CN113444156B - 新型冠状病毒肺炎重组人5型腺病毒疫苗 - Google Patents
新型冠状病毒肺炎重组人5型腺病毒疫苗 Download PDFInfo
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Abstract
本发明提供一种包含改造的SARS‑CoV‑2的刺突蛋白的疫苗组合物，该疫苗组合物将复制缺陷型人5型腺病毒rAd病毒株与新型改造的SARS‑CoV‑2的刺突蛋白(S6P)或其免疫原性衍生物结合构建重组复制缺陷型人5型腺病毒，用于预防新型冠状病毒的感染，尤其是针对哺乳动物的新型冠状病毒的感染。
Description
技术领域
本发明涉及针对哺乳动物新型冠状病毒肺炎的预防性疫苗组合物和方法，进一步涉及针对哺乳动物新型冠状病毒肺炎的重组人5型腺病毒的预防性疫苗组合物和方法。
背景技术
2019冠状病毒病(COVID-19)是由新型冠状病毒(Severe Acute RespiratorySyndrome Coronavirus 2,SARS-CoV-2)引起的传播能力极强的人兽共患病。COVID-19在全球仍然持续流行，不断危害人类生命健康。截止2021年5月4日，世界卫生组织(WorldHealth Organization，WHO)报告共计约有确诊病例超过1.5亿，死亡病例近321万例，目前SARS-CoV-2的溯源工作尚未完成，研究初步提示，SARS-CoV-2自然宿主可能为某些种类的蝙蝠，中间宿主可能涉及穿山甲，但这些假设仍需更有力的证据支持。仓鼠、兔子、雪貂、食蟹猴、恒河猴对SARS-CoV-2均易感，埃及果蝠、猫、水貂和貉子高度易感。农场自然条件下，SARS-CoV-2感染者将病毒传给水貂，引起水貂中间的广泛传播流传；丹麦发生了水貂将病毒传给人的情况，北美发现农场水貂将病毒传给了野生水貂。水貂是特种经济动物，一旦感染新冠肺炎为防止其扩散而大规模扑杀，会导致巨大的经济损失。猫是与人类密切接触的伴侣动物，部分猫感染SARS-CoV-2后严重发病，是SARS-CoV-2潜在的传播宿主或储存宿主。为预防SARS-CoV-2在动物与人、动物与动物间的传播，动物的COVID-19防控同样不可忽视。预防SARS-CoV-2感染、控制病毒感染扩散，接种疫苗是最经济、有效的方式。
复制缺陷型人5型腺病毒作为载体在疫苗构建中发挥了重要作用，目前以腺病毒为载体制备的新冠疫苗在我国已获批附条件上市。
本发明研究人员在对SARS-CoV-2病毒抗原研究的基础上，构建了针对哺乳动物SARS-CoV-2的重组复制缺陷型人5型腺病毒，从而完成了本发明。
发明内容
SARS-CoV-2的刺突蛋白(Spike protein,S)是病毒受体结合蛋白和主要毒力因子之一，决定着病毒的感染谱和致病力，同时也是一个有效的免疫原，是抗SARS-CoV-2感染过程中诱导宿主免疫反应的主要免疫原。本发明人通过专注研究冠状病毒S蛋白部分位点氨基酸的改变对S蛋白三聚体的空间构象的影响，以及Furin裂解位点的突变失活对S蛋白空间构象的稳定性影响的研究构建了改造的SARS-CoV-2的刺突蛋白。
因此，本发明首先提供了一种包含改造的SARS-CoV-2的刺突蛋白(SA)的疫苗组合物，该改造的SARS-CoV-2的刺突蛋白(SA)包含组织型纤溶酶原激活因子信号肽(tPA)。
进一步，本发明改造的SARS-CoV-2的刺突蛋白(SA)是将S蛋白基因信号肽替换为组织型纤溶酶原激活因子信号肽(tPA)。
进一步的，该改造的SARS-CoV-2的刺突蛋白(SA)还进一步将如下6个位点氨基酸残基均突变为脯氨酸：F817P、A892P、A899P、A942P、K986P、V987P，获得改造的SARS-CoV-2的刺突蛋白(S6PA)。
在一个具体实施方案中，本发明的疫苗组合物包含改造的SARS-CoV-2的刺突蛋白(SA)，该改造的SARS-CoV-2的刺突蛋白(SA)选自命名为SA-tPA-1(SEQ ID NO：1)的刺突蛋白,进一步SA蛋白Furin裂解位点突变失活，获得改造的SARS-CoV-2的刺突蛋白(SB)选自命名为SB-tPA-1(SEQ ID NO：2)的刺突蛋白。
在一个具体实施方案中，该疫苗组合物包含改造的SARS-CoV-2的刺突蛋白(S6PA)，该改造的SARS-CoV-2的刺突蛋白(S6PA)选自命名为S6PA-tPA-1(SEQ ID NO：3)的刺突蛋白,进一步S6PA蛋白Furin裂解位点突变失活，获得改造的SARS-CoV-2的刺突蛋白(S6PB)选自命名为S6PB-tPA-1(SEQ ID NO：4)的刺突蛋白。
在一个实施方案中，该改造的SARS-CoV-2的刺突蛋白(SA)或其免疫原性衍生物包含来自SEQ ID NO：1的氨基酸序列。
在一个实施方案中，该改造的SARS-CoV-2的刺突蛋白(SB)或其免疫原性衍生物包含来自SEQ ID NO：2的氨基酸序列。
在一个实施方案中，该改造的SARS-CoV-2的刺突蛋白(S6PA)或其免疫原性衍生物包含来自SEQ ID NO：3的氨基酸序列。
在一个实施方案中，该改造的SARS-CoV-2的刺突蛋白(S6PB)或其免疫原性衍生物包含来自SEQ ID NO：4的氨基酸序列。
进一步的，该改造的SARS-CoV-2的刺突蛋白(SA/SB)或(S6PA/S6PB)或其免疫原性衍生物由病毒载体编码，所述病毒载体为复制缺陷型人5型腺病毒。
其次，本发明提供一种重组复制缺陷型人5型腺病毒载体的疫苗组合物，所述疫苗组合物包括由病毒载体编码改造的SARS-CoV-2的刺突蛋白(SA/SB)或(S6PA/S6PB)，所述病毒载体优选人5型腺病毒载体，进一步优选rAd病毒株。
在一个具体实施方式中，本发明的重组复制缺陷型人5型腺病毒载体疫苗组合物包括由病毒载体编码改造的SARS-CoV-2的刺突蛋白(SA)，所述病毒载体为rAd病毒株,该改造的SARS-CoV-2的刺突蛋白(SA)包含来自SEQ ID NO：1的氨基酸序列。
在一个具体实施方式中，本发明的重组复制缺陷型人5型腺病毒载体疫苗组合物包括由病毒载体编码改造的SARS-CoV-2的刺突蛋白(SB)，所述病毒载体为rAd病毒株,该改造的SARS-CoV-2的刺突蛋白(SB)包含来自SEQ ID NO：2的氨基酸序列。
在一个具体实施方式中，本发明的重组复制缺陷型人5型腺病毒载体疫苗组合物包括由病毒载体编码改造的SARS-CoV-2的刺突蛋白(S6PA)，所述病毒载体为rAd病毒株,该改造的SARS-CoV-2的刺突蛋白(S6PA)包含来自SEQ ID NO：3的氨基酸序列。
在一个具体实施方式中，本发明的重组复制缺陷型人5型腺病毒载体疫苗组合物包括由病毒载体编码改造的SARS-CoV-2的刺突蛋白(S6PB)，所述病毒载体为rAd病毒株,该改造的SARS-CoV-2的刺突蛋白(S6PB)包含来自SEQ ID NO：4的氨基酸序列。
进一步，重组复制缺陷型人5型腺病毒载体被命名为重组rAd-tPASoptiA或rAd-tPASoptiB，或rAd-tPASopti6PA或rAd-tPASopti6PB。
本发明的疫苗组合物可以是注射疫苗，如肌肉注射，也可以是口服疫苗或滴鼻疫苗。在一个具体的实施方案中，本发明的疫苗组合物是亚单位疫苗.
