5280

Lys Leu His Asp Glu Leu Thr Gly His Met Leu Asp Met Tyr Ser Val

5285 5290 5295

Met Leu Thr Asn Asp Asn Thr Ser Arg Tyr Trp Glu Pro Glu Phe Tyr

5300 5305 5310

Glu Ala Met Tyr Thr Pro His Thr Val Leu Gln Ala Val Gly Ala Cys

5315 5320 5325

Val Leu Cys Asn Ser Gln Thr Ser Leu Arg Cys Gly Ala Cys Ile Arg

5330 5335 5340

Arg Pro Phe Leu Cys Cys Lys Cys Cys Tyr Asp His Val Ile Ser Thr

5345 5350 5355 5360

Ser His Lys Leu Val Leu Ser Val Asn Pro Tyr Val Cys Asn Ala Pro

5365 5370 5375

Gly Cys Asp Val Thr Asp Val Thr Gln Leu Tyr Leu Gly Gly Met Ser

5380 5385 5390

Tyr Tyr Cys Lys Ser His Lys Pro Pro Ile Ser Phe Pro Leu Cys Ala

5395 5400 5405

Asn Gly Gln Val Phe Gly Leu Tyr Lys Asn Thr Cys Val Gly Ser Asp

5410 5415 5420

Asn Val Thr Asp Phe Asn Ala Ile Ala Thr Cys Asp Trp Thr Asn Ala

5425 5430 5435 5440

Gly Asp Tyr Ile Leu Ala Asn Thr Cys Thr Glu Arg Leu Lys Leu Phe

5445 5450 5455

Ala Ala Glu Thr Leu Lys Ala Thr Glu Glu Thr Phe Lys Leu Ser Tyr

5460 5465 5470

Gly Ile Ala Thr Val Arg Glu Val Leu Ser Asp Arg Glu Leu His Leu

5475 5480 5485

Ser Trp Glu Val Gly Lys Pro Arg Pro Pro Leu Asn Arg Asn Tyr Val

5490 5495 5500

Phe Thr Gly Tyr Arg Val Thr Lys Asn Ser Lys Val Gln Ile Gly Glu

5505 5510 5515 5520

Tyr Thr Phe Glu Lys Gly Asp Tyr Gly Asp Ala Val Val Tyr Arg Gly

5525 5530 5535

Thr Thr Thr Tyr Lys Leu Asn Val Gly Asp Tyr Phe Val Leu Thr Ser

5540 5545 5550

His Thr Val Met Pro Leu Ser Ala Pro Thr Leu Val Pro Gln Glu His

5555 5560 5565

Tyr Val Arg Ile Thr Gly Leu Tyr Pro Thr Leu Asn Ile Ser Asp Glu

5570 5575 5580

Phe Ser Ser Asn Val Ala Asn Tyr Gln Lys Val Gly Met Gln Lys Tyr

5585 5590 5595 5600

Ser Thr Leu Gln Gly Pro Pro Gly Thr Gly Lys Ser His Phe Ala Ile

5605 5610 5615

Gly Leu Ala Leu Tyr Tyr Pro Ser Ala Arg Ile Val Tyr Thr Ala Cys

5620 5625 5630

Ser His Ala Ala Val Asp Ala Leu Cys Glu Lys Ala Leu Lys Tyr Leu

5635 5640 5645

Pro Ile Asp Lys Cys Ser Arg Ile Ile Pro Ala Arg Ala Arg Val Glu

5650 5655 5660

Cys Phe Asp Lys Phe Lys Val Asn Ser Thr Leu Glu Gln Tyr Val Phe

5665 5670 5675 5680

Cys Thr Val Asn Ala Leu Pro Glu Thr Thr Ala Asp Ile Val Val Phe

5685 5690 5695

Asp Glu Ile Ser Met Ala Thr Asn Tyr Asp Leu Ser Val Val Asn Ala

5700 5705 5710

Arg Leu Arg Ala Lys His Tyr Val Tyr Ile Gly Asp Pro Ala Gln Leu

5715 5720 5725

Pro Ala Pro Arg Thr Leu Leu Thr Lys Gly Thr Leu Glu Pro Glu Tyr

5730 5735 5740

Phe Asn Ser Val Cys Arg Leu Met Lys Thr Ile Gly Pro Asp Met Phe

5745 5750 5755 5760

Leu Gly Thr Cys Arg Arg Cys Pro Ala Glu Ile Val Asp Thr Val Ser

5765 5770 5775

Ala Leu Val Tyr Asp Asn Lys Leu Lys Ala His Lys Asp Lys Ser Ala

5780 5785 5790

Gln Cys Phe Lys Met Phe Tyr Lys Gly Val Ile Thr His Asp Val Ser

5795 5800 5805

Ser Ala Ile Asn Arg Pro Gln Ile Gly Val Val Arg Glu Phe Leu Thr

5810 5815 5820

Arg Asn Pro Thr Trp Arg Lys Ala Val Phe Ile Ser Pro Tyr Asn Ser

5825 5830 5835 5840

Gln Asn Ala Val Ala Ser Lys Ile Leu Gly Leu Pro Thr Gln Thr Val

5845 5850 5855

Asp Ser Ser Gln Gly Ser Glu Tyr Asp Tyr Val Ile Phe Thr Gln Thr

5860 5865 5870

Thr Glu Thr Ala His Ser Cys Asn Val Asn Arg Phe Asn Val Ala Ile

5875 5880 5885

Thr Arg Ala Lys Val Gly Ile Leu Cys Ile Met Ser Asp Arg Asp Leu

5890 5895 5900

