CN116056764A - 2019-ncov(sars-cov-2)疫苗 - Google Patents
2019-ncov(sars-cov-2)疫苗 Download PDFInfo
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Abstract
本发明涉及冠状病毒2019‑nCoV刺突蛋白、编码所述刺突蛋白的多核苷酸、抗体和疫苗,用于治疗或预防2019‑nCoV感染。一个实施方案涉及分离的多核苷酸,其编码来自2019‑nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中针对重组表达对所述多核苷酸进行优化。在特定的实施方案中,针对在选自:(a)大肠杆菌,(b)酵母,优选Komagataella或酵母属(Saccharomyces);和/或(c)哺乳动物细胞,优选人细胞的宿主细胞中的表达对多核苷酸进行优化。
Description
发明领域
本发明涉及用于治疗或预防2019-nCoV感染的冠状病毒2019-nCoV刺突蛋白、编码所述刺突蛋白的多核苷酸、抗体和疫苗。
发明背景
冠状病毒可引起多种动物的多系统感染,且主要是人类呼吸道感染,如严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS)。大多数患者症状轻微,且预后良好。
到目前为止,有少数2019-nCoV患者出现严重肺炎、肺水肿、ARDS或多器官功能衰竭并死亡。目前,有关2019-nCoV引起的肺炎的流行病学和临床特征的信息很少,也没有可用的疫苗。因此,一直需要研发可用于预防和治疗2019-nCoV感染的疫苗中的抗原。此外,需要提供可以廉价地大规模生产的抗原。
本发明通过提供编码2019-nCoV抗原,特别是来自2019-nCoV的刺突蛋白的抗原的多核苷酸、包含所述多核苷酸的载体、编码所述抗原的载体和针对该抗原产生的结合化合物(特别是抗体和抗体样分子,包括适配体和肽),及其(单独或组合)在预防或治疗2019-nCoV感染中的用途。针对在目的宿主细胞中的表达,优化编码该抗原的多核苷酸。针对该抗原产生的抗体和抗体样分子可以结合(例如特异性结合)抗原。
发明概述
迄今为止,尚未研发出针对2019-nCoV的疫苗。本发明人研发了编码2019-nCoV刺突蛋白的多核苷酸,所述多核苷酸针对在常用表达系统中的表达进行了优化。这些多核苷酸提高了2019-nCoV刺突蛋白的表达水平和持续时间,使其有利于这种抗原的大规模生产。此外,本发明人设计的多核苷酸以保留天然刺突蛋白构象的形式编码刺突蛋白氨基酸序列。因此,根据本发明产生的刺突蛋白可以引起免疫保护反应,特别是通过中和抗体的产生。
因此,本发明提供了一种分离的多核苷酸,其编码来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中所述多核苷酸针对重组表达进行了优化。
所述多核苷酸可针对在选自以下的宿主细胞中的表达进行优化:大肠杆菌(Escherichia coli);酵母,优选Komagataella或酵母属(Saccharomyces);和/或哺乳动物细胞,优选人细胞。可以通过省略一个或多个顺式作用序列基序进行优化,所述一个或多个顺式作用序列基序独立地选自:内部TATA盒;chi-位点;核糖体进入位点;富含AT和/或富含GC的序列段;RNA不稳定性基序;重复序列和/或RNA二级结构;隐蔽剪接供体位点;隐蔽剪接接受位点;和/或(a)至(i)的任何组合。所述多核苷酸可以整合到宿主细胞基因组中。所述多核苷酸可具有至少约0.80、优选至少约0.9、更优选至少约0.93的密码子适应指数(CAI)。本发明的多核苷酸可以包含与SEQ ID NO:2至8、13、14、26、27、28、30或32中的任一个具有至少90%同一性的核酸序列或由其组成。本发明的多核苷酸通常编码刺突蛋白或其片段,其:(i)保留存在于天然2019-nCoV刺突蛋白中的构象表位;(ii)当将核酸或编码的刺突蛋白或其片段施用于受试者时,导致刺突蛋白或其片段特异性的中和抗体的产生;和/或(iii)包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:5具有至少90%同一性。
本发明进一步提供了包含本发明的多核苷酸的表达构建体,其可操作地连接启动子。
本发明还提供了一种疫苗组合物,其包含来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ IDNO:15具有至少90%的同一性。当施用于受试者时,所述疫苗通常导致刺突蛋白或片段特异性的中和抗体的产生。
本发明还提供了一种病毒载体、RNA疫苗或DNA质粒,其表达来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:15具有至少90%的同一性。所述病毒载体、RNA疫苗或DNA质粒可以进一步编码信号肽。信号肽可以指导从人细胞分泌。本发明的病毒载体、RNA疫苗或DNA质粒可以进一步表达一种或多种其他抗原或其片段,优选地来自2019-nCoV的一种或多种其他抗原或其片段。刺突蛋白或其片段和一种或多种其他抗原或其片段可以:作为融合蛋白表达;或在分开的病毒载体、RNA疫苗或DNA质粒中表达,以供组合使用。所述病毒载体、RNA疫苗或DNA质粒可包含本发明的一个或多个多核苷酸或表达构建体。
本发明还提供了一种融合蛋白,其包含来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ IDNO:15具有至少90%的同一性。所述VLP或融合蛋白还可包含:乙型肝炎表面抗原(HBSAg),或其与所述HBSAg具有共同抗原交叉反应性的片段;HPV 18L1蛋白,或其与所述HPV 18L1蛋白具有共同抗原交叉反应性的片段;戊型肝炎P239蛋白(HEV),或其与所述戊型肝炎P239蛋白具有共同抗原交叉反应性的片段;和/或HPV 16L1蛋白,或其与所述HPV 16L1蛋白具有共同抗原交叉反应性的片段。该融合蛋白可由多核苷酸编码,所述多核苷酸包含与SEQ IDNO:3、5、6、8、26、27、29、30或32中的任一个具有至少90%同一性的核酸序列或由其组成;和/或该融合蛋白可以包含与SEQ ID NO:9、10、11、12、28、31或33中的任一个具有至少90%同一性的氨基酸序列或由其组成。
本发明还提供了一种病毒样颗粒(VLP),其包含来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:15具有至少90%的同一性。优选地,该VLP包含本发明的融合蛋白或由其组成。
本发明还提供了特异性结合如本文的2091-nCoV刺突蛋白抗原或其片段的抗体或其结合片段。所述抗体或其结合片段可以是单克隆或多克隆抗体。所述抗体或其结合片段可以是Fab、F(ab')2、Fv、scFv、Fd或dAb。
本发明还提供了特异性结合如本文限定的2091-nCoV刺突蛋白抗原或其片段的寡核苷酸适配体。
本发明提供了包含本发明的病毒载体,和/或RNA疫苗和/或DNA质粒的疫苗组合物。
本发明还提供了本发明的多核苷酸,和/或本发明的表达构建体,和/或本发明的疫苗组合物,和/或本发明的病毒载体和/或RNA疫苗和/或DNA质粒和/或或本发明的病毒样颗粒,和/或本发明的融合蛋白,和/或本发明的抗体和/或本发明的适配体,用于治疗和/或预防2019-nCoV感染。
本发明还提供了本发明的多核苷酸,和/或本发明的表达构建体,和/或本发明的疫苗组合物,和/或本发明的病毒载体和/或RNA疫苗和/或DNA质粒和/或本发明的病毒样颗粒,和/或本发明的融合蛋白,和/或本发明的抗体和/或本发明的适配体在制备用于预防和/或治疗2019-nCoV感染的药物中的用途。
本发明还提供了一种生产来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白或其片段的方法,包括在宿主细胞中表达本发明的多核苷酸,并任选地纯化该刺突蛋白或片段。所述方法可以进一步包括将所述刺突蛋白或其片段与药学上可接受的载体或稀释剂一起配制。
附图描述
图1:冠状病毒的结构和结构蛋白的功能的示意图。
图2:在施用2019-nCoV刺突蛋白和包含根据本发明产生的2019-nCoV刺突蛋白的融合蛋白后第0天和第14天的ELISA报告抗体滴度的列表结果。
图3:显示了分泌的蛋白质HBSAg(EAAAK)3RBD在40小时后释放到培养基中的蛋白质印迹(通过离心过滤浓缩后)。左印迹=HBSAg抗体。右印迹=2019-nCoV抗体。对于这两个印迹,泳道M=标记;泳道1=HEV-GGGS-RBD#10B;泳道2=HBSAg-EAAK-RBD#2A(293F分泌的,通过Bradford测定的总蛋白含量=750μg/ml);泳道3=HBSAg-EAAAK-RBD#2B(293F分泌的,通过Bradford测定的总蛋白含量=500μg/ml);泳道4=CoV-s#17(293F表面结合的HisTag)
图4:图表说明了单独或使用氢氧化铝或AddavaxTM佐剂,在接种了在HEK细胞中产生的HBSAg(EAAAK)3RBD的小鼠中在d14(A)和d42(B)的滴度。
图5:显示由大肠杆菌产生的分泌蛋白HEV-(GGGGS)3-RBD的蛋白质印迹。左印迹=#10A。中间印迹=#10B。右印迹=#10C。对于所有印迹,使用了1:4000稀释的抗HEV mAB。
图6:图表说明了单独或使用氢氧化铝或AddavaxTM佐剂,在接种了大肠杆菌中产生的HEV-GGGGS-RBD的小鼠中d14(A)和d42(B)的滴度。
图7:在HEK 293细胞中表达的重组HBSAg-(EAAAK)3-全长2019-nCoV刺突蛋白融合蛋白(HBSAg-(EAAAK)3-CoV-s)克隆D8-SA01-01-01(4×)和克隆D8-SA01-02-01(5×)的蛋白质印迹。
发明详述
除非本文另有定义,否则与本发明相关使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。术语的含义和范围应清楚;然而,在存在任何潜在的歧义的情况下,本文提供的定义优先于任何字典或外部定义。应当理解,本发明不限于本文所述的特定方法、方案和试剂等,且因此可以变化。本文使用的术语仅用于描述特定实施方案的目的,并不旨在限制本发明的范围,本发明的范围仅由权利要求限定。此外,除非上下文另有要求,否则单数术语应包括复数,复数术语应包括单数。在本申请中,除非另有说明,否则“或”的使用是指“和/或”。此外,术语“包括(including)”以及如“包括(includes)”和“包括(included)”的其他形式的使用不是限制性的。
本公开的实施方案的描述并非旨在穷举或将本公开限于所公开的精确形式。虽然出于说明性目的在本文中描述了本公开的具体实施方案和实施例,但是如相关领域的技术人员将认识到的,在本公开的范围内的各种等同修改是可能的。例如,虽然以给定顺序呈现方法步骤或功能,但是替代实施方案可以以不同的顺序执行功能,或者可以基本上同时执行功能。本文提供的本公开的教导可以适当地应用于其他程序或方法。可以组合本文所述的各种实施方案以提供更多实施方案。如果需要,可以修改本公开的方面,以采用上述参考文献和申请的组合物、功能和概念来提供本公开的更多实施方案。此外,由于生物功能等效性考虑,可以在蛋白质结构中进行一些改变而不影响生物或化学作用的种类或量。根据详细描述,可以对本公开进行这些和其他改变。所有这些修改旨在包括在所附权利要求的范围内。
提供本文所讨论的出版物仅仅是因为它们在本申请的提交日之前的公开内容。本文中的任何内容都不应被解释为承认这些出版物构成所附权利要求的现有技术。
冠状病毒
冠状病毒属于巢状病毒目的冠状病毒科中的冠状病毒亚科。有四个属:α冠状病毒属、β-冠状病毒属、γ冠状病毒属和δ冠状病毒属。α冠状病毒和β冠状病毒感染哺乳动物物种,γ冠状病毒感染鸟类物种,而δ冠状病毒感染哺乳动物和鸟类物种。
CoV是大的有包膜的单正义RNA病毒。RNA病毒的突变率大于DNA病毒,表明存活的适应过程更有效。
CoV在所有RNA病毒中具有最大的基因组,通常范围为27至32kb。CoV基因组编码至少四种主要结构蛋白:刺突(S)、膜(M)、包膜(E)、核衣壳(N)蛋白和其他辅助复制过程并促进进入细胞的辅助蛋白。图1概括了冠状病毒的结构和结构蛋白的功能。简言之,CoV基因组包装在由核衣壳形成的螺旋衣壳内,并进一步被包膜包围。与病毒包膜相关的是至少三种结构蛋白:参与病毒装配的膜和包膜蛋白,以及介导病毒进入宿主细胞中的刺突蛋白。一些冠状病毒还编码包膜相关的血凝素-酯酶蛋白(HE)。刺突蛋白从病毒表面形成大的突起,使冠状病毒具有冠状外观,由此得名“冠状病毒”。除了介导病毒进入之外,刺突蛋白是病毒宿主范围和组织嗜性的关键决定因素,并且是宿主免疫应答的主要诱导剂。
2019-nCoV(正式命名为严重急性呼吸综合征冠状病毒2,SARS-CoV-2,这两个术语在本文中可互换使用)是2019冠状病毒病(COVID-19)的病原体,并在人类中具有传染性。认为2019-nCoV起源于动物,鉴于2019-nCoV与SARS-CoV(79.5%)和蝙蝠冠状病毒(96%)的遗传相似性,蝙蝠是可能的来源。本文中关于CoV的任何公开内容也直接适用于且不限于2019-nCoV。
CoV刺突蛋白包含三个结构域:(i)大的胞外结构域;(ii)跨膜结构域(其单程通过病毒包膜);和(iii)短的胞内尾部。胞外结构域由三个受体结合亚基(3×S1)以及由三个膜融合亚基(3×S2)构成的三聚体茎组成。在病毒进入期间,S1与宿主细胞表面上的受体结合用于病毒附着,而S2融合宿主和病毒膜,允许病毒基因组进入宿主细胞。受体结合和膜融合是冠状病毒感染周期的最初和关键步骤。不同CoV靶向的受体存在显著差异。
2019-nCoV刺突蛋白或其免疫原性片段具有作为用于对抗2019-nCoV感染的疫苗的抗原的治疗潜力。
因此,如本文所述的,本发明涉及与SEQ ID NO:1具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的2019-nCoV刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段。优选地,本发明涉及来自2019-nCoV的与SEQ ID NO:1具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段。更优选地,本发明涉及来自2019-nCoV的与SEQ ID NO:1具有至少98%、至少99%或更多的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段。来自2019-nCoV的刺突蛋白可以包含SEQ ID NO:1或其与所述刺突蛋白具有共同抗原交叉反应性的片段或由其组成。
根据本发明,由本发明的多核苷酸编码的2019-nCoV刺突蛋白或其片段维持天然2019-nCoV刺突蛋白中存在的一个或多个构象表位。因此,由本发明的多核苷酸编码的2019-nCoV刺突蛋白或其片段能够产生免疫保护作用。通常,所述免疫保护作用包括中和抗体(nAb)的产生,所述中和抗体与由本发明的多核苷酸编码的2019-nCoV刺突蛋白或其片段的一个或多个构象表位特异性结合。CoV刺突蛋白的构象表位具有在CoV刺突蛋白的三级结构中发现的特定三维结构。所述一个或多个构象表位通常在刺突蛋白的胞外结构域内。优选地,由本发明的多核苷酸编码的2019-nCoV刺突蛋白或其片段保留天然2019-nCoV刺突蛋白中存在的所有构象表位。
在一些优选的实施方案中,本发明涉及2019-nCoV刺突蛋白的免疫原性片段,其是2019-nCoV刺突蛋白的受体结合结构域(RBD)。这个RBD负责2019-nCoV与宿主细胞的结合,从而促进2019-nCoV颗粒进入宿主细胞中。RBD对应于SEQ ID NO:1的氨基酸残基319至529,如本文所述的,称为SEQ ID NO:15。RBD由对应于2019-nCoV病毒(Genbank登录号MN908947,其版本3(MN908947.3)于2020年1月17日保藏)的基因组中的位置955至1597的碱基编码。因此,如本文所述的,本发明涉及2019-nCoV刺突蛋白的RBD,其与SEQ ID NO:15具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高的同一性。优选地,本发明涉及与SEQ ID NO:15具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的2019-nCoV刺突蛋白的RBD。更优选地,本发明涉及与SEQ ID NO:15具有至少98%、至少99%或更多的2019-nCoV刺突蛋白的RBD。2019-nCoV刺突蛋白的RBD可包含SEQ ID NO:15或由其组成。本文涉及2019-nCoV刺突蛋白的任何和所有公开内容(例如,关于多核苷酸、病毒载体、DNA质粒、RNA疫苗、病毒样颗粒(VLP)、融合蛋白、抗体、组合物和药物组合物、制剂和治疗适应症)同样适用于且不限于2019-nCoV刺突蛋白的RBD。本文提及RBD是指2019-nCoV刺突蛋白的RBD。
CoV是大的有包膜的单正义RNA病毒。RNA病毒的突变率大于DNA病毒,表明存活的适应过程更有效。因此,抗原漂移也将成为2019-nCoV的特征,或者一旦大流行消退,2019-nCoV是否在人群中成为地方性流行,存在风险。实际上,迄今为止的研究已经鉴定了2019-nCoV的刺突蛋白的受体结合结构域(RBD)内的突变,特别是G476S和V483A/G,以及S1/S2位点附近的普遍D614G突变(Saha等,ChemRXIVTM http://doi.org/10.26434/ chemrxiv.12320567.v1),证据表明这可以通过2019-nCoV病毒粒子增强细胞进入,并且还拓宽宿主细胞向性。在2019-nCoV刺突蛋白中报道的其他突变包括S943(特别是S943P)、L5(特别是L5F)、L8(特别是L8F)、V367(特别是V367F)、H49(特别是H49Y)、Y145(特别是Y145H/del)、Q239(特别是Q239K)、A831(特别是A831V)、D839(特别是D839Y/N/E)和P1263(特别是P1263L),或其任何组合(Korber等,BioRxivTM https://doi.org/10.1101/ 2020.04.29.069054)。
因此,如果需要,本发明有利地允许修饰2019-nCoV疫苗抗原,以在它们产生时提供增强的对抗具有突变的刺突蛋白的毒株的免疫力。作为非限制性实例,根据本发明的任何2019-nCoV刺突蛋白或其片段可以在位置(i)D614、(ii)V483、(iii)G476、(iv)K417、(v)E484、(vi)N501、(vii)A570和(viii)P681或(i)至(viii)中的任何组合(包括任何两个、任何三个、任何四个、任何五个、任何六个、任何七个或全部八个)处进行修饰(特别是通过取代)。替换地或另外地,2019-nCoV刺突蛋白或其片段可包含缺失突变,包括在氨基酸残基69、70和/或144中的一个或多个处的缺失。如本文所述的,突变/修饰的位置通常对应于本发明的SEQ ID NO:1中的氨基酸编号。
在位置D614处的修饰,特别是D614G取代是优选的。特别地,根据本发明的任何2019-nCoV刺突蛋白或其片段可包含以下取代(i)G476S、(ii)V483A/G、(iii)D614G、(iv)K417N/T、(v)E484K、(vi)N501Y、(vii)A570D和(viii)P681H,或(i)至(viii)的任何组合(包括任何两个、任何三个、任何四个、任何五个、任何六个、任何七个或全部八个)。
本发明还涉及来自变体2019-nCoV的2019-nCoV刺突蛋白或其片段。特别地,本发明可以涉及来自B.1.1.7株(也称为201/501Y.V1,其在英国首次检测到);B.1.351株(也称为20H/501.V2,其首次在南非检测到)和/或P1株(也称为20J/501Y.V3,其首次在日本和巴西检测到)的2019-nCoV刺突蛋白或其片段。B.1.1.7株的关键突变包括残基69/70和144Y的缺失,以及N501Y、A570D、D614G和P681H取代。B.1.351株的关键突变包括K417N、E484K、N501Y和D614G取代。P.1株的关键突变包括E484K、K417N.T、N501Y和D614G。
除非明确说明,否则本文关于多核苷酸、刺突蛋白及其片段、VLP、融合蛋白和DNA/RNA疫苗的所有公开内容同样适用于2019-nCoV的不同变体和毒株。
多核苷酸
本发明提供了编码或表达(术语“编码”和“表达”在本文中可互换使用)本发明的蛋白或免疫原性片段的多核苷酸。术语多核苷酸包括DNA和RNA序列。在本文中,术语“核酸”、“核酸分子”和“多核苷酸”可互换使用。
本发明提供了分离的多核苷酸,其编码来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段。例如,多核苷酸可以编码2019-nCoV刺突蛋白的RBD,优选其中所述RBD与SEQ ID NO:15具有至少90%的同一性。编码RBD的示例性多核苷酸显示于SEQ ID NO:13,以及SEQ ID NO:14的密码子优化序列中。
本发明还涵盖编码如上所述的来自2019-nCoV的变体刺突蛋白或其与所述变体刺突蛋白具有共同抗原交叉反应性的片段的多核苷酸。所述变体刺突蛋白通常与SEQ ID NO:1具有至少90%的同一性。
本发明的多核苷酸可用于重组表达本发明的蛋白质或免疫原性片段(包括以VLP或融合蛋白的形式),或作为DNA/RNA疫苗。
本发明人首次提供了改进的编码2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸。特别地,本发明人已经设计了针对重组表达优化的多核苷酸。可以针对在一种或多种特定细胞类型,例如真核细胞(例如哺乳动物细胞、酵母细胞、昆虫细胞或植物细胞)或原核细胞(细菌细胞)中表达来优化本发明的多核苷酸。通常,针对在细菌细胞、酵母细胞或哺乳动物细胞中表达来优化多核苷酸。优选地,所述多核苷酸被优化用于在大肠杆菌(例如,BL21(DE3)、RV308(DE3)、HMS174(DE3)或K12菌株)、Komagataella(正式指定为毕赤酵母,特别是Komagataella pastoris或Komagataella phaffii)、酵母属(特别是酿酒酵母)或人细胞(优选293F细胞、HEK 293细胞、HEK 293T细胞或HeLa细胞)中表达。其他目的细胞类型/表达系统包括安格斯毕赤酵母、多形汉逊酵母、中国仓鼠卵巢(CHO)细胞和/或基于昆虫细胞杆状病毒的表达系统。
如本文所用的,术语“优化的”涉及对2019-nCoV刺突蛋白或其免疫原性片段的重组表达的优化,并且包括密码子优化和/或对多核苷酸的其他修饰(在核酸序列和其他修饰方面),其增加多核苷酸的2019-nCoV刺突蛋白在宿主细胞/生物体内的表达水平和/或持续时间,或当从本发明的多核苷酸表达2019-nCoV刺突蛋白或其片段时提供优势。
术语“密码子优化的”是指用待表达多核苷酸的宿主生物体或细胞优先使用的密码子替换碱基多核苷酸序列内的至少一个密码子。通常,将宿主生物体中最常用的密码子用于密码子优化的多核苷酸序列中。密码子优化的方法是本领域熟知的。
作为非限制性实例,另一种形式的多核苷酸优化是使RNA结构最小化的修饰,因为涉及或以其他方式封闭原核生物中表达的基因中的RBS和/或起始密码子的结构可损害表达。优化还包括对多核苷酸的修饰,其通过增加翻译速率或通过平衡翻译速率与允许有效的“自身”或伴侣蛋白辅助的蛋白质折叠的需要来优化翻译,其中策略性地放置的较慢密码子或密码子运行(例如在蛋白质结构域边界)可以使折叠效率最大化,同时保持高的总翻译速率。优化还可以包括去除该多核苷酸的核酸序列内的有害基序。作为非限制性实例,在大肠杆菌中在T7启动子控制下表达基因,优选避免I类和II类转录终止位点。编码序列内的Shine-Dalgarno样序列可在原核宿主中引起不正确的下游启动或翻译暂停。为了在真核宿主/细胞中表达,可以去除潜在的剪接信号、多腺苷酸化信号和影响mRNA加工和稳定性的其他基序。其他类别的有害基序包括促进核糖体移码和暂停的序列。可以对本发明的多核苷酸进行任何修饰组合以优化在目的宿主细胞中的表达。
通常,针对在细菌细胞(特别是大肠杆菌)中表达而优化的本发明的多核苷酸包括克隆的N-末端和/或C-末端缺失的氨基酸。优选包括约1至20个,更优选约1至15个,最优选约5至10个克隆的N-末端和/或C-末端缺失的氨基酸。
本领域技术人员将理解,由于遗传密码的简并性,许多不同的多核苷酸可以编码相同的多肽。还应理解,技术人员可以使用常规技术进行不影响由核酸分子编码的多肽序列的核苷酸取代,以反映其中待表达多肽的任何特定宿主生物体的密码子使用。因此,除非另有说明,否则“编码本发明的蛋白质或免疫原性片段的多核苷酸”包括彼此为简并形式并且编码相同氨基酸序列的所有多核苷酸序列。
本发明的多核苷酸通常被设计成使得其能够整合到目的宿主细胞的基因组中。根据所需的宿主细胞,可以使用不同的优化策略来促进整合。
通常,通过去除或省略一个或多个顺式作用序列基序(也可互换地称为顺式作用元件或顺式作用调节元件)来优化本发明的多核苷酸。顺式作用序列基序是基因表达所需的基因结构部分附近的序列。所述一个或多个顺式作用序列基序可以独立地选自:(a)内部TATA盒;(b)Chi位点;(c)核糖体进入位点;(d)富含AT和/或富含GC的序列段;(e)RNA不稳定性基序;(f)重复序列和/或RNA二级结构;(g)隐蔽剪接供体位点;(h)隐蔽剪接接受位点;和/或(i)(a)至(i)的任何组合。这些顺式作用序列基序是本领域已知的。作为非限制性实例,省略了高GC含量(例如高于约70%,优选高于约80%)和/或低GB含量(例如低于约40%,优选低于约30%)的区域。优选地,省略高GC含量和低GC含量的两个区域,结合去除或省略一个或多个其他顺式作用序列基序。
本发明的多核苷酸也可以是如本文所述的“密码子优化的”。除了去除或省略如本文所述的一个或多个顺式作用序列基序之外,还优选进行密码子优化。
还可以改变本发明的多核苷酸的平均GC含量以优化所述多核苷酸的表达。例如,多核苷酸的平均GC含量可以在约40%至约60%,优选约40%至约57%,更优选约45%至约56%的范围内。
本发明的多核苷酸通常具有至少约0.80,优选至少约0.9,更优选至少约0.91,至少约0.92,至少约0.93,至少约0.94,至少约0.95,至少约0.96,至少约0.97,至少约0.98,至少约0.99,或更多至约1.0的密码子适应指数(CAI)。
作为优化修饰的结果,与相应的未优化的多核苷酸序列相比,本发明的多核苷酸可以将编码的2019-NCoV刺突蛋白或其片段的表达增加至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%或更多。优选地,与相应的未优化的多核苷酸相比,表达水平增加至少50%、至少60%、至少70%、至少80%、至少90%、至少100%或更多,更优选至少70%、至少80%、至少90%、至少100%或更多。
本发明的多核苷酸能够在宿主细胞中表达至少一周、至少两周、至少三周、至少一个月、至少两个月、至少三个月、至少四个月或更长时间,优选至少一个月、至少两个月、至少三个月、至少四个月或更长时间。
本发明人已经证明了2019-nCoV刺突蛋白和包含2019-nCoV刺突蛋白的融合蛋白可以使用其合理设计的优化多核苷酸在各种表达系统/宿主细胞中以高水平表达。此外,本发明已经令人惊讶地证明了2019-nCoV刺突蛋白和包含2019-nCoV刺突蛋白的融合蛋白可以在小鼠中产生强抗体应答,这证明了其潜在的治疗效用。本发明人通过设计和产生优化的多核苷酸和融合蛋白来举例说明了其优化方法,如下文实施例中所述的。
因此,本发明的多核苷酸可以包含与SEQ ID NO:2、3、4、5、6、7或8中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成。优选地,本发明的多核苷酸可以包含与SEQ IDNO:2、3、4、5、6、7、8、13、14、26、27、29、30或32中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成。更优选地,本发明的多核苷酸可以包含与SEQ ID NO:2、3、4、5、6、7、8、13、14、26、27、29、30或32中的任一个具有至少98%、至少99%或更高同一性的核酸序列或由其组成。本发明的多核苷酸可以包含SEQ ID NO:2、3、4、5、6、7、8、13、14、26、27、29、30或32中任一个的核酸序列或由其组成。此外,SEQ ID NO:2、3、4、5、6、7、8、13、14、26、27、29、30或32,或如本文所述的其任何变体中鉴定的5’克隆位点、3’克隆位点,或5’和3’克隆位点可以缺失。因此,本发明提供了包含SEQID NO:2、3、4、5、6、7、8、13、14、26、27、29、30或32中任一个或由其组成,但缺少SEQ ID NO:2、3、4、5、6、7、8、13、14、26、27、29、30或32任一个中鉴定的5’克隆位点、3’克隆位点,或5’和3’克隆位点的多核苷酸。或者,如本文所述的SEQ ID NO:2、3、4、5、6、7、8、13、14、26、27、29、30或32或其任何变体中鉴定的5’克隆位点、3’克隆位点,或5’和3’克隆位点可以用另一个合适的克隆位点独立地替换。合适的替代克隆位点是本领域熟知的。
本发明特别提供了编码2019-nCoV刺突蛋白的RBD的多核苷酸。因此,本发明的多核苷酸可以包含与SEQ ID NO:13或与SEQ ID NO:14的密码子优化序列具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成。优选地,本发明的多核苷酸可以包含与SEQ ID NO:13或与SEQID NO:14的密码子优化序列具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成。更优选地,本发明的多核苷酸可以包含与SEQID NO:13或与SEQ ID NO:14的密码子优化序列核酸序列具有至少98%、至少99%或更高同一性的核酸序列或由其组成。本发明的多核苷酸可以包含SEQ ID NO:13的核酸序列或SEQID NO:14的密码子优化序列或由其组成。
本发明的多核苷酸通常编码2019-nCoV刺突蛋白或其免疫原性片段,其:(a)保留天然2019-nCoV刺突蛋白中存在的构象表位;和/或(b)当将核酸或编码的刺突蛋白或其片段施用于受试者时,导致刺突蛋白或其片段特异性的中和抗体的产生。
本发明的多核苷酸通常表达来自2019-nCoV的与SEQ ID NO:1具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段。优选地,本发明的多核苷酸表达来自2019-nCoV的与SEQ ID NO:1具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。更优选地,本发明的多核苷酸表达来自2019-nCoV的与SEQ ID NO:1具有至少98%、至少99%或更多的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。本发明的多核苷酸可以表达来自2019-nCoV的包含SEQ ID NO:1或由SEQ ID NO:1组成的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。
本发明的多核苷酸可以包含在表达构建体中以促进2019-nCoV刺突蛋白或其片段的表达。因此,本发明还提供了包含本发明的多核苷酸的表达构建体。通常,在这样的表达构建体中,本发明的多核苷酸与合适的启动子可操作地连接。多核苷酸可以与合适的终止子序列连接。多核苷酸可以与启动子和终止子两者连接。合适的启动子和终止子序列是本领域熟知的。
启动子的选择将取决于多核苷酸的最终表达将在何处发生。通常,优选组成型启动子,但同样可以使用诱导型启动子。以这种方式产生的构建体包括载体的至少一部分,特别是调控元件。载体优选能够在给定的宿主细胞中表达核酸。可以使用任何合适的宿主细胞,如哺乳动物、细菌、昆虫、酵母和/或植物宿主细胞。此外,可以使用无细胞表达系统。此类表达系统和宿主细胞是本领域标准的。
由本发明的多核苷酸编码或表达(这两个术语在本文中可互换使用)的2019-nCoV刺突蛋白或其免疫原性片段通常保留与天然2019-nCoV刺突蛋白相同的受体结合亲和力。在本发明的上下文中,这可能意味着对2019-nCoV刺突蛋白受体的结合亲和力为天然2019-nCoV刺突蛋白的结合亲和力的至少80%、至少85%、至少90%、至少95%、至少99%或更高。优选地,由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段对2019-nCoV刺突蛋白的结合亲和力为天然2019-nCoV刺突蛋白的结合亲和力的至少90%、至少95%、至少99%或更高。
在一些实施方案中,由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段对2019-nCoV刺突蛋白受体的结合亲和力大于全长蛋白的结合亲和力。例如,由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段可以具有天然2019-nCoV刺突蛋白的结合亲和力的至少100%、至少110%、至少120%或至少150%或更高的结合亲和力。
在其他实施方案中,由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段对2019-nCoV刺突蛋白受体的结合亲和力可以小于天然2019-nCoV刺突蛋白的结合亲和力。例如,由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段可以具有天然2019-nCoV刺突蛋白的结合亲和力的小于80%、小于70%、小于60%、小于50%或更小的结合亲和力。
由本发明的多核苷酸表达的2019-NCoV刺突蛋白或其免疫原性片段对其受体的结合亲和力可以根据解离常数(Kd)来定量。Kd可以使用任何合适的技术来测定,但在本发明的上下文中通常优选SPR。
由本发明的多核苷酸表达的2019-nCoV刺突蛋白的免疫原性片段的长度通常大于200个氨基酸。本发明的2019-nCoV刺突蛋白片段的长度可包含至少200个、至少300个、至少400个、至少500个、至少600个、至少700个、至少800个、至少900个、至少1000个、至少1100个或更多个氨基酸残基或由其组成。本发明的片段与2019-nCoV刺突蛋白具有共同的抗原交叉反应性。在一些优选的实施方案中,由本发明的多核苷酸表达的2019-nCoV刺突蛋白的免疫原性片段是如本文所定义的2019-nCoV刺突蛋白的RBD,优选地其中所述RBD与SEQ IDNO:15具有至少90%的同一性。
由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段可另外包含前导序列,例如以帮助2019-nCoV刺突蛋白或其免疫原性片段的重组产生和/或分泌。可以使用任何合适的前导序列,包括本领域已知的常规前导序列。合适的前导序列包括Bip前导序列和人组织纤溶酶原激活物前导序列(tPA),所述BiP前导序列在本领域中通常用于帮助从昆虫细胞分泌,所述人组织纤溶酶原激活物前导序列(tPA)常规用于基于病毒和DNA的疫苗以及用于蛋白质疫苗以帮助从哺乳动物细胞表达平台分泌。
由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段可另外包含N-或C-末端标签,例如以帮助2019-nCoV刺突蛋白或其免疫原性片段的重组产生和/或纯化。可以使用任何N-或C-末端标签,包括本领域已知的常规标签。合适的标签序列包括C-末端六组氨酸标签和“C-标签”(在C-末端的四个氨基酸EPEA),其在本领域中通常用于帮助从异源表达系统(例如昆虫细胞、哺乳动物细胞、细菌或酵母)纯化。在其他实施方案中,由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段从异源表达系统中纯化,而不需要使用纯化标签。
由本发明的多核苷酸表达的2019-nCoV刺突蛋白或其免疫原性片段可包含如本文所定义的前导序列和/或标签。
病毒载体、DNA质粒和RNA疫苗
本发明还提供了一种载体:(a)包含本发明的多核苷酸;和/或(b)编码本发明的2019-nCoV刺突蛋白或其免疫原性片段。载体可以以疫苗组合物或制剂的形式存在。
本发明的载体通常表达来自2019-nCoV的与SEQ ID NO:1具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。优选地,本发明的载体表达来自2019-nCoV的与SEQ ID NO:1具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。更优选地,本发明的载体表达来自2019-nCoV的与SEQ ID NO:1具有至少98%、至少99%或更多的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。本发明的载体可以表达来自2019-nCoV的包含SEQ ID NO:1或由SEQ ID NO:1组成的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。在一些优选的实施方案中,由本发明的载体表达的2019-nCoV刺突蛋白的免疫原性片段是如本文所定义的2019-nCoV刺突蛋白的RBD,优选地其中所述RBD与SEQ ID NO:15具有至少90%的同一性。
本发明的载体可以表达如本文所定义的刺突蛋白或其免疫原性片段,其还包含信号肽。通常,所述信号肽指导2019-nCoV刺突蛋白或其片段从目的宿主细胞(如人细胞、大肠杆菌细胞或酵母细胞)分泌。
本发明的载体可以进一步表达一种或多种另外的抗原或其片段。刺突蛋白或其片段和一种或多种另外的抗原或其片段可以表达为融合蛋白。或者,可以使用分开的表达2019-nCoV刺突蛋白或其片段和一种或多种另外的抗原或其片段的载体。在这种情况下,所述分开的载体可以顺序或同时组合使用。一种或多种另外的抗原可以是与2019-nCoV或其片段相同的抗原或不同的抗原。更优选地,所述一种或多种另外的抗原是与2019-nCoV不同的抗原,如来自2019-CoV膜蛋白或包膜蛋白的抗原。
本发明的载体可以包含如本文所定义的任何多核苷酸或表达构建体,或其任何组合。
载体可以是病毒载体。这样的病毒载体可以是腺病毒(人血清型的,如AdHu5,猿猴血清型的,如ChAd63、ChAdOX1或ChAdOX2,或另一种形式)、腺相关病毒(AAV)或痘病毒载体(如修饰的安卡拉痘苗(MVA))或腺相关病毒(AAV)。ChAdOX1和ChAdOX2公开于WO2012/172277(通过引用整体并入本文)中。ChAdOX2是BAC衍生的且E4修饰的基于AdC68的病毒载体。优选地,所述病毒载体是AAV载体腺病毒。
病毒载体通常是非复制或复制受损的载体,这意味着病毒载体不能在正常细胞(例如正常人细胞)中以任何显著程度复制,如通过常规手段测量的-例如,通过测量DNA合成和/或病毒滴度。非复制或复制受损的载体可能已经变得如此自然地(即,它们已经按原样从自然界中分离出来)或人工地(例如,通过体外育种或通过遗传操纵)。通常存在至少一种细胞类型-复制受损的病毒载体可以在其中生长-例如,修饰的安卡拉痘苗(MVA)可以在CEF细胞中生长。作为非限制性实例,载体可以选自人或猿猴腺病毒或痘病毒载体。