在一个方面，本发明的疫苗组合物还包含佐剂。在一个实施方案中，佐剂选自：水包油佐剂、聚合物和水佐剂、油包水佐剂、氢氧化铝佐剂、维生素E佐剂及其组合。在一个具体实施方案中，佐剂包含油乳剂，该油乳剂包含聚氧乙烯-聚氧丙烯嵌段共聚物、角鲨烷、聚氧乙烯山梨醇酐单油酸酯和缓冲盐溶液(SP-油)。在一个实施方案中，本发明的疫苗组合物还包含药学上可接受的载体。
在另一个实施方案中，本发明的疫苗组合物还可以包含至少一种额外的抗原。在某些实施方案中，至少一种额外的抗原保护性地抵御可以引起哺乳动物疾病的微生物。
第三方面，本发明提供一种嵌合核酸分子，其包含编码人5型腺病毒rAd病毒株的核酸分子和编码改造的SARS-CoV-2的刺突蛋白(SA/SB)或(S6PA/S6PB)的核酸分子(SEQ IDNO：5、SEQ ID NO：6、SEQ ID NO：7、SEQ ID NO：8)。
在一个具体实施方式中，本发明的嵌合核酸分子其包含编码人5型腺病毒rAd病毒株的核酸分子和编码改造的SARS-CoV-2的刺突蛋白(SA)的核酸分子，所述改造的SARS-CoV-2的刺突蛋白(SA)的核酸分子包含来自SEQ ID NO：5的核酸序列。
在一个具体实施方式中，本发明的嵌合核酸分子其包含编码人5型腺病毒rAd病毒株的核酸分子和编码改造的SARS-CoV-2的刺突蛋白(SB)的核酸分子，所述改造的SARS-CoV-2的刺突蛋白(SB)的核酸分子包含来自SEQ ID NO：6的核酸序列。
在一个具体实施方式中，本发明的嵌合核酸分子其包含编码人5型腺病毒rAd病毒株的核酸分子和编码改造的SARS-CoV-2的刺突蛋白(S6PA)的核酸分子，所述改造的SARS-CoV-2的刺突蛋白(S6PA)的核酸分子包含来自SEQ ID NO：7的核酸序列。
在一个具体实施方式中，本发明的嵌合核酸分子其包含编码人5型腺病毒rAd病毒株的核酸分子和编码改造的SARS-CoV-2的刺突蛋白(S6PB)的核酸分子，所述改造的SARS-CoV-2的刺突蛋白(S6PB)的核酸分子包含来自SEQ ID NO：8的核酸序列。
第四方面，本发明还提供了保护哺乳动物免受新型冠状病毒SARS-CoV-2感染的方法。该方法包括向哺乳动物施用免疫有效量的本发明公开的疫苗组合物、嵌合核酸分子。在多种实施方案中，该方法包括通过选自经注射、口服、胃肠道外、经鼻、皮内和经皮的一种或多于一种途径向哺乳动物施用疫苗组合物、嵌合核酸分子。在另一个实施方案中，疫苗组合物、嵌合核酸分子以单剂量施用。在另一个实施方案中，组合物与至少一种额外的抗原联合施用，该额外的抗原保护性地抵御可以引起哺乳动物疾病的微生物。
附图说明
图1：间接免疫荧光检测tPASopti6PB蛋白基因在重组腺病毒感染的293A细胞中的表达左：未感染的293A细胞；右：rAd-tPASopti6PB感染的293A细胞
图2：Western blot分析SARS-CoV-2S蛋白在rAd-tPASopti6PB感染的293A细胞中的表达
M：蛋白质Maker；1：293A细胞；2：野生型rAd感染的293A细胞；3：rAd-tPASopti6PB感染的293A细胞。
图3：重组腺病毒肌肉免疫小鼠中和抗体与攻毒保护结果
(A)为小鼠中和抗体检测结果；(B)为小鼠攻毒后体内SARS-CoV-2的RNA拷贝数；(C)为小鼠攻毒后体内具有感染性的SARS-CoV-2的滴定。NT代表小鼠鼻甲；LU代表小鼠肺脏。
图4：重组腺病毒滴鼻免疫小鼠中和抗体与攻毒保护结果
(A)为小鼠中和抗体检测结果；(B)为小鼠攻毒后体内SARS-CoV-2的RNA拷贝数；(C)为小鼠攻毒后体内具有感染性的SARS-CoV-2的滴定。NT代表小鼠鼻甲；LU代表小鼠肺脏。
图5：重组腺病毒口服免疫小鼠中和抗体与攻毒保护结果
(A)为小鼠中和抗体检测结果；(B)为小鼠攻毒后体内SARS-CoV-2的RNA拷贝数；(C)为小鼠攻毒后体内具有感染性的SARS-CoV-2的滴定。NT代表小鼠鼻甲；LU代表小鼠肺脏。
具体实施方式
虽然下面详细讨论了本发明各种实施方案的进行和使用，但应该理解，本发明提供了许多可以在各种特定情况下使用的可适用的发明概念。这里讨论的具体实施方案仅说明进行和使用本发明的具体方式，并不限制本发明的范围。
S蛋白单体情况下，RBD区存在关闭沉降和上升开放两种状态。RBD的关闭沉降状态覆盖了S2亚基部分氨基酸，削弱S蛋白的免疫原性；RBD上升开放状态则是解离S2亚基，可充分发挥其免疫原性。相较野生型S蛋白，K986P、V987P这两个联合突变可使具有高免疫原性和可移动特性的RBD处于稳定的上升开放状态，提高表达S蛋白的免疫原性；F817P、A892P、A899P、A942P突变则可使S蛋白的表达量增高约10倍，并具有耐热、室温贮藏和3次冻融循环的能力；SARS-CoV-2S蛋白基因的Furin裂解位点突变失活可保留了SB蛋白的预融合构像，不裂解成S1和S2亚基，提高了SB和S6PB蛋白的抗原性。
本发明通过例举性的实施在新型冠状病毒S蛋白基因密码子优化的基础上，用组织型纤溶酶原激活因子信号肽(Tissue plasminogen activator signal sequence,tPA)基因序列替换S蛋白信号肽基因序列，同时将6个位点氨基酸残基均突变为脯氨酸(F817P、A892P、A899P、A942P、K986P、V987P)，再将S蛋白Furin裂解位点突变缺失，人工合成新型冠状病毒S蛋白变体S6PB基因。以人5型腺病毒rAd病毒株为疫苗载体，构建了表达新型冠状病毒S蛋白变体基因的重组人5型腺病毒rAd-tPASopti6PB病毒株。
经重组腺病毒rAd-tPASopti6PB三种免疫方式(肌肉注射、滴鼻、口服)免疫的小鼠诱导的免疫反应均能有效保护小鼠免受SARS-CoV-2感染。
为了便于理解本发明，下面定义了许多术语。本发明定义的术语具有本发明相关领域中普通技术人员通常理解的含义。
如本发明所用术语“包含”、“包括”、“含有”旨在表示组合物和方法包括所列举的要素，但不排除其他要素。
术语“抗原”是指可以在动物中刺激抗体或T细胞应答或两者的产生的化合物、组合物或免疫原性物质，其包括口服、注射或吸收到动物体内的组合物。可以对整个分子或分子的一部分(例如表位或半抗原)产生免疫应答。
如本发明所定义的，“免疫原性组合物或免疫组合物”是指包含至少一种抗原的物质的组合物，该抗原在宿主中引发对感兴趣的组合物或疫苗的细胞的免疫应答和/或抗体介导的免疫应答。
本发明所用的“佐剂”是指由一种或多于一种增强对抗原的免疫应答的物质组成的组合物。佐剂如何起作用的机制尚不完全清楚。一些佐剂被认为通过缓慢释放抗原来增强免疫应答，而其他佐剂本身具有强免疫原性并被认为起到协同作用。
本发明所用的术语“哺乳动物”是指包括人、及对新型冠状病毒易感的哺乳动物，例如人、蝙蝠、狮子、老虎、恒河猴、食蟹猴、水貂、雪貂、猫、狗等。
如本文所用术语“药学上可接受的载体”是指用于包含可以口服、注射或经粘膜给到宿主中且没有副作用的疫苗抗原的流体载体。本领域已知的合适的药学上可接受的载体包括但不限于无菌水、盐水、葡萄糖、右旋糖或缓冲溶液等。载体可包括助剂包括但不限于稀释剂、稳定剂(糖和氨基酸)、防腐剂、润湿剂、乳化剂、pH缓冲剂、黏度增强添加剂、着色剂等。
如本文所用术语“疫苗组合物”包括在药学上可接受的载体中的至少一种抗原或免疫原，其可用于在宿主中诱导免疫应答。疫苗组合物可以按剂量施用并通过医学或兽医领域技术人员熟知的技术施用，同时考虑例如接受体动物的年龄、性别、体重、物种和状况、以及给药途径等因素。给药途径可以是经皮(通过皮内、经皮、皮下、肌内途径而穿过皮肤或通过口腔、鼻腔、肛门、阴道而穿过黏膜)或通过肠胃外途径(静脉内或腹膜内)。疫苗组合物可以单独施用，或者可以与其他治疗或疗法共同施用或按顺序施用。给药形式可包括混悬剂、糖浆剂或酏剂，以及用于肠胃外、皮下、皮内、肌内或静脉内给药(例如注射给药)的制剂，例如无菌混悬剂或乳剂。疫苗组合物可以以喷雾形式给药或混合于食物和/或水中或与合适的载体、稀释剂、或赋形剂如无菌水、生理盐水、葡萄糖等混合递送。该组合物可含有辅助物质，如润湿剂或乳化剂、pH缓冲剂、佐剂、凝胶化或黏度增强添加剂、防腐剂、调味剂、着色剂等，这取决于给药途径和所需制剂。
为了公开的完整性，包括了以下实施例以说明制备本发明组合物和复合物的方法以及呈现组合物的某些特征。这些实施例决不旨在限制本公开的范围或教导。
实施例1：材料与方法
1材料与方法
1.1病毒株
表达经哺乳动物密码子偏嗜性进行优化的SARS-CoV-2S蛋白重组人5型腺病毒株rAd-tPASopti由中国农业科学院哈尔滨兽医研究所重要人兽共患病与烈性外来病创新团队构建、保存。SARS-CoV-2分离株HRB25、SARS-CoV-2小鼠适应株HRB26M是由中国农业科学院哈尔滨兽医研究所重要人兽共患病与烈性外来病创新团队分离鉴定并保存。
1.2细胞
Vero E6细胞(ATCC，No.CRL-1586)由中国农业科学院哈尔滨兽医研究所重要人兽共患病与烈性外来病创新团队保存、培养。表达人5型腺病毒E1蛋白的293A细胞由中国农业科学院哈尔滨兽医研究所重要人兽共患病与烈性外来病创新团队保存。Vero-E6和293A细胞培养液为含10％胎牛血清的DMEM。
1.3质粒与试剂
重组腺病毒的穿梭载体pShuttle-CMV由中国农业科学院哈尔滨兽医研究所重要人兽共患病与烈性外来病创新团队保存。高保真DNA聚合酶(Phanta Max Super-FidelityDNA Polymerase)购自南京诺维赞生物科技股份有限公司。大肠杆菌BJ5183-AD-1感受态细胞购自北京博迈德基因技术有限公司。LipofectamineTM3000Reagent转染试剂购自Invitrogen公司。抗SARS-CoV-2S蛋白多克隆抗体由中国农业科学院哈尔滨兽医研究所重要人兽共患病与烈性外来病创新团队制备。抗SARS-CoV-2S蛋白单克隆抗体由购自北京义翘神州科技股份有限公司。绿色荧光素(FITC)标记的山羊抗鼠IgG、辣根过氧化物酶(HRP)标记的山羊抗兔IgG购自北京中杉金桥生物技术有限公司。胎牛血清购自赛默飞世尔科技有限公司。DMEM培养液购自西格玛奥德里奇贸易有限公司。
通过基因合成的方法合成SARS-CoV-2S蛋白突变体tPASopti6PB基因，并将其克隆至pBluescriptⅡ(+/-)(Clontech)的EcoRⅤ位点，命名为pBlue-tPASopti6PB。将组织型纤溶酶原激活因子(Tissue plasminogen activator,tPA)的信号肽基因替代SARS-CoV-2S蛋白信号肽基因构成tPASopti6PB基因，同时在tPASopti6PB基因的起始密码子ATG前插入Kozak序列“GCCGCCACC”。tPASopti6P基因是在SARS-CoV-2S蛋白基因按哺乳动物密码子偏嗜性进行优化的基础上，将该蛋白基因2449-2451位、2674-2676位、2695-2697位、2824-2826位、2956-2958位和2959-2961位碱基均突变为“CCC”，由此将上述碱基编码的第817位苯丙氨酸(Phenylalanine,Phe,F)、第892位丙氨酸(Alanine,Ala,A)、第899位丙氨酸(Alanine,Ala,A)、第942位丙氨酸(Alanine,Ala,A)、第986位赖氨酸(Lysine,Lys,K)和第987位缬氨酸(Valine,Val,V)均突变为脯氨酸(Proline,Pro,P)；将SARS-CoV-2S蛋白裂解位点基因2044-2055位碱基突变为“GGCTCCGCCTCC”，由此裂解位点氨基酸由“RRAR”突变为“GSAS”[精氨酸(Arginine,Arg,R)，甘氨酸(Glycine,Gly,G)丝氨酸(Serine,Ser,S)]。
1.4引物设计与合成
根据tPASopti6PB蛋白基因序列和重组穿梭载体pShuttle-CMV中多克隆位点基因序列，设计了构建表达tPASopti6PB蛋白基因重组穿梭载体所用引物(表1)，引物由吉林省库美生物科技有限公司合成。
表1表达SARS-CoV-2tPASopti6PB基因重组腺病毒穿梭载体所用引物
1.5表达tPASopti6PB蛋白基因重组腺病毒的构建
用限制性内切酶KpnⅠ和XhoⅠ酶切、线性化穿梭载体pShuttle-CMV，胶回收纯化线性化穿梭载体。采用PCR方法，以pBlue-tPASopti6PB为模板，用引物pShuttle-CMV-F和pShuttle-CMV-R扩增得到tPASopti6PB蛋白基因，胶回收纯化tPASopti6PB蛋白基因。用限制性内切酶KpnⅠ和XhoⅠ酶切tPASopti6PB蛋白基因，胶回收纯化tPASopti6PB蛋白基因。利用T4连接酶试剂盒将tPASopti6PB蛋白基因顺序克隆至穿梭载体pShuttle-CMV的KpnⅠ和XhoⅠ位点，构成含有tPASopti6PB蛋白基因的重组穿梭载体pShuttle-CMV-tPASopti6PB。
将经限制性内切酶PmeⅠ线性化的重组穿梭载体pShuttle-CMV-tPASopti6PB质粒转化大肠杆菌BJ5183-AD-1感受态细胞，进行同源重组，在卡那霉素抗性的培养基上筛选，挑取单克隆，用PacⅠ酶切鉴定后，得到重组腺病毒载体pAdEasy-1-tPASopti6PB质粒。将经限制性内切酶PacⅠ线性化的重组质粒pAdEasy-1-tPASopti6PB进行质粒抽提。
293A细胞接种于35mm六孔板中，待过夜生长至80％～90％单层时，将抽提的质粒pAdEasy-1-tPASopti6P，采用脂质体转染的方法，按2μg每孔的剂量，转染293A细胞。待细胞出现圆缩病变后，收取细胞和上清，冻融三次，1：40、1:200和1:800稀释病毒液，接种293A细胞，5％CO2、37℃温箱培养至72小时后，将细胞圆缩病变达80％的细胞提取基因组DNA进行PCR鉴定，经PCR鉴定正确后，表达tPASopti6PB蛋白基因的腺病毒命名为rAd-tPASopti6PB。
1.6间接免疫荧光法检测重组病毒中外源蛋白的表达
293A细胞接种于细胞培养皿中，待生长至80％～90％单层时，将重组病毒rAd-tPASopti6PB感染293A细胞，48h后，弃去培养上清，PBS洗涤细胞2次，预冷的3％多聚甲醛室温固定30min。以1:100倍稀释抗SARS-CoV-2S蛋白小鼠血清为一抗，作用30min。PBST洗涤后加入1:200倍稀释FITC标记的山羊抗鼠IgG为二抗，作用30min，PBST洗涤后荧光显微镜观察结果。
1.7 Western blotting法检测重组腺病毒中tPASopti6PB基因的表达
取重组病毒rAd-tPASopti6PB、野生型腺病毒rAd，分别感染293A细胞，48h后收集细胞，裂解细胞产物进行SDS-PAGE，再转印至NC膜上。以1：1000稀释的兔抗SARS-CoV-2S蛋白单克隆抗体为一抗，HRP标记山羊抗兔IgG为二抗，通过化学发光成像系统成像并分析tPASopti6PB蛋白表达情况。
1.8重组病毒rAd-tPASopti和rAd-tPASopti6PB对BALB/c小鼠的免疫试验