Tyr Asp Lys Leu Gln Phe Thr Ser Leu Glu Ile Pro Arg Arg Asn Val

5905 5910 5915 5920

Ala Thr Leu Gln Ala Glu Asn Val Thr Gly Leu Phe Lys Asp Cys Ser

5925 5930 5935

Lys Val Ile Thr Gly Leu His Pro Thr Gln Ala Pro Thr His Leu Ser

5940 5945 5950

Val Asp Thr Lys Phe Lys Thr Glu Gly Leu Cys Val Asp Ile Pro Gly

5955 5960 5965

Ile Pro Lys Asp Met Thr Tyr Arg Arg Leu Ile Ser Met Met Gly Phe

5970 5975 5980

Lys Met Asn Tyr Gln Val Asn Gly Tyr Pro Asn Met Phe Ile Thr Arg

5985 5990 5995 6000

Glu Glu Ala Val Arg His Val Arg Ala Trp Ile Gly Phe Asp Val Glu

6005 6010 6015

Gly Cys His Ala Thr Arg Glu Ala Ile Gly Thr Asn Leu Pro Leu Gln

6020 6025 6030

Leu Gly Phe Ser Thr Gly Val Asn Leu Val Ala Val Pro Thr Gly Tyr

6035 6040 6045

Val Asp Thr Pro Asn Asn Thr Asp Phe Ser Arg Val Ser Ala Lys Pro

6050 6055 6060

Pro Pro Gly Asp Gln Phe Lys His Leu Ile Pro Leu Met Tyr Lys Gly

6065 6070 6075 6080

Leu Pro Trp Asn Val Val Arg Ile Lys Ile Val Gln Met Leu Ser Asp

6085 6090 6095

Thr Leu Lys Asn Leu Ser Asp Arg Val Val Phe Val Leu Trp Ala His

6100 6105 6110

Gly Phe Glu Leu Thr Ser Met Lys Tyr Phe Val Lys Ile Gly Pro Glu

6115 6120 6125

Arg Thr Cys Cys Leu Cys Asp Lys Arg Ala Thr Cys Phe Ser Thr Ala

6130 6135 6140

Ser Asp Thr Tyr Ala Cys Trp His His Ser Ile Gly Phe Asp Tyr Val

6145 6150 6155 6160

Tyr Asn Pro Phe Met Ile Asp Val Gln Gln Trp Gly Phe Thr Gly Asn

6165 6170 6175

Leu Gln Ser Asn His Asp Arg Tyr Cys Gln Val His Gly Asn Ala His

6180 6185 6190

Val Ala Ser Cys Asp Ala Ile Met Thr Arg Cys Leu Ala Val His Glu

6195 6200 6205

Cys Phe Val Lys Arg Val Asp Trp Thr Ile Glu Tyr Pro Ile Ile Gly

6210 6215 6220

Asp Glu Leu Lys Ile Asn Ala Ala Cys Arg Lys Val Gln His Met Val

6225 6230 6235 6240

Val Lys Ala Ala Leu Leu Ala Asp Lys Phe Pro Val Leu His Asp Ile

6245 6250 6255

Gly Asn Pro Lys Ala Ile Lys Cys Val Pro Gln Ala Asp Val Glu Trp

6260 6265 6270

Lys Phe Tyr Asp Ala Gln Pro Cys Ser Asp Lys Ala Tyr Lys Ile Glu

6275 6280 6285

Glu Leu Phe Tyr Ser Tyr Ala Thr His Ser Asp Lys Phe Thr Asp Gly

6290 6295 6300

Val Cys Leu Phe Trp Asn Cys Asn Val Asp Arg Tyr Pro Ala Asn Ser

6305 6310 6315 6320

Ile Val Cys Arg Phe Asp Thr Arg Val Leu Ser Asn Leu Asn Leu Pro

6325 6330 6335

Gly Cys Asp Gly Gly Ser Leu Tyr Val Asn Lys His Ala Phe His Thr

6340 6345 6350

Pro Ala Phe Asp Lys Ser Ala Phe Val Asn Leu Lys Gln Leu Pro Phe

6355 6360 6365

Phe Tyr Tyr Ser Asp Ser Pro Cys Glu Ser His Gly Lys Gln Val Val

6370 6375 6380

Ser Asp Ile Asp Tyr Val Pro Leu Lys Ser Ala Thr Cys Ile Thr Arg

6385 6390 6395 6400

Cys Asn Leu Gly Gly Ala Val Cys Arg His His Ala Asn Glu Tyr Arg

6405 6410 6415

Leu Tyr Leu Asp Ala Tyr Asn Met Met Ile Ser Ala Gly Phe Ser Leu

6420 6425 6430

Trp Val Tyr Lys Gln Phe Asp Thr Tyr Asn Leu Trp Asn Thr Phe Thr

6435 6440 6445

Arg Leu Gln Ser Leu Glu Asn Val Ala Phe Asn Val Val Asn Lys Gly

6450 6455 6460

His Phe Asp Gly Gln Gln Gly Glu Val Pro Val Ser Ile Ile Asn Asn

6465 6470 6475 6480

Thr Val Tyr Thr Lys Val Asp Gly Val Asp Val Glu Leu Phe Glu Asn

6485 6490 6495

Lys Thr Thr Leu Pro Val Asn Val Ala Phe Glu Leu Trp Ala Lys Arg

6500 6505 6510

Asn Ile Lys Pro Val Pro Glu Val Lys Ile Leu Asn Asn Leu Gly Val

6515 6520 6525