通常,病毒载体不能在动物受试者中(通常在哺乳动物受试者,如人或其他灵长类动物中)引起显著感染。
载体可以是DNA载体,如DNA质粒。载体可以是RNA载体,如mRNA载体或自扩增RNA载体。本发明的DNA和/或RNA载体可以能够在真核和/或原核细胞,特别是本文所述的任何宿主细胞类型中表达,或在待治疗的受试者中表达。
通常,DNA和/或RNA载体能够在人、大肠杆菌或酵母细胞中表达。
本发明可以是噬菌体载体,如Hajitou等,Cell 2006;125(2)pp.385-398中描述的AAV/噬菌体杂合载体;通过引用并入本文。
本发明的核酸分子可以使用本领域已知的任何合适的方法来制备。因此,可以使用化学合成技术来制备核酸分子。或者,可以使用分子生物学技术来制备本发明的核酸分子。
本发明的载体可以在计算机上设计,然后通过常规的多核苷酸合成技术合成。
病毒样颗粒
病毒样颗粒(VLP)是类似于病毒但不含病毒核酸的颗粒,因此是非感染性的。它们通常含有一种或多种能够自组装的病毒衣壳或包膜蛋白以形成VLP。VLP已经由多种病毒家族的组分产生(Noad和Roy(2003),Trends in Microbiology,11:43 8-444;Grgacic等,(2006),Methods,40:60-65)。一些VLP已被批准作为治疗性疫苗,例如Engerix-B(用于乙型肝炎)、Cervarix和Gardasil(用于人乳头瘤病毒)。
因此,本发明提供了包含本发明的2019-nCoV刺突蛋白或其免疫原性片段的VLP。本发明的VLP通常包含来自2019-nCoV的与SEQ ID NO:1具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段。优选地,本发明的VLP包含来自2019-nCoV的与SEQ ID NO:1具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。更优选地,本发明的VLP包含来自2019-nCoV的与SEQ ID NO:1具有至少98%、至少99%或更多的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。本发明的VLP可包含来自2019-nCoV的包含SEQ ID NO:1或由SEQ ID NO:1组成的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。在一些优选的实施方案中,本发明的VLP中包含的2019-nCoV刺突蛋白的免疫原性片段是如本文所定义的2019-nCoV刺突蛋白的RBD,优选地其中所述RBD与SEQ ID NO:15具有至少90%的同一性。
本领域技术人员将理解,可以通过病毒结构蛋白的单独表达来合成VLP,其然后可以自组装成病毒样结构。来自不同病毒的结构衣壳蛋白的组合可用于产生重组VLP。此外,抗原或其免疫原性片段可以与VLP的表面融合。作为非限制性实例,可以使用SpyCatcher-SpyTag系统(如Brune、Biswas、Howarth所述的)将本发明的抗原或其免疫原性片段与VLP偶联。
本发明的VLP可包含一种或多种另外的蛋白质抗原。所述一种或多种另外的抗原可以是与2019-nCoV或其片段相同的抗原或不同的抗原。更优选地,所述一种或多种另外的抗原是与2019-nCoV不同的抗原,如来自2019-CoV膜蛋白或包膜蛋白的抗原。
本发明的VLP可包含如本文所述的融合蛋白。本发明的VLP可包含2019-nCoV刺突蛋白或其免疫原性片段与乙型肝炎表面抗原(HBsAg)、人乳头瘤病毒(HPV)18LI蛋白、HPV16LI蛋白和/或戊型肝炎P239(优选乙型肝炎表面抗原)的融合蛋白。尽管这些其他病毒蛋白已经在先前的融合蛋白中描述,但迄今为止,没有成功产生包含2019-nCoV刺突蛋白大小的蛋白质的融合蛋白的报道。此外,关于此类融合蛋白的表达系统的选择存在已知的限制。本发明人令人惊讶地证明了包含2019-nCoV刺突蛋白的VLP/融合蛋白可以在大肠杆菌、酵母和人细胞中重组产生,并且这些VLP/融合蛋白可以在动物模型中引发(免疫保护性)抗体应答。
因此,本发明的VLP可以由包含与SEQ ID NO:3、5、6或8中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。优选地,本发明的VLP可以由包含与SEQ IDNO:3、5、6或8中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。更优选地,本发明的VLP可以由包含与SEQ ID NO:3、5、6或8中的任一个具有至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。本发明的VLP可以由包含SEQ ID NO:3、5、6或8中任一个的核酸序列或由其组成的多核苷酸编码。
本发明的VLP可以由包含与SEQ ID NO:26、27、29、30或32中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。优选地,本发明的VLP可以由包含与SEQ ID NO:26、27、29、30或32中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。更优选地,本发明的VLP可以由包含与SEQ ID NO:26、27、29、30或32中的任一个具有至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。本发明的VLP可以由包含SEQ ID NO:26、27、29、30或32中任一个的核酸序列或由其组成的多核苷酸编码。
本发明的VLP可包含与SEQ ID NO:9、10、11或12中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。优选地,本发明的VLP可包含与SEQ ID NO:9、10、11或12中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。更优选地,本发明的VLP可包含与SEQ ID NO:9、10、11或12中的任一个具有至少98%、至少99%或更高同一性的氨基酸序列或由其组成。本发明的VLP可包含SEQ ID NO:9、10、11或12中任一个的氨基酸序列或由其组成。
本发明的VLP可包含与SEQ ID NO:28、31或33中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。优选地,本发明的VLP可包含与SEQ ID NO:28、31或33中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。更优选地,本发明的VLP可包含与SEQ ID NO:28、31或33中的任一个具有至少98%、至少99%或更高同一性的氨基酸序列或由其组成。本发明的VLP可包含SEQID NO:28、31或33中任一个的氨基酸序列或由其组成。
VLP的使用可以增加由2019-nCoV刺突蛋白或免疫原性片段诱导的免疫保护应答的功效和/或可以增加如本文所定义的免疫保护应答的持续时间。
融合蛋白
本发明还提供了包含本发明的2019-nCoV刺突蛋白或其免疫原性片段的融合蛋白。本发明的融合蛋白通常包含来自2019-nCoV的与SEQ ID NO:1具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。优选地,本发明的融合蛋白包含来自2019-nCoV的与SEQ ID NO:1具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。更优选地,本发明的融合蛋白包含来自2019-nCoV的与SEQ ID NO:1具有至少98%、至少99%或更多的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。本发明的融合蛋白可以包含来自2019-nCoV的包含SEQ ID NO:1或由SEQ ID NO:1组成的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段。在一些优选的实施方案中,包含在本发明的融合蛋白中的2019-nCoV刺突蛋白的免疫原性片段是如本文所定义的2019-nCoV刺突蛋白的RBD,优选地其中所述RBD与SEQ ID NO:15具有至少90%的同一性。
本发明的融合蛋白通常还包含非2019-nCoV结构域或元件,通常为非2019-nCoV蛋白、多肽或肽结构域或元件。本发明的融合蛋白可以包含2019-nCoV刺突蛋白或其免疫原性片段和以下中的一种或多种:乙型肝炎表面抗原(HBsAg);人乳头瘤病毒(HPV)18L1蛋白;HPV 16LI蛋白;和/或戊型肝炎P239(HEV),优选乙型肝炎表面抗原。如上文在VLP内容中所述的,本发明人惊奇地证明了包含2019-nCoV刺突蛋白的融合蛋白可以在大肠杆菌、酵母和人细胞中重组产生,并且这些融合蛋白可以在动物模型中引发(免疫保护性)抗体应答。
本发明的融合蛋白可以由包含与SEQ ID NO:3、5、6或8中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。优选地,本发明的融合蛋白可以由包含与SEQ ID NO:3、5、6或8中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。更优选地,本发明的融合蛋白可以由包含与SEQ ID NO:3、5、6或8中的任一个具有至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。本发明的VLP可以由包含SEQ ID NO:3、5、6或8中任一个的核酸序列或由其组成的多核苷酸编码。
本发明的融合蛋白可以由包含与SEQ ID NO:26、27、29、30或32中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。优选地,本发明的融合蛋白可以由包含与SEQ ID NO:26、27、29、30或32中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。更优选地,本发明的融合蛋白可以由包含与SEQ ID NO:26、27、29、30或32中的任一个具有至少98%、至少99%或更高同一性的核酸序列或由其组成的多核苷酸编码。本发明的融合蛋白可以由包含SEQ ID NO:26、27、29、30或32中任一个的核酸序列或由其组成的多核苷酸编码。
本发明的融合蛋白可包含与SEQ ID NO:9、10、11或12中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。优选地,本发明的融合蛋白可以包含与SEQ ID NO:9、10、11或12中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。更优选地,本发明的融合蛋白可以包含与SEQ ID NO:9、10、11或12中的任一个具有至少98%、至少99%或更高同一性的氨基酸序列或由其组成。本发明的融合蛋白可包含SEQ ID NO:9、10、11或12中任一个的氨基酸序列或由其组成。
本发明的融合蛋白可包含与SEQ ID NO:28、31或33中的任一个具有至少70%、至少75%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。优选地,本发明的融合蛋白可以包含与SEQ ID NO:28、31或33中的任一个具有至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或更高同一性的氨基酸序列或由其组成。更优选地,本发明的融合蛋白可包含与SEQ ID NO:28、31或33中的任一个具有至少98%、至少99%或更高同一性的氨基酸序列或由其组成。本发明的融合蛋白可包含SEQ ID NO:28、31或33中任一个的氨基酸序列或由其组成。
本发明的融合蛋白可以包含接头(在本文中也可互换地称为接头肽、间隔物或间隔肽)。接头可用于连接本发明的融合蛋白的两个或更多个功能结构域。通常,在存在接头的情况下,其用于将融合蛋白的2019-nCoV刺突蛋白或其免疫原性片段结构域连接融合蛋白的非2019-nCoV刺突蛋白结构域。在融合蛋白中使用接头是本领域常规的,并且任何常规接头蛋白可用于本发明的融合蛋白中,只要所得融合蛋白保留2019-nCoV刺突蛋白或其免疫原性片段的所需功能特性和非2019-nCoV刺突蛋白结构域的所需功能特性。
接头可以是长度多达约30个氨基酸,如约5-30个氨基酸、约5-25个氨基酸、约5-20个氨基酸、约10-20个氨基酸、约5-15个氨基酸或约10-15个氨基酸的短肽。在一些实施方案中,接头的长度为约10、约11、约12、约13、约14、约15、约16、约17、约18、约19或约20个氨基酸。
在一些实施方案中,刚性接头可用于本发明的融合蛋白中。当需要保持融合蛋白的不同结构域/部分之间的固定距离并保持其独立功能时,通常使用刚性接头。当融合蛋白结构域的空间分离对于保持融合蛋白的稳定性或生物活性至关重要时,也可以使用刚性接头。具有序列A(EAAAK)nA(n=2-5)SEQ ID NO:16)的经验刚性接头显示出α-螺旋构象,其通过Glu--Lys+盐桥稳定。可以通过改变拷贝数来调节接头的长度,以实现结构域之间的最佳距离。螺旋接头还可以改善融合蛋白折叠和稳定性。
刚性接头的非限制性实例是EAAAKEAAAKEAAAK(也称为(EAAAK)3,SEQ ID NO:18),其可以由核酸序列(SEQ ID NO:17)编码。接头的长度和结构控制功能结构域之间的距离,影响融合蛋白的稳定性。本发明的RBD融合蛋白的稳定性和活性通常在(EAAAK)3接头插入后显著改善,如本文实施例中所示的。使用接头,特别是(EAAAK)3,也可以提高本发明的重组融合蛋白的产量。
因此,刚性接头,特别是(EAAAK)3(SEQ ID NO:18),可以优选用于在哺乳动物细胞(如HEK 293细胞)中表达本发明的融合蛋白。
在一些实施方案中,柔性接头可用于本发明的融合蛋白中。当连接的结构域需要一定程度的移动或相互作用时,通常使用柔性接头。柔性接头通常包含小氨基酸残基或由小氨基酸残基组成,如甘氨酸、苏氨酸、精氨酸、丝氨酸、天冬酰胺、谷氨酰胺、丙氨酸、天冬氨酸、脯氨酸、谷氨酸、赖氨酸、亮氨酸和/或缬氨酸,特别是甘氨酸、丝氨酸、丙氨酸、亮氨酸和/或缬氨酸。包含甘氨酸、丝氨酸和/或丙氨酸或由甘氨酸、丝氨酸和/或丙氨酸组成的柔性接头是优选的,其中甘氨酸和丝氨酸是特别优选的。因此,最常用的柔性接头具有主要由Gly和Ser残基的片段组成的序列(“GS”接头),其包含(Gly-Gly-Gly-Gly-Ser)n(SEQ IDNO:19)的序列。GS接头的非限制性实例包括GS5或(GGGGS)1(SEQ ID NO:20);GS10或(GGGGS)2(SEQ ID NO:21);GS15或(GGGGS)3(SEQ ID NO:23);GS20或(GGGGS)4(SEQ ID NO:24);和GS25或(GGGGS)5(SEQ ID NO:25)。优选地,可以使用GS15,其可以由(SEQ ID NO:22)编码。柔性接头可优选用于在细菌细胞(如大肠杆菌细胞)中表达本发明的融合蛋白。
任何合适的接头,如本文所述的示例性接头,可与本发明的任何融合蛋白(包含任何2019-NCoV刺突蛋白或免疫原性片段结构域和任何非219-NCoV刺突蛋白结构域)一起使用。作为非限制性实例,本发明的融合蛋白可以包含(或由其组成)HBsAg-(EAAAK)3-RBD(SEQ ID NO:28),或与其具有至少90%序列同一性的变体(其可以由SEQ ID NO:26或27编码),或与其具有至少90%序列同一性的变体。作为更多非限制性实例,本发明的融合蛋白可以包含(或由其组成)HBsAg-(EAAAK)3-全长2019-nCoV刺突蛋白(SEQ ID NO:33),或与其具有至少90%序列同一性的变体(其可以由SEQ ID NO:32编码),或与其具有至少90%序列同一性的变体。作为更多非限制性实例,本发明的融合蛋白可以包含(或由其组成)HEV-GS15-RBD(SEQ ID NO:31),或与其具有至少90%序列同一性的变体(其可以由(SEQ ID NO:29或30)编码),或与其具有至少90%序列同一性的变体。
本发明的融合蛋白可以优选采用VLP的形式。不受理论的约束,这是因为已知HBsAg、HPV 18LI蛋白、HPB 16LI蛋白和戊型肝炎P239蛋白在重组表达时自发形成VLP,并且当HBsAg、HPV 18LI蛋白、HPB 16LI蛋白和/或戊型肝炎P239蛋白以与本发明的2019-nCoV刺突蛋白(或其免疫原性片段)组合的融合蛋白形式存在时,该结构得以保留。
抗体
如本文所述的,由本发明的多核苷酸编码的2019-nCoV刺突蛋白或其片段引发特异性结合天然2019-nCoV中发现的一个或多个构象表位的抗体的产生。所述抗体通常是如下所述的中和抗体(nAb)。这些nAb能够介导对抗2019-nCoV的免疫保护作用。
如本文所用的,术语“抗体”泛指由四条多肽链(两条重(H)链和两条轻(L)链)组成的任何免疫球蛋白(Ig)分子,或其任何功能性片段、突变体、变体或衍生物,其保留Ig分子的基本表位结合特征。此类突变体、变体或衍生抗体实体是本领域已知的,其非限制性实施方案在下文讨论。
在全长抗体中,每条重链由重链可变区(本文缩写为VH)和重链恒定区组成。重链恒定区由三个结构域CHI、CH2和CH3组成。每条轻链由轻链可变区(本文缩写为VL)和轻链恒定区组成。轻链恒定区由一个结构域CL组成。VH和VL区可以进一步细分为超变区,称为互补决定区(CDR),散布着更保守的区域,称为框架区(FR)。每个VH和VL由三个CDR和四个FR组成,从氨基末端到羧基末端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。抗体可以是多克隆的(pAb)或单克隆的(mAb)。当在治疗上使用(即提供被动免疫)时,优选施用mAb。
根据本发明,抗体可以是任何类型(例如,IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如,IgGl、IgG2、IgG3、IgG4、IgAl和IgA2)或亚类,并且可以来自任何物种(例如,小鼠、人、鸡、大鼠、兔、绵羊、鲨鱼和骆驼科动物)。
如本文所用的,术语抗体的“抗原结合片段”(或简称“结合片段”)是指保留特异性结合抗原的能力的抗体的一个或多个片段。已经显示了抗体的抗原结合功能可以由全长抗体的一个或多个片段来执行。也包括单链抗体。此类抗原结合片段也可以是双特异性的、双重特异性的或多特异性的,特异性地结合两种或更多种不同的抗原。因此,涵盖在术语抗体的“抗原结合片段”内的结合片段的实例包括Fab、Fv、scFv、dAb、Fd、Fab'或F(ab')2、串联scFv和双抗体。
还涵盖抗体构建体,定义为包含一个或多个与接头多肽或免疫球蛋白恒定结构域连接的本发明的抗原结合片段的多肽。接头多肽包含通过肽键连接的两个或更多个氨基酸残基,并且用于连接一个或多个抗原结合部分。
如本文所用的,术语“抗体”可以是人抗体;定义为具有衍生自人种系免疫球蛋白序列的可变区和恒定区的抗体,但其可以包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机或位点特异性诱变或通过体内体细胞突变引入的突变),例如在CDR中,特别是在CDR3中。还涵盖重组人抗体。
本发明的抗体可以是“嵌合抗体”;定义为包含来自一个物种的重链和轻链可变区序列和来自另一个物种的恒定区序列的抗体。本发明包括具有例如与人恒定区连接的鼠重链和轻链可变区的嵌合抗体。
本发明的抗体可以是“CDR嫁接抗体”;定义为包含来自一个物种的重链和轻链可变区序列但其中VH和/或VL的一个或多个CDR区的序列被另一个物种的CDR序列替换的抗体,如具有鼠重链和轻链可变区的抗体,其中一个或多个鼠CDR(例如CDR3或所有三个CDR)已被人CDR序列替换。
本发明的抗体可以是“人源化抗体”;定义为包含来自非人物种(例如小鼠)的重链和轻链可变区序列,但其中VH和/或VL序列的至少一部分已被改变为更“人样”,即更类似于人种系可变序列的抗体。一种类型的人源化抗体是CDR嫁接抗体,其中将人CDR序列引入非人VH和VL序列中以替换相应的非人CDR序列。
术语“Kabat编号”、“Kabat定义”和“Kabat标记”在本文可互换使用。本领域公认的这些术语是指对比抗体的重链和轻链可变区或其抗原结合部分中的其他氨基酸残基更可变(即超变)的氨基酸残基进行编号的系统(Kabat等(1971)Ann.NY Acad,Sci.190:382-391和Kabat,E.A.等(1991)Sequences of Proteins of Immunological Interest,第五版,U.S.Department of Health and Human Services,NIH Publication No.91-3242)。
本发明的抗体不限于特定的产生或生产方法。因此,本发明提供了由分泌抗体的杂交瘤制备的抗体,以及由重组产生的细胞产生的抗体,所述重组产生的细胞已经用编码抗体的一个或多个多核苷酸转化或转染。此类杂交瘤、重组产生的细胞和多核苷酸形成本发明的一部分。
本发明的抗体或其抗原结合片段是对如本文所述的2019-nCoV刺突蛋白或2019-nCoV刺突蛋白的特定表位(优选构象表位)选择性或特异性的。特异性,应当理解,抗体结合目的分子,在本案中是2019-nCoV刺突蛋白或其片段,与任何其他分子,特别是任何其他蛋白质没有显著的交叉反应性。例如,本发明的特定2019-nCoV刺突蛋白表位特异性的本发明的结合化合物或抗体将不显示与其他2019-nCoV刺突蛋白表位的显著交叉反应性。作为另一个实例,2019-nCoV刺突蛋白特异性的本发明的结合化合物或抗体将不显示与2019-nCoV膜蛋白的显著交叉反应性。可以通过任何合适的方法评估交叉反应性。如果结合化合物(例如,抗体)以其结合2019-nCoV刺突蛋白表位的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或100%那样强结合其他分子,则认为2019-nCoV刺突蛋白表位的结合化合物(例如抗体)与另一种2019-nCoV刺突蛋白表位或除2019-nCoV刺突蛋白以外的蛋白质的交叉反应性是显著的。对2019-nCoV刺突蛋白或其片段特异性的结合化合物(例如抗体)可以以小于其结合2019-nCoV刺突蛋白表位的强度的90%、85%、80%、75%、70%、65%、60%、55%、50%、45%、40%、35%、30%、25%或20%结合另一个分子,如2019-nCoV膜蛋白。优选地,结合化合物(例如抗体)以小于其结合2019-nCoV刺突蛋白表位的强度的20%、小于15%、小于10%或小于5%、小于2%或小于1%结合另一个分子。结合亲和力可以以任何合适的方式来定量,例如通过KD。
本发明的2019-nCoV刺突蛋白抗体(优选中和)对2019-nCoV刺突蛋白的结合亲和力可以根据解离常数(KD)来定量。可以使用任何合适的技术来测定KD,但在本发明的内容中通常优选SPR。本发明的2019-nCoV刺突蛋白抗体可以以小于1μM、小于100nM、小于50nM、小于25nM、小于10nM、小于1nM、小于900pM、小于800pM、小于700pM、小于600pM、小于500pM、小于400pM、小于300pM、小于200pM、小于100pM、小于50pM、小于25pM、小于10pM、小于5pM或更小的KD结合2019-nCoV刺突蛋白。通常,本发明的2019-nCoV刺突蛋白抗体以小于50nM、小于10nM或小于1nM的KD结合2019-nCoV刺突蛋白。
可以通过产生本发明的抗体的变体来产生与本发明的表位/抗原结合的其他抗体。此类变体可以具有与本发明的抗体的CDR共享高水平同一性的CDR,例如可以具有各自可以独立地与由此衍生变体抗体的本发明的抗体有一个或两个氨基酸不同的CDR,并且其中变体保留本发明的抗体的结合和功能特性。另外,此类抗体可在框架区中具有一个或多个变异(例如,保守氨基酸取代)。本发明抗体的氨基酸序列中的变异应维持至少75%、至少80%、至少85%、至少90%、至少95%和高达99%的序列同一性。特别考虑与本发明的抗体,特别是本文例示的特定抗体具有至少90%序列同一性的变体。变异可以或可以不限于框架区并且不存在于CDR中。
术语“中和抗体”在本文中定义为意指其自身(在不存在任何其他2019-nCoV刺突蛋白抗体或针对另一种2019-nCov蛋白的其他抗体的情况下)具有影响其结合的刺突蛋白的功能的能力的抗体。特别地,中和抗体通过中和或抑制刺突蛋白的生物活性来降低表达刺突蛋白的2019-nCoV病毒颗粒感染细胞的能力。
这种中和活性可以使用任何合适的技术来定量并以任何合适的单位来测量。本公开同样适用于本发明的中和抗体(以及如本文所述的其他结合化合物)。例如,2019-nCoV刺突蛋白或其免疫原性片段的有效性可以根据其半最大有效浓度(EC50)、刺激的抗体滴度(以抗体单位,AU)和/或以AU的EC50给出。这些中的后者给出了由本发明的2019-nCoV刺突蛋白或其免疫原性片段刺激的抗体应答的质量的指示。可以使用任何合适的技术来确定EC50、AU或EC50/AU。常规技术是本领域已知的。
产生的抗体的量可以使用任何合适的方法来定量,标准技术是本领域已知的。例如,产生的抗体的量可以根据由本发明的2019-nCoV刺突蛋白或其免疫原性片段诱导的血清IgG应答通过ELISA来测量。产生的抗体的量可以以任意抗体单位(AU)给出。
对本发明的2019-nCoV刺突蛋白或其免疫原性片段的免疫应答(或免疫原性),特别是抗体应答,可以根据产生的抗体量,以半最大有效浓度,即EC50/AU,给出。这给出了针对2019-nCoV刺突蛋白或其免疫原性片段产生的免疫应答的质量的指示。例如,产生的低EC50(即有效应答)但高数量的抗体单位比低EC50和低数量的抗体单位有效性更低(并且给出更高的EC50/AU)。因此,这个值通过将中和抗体活性(以EC50测量)表示为产生的抗2019-NCoV刺突蛋白或其免疫原性片段IgG抗体的总量(通过ELISA测量的,以AU计)的比例来指示抗体应答的质量。因此,更有效的疫苗以较少的抗体(较低的AU)诱导EC50。
通常,本发明的中和2019-nCoV刺突蛋白抗体将2019-nCoV颗粒的感染性降低至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或更多。
与天然2019-nCoV刺突蛋白或其免疫原性片段或由非优化的多核苷酸产生的2019-nCoV刺突蛋白或其免疫原性片段相比,本发明的2019-nCoV刺突蛋白或其免疫原性片段可引发改善的免疫应答,特别是改善的抗体应答。
本文关于结合化合物的任何和所有公开内容优选涉及如本文所述的抗体。
或者,其他结合化合物,如DNA寡核苷酸适配体、RNA寡核苷酸适配体和针对2019-nCoV刺突蛋白或其片段的其他工程化生物聚合物,特别是所述2019-nCoV刺突蛋白或片段内的表位,也可能够复制本文所述的抗体及其组合的活性。所述替代结合化合物可以特异性地结合本发明的蛋白质或其免疫原性片段。
可以使用公认的方法鉴定或合成寡核苷酸适配体。适配体可以进一步优化以使其适合于治疗用途,例如它可以与单克隆抗体缀合以改变其药代动力学和/或募集Fc依赖性免疫功能。
组合物和治疗适应症
如本文所述的,本发明人已经证明了用由本发明的多核苷酸表达的2019-nCoV刺突蛋白进行免疫接种能够产生稳健的抗体应答。
因此,本发明提供了表达本发明的2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段,或结合化合物,用作疫苗。
本发明还提供了疫苗组合物,其包含所述表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段,或结合化合物。疫苗组合物可任选地包含药学上可接受的赋形剂、稀释剂、载体、推进剂、盐和/或添加剂。
在一些实施方案中,疫苗组合物包含至少两种不同的根据本发明的蛋白质或免疫原性片段,和/或至少两种不同的根据本发明的多核苷酸分子。作为非限制性实例,疫苗组合物可包含编码2019-nCoV刺突蛋白的多核苷酸和编码2019-nCoV膜蛋白的多核苷酸。
本发明还提供了使用表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段,或本发明的结合化合物(如上所述的)刺激或诱导受试者中的免疫应答的方法。
所述刺激或诱导受试者的免疫应答的方法可包括将本发明的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段,或结合化合物(如上所述)施用于受试者。
在治疗用途和方法的内容中,“受试者”是将受益于针对2019-nCoV的免疫保护性应答的刺激或诱导的任何动物受试者。典型的动物受试者是哺乳动物,如灵长类动物,例如人。
因此,本发明提供了用于治疗或预防2019-nCoV感染的方法。所述方法通常包括将本发明的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段、疫苗组合物或结合化合物施用于需要的受试者。
本发明还提供了用于预防或治疗2019-nCoV感染的本发明的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段、疫苗组合物或结合化合物。
本发明还提供了本发明的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段、疫苗组合物或结合化合物在制备用于预防或治疗2019-nCoV感染的药物中的用途。
如本文所用的,术语“治疗(treatment)”或“治疗(treating)”包括治疗性或预防性/预防性措施,并且包括2019-nCoV感染的感染后治疗和改善。
如本文所用的,术语“预防”包括预防由2019-nCoV引发感染和/或降低2019-nCoV感染的严重程度或强度。术语“预防”包括诱导或提供针对2019-nCoV感染的保护性免疫。对2019-nCoV感染的免疫力可以使用任何合适的技术来定量,其实例是本领域已知的。
本文定义的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段、疫苗组合物或结合化合物,可以施用于已经患有2019-nCoV感染、与2019-nCoV感染相关的病症或症状的受试者(通常是哺乳动物受试者,如人或其他灵长类动物),以治疗或预防2019-nCoV感染。例如,受试者可能被怀疑与2019-nCoV接触,或已知与2019-nCoV接触,但尚未显示暴露的症状。
当施用于已经患有2019-nCoV感染或显示出与2019-nCoV感染相关症状的受试者(例如,哺乳动物,如人或其他灵长类)时,所定义的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段、疫苗组合物或结合化合物可以治愈、延迟、降低一种或多种症状的严重程度或改善一种或多种症状,和/或延长受试者的存活超过在没有这种治疗的情况下预期的存活。
或者,可以将本文定义的表达2019-nCoV刺突蛋白或其免疫原性片段的多核苷酸、表达构建体、病毒载体、DNA质粒或RNA疫苗,或2019-nCoV刺突蛋白或其免疫原性片段、疫苗组合物或结合化合物施用于最终可能感染2019-nCov的受试者(例如,哺乳动物,如人或其他灵长类),以预防、治愈、延迟、降低所述2019-nCoV感染的严重程度或改善所述2019-nCoV感染的一种或多种症状,或者为了延长受试者的存活超过在没有这种治疗的情况下预期的存活,或者为了帮助防止受试者传播2019-nCoV感染。
本发明的治疗和预防性疗法适用于不同年龄的各种不同受试者。在人类的情况下,治疗适用于儿童(例如,婴儿、5岁以下儿童、较大儿童或青少年)和成人。在其他动物受试者(例如,哺乳动物,如灵长类动物)的情况下,治疗适用于未成熟受试者和成熟/成年受试者。如本文所用的,术语“预防”包括预防2019-nCoV感染的开始和/或降低2019-nCoV感染的严重程度或强度。术语“预防”包括诱导或提供针对2019-nCoV感染的保护性免疫。对2019-nCoV感染的免疫力可以使用任何合适的技术进行定量,其实例是本领域已知的。
如本文所用的,“疫苗”是当施用于动物受试者(如哺乳动物(例如,人或其他灵长类动物))时刺激针对2019-nCoV感染的保护性免疫应答的制剂。免疫应答可以是体液和/或细胞介导的免疫应答。本发明的疫苗可用于例如保护受试者免受2019-nCoV感染的影响。
药物组合物和制剂
术语“疫苗”在本文中可与术语“治疗/预防组合物”、“制剂”或“药物”互换使用。
除了药学上可接受的载体之外,本发明的疫苗(如上定义的)可以组合或施用。可选地或另外地,本发明的疫苗可以进一步与盐、赋形剂、稀释剂、佐剂、免疫调节剂和/或抗微生物化合物中的一种或多种组合。
药学上可接受的盐包括与无机酸(如,例如盐酸或磷酸)或与有机酸(如乙酸、草酸、酒石酸、马来酸等)形成的酸加成盐。与游离羧基形成的盐也可以衍生自无机碱,如,例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,以及诸如异丙胺、三甲胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的有机碱。
免疫原性组合物、治疗制剂、药物和预防制剂(例如疫苗)的施用通常通过常规途径,例如静脉内、皮下、腹膜内或粘膜途径。施用可以通过肠胃外注射,例如皮下、皮内或肌内注射。包含中和抗体的制剂可以特别适于静脉内、肌内、皮内或皮下施用。
因此,本发明的免疫原性组合物、治疗性制剂、药物和预防性制剂(例如疫苗)通常被制成注射剂,作为液体溶液或悬浮液。或者,可以制备适于在注射前溶解或悬浮在液体中的固体形式。还可以将制剂乳化,或者将肽包封在脂质体或微胶囊中。
活性免疫原性成分(如2019-nCoV刺突蛋白、其片段、编码所述刺突蛋白的核酸、表达载体、病毒载体、DNA质粒、RNA疫苗、融合蛋白和疫苗组合物)常常与药学上可接受的并且与活性成分相容的载体、稀释剂、赋形剂或类似物混合。合适的赋形剂是例如水、盐水、右旋糖、甘油、乙醇等及其组合。此外,如果需要,疫苗可以含有少量辅助物质,如润湿剂或乳化剂、pH缓冲剂和/或增强疫苗有效性的佐剂。
通常,载体、稀释剂、赋形剂或类似物是药学上可接受的载体。药学上可接受的载体的非限制性实例包括水、盐水和磷酸盐缓冲盐水。然而,在一些实施方案中,组合物是冻干形式,在这种情况下,其可以包含稳定剂,如BSA。在一些实施方案中,可能需要用防腐剂(如硫柳汞或叠氮化钠)配制组合物,以促进长期储存。
可能有效的其他佐剂的实例包括但不限于:完全弗氏佐剂(CFA)、不完全弗氏佐剂(IFA)、皂苷、皂苷的纯化提取物级分,如Quil A,皂苷的衍生物,如QS-21、基于皂苷的脂质颗粒,如ISCOM/ISCOMATRIX、大肠杆菌热不稳定性毒素(LT)突变体,如LTK63和/或LTK72、氢氧化铝、N-乙酰基-胞壁酰-L-苏氨酰-D-异谷氨酰胺(thr-MDP)、N-乙酰基-去甲-胞壁酰-L-丙氨酰-D-异谷氨酰胺(CGP11637,称为去甲-MDP)、N-乙酰胞壁酰-L-丙氨酰-D-异谷氨酰胺酰-L-丙氨酸-2-(1’-2’-二棕榈酰-sn-甘油基-3-羟基磷酰氧基)-乙胺(CGP 19835A,称为MTP-PE)和RIBI,其含有从细菌提取的三种组分,在2%角鲨烯/吐温80乳液中的GLA-SE(GLA是合成的脂质A衍生物,在GLA-SE中,使用角鲨烯油将这配制成水包油乳液)、单磷酰脂质A、海藻糖二霉菌酸酯和细胞壁骨架(MPL+TDM+CWS)、由Novartis开发的MF59制剂以及由GSKBiologicals开发的AS02、AS01、AS03和AS04佐剂制剂(Rixensart,比利时)。优选的佐剂包括:氢氧化铝和磷酸铝凝胶、氢氧化铝和单磷酰脂质A(MPL);和5%角鲨烯(MF59)。其它优选的佐剂包括明矾或氢氧化铝和/或磷酸铝、GLA-SE和/或基于角鲨烯的佐剂,如MF59或AddaVaxTM,或其任何组合。优选使用氢氧化铝和/或磷酸铝、GLA-SE和AddaVaxTM的组合。
缓冲剂的实例包括但不限于琥珀酸钠(pH 6.5)和磷酸盐缓冲盐水(PBS,pH 6.5和7.5)。
适用于其他给药方式的其他制剂包括栓剂,并且在一些情况下,口服制剂或适于作为气溶胶分布的制剂。对于栓剂,传统的粘合剂和载体可包括例如聚亚烷基二醇或甘油三酯;这种栓剂可以由含有0.5%至10%、优选1%-2%范围内的活性成分的混合物形成。
口服制剂包括此类通常使用的赋形剂,如,例如,药物级甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这些组合物采取溶液、悬浮液、片剂、丸剂、胶囊、持续释放制剂或粉末的形式。
定义
如本文所用的,与动词一起使用时,术语“能够”涵盖或意指相应动词的作用。例如,“能够相互作用”还表示相互作用,“能够分裂”还表示分裂,“能够结合”还表示结合和“能够特异性靶向……”还表示特异性靶向。
关于蛋白质使用时,术语“变体”意指含有氨基酸(例如非天然氨基酸)的一个或多个类似物或取代的连接的蛋白质的肽或肽片段。
关于蛋白质使用时,术语“衍生物”意指包含所讨论的蛋白质和另外的肽序列的蛋白质。另外的肽序列应优选不干扰原始蛋白质的基础折叠且因此不干扰其构象结构。两个或更多个肽(或片段,或变体)可以连接在一起以形成衍生物。或者,肽(或片段,或变体)可以与不相关的分子(例如,第二不相关的肽)连接。衍生物可以化学合成,但通常将通过重组核酸方法制备。可以包括另外的组分,如脂质,和/或多糖,和/或多肽组分。
在本说明书中提及2019-nCoV多核苷酸和/或蛋白质包括其片段和变体。变体2019-nCoV刺突蛋白保留了天然刺突蛋白的一个或多个构象表位以及引发产生中和抗体和/或免疫保护应答的能力。本发明的变体2019-nCoV刺突蛋白多核苷酸编码此类刺突蛋白。举例来说,变体可以与参考序列(例如本发明的2019-nCoV多核苷酸和/或蛋白质,特别是本说明书中提供的定义2019-nCoV多核苷酸和/或蛋白质的任何SEQ ID NO)具有至少80%、优选至少90%、更优选至少95%并且最优选至少97%或至少99%的氨基酸序列同源性。因此,变体可以包括多核苷酸(例如非天然核酸)的一种或多种类似物,或取代的连接。此外,举例来说,关于2019-nCoV多核苷酸和/或蛋白质使用时,术语片段意指具有参考2019-nCoV多核苷酸和/或蛋白质的至少十个、优选至少十五个、更优选至少二十个核酸残基的多核苷酸。术语片段还涉及上述变体。因此,举例来说,本发明的2019-nCoV多核苷酸和/或蛋白质的片段可以包含具有至少10、20或30个核酸的核酸序列,其中多核苷酸序列与参考2019-nCoV多核苷酸和/或蛋白质序列的相应(连续的)核酸序列具有至少80%的序列同源性。片段和变体的这些定义也适用于本发明的其他多核苷酸。在肽序列的内容中,术语片段是指具有参考蛋白的至少十个,优选至少十五个,更优选至少二十个氨基酸残基的肽。术语片段还涉及上述变体。因此,举例来说,片段可以包含具有至少10、20或30个氨基酸的氨基酸序列,其中氨基酸序列与参考序列的(连续的)氨基酸的相应氨基酸序列具有至少80%的序列同源性。
本文中的一些示例性多核苷酸包含另外的基序,特别是限制酶位点、KOZAC序列和/或基序(例如tga taa)以驱动蛋白质分泌。本领域技术人员将理解,可以省略这些另外的序列。因此,本发明涵盖包含特定基序的示例性核酸序列,以及缺少这些基序中的一个或多个的核酸序列。