为了评估和比较分别表达SARS-CoV-2S蛋白的重组病毒rAd-tPASopti和rAd-tPASopti6PB在小鼠上的免疫效力，取6周龄雌性BALB/c小鼠70只，分为7组，每组10只，免疫途径和剂量分别为：Ⅰ.肌肉注射无菌PBS 100μL/只；Ⅱ.肌肉注射rAd-tPASopti 1×107.5TCID50/100μL/只；Ⅲ.滴鼻途径免疫rAd-tPASopti 5×106.5TCID50/50μL/只；Ⅳ.口服途径免疫rAd-tPASopti 1×107.5TCID50/100μL/只；Ⅴ.肌肉注射免疫rAd-tPASopti6PB 1×107.5TCID50/100μL/只；Ⅵ.滴鼻途径免疫rAd-tPASopti6PB 5×106.5TCID50/50μL/只；Ⅶ.口服途径免疫rAd-tPASopti6PB 1×107.5TCID50/100μL/只。间隔3周以相同剂量和途径对所有小鼠加强免疫一次。在小鼠免疫前、初次免疫后第3周和第5周经眶下静脉丛采血，分离血清，同组小鼠同一时间点的血清混合后，在56℃水浴灭活30min，用病毒中和实验法检测SARS-CoV-2中和抗体。
1.9免疫小鼠的攻毒保护试验
初次免疫后第6周，重组疫苗免疫小鼠和对照小鼠经眶下静脉丛采血，分离血清，用于SARS-CoV-2中和抗体检测。同时，按103.6PFU/50μL/只的剂量，用SARS-CoV-2HRB26M株病毒经滴鼻途径接种。攻毒后第3天和第5天，每组各解剖3只小鼠，采集鼻甲和肺脏，用实时荧光定量PCR和病毒蚀斑滴定法进行病毒核酸载量和感染性病毒滴度检测。
1.10中和试验
检测血清中SARS-CoV-2中和抗体的中和试验在24孔板上进行，步骤如下：首先将血清样品置于56℃水浴30min进行灭活，再将血清样品分别以不完全DMEM连续倍比稀释，每稀释度体积为50μL，与50μL约含100PFU的SARS-CoV-2HRB25株病毒液混合，37℃感作1h后，加入至长成单层的Vero E6细胞，5％CO2、37℃培养48h后，置于显微镜下观察SARS-CoV-2HRB25株病毒感染形成的蚀斑情况。血清中SARS-CoV-2中和抗体滴度被定义为能抑制50％蚀斑产生的最高血清稀释倍数。
1.11实时荧光定量PCR
采用实时荧光定量PCR方法测定组织样品中的病毒载量。针对SARS-CoV-2N基因的实时荧光定量PCR特异性引物和荧光探针均参照中国疾病预防控制中心病毒病预防控制所发布的信息(http://nmdc.cn/nCoV)，具体如下：上游引物：5’-GGG GAA CTT CTC CTG CTAGAA T-3’；下游引物,5’-CAG ACA TTT TGC TCT CAA GCT G-3’，荧光探针为：5’-FAM-TTGCTG CTG CTT GAC AGA TT-TAMRA-3’。利用病毒RNA提取试剂盒QIAamp vRNA Minikit(Qiagen)提取病毒RNA后，应用HiScript II Q RT SuperMix for qPCR(Vazyme)试剂盒进行反转录，再应用DNA聚合酶Premix Ex Taq for probe qPCR(TaRaKa,China)，在实时荧光定量PCR仪(Applied Biosystems QuantStudio 5Real-Time PCR System,ThermoScientific)上进行qPCR。SARS-CoV-2RNA的拷贝数是通过利用质粒pBluescript II SK-N(将全长的SARS-CoV-2N基因克隆到pBluescript II SK上构成)绘制的标准曲线进行计算、校正。该qPCR方法的检测下限为1000拷贝/mL。
1.12蚀斑滴定
检测小鼠肺脏样品中SARS-CoV-2感染性病毒的蚀斑滴定试验在24孔板上进行，步骤如下：首先将0.1克样品加入1mL无菌PBS，放入组织匀浆仪中进行研磨，再将研磨后样品离心，取上清分别以完全DMEM做连续10倍比稀释，每稀释度取体积为100μL，加入至长成单层的Vero E6细胞，37℃感作1h后，在细胞表面加入0.5mL含0.8％琼脂糖的2％FBS 2×DMEM完全培养基覆盖，待其凝固，放入培养箱5％CO2、37℃培养48h，用10％福尔马林固定1h，去除上层凝胶，干燥后观察病毒感染形成的蚀斑情况。
实施例2：实验结果
2.1表达tPASopti6PB蛋白基因重组腺病毒的构建与拯救
采用PCR方法，以pBlue-tPASopti6PB为模板，用引物pShuttle-CMV-F和pShuttle-CMV-R扩增tPASopti6PB蛋白基因。通过酶切和连接将tPASopti6PB蛋白基因克隆至穿梭载体pShuttle-CMV的KpnⅠ和XhoⅠ位点，构成含有tPASopti6PB蛋白基因重组穿梭载体pShuttle-CMV-tPASopti6PB。酶切和序列测定结果表明，tPASopti6PB蛋白基因成功克隆至pShuttle-CMV载体。将经限制性内切酶PmeⅠ线性化的穿梭载体pShuttle-CMV-tPASopti6PB质粒转化大肠杆菌BJ5183-AD-1感受态细胞，将tPASopti6PB蛋白基因同源重组至pAdEasy-1载体，提取基因组DNA，经特异性引物PCR扩增鉴定，证明tPASopti6PB蛋白基因成功重组至pAdEasy-1载体。将获得含有tPASopti6PB蛋白基因的重组质粒pAdEasy-1-tPASopti6PB利用限制性内切酶PacⅠ进行线性化，利用酚/氯仿进行质粒抽提。
采用脂质体转染的方法，用经线性化并抽提的质粒pAdEasy-1-tPASopti6PB转染293A细胞，拯救表达tPASopti6PB蛋白基因的重组腺病毒。提取细胞基因组DNA，进行PCR鉴定，结果所获PCR产物序列与预期目的片段大小相符，证明成功拯救获得表达tPASopti6PB蛋白基因重组腺病毒rAd-tPASopti6PB。
2.2间接免疫荧光检测重组腺病毒中tPASopti6PB基因的表达
拯救的重组病毒rAd-tPASopti6PB以MOI为0.01感染293A细胞，同时设定未感染细胞作为阴性对照。接种细胞37℃培养48h后以抗SARS-CoV-2S蛋白小鼠血清为一抗，以绿色荧光素(FITC)标记的山羊抗鼠IgG为二抗，进行荧光染色。结果如图1所示：抗SARS-CoV-2S蛋白小鼠血清检测重组病毒rAd-tPASopti6PB感染293A细胞呈现阳性荧光信号；而未感染293A细胞未检测到荧光信号。
2.3 Western bloting检测重组腺病毒S蛋白的表达
为了进一步鉴定重组腺病毒，分别用重组病毒rAd-tPASopti6PB和野生型rAd感染的293A细胞制备裂解液，进行SDS-PAGE和Western blot分析。结果如图2显示：以兔抗SARS-CoV-2S蛋白单克隆抗体检测重组病毒rAd-tPASopti6PB在293A细胞中表达的蛋白时，显示出特异的蛋白条带，与SARS-CoV-2S蛋白的预期值相符；而在野生型rAd感染的293A细胞或未感染的293A细胞中，未显示出特异蛋白条带。结果表明，成功拯救获得表达tPASopti6PB蛋白基因的重组腺病毒rAd-tPASopti6PB，且tPASopti6PB基因蛋白能够在重组腺病毒感染细胞中正确表达。
2.4重组腺病毒免疫小鼠的中和抗体与攻毒保护
2.4.1肌肉注射免疫
为了评估重组腺病毒rAd-tPASopti和rAd-tPASopti6PB对小鼠的免疫原性，将重组病毒rAd-tPASopti和rAd-tPASopti6PB经以肌肉注射途径各免疫小鼠10只，每只1×107.5TCID50/100μL，所有小鼠间隔3周进行加强免疫。结果显示：初次免疫后3周，可在重组病毒rAd-tPASopti6PB免疫小鼠中检测到中和抗体，平均中和抗体为1：256，rAd-tPASopti免疫小鼠未检测到中和抗体；加强免疫后，经重组病毒rAd-tPASopti和rAd-tPASopti6PB免疫的小鼠血清中均能检测到SARS-CoV-2中和抗体，抗体滴度分别为1：128和1：1024。免疫对照小鼠血清中则检测不到SARS-CoV-2中和抗体(图3A)。
为了评估表达SARS-CoV-2S蛋白基因的重组腺病毒rAd-tPASopti和rAd-tPASopti6PB通过肌肉注射免疫对小鼠的攻毒保护效力，加强免疫后2周，每组随机各选取6只重组腺病毒rAd-tPASopti、rAd-tPASopti6PB免疫接种小鼠和6只PBS免疫接种小鼠，用于SARS-CoV-2攻击试验。
用SARS-CoV-2HRB26M株病毒，经滴鼻途径攻击rAd-tPASopti、rAd-tPASopti6PB免疫小鼠和PBS免疫接种小鼠。qPCR检测和病毒滴定结果如图3B和图3C显示：攻毒后第3天，PBS免疫接种小鼠的鼻甲和肺脏均能检测到高水平的病毒RNA和高滴度的病毒；经rAd-tPASopti免疫的小鼠鼻甲和肺脏内可以检测到病毒RNA，但未检测到具有感染性的病毒，与PBS免疫小鼠相比，经rAd-tPASopti免疫的小鼠病毒RNA拷贝数降低约300倍；而在所有经rAd-tPASopti6PB肌肉注射免疫的小鼠鼻甲和肺脏均检测不到病毒RNA或具有感染性的病毒。攻毒后第5天，PBS免疫接种小鼠的鼻甲和肺脏均能检测到高水平的病毒RNA和高滴度的病毒；经rAd-tPASopti免疫的小鼠鼻甲和肺脏内可以检测到病毒RNA，但未检测到具有感染性的病毒；而在所有经rAd-tPASopti6PB免疫的小鼠鼻甲和肺脏均检测不到病毒RNA或具有感染性的病毒。
2.4.2滴鼻免疫
将重组病毒rAd-tPASopti和rAd-tPASopti6PB经以滴鼻免疫途径各免疫小鼠10只，每只5×106.5TCID50/50μL，所有小鼠间隔3周以相同方式和剂量进行加强免疫。结果显示：初次免疫后3周，经重组病毒滴鼻免疫的两组小鼠均产生SARS-CoV-2中和抗体，重组病毒rAd-tPASopti免疫小鼠平均中和抗体为1:32，重组病毒rAd-tPASopti6PB免疫小鼠平均中和抗体为1：64；加强免疫后，小鼠中和抗体水平均上升，重组病毒rAd-tPASopti免疫小鼠平均中和抗体为1:256，rAd-tPASopti免疫小鼠平均中和抗体为1:512。免疫对照小鼠血清中则检测不到SARS-CoV-2中和抗体(图4A)。
为了评估表达SARS-CoV-2S蛋白基因的重组腺病毒rAd-tPASopti和rAd-tPASopti6PB对小鼠的攻毒保护效力，加强免疫后2周，每组随机各选取6只重组腺病毒rAd-tPASopti、rAd-tPASopti6PB滴鼻免疫接种小鼠和6只PBS免疫接种小鼠，用于SARS-CoV-2攻击试验，攻毒途径和方法与1.9相同。qPCR检测和病毒滴定结果如图4B和4C显示：攻毒后第3天和第5天，PBS免疫接种小鼠的鼻甲和肺脏均能检测到高水平的病毒RNA和高滴度的病毒；而在所有经重组病毒滴鼻免疫的小鼠鼻甲和肺脏均检测不到病毒RNA或具有感染性的病毒。
2.4.3口服免疫
将重组病毒rAd-tPASopti和rAd-tPASopti6PB经口服途径各免疫小鼠10只，每只1×107.5TCID50/100μL，所有小鼠间隔3周以相同方式和剂量进行加强免疫。结果显示：初次免疫后3周，经重组病毒rAd-tPASopti免疫的小鼠未产生针对SARS-CoV-2的中和抗体，重组病毒rAd-tPASopti6PB免疫小鼠平均中和抗体为1:128；加强免疫后，小鼠中和抗体水平均上升，重组病毒rAd-tPASopti免疫小鼠平均中和抗体为1:128，rAd-tPASopti6PB免疫小鼠平均中和抗体为1:1024。免疫对照小鼠血清中则检测不到SARS-CoV-2中和抗体(图5A)。
为了评估表达SARS-CoV-2S蛋白基因的重组腺病毒rAd-tPASopti和rAd-tPASopti6PB对小鼠的攻毒保护效力，加强免疫后2周，每组随机各选取6只重组腺病毒rAd-tPASopti、rAd-tPASopti6PB口服免疫接种小鼠和6只PBS免疫接种小鼠，用于SARS-CoV-2攻击试验，攻毒途径和方法与1.9相同。qPCR检测和病毒滴定结果如图5B和5C显示：攻毒后第3天和第5天，PBS免疫接种小鼠的鼻甲和肺脏均能检测到高水平的病毒RNA和高滴度的病毒；而在所有经重组病毒口服免疫的小鼠鼻甲和肺脏均检测不到病毒RNA或具有感染性的病毒。
以上结果表明，重组腺病毒rAd-tPASopti和rAd-tPASopti6PB具有优秀的免疫原性，rAd-tPASopti6PB免疫小鼠能诱导比rAd-tPASopti更高水平的SARS-CoV-2中和抗体反应；经重组腺病毒rAd-tPASopti6PB三种免疫方式(肌肉注射、滴鼻、口服)免疫的小鼠诱导的免疫反应均能有效保护小鼠免受SARS-CoV-2感染。
序列表
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Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe
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Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu
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Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe
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Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly
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Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
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His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val
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Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly
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Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly
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Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu
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Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile
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Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp
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Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr
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Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg
645 650 655
Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys
660 665 670
Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr
675 680 685
Asn Ser Pro Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser
690 695 700
Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile
705 710 715 720
Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser
725 730 735
Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser
740 745 750
Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln
755 760 765
Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr
770 775 780
Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile
785 790 795 800
Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser
805 810 815
Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val
820 825 830
Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly
835 840 845
Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu
850 855 860
Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr
865 870 875 880
Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala
885 890 895
Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe
900 905 910
Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu
915 920 925
Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu
930 935 940
Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln
945 950 955 960
Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe
965 970 975
Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys
980 985 990
Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln
995 1000 1005
Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile
1010 1015 1020
Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu
1025 1030 1035 1040
Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met
1045 1050 1055
Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr
1060 1065 1070
Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys
1075 1080 1085
His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1090 1095 1100
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile
1105 1110 1115 1120
Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile
1125 1130 1135
Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp
1140 1145 1150
Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro
1155 1160 1165
Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn
1170 1175 1180
Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn
1185 1190 1195 1200
Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile
1205 1210 1215
Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala
1220 1225 1230
Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser
1235 1240 1245
Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu
1250 1255 1260
Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270 1275
<210> 3
<211> 1283
<212> PRT
<213> 重组蛋白()
<400> 3
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Ala Arg Gln Cys Val Asn Leu Thr Thr Arg Thr
20 25 30
Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr
35 40 45
Pro Asp Lys Val Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu
50 55 60
Phe Leu Pro Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val
65 70 75 80
Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe
85 90 95
Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg
100 105 110
Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu
115 120 125
Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln
130 135 140
Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys
145 150 155 160
Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys
165 170 175
Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys
180 185 190
Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp
195 200 205
Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg
210 215 220
Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro
225 230 235 240
Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg
245 250 255
Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala
260 265 270
Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys
275 280 285
Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp
290 295 300
Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys
305 310 315 320
Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile
325 330 335
Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe
340 345 350
Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile
355 360 365
Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe
370 375 380
Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu
385 390 395 400
Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu
405 410 415
Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn
420 425 430
Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser
435 440 445
Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg
450 455 460
Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr
465 470 475 480
Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe
485 490 495
Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly
500 505 510
Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
515 520 525
His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val
530 535 540
Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly
545 550 555 560
Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly
565 570 575
Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu
580 585 590
Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile
595 600 605
Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp
610 615 620
Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr
625 630 635 640
Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg
645 650 655
Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys
660 665 670
Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr
675 680 685
Asn Ser Pro Arg Arg Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala
690 695 700
Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn
705 710 715 720
Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile
725 730 735
Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile
740 745 750
Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser
755 760 765
Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln
770 775 780
Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys
785 790 795 800
Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu
805 810 815
Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Pro Ile Glu Asp Leu Leu
820 825 830
Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly
835 840 845
Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys
850 855 860
Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile
865 870 875 880
Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp
885 890 895
Thr Phe Gly Ala Gly Pro Ala Leu Gln Ile Pro Phe Pro Met Gln Met
900 905 910
Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu
915 920 925
Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile
930 935 940
Gln Asp Ser Leu Ser Ser Thr Pro Ser Ala Leu Gly Lys Leu Gln Asp
945 950 955 960
Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu
965 970 975
Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser
980 985 990
Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr
995 1000 1005
Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg
1010 1015 1020
Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser
1025 1030 1035 1040
Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly
1045 1050 1055
Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe
1060 1065 1070
Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala
1075 1080 1085
Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val
1090 1095 1100
Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr
1105 1110 1115 1120
Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1125 1130 1135
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln
1140 1145 1150
Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1155 1160 1165
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala
1170 1175 1180
Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala
1185 1190 1195 1200
Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
1205 1210 1215
Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala
1220 1225 1230
Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr
1235 1240 1245
Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys
1250 1255 1260
Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu
1265 1270 1275 1280
His Tyr Thr
<210> 4
<211> 1283
<212> PRT
<213> 重组蛋白()
<400> 4
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Ala Arg Gln Cys Val Asn Leu Thr Thr Arg Thr
20 25 30
Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr
35 40 45
Pro Asp Lys Val Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu
50 55 60
Phe Leu Pro Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val
65 70 75 80
Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe
85 90 95
Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg
100 105 110
Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu
115 120 125
Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln
130 135 140
Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys
145 150 155 160
Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys
165 170 175
Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys
180 185 190
Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp
195 200 205
Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg
210 215 220
Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro
225 230 235 240
Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg
245 250 255
Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala
260 265 270
Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys
275 280 285
Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp
290 295 300
Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys
305 310 315 320
Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile
325 330 335
Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe
340 345 350
Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile
355 360 365
Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe
370 375 380
Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu
385 390 395 400
Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu
405 410 415
Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn
420 425 430
Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser
435 440 445
Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg
450 455 460
Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr
465 470 475 480
Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe
485 490 495
Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly
500 505 510
Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
515 520 525
His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val
530 535 540
Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly
545 550 555 560
Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly
565 570 575
Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu
580 585 590
Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile
595 600 605
Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp
610 615 620
Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr
625 630 635 640
Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg
645 650 655
Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys
660 665 670
Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr
675 680 685
Asn Ser Pro Gly Ser Ala Ser Ser Val Ala Ser Gln Ser Ile Ile Ala
690 695 700
Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn
705 710 715 720
Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile
725 730 735
Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile
740 745 750
Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser
755 760 765
Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln
770 775 780
Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys
785 790 795 800
Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu
805 810 815
Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Pro Ile Glu Asp Leu Leu
820 825 830
Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly
835 840 845
Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys
850 855 860
Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile
865 870 875 880
Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp
885 890 895
Thr Phe Gly Ala Gly Pro Ala Leu Gln Ile Pro Phe Pro Met Gln Met
900 905 910
Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu
915 920 925
Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile
930 935 940