Asp Ile Ala Ala Asn Thr Val Ile Trp Asp Tyr Lys Arg Asp Ala Pro

6530 6535 6540

Ala His Ile Ser Thr Ile Gly Val Cys Ser Met Thr Asp Ile Ala Lys

6545 6550 6555 6560

Lys Pro Thr Glu Asn Ile Cys Ala Pro Leu Thr Val Phe Phe Asp Gly

6565 6570 6575

Arg Val Asn Gly Gln Val Asp Leu Phe Arg Asn Ala Arg Asn Gly Val

6580 6585 6590

Leu Ile Thr Glu Gly Ser Val Lys Gly Leu Gln Pro Ser Val Gly Pro

6595 6600 6605

Lys Gln Ala Ser Leu Asn Gly Val Thr Leu Ile Gly Glu Ala Leu Lys

6610 6615 6620

Thr Gln Phe Asn Tyr Tyr Lys Lys Val Asn Gly Val Val Gln Gln Leu

6625 6630 6635 6640

Pro Glu Thr Tyr Phe Thr Gln Ser Arg Asn Leu Lys Glu Phe Lys Pro

6645 6650 6655

Arg Ser Gln Met Glu Ile Asp Phe Leu Glu Leu Ala Met Asp Glu Phe

6660 6665 6670

Ile Glu Arg Tyr Lys Leu Glu Gly Tyr Ala Phe Glu His Ile Val Tyr

6675 6680 6685

Gly Asp Phe Ser His Arg Gln Leu Gly Gly Leu His Leu Leu Ile Gly

6690 6695 6700

Leu Ala Lys Arg Ser Lys Glu Ser Pro Leu Glu Leu Glu Asp Phe Ile

6705 6710 6715 6720

Pro Met Asp Ser Thr Val Lys Asn Tyr Phe Ile Thr Asp Ala Gln Thr

6725 6730 6735

Gly Ser Ser Lys Cys Val Cys Ser Val Ile Asp Leu Leu Leu Asp Asp

6740 6745 6750

Phe Val Glu Ile Ile Lys Ser Gln Asp Leu Ser Val Val Ser Lys Val

6755 6760 6765

Val Lys Val Thr Ile Asp Tyr Thr Glu Ile Ser Phe Met Leu Trp Cys

6770 6775 6780

Lys Asp Gly His Val Glu Thr Phe Tyr Pro Lys Leu Gln Ser Ser Gln

6785 6790 6795 6800

Ala Trp Gln Pro Gly Val Ala Met Pro Asn Leu Tyr Lys Met Gln Arg

6805 6810 6815

Met Leu Leu Glu Lys Cys Asp Leu Gln Asn Tyr Gly Asp Ser Ala Thr

6820 6825 6830

Leu Pro Lys Gly Ile Met Met Asn Val Ala Lys Tyr Thr Gln Leu Cys

6835 6840 6845

Gln Tyr Leu Asn Thr Leu Thr Leu Ala Val Pro Tyr Asn Met Arg Val

6850 6855 6860

Ile His Phe Gly Ala Gly Ser Asp Lys Gly Val Ala Pro Gly Thr Ala

6865 6870 6875 6880

Val Leu Arg Gln Trp Leu Pro Thr Gly Thr Leu Leu Val Asp Ser Asp

6885 6890 6895

Leu Asn Asp Phe Val Ser Asp Ala Asp Ser Thr Leu Ile Gly Asp Cys

6900 6905 6910

Ala Thr Val His Thr Ala Asn Lys Trp Asp Leu Ile Ile Ser Asp Met

6915 6920 6925

Tyr Asp Pro Lys Thr Lys Asn Val Thr Lys Glu Asn Asp Ser Lys Glu

6930 6935 6940

Gly Phe Phe Thr Tyr Ile Cys Gly Phe Ile Gln Gln Lys Leu Ala Leu

6945 6950 6955 6960

Gly Gly Ser Val Ala Ile Lys Ile Thr Glu His Ser Trp Asn Ala Asp

6965 6970 6975

Leu Tyr Lys Leu Met Gly His Phe Ala Trp Trp Thr Ala Phe Val Thr

6980 6985 6990

Asn Val Asn Ala Ser Ser Ser Glu Ala Phe Leu Ile Gly Cys Asn Tyr

6995 7000 7005

Leu Gly Lys Pro Arg Glu Gln Ile Asp Gly Tyr Val Met His Ala Asn

7010 7015 7020

Tyr Ile Phe Trp Arg Asn Thr Asn Pro Ile Gln Leu Ser Ser Tyr Ser

7025 7030 7035 7040

Leu Phe Asp Met Ser Lys Phe Pro Leu Lys Leu Arg Gly Thr Ala Val

7045 7050 7055

Met Ser Leu Lys Glu Gly Gln Ile Asn Asp Met Ile Leu Ser Leu Leu

7060 7065 7070

Ser Lys Gly Arg Leu Ile Ile Arg Glu Asn Asn Arg Val Val Ile Ser

7075 7080 7085

Ser Asp Val Leu Val Asn Asn Met Phe Val Phe Leu Val Leu Leu Pro

7090 7095 7100

Leu Val Ser Ser Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro

7105 7110 7115 7120

Pro Ala Tyr Thr Asn Ser Ser Thr Arg Gly Val Tyr Tyr Pro Asp Lys

7125 7130 7135

Val Phe Arg Ser Ser Val Leu His Leu Thr Gln Asp Leu Phe Leu Pro

7140 7145 7150

Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr

7155 7160 7165

Asn Gly Ile Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly

7170 7175 7180

Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile

7185 7190 7195 7200

Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn

7205 7210 7215

Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn

7220 7225 7230

Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met

7235 7240 7245

Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu

7250 7255 7260

Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn

7265 7270 7275 7280

Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe

7285 7290 7295

Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro

7300 7305 7310

Pro Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile

7315 7320 7325

Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu

7330 7335 7340

Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr

7345 7350 7355 7360

Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu

7365 7370 7375

Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser

7380 7385 7390

Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr

7395 7400 7405

Gln Thr Ser Asn Phe Arg Val Gln Pro Thr Asp Ser Ile Val Arg Phe

7410 7415 7420

Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr

7425 7430 7435 7440

Thr Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys

7445 7450 7455

Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe

7460 7465 7470

Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr

7475 7480 7485

Asn Val Tyr Ala Asp Ser Phe Val Ile Thr Gly Asp Glu Val Arg Gln

7490 7495 7500

Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu

7505 7510 7515 7520

Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Lys His Ile

7525 7530 7535

Asp Ala Lys Glu Gly Gly Asn Phe Asn Tyr Leu Tyr Arg Leu Phe Arg

7540 7545 7550

Lys Ala Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr

7555 7560 7565

Gln Ala Gly Ser Lys Pro Cys Asn Gly Gln Thr Gly Leu Asn Cys Tyr

7570 7575 7580

Tyr Pro Leu Tyr Arg Tyr Gly Phe Tyr Pro Thr Asp Gly Val Gly His

7585 7590 7595 7600

Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro

7605 7610 7615

Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys

7620 7625 7630

Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr

7635 7640 7645

Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile

7650 7655 7660

Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu

7665 7670 7675 7680

Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly

7685 7690 7695

Thr Asn Ala Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys

7700 7705 7710

Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp

7715 7720 7725

Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys

7730 7735 7740

Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro

7745 7750 7755 7760

Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg

7765 7770 7775

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

7780 7785 7790

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

7795 7800 7805

Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys

7810 7815 7820

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

7825 7830 7835 7840