术语“减少”、“降低的”、“降低”或“抑制”在本文中均用于意指减少统计学上显著的量。术语“降低(reduce)”、“降低(reduction)”或“减少(decrease)”或“抑制(inhibit)”通常意指与参考水平(例如,不存在给定的治疗)相比减少至少10%,并且可以包括例如减少至少约10%、至少约20%、至少约25%、至少约30%、至少约35%、至少约40%、至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或更多。如本文所用的,“降低”或“抑制”不包括与参考水平相比的完全抑制或降低。“完全抑制”是与参考水平相比100%抑制。降低可以优选降低至在没有给定病症的个体的正常范围内接受的水平。
术语“增加的”、“增加”、“增强”或“激活”在本文中均用于意指增加统计学上显著的量。术语“增加的”、“增加”、“增强”或“激活”可以意指与参照水平相比至少10%的增加,例如与参照水平相比至少约20%、或至少约30%、或至少约40%、或至少约50%、或至少约60%、或至少约70%、或至少约80%、或至少约90%或至多并包括100%增加或10-100%之间的任何增加,或至少约2倍、或至少约3倍、或至少约4倍,或至少约5倍或至少约10倍的增加,或2倍和10倍之间的或更大的任何增加。在标志物或症状的情况下,“增加”是这种水平的统计学上显著的增加。
如本文所用的,“受试者”意指人或动物。通常,动物是脊椎动物,如灵长类动物、啮齿动物、家畜或狩猎动物。灵长类动物包括黑猩猩、食蟹猴、蜘蛛猴和猕猴,例如恒河猴。啮齿动物包括小鼠、大鼠、土拨鼠、雪貂、兔和仓鼠。家畜和狩猎动物包括牛、马、猪、鹿、野牛、水牛、猫科动物物种(例如家猫)、犬科动物物种(例如狗、狐狸、狼)、鸟类物种(例如鸡、鸸鹋、鸵鸟)和鱼类(例如鳟鱼、鲶鱼和鲑鱼)。优选地,受试者是哺乳动物,例如灵长类动物,例如人。术语“个体”、“患者”和“受试者”在本文中可互换使用。
优选地,受试者是哺乳动物。哺乳动物可以是人、非人灵长类动物、小鼠、大鼠、狗、猫、马或牛,但不限于这些实例。除人以外的哺乳动物可有利地用作代表疼痛动物模型的受试者。受试者可以是男性或女性、成人或青少年。
受试者可以是先前已被诊断为患有或被鉴定为患有或具有需要治疗的病症或与这种病症相关的一种或多种并发症,并且任选地,已经经历了针对如本文所定义的病症或与所述病症相关的一种或多种并发症的治疗的受试者。或者,受试者也可以是先前未被诊断为患有如本文所定义的病症或与所述病症相关的一种或多种并发症的受试者。例如,受试者可以是表现出病症或与所述病症相关的一种或多种并发症的一种或多种风险因素的受试者或不表现出风险因素的受试者。
针对特定病症“需要治疗的受试者”可以是患有该病症、被诊断为患有该病症或处于发展该病症的风险中的受试者。
如本文所用,术语“蛋白质”和“多肽”在本文中可互换使用,以表示通过相邻残基的α-氨基和羧基之间的肽键彼此连接的一系列氨基酸残基。术语“蛋白质”和“多肽”是指氨基酸的聚合物,包括修饰的氨基酸(例如,磷酸化、糖化、糖基化等)和氨基酸类似物,无论其大小或功能如何。“蛋白质”和“多肽”通常用于指相对大的多肽,而术语“肽”通常用于指小的多肽,但本领域中这些术语的使用重叠。当提及基因产物及其片段时,术语“蛋白质”和“多肽”在本文中可互换使用。因此,示例性多肽或蛋白质包括基因产物、天然存在的蛋白质、同源物、直系同源物、旁系同源物、片段和其他等同物,前述的变体、片段和类似物。
多肽,例如融合多肽或其部分(例如结构域),可以是本文所述序列的变体。优选地,变体是保守取代变体。如本文所提及的“变体”是与天然或参考多肽基本上同源的多肽,但其由于一个或多个缺失、插入或取代而具有与天然或参考多肽的氨基酸序列不同的氨基酸序列。编码多肽的DNA序列涵盖当与天然或参考DNA序列相比时包含一个或多个核苷酸的添加、缺失或取代,但编码相对于参考蛋白质保留相关生物活性(例如野生型参考蛋白质的至少50%)的变体蛋白质或其片段的序列。关于氨基酸序列,技术人员将认识到,改变编码序列中的单个氨基酸或小百分比(即5%或更少,例如4%或更少,或3%或更少,或1%或更少)的氨基酸的核酸、肽、多肽或蛋白质序列的单个取代、缺失或添加是“保守修饰的变体”,其中改变导致氨基酸被化学上相似的氨基酸取代。预期一些变化可以潜在地改善相关活性,使得变体(无论是否保守)具有超过100%的野生型活性,例如110%、125%、150%、175%、200%、500%、1000%或更多。
给定的氨基酸可以被具有相似生理化学特征的残基替代,例如,用一个脂肪族残基取代另一个(如用Ile、Val、Leu或Ala替代另一个),或用一个极性残基取代另一个(如在Lys和Arg;Glu和Asp;或Gln和Asn之间)。其他此类保守取代,例如具有相似疏水性特征的整个区域的取代是已知的。可以在本文所述的任何一种测定中测试包含保守氨基酸取代的多肽,以确认保留天然或参考多肽的所需活性。提供功能上相似的氨基酸的保守取代表是本领域熟知的。此类保守修饰的变体是与本公开一致的多态变体、种间同源物和等位基因的补充,并且不排除与本公开一致的多态变体、种间同源物和等位基因。通常,彼此的保守取代包括:1)丙氨酸(A)、甘氨酸(G);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W);7)丝氨酸(S)、苏氨酸(T)和8)半胱氨酸(C)、甲硫氨酸(M)(参见,例如,Creighton,Proteins(1984))。
不参与维持多肽的适当构象的任何半胱氨酸残基也可以被取代,通常用丝氨酸取代,以改善分子的氧化稳定性并防止异常交联。相反,可以将半胱氨酸键添加到多肽中以改善其稳定性或促进寡聚化。
如本文所述的多肽可包含至少一个肽键置换。可以置换单个肽键或多个肽键,例如2个键、3个键、4个键、5个键或6个或更多个键,或所有肽键。如本文所述的分离的肽可包含一种类型的肽键置换或多种类型的肽键置换,例如2种类型、3种类型、4种类型、5种类型或更多种类型的肽键置换。肽键置换的非限制性实例包括脲、硫脲、氨基甲酸酯、磺酰脲、三氟乙胺、邻-(氨基烷基)-苯乙酸、对-(氨基烷基)-苯乙酸、间-(氨基烷基)-苯乙酸、硫代酰胺、四唑、硼酸酯、烯属基团,及其衍生物。
如本文所述的多肽可包含在由活生物体产生的多肽和/或蛋白质中常见的天然存在的氨基酸,例如Ala(A)、Val(V)、Leu(L)、Ile(I)、Pro(P)、Phe(F)、Trp(W)、Met(M)、Gly(G)、Ser(S)、Thr(T)、Cys(C)、Tyr(Y)、Asn(N)、Gln(Q)、Asp(D)、Glu(E)、Lys(K)、Arg(R)和His(H)。如本文所述的多肽可包含替代氨基酸。替代氨基酸的非限制性实例包括D氨基酸、β-氨基酸、高半胱氨酸、磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、羟脯氨酸、γ-羧基谷氨酸;马尿酸、八氢吲哚-2-羧酸、他汀、1,2,3,4-四氢异喹啉-3-羧酸、青霉胺(3-巯基-D-缬氨酸)、鸟氨酸、瓜氨酸、α-甲基-丙氨酸、对-苯甲酰基苯丙氨酸、对氨基苯丙氨酸、对氟苯丙氨酸、苯基甘氨酸、炔丙基甘氨酸、肌氨酸和叔丁基甘氨酸)、二氨基丁酸、7-羟基-四氢异喹啉羧酸、萘基丙氨酸、联苯丙氨酸、环己基丙氨酸、氨基-异丁酸、正缬氨酸、正亮氨酸、叔亮氨酸、四氢异喹啉羧酸、哌啶酸、苯基甘氨酸、高苯丙氨酸、环己基甘氨酸、脱氢亮氨酸、2,2-二乙基甘氨酸、1-氨基-1-环戊烷羧酸、1-氨基-1-环己烷羧酸、氨基-苯甲酸、氨基-萘甲酸、γ-氨基丁酸、二氟苯丙氨酸、哌啶甲酸、α-氨基丁酸、噻吩基丙氨酸、叔丁基甘氨酸、三氟缬氨酸;六氟亮氨酸;氟化类似物;叠氮修饰的氨基酸;炔烃修饰的氨基酸;氰基修饰的氨基酸;及其衍生物。
可以修饰多肽,例如通过向包含肽的一个或多个氨基酸添加部分。如本文所述的多肽可包含一个或多个部分分子,例如每个肽1个或多个部分分子,每个肽2个或更多个部分分子,每个肽5个或更多个部分分子,每个肽10个或更多个部分分子或每个肽更多个部分分子。如本文所述的多肽可包含一种或多种类型的修饰和/或部分,例如1种类型的修饰、2种类型的修饰、3种类型的修饰或更多种类型的修饰。修饰和/或部分的非限制性实例包括聚乙二醇化;糖基化;羟乙基淀粉化;ELP化;脂质化;乙酰化;酰胺化;封端修饰;氰基;磷酸化;白蛋白和环化。
原始氨基酸序列的改变可以通过本领域技术人员已知的许多技术中的任一种来完成。例如,可以通过合成在编码待改变的氨基酸的核苷酸序列中含有密码子改变的寡核苷酸,在特定位置引入氨基酸取代,所述核苷酸序列侧翼为允许与原始序列的片段连接的限制性位点。连接后,所得重建序列编码具有所需氨基酸插入、取代或缺失的类似物。或者,可以采用寡核苷酸指导的位点特异性诱变程序来提供具有根据所需的取代、缺失或插入而改变的特定密码子的改变的核苷酸序列。进行这种改变的技术包括Walder等(Gene 42:133,1986);Bauer等(Gene37:73,1985);Craik(Biotechniques,1985年1月,12-19);Smith等(Genetic Engineering:Principles and Methods,Plenum Press,1981);以及美国专利号4,518,584和4,737,462中公开的那些,其通过引用整体并入本文。如本文所述的多肽可以是化学合成的,并且突变可以作为化学合成过程的一部分并入。
如本文所用的,术语“多核苷酸”、“核酸”和“核酸序列”是指掺入核糖核酸、脱氧核糖核酸或其类似物单元的任何分子,优选聚合分子。核酸可以是单链或双链的。单链核酸可以是变性双链DNA的一条核酸链。或者,可以是不源自任何双链DNA的单链核酸。在一个方面中,核酸可以是DNA。在另一个方面中,核酸可以是RNA。合适的核酸分子是DNA,包括基因组DNA或cDNA。其他合适的核酸分子是RNA,包括mRNA。
如本文所用的,术语“包含(comprising)”或“包含(comprises)”用于指组合物、方法及其相应组分,其对于方法或组合物是必需的,但对于包括未指定的要素(无论是否必需)是开放的。
术语“由……组成”是指如本文所述的组合物、方法及其相应组分,其不包括本发明描述中未列举的任何要素。
本文所用的术语“基本上由……组成”是指给定发明所需的那些要素。该术语允许存在不会实质上影响本发明的基本和新的或功能特征的要素。
序列同源性
可以使用多种序列比对方法中的任一种来确定同一性百分比,包括但不限于全局方法、局部方法和杂交方法,如,例如,区段逼近方法。确定同一性百分比的方案是本领域技术人员范围内的常规程序。全局方法从分子的开始到结束比对序列,并通过将各个残基对的得分相加并通过施加空位罚分来确定最佳比对。非限制性方法包括例如CLUSTAL W,参见,例如Julie D.Thompson等,CLUSTAL W:Improving the Sensitivity of ProgressiveMultiple Sequence Alignment Through Sequence Weighting,Position-Specific GapPenalties and Weight Matrix Choice,22(22)Nucleic Acids Research 4673-4680(1994);和迭代精修,参见,例如Osamu Gotoh,Significant Improvement in Accuracy ofMultiple Protein.Sequence Alignments by Iterative Refinement as Assessed byReference to Structural Alignments,264(4)J.MoI.Biol.823-838(1996)。局部方法通过鉴定由所有输入序列共享的一个或多个保守基序来比对序列。非限制性方法包括例如匹配框,参见,例如Eric Depiereux和Ernest Feytmans,Match-Box:A Fundamentally NewAlgorithm for the Simultaneous Alignment of Seumber Protein Sequences,8(5)CABIOS 501-509(1992);Gibbs取样,参见,例如C.E.Lawrence等,Detecting SubtleSequence Signals:A Gibbs Sampling Strategy for Multiple Alignment,262(5131)Science 208-214(1993);比对-M,参见,例如Ivo van Walle等,Align-M-A New Algorithmfor Multiple Alignment of Highly Divergent Sequences,20(9)Bioinformatics:1428-1435(2004)。
因此,通过常规方法确定序列同一性百分比。参见,例如,Altschul等,Bull.Math.Bio.48:603-16,1986以及Henikoff和Henikoff,Proc.Natl.Acad.Sci.USA89:10915-19,1992。简而言之,使用空位开放罚分10、空位延伸罚分1和如下所示的Henikoff和Henikoff(同上)的“blosum 62”评分矩阵(氨基酸由标准单字母代码表示)比对两个氨基酸序列以优化比对评分。
用于确定序列同一性的比对评分
BLOSUM62表
然后将同一性百分比计算为:
相同匹配的总数/[较长序列的长度加上为了比对两个序列引入较长序列中的空位数]×100
基本上同源的多肽的特征在于具有一个或多个氨基酸取代、缺失或添加。这些变化优选具有次要的性质,即保守性氨基酸取代(参见下文)和不显著影响多肽的折叠或活性的其他取代;小的缺失,通常为1至约30个氨基酸;和小的氨基末端或羧基末端延伸,如氨基末端甲硫氨酸残基,多达约20-25个残基的小接头肽,或亲和标签。
保守性氨基酸取代:
碱性:精氨酸
赖氨酸
组氨酸
酸性:谷氨酸
天冬氨酸
极性:谷氨酰胺
天冬酰胺
疏水性:亮氨酸
异亮氨酸
缬氨酸
芳香族:苯丙氨酸
色氨酸
酪氨酸
小的:甘氨酸
丙氨酸
丝氨酸
苏氨酸
甲硫氨酸
除了20种标准氨基酸之外,非标准氨基酸(如4-羟基脯氨酸、6-N-甲基赖氨酸、2-氨基异丁酸、异缬氨酸和α-甲基丝氨酸)可以取代本发明多肽的氨基酸残基。有限数量的非保守性氨基酸、不由遗传密码编码的氨基酸和非天然氨基酸可以取代梭菌多肽氨基酸残基。本发明的多肽还可以包含非天然存在的氨基酸残基。
非天然存在的氨基酸包括但不限于反式-3-甲基脯氨酸、2,4-亚甲基-脯氨酸、顺式-4-羟基脯氨酸、反式-4-羟基-脯氨酸、N-甲基甘氨酸、别苏氨酸、甲基-苏氨酸、羟基-乙基半胱氨酸、羟基乙基高半胱氨酸、硝基-谷氨酰胺、高谷氨酰胺、哌啶酸、叔亮氨酸、正缬氨酸、2-氮杂苯丙氨酸、3-氮杂苯丙氨酸、4-氮杂苯丙氨酸和4-氟苯丙氨酸。几种方法是本领域已知用于将非天然存在的氨基酸残基掺入蛋白质中。例如,可以采用体外系统,其中使用化学氨基酰化的抑制子tRNA抑制无义突变。用于合成氨基酸和氨酰化tRNA的方法是本领域已知的。含有无义突变的质粒的转录和翻译在包含大肠杆菌S30提取物和市售酶和其他试剂的无细胞系统中进行。通过色谱法纯化蛋白质。参见,例如,Robertson等,J.Am.Chem.Soc.113,2722,1991;Ellman等,Methods Enzymol.202:301,1991;Chung等,Science 259:806-9,193;和Chung等,Proc.Natl.Acad.Sci.USA 90:10145-9,1993)。在第二种方法中,通过显微注射突变的mRNA和化学氨基酰化的抑制子tRNAs在非洲爪蟾卵母细胞中进行翻译(Turcatti等,J.Biol.Chem.271:19991-8,1996)。在第三种方法中,在不存在待置换的天然氨基酸(例如苯丙氨酸)和存在所需的非天然存在的氨基酸(例如2-氮杂苯丙氨酸、3-氮杂苯丙氨酸、4-氮杂苯丙氨酸或4-氟苯丙氨酸)的情况下培养大肠杆菌细胞。将非天然存在的氨基酸掺入多肽中以代替其天然对应物。参见,Koide等,Biochem.33:7470-6,1994。天然存在的氨基酸残基可以通过体外化学修饰转化成非天然存在的种类。化学修饰可以与定点诱变组合以进一步扩大取代范围(Wynn和Richards,Protein Sci.2:395-403,1993)。
有限数量的非保守性氨基酸、不由遗传密码编码的氨基酸、非天然存在的氨基酸和非天然氨基酸可以取代本发明多肽的氨基酸残基。
本发明的多肽中的必需氨基酸可以根据本领域已知的程序鉴定,如定点诱变或丙氨酸扫描诱变(Cunningham和Wells,Science 244:1081-5,1989)。生物相互作用的位点也可以通过结构的物理分析来确定,如通过诸如核磁共振、晶体学、电子衍射或光亲和标记的技术结合推定的接触位点氨基酸的突变来确定。参见,例如de Vos等,Science 255:306-12,199 2;Smith等,J.Mol.Biol.224:899-904,1992;Wlodaver等,FEBS Lett.309:59-64,1992。还可以从与本发明多肽的相关组分(例如,易位或蛋白酶组分)的同源性分析推断必需氨基酸的身份。
可以使用已知的诱变和筛选方法进行和测试多个氨基酸取代,如Reidhaar-Olson和Sauer(Science 241:53-7,1988)或Bowie和Sauer(Proc.Natl.Acad.Sci.USA86:2152-6,1989)公开的那些。简而言之,这些作者公开了用于同时随机化多肽中的两个或更多个位置,选择功能性多肽,然后对诱变的多肽进行测序以确定每个位置处可允许的取代谱的方法。可以使用的其他方法包括噬菌体展示(例如,Lowman等,Biochem.30:10832-7,1991;Ladner等,美国专利号5,223,409;Huse,WIPO公开WO 92/06204)和区域定向诱变(Derbyshire等,Gene 46:145,1986;Ner等,DNA7:127,1988)。
以下实施例说明本发明。
实施例
编码2019-nCoV刺突蛋白(S)的核酸已被修饰用于在各种表达系统(包括大肠杆菌、酵母和人细胞)中表达,以诱导中和抗体应答来防止2019-nCoV感染。
克隆N和C末端缺失的氨基酸(5-10个)以在大肠杆菌系统中以冠状病毒的天然构象表达和重折叠S蛋白,而其他(酵母和人细胞)作为全蛋白。还将来自冠状病毒的S蛋白与戊型肝炎病毒样颗粒(P239)和人乳头瘤病毒样颗粒(18L1)组合并表达为融合蛋白,以增加免疫保护性应答的功效和寿命。
实施例1:基于大肠杆菌的2019-nCoV刺突蛋白表达
使用用于密码子优化的Geneart针对在大肠杆菌中的表达对冠状病毒S蛋白的核酸序列(Wuhan-Hu-L-CoV-S,GenBank:MN908947.3)进行了密码子优化并含有SacI和NotI单克隆位点以设计SEQ ID NO:2的核酸序列。
使密码子使用适应大肠杆菌基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(平均GC含量45%)以延长mRNA半衰期。使密码子使用适应大肠杆菌的偏好,导致CAI(密码子适应指数)值为0.96。优化的基因已被设计成允许在大肠杆菌中高且稳定的表达速率。
实施例2:戊型肝炎病毒样颗粒中的2019-nCoV刺突蛋白
针对在大肠杆菌中的表达优化了冠状病毒S蛋白的核酸序列,并用于产生包含S蛋白的戊型肝炎病毒样颗粒(Wuhan-Hu-L-HEV-CoV-S)。
通过Geneart针对在大肠杆菌中的表达对基因合成进行了密码子优化,使用SacI和NotI单克隆位点来设计SEQ ID NO:3的核酸序列。
使密码子使用适应大肠杆菌基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(46%)以延长mRNA半衰期。使密码子使用适应大肠杆菌的偏好,导致CAI值为0.96。优化的基因已被设计成允许在大肠杆菌中高且稳定的表达速率。
实施例3:基于Komagataella pastoris的2019-NCoV刺突蛋白表达
使用用于密码子优化的Geneart针对在K.pastoris中的表达对冠状病毒S蛋白的核酸序列(Wuhan-Hu-L-CoV-S)进行了密码子优化并含有BstBI-NotI单克隆位点以设计SEQID NO:4的核酸序列。
使密码子使用适应K.pastoris基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(48%)以延长mRNA半衰期。使密码子使用适应K.pastoris的偏好,导致CAI值为0.84。优化的基因已被设计成允许在K.pastoris中高且稳定的表达速率。
实施例4:在K.pastoris中表达包含2019-NCoV刺突蛋白的融合蛋白
针对作为与HPV 18L1的融合蛋白在K.pastoris中的表达将冠状病毒S蛋白(Wuhan-Hu-1-HPVI8L1-CoV-S)的核酸序列进行了优化。BstBI和NotI是用于设计SEQ IDNO:5的核酸序列的单克隆位点。
使密码子使用适应K.pastoris基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(48%)以延长mRNA半衰期。使密码子使用适应K.pastoris的偏好,导致CAI值为0.84。优化的基因已被设计成允许在K.pastoris中高且稳定的表达速率。
实施例5:在K.pastoris中表达包含2019-NCoV刺突蛋白的融合蛋白
针对作为与HPV 16L1的融合蛋白在K.pastoris中的表达将冠状病毒S蛋白(Wuhan-Hu-1-HPVI8L1-CoV-S)的核酸序列进行了优化。BstBI和NotI是用于设计SEQ IDNO:6的核酸序列的单克隆位点。
使密码子使用适应K.pastoris基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(48%)以延长mRNA半衰期。使密码子使用适应K.pastoris的偏好,导致CAI值为0.84。优化的基因已被设计成允许在K.pastoris中高且稳定的表达速率。
实施例6:2019-NCoV刺突蛋白在人293F细胞中的表达
使用用于密码子优化的Geneart针对在人293F细胞中的表达对冠状病毒S蛋白的核酸序列(Wuhan-Hu-L-CoV-S表面结合的蛋白,其在293F细胞的外表面表达并与293F细胞的外表面结合)进行了密码子优化并含有NheI-NotI单克隆位点以设计SEQ ID NO:7的核酸序列。
使密码子使用适应智人(Homo sapiens)基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(56%)以延长mRNA半衰期。使密码子使用适应智人的偏好,导致CAI值为0.94。优化的基因已被设计成允许在人细胞中高且稳定的表达速率。
实施例7:在293F细胞中表达包含2019-NCoV刺突蛋白的融合蛋白
针对作为与乙型肝炎表面抗原的融合蛋白在293F细胞中的表达对冠状病毒S蛋白(Wuhan-Hu-1-HBsAg-CoV-S)的核酸序列进行了优化。序列含有NheI-NotI单克隆位点以设计SEQ ID NO:8的核酸序列。
使密码子使用适应智人基因的密码子偏好。此外,在可能的情况下,已经避免了GC含量非常高(>80%)或非常低(<30%)的区域。在任何可能的情况下消除了可能负面影响表达的负顺式作用位点(如剪接位点、TATA盒等)。调节了GC含量(56%)以延长mRNA半衰期。使密码子使用适应智人的偏好,导致CAI*(密码子适应指数)值为0.94。优化的基因已被设计成允许在人细胞中高且稳定的表达速率。
实施例8:使用氢氧化铝和磷酸铝凝胶佐剂化2019-nCoV刺突蛋白
将实施例1、3和6的2019-nCoV刺突蛋白及其融合蛋白吸附在0.5mg氢氧化铝和磷酸铝凝胶中,用于佐剂化。
实施例9:使用单磷酰脂质和氢氧化铝佐剂化2019-nCoV刺突蛋白
将实施例1、3和6的2019-nCoV刺突蛋白及其融合蛋白在单磷酰脂质(MPL)和氢氧化铝中混合,用于佐剂化。
实施例10:使用MF59佐剂化2019-NCoV刺突蛋白
将实施例1、3和6的2019-nCoV刺突蛋白及其融合蛋白在MF59(5%角鲨烯)中混合,用于佐剂化。
实施例11:在用2019-nCoV刺突蛋白免疫的小鼠中产生抗体应答
在BALB/c小鼠(每组5只)中测试了包含实施例2、4、5和7的2019-CoV刺突蛋白但不含佐剂的制剂以及实施例1、3和6的佐剂化制剂的免疫原性。在第0天和第7天每次施用2μg抗原进行了疫苗接种。在第0天和第14天,通过间接ELISA测试了血清样品的血清阴性(第0天)和针对S蛋白的抗体应答(第14天)。所有制剂在第14天都诱导高抗体滴度,而佐剂化制剂诱导了最大应答(图2)。
实施例12:HBsAg-(EAAAK)3-RBD)融合蛋白在HEK细胞(293F)中的表达
使用SEQ ID NO:27的密码子优化的核酸序列,在HEK细胞中表达了SEQ ID NO:28的HBsAg-(EAAAK)3-RBD融合蛋白。简言之,针对人细胞(293F)表达优化HBsAg-(EAAAK)3-RBD基因,使用Nhe-NotI克隆到pcDNA3.1(+)中,并在转染到悬浮培养的293F细胞中之前进行了克隆选择。在40小时后收集分泌的HBsAg-(EAAAK)3-RBD融合蛋白。
使用针对2019-nCoV刺突蛋白的多克隆抗体(1:250)和针对HBsAg的小鼠单克隆抗体(1:1,000)的Western印迹证明了在两种分开的培养物-#2A和#2B中,HEK细胞强烈分泌该融合蛋白(图3)。
实施例13:在用HEK细胞中的HBsAg-(EAAAK)3-RBD融合物免疫的小鼠中产生抗体
应答
将来自实施例12的HBsAg-(EAAAK)3-RBD(#2A)通过以4000rpm×40分钟旋转的3KAmicon 15ml离心过滤装置浓缩。
然后用(i)50μg/剂(100μl);或(ii)50pg/剂量(70μl),以1:1v/v比例使用氢氧化铝或AddavaxTM(施用的总体积=140μl),将Balb/c小鼠免疫。小鼠在d0用疫苗初免,然后在d7第一次加强,在d14第二次加强(出血用于分析)和在d28第三次加强。用于分析的最终出血在d42进行。实验组示于下表1中。
表1:用HBsAg-(EAAAK)3-RBD免疫的小鼠的实验组
使用ELISA在d14和d42评估了抗体滴度。如图4所示,HBsAg-(EAAAK)3-RBD的VLP能够在d14和d42达到显著的IgG滴度,在d42观察到的滴度较高。与任一佐剂(氢氧化铝或AddavaxTM)一起施用进一步增加了滴度,再次如图4所示。
还使用用HBsAg-(EAAAK)3-RBD(单独或与氢氧化铝或AddavaxTM一起)的VLP免疫的小鼠进行了中和测定。结果示于以下表2中。平均中和滴度为1:1,200-1:2,700。达到的最高滴度为1:5,120,最低滴度为1:640。
表2:使用HBsAg-EAAAK3-RBD的中和测定的结果
实施例14:HEV-(GGGGS)3-RBD融合体在大肠杆菌中的表达
使用针对在大肠杆菌中表达而密码子优化的SEQ ID NO:30的核酸序列在大肠杆菌中表达SEQ ID NO:31的HEV-(GGGGS)3-RBD融合蛋白。使用SacI-NotI将这个核酸序列克隆到pET26(+)中。选择阳性克隆(#10)并在BL21中表达。筛选三个不同的阳性克隆(#10A、#10B和#10C)用于蛋白质表达,对于所有#10A、#10B和#10C,使用IPTG诱导(6小时)评估HEV-RBD表达。使用针对HEV的抗体的Western印迹用于确认所有#10A、#10B和#10C中的融合蛋白表达(图5)。选择克隆#10B用于将来的研究,并使用pH 7.2的50mM磷酸盐缓冲液作为结合缓冲液使用阴离子交换色谱法纯化(数据未显示)。
实施例15:在用大肠杆菌中产生的HEV-(GGGGS)3-RBD融合蛋白免疫的小鼠中产生
抗体应答
使用来自实施例14的HEV-(GGGGS)3-RBD(#10B)使用50μg/剂量以1:1v/v比例与氢氧化铝或AddavaxTM(施用的总体积=100μl)免疫Balb/c小鼠。小鼠在d0用疫苗初免,然后在d7第一次加强,d14第二次加强(出血用于分析)和d28第三次加强。用于分析的最终出血在d42进行。实验组示于以下表3中。
表3:用HEV-(GGGGS)3-RBD免疫的小鼠的实验组
使用ELISA在d14和d42天评估了抗体滴度。HEV-(GGGGS)3-RBD的VLP能够在d14和d42达到显著的中和滴度,d42观察到的滴度较高。与任一佐剂(氢氧化铝或AddavaxTM)一起施用进一步增加了滴度,如图6所示。
实施例16:在HEK293细胞中表达包含HBsAg-(EAAAK)3-全长2019-nCoV刺突蛋白的
融合蛋白
使用SEQ ID NO:32的密码子优化的核酸序列,在HEK细胞中表达SEQ ID NO:33的HBsAg-(EAAAK)3-全长2019-nCoV刺突蛋白融合蛋白(HBsAg-(EAAAK)3-CoV-s)。简言之,针对人细胞(293F)表达优化了HBsAg-(EAAAK)3-CoV-s,并在转染到悬浮培养的293F细胞中之前进行了克隆选择。40小时后收集分泌的HBsAg-(EAAAK)3-CoV-s。
使用1:250稀释的兔COVID-19刺突蛋白多克隆抗体(My Biosource,MBS434243),通过蛋白质印迹分析了纯化的重组蛋白HBsAg-Co-V-s的两个不同克隆,D8-SA01-01-01(4X)和D8-SA01-02-01(5x)。如图7所示,两个克隆产生了预期大小的清晰且高度表达的条带,表明该融合蛋白的强烈表达。
序列信息
SEQ ID NO:1-2019-nCoV刺突蛋白氨基酸序列
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTF KCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYR LFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
刺突蛋白的RDB结构域(残基319至529)是下划线的。
SEQ ID NO:2-2019-nCoV刺突蛋白核酸序列-针对在大肠杆菌中表达进行了优化并含有SacI和NotI单一克隆位点。描述于实施例1中
5’SacI单克隆位点是带有单下划线的
3’NotI单克隆位点是带有短划线的;
ATG起始密码子用粗体和斜体标出
SEQ ID NO:2的核酸序列翻译得到SEQ ID NO:1的天然2019-NCoV刺突蛋白
SEQ ID NO:3-编码融合蛋白HEV-2019-nCoV刺突蛋白的核酸-针对在大肠杆菌中表达进行了优化并含有SacI和NotI单一克隆位点。描述于实施例2中
5’SacI单克隆位点是带有单下划线的
HEV(p239片段)序列以大写字母显示
2019-nCoV刺突蛋白编码序列以小写字母显示
3’NotI单克隆位点是带有短划线的
SEQ ID NO:4-2019-nCoV刺突蛋白核酸序列-针对在Komagataella pastoris表达进行了优化并含有BstB1和NotI单一克隆位点。描述于实施例3中
5’BstBI单克隆位点是带有单下划线的
3’NotI单克隆位点是带有短划线的
紧接着5’SacI的是ACG密码子(需要编码序列与紧接着ACG的ATG起始密码子在框内)。这两个密码子以粗体和斜体显示。
SEQ ID NO:4的核酸序列翻译得到SEQ ID NO:1的天然2019-NCoV刺突蛋白
SEQ ID NO:5-编码融合蛋白HPV18LL/2019-nCoV刺突蛋白的核酸-针对在K.pastoris表达进行了优化并含有BstB1和NotI单一克隆位点。描述于实施例4中
5’BstBI单克隆位点是带有单下划线的
HPV18L1序列以小写字母显示
2019-nCoV刺突蛋白编码序列以大写字母显示
3’NotI单克隆位点是带有短划线的
紧接着5’BstBI的是ACG密码子(需要编码序列与紧接着ACG的ATG起始密码子在框内)。这两个密码子以粗体和斜体显示。
SEQ ID NO:6-编码融合蛋白HPV16LL/2019-nCoV刺突蛋白的核酸-针对在K.pastoris表达进行了优化并含有BstB1和NotI单一克隆位点。描述于实施例5中
5’BstBI单克隆位点是带有单下划线的
HPV16L1序列以小写字母显示
2019-nCoV刺突蛋白编码序列以大写字母显示
3’NotI单克隆位点是带有短划线的
紧接着5’BstBI的是ACG密码子(需要编码序列与紧接着ACG的ATG起始密码子在框内)。这两个密码子以粗体和斜体显示。
SEQ ID NO:7-2019-nCoV刺突蛋白核酸序列-针对在人(293F)中的表达进行了优化并含有NheI和NotI单一克隆位点。描述于实施例6中
5’NheI单克隆位点是带有单下划线的
3’NotI单克隆位点是带有短划线的
紧接着5’NheI的是GAC密码子(需要编码序列与紧接着GAC的ATG起始密码子在框内)。这两个密码子以粗体和斜体显示。
SEQ ID NO:7的核酸序列翻译得到SEQ ID NO:1的天然2019-NCoV刺突蛋白
SEQ ID NO:8-编码融合蛋白HBsAg/2019-nCoV刺突蛋白的核酸-针对在人(293F)中的表达进行了优化并含有NheI和NotI单一克隆位点。描述于实施例7中
5’NheI单克隆位点是带有单下划线的
HBSAg序列以小写字母显示
2019-nCoV刺突蛋白编码序列以大写字母显示
3’NotI单克隆位点是带有短划线的
紧接着5’NheI的是GAC密码子(需要编码序列与紧接着GAC的ATG起始密码子在框内)。这两个密码子以粗体和斜体显示。
SEQ ID NO:9-对应于SEQ ID NO:3的氨基酸序列
(融合蛋白HEV-2019-nCoV刺突蛋白-针对在大肠杆菌中表达进行了优化并含有SacI和NotI单一克隆位点。描述于实施例2中)
MIALTLFNLADTLLGGLPTELISSAGGQLFYSRPVVSANGEPTVKLYTSVENAQQDKGIAIPHDIDLGESRVVIQDYDNQHEQDRPTPSPAPSRPFSVLRANDVLWLSLTAAEYDQSTYGSSTGPVYVSDSVTLVNVATGAQAVARSLDWTKVTLDGRPLSTIQQYSKTFFVLPLRGKLSFWEAGTTKAGYPYNYNTTASDQLLVENAAGHRVAISTYTTSLGAGPVSISAVAVLAPHSAFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:10-对应于SEQ ID NO:5的氨基酸序列
(融合蛋白HPV18LL/2019-nCoV刺突蛋白-针对在K.pastoris中表达进行了优化并含有BstBI和NotI单一克隆位点。描述于实施例4中)
MALWRPSDNTVYLPPPSVARVVNTDDYVTRTSIFYHAGSSRLLTVGNPYFRVPAGGGNKQDIPKVSAYQYRVFRVQLPDPNKFGLPDTSIYNPETQRLVWACAGVEIGRGQPLGVGLSGHPFYNKLDDTESSHAATSNVSEDVRDNVSVDYKQTQLCILGCAPAIGEHWAKGTACKSRPLSQGDCPPLELKNTVLEDGDMVDTGYGAMDFSTLQDTKCEVPLDICQSICKYPDYLQMSADPYGDSMFFCLRREQLFARHFWNRAGTMGDTVPQSLYIKGTGMRASPGSCVYSPSPSGSIVTSDSQLFNKPYWLHKAQGHNNGVCWHNQLFVTVVDTTRSTNLTICASTQSPVPGQYDATKFKQYSRHVEEYDLQFIFQLCTITLTADVMSYIHSMNSSILEDWNFGVPPPPTTSLVDTYRFVQSVAITCQKDAAPAENKDPYDKLKFWNVDLKEKFSLDLDQYPLGRKFLVQAGLRRKPTIGPRKRSAPSATTSSKPAKRVRVRARKFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:11-对应于SEQ ID NO:6的氨基酸序列
(融合蛋白HPV16LL/2019-nCoV刺突蛋白-针对在K.pastoris中表达进行了优化并含有BstBI和NotI单一克隆位点。描述于实施例5中)
MSLWLPSEATVYLPPVPVSKVVSTDEYVARTNIYYHAGTSRLLAVGHPYFPIKKPNNNKILVPKVSGLQYRVFRIHLPDPNKFGFPDTSFYNPDTQRLVWACVGVEVGRGQPLGVGISGHPLLNKLDDTENASAYAANAGVDNRECISMDYKQTQLCLIGCKPPIGEHWGKGSPCTNVAVNPGDCPPLELINTVIQDGDMVDTGFGAMDFTTLQANKSEVPLDICTSICKYPDYIKMVSEPYGDSLFFYLRREQMFVRHLFNRAGAVGENVPDDLYIKGSGSTANLASSNYFPTPSGSMVTSDAQIFNKPYWLQRAQGHNNGICWGNQLFVTVVDTTRSTNMSLCAAISTSETTYKNTNFKEYLRHGEEYDLQFIFQLCKITLTADVMTYIHSMNSTILEDWNFGLQPPPGGTLEDTYRFVTSQAIACQKHTPPAPKEDPLKKYTFWEVNLKEKFSADLDQFPLGRKFLLQAGLKAKPKFTLGKRKATPTTSSTSTTAKRKKRKLFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:12-对应于SEQ ID NO:8的氨基酸序列
(融合蛋白HBsAg/2019-nCoV刺突蛋白-针对在人(293F)中表达进行了优化并含有NheI和NotI单一克隆位点。描述于实施例7中)
MNFLGGTTVCLGQNSQSPTSNHSPTSCPPTCPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCTTPAQGTSMYPSCCCTKPSDGNCTCIPIPSSWAFGKFLWEWASARFSFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYTAA
SEQ ID NO:13-RBD 2019-NCoV刺突蛋白核酸序列
在起始ATG(粗体)前添加KOZAC序列(gcc acc,带有下划线的)。
在NotI前添加分泌形式tga taa(带有双下划线的)-这个tga taa序列是“两个终止密码子”基序,其中断蛋白质合成,促进分泌到胞外培养基中(也包括在其他序列中,如下所述)。
已经分别在5'端NheI和3'端NotI添加了唯一的限制性位点,NotI(带有短划线的)
SEQ ID NO:14-RBD 2019-NCoV刺突蛋白核酸序列-针对293F(HEK)细胞表达优化的人密码子。
在起始ATG(粗体)前添加KOZAC序列(gcc acc,带有下划线的)。
在NotI前添加分泌形式tga taa(带有双下划线的)
已经分别在5'端NheI和3'端NotI添加了唯一的限制性位点(带有短划线的)
SEQ ID NO:15-对应于SEQ ID NO:13和14的RBD 2019-nCoV刺突蛋白氨基酸序列
MRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKK
SEQ ID NO:16-刚性EAAAK接头共有氨基酸序列
A(EAAAK)nA(n=2-5)
SEQ ID NO:17-刚性(EAAAK)3接头核酸序列
GAAGCC GCC GCT AAA GAG GCC GCT GCC AAA GAA GCT GCT GCT AAG