Gln Asp Ser Leu Ser Ser Thr Pro Ser Ala Leu Gly Lys Leu Gln Asp
945 950 955 960
Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu
965 970 975
Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser
980 985 990
Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr
995 1000 1005
Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg
1010 1015 1020
Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser
1025 1030 1035 1040
Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly
1045 1050 1055
Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe
1060 1065 1070
Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala
1075 1080 1085
Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val
1090 1095 1100
Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr
1105 1110 1115 1120
Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1125 1130 1135
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln
1140 1145 1150
Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1155 1160 1165
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala
1170 1175 1180
Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala
1185 1190 1195 1200
Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
1205 1210 1215
Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala
1220 1225 1230
Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr
1235 1240 1245
Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys
1250 1255 1260
Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu
1265 1270 1275 1280
His Tyr Thr
<210> 5
<211> 3852
<212> PRT
<213> 重组核苷酸()
<400> 5
Ala Thr Gly Gly Ala Cys Gly Cys Cys Ala Thr Gly Ala Ala Gly Cys
1 5 10 15
Gly Cys Gly Gly Cys Cys Thr Gly Thr Gly Cys Thr Gly Cys Gly Thr
20 25 30
Gly Cys Thr Gly Cys Thr Gly Cys Thr Gly Thr Gly Cys Gly Gly Cys
35 40 45
Gly Cys Cys Gly Thr Gly Thr Thr Cys Gly Thr Gly Thr Cys Cys Gly
50 55 60
Cys Cys Cys Gly Cys Cys Ala Gly Thr Gly Cys Gly Thr Gly Ala Ala
65 70 75 80
Cys Cys Thr Gly Ala Cys Cys Ala Cys Cys Cys Gly Cys Ala Cys Cys
85 90 95
Cys Ala Gly Cys Thr Gly Cys Cys Cys Cys Cys Cys Gly Cys Cys Thr
100 105 110
Ala Cys Ala Cys Cys Ala Ala Cys Thr Cys Cys Thr Thr Cys Ala Cys
115 120 125
Cys Cys Gly Cys Gly Gly Cys Gly Thr Gly Thr Ala Cys Thr Ala Cys
130 135 140
Cys Cys Cys Gly Ala Cys Ala Ala Gly Gly Thr Gly Thr Thr Cys Cys
145 150 155 160
Gly Cys Thr Cys Cys Thr Cys Cys Gly Thr Gly Cys Thr Gly Cys Ala
165 170 175
Cys Thr Cys Cys Ala Cys Cys Cys Ala Gly Gly Ala Cys Cys Thr Gly
180 185 190
Thr Thr Cys Cys Thr Gly Cys Cys Cys Thr Thr Cys Thr Thr Cys Thr
195 200 205
Cys Cys Ala Ala Cys Gly Thr Gly Ala Cys Cys Thr Gly Gly Thr Thr
210 215 220
Cys Cys Ala Cys Gly Cys Cys Ala Thr Cys Cys Ala Cys Gly Thr Gly
225 230 235 240
Thr Cys Cys Gly Gly Cys Ala Cys Cys Ala Ala Cys Gly Gly Cys Ala
245 250 255
Cys Cys Ala Ala Gly Cys Gly Cys Thr Thr Cys Gly Ala Cys Ala Ala
260 265 270
Cys Cys Cys Cys Gly Thr Gly Cys Thr Gly Cys Cys Cys Thr Thr Cys
275 280 285
Ala Ala Cys Gly Ala Cys Gly Gly Cys Gly Thr Gly Thr Ala Cys Thr
290 295 300
Thr Cys Gly Cys Cys Thr Cys Cys Ala Cys Cys Gly Ala Gly Ala Ala
305 310 315 320
Gly Thr Cys Cys Ala Ala Cys Ala Thr Cys Ala Thr Cys Cys Gly Cys
325 330 335
Gly Gly Cys Thr Gly Gly Ala Thr Cys Thr Thr Cys Gly Gly Cys Ala
340 345 350
Cys Cys Ala Cys Cys Cys Thr Gly Gly Ala Cys Thr Cys Cys Ala Ala
355 360 365
Gly Ala Cys Cys Cys Ala Gly Thr Cys Cys Cys Thr Gly Cys Thr Gly
370 375 380
Ala Thr Cys Gly Thr Gly Ala Ala Cys Ala Ala Cys Gly Cys Cys Ala
385 390 395 400
Cys Cys Ala Ala Cys Gly Thr Gly Gly Thr Gly Ala Thr Cys Ala Ala
405 410 415
Gly Gly Thr Gly Thr Gly Cys Gly Ala Gly Thr Thr Cys Cys Ala Gly
420 425 430
Thr Thr Cys Thr Gly Cys Ala Ala Cys Gly Ala Cys Cys Cys Cys Thr
435 440 445
Thr Cys Cys Thr Gly Gly Gly Cys Gly Thr Gly Thr Ala Cys Thr Ala
450 455 460
Cys Cys Ala Cys Ala Ala Gly Ala Ala Cys Ala Ala Cys Ala Ala Gly
465 470 475 480
Thr Cys Cys Thr Gly Gly Ala Thr Gly Gly Ala Gly Thr Cys Cys Gly
485 490 495
Ala Gly Thr Thr Cys Cys Gly Cys Gly Thr Gly Thr Ala Cys Thr Cys
500 505 510
Cys Thr Cys Cys Gly Cys Cys Ala Ala Cys Ala Ala Cys Thr Gly Cys
515 520 525
Ala Cys Cys Thr Thr Cys Gly Ala Gly Thr Ala Cys Gly Thr Gly Thr
530 535 540
Cys Cys Cys Ala Gly Cys Cys Cys Thr Thr Cys Cys Thr Gly Ala Thr
545 550 555 560
Gly Gly Ala Cys Cys Thr Gly Gly Ala Gly Gly Gly Cys Ala Ala Gly
565 570 575
Cys Ala Gly Gly Gly Cys Ala Ala Cys Thr Thr Cys Ala Ala Gly Ala
580 585 590
Ala Cys Cys Thr Gly Cys Gly Cys Gly Ala Gly Thr Thr Cys Gly Thr
595 600 605
Gly Thr Thr Cys Ala Ala Gly Ala Ala Cys Ala Thr Cys Gly Ala Cys
610 615 620
Gly Gly Cys Thr Ala Cys Thr Thr Cys Ala Ala Gly Ala Thr Cys Thr
625 630 635 640
Ala Cys Thr Cys Cys Ala Ala Gly Cys Ala Cys Ala Cys Cys Cys Cys
645 650 655
Cys Ala Thr Cys Ala Ala Cys Cys Thr Gly Gly Thr Gly Cys Gly Cys
660 665 670
Gly Ala Cys Cys Thr Gly Cys Cys Cys Cys Ala Gly Gly Gly Cys Thr
675 680 685
Thr Cys Thr Cys Cys Gly Cys Cys Cys Thr Gly Gly Ala Gly Cys Cys
690 695 700
Cys Cys Thr Gly Gly Thr Gly Gly Ala Cys Cys Thr Gly Cys Cys Cys
705 710 715 720
Ala Thr Cys Gly Gly Cys Ala Thr Cys Ala Ala Cys Ala Thr Cys Ala
725 730 735
Cys Cys Cys Gly Cys Thr Thr Cys Cys Ala Gly Ala Cys Cys Cys Thr
740 745 750
Gly Cys Thr Gly Gly Cys Cys Cys Thr Gly Cys Ala Cys Cys Gly Cys
755 760 765
Thr Cys Cys Thr Ala Cys Cys Thr Gly Ala Cys Cys Cys Cys Cys Gly
770 775 780
Gly Cys Gly Ala Cys Thr Cys Cys Thr Cys Cys Thr Cys Cys Gly Gly
785 790 795 800
Cys Thr Gly Gly Ala Cys Cys Gly Cys Cys Gly Gly Cys Gly Cys Cys
805 810 815
Gly Cys Cys Gly Cys Cys Thr Ala Cys Thr Ala Cys Gly Thr Gly Gly
820 825 830
Gly Cys Thr Ala Cys Cys Thr Gly Cys Ala Gly Cys Cys Cys Cys Gly
835 840 845
Cys Ala Cys Cys Thr Thr Cys Cys Thr Gly Cys Thr Gly Ala Ala Gly
850 855 860
Thr Ala Cys Ala Ala Cys Gly Ala Gly Ala Ala Cys Gly Gly Cys Ala
865 870 875 880
Cys Cys Ala Thr Cys Ala Cys Cys Gly Ala Cys Gly Cys Cys Gly Thr
885 890 895
Gly Gly Ala Cys Thr Gly Cys Gly Cys Cys Cys Thr Gly Gly Ala Cys
900 905 910
Cys Cys Cys Cys Thr Gly Thr Cys Cys Gly Ala Gly Ala Cys Cys Ala
915 920 925
Ala Gly Thr Gly Cys Ala Cys Cys Cys Thr Gly Ala Ala Gly Thr Cys
930 935 940
Cys Thr Thr Cys Ala Cys Cys Gly Thr Gly Gly Ala Gly Ala Ala Gly
945 950 955 960
Gly Gly Cys Ala Thr Cys Thr Ala Cys Cys Ala Gly Ala Cys Cys Thr
965 970 975
Cys Cys Ala Ala Cys Thr Thr Cys Cys Gly Cys Gly Thr Gly Cys Ala
980 985 990
Gly Cys Cys Cys Ala Cys Cys Gly Ala Gly Thr Cys Cys Ala Thr Cys
995 1000 1005
Gly Thr Gly Cys Gly Cys Thr Thr Cys Cys Cys Cys Ala Ala Cys Ala
1010 1015 1020