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

7845 7850 7855

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

7860 7865 7870

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

7875 7880 7885

Gly Gly Phe Asn Phe Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala

7890 7895 7900

Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr

7905 7910 7915 7920

Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala

7925 7930 7935

Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn

7940 7945 7950

Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln

7955 7960 7965

Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val

7970 7975 7980

Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser

7985 7990 7995 8000

Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg

8005 8010 8015

Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly

8020 8025 8030

Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala

8035 8040 8045

Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu

8050 8055 8060

Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr

8065 8070 8075 8080

His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu

8085 8090 8095

His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro

8100 8105 8110

Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe

8115 8120 8125

Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

8130 8135 8140

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Ser Cys Asp

8145 8150 8155 8160

Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

8165 8170 8175

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His

8180 8185 8190

Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

8195 8200 8205

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys

8210 8215 8220

Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu

8225 8230 8235 8240

Gln Gly Val Lys Leu His Tyr Thr Met Asp Leu Phe Met Arg Ile Phe

8245 8250 8255

Thr Leu Gly Thr Val Thr Leu Lys Gln Gly Glu Ile Lys Asp Ala Thr

8260 8265 8270

Pro Ser Asp Ser Val Arg Ala Thr Ala Thr Ile Pro Ile Gln Ala Ser

8275 8280 8285

Leu Pro Phe Gly Trp Leu Ile Val Gly Val Ala Phe Leu Ala Val Phe

8290 8295 8300

Gln Ser Ala Ser Lys Ile Ile Thr Leu Lys Lys Arg Trp Gln Leu Ala

8305 8310 8315 8320

Leu Ser Lys Gly Ile His Phe Ile Cys Asn Leu Leu Leu Leu Phe Val

8325 8330 8335

Thr Val Tyr Ser His Leu Leu Leu Val Ala Ala Gly Leu Glu Ala Pro

8340 8345 8350

Phe Leu Tyr Leu Tyr Ala Leu Val Tyr Phe Leu Gln Ser Ile Asn Phe

8355 8360 8365

Val Arg Ile Ile Met Arg Leu Trp Leu Cys Trp Lys Cys Arg Ser Lys

8370 8375 8380

Asn Pro Leu Leu Tyr Asp Ala Asn Tyr Phe Leu Cys Trp His Thr Asn

8385 8390 8395 8400

Cys Tyr Asp Tyr Cys Ile Pro Tyr Asn Ser Val Thr Ser Ser Ile Val

8405 8410 8415

Ile Thr Ser Gly Asp Gly Thr Thr Ser Pro Ile Ser Glu His Asp Tyr

8420 8425 8430

Gln Ile Gly Gly Tyr Thr Glu Lys Trp Glu Ser Gly Val Lys Asp Cys

8435 8440 8445

Val Val Leu His Ser Tyr Phe Thr Ser Asp Tyr Tyr Gln Leu Tyr Ser

8450 8455 8460

Thr Gln Leu Ser Thr Asp Thr Gly Val Glu His Val Thr Phe Phe Ile

8465 8470 8475 8480

Tyr Asn Lys Ile Val Asp Glu Pro Glu Glu His Val Gln Ile His Thr

8485 8490 8495

Ile Asp Gly Ser Ser Gly Val Val Asn Pro Ala Met Glu Pro Ile Tyr