SEQ ID NO:18-刚性(EAAAK)3接头氨基酸序列
EAAAKEAAAKEAAAK
SEQ ID NO:19-柔性GSn接头共有氨基酸序列
(Gly-Gly-Gly-Gly-Ser)n(n=1-6)
SEQ ID NO:20–柔性GS5((GGGGS)1)接头氨基酸序列
GGGGS
SEQ ID NO:21-柔性GS10((GGGGS)2)接头氨基酸序列
GGGGSGGGGS
SEQ ID NO:22-柔性GS15接头核酸序列
GGT GGT GGT GGT AGC GGT GGT GGC GGT TCA GGT GGC GGT GGT TCA
SEQ ID NO:23-柔性GS15((GGGGS)3)接头氨基酸序列
GGGGSGGGGSGGGGS
SEQ ID NO:24-柔性GS20((GGGGS)4)接头氨基酸序列
GGGGSGGGGSGGGGSGGGGS
SEQ ID NO:25-柔性GS25((GGGGS)5)接头氨基酸序列
GGGGSGGGGSGGGGSGGGGSGGGGS
SEQ ID NO:26-HBsAg-(EAAAK)3-RBD核酸序列
在起始ATG(粗体)前添加KOZAC序列(gcc acc,带有下划线的)。
在NotI前添加分泌形式tga taa(带有双下划线的)
已经分别在5'端NheI和3'端NotI添加了唯一的限制性位点(带有短划线的)
粗体和点划线序列对应于(EAAAK)3接头。
SEQ ID NO:27-HBsAg-(EAAAK)3-RBD核酸序列针对293f(HEK)细胞表达优化的人密码子
在起始ATG(粗体)前添加KOZAC序列(gcc acc,带有下划线的)。
在NotI前添加分泌形式tga taa(带有双下划线的)
已经分别在5'端NheI和3'端NotI添加了唯一的限制性位点(带有短划线的)
粗体和点划线序列对应于(EAAAK)3接头。
SEQ ID NO:28-对应于SEQ ID NO:26和27的HBsAg-(EAAAK)3-RBD氨基酸序列
MNFLGGTTVCLGQNSQSPTSNHSPTSCPPTCPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCTTPAQGTSMYPSCCCTKPSDGNCTCIPIPSSWAFGKFLWEWASARFSEAAAKEAAAKEAA AKRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKK
(EAAAK)3接头是带有下划线的。
SEQ ID NO:29-HEV-GS15-RBD核酸序列
起始ATG(粗体)
已经分别在5'末端SacI和3'末端NotI添加了唯一的限制性位点(带有短划线的)
在NotI之前添加分泌形式tga taa(带有双下划线的)
粗体和点划线的序列对应于GS15接头。
SEQ ID NO:30-针对大肠杆菌表达优化的HEV-GS15-RBD核酸序列
起始ATG(粗体)
在NotI之前添加分泌形式tga taa(带有双下划线的)
已经分别在5'末端SacI和3'末端NotI添加了唯一的限制性位点(带有短划线的)
粗体和点划线序列对应于GS15接头。
SEQ ID NO:31-对应于SEQ ID NO:29和30的HEV-GS15-RBD氨基酸序列
MIALTLFNLADTLLGGLPTELISSAGGQLFYSRPVVSANGEPTVKLYTSVENAQQDKGIAIPHDIDLGESRVVIQDYDNQHEQDRPTPSPAPSRPFSVLRANDVLWLSLTAAEYDQSTYGSSTGPVYVSDSVTLVNVATGAQAVARSLDWTKVTLDGRPLSTIQQYSKTFFVLPLRGKLSFWEAGTTKAGYPYNYNTTASDQLLVENAAGHRVAISTYTTSLGAGPVSISAVAVLAPHSAGGGGSGGGGSGGGGSRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKK
GS15接头是带有下划线的
SEQ ID NO:32-针对293f(HEK)细胞表达人密码子优化的HBsAg-(EAAAK)3-全长2019-nCoV刺突蛋白核酸序列
在起始ATG(粗体)之前添加KOZAC序列(gcc acc,带有下划线的)。
粗体和点划线的序列对应于(EAAAK)3接头。
SEQ ID NO:33-对应于SEQ ID NO:32的HBsAg-(EAAAK)3-全长2019-nCoV刺突蛋白氨基酸序列
MENITSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGSPVCLGQNSQSPTSNHSPTSCPPICPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSTTTNTGPCKTCTTPAQGNSMFPSCCCTKPTDGNCTCIPIPSSWAFAKYLWEWASVRFSWLSLLVPFVQWFVGLSPTVWLSAIWMMWYWGPSLYSIVSPFIPLLPIFFCLWVYIEAAAKEAAAKEAAAKFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
(EAAAK)3接头是带有下划线的。
序列表
<110> 疫苗生物有限公司(Vaxbio Ltd.)
<120> 2019-NCOV(SARS-COV-2)疫苗
<130> P66542WO
<150> GB 2002166.3
<151> 2020-02-17
<160> 33
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1273
<212> PRT
<213> SARS-CoV-2
<400> 1
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1205 1210 1215
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1220 1225 1230
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1250 1255 1260
Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 2
<211> 3839
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(3839)
<223> SARS-CoV2刺突蛋白核酸-针对大肠杆菌表达优化的
<400> 2
gagctcatgt ttgtttttct ggttctgctg ccgctggtta gcagccagtg tgttaatctg 60
accacacgta cccagctgcc tccggcatat accaatagct ttacccgtgg tgtttattat 120
ccggacaaag tttttcgtag cagcgttctg catagcaccc aggacctgtt tctgccgttt 180
tttagcaatg ttacctggtt tcatgccatt catgttagcg gcaccaatgg caccaaacgt 240
tttgataatc cggtgctgcc gtttaatgat ggtgtgtatt ttgcaagcac cgaaaaaagc 300
aacattattc gcggttggat ttttggtaca accctggata gcaaaaccca gagcctgctg 360
attgttaata atgccaccaa tgtggtgatc aaagtgtgcg aatttcagtt ttgcaatgat 420
ccgtttctgg gcgtgtatta ccacaaaaat aacaagagct ggatggaaag cgaatttcgt 480
gtttatagca gcgccaataa ttgcaccttt gaatatgtta gccagccgtt tctgatggat 540
ctggaaggta aacagggtaa ctttaaaaac ctgcgcgagt tcgtgttcaa aaacatcgat 600
ggttacttca aaatctatag caaacacacc ccgattaatc tggttcgtga tctgccgcag 660
ggttttagcg cactggaacc gctggttgat ctgccaattg gtattaacat tacccgtttt 720
cagaccctgc tggcactgca tcgtagctat ctgacaccgg gtgatagcag cagcggttgg 780
accgcaggcg cagcagcata ttatgttggt tatctgcagc ctcgtacctt tctgctgaaa 840
tataacgaaa atggcacaat taccgatgcc gttgattgtg ccctggatcc gctgagcgaa 900
accaaatgta ccctgaaaag ctttaccgtt gagaaaggta tttatcagac cagcaatttt 960
cgtgtgcagc cgaccgaaag cattgttcgt tttccgaata tcaccaatct gtgtccgttt 1020
ggcgaagttt ttaatgcaac ccgttttgcc agcgtttatg catggaatcg taaacgtatt 1080
agcaattgcg ttgccgatta tagcgttctg tataatagcg caagcttcag cacctttaaa 1140
tgctatggtg ttagcccgac caaactgaat gatctgtgtt ttaccaatgt gtatgccgat 1200
agctttgtga ttcgtggtga tgaagttcgt cagattgcac cgggtcagac cggtaaaatt 1260
gcagattata actataaact gccggatgat tttacgggtt gtgttattgc ctggaatagc 1320
aataatctgg acagcaaagt tggtggcaac tataactatc tgtatcgcct gtttcgtaag 1380
agcaatctga aaccgtttga acgtgatatt agcaccgaga tttatcaggc aggtagcacc 1440
ccgtgtaatg gtgttgaagg ttttaattgc tattttccgc tgcagagcta tggttttcag 1500
ccgacaaatg gtgtgggtta tcagccgtat cgtgttgttg ttctgtcatt tgaactgctg 1560
catgcaccgg caaccgtttg tggtccgaaa aaaagtacca atctggtgaa aaataagtgc 1620
gtgaacttta actttaatgg tctgaccggc accggtgttc tgaccgaaag taacaaaaaa 1680
ttcctgccgt ttcagcagtt tggccgtgat attgcagata ccaccgatgc agttcgcgat 1740
ccgcagacac tggaaattct ggatattacc ccgtgcagct ttggtggtgt ttcagttatt 1800
acaccgggta caaataccag caatcaggtt gcagttctgt atcaggatgt taattgtacc 1860
gaagttccgg ttgcaattca tgcagatcag ctgaccccga cctggcgtgt gtatagcacc 1920
ggtagcaatg tgtttcagac acgtgcaggt tgtctgattg gtgcagaaca tgtgaataat 1980
agctatgaat gcgatattcc gattggtgcg ggtatttgtg ccagctatca gacccagacc 2040
aatagtccgc gtcgtgcacg tagcgttgca agccagagca ttattgccta taccatgagc 2100
ctgggtgcag aaaatagcgt tgcctatagt aataacagca ttgccattcc gaccaacttt 2160
accattagcg ttaccaccga aattctgccg gttagcatga ccaaaaccag cgttgattgc 2220
accatgtata tttgtggtga tagtaccgaa tgtagcaatc tgctgctgca gtatggtagc 2280
ttttgcaccc agctgaatcg tgcactgacc ggtattgcag ttgaacagga taaaaacacg 2340
caagaagttt ttgcacaggt caagcagatc tataaaaccc ctccgattaa agattttggc 2400
ggtttcaatt ttagccagat cctgccggat ccgagcaaac cgagtaaacg tagctttatt 2460
gaagatctgc tgttcaacaa agtgaccctg gcagatgcag gttttatcaa acagtatggt 2520
gattgcctgg gcgatattgc cgcacgtgat ctgatttgtg cacagaaatt taacggcctg 2580
accgttctgc ctccgctgct gaccgatgaa atgattgcac agtataccag cgcactgctg 2640
gcaggcacca ttaccagtgg ttggaccttt ggtgccggtg ccgcactgca gattccgttt 2700
gcaatgcaga tggcatatcg ttttaatggt attggtgtta cccagaacgt gctgtatgaa 2760
aaccagaaac tgattgccaa ccagtttaat agcgccattg gcaaaattca ggatagcctg 2820
agcagcaccg caagtgcact gggtaaactg caggacgttg ttaatcagaa tgcacaggca 2880
ctgaataccc tggttaaaca gctgagcagt aattttggtg caatttcaag cgtgctgaac 2940
gatattctga gccgtctgga taaagttgaa gcagaagttc agattgatcg tctgattacc 3000
ggtcgtctgc aaagcctgca gacctatgtg acccagcagc tgattcgcgc agcagaaatt 3060
cgtgcaagcg caaatctggc agccaccaaa atgagcgaat gtgttctggg tcagagcaaa 3120
cgtgttgatt tttgcggcaa aggttatcac ctgatgagct ttccgcagag cgcaccgcat 3180
ggtgttgtgt ttctgcatgt tacctatgtt ccggcacaag aaaaaaactt tacaaccgct 3240
ccggcaattt gccatgatgg taaagcacat tttccgcgtg aaggtgtttt tgttagtaat 3300
ggcacccatt ggtttgttac acagcgcaac ttttatgaac cgcagattat tacaaccgac 3360
aacacctttg ttagcggtaa ctgtgatgtt gtgattggca ttgtgaataa caccgtttat 3420
gatccactgc agccggaact ggatagcttt aaagaagaac tggacaaata tttcaaaaac 3480
cacaccagtc cggatgttga tctgggtgat atttcaggta ttaatgccag cgtggtgaac 3540
atccagaaag aaattgatcg cctgaatgaa gtggccaaaa atctgaatga aagcctgatt 3600
gatctgcaag aactggggaa atatgagcag tatatcaaat ggccgtggta tatttggctg 3660
ggttttattg caggcctgat tgcaattgtt atggtgacca ttatgctgtg ttgtatgacc 3720
agctgttgta gctgtctgaa aggttgttgc agctgcggta gctgttgcaa atttgatgaa 3780
gatgatagcg aaccggtgct gaaaggtgtt aaactgcatt atacctaatg agcggccgc 3839
<210> 3
<211> 4556
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(4556)
<223> 编码融合蛋白HEV-SARS-CoV-2刺突蛋白的核酸-针对在大肠杆菌中表达优化的
<400> 3
gagctcatga ttgcactgac cctgtttaat ctggcagata ccctgttagg tggtctgccg 60
accgaactga ttagcagtgc cggtggtcag ctgttttata gccgtccggt tgttagcgca 120
aatggtgaac cgaccgttaa actgtatacc agcgttgaaa atgcacagca ggataaaggt 180
attgcaattc cgcatgatat tgatctgggt gaaagccgtg ttgtgattca ggattatgat 240
aatcagcatg aacaggatcg tccgacaccg agtccggcac cgagccgtcc gtttagcgtt 300
ctgcgtgcaa atgatgttct gtggctgagc ctgaccgcag cagaatatga tcagagcacc 360
tatggtagca gcaccggtcc ggtttatgtt agcgatagcg ttaccctggt taatgttgca 420
accggtgcac aggcagttgc acgtagcctg gattggacca aagtgaccct ggatggtcgt 480
ccgctgagca ccattcagca gtatagcaaa accttttttg ttctgccgct gcgtggtaaa 540
ctgagctttt gggaagcagg caccaccaaa gcaggttatc cgtataacta taataccacc 600
gcaagcgatc agctgctggt tgaaaacgca gcaggtcatc gtgttgcaat tagcacctat 660
accaccagtt taggtgcagg tccggttagc attagcgcag ttgcagttct ggcaccgcat 720
agcgcatttg tttttctggt tctgctgccg ctggttagca gccagtgtgt taatctgacc 780
acacgtaccc agctgcctcc ggcatatacc aatagcttta cccgtggtgt ttattatccg 840
gacaaagttt ttcgtagcag cgttctgcat agcacccagg acctgtttct gccgtttttt 900
agcaatgtta cctggtttca tgccattcat gttagcggca ccaatggcac caaacgtttt 960
gataatccgg tgctgccgtt taatgatggt gtgtattttg caagcaccga aaaaagcaac 1020
attattcgcg gttggatttt tggtacaacc ctggatagca aaacccagag cctgctgatt 1080
gttaataatg ccaccaatgt ggtgatcaaa gtgtgcgaat ttcagttttg caatgatccg 1140
tttctgggcg tgtattacca caaaaataac aagagctgga tggaaagcga atttcgtgtt 1200
tatagcagcg ccaataattg cacctttgaa tatgttagcc agccgtttct gatggatctg 1260
gaaggtaaac agggtaactt taaaaacctg cgcgagttcg tgttcaaaaa catcgatggt 1320
tacttcaaaa tctatagcaa acacaccccg attaatctgg ttcgtgatct gccgcagggt 1380
tttagcgcac tggaaccgct ggttgatctg ccaattggta ttaacattac ccgttttcag 1440
accctgctgg cactgcatcg tagctatctg acaccgggtg atagcagcag cggttggacc 1500
gcaggcgcag cagcatatta tgttggttat ctgcagcctc gtacctttct gctgaaatat 1560
aacgaaaatg gcacaattac cgatgccgtt gattgtgccc tggatccgct gagcgaaacc 1620
aaatgtaccc tgaaaagctt taccgttgag aaaggtattt atcagaccag caattttcgt 1680
gtgcagccga ccgaaagcat tgttcgtttt ccgaatatca ccaatctgtg tccgtttggc 1740
gaagttttta atgcaacccg ttttgccagc gtttatgcat ggaatcgtaa acgtattagc 1800
aattgcgttg ccgattatag cgttctgtat aatagcgcaa gcttcagcac ctttaaatgc 1860
tatggtgtta gcccgaccaa actgaatgat ctgtgtttta ccaatgtgta tgccgatagc 1920
tttgtgattc gtggtgatga agttcgtcag attgcaccgg gtcagaccgg taaaattgca 1980
gattataact ataaactgcc ggatgatttt acgggttgtg ttattgcctg gaatagcaat 2040
aatctggaca gcaaagttgg tggcaactat aactatctgt atcgcctgtt tcgtaagagc 2100
aatctgaaac cgtttgaacg tgatattagc accgagattt atcaggcagg tagcaccccg 2160
tgtaatggtg ttgaaggttt taattgctat tttccgctgc agagctatgg ttttcagccg 2220
acaaatggtg tgggttatca gccgtatcgt gttgttgttc tgtcatttga actgctgcat 2280
gcaccggcaa ccgtttgtgg tccgaaaaaa agtaccaatc tggtgaaaaa taagtgcgtg 2340
aactttaact ttaatggtct gaccggcacc ggtgttctga ccgaaagtaa caaaaaattc 2400
ctgccgtttc agcagtttgg ccgtgatatt gcagatacca ccgatgcagt tcgcgatccg 2460
cagacactgg aaattctgga tattaccccg tgcagctttg gtggtgtttc agttattaca 2520
ccgggtacaa ataccagcaa tcaggttgca gttctgtatc aggatgttaa ttgtaccgaa 2580
gttccggttg caattcatgc agatcagctg accccgacct ggcgtgtgta tagcaccggt 2640
agcaatgtgt ttcagacacg tgcaggttgt ctgattggtg cagaacatgt gaataatagc 2700
tatgaatgcg atattccgat tggtgcgggt atttgtgcca gctatcagac ccagaccaat 2760
agtccgcgtc gtgcacgtag cgttgcaagc cagagcatta ttgcctatac catgagcctg 2820
ggtgcagaaa atagcgttgc ctatagtaat aacagcattg ccattccgac caactttacc 2880
attagcgtta ccaccgaaat tctgccggtt agcatgacca aaaccagcgt tgattgcacc 2940
atgtatattt gtggtgatag taccgaatgt agcaatctgc tgctgcagta tggtagcttt 3000
tgcacccagc tgaatcgtgc actgaccggt attgcagttg aacaggataa aaacacgcaa 3060
gaagtttttg cacaggtcaa gcagatctat aaaacccctc cgattaaaga ttttggcggt 3120
ttcaatttta gccagatcct gccggatccg agcaaaccga gtaaacgtag ctttattgaa 3180
gatctgctgt tcaacaaagt gaccctggca gatgcaggtt ttatcaaaca gtatggtgat 3240
tgcctgggcg atattgccgc acgtgatctg atttgtgcac agaaatttaa cggcctgacc 3300
gttctgcctc cgctgctgac cgatgaaatg attgcacagt ataccagcgc actgctggca 3360
ggcaccatta ccagtggttg gacctttggt gccggtgccg cactgcagat tccgtttgca 3420
atgcagatgg catatcgttt taatggtatt ggtgttaccc agaacgtgct gtatgaaaac 3480
cagaaactga ttgccaacca gtttaatagc gccattggca aaattcagga tagcctgagc 3540
agcaccgcaa gtgcactggg taaactgcag gacgttgtta atcagaatgc acaggcactg 3600
aataccctgg ttaaacagct gagcagtaat tttggtgcaa tttcaagcgt gctgaacgat 3660
attctgagcc gtctggataa agttgaagca gaagttcaga ttgatcgtct gattaccggt 3720
cgtctgcaaa gcctgcagac ctatgtgacc cagcagctga ttcgcgcagc agaaattcgt 3780
gcaagcgcaa atctggcagc caccaaaatg agcgaatgtg ttctgggtca gagcaaacgt 3840
gttgattttt gcggcaaagg ttatcacctg atgagctttc cgcagagcgc accgcatggt 3900
gttgtgtttc tgcatgttac ctatgttccg gcacaagaaa aaaactttac aaccgctccg 3960
gcaatttgcc atgatggtaa agcacatttt ccgcgtgaag gtgtttttgt tagtaatggc 4020
acccattggt ttgttacaca gcgcaacttt tatgaaccgc agattattac aaccgacaac 4080
acctttgtta gcggtaactg tgatgttgtg attggcattg tgaataacac cgtttatgat 4140
ccactgcagc cggaactgga tagctttaaa gaagaactgg acaaatattt caaaaaccac 4200
accagtccgg atgttgatct gggtgatatt tcaggtatta atgccagcgt ggtgaacatc 4260
cagaaagaaa ttgatcgcct gaatgaagtg gccaaaaatc tgaatgaaag cctgattgat 4320
ctgcaagaac tggggaaata tgagcagtat atcaaatggc cgtggtatat ttggctgggt 4380
tttattgcag gcctgattgc aattgttatg gtgaccatta tgctgtgttg tatgaccagc 4440
tgttgtagct gtctgaaagg ttgttgcagc tgcggtagct gttgcaaatt tgatgaagat 4500
gatagcgaac cggtgctgaa aggtgttaaa ctgcattata cctaatgagc ggccgc 4556
<210> 4
<211> 3839
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(3839)
<223> SARS-CoV-2刺突蛋白核酸序列-针对在Komagataella pastoris中表达优化的
<400> 4
ttcgaaacga tgttcgtgtt cttggtcctg ttgccattgg tttcttccca gtgtgttaac 60
ctgaccacta gaactcaatt gcctccagcc tacaccaatt ccttcaccag aggtgtttac 120
tacccagaca aggtgttcag atcttccgtc ttgcactcca ctcaggactt gttcttgcca 180
ttcttctcca acgttacctg gttccacgct attcacgttt ccggaactaa cggtactaag 240
agattcgaca acccagtcct gccattcaac gatggtgtct acttcgcttc taccgagaag 300
tccaacatca tcagaggttg gatcttcggt actaccctgg actctaagac tcagtccttg 360
ctgatcgtta acaacgccac caacgttgtc atcaaggttt gcgagttcca gttctgcaac 420
gacccattct tgggtgtgta ctaccacaag aacaacaagt cttggatgga atccgagttc 480
agagtttact cctccgccaa caactgtacc ttcgagtacg tttcccagcc attcttgatg 540
gacttggagg gtaagcaggg taacttcaag aacctgagag agttcgtttt caagaacatc 600
gacggttact tcaagatcta ctccaagcac accccaatca acctggttag agatttgcca 660
caaggtttct ccgctttgga gcctttggtt gacttgccaa tcggtatcaa catcaccaga 720
ttccagacct tgttggcctt gcacagatcc tacttgactc caggtgattc ttcttccggt 780
tggactgctg gtgctgctgc ttactatgtt ggttacttgc agccaagaac cttcctgctg 840
aagtacaacg agaacggaac tatcactgac gctgttgact gtgctttgga cccattgtct 900
gagactaagt gcaccttgaa gtccttcacc gttgagaagg gtatctacca gacctccaac 960
ttcagagttc agccaactga gtccatcgtc agattcccaa acatcactaa cttgtgccca 1020
ttcggtgagg tgttcaacgc tactagattc gcttctgttt acgcctggaa cagaaagaga 1080
atctccaact gcgttgctga ctactccgtc ttgtacaact ctgcttcatt ctccaccttc 1140
aagtgctacg gtgtttcccc aactaagttg aacgacctgt gtttcactaa cgtctacgcc 1200
gactccttcg ttattagagg tgacgaggtt agacagatcg ctccaggtca aactggtaag 1260
atcgctgact acaactacaa gctgccagac gacttcaccg gttgtgttat tgcttggaac 1320
tccaacaacc tggactccaa ggttggtggt aactacaatt acctgtaccg tctgttcaga 1380
aagtccaact tgaagccatt cgagagagac atctccaccg agatctacca agctggttct 1440
actccatgta acggtgtcga gggtttcaac tgctacttcc cattgcaatc ctacggtttc 1500
caacctacca acggtgttgg ataccagcca tacagagttg tcgttttgtc cttcgagttg 1560
ttgcacgctc cagctactgt ttgtggtcca aagaagtcca ccaacttggt caagaacaaa 1620
tgcgtcaact ttaacttcaa cggcctgacc ggtactggtg ttttgactga atccaacaag 1680
aagttcctgc ctttccagca gttcggtaga gacattgctg acactactga cgccgttaga 1740
gatccacaga ctttggagat cttggacatc accccatgtt ccttcggtgg tgtttccgtt 1800
attacccctg gaactaacac ctccaatcag gtcgctgtct tgtaccagga cgttaactgt 1860
actgaggttc cagttgctat ccacgctgac caattgactc caacttggag agtctactcc 1920
accggttcca acgttttcca aactagagcc ggttgtttga tcggtgctga acacgtcaac 1980
aactcctacg agtgtgacat tccaattggt gctggtatct gtgcctccta ccaaactcaa 2040
actaactccc caagaagggc tagatccgtt gcttcccaat ccattatcgc ttacaccatg 2100
tctttgggtg ccgagaactc tgttgcctac tctaacaact ctatcgctat ccctaccaac 2160
ttcaccatct ccgttaccac tgagatcttg ccagtctcca tgaccaagac ttccgttgac 2220
tgtaccatgt acatctgtgg tgactccact gagtgttcca acttgttgct gcaatacggt 2280
tccttctgca cccagttgaa cagagctttg actggtattg ctgtcgagca agacaagaac 2340
actcaagagg ttttcgccca ggtgaagcag atctacaaga ctccacctat taaggacttc 2400
ggtggcttca acttctccca gattttgcca gatccatcta agccctccaa gagatccttc 2460
attgaggacc tgctgttcaa caaggttact ttggctgacg ccggtttcat caagcagtac 2520
ggtgattgct tgggtgacat tgcagctaga gacttgatct gtgcccagaa gttcaacggt 2580
ttgaccgttt tgccaccttt gttgaccgac gagatgatcg ctcagtacac ttctgctttg 2640
ttggccggta ctatcacttc tggttggaca tttggagctg gtgccgcatt gcaaattcca 2700
ttcgctatgc aaatggccta cagattcaac ggtatcggtg ttacccagaa cgtcctgtac 2760
gagaaccaga agcttatcgc caaccagttc aactccgcta tcggtaagat tcaggactcc 2820
ttgtcctcta ctgcttctgc cttgggaaag ttgcaggatg ttgttaacca gaatgcccag 2880
gctttgaaca ccctggttaa gcaactgtcc tctaacttcg gtgctatctc ctccgttttg 2940
aacgacatct tgtcccgttt ggacaaggtt gaggctgagg ttcagatcga cagattgatc 3000
actggtagat tgcagtccct gcagacttac gttactcagc agttgattag agctgccgag 3060
attagagcct ctgctaactt ggctgctact aagatgtccg agtgtgtttt gggtcagtcc 3120
aagagagttg acttctgcgg taagggttac cacctgatgt ctttcccaca atctgctcca 3180
cacggtgtcg ttttcttgca cgttacttac gttccagctc aagagaagaa cttcactact 3240
gctccagcca tttgtcacga tggtaaggct cactttcctc gtgagggtgt tttcgtttcc 3300
aacggtactc actggttcgt cacccagaga aacttttacg agccacagat catcaccacc 3360
gacaacactt tcgtttctgg taactgtgac gtcgtcatcg gtatcgtgaa caacactgtc 3420
tacgatccat tgcagccaga attggactcc ttcaaagagg aactggacaa gtactttaag 3480