Thr Cys Ala Cys Cys Ala Ala Cys Cys Thr Gly Thr Gly Cys Cys Cys
1025 1030 1035 1040
Cys Thr Thr Cys Gly Gly Cys Gly Ala Gly Gly Thr Gly Thr Thr Cys
1045 1050 1055
Ala Ala Cys Gly Cys Cys Ala Cys Cys Cys Gly Cys Thr Thr Cys Gly
1060 1065 1070
Cys Cys Thr Cys Cys Gly Thr Gly Thr Ala Cys Gly Cys Cys Thr Gly
1075 1080 1085
Gly Ala Ala Cys Cys Gly Cys Ala Ala Gly Cys Gly Cys Ala Thr Cys
1090 1095 1100
Thr Cys Cys Ala Ala Cys Thr Gly Cys Gly Thr Gly Gly Cys Cys Gly
1105 1110 1115 1120
Ala Cys Thr Ala Cys Thr Cys Cys Gly Thr Gly Cys Thr Gly Thr Ala
1125 1130 1135
Cys Ala Ala Cys Thr Cys Cys Gly Cys Cys Thr Cys Cys Thr Thr Cys
1140 1145 1150
Thr Cys Cys Ala Cys Cys Thr Thr Cys Ala Ala Gly Thr Gly Cys Thr
1155 1160 1165
Ala Cys Gly Gly Cys Gly Thr Gly Thr Cys Cys Cys Cys Cys Ala Cys
1170 1175 1180
Cys Ala Ala Gly Cys Thr Gly Ala Ala Cys Gly Ala Cys Cys Thr Gly
1185 1190 1195 1200
Thr Gly Cys Thr Thr Cys Ala Cys Cys Ala Ala Cys Gly Thr Gly Thr
1205 1210 1215
Ala Cys Gly Cys Cys Gly Ala Cys Thr Cys Cys Thr Thr Cys Gly Thr
1220 1225 1230
Gly Ala Thr Cys Cys Gly Cys Gly Gly Cys Gly Ala Cys Gly Ala Gly
1235 1240 1245
Gly Thr Gly Cys Gly Cys Cys Ala Gly Ala Thr Cys Gly Cys Cys Cys
1250 1255 1260
Cys Cys Gly Gly Cys Cys Ala Gly Ala Cys Cys Gly Gly Cys Ala Ala
1265 1270 1275 1280
Gly Ala Thr Cys Gly Cys Cys Gly Ala Cys Thr Ala Cys Ala Ala Cys
1285 1290 1295
Thr Ala Cys Ala Ala Gly Cys Thr Gly Cys Cys Cys Gly Ala Cys Gly
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1795 1800 1805
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1810 1815 1820
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1825 1830 1835 1840
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1845 1850 1855
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1860 1865 1870
Gly Thr Gly Ala Ala Cys Thr Gly Cys Ala Cys Cys Gly Ala Gly Gly
1875 1880 1885
Thr Gly Cys Cys Cys Gly Thr Gly Gly Cys Cys Ala Thr Cys Cys Ala
1890 1895 1900
Cys Gly Cys Cys Gly Ala Cys Cys Ala Gly Cys Thr Gly Ala Cys Cys
1905 1910 1915 1920
Cys Cys Cys Ala Cys Cys Thr Gly Gly Cys Gly Cys Gly Thr Gly Thr
1925 1930 1935
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1940 1945 1950
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1955 1960 1965
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1970 1975 1980
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1985 1990 1995 2000
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2005 2010 2015
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2020 2025 2030
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2065 2070 2075 2080
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2085 2090 2095
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2100 2105 2110
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2115 2120 2125
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2130 2135 2140
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2145 2150 2155 2160
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2165 2170 2175
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2195 2200 2205
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2210 2215 2220
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2225 2230 2235 2240
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2245 2250 2255
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2260 2265 2270
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2325 2330 2335
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2450 2455 2460
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2465 2470 2475 2480
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2500 2505 2510
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2515 2520 2525
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2580 2585 2590
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2595 2600 2605
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2385 2390 2395 2400
Ala Ala Gly Gly Ala Cys Thr Thr Cys Gly Gly Cys Gly Gly Cys Thr
2405 2410 2415
Thr Cys Ala Ala Cys Thr Thr Cys Thr Cys Cys Cys Ala Gly Ala Thr
2420 2425 2430
Cys Cys Thr Gly Cys Cys Cys Gly Ala Cys Cys Cys Cys Thr Cys Cys
2435 2440 2445
Ala Ala Gly Cys Cys Cys Thr Cys Cys Ala Ala Gly Cys Gly Cys Thr
2450 2455 2460
Cys Cys Thr Thr Cys Ala Thr Cys Gly Ala Gly Gly Ala Cys Cys Thr
2465 2470 2475 2480
Gly Cys Thr Gly Thr Thr Cys Ala Ala Cys Ala Ala Gly Gly Thr Gly
2485 2490 2495
Ala Cys Cys Cys Thr Gly Gly Cys Cys Gly Ala Cys Gly Cys Cys Gly
2500 2505 2510
Gly Cys Thr Thr Cys Ala Thr Cys Ala Ala Gly Cys Ala Gly Thr Ala
2515 2520 2525
Cys Gly Gly Cys Gly Ala Cys Thr Gly Cys Cys Thr Gly Gly Gly Cys
2530 2535 2540
Gly Ala Cys Ala Thr Cys Gly Cys Cys Gly Cys Cys Cys Gly Cys Gly
2545 2550 2555 2560
Ala Cys Cys Thr Gly Ala Thr Cys Thr Gly Cys Gly Cys Cys Cys Ala
2565 2570 2575
Gly Ala Ala Gly Thr Thr Cys Ala Ala Cys Gly Gly Cys Cys Thr Gly
2580 2585 2590
Ala Cys Cys Gly Thr Gly Cys Thr Gly Cys Cys Cys Cys Cys Cys Cys
2595 2600 2605
Thr Gly Cys Thr Gly Ala Cys Cys Gly Ala Cys Gly Ala Gly Ala Thr
2610 2615 2620
Gly Ala Thr Cys Gly Cys Cys Cys Ala Gly Thr Ala Cys Ala Cys Cys
2625 2630 2635 2640
Thr Cys Cys Gly Cys Cys Cys Thr Gly Cys Thr Gly Gly Cys Cys Gly
2645 2650 2655
Gly Cys Ala Cys Cys Ala Thr Cys Ala Cys Cys Thr Cys Cys Gly Gly
2660 2665 2670
Cys Thr Gly Gly Ala Cys Cys Thr Thr Cys Gly Gly Cys Gly Cys Cys
2675 2680 2685
Gly Gly Cys Gly Cys Cys Gly Cys Cys Cys Thr Gly Cys Ala Gly Ala
2690 2695 2700
Thr Cys Cys Cys Cys Thr Thr Cys Gly Cys Cys Ala Thr Gly Cys Ala
2705 2710 2715 2720
Gly Ala Thr Gly Gly Cys Cys Thr Ala Cys Cys Gly Cys Thr Thr Cys
2725 2730 2735
Ala Ala Cys Gly Gly Cys Ala Thr Cys Gly Gly Cys Gly Thr Gly Ala
2740 2745 2750
Cys Cys Cys Ala Gly Ala Ala Cys Gly Thr Gly Cys Thr Gly Thr Ala
2755 2760 2765
Cys Gly Ala Gly Ala Ala Cys Cys Ala Gly Ala Ala Gly Cys Thr Gly
2770 2775 2780
Ala Thr Cys Gly Cys Cys Ala Ala Cys Cys Ala Gly Thr Thr Cys Ala
2785 2790 2795 2800
Ala Cys Thr Cys Cys Gly Cys Cys Ala Thr Cys Gly Gly Cys Ala Ala
2805 2810 2815
Gly Ala Thr Cys Cys Ala Gly Gly Ala Cys Thr Cys Cys Cys Thr Gly
2820 2825 2830
Thr Cys Cys Thr Cys Cys Ala Cys Cys Gly Cys Cys Thr Cys Cys Gly
2835 2840 2845
Cys Cys Cys Thr Gly Gly Gly Cys Ala Ala Gly Cys Thr Gly Cys Ala
2850 2855 2860
Gly Gly Ala Cys Gly Thr Gly Gly Thr Gly Ala Ala Cys Cys Ala Gly
2865 2870 2875 2880
Ala Ala Cys Gly Cys Cys Cys Ala Gly Gly Cys Cys Cys Thr Gly Ala
2885 2890 2895
Ala Cys Ala Cys Cys Cys Thr Gly Gly Thr Gly Ala Ala Gly Cys Ala
2900 2905 2910