8500 8505 8510

Asp Glu Pro Thr Thr Thr Thr Ser Val Pro Leu Met Tyr Ser Phe Val

8515 8520 8525

Ser Glu Glu Thr Gly Thr Leu Ile Val Asn Ser Val Leu Leu Phe Leu

8530 8535 8540

Ala Phe Val Val Phe Leu Leu Val Thr Leu Ala Ile Leu Thr Ala Leu

8545 8550 8555 8560

Arg Leu Cys Ala Tyr Cys Cys Asn Ile Val Asn Val Ser Leu Val Lys

8565 8570 8575

Pro Ser Phe Tyr Val Tyr Ser Arg Val Lys Asn Leu Asn Ser Ser Arg

8580 8585 8590

Val Pro Asp Leu Leu Val Met Ala Asp Asn Gly Thr Ile Thr Val Glu

8595 8600 8605

Glu Leu Lys Lys Leu Leu Glu Gln Trp Asn Leu Val Ile Gly Phe Leu

8610 8615 8620

Phe Leu Thr Trp Ile Cys Leu Leu Gln Phe Ala Tyr Ala Asn Arg Asn

8625 8630 8635 8640

Arg Phe Leu Tyr Ile Ile Lys Leu Ile Phe Leu Trp Leu Leu Trp Pro

8645 8650 8655

Val Thr Leu Ala Cys Phe Val Leu Ala Ala Val Tyr Arg Ile Asn Trp

8660 8665 8670

Ile Thr Gly Gly Ile Ala Ile Ala Met Ala Cys Leu Val Gly Leu Met

8675 8680 8685

Trp Leu Ser Tyr Phe Ile Ala Ser Phe Arg Leu Phe Ala Arg Thr Arg

8690 8695 8700

Ser Met Trp Ser Phe Asn Pro Glu Thr Asn Ile Leu Leu Asn Val Pro

8705 8710 8715 8720

Leu His Gly Thr Ile Leu Thr Arg Pro Leu Leu Glu Ser Glu Leu Val

8725 8730 8735

Ile Gly Ala Val Ile Leu Arg Gly His Leu Arg Ile Ala Gly His His

8740 8745 8750

Leu Gly Arg Cys Asp Ile Leu Val Gln Met Phe His Leu Val Asp Phe

8755 8760 8765

Gln Val Thr Ile Ala Glu Ile Leu Leu Ile Ile Met Arg Thr Phe Lys

8770 8775 8780

Val Ser Ile Trp Asn Leu Asp Tyr Ile Ile Asn Leu Ile Ile Lys Asn

8785 8790 8795 8800

Leu Ser Lys Ser Leu Thr Glu Asn Lys Tyr Ser Gln Leu Asp Glu Glu

8805 8810 8815

Gln Pro Met Glu Ile Asp Met Lys Ile Ile Leu Phe Leu Val Leu Val

8820 8825 8830

Thr Leu Ala Thr Cys Glu Leu Tyr His Tyr Gln Glu Cys Val Arg Gly

8835 8840 8845

Thr Thr Val Leu Leu Lys Glu Pro Cys Ser Ser Gly Thr Tyr Glu Gly

8850 8855 8860

Asn Ser Pro Phe His Pro Leu Ala Asp Asn Lys Phe Ala Leu Thr Cys

8865 8870 8875 8880

Phe Ser Thr Gln Phe Ala Phe Ala Cys Pro Asp Gly Val Lys His Val

8885 8890 8895

Tyr Gln Leu Arg Ala Arg Ser Val Ser Pro Lys Leu Phe Ile Arg Gln

8900 8905 8910

Glu Glu Val Gln Glu Leu Tyr Ser Pro Ile Phe Leu Ile Ile Ala Ala

8915 8920 8925

Ile Val Phe Ile Thr Leu Cys Phe Thr Leu Lys Arg Lys Thr Glu Met

8930 8935 8940

Ser Glu Leu Ser Leu Ile Asp Phe Tyr Leu Cys Phe Leu Ala Phe Leu

8945 8950 8955 8960

Leu Phe Leu Val Leu Ile Met Leu Ile Ile Phe Trp Phe Ser Leu Glu

8965 8970 8975

Leu Gln Asp His Asn Glu Thr Cys His Ala Met Lys Leu Leu Val Phe

8980 8985 8990

Leu Gly Ile Leu Thr Thr Val Thr Ala Phe His Gln Glu Cys Ser Leu

8995 9000 9005

Gln Ser Cys Ala Gln His Gln Pro Tyr Val Val Asp Asp Pro Cys Pro

9010 9015 9020

Ile His Phe Tyr Ser Lys Trp Tyr Ile Arg Val Gly Ala Arg Lys Ser

9025 9030 9035 9040

Ala Pro Leu Ile Glu Leu Cys Val Asp Glu Val Gly Ser Lys Ser Pro

9045 9050 9055

Ile Gln Tyr Ile Asp Ile Gly Asn Tyr Thr Val Ser Cys Ser Pro Phe

9060 9065 9070

Thr Ile Asn Cys Gln Glu Pro Lys Leu Gly Ser Leu Val Val Arg Cys

9075 9080 9085

Ser Phe Tyr Glu Asp Phe Leu Glu Tyr His Asp Val Arg Val Val Leu

9090 9095 9100

Asp Phe Ile Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro

9105 9110 9115 9120

Arg Ile Thr Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn

9125 9130 9135

Gly Glu Arg Ser Gly Ala Arg Pro Lys Gln Arg Arg Pro Gln Gly Leu

9140 9145 9150

Pro Asn Asn Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys

9155 9160 9165

Glu Asp Leu Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn

9170 9175 9180

Ser Ser Pro Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg

9185 9190 9195 9200

Ile Arg Gly Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr

9205 9210 9215

Phe Tyr Tyr Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala

9220 9225 9230

Asn Lys Asp Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr

9235 9240 9245

Pro Lys Asp His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile

9250 9255 9260

Val Leu Gln Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala

9265 9270 9275 9280

Glu Gly Ser Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg

9285 9290 9295

Ser Arg Asn Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr

9300 9305 9310

Ser Pro Ala Arg Met Ala Gly Asn Gly Ser Asp Ala Ala Leu Ala Leu

9315 9320 9325

Leu Leu Leu Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys

9330 9335 9340

Gly Gln Gln Gln Gln Ser Gln Thr Val Thr Lys Lys Ser Ala Ala Glu

9345 9350 9355 9360

Ala Ser Lys Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Gln Tyr Asn

9365 9370 9375

Val Thr Gln Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn

9380 9385 9390

Phe Gly Asp Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp

9395 9400 9405

Pro Gln Ile Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met

9410 9415 9420

Ser Arg Ile Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr

9425 9430 9435 9440

Thr Gly Ala Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln

9445 9450 9455

Val Ile Leu Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro

9460 9465 9470

Thr Glu Pro Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala

9475 9480 9485

Leu Pro Gln Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala

9490 9495 9500

Ala Asp Leu Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser

9505 9510 9515 9520

Ala Asp Ser Thr Gln Ala

9525

Claims (9)

1.一种用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于，采用与SARS-CoV-2病毒具有生物同源性的SARS-CoV-2的弱毒性原型或父本株制备疫苗。

2.根据权利要求1所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述SARS-CoV-2的弱毒性原型或父本株与SARS-CoV-2病毒在RNA序列上具有至少96％同源性、在蛋白氨基酸序列上具有至少97％同源性。

3.根据权利要求2所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述SARS-CoV-2的弱毒性原型或父本株为蝙蝠冠状病毒Bat/CovRaTG13株。

4.根据权利要求2所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述SARS-CoV-2的弱毒性原型或父本株为与蝙蝠冠状病毒Bat/CovRaTG13株具有同源序列性的任一亚属病毒株。

5.根据权利要求1～4任一项用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述疫苗为通过所述SARS-CoV-2的弱毒性原型或父本株制备的活疫苗、灭活性疫苗或重组疫苗。

6.根据权利要求5所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述活疫苗通过所述SARS-CoV-2的弱毒性原型或父本株经细胞培养、纯化、制剂制备而成，不在体外进行基因修饰。

7.根据权利要求5所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述灭活疫苗通过所述SARS-CoV-2的弱毒性原型或父本株经细胞培养、纯化、灭活、制剂制备而成，不在体外进行基因修饰。

8.根据权利要求7所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述灭活疫苗通过福尔马林对病毒灭活；所述灭活疫苗还包括铝佐剂。

9.根据权利要求5所述的用于预防COVID-19的蝙蝠源性冠状病毒疫苗，其特征在于：所述重组疫苗为通过人工点突变和/或将基因片段插入Bat/CovRaTG13的任一基因中而产生的基因修饰的可复制疫苗。

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