aaccacactt ccccagacgt tgacctgggt gatatttccg gtattaacgc ctccgttgtc 3540
aacatccaaa aagagatcga ccgtttgaac gaggtcgcca agaacttgaa cgagtccttg 3600
attgacttgc aagagctggg caagtacgag cagtacatta agtggccatg gtacatttgg 3660
ctgggtttca ttgctggttt gatcgccatc gttatggtca ccatcatgtt gtgctgtatg 3720
acctcctgtt gctcctgttt gaagggttgt tgttcctgcg gttcctgttg taagttcgac 3780
gaagatgact ccgagccagt cttgaagggt gttaagttgc actacactta agcggccgc 3839
<210> 5
<211> 5357
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(5357)
<223> 编码融合蛋白HPV18L1/SARS-CoV-2 刺突蛋白的核酸-针对在 K. pastoris中表达优化的
<400> 5
ttcgaaacga tggctctttg gagaccatcc gacaacactg tttacttgcc accaccatcc 60
gttgctagag ttgttaacac tgacgactac gttactagaa cttccatctt ctaccacgct 120
ggttcttcca gattgttgac tgttggtaac ccatacttca gagttccagc tggaggtggt 180
aacaagcaag acatcccaaa ggtttccgct taccagtaca gagttttcag agttcagttg 240
ccagacccaa acaagtttgg attgccagac acttccatct acaacccaga gactcagaga 300
cttgtttggg cttgtgctgg tgttgaaatc ggtagaggac agccattggg tgttggtttg 360
tctggtcacc cattctacaa caagttggac gacactgaat cttctcacgc tgctacttct 420
aacgtttccg aggatgttag agacaacgtt tccgttgact acaagcagac tcagttgtgt 480
atcttgggtt gtgctccagc tattggtgaa cattgggcta agggtactgc ttgtaagtcc 540
agaccattgt ctcagggaga ttgtccacca ttggagttga agaacactgt tttggaggac 600
ggtgatatgg ttgatactgg ttacggtgct atggacttct ctactttgca ggacactaag 660
tgtgaagttc cattggacat ctgtcagtcc atctgtaagt acccagacta cttgcaaatg 720
tccgctgatc catacggtga ctctatgttc ttctgtttga gaagagagca gttgttcgct 780
agacacttct ggaacagagc tggtactatg ggtgacactg ttccacaatc cttgtacatc 840
aagggtactg gaatgagagc ttctcctggt tcttgtgttt actctccatc tccatccggt 900
tccattgtta cttccgactc ccagttgttc aacaagccat actggttgca taaggctcaa 960
ggtcacaaca acggtgtttg ttggcacaac cagttgttcg ttactgttgt tgacactact 1020
agatccacta acttgactat ctgtgcttcc actcaatctc cagttccagg acaatacgac 1080
gctactaagt tcaagcagta ctccagacac gttgaagagt acgacttgca gttcatcttc 1140
cagttgtgta ctatcacttt gactgctgat gttatgtcct acatccactc tatgaactcc 1200
tccattttgg aggattggaa cttcggtgtt ccaccaccac caactacttc attggttgac 1260
acttacagat tcgttcagtc cgttgctatc acttgtcaaa aggacgctgc tccagctgaa 1320
aacaaggacc catacgacaa gttgaagttc tggaacgttg acttgaaaga gaagttctcc 1380
ttggacttgg accaataccc attgggtaga aagtttttgg ttcaggctgg attgagaaga 1440
aagccaacta tcggtccaag aaagagatca gctccatccg ctactacttc atccaagcca 1500
gctaagagag ttagagttag agctagaaag ttcgtgttct tggtcctgtt gccattggtt 1560
tcttcccagt gtgttaacct gaccactaga actcaattgc ctccagccta caccaattcc 1620
ttcaccagag gtgtttacta cccagacaag gtgttcagat cttccgtctt gcactccact 1680
caggacttgt tcttgccatt cttctccaac gttacctggt tccacgctat tcacgtttcc 1740
ggaactaacg gtactaagag attcgacaac ccagtcctgc cattcaacga tggtgtctac 1800
ttcgcttcta ccgagaagtc caacatcatc agaggttgga tcttcggtac taccctggac 1860
tctaagactc agtccttgct gatcgttaac aacgccacca acgttgtcat caaggtttgc 1920
gagttccagt tctgcaacga cccattcttg ggtgtgtact accacaagaa caacaagtct 1980
tggatggaat ccgagttcag agtttactcc tccgccaaca actgtacctt cgagtacgtt 2040
tcccagccat tcttgatgga cttggagggt aagcagggta acttcaagaa cctgagagag 2100
ttcgttttca agaacatcga cggttacttc aagatctact ccaagcacac cccaatcaac 2160
ctggttagag atttgccaca aggtttctcc gctttggagc ctttggttga cttgccaatc 2220
ggtatcaaca tcaccagatt ccagaccttg ttggccttgc acagatccta cttgactcca 2280
ggtgattctt cttccggttg gactgctggt gctgctgctt actatgttgg ttacttgcag 2340
ccaagaacct tcctgctgaa gtacaacgag aacggaacta tcactgacgc tgttgactgt 2400
gctttggacc cattgtctga gactaagtgc accttgaagt ccttcaccgt tgagaagggt 2460
atctaccaga cctccaactt cagagttcag ccaactgagt ccatcgtcag attcccaaac 2520
atcactaact tgtgcccatt cggtgaggtg ttcaacgcta ctagattcgc ttctgtttac 2580
gcctggaaca gaaagagaat ctccaactgc gttgctgact actccgtctt gtacaactct 2640
gcttcattct ccaccttcaa gtgctacggt gtttccccaa ctaagttgaa cgacctgtgt 2700
ttcactaacg tctacgccga ctccttcgtt attagaggtg acgaggttag acagatcgct 2760
ccaggtcaaa ctggtaagat cgctgactac aactacaagc tgccagacga cttcaccggt 2820
tgtgttattg cttggaactc caacaacctg gactccaagg ttggtggtaa ctacaattac 2880
ctgtaccgtc tgttcagaaa gtccaacttg aagccattcg agagagacat ctccaccgag 2940
atctaccaag ctggttctac tccatgtaac ggtgtcgagg gtttcaactg ctacttccca 3000
ttgcaatcct acggtttcca acctaccaac ggtgttggat accagccata cagagttgtc 3060
gttttgtcct tcgagttgtt gcacgctcca gctactgttt gtggtccaaa gaagtccacc 3120
aacttggtca agaacaaatg cgtcaacttt aacttcaacg gcctgaccgg tactggtgtt 3180
ttgactgaat ccaacaagaa gttcctgcct ttccagcagt tcggtagaga cattgctgac 3240
actactgacg ccgttagaga tccacagact ttggagatct tggacatcac cccatgttcc 3300
ttcggtggtg tttccgttat tacccctgga actaacacct ccaatcaggt cgctgtcttg 3360
taccaggacg ttaactgtac tgaggttcca gttgctatcc acgctgacca attgactcca 3420
acttggagag tctactccac cggttccaac gttttccaaa ctagagccgg ttgtttgatc 3480
ggtgctgaac acgtcaacaa ctcctacgag tgtgacattc caattggtgc tggtatctgt 3540
gcctcctacc aaactcaaac taactcccca agaagggcta gatccgttgc ttcccaatcc 3600
attatcgctt acaccatgtc tttgggtgcc gagaactctg ttgcctactc taacaactct 3660
atcgctatcc ctaccaactt caccatctcc gttaccactg agatcttgcc agtctccatg 3720
accaagactt ccgttgactg taccatgtac atctgtggtg actccactga gtgttccaac 3780
ttgttgctgc aatacggttc cttctgcacc cagttgaaca gagctttgac tggtattgct 3840
gtcgagcaag acaagaacac tcaagaggtt ttcgcccagg tgaagcagat ctacaagact 3900
ccacctatta aggacttcgg tggcttcaac ttctcccaga ttttgccaga tccatctaag 3960
ccctccaaga gatccttcat tgaggacctg ctgttcaaca aggttacttt ggctgacgcc 4020
ggtttcatca agcagtacgg tgattgcttg ggtgacattg cagctagaga cttgatctgt 4080
gcccagaagt tcaacggttt gaccgttttg ccacctttgt tgaccgacga gatgatcgct 4140
cagtacactt ctgctttgtt ggccggtact atcacttctg gttggacatt tggagctggt 4200
gccgcattgc aaattccatt cgctatgcaa atggcctaca gattcaacgg tatcggtgtt 4260
acccagaacg tcctgtacga gaaccagaag cttatcgcca accagttcaa ctccgctatc 4320
ggtaagattc aggactcctt gtcctctact gcttctgcct tgggaaagtt gcaggatgtt 4380
gttaaccaga atgcccaggc tttgaacacc ctggttaagc aactgtcctc taacttcggt 4440
gctatctcct ccgttttgaa cgacatcttg tcccgtttgg acaaggttga ggctgaggtt 4500
cagatcgaca gattgatcac tggtagattg cagtccctgc agacttacgt tactcagcag 4560
ttgattagag ctgccgagat tagagcctct gctaacttgg ctgctactaa gatgtccgag 4620
tgtgttttgg gtcagtccaa gagagttgac ttctgcggta agggttacca cctgatgtct 4680
ttcccacaat ctgctccaca cggtgtcgtt ttcttgcacg ttacttacgt tccagctcaa 4740
gagaagaact tcactactgc tccagccatt tgtcacgatg gtaaggctca ctttcctcgt 4800
gagggtgttt tcgtttccaa cggtactcac tggttcgtca cccagagaaa cttttacgag 4860
ccacagatca tcaccaccga caacactttc gtttctggta actgtgacgt cgtcatcggt 4920
atcgtgaaca acactgtcta cgatccattg cagccagaat tggactcctt caaagaggaa 4980
ctggacaagt actttaagaa ccacacttcc ccagacgttg acctgggtga tatttccggt 5040
attaacgcct ccgttgtcaa catccaaaaa gagatcgacc gtttgaacga ggtcgccaag 5100
aacttgaacg agtccttgat tgacttgcaa gagctgggca agtacgagca gtacattaag 5160
tggccatggt acatttggct gggtttcatt gctggtttga tcgccatcgt tatggtcacc 5220
atcatgttgt gctgtatgac ctcctgttgc tcctgtttga agggttgttg ttcctgcggt 5280
tcctgttgta agttcgacga agatgactcc gagccagtct tgaagggtgt taagttgcac 5340
tacacttaag cggccgc 5357
<210> 6
<211> 5351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(5351)
<223> 编码融合蛋白HPV16L1/SARS-CoV-2刺突蛋白的核酸-针对在K. pastoris中表达优化的
<400> 6
ttcgaaacga tgtctttgtg gttgccatct gaagctactg tttacttgcc accagttcca 60
gtttctaaag ttgtttccac tgacgaatac gttgctagaa ctaacatcta ctaccacgct 120
ggtacttcta gattgttggc tgttggtcat ccatacttcc caattaagaa gccaaacaac 180
aacaagattt tggttccaaa ggtttccgga ttgcaataca gagttttcag aatccatttg 240
ccagatccaa acaagtttgg tttcccagat acttctttct acaacccaga cactcaaaga 300
cttgtttggg cttgtgttgg tgttgaagtt ggtagaggtc aaccattggg tgttggtatt 360
tctggtcacc cattgttgaa caagttggac gatactgaaa acgcttctgc ttacgctgct 420
aacgctggtg ttgataacag agaatgtatt tctatggact acaagcaaac tcaattgtgt 480
ttgattggtt gtaagccacc aattggtgaa cattggggaa agggttctcc atgtactaat 540
gttgctgtta accctggtga ttgtccacca ttggaattga ttaacactgt tattcaagac 600
ggtgatatgg ttgatactgg tttcggtgct atggatttca ctactttgca agctaacaag 660
tctgaagttc cattggacat ttgtacttcc atctgtaagt acccagacta cattaagatg 720
gtttctgaac catacggtga ttctttgttc ttctacttga gaagagaaca aatgtttgtt 780
agacacttgt tcaacagagc tggtgctgtt ggtgaaaacg ttccagatga cttgtacatt 840
aagggttctg gttctactgc taacttggct tcttctaact actttccaac tccatctggt 900
tctatggtta cttctgacgc tcaaattttc aacaagccat actggttgca aagagcacaa 960
ggtcataaca acggtatttg ttggggtaac caattgttcg ttactgttgt tgacactact 1020
agatccacta acatgtcctt gtgtgctgct atttctactt ctgaaactac ttacaagaac 1080
actaacttca aagagtactt gagacacgga gaagaatacg acttgcaatt cattttccaa 1140
ttgtgtaaga ttactttgac tgctgacgtt atgacttaca ttcactctat gaactctact 1200
attttggaag attggaactt cggattgcaa ccaccaccag gtggtacttt ggaagatact 1260
tacagattcg ttacttctca agctattgct tgtcaaaagc atactccacc tgctccaaaa 1320
gaagatccat tgaagaagta cactttctgg gaagttaact tgaaagaaaa gttctctgct 1380
gatttggatc aattcccatt gggtagaaag tttttgttgc aagctggatt gaaggctaaa 1440
ccaaagttca ctttgggaaa gagaaaggct actccaacta cttcttctac ttctactact 1500
gctaagagaa agaagagaaa attgttcgtg ttcttggtcc tgttgccatt ggtttcttcc 1560
cagtgtgtta acctgaccac tagaactcaa ttgcctccag cctacaccaa ttccttcacc 1620
agaggtgttt actacccaga caaggtgttc agatcttccg tcttgcactc cactcaggac 1680
ttgttcttgc cattcttctc caacgttacc tggttccacg ctattcacgt ttccggaact 1740
aacggtacta agagattcga caacccagtc ctgccattca acgatggtgt ctacttcgct 1800
tctaccgaga agtccaacat catcagaggt tggatcttcg gtactaccct ggactctaag 1860
actcagtcct tgctgatcgt taacaacgcc accaacgttg tcatcaaggt ttgcgagttc 1920
cagttctgca acgacccatt cttgggtgtg tactaccaca agaacaacaa gtcttggatg 1980
gaatccgagt tcagagttta ctcctccgcc aacaactgta ccttcgagta cgtttcccag 2040
ccattcttga tggacttgga gggtaagcag ggtaacttca agaacctgag agagttcgtt 2100
ttcaagaaca tcgacggtta cttcaagatc tactccaagc acaccccaat caacctggtt 2160
agagatttgc cacaaggttt ctccgctttg gagcctttgg ttgacttgcc aatcggtatc 2220
aacatcacca gattccagac cttgttggcc ttgcacagat cctacttgac tccaggtgat 2280
tcttcttccg gttggactgc tggtgctgct gcttactatg ttggttactt gcagccaaga 2340
accttcctgc tgaagtacaa cgagaacgga actatcactg acgctgttga ctgtgctttg 2400
gacccattgt ctgagactaa gtgcaccttg aagtccttca ccgttgagaa gggtatctac 2460
cagacctcca acttcagagt tcagccaact gagtccatcg tcagattccc aaacatcact 2520
aacttgtgcc cattcggtga ggtgttcaac gctactagat tcgcttctgt ttacgcctgg 2580
aacagaaaga gaatctccaa ctgcgttgct gactactccg tcttgtacaa ctctgcttca 2640
ttctccacct tcaagtgcta cggtgtttcc ccaactaagt tgaacgacct gtgtttcact 2700
aacgtctacg ccgactcctt cgttattaga ggtgacgagg ttagacagat cgctccaggt 2760
caaactggta agatcgctga ctacaactac aagctgccag acgacttcac cggttgtgtt 2820
attgcttgga actccaacaa cctggactcc aaggttggtg gtaactacaa ttacctgtac 2880
cgtctgttca gaaagtccaa cttgaagcca ttcgagagag acatctccac cgagatctac 2940
caagctggtt ctactccatg taacggtgtc gagggtttca actgctactt cccattgcaa 3000
tcctacggtt tccaacctac caacggtgtt ggataccagc catacagagt tgtcgttttg 3060
tccttcgagt tgttgcacgc tccagctact gtttgtggtc caaagaagtc caccaacttg 3120
gtcaagaaca aatgcgtcaa ctttaacttc aacggcctga ccggtactgg tgttttgact 3180
gaatccaaca agaagttcct gcctttccag cagttcggta gagacattgc tgacactact 3240
gacgccgtta gagatccaca gactttggag atcttggaca tcaccccatg ttccttcggt 3300
ggtgtttccg ttattacccc tggaactaac acctccaatc aggtcgctgt cttgtaccag 3360
gacgttaact gtactgaggt tccagttgct atccacgctg accaattgac tccaacttgg 3420
agagtctact ccaccggttc caacgttttc caaactagag ccggttgttt gatcggtgct 3480
gaacacgtca acaactccta cgagtgtgac attccaattg gtgctggtat ctgtgcctcc 3540
taccaaactc aaactaactc cccaagaagg gctagatccg ttgcttccca atccattatc 3600
gcttacacca tgtctttggg tgccgagaac tctgttgcct actctaacaa ctctatcgct 3660
atccctacca acttcaccat ctccgttacc actgagatct tgccagtctc catgaccaag 3720
acttccgttg actgtaccat gtacatctgt ggtgactcca ctgagtgttc caacttgttg 3780
ctgcaatacg gttccttctg cacccagttg aacagagctt tgactggtat tgctgtcgag 3840
caagacaaga acactcaaga ggttttcgcc caggtgaagc agatctacaa gactccacct 3900
attaaggact tcggtggctt caacttctcc cagattttgc cagatccatc taagccctcc 3960
aagagatcct tcattgagga cctgctgttc aacaaggtta ctttggctga cgccggtttc 4020
atcaagcagt acggtgattg cttgggtgac attgcagcta gagacttgat ctgtgcccag 4080
aagttcaacg gtttgaccgt tttgccacct ttgttgaccg acgagatgat cgctcagtac 4140
acttctgctt tgttggccgg tactatcact tctggttgga catttggagc tggtgccgca 4200
ttgcaaattc cattcgctat gcaaatggcc tacagattca acggtatcgg tgttacccag 4260
aacgtcctgt acgagaacca gaagcttatc gccaaccagt tcaactccgc tatcggtaag 4320
attcaggact ccttgtcctc tactgcttct gccttgggaa agttgcagga tgttgttaac 4380
cagaatgccc aggctttgaa caccctggtt aagcaactgt cctctaactt cggtgctatc 4440
tcctccgttt tgaacgacat cttgtcccgt ttggacaagg ttgaggctga ggttcagatc 4500
gacagattga tcactggtag attgcagtcc ctgcagactt acgttactca gcagttgatt 4560
agagctgccg agattagagc ctctgctaac ttggctgcta ctaagatgtc cgagtgtgtt 4620
ttgggtcagt ccaagagagt tgacttctgc ggtaagggtt accacctgat gtctttccca 4680
caatctgctc cacacggtgt cgttttcttg cacgttactt acgttccagc tcaagagaag 4740
aacttcacta ctgctccagc catttgtcac gatggtaagg ctcactttcc tcgtgagggt 4800
gttttcgttt ccaacggtac tcactggttc gtcacccaga gaaactttta cgagccacag 4860
atcatcacca ccgacaacac tttcgtttct ggtaactgtg acgtcgtcat cggtatcgtg 4920
aacaacactg tctacgatcc attgcagcca gaattggact ccttcaaaga ggaactggac 4980
aagtacttta agaaccacac ttccccagac gttgacctgg gtgatatttc cggtattaac 5040
gcctccgttg tcaacatcca aaaagagatc gaccgtttga acgaggtcgc caagaacttg 5100
aacgagtcct tgattgactt gcaagagctg ggcaagtacg agcagtacat taagtggcca 5160
tggtacattt ggctgggttt cattgctggt ttgatcgcca tcgttatggt caccatcatg 5220
ttgtgctgta tgacctcctg ttgctcctgt ttgaagggtt gttgttcctg cggttcctgt 5280
tgtaagttcg acgaagatga ctccgagcca gtcttgaagg gtgttaagtt gcactacact 5340
taagcggccg c 5351
<210> 7
<211> 3836
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(3836)
<223> SARS-CoV-2刺突蛋白核酸序列-针对在人中表达优化的
<400> 7
gctagcgaca tgttcgtgtt tctggtgctg ctgcctctgg tgtccagcca gtgtgtgaac 60
ctgaccacca gaacacagct gcctccagcc tacaccaata gcttcaccag gggcgtgtac 120
taccccgaca aggtgttcag atctagcgtg ctgcacagca cccaggacct gtttctgccc 180
ttcttcagca acgtgacctg gttccacgcc atccacgtgt ccggcaccaa tggcaccaag 240
agattcgaca accccgtgct gcccttcaac gatggggtgt actttgccag caccgagaag 300
tccaacatca tcagaggctg gatcttcggc accacactgg acagcaagac ccagagcctg 360
ctgatcgtga acaacgccac caacgtggtc atcaaagtgt gcgagttcca gttctgcaac 420
gacccattcc tgggagtcta ctaccacaag aacaacaaga gctggatgga aagcgagttc 480
cgggtgtaca gcagcgccaa caactgcacc ttcgagtacg tgtcccagcc tttcctgatg 540
gacctggaag gcaagcaggg caacttcaag aacctgcgcg agttcgtgtt caagaacatc 600
gacggctact tcaagatcta cagcaagcac acccctatca acctcgtgcg ggatctgcct 660
cagggctttt ctgctctgga acctctggtg gacctgccta tcggcatcaa catcacccgg 720
tttcagaccc tgctggccct gcacagatct tacctgacac ctggcgatag cagctctgga 780
tggacagctg gcgccgctgc ctattatgtg ggctacctgc agcctcggac cttcctgctg 840
aagtacaacg agaacggcac catcaccgac gccgtggatt gtgctctgga tcccctgagc 900
gagacaaagt gcaccctgaa gtccttcacc gtggaaaagg gcatctacca gaccagcaac 960
ttcagagtgc agcccaccga gagcatcgtg cggttcccca atatcaccaa tctgtgcccc 1020
ttcggcgagg tgttcaatgc cacaagattt gccagcgtgt acgcctggaa ccggaagaga 1080
atcagcaact gcgtggccga ctacagcgtg ctgtacaata gcgccagctt cagcaccttc 1140
aagtgctacg gcgtgtcccc taccaagctg aacgacctgt gcttcaccaa tgtgtacgcc 1200
gacagcttcg tgatcagagg cgacgaagtt cggcagatcg ctcctggaca gacaggcaag 1260
atcgccgatt acaactacaa gctgcccgac gacttcaccg gctgcgtgat cgcctggaat 1320
agcaacaacc tggactccaa agtcggcggc aactacaact acctgtaccg gctgttccgg 1380
aagtccaatc tgaagccctt cgagcgggac atctccaccg aaatctatca ggccggcagc 1440
accccttgta acggcgtgga aggcttcaac tgctacttcc cactgcagtc ctacggcttt 1500
cagcctacca atggcgtggg ctatcagccc tatagagtgg tggtgctgag cttcgaactg 1560
ctgcatgccc ctgctaccgt gtgcggccct aagaagtcta ccaacctggt caagaacaaa 1620
tgcgtgaact tcaacttcaa cggcctgacc ggcacaggcg tgctgacaga gagcaacaag 1680
aagttcctgc ctttccagca gtttggccgg gatatcgccg ataccacaga cgccgttaga 1740
gatccccaga cactggaaat cctggacatc accccatgca gctttggcgg agtgtctgtg 1800
atcacccctg gcaccaatac cagcaatcag gtggccgtgc tgtatcagga cgtgaactgt 1860
acagaggtgc ccgtggccat tcacgccgat caactgacac ccacttggag agtgtactcc 1920
accggctcca acgtgttcca gactagagcc ggatgtctga tcggagccga gcacgtgaac 1980
aatagctacg agtgcgacat ccccatcggc gctggcatct gtgccagcta ccagacacag 2040
acaaatagcc ccagacgggc cagaagcgtg gcctctcaga gcatcattgc ctacacaatg 2100
agcctgggcg ccgagaattc tgtggcctac agcaacaact ctatcgctat ccccaccaac 2160
ttcaccatca gcgtgaccac cgagatcctg cctgtgtcca tgaccaagac cagcgtggac 2220
tgcaccatgt acatctgcgg cgattccacc gagtgcagca acctgctgct gcagtacggc 2280
agcttctgca cccagctgaa tagagccctg acagggatcg ccgtggaaca ggacaagaac 2340
acccaagagg tgttcgccca agtgaagcag atctacaaga cccctcctat caaggacttc 2400
ggcggcttca atttcagcca gattctgccc gatcctagca agcccagcaa gcggagcttt 2460
atcgaggacc tgctgttcaa caaagtgaca ctggccgacg ccggcttcat caagcagtat 2520
ggcgattgcc tgggcgacat tgccgccaga gatctgattt gcgcccagaa gtttaacgga 2580
ctgacagtgc tgcctcctct gctgaccgat gagatgatcg cccagtacac atctgctctg 2640
ctggccggca caatcaccag cggatggaca tttggagctg gcgcagccct gcagatcccc 2700
tttgctatgc agatggccta ccggttcaac ggcatcggag tgacccagaa tgtgctgtac 2760
gagaaccaga agctgatcgc caaccagttc aacagcgcca tcggcaagat ccaggatagc 2820
ctgtctagca cagccagcgc tctgggcaaa ctgcaggacg tggtcaatca gaacgctcag 2880
gccctgaaca ccctcgtgaa gcagctgagc agcaatttcg gcgccatcag ctccgtgctg 2940
aacgatatcc tgagccggct ggataaggtg gaagccgagg tgcagatcga cagactgatc 3000
acaggcagac tgcagagcct ccagacatac gtgacccagc agctgatcag agccgccgag 3060
attagagcct ctgccaatct ggccgccacc aagatgtctg agtgtgtgct gggccagagc 3120