Gly Cys Thr Gly Thr Cys Cys Thr Cys Cys Ala Ala Cys Thr Thr Cys
2915 2920 2925
Gly Gly Cys Gly Cys Cys Ala Thr Cys Thr Cys Cys Thr Cys Cys Gly
2930 2935 2940
Thr Gly Cys Thr Gly Ala Ala Cys Gly Ala Cys Ala Thr Cys Cys Thr
2945 2950 2955 2960
Gly Thr Cys Cys Cys Gly Cys Cys Thr Gly Gly Ala Cys Ala Ala Gly
2965 2970 2975
Gly Thr Gly Gly Ala Gly Gly Cys Cys Gly Ala Gly Gly Thr Gly Cys
2980 2985 2990
Ala Gly Ala Thr Cys Gly Ala Cys Cys Gly Cys Cys Thr Gly Ala Thr
2995 3000 3005
Cys Ala Cys Cys Gly Gly Cys Cys Gly Cys Cys Thr Gly Cys Ala Gly
3010 3015 3020
Thr Cys Cys Cys Thr Gly Cys Ala Gly Ala Cys Cys Thr Ala Cys Gly
3025 3030 3035 3040
Thr Gly Ala Cys Cys Cys Ala Gly Cys Ala Gly Cys Thr Gly Ala Thr
3045 3050 3055
Cys Cys Gly Cys Gly Cys Cys Gly Cys Cys Gly Ala Gly Ala Thr Cys
3060 3065 3070
Cys Gly Cys Gly Cys Cys Thr Cys Cys Gly Cys Cys Ala Ala Cys Cys
3075 3080 3085
Thr Gly Gly Cys Cys Gly Cys Cys Ala Cys Cys Ala Ala Gly Ala Thr
3090 3095 3100
Gly Thr Cys Cys Gly Ala Gly Thr Gly Cys Gly Thr Gly Cys Thr Gly
3105 3110 3115 3120
Gly Gly Cys Cys Ala Gly Thr Cys Cys Ala Ala Gly Cys Gly Cys Gly
3125 3130 3135
Thr Gly Gly Ala Cys Thr Thr Cys Thr Gly Cys Gly Gly Cys Ala Ala
3140 3145 3150
Gly Gly Gly Cys Thr Ala Cys Cys Ala Cys Cys Thr Gly Ala Thr Gly
3155 3160 3165
Thr Cys Cys Thr Thr Cys Cys Cys Cys Cys Ala Gly Thr Cys Cys Gly
3170 3175 3180
Cys Cys Cys Cys Cys Cys Ala Cys Gly Gly Cys Gly Thr Gly Gly Thr
3185 3190 3195 3200
Gly Thr Thr Cys Cys Thr Gly Cys Ala Cys Gly Thr Gly Ala Cys Cys
3205 3210 3215
Thr Ala Cys Gly Thr Gly Cys Cys Cys Gly Cys Cys Cys Ala Gly Gly
3220 3225 3230
Ala Gly Ala Ala Gly Ala Ala Cys Thr Thr Cys Ala Cys Cys Ala Cys
3235 3240 3245
Cys Gly Cys Cys Cys Cys Cys Gly Cys Cys Ala Thr Cys Thr Gly Cys
3250 3255 3260
Cys Ala Cys Gly Ala Cys Gly Gly Cys Ala Ala Gly Gly Cys Cys Cys
3265 3270 3275 3280
Ala Cys Thr Thr Cys Cys Cys Cys Cys Gly Cys Gly Ala Gly Gly Gly
3285 3290 3295
Cys Gly Thr Gly Thr Thr Cys Gly Thr Gly Thr Cys Cys Ala Ala Cys
3300 3305 3310
Gly Gly Cys Ala Cys Cys Cys Ala Cys Thr Gly Gly Thr Thr Cys Gly
3315 3320 3325
Thr Gly Ala Cys Cys Cys Ala Gly Cys Gly Cys Ala Ala Cys Thr Thr
3330 3335 3340
Cys Thr Ala Cys Gly Ala Gly Cys Cys Cys Cys Ala Gly Ala Thr Cys
3345 3350 3355 3360
Ala Thr Cys Ala Cys Cys Ala Cys Cys Gly Ala Cys Ala Ala Cys Ala
3365 3370 3375
Cys Cys Thr Thr Cys Gly Thr Gly Thr Cys Cys Gly Gly Cys Ala Ala
3380 3385 3390
Cys Thr Gly Cys Gly Ala Cys Gly Thr Gly Gly Thr Gly Ala Thr Cys
3395 3400 3405
Gly Gly Cys Ala Thr Cys Gly Thr Gly Ala Ala Cys Ala Ala Cys Ala
3410 3415 3420
Cys Cys Gly Thr Gly Thr Ala Cys Gly Ala Cys Cys Cys Cys Cys Thr
3425 3430 3435 3440
Gly Cys Ala Gly Cys Cys Cys Gly Ala Gly Cys Thr Gly Gly Ala Cys
3445 3450 3455
Thr Cys Cys Thr Thr Cys Ala Ala Gly Gly Ala Gly Gly Ala Gly Cys
3460 3465 3470
Thr Gly Gly Ala Cys Ala Ala Gly Thr Ala Cys Thr Thr Cys Ala Ala
3475 3480 3485
Gly Ala Ala Cys Cys Ala Cys Ala Cys Cys Thr Cys Cys Cys Cys Cys
3490 3495 3500
Gly Ala Cys Gly Thr Gly Gly Ala Cys Cys Thr Gly Gly Gly Cys Gly
3505 3510 3515 3520
Ala Cys Ala Thr Cys Thr Cys Cys Gly Gly Cys Ala Thr Cys Ala Ala
3525 3530 3535
Cys Gly Cys Cys Thr Cys Cys Gly Thr Gly Gly Thr Gly Ala Ala Cys
3540 3545 3550
Ala Thr Cys Cys Ala Gly Ala Ala Gly Gly Ala Gly Ala Thr Cys Gly
3555 3560 3565
Ala Cys Cys Gly Cys Cys Thr Gly Ala Ala Cys Gly Ala Gly Gly Thr
3570 3575 3580
Gly Gly Cys Cys Ala Ala Gly Ala Ala Cys Cys Thr Gly Ala Ala Cys
3585 3590 3595 3600
Gly Ala Gly Thr Cys Cys Cys Thr Gly Ala Thr Cys Gly Ala Cys Cys
3605 3610 3615
Thr Gly Cys Ala Gly Gly Ala Gly Cys Thr Gly Gly Gly Cys Ala Ala
3620 3625 3630
Gly Thr Ala Cys Gly Ala Gly Cys Ala Gly Thr Ala Cys Ala Thr Cys
3635 3640 3645
Ala Ala Gly Thr Gly Gly Cys Cys Cys Thr Gly Gly Thr Ala Cys Ala
3650 3655 3660
Thr Cys Thr Gly Gly Cys Thr Gly Gly Gly Cys Thr Thr Cys Ala Thr
3665 3670 3675 3680
Cys Gly Cys Cys Gly Gly Cys Cys Thr Gly Ala Thr Cys Gly Cys Cys
3685 3690 3695
Ala Thr Cys Gly Thr Gly Ala Thr Gly Gly Thr Gly Ala Cys Cys Ala
3700 3705 3710
Thr Cys Ala Thr Gly Cys Thr Gly Thr Gly Cys Thr Gly Cys Ala Thr
3715 3720 3725
Gly Ala Cys Cys Thr Cys Cys Thr Gly Cys Thr Gly Cys Thr Cys Cys
3730 3735 3740
Thr Gly Cys Cys Thr Gly Ala Ala Gly Gly Gly Cys Thr Gly Cys Thr
3745 3750 3755 3760
Gly Cys Thr Cys Cys Thr Gly Cys Gly Gly Cys Thr Cys Cys Thr Gly
3765 3770 3775
Cys Thr Gly Cys Ala Ala Gly Thr Thr Cys Gly Ala Cys Gly Ala Gly
3780 3785 3790
Gly Ala Cys Gly Ala Cys Thr Cys Cys Gly Ala Gly Cys Cys Cys Gly
3795 3800 3805
Thr Gly Cys Thr Gly Ala Ala Gly Gly Gly Cys Gly Thr Gly Ala Ala
3810 3815 3820
Gly Cys Thr Gly Cys Ala Cys Thr Ala Cys Ala Cys Cys Thr Ala Ala
3825 3830 3835 3840
<210> 7
<211> 3852
<212> PRT
<213> 重组核苷酸()
<400> 7
Claims (3)
1.一种重组人5型腺病毒rAd-tPASopti6PB，其是在SARS-CoV-2的刺突蛋白SA的基础上将S蛋白基因信号肽替换为组织型纤溶酶原激活因子信号肽tPA，同时将F817P、A892P、A899P、A942P、K986P、V987P这6个位点氨基酸残基均突变为脯氨酸，再将SA蛋白基因2044-2055位碱基突变为“GGCTCCGCCTCC”，使得Furin裂解位点突变失活，获得改造的SARS-CoV-2的刺突蛋白(S6PB)，该改造的SARS-CoV-2的刺突蛋白(S6PB)由病毒载体编码，所述病毒载体为复制缺陷型人5型腺病毒rAd病毒株，构建了表达新型冠状病毒SA蛋白变体的S6PB基因的重组人5型腺病毒rAd-tPASopti6PB。
2.一种疫苗组合物，包含权利要求1所述的重组人5型腺病毒rAd-tPASopti6PB。
3.权利要求1所述重组人5型腺病毒rAd-tPASopti6PB的制备方法，其特征在于通过基因合成的方法合成SARS-CoV-2S蛋白突变体tPASopti6PB基因，并将其克隆至pBluescriptⅡ(+/-)的EcoRⅤ位点，命名为pBlue-tPASopti6PB，将组织型纤溶酶原激活因子的信号肽基因替代SARS-CoV-2S蛋白信号肽基因构成tPASopti6PB基因，同时在tPASopti6PB基因的起始密码子ATG前插入Kozak序列“GCCGCCACC”，tPASopti6PB基因是在SARS-CoV-2S蛋白基因按哺乳动物密码子偏嗜性进行优化的基础上，将该蛋白基因2449-2451位、2674-2676位、2695-2697位、2824-2826位、2956-2958位和2959-2961位碱基均突变为“CCC”，由此将上述碱基编码的第817位苯丙氨酸、第892位丙氨酸、第899位丙氨酸、第942位丙氨酸、第986位赖氨酸和第987位缬氨酸均突变为脯氨酸；将SARS-CoV-2S蛋白裂解位点基因2044-2055位碱基突变为“GGCTCCGCCTCC”，由此裂解位点氨基酸由“RRAR”突变为“GSAS”,根据tPASopti6PB蛋白基因序列和重组穿梭载体pShuttle-CMV中多克隆位点基因序列，设计了构建表达tPASopti6PB蛋白基因重组穿梭载体所用引物，
用限制性内切酶KpnⅠ和XhoⅠ酶切、线性化穿梭载体pShuttle-CMV，胶回收纯化线性化穿梭载体，采用PCR方法，以pBlue-tPASopti6PB为模板，用引物pShuttle-CMV-F和pShuttle-CMV-R扩增得到tPASopti6PB蛋白基因，胶回收纯化tPASopti6PB蛋白基因，用限制性内切酶KpnⅠ和XhoⅠ酶切tPASopti6PB蛋白基因，胶回收纯化tPASopti6PB蛋白基因，利用T4连接酶试剂盒将tPASopti6PB蛋白基因顺序克隆至穿梭载体pShuttle-CMV的KpnⅠ和XhoⅠ位点，构成含有tPASopti6PB蛋白基因的重组穿梭载体pShuttle-CMV-tPASopti6PB，将经限制性内切酶PmeⅠ线性化的重组穿梭载体pShuttle-CMV-tPASopti6PB质粒转化大肠杆菌BJ5183-AD-1感受态细胞，进行同源重组，在卡那霉素抗性的培养基上筛选，挑取单克隆，用PacⅠ酶切鉴定后，得到重组腺病毒载体pAdEasy-1-tPASopti6PB质粒，将经限制性内切酶PacⅠ线性化的重组质粒pAdEasy-1-tPASopti6PB进行质粒抽提，293A细胞接种于35mm六孔板中，待过夜生长至80％～90％单层时，将抽提的质粒pAdEasy-1-tPASopti6BP，采用脂质体转染的方法，按2μg每孔的剂量，转染293A细胞，待细胞出现圆缩病变后，收取细胞和上清，冻融三次，1：40、1:200和1:800稀释病毒液，接种293A细胞，5％CO2、37℃温箱培养至72小时后，将细胞圆缩病变达80％的细胞提取基因组DNA进行PCR鉴定，经PCR鉴定正确后，表达tPASopti6PB蛋白基因的腺病毒命名为rAd-tPASopti6PB。
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