aagagagtgg atttctgcgg caagggctac cacctgatga gctttccaca gtctgctcct 3180
cacggcgtgg tgtttctgca cgtgacctat gtgcccgctc aagagaagaa cttcacaaca 3240
gcccctgcca tctgccacga cggaaaggcc cattttccta gagaaggcgt gttcgtgtcc 3300
aacggcaccc attggttcgt gacacagcgg aacttctacg agccccagat catcaccacc 3360
gacaacacct tcgtgtctgg caactgtgac gtcgtgatcg gcattgtgaa caacaccgtg 3420
tacgaccctc tgcagcccga gctggacagc ttcaaagagg aactggacaa gtactttaag 3480
aaccacacaa gccccgacgt ggacctgggc gatattagcg gcatcaatgc ctccgtggtc 3540
aacatccaga aagagatcga ccggctgaac gaggtggcca agaatctgaa cgagagcctg 3600
atcgacctgc aagaactggg gaagtacgag cagtacatca agtggccctg gtacatctgg 3660
ctgggcttta tcgccggact gattgccatc gtgatggtca caatcatgct gtgctgcatg 3720
accagctgct gtagctgcct gaagggctgt tgcagctgtg gcagctgctg caagttcgac 3780
gaggatgata gcgagcctgt gctgaagggc gtgaaactgc actacaccgc ggccgc 3836
<210> 8
<211> 4232
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(4232)
<223> 编码融合蛋白HBSAg/SARS-CoV-2刺突蛋白的核酸-针对在人中表达优化的
<400> 8
gctagcgaca tgaactttct gggcggtacg acagtatgcc ttggacaaaa ttcacaatct 60
ccgacgtcta atcactcccc tacaagttgt ccaccgactt gccccggcta taggtggatg 120
tgtctcagac gattcataat ctttctcttc attcttcttc tgtgcctgat attcttgctg 180
gtccttctgg attaccaggg aatgcttccc gtgtgtcctc tgattcctgg ttcatccact 240
acatctacgg gtccctgtag aacatgcacc acacctgcac agggcacctc catgtatccg 300
tcatgctgct gcacgaaacc atcagatggt aactgcacgt gcataccgat cccctcatca 360
tgggcgtttg ggaaatttct gtgggagtgg gcctcagccc ggttttcctt cgtgtttctg 420
gtgctgctgc ctctggtgtc cagccagtgt gtgaacctga ccaccagaac acagctgcct 480
ccagcctaca ccaatagctt caccaggggc gtgtactacc ccgacaaggt gttcagatct 540
agcgtgctgc acagcaccca ggacctgttt ctgcccttct tcagcaacgt gacctggttc 600
cacgccatcc acgtgtccgg caccaatggc accaagagat tcgacaaccc cgtgctgccc 660
ttcaacgatg gggtgtactt tgccagcacc gagaagtcca acatcatcag aggctggatc 720
ttcggcacca cactggacag caagacccag agcctgctga tcgtgaacaa cgccaccaac 780
gtggtcatca aagtgtgcga gttccagttc tgcaacgacc cattcctggg agtctactac 840
cacaagaaca acaagagctg gatggaaagc gagttccggg tgtacagcag cgccaacaac 900
tgcaccttcg agtacgtgtc ccagcctttc ctgatggacc tggaaggcaa gcagggcaac 960
ttcaagaacc tgcgcgagtt cgtgttcaag aacatcgacg gctacttcaa gatctacagc 1020
aagcacaccc ctatcaacct cgtgcgggat ctgcctcagg gcttttctgc tctggaacct 1080
ctggtggacc tgcctatcgg catcaacatc acccggtttc agaccctgct ggccctgcac 1140
agatcttacc tgacacctgg cgatagcagc tctggatgga cagctggcgc cgctgcctat 1200
tatgtgggct acctgcagcc tcggaccttc ctgctgaagt acaacgagaa cggcaccatc 1260
accgacgccg tggattgtgc tctggatccc ctgagcgaga caaagtgcac cctgaagtcc 1320
ttcaccgtgg aaaagggcat ctaccagacc agcaacttca gagtgcagcc caccgagagc 1380
atcgtgcggt tccccaatat caccaatctg tgccccttcg gcgaggtgtt caatgccaca 1440
agatttgcca gcgtgtacgc ctggaaccgg aagagaatca gcaactgcgt ggccgactac 1500
agcgtgctgt acaatagcgc cagcttcagc accttcaagt gctacggcgt gtcccctacc 1560
aagctgaacg acctgtgctt caccaatgtg tacgccgaca gcttcgtgat cagaggcgac 1620
gaagttcggc agatcgctcc tggacagaca ggcaagatcg ccgattacaa ctacaagctg 1680
cccgacgact tcaccggctg cgtgatcgcc tggaatagca acaacctgga ctccaaagtc 1740
ggcggcaact acaactacct gtaccggctg ttccggaagt ccaatctgaa gcccttcgag 1800
cgggacatct ccaccgaaat ctatcaggcc ggcagcaccc cttgtaacgg cgtggaaggc 1860
ttcaactgct acttcccact gcagtcctac ggctttcagc ctaccaatgg cgtgggctat 1920
cagccctata gagtggtggt gctgagcttc gaactgctgc atgcccctgc taccgtgtgc 1980
ggccctaaga agtctaccaa cctggtcaag aacaaatgcg tgaacttcaa cttcaacggc 2040
ctgaccggca caggcgtgct gacagagagc aacaagaagt tcctgccttt ccagcagttt 2100
ggccgggata tcgccgatac cacagacgcc gttagagatc cccagacact ggaaatcctg 2160
gacatcaccc catgcagctt tggcggagtg tctgtgatca cccctggcac caataccagc 2220
aatcaggtgg ccgtgctgta tcaggacgtg aactgtacag aggtgcccgt ggccattcac 2280
gccgatcaac tgacacccac ttggagagtg tactccaccg gctccaacgt gttccagact 2340
agagccggat gtctgatcgg agccgagcac gtgaacaata gctacgagtg cgacatcccc 2400
atcggcgctg gcatctgtgc cagctaccag acacagacaa atagccccag acgggccaga 2460
agcgtggcct ctcagagcat cattgcctac acaatgagcc tgggcgccga gaattctgtg 2520
gcctacagca acaactctat cgctatcccc accaacttca ccatcagcgt gaccaccgag 2580
atcctgcctg tgtccatgac caagaccagc gtggactgca ccatgtacat ctgcggcgat 2640
tccaccgagt gcagcaacct gctgctgcag tacggcagct tctgcaccca gctgaataga 2700
gccctgacag ggatcgccgt ggaacaggac aagaacaccc aagaggtgtt cgcccaagtg 2760
aagcagatct acaagacccc tcctatcaag gacttcggcg gcttcaattt cagccagatt 2820
ctgcccgatc ctagcaagcc cagcaagcgg agctttatcg aggacctgct gttcaacaaa 2880
gtgacactgg ccgacgccgg cttcatcaag cagtatggcg attgcctggg cgacattgcc 2940
gccagagatc tgatttgcgc ccagaagttt aacggactga cagtgctgcc tcctctgctg 3000
accgatgaga tgatcgccca gtacacatct gctctgctgg ccggcacaat caccagcgga 3060
tggacatttg gagctggcgc agccctgcag atcccctttg ctatgcagat ggcctaccgg 3120
ttcaacggca tcggagtgac ccagaatgtg ctgtacgaga accagaagct gatcgccaac 3180
cagttcaaca gcgccatcgg caagatccag gatagcctgt ctagcacagc cagcgctctg 3240
ggcaaactgc aggacgtggt caatcagaac gctcaggccc tgaacaccct cgtgaagcag 3300
ctgagcagca atttcggcgc catcagctcc gtgctgaacg atatcctgag ccggctggat 3360
aaggtggaag ccgaggtgca gatcgacaga ctgatcacag gcagactgca gagcctccag 3420
acatacgtga cccagcagct gatcagagcc gccgagatta gagcctctgc caatctggcc 3480
gccaccaaga tgtctgagtg tgtgctgggc cagagcaaga gagtggattt ctgcggcaag 3540
ggctaccacc tgatgagctt tccacagtct gctcctcacg gcgtggtgtt tctgcacgtg 3600
acctatgtgc ccgctcaaga gaagaacttc acaacagccc ctgccatctg ccacgacgga 3660
aaggcccatt ttcctagaga aggcgtgttc gtgtccaacg gcacccattg gttcgtgaca 3720
cagcggaact tctacgagcc ccagatcatc accaccgaca acaccttcgt gtctggcaac 3780
tgtgacgtcg tgatcggcat tgtgaacaac accgtgtacg accctctgca gcccgagctg 3840
gacagcttca aagaggaact ggacaagtac tttaagaacc acacaagccc cgacgtggac 3900
ctgggcgata ttagcggcat caatgcctcc gtggtcaaca tccagaaaga gatcgaccgg 3960
ctgaacgagg tggccaagaa tctgaacgag agcctgatcg acctgcaaga actggggaag 4020
tacgagcagt acatcaagtg gccctggtac atctggctgg gctttatcgc cggactgatt 4080
gccatcgtga tggtcacaat catgctgtgc tgcatgacca gctgctgtag ctgcctgaag 4140
ggctgttgca gctgtggcag ctgctgcaag ttcgacgagg atgatagcga gcctgtgctg 4200
aagggcgtga aactgcacta caccgcggcc gc 4232
<210> 9
<211> 1512
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(1512)
<223> 融合蛋白HEV-SARS-CoV-2刺突蛋白
<400> 9
Met Ile Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly
1 5 10 15
Leu Pro Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser
20 25 30
Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr
35 40 45
Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp
50 55 60
Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln
65 70 75 80
His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe
85 90 95
Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala
100 105 110
Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val
115 120 125
Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val
130 135 140
Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu
145 150 155 160
Ser Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg
165 170 175
Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro
180 185 190
Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala
195 200 205
Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala
210 215 220
Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Ala
225 230 235 240
Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val Asn
245 250 255
Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe Thr
260 265 270
Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu His
275 280 285
Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp Phe
290 295 300
His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn
305 310 315 320
Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys
325 330 335
Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys
340 345 350
Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys
355 360 365
Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr Tyr
370 375 380
His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser
385 390 395 400
Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met
405 410 415
Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val
420 425 430
Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro
435 440 445
Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro
450 455 460
Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu
465 470 475 480
Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly
485 490 495
Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg
500 505 510
Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val
515 520 525
Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser
530 535 540
Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln
545 550 555 560
Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro
565 570 575
Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp
580 585 590
Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr
595 600 605
Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr
610 615 620
Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val
625 630 635 640
Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys
645 650 655
Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val
660 665 670
Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr
675 680 685
Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu
690 695 700
Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn
705 710 715 720
Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe
725 730 735
Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu
740 745 750
Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys
755 760 765
Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly
770 775 780
Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro
785 790 795 800
Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg
805 810 815
Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly
820 825 830
Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala
835 840 845
Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile His
850 855 860
Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn
865 870 875 880
Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn
885 890 895
Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser
900 905 910
Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala Ser
915 920 925
Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val
930 935 940
Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser
945 950 955 960
Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp
965 970 975
Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu
980 985 990
Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly
995 1000 1005
Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val
1010 1015 1020
Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn
1025 1030 1035 1040
Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe
1045 1050 1055
Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe
1060 1065 1070
Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu
1075 1080 1085
Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu
1090 1095 1100
Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr
1105 1110 1115 1120
Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro
1125 1130 1135
Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln
1140 1145 1150
Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser
1155 1160 1165
Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu
1170 1175 1180
Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr
1185 1190 1195 1200
Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu
1205 1210 1215
Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln Ile
1220 1225 1230
Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr
1235 1240 1245
Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala
1250 1255 1260
Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp
1265 1270 1275 1280
Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro
1285 1290 1295
His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys
1300 1305 1310
Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe
1315 1320 1325
Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val Thr
1330 1335 1340
Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe
1345 1350 1355 1360
Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr Val
1365 1370 1375
Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp
1380 1385 1390
Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile
1395 1400 1405
Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg
1410 1415 1420
Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln
1425 1430 1435 1440
Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp
1445 1450 1455
Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1460 1465 1470
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser
1475 1480 1485
Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu
1490 1495 1500
Lys Gly Val Lys Leu His Tyr Thr
1505 1510
<210> 10
<211> 1779
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(1779)
<223> 融合蛋白HPV18L1/SARS-CoV-2刺突蛋白
<400> 10
Met Ala Leu Trp Arg Pro Ser Asp Asn Thr Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Thr Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly Asn Pro
35 40 45
Tyr Phe Arg Val Pro Ala Gly Gly Gly Asn Lys Gln Asp Ile Pro Lys
50 55 60
Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Gln Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Leu Pro Asp Thr Ser Ile Tyr Asn Pro Glu Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Ala Gly Val Glu Ile Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu Asp Asp
115 120 125
Thr Glu Ser Ser His Ala Ala Thr Ser Asn Val Ser Glu Asp Val Arg
130 135 140
Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Leu Gly
145 150 155 160
Cys Ala Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Ala Cys Lys
165 170 175
Ser Arg Pro Leu Ser Gln Gly Asp Cys Pro Pro Leu Glu Leu Lys Asn
180 185 190
Thr Val Leu Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly Ala Met
195 200 205
Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu Asp Ile
210 215 220
Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp
225 230 235 240
Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu Phe
245 250 255
Ala Arg His Phe Trp Asn Arg Ala Gly Thr Met Gly Asp Thr Val Pro
260 265 270
Gln Ser Leu Tyr Ile Lys Gly Thr Gly Met Arg Ala Ser Pro Gly Ser
275 280 285
Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Val Thr Ser Asp Ser
290 295 300
Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn
305 310 315 320
Asn Gly Val Cys Trp His Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Cys Ala Ser Thr Gln Ser Pro Val
340 345 350
Pro Gly Gln Tyr Asp Ala Thr Lys Phe Lys Gln Tyr Ser Arg His Val
355 360 365
Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Ile Thr Leu
370 375 380
Thr Ala Asp Val Met Ser Tyr Ile His Ser Met Asn Ser Ser Ile Leu
385 390 395 400
Glu Asp Trp Asn Phe Gly Val Pro Pro Pro Pro Thr Thr Ser Leu Val
405 410 415
Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Ile Thr Cys Gln Lys Asp
420 425 430
Ala Ala Pro Ala Glu Asn Lys Asp Pro Tyr Asp Lys Leu Lys Phe Trp
435 440 445
Asn Val Asp Leu Lys Glu Lys Phe Ser Leu Asp Leu Asp Gln Tyr Pro
450 455 460
Leu Gly Arg Lys Phe Leu Val Gln Ala Gly Leu Arg Arg Lys Pro Thr
465 470 475 480
Ile Gly Pro Arg Lys Arg Ser Ala Pro Ser Ala Thr Thr Ser Ser Lys
485 490 495
Pro Ala Lys Arg Val Arg Val Arg Ala Arg Lys Phe Val Phe Leu Val
500 505 510
Leu Leu Pro Leu Val Ser Ser Gln Cys Val Asn Leu Thr Thr Arg Thr
515 520 525
Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr
530 535 540
Pro Asp Lys Val Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu
545 550 555 560
Phe Leu Pro Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val
565 570 575
Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe
580 585 590
Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg
595 600 605
Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu
610 615 620
Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln
625 630 635 640
Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys
645 650 655
Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys
660 665 670
Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys
675 680 685
Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp
690 695 700
Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg
705 710 715 720
Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro
725 730 735
Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg
740 745 750
Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala
755 760 765
Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys
770 775 780
Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp
785 790 795 800
Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys
805 810 815
Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile
820 825 830
Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe
835 840 845
Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile
850 855 860
Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe
865 870 875 880
Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu
885 890 895
Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu
900 905 910
Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn
915 920 925
Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser
930 935 940
Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg
945 950 955 960
Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr
965 970 975
Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe
980 985 990
Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly
995 1000 1005
Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
1010 1015 1020
His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val
1025 1030 1035 1040
Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly
1045 1050 1055
Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly
1060 1065 1070
Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu
1075 1080 1085
Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile
1090 1095 1100
Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp
1105 1110 1115 1120
Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr
1125 1130 1135
Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg
1140 1145 1150
Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys
1155 1160 1165
Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr
1170 1175 1180
Asn Ser Pro Arg Arg Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala
1185 1190 1195 1200
Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn
1205 1210 1215
Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile
1220 1225 1230
Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile
1235 1240 1245
Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser
1250 1255 1260
Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln
1265 1270 1275 1280
Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys
1285 1290 1295
Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu
1300 1305 1310
Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu
1315 1320 1325
Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly
1330 1335 1340
Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys
1345 1350 1355 1360
Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile
1365 1370 1375
Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp
1380 1385 1390
Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met
1395 1400 1405
Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu
1410 1415 1420
Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile
1425 1430 1435 1440
Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp
1445 1450 1455
Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu
1460 1465 1470
Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser
1475 1480 1485
Arg Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr
1490 1495 1500
Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg
1505 1510 1515 1520
Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser
1525 1530 1535
Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly
1540 1545 1550
Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe
1555 1560 1565
Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala
1570 1575 1580
Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val
1585 1590 1595 1600
Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr
1605 1610 1615
Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1620 1625 1630
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln
1635 1640 1645
Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1650 1655 1660
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala
1665 1670 1675 1680
Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala
1685 1690 1695
Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
1700 1705 1710
Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala
1715 1720 1725
Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr
1730 1735 1740
Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys
1745 1750 1755 1760
Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu
1765 1770 1775
His Tyr Thr
<210> 11
<211> 1777
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(1777)
<223> 融合蛋白HPV16L1/SARS-CoV-2刺突蛋白
<400> 11
Met Ser Leu Trp Leu Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ala Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Thr Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Phe Pro Ile Lys Lys Pro Asn Asn Asn Lys Ile Leu Val Pro Lys
50 55 60
Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Ile His Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp
115 120 125
Thr Glu Asn Ala Ser Ala Tyr Ala Ala Asn Ala Gly Val Asp Asn Arg
130 135 140
Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly
145 150 155 160
Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys Thr
165 170 175
Asn Val Ala Val Asn Pro Gly Asp Cys Pro Pro Leu Glu Leu Ile Asn
180 185 190
Thr Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met
195 200 205
Asp Phe Thr Thr Leu Gln Ala Asn Lys Ser Glu Val Pro Leu Asp Ile
210 215 220
Cys Thr Ser Ile Cys Lys Tyr Pro Asp Tyr Ile Lys Met Val Ser Glu
225 230 235 240
Pro Tyr Gly Asp Ser Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Leu Phe Asn Arg Ala Gly Ala Val Gly Glu Asn Val Pro
260 265 270
Asp Asp Leu Tyr Ile Lys Gly Ser Gly Ser Thr Ala Asn Leu Ala Ser
275 280 285
Ser Asn Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala
290 295 300
Gln Ile Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Met Ser Leu Cys Ala Ala Ile Ser Thr Ser Glu
340 345 350
Thr Thr Tyr Lys Asn Thr Asn Phe Lys Glu Tyr Leu Arg His Gly Glu
355 360 365
Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr
370 375 380
Ala Asp Val Met Thr Tyr Ile His Ser Met Asn Ser Thr Ile Leu Glu
385 390 395 400
Asp Trp Asn Phe Gly Leu Gln Pro Pro Pro Gly Gly Thr Leu Glu Asp
405 410 415
Thr Tyr Arg Phe Val Thr Ser Gln Ala Ile Ala Cys Gln Lys His Thr
420 425 430
Pro Pro Ala Pro Lys Glu Asp Pro Leu Lys Lys Tyr Thr Phe Trp Glu
435 440 445
Val Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Phe
465 470 475 480
Thr Leu Gly Lys Arg Lys Ala Thr Pro Thr Thr Ser Ser Thr Ser Thr
485 490 495
Thr Ala Lys Arg Lys Lys Arg Lys Leu Phe Val Phe Leu Val Leu Leu
500 505 510
Pro Leu Val Ser Ser Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu
515 520 525
Pro Pro Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp
530 535 540
Lys Val Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu
545 550 555 560
Pro Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly
565 570 575
Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp
580 585 590
Gly Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp
595 600 605
Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val
610 615 620
Asn Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys
625 630 635 640
Asn Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp
645 650 655
Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe
660 665 670
Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly
675 680 685
Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr
690 695 700
Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu
705 710 715 720
Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly
725 730 735
Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr
740 745 750
Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala
755 760 765
Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn
770 775 780
Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu
785 790 795 800
Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile
805 810 815
Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg
820 825 830
Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala
835 840 845
Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn
850 855 860
Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr
865 870 875 880
Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe
885 890 895
Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg
900 905 910
Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys
915 920 925
Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn
930 935 940
Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
945 950 955 960
Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
965 970 975
Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys
980 985 990
Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly
995 1000 1005
Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala
1010 1015 1020
Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn
1025 1030 1035 1040
Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu
1045 1050 1055
Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp
1060 1065 1070
Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile
1075 1080 1085
Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro
1090 1095 1100
Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn
1105 1110 1115 1120
Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr
1125 1130 1135
Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly
1140 1145 1150
Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile
1155 1160 1165
Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser
1170 1175 1180
Pro Arg Arg Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr
1185 1190 1195 1200
Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile
1205 1210 1215
Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro
1220 1225 1230
Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly
1235 1240 1245
Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys
1250 1255 1260
Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys
1265 1270 1275 1280
Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro
1285 1290 1295
Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp
1300 1305 1310
Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn
1315 1320 1325
Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys
1330 1335 1340
Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn
1345 1350 1355 1360
Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln
1365 1370 1375
Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe
1380 1385 1390
Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr
1395 1400 1405
Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln
1410 1415 1420
Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp
1425 1430 1435 1440
Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val
1445 1450 1455
Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser
1460 1465 1470
Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu
1475 1480 1485
Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg
1490 1495 1500
Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala
1505 1510 1515 1520
Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys
1525 1530 1535
Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His
1540 1545 1550
Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His
1555 1560 1565
Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala
1570 1575 1580
Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val
1585 1590 1595 1600
Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro
1605 1610 1615
Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1620 1625 1630
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu
1635 1640 1645
Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr
1650 1655 1660
Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val
1665 1670 1675 1680
Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn
1685 1690 1695
Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln
1700 1705 1710
Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu
1715 1720 1725
Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys
1730 1735 1740
Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe
1745 1750 1755 1760
Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr
1765 1770 1775
Thr
<210> 12
<211> 1407
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(1407)
<223> 融合蛋白HBSAg/SARS-CoV-2刺突蛋白
<400> 12
Met Asn Phe Leu Gly Gly Thr Thr Val Cys Leu Gly Gln Asn Ser Gln
1 5 10 15
Ser Pro Thr Ser Asn His Ser Pro Thr Ser Cys Pro Pro Thr Cys Pro
20 25 30
Gly Tyr Arg Trp Met Cys Leu Arg Arg Phe Ile Ile Phe Leu Phe Ile
35 40 45
Leu Leu Leu Cys Leu Ile Phe Leu Leu Val Leu Leu Asp Tyr Gln Gly
50 55 60
Met Leu Pro Val Cys Pro Leu Ile Pro Gly Ser Ser Thr Thr Ser Thr
65 70 75 80
Gly Pro Cys Arg Thr Cys Thr Thr Pro Ala Gln Gly Thr Ser Met Tyr
85 90 95
Pro Ser Cys Cys Cys Thr Lys Pro Ser Asp Gly Asn Cys Thr Cys Ile
100 105 110
Pro Ile Pro Ser Ser Trp Ala Phe Gly Lys Phe Leu Trp Glu Trp Ala
115 120 125
Ser Ala Arg Phe Ser Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser
130 135 140
Ser Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr
145 150 155 160
Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg
165 170 175
Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser
180 185 190
Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr
195 200 205
Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe
210 215 220
Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr
225 230 235 240
Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr
245 250 255
Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe
260 265 270
Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu
275 280 285
Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser
290 295 300
Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn
305 310 315 320
Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr
325 330 335
Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe
340 345 350
Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr
355 360 365
Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly
370 375 380
Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly
385 390 395 400
Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr
405 410 415
Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys
420 425 430
Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser
435 440 445
Asn Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile
450 455 460
Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala
465 470 475 480
Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp
485 490 495
Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr
500 505 510
Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr
515 520 525
Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro
530 535 540
Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp
545 550 555 560
Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys
565 570 575
Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn
580 585 590
Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly
595 600 605
Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu
610 615 620
Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr
625 630 635 640
Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val
645 650 655
Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn
660 665 670
Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn
675 680 685
Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr
690 695 700
Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr
705 710 715 720
Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr
725 730 735
Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val
740 745 750
Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr
755 760 765
Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly
770 775 780
Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala
785 790 795 800
Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala
805 810 815
Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly
820 825 830
Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr
835 840 845
Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr
850 855 860
Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu
865 870 875 880
Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn
885 890 895
Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu
900 905 910
Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp
915 920 925
Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro
930 935 940
Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu
945 950 955 960
Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile
965 970 975
Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val
980 985 990
Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala
995 1000 1005
Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala
1010 1015 1020
Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly
1025 1030 1035 1040
Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala
1045 1050 1055
Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser
1060 1065 1070
Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala
1075 1080 1085
Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala
1090 1095 1100
Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu
1105 1110 1115 1120
Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu
1125 1130 1135
Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala
1140 1145 1150
Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln
1155 1160 1165
Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe
1170 1175 1180
Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1185 1190 1195 1200
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp
1205 1210 1215
Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr
1220 1225 1230
His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr
1235 1240 1245
Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile
1250 1255 1260
Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe
1265 1270 1275 1280
Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val
1285 1290 1295
Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln
1300 1305 1310
Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser
1315 1320 1325
Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp
1330 1335 1340
Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val
1345 1350 1355 1360
Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu
1365 1370 1375
Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp
1380 1385 1390
Ser Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr Thr Ala Ala
1395 1400 1405
<210> 13
<211> 665
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(665)
<223> RBD SARS-CoV-2刺突蛋白核酸
<400> 13
gctagcgacg ccaccatgag agtccaacca acagaatcta ttgttagatt tcctaatatt 60
acaaacttgt gcccttttgg tgaagttttt aacgccacca gatttgcatc tgtttatgct 120
tggaacagga agagaatcag caactgtgtt gctgattatt ctgtcctata taattccgca 180
tcattttcca cttttaagtg ttatggagtg tctcctacta aattaaatga tctctgcttt 240
actaatgtct atgcagattc atttgtaatt agaggtgatg aagtcagaca aatcgctcca 300
gggcaaactg gaaagattgc tgattataat tataaattac cagatgattt tacaggctgc 360
gttatagctt ggaattctaa caatcttgat tctaaggttg gtggtaatta taattacctg 420
tatagattgt ttaggaagtc taatctcaaa ccttttgaga gagatatttc aactgaaatc 480
tatcaggccg gtagcacacc ttgtaatggt gttgaaggtt ttaattgtta ctttccttta 540
caatcatatg gtttccaacc cactaatggt gttggttacc aaccatacag agtagtagta 600
ctttcttttg aacttctaca tgcaccagca actgtttgtg gacctaaaaa gtgataagcg 660
gccgc 665
<210> 14
<211> 665
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(665)
<223> RBD SARS-CoV-2刺突蛋白核酸序列-人密码子优化的
<400> 14
gctagcgacg ccaccatgag agtgcagcct acagagtcta tcgtgcggtt ccccaacatc 60
accaatctgt gccctttcgg cgaggtgttc aacgccacaa gatttgccag cgtgtacgcc 120
tggaaccgga agagaatcag caactgcgtg gccgactaca gcgtgctgta caatagcgcc 180
agcttcagca ccttcaagtg ctacggcgtg tcccctacca agctgaacga cctgtgcttc 240
accaatgtgt acgccgacag cttcgtgatc agaggcgacg aagttcggca gatcgctcct 300
ggacagacag gcaagatcgc cgattacaac tacaagctgc ccgacgactt caccggctgc 360
gtgatcgcct ggaatagcaa caacctggac agcaaagtcg gcggcaacta caactacctg 420
taccggctgt tccggaagtc caacctgaag cctttcgagc gggacatcag caccgagatc 480
tatcaggccg gcagcacccc ttgtaatggc gtggaaggct tcaactgcta cttcccactg 540
cagtcctacg gcttccagcc tacaaacggc gtgggctacc agccttatag agtggtggtg 600
ctgagcttcg aactgctgca tgcccctgct acagtgtgcg gccccaagaa gtgataagcg 660
gccgc 665
<210> 15
<211> 212
<212> PRT
<213> SARS-CoV-2
<400> 15
Met Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr
1 5 10 15
Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser
20 25 30
Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr
35 40 45
Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly
50 55 60
Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala
65 70 75 80
Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly
85 90 95
Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe
100 105 110
Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val
115 120 125
Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu
130 135 140
Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser
145 150 155 160
Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln
165 170 175
Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg
180 185 190
Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys
195 200 205
Gly Pro Lys Lys
210
<210> 16
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(7)
<223> EAAAK接头共有序列
<400> 16
Ala Glu Ala Ala Ala Lys Ala
1 5
<210> 17
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(45)
<223> (EAAAK)3接头
<400> 17
gaagccgccg ctaaagaggc cgctgccaaa gaagctgctg ctaag 45
<210> 18
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(15)
<223> (EAAAK)3接头
<400> 18
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
<210> 19
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(5)
<223> GS接头共有序列
<400> 19
Gly Gly Gly Gly Ser
1 5
<210> 20
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(5)
<223> GS5接头
<400> 20
Gly Gly Gly Gly Ser
1 5
<210> 21
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(10)
<223> GS10接头
<400> 21
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 22
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(45)
<223> GS15接头
<400> 22
ggtggtggtg gtagcggtgg tggcggttca ggtggcggtg gttca 45
<210> 23
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(15)
<223> GS15接头
<400> 23
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 24
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(20)
<223> GS20接头
<400> 24
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 25
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(25)
<223> GS25接头
<400> 25
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 26
<211> 1427
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(1427)
<223> HBSAg-(EAAAK)3-RBD
<400> 26
gctagcgacg ccaccatgat tgcactgacc ctgtttaatc tggcagatac cctgttaggt 60
ggtctgccga ccgaactgat tagcagtgcc ggtggtcagc tgttttatag ccgtccggtt 120
gttagcgcaa atggtgaacc gaccgttaaa ctgtatacca gcgttgaaaa tgcacagcag 180
gataaaggta ttgcaattcc gcatgatatt gatctgggtg aaagccgtgt tgtgattcag 240
gattatgata atcagcatga acaggatcgt ccgacaccga gtccggcacc gagccgtccg 300
tttagcgttc tgcgtgcaaa tgatgttctg tggctgagcc tgaccgcagc agaatatgat 360
cagagcacct atggtagcag caccggtccg gtttatgtta gcgatagcgt taccctggtt 420
aatgttgcaa ccggtgcaca ggcagttgca cgtagcctgg attggaccaa agtgaccctg 480
gatggtcgtc cgctgagcac cattcagcag tatagcaaaa ccttttttgt tctgccgctg 540
cgtggtaaac tgagcttttg ggaagcaggc accaccaaag caggttatcc gtataactat 600
aataccaccg caagcgatca gctgctggtt gaaaacgcag caggtcatcg tgttgcaatt 660
agcacctata ccaccagttt aggtgcaggt ccggttagca ttagcgcagt tgcagttctg 720
gcaccgcatt cagccgaagc agccgctaaa gaagcagccg ctaaagaagc agccgctaaa 780
agagtccaac caacagaatc tattgttaga tttcctaata ttacaaactt gtgccctttt 840
ggtgaagttt ttaacgccac cagatttgca tctgtttatg cttggaacag gaagagaatc 900
agcaactgtg ttgctgatta ttctgtccta tataattccg catcattttc cacttttaag 960
tgttatggag tgtctcctac taaattaaat gatctctgct ttactaatgt ctatgcagat 1020
tcatttgtaa ttagaggtga tgaagtcaga caaatcgctc cagggcaaac tggaaagatt 1080
gctgattata attataaatt accagatgat tttacaggct gcgttatagc ttggaattct 1140
aacaatcttg attctaaggt tggtggtaat tataattacc tgtatagatt gtttaggaag 1200
tctaatctca aaccttttga gagagatatt tcaactgaaa tctatcaggc cggtagcaca 1260
ccttgtaatg gtgttgaagg ttttaattgt tactttcctt tacaatcata tggtttccaa 1320
cccactaatg gtgttggtta ccaaccatac agagtagtag tactttcttt tgaacttcta 1380
catgcaccag caactgtttg tggacctaaa aagtgataag cggccgc 1427
<210> 27
<211> 1106
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(1106)
<223> 人密码子优化的HBSAg-(EAAAK)3-RBD核酸序列
<400> 27
gctagcgacg ccaccatgaa ttttctcggc ggcacaacag tgtgcctggg ccagaatagc 60
cagtctccta ccagcaatca cagccccacc agctgtcctc caacctgtcc tggctacaga 120
tggatgtgcc tgcggcggtt catcatcttt ctgttcatcc tgctgctgtg cctgatcttc 180
ctgctggtgc tgctggatta ccagggaatg ctgcctgtgt gtcctctgat ccctggcagc 240
agcacaacaa gcacaggccc ttgcagaacc tgcacaacac cagctcaggg caccagcatg 300
taccctagct gctgttgtac caagcctagc gacggcaact gcacatgcat ccccattcct 360
agcagctggg ccttcggcaa gtttctgtgg gaatgggcca gcgccagatt ttccgaagcc 420
gccgctaaag aggccgctgc caaagaagct gctgctaaga gagtgcagcc caccgagtct 480
atcgtgcggt tccccaacat caccaatctg tgccctttcg gcgaggtgtt caacgccaca 540
agatttgcca gcgtgtacgc ctggaaccgg aagagaatca gcaactgcgt ggccgactac 600
agcgtgctgt acaatagcgc cagcttcagc accttcaagt gctacggcgt gtcccctacc 660
aagctgaacg acctgtgctt caccaatgtg tacgccgaca gcttcgtgat cagaggcgac 720
gaagttcggc agatcgctcc tggacagaca ggcaagatcg ccgattacaa ctacaagctg 780
cccgacgact tcaccggctg cgtgatcgcc tggaatagca acaacctgga cagcaaagtc 840
ggcggcaact acaactacct gtaccggctg ttccggaagt ccaacctgaa gcctttcgag 900
cgggacatca gcaccgaaat ctaccaggcc ggcagcaccc cttgtaatgg cgtggaaggc 960
ttcaactgct acttcccact gcagtcctac ggcttccagc ctacaaacgg cgtgggctac 1020
cagccttata gagtggtggt gctgagcttc gaactgctgc atgcccctgc tacagtgtgc 1080
ggccccaaga agtgataagc ggccgc 1106
<210> 28
<211> 359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(359)
<223> HBSAg-(EAAAK)3-RBD
<400> 28
Met Asn Phe Leu Gly Gly Thr Thr Val Cys Leu Gly Gln Asn Ser Gln
1 5 10 15
Ser Pro Thr Ser Asn His Ser Pro Thr Ser Cys Pro Pro Thr Cys Pro
20 25 30
Gly Tyr Arg Trp Met Cys Leu Arg Arg Phe Ile Ile Phe Leu Phe Ile
35 40 45
Leu Leu Leu Cys Leu Ile Phe Leu Leu Val Leu Leu Asp Tyr Gln Gly
50 55 60
Met Leu Pro Val Cys Pro Leu Ile Pro Gly Ser Ser Thr Thr Ser Thr
65 70 75 80
Gly Pro Cys Arg Thr Cys Thr Thr Pro Ala Gln Gly Thr Ser Met Tyr
85 90 95
Pro Ser Cys Cys Cys Thr Lys Pro Ser Asp Gly Asn Cys Thr Cys Ile
100 105 110
Pro Ile Pro Ser Ser Trp Ala Phe Gly Lys Phe Leu Trp Glu Trp Ala
115 120 125
Ser Ala Arg Phe Ser Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
130 135 140
Ala Ala Ala Lys Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro
145 150 155 160
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg
165 170 175
Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
180 185 190
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys
195 200 205
Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
210 215 220
Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile
225 230 235 240
Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
245 250 255
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp
260 265 270
Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys
275 280 285
Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
290 295 300
Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe
305 310 315 320
Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln
325 330 335
Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala
340 345 350
Thr Val Cys Gly Pro Lys Lys
355
<210> 29
<211> 1418
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(1418)
<223> HEV-GS15-RBD
<400> 29
gagctcatga ttgcactgac cctgtttaat ctggcagata ccctgctggg tggtctgccg 60
accgaactga ttagcagtgc cggtggtcag ctgttttata gccgtccggt tgttagcgca 120
aatggtgaac cgaccgttaa actgtatacc agcgttgaaa atgcacagca ggataaaggt 180
attgcaattc cgcatgatat tgatctgggt gaaagccgtg ttgtgattca ggattatgat 240
aatcagcatg aacaggatcg tccgaccccg agtccggcac cgagccgtcc gtttagcgtt 300
ctgcgtgcaa atgatgttct gtggctgagc ctgaccgcag cagaatatga tcagagcacc 360
tatggtagca gcaccggtcc ggtttatgtt agcgatagcg ttaccctggt taatgttgca 420
accggtgcac aggcagttgc acgtagcctg gattggacca aagtgaccct ggatggtcgt 480
ccgctgagca ccattcagca gtatagcaaa accttttttg ttctgccgct gcgtggtaaa 540
ctgagctttt gggaagcagg caccaccaaa gcaggttatc cgtataacta taataccacc 600
gcaagcgatc agctgctggt tgaaaacgca gcaggtcatc gtgttgcaat tagcacctat 660
accaccagtc tgggtgcagg tccggttagc attagcgcag ttgcagttct ggcaccgcat 720
agcgcaggtg gaggaggttc tggaggcggt ggaagtggtg gcggaggtag cagagtccaa 780
ccaacagaat ctattgttag atttcctaat attacaaact tgtgcccttt tggtgaagtt 840
tttaacgcca ccagatttgc atctgtttat gcttggaaca ggaagagaat cagcaactgt 900
gttgctgatt attctgtcct atataattcc gcatcatttt ccacttttaa gtgttatgga 960
gtgtctccta ctaaattaaa tgatctctgc tttactaatg tctatgcaga ttcatttgta 1020
attagaggtg atgaagtcag acaaatcgct ccagggcaaa ctggaaagat tgctgattat 1080
aattataaat taccagatga ttttacaggc tgcgttatag cttggaattc taacaatctt 1140
gattctaagg ttggtggtaa ttataattac ctgtatagat tgtttaggaa gtctaatctc 1200
aaaccttttg agagagatat ttcaactgaa atctatcagg ccggtagcac accttgtaat 1260
ggtgttgaag gttttaattg ttactttcct ttacaatcat atggtttcca acccactaat 1320
ggtgttggtt accaaccata cagagtagta gtactttctt ttgaacttct acatgcacca 1380
gcaactgttt gtggacctaa aaagtgataa gcggccgc 1418
<210> 30
<211> 1418
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(1418)
<223> 针对大肠杆菌表达优化的HEV-GS15-RBD核酸序列
<400> 30
gagctcatga ttgcactgac cctgtttaat ctggcagata ccctgttagg tggtctgccg 60
accgaactga ttagcagtgc cggtggtcag ctgttttata gccgtccggt tgttagcgca 120
aatggtgaac cgaccgttaa actgtatacc agcgttgaaa atgcacagca ggataaaggt 180
attgcaattc cgcatgatat tgatctgggt gaaagccgtg ttgtgattca ggattatgat 240
aatcagcatg aacaggatcg tccgacaccg agtccggcac cgagccgtcc gtttagcgtt 300
ctgcgtgcaa atgatgttct gtggctgagc ctgaccgcag cagaatatga tcagagcacc 360
tatggtagca gcaccggtcc ggtttatgtt agcgatagcg ttaccctggt taatgttgca 420
accggtgcac aggcagttgc acgtagcctg gattggacca aagtgaccct ggatggtcgt 480
ccgctgagca ccattcagca gtatagcaaa accttttttg ttctgccgct gcgtggtaaa 540
ctgagctttt gggaagcagg caccaccaaa gcaggttatc cgtataacta taataccacc 600
gcaagcgatc agctgctggt tgaaaacgca gcaggtcatc gtgttgcaat tagcacctat 660
accaccagtt taggtgcagg tccggttagc attagcgcag ttgcagttct ggcaccgcat 720
tcagccggtg gtggtggtag cggtggtggc ggttcaggtg gcggtggttc acgtgttcag 780
ccgacagaaa gcattgttcg ttttccgaat atcaccaatc tgtgtccgtt tggcgaagtt 840
tttaatgcaa cccgttttgc aagcgtttat gcctggaatc gtaaacgtat tagcaattgc 900
gttgccgatt atagcgtgct gtataatagc gcaagcttta gcacctttaa atgctatggt 960
gttagcccga ccaaactgaa tgatctgtgt tttaccaatg tgtatgccga tagctttgtg 1020
attcgtggtg atgaagttcg tcagattgca ccgggtcaga ccggtaaaat tgcagattat 1080
aactacaaac tgccggatga ttttacgggt tgtgttattg catggaatag caataacctg 1140
gatagcaaag ttggtggcaa ctataactat ctgtatcgcc tgtttcgtaa gagcaatctg 1200
aaaccgtttg aacgtgatat tagcaccgaa atttatcagg caggtagcac cccgtgcaat 1260
ggtgttgaag gttttaattg ttattttccg ctgcagagct atggttttca gcctaccaat 1320
ggtgtgggtt atcagccgta tcgtgttgtt gttctgtcat ttgaactgct gcatgcaccg 1380
gcaaccgttt gtggtccgaa aaaatgataa gcggccgc 1418
<210> 31
<211> 466
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(466)
<223> HEV-GS15-RBD
<400> 31
Met Ile Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly
1 5 10 15
Leu Pro Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser
20 25 30
Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr
35 40 45
Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp
50 55 60
Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln
65 70 75 80
His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe
85 90 95
Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala
100 105 110
Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val
115 120 125
Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val
130 135 140
Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu
145 150 155 160
Ser Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg
165 170 175
Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro
180 185 190
Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala
195 200 205
Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala
210 215 220
Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Ala
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
245 250 255
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
260 265 270
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
275 280 285
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
290 295 300
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
305 310 315 320
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
325 330 335
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
340 345 350
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
355 360 365
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
370 375 380
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
385 390 395 400
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
405 410 415
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
420 425 430
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
435 440 445
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
450 455 460
Lys Lys
465
<210> 32
<211> 4566
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(4566)
<223> 人密码子优化的HBSAg-(EAAAK)3-全长SARS-CoV-2刺突蛋白核酸序列
<400> 32
aagcttgccg ccaccatgga gaacatcaca tcaggattcc taggacccct gctcgtgtta 60
caggcggggt ttttcttgtt gacaagaatc ctcacaatac cacagagtct agactcgtgg 120
tggacttctc tcaattttct agggggatca cccgtgtgtc tgggccaaaa ttcgcagtcc 180
ccaacctcca atcactcacc aacctcttgt cctccaattt gtcctggcta tcgctggatg 240
tgtctgcggc gttttatcat attcctcttc atcctgctgc tatgcctcat cttcttgttg 300
gttcttctgg actaccaggg tatgttgccc gtttgtcctc taattccagg atcaacaact 360
accaacacgg gaccatgcaa gacctgcacg actcctgctc aaggaaactc tatgtttccc 420
tcttgttgct gtacaaaacc taccgacgga aactgcactt gtattcccat cccatcatcc 480
tgggctttcg caaaatacct atgggagtgg gcctcagtcc gtttctcctg gctcagttta 540
ctagtgccat ttgttcagtg gttcgtaggg ctttccccca ctgtttggct ttccgctata 600
tggatgatgt ggtattgggg gccaagtctg tacagcatcg tgagtccctt tatacctcta 660
ttaccaattt tcttttgtct ttgggtatac attgaggctg ccgcaaagga agccgcagct 720
aaagaggcag ctgccaagtt cgtgttcctg gttctgctgc ccctggtgtc tagccagtgc 780
gtgaacctga ccaccagaac acagctgcct ccagcctaca ccaacagctt caccagaggc 840
gtgtactacc ccgacaaggt gttccggtcc tccgtgctgc attctaccca ggacctgttc 900
ctgcctttct tctccaacgt gacctggttc cacgccatcc atgtgtctgg caccaacggc 960
accaagagat tcgacaaccc cgtgctgcct ttcaacgacg gggtgtactt tgcctccacc 1020
gagaagtcca acatcatcag aggctggatc ttcggcacaa ccctggacag caagacccag 1080
agcctgctga tcgtgaacaa cgccaccaac gtggtcatca aagtgtgcga gttccagttc 1140
tgcaacgacc ccttcctggg cgtctactac cacaagaaca acaagtcctg gatggaatcc 1200
gagttccggg tgtactcctc cgccaacaac tgcaccttcg aatacgtgtc ccagcctttc 1260
ctgatggacc tggaaggcaa gcagggcaac ttcaagaacc tgcgcgagtt cgtgttcaag 1320
aacatcgacg gctacttcaa gatctactcc aagcacaccc ctatcaacct cgtgcgggat 1380
ctgcctcagg gcttctctgc tctggaaccc ctggtggatc tgcccatcgg catcaacatc 1440
acccggtttc agaccctgct ggccctgcac cggtcttatt tgacccctgg cgactcctct 1500
tctggctgga ctgctggcgc cgctgcttac tatgtgggct acctgcagcc tcggaccttt 1560
ctgctgaagt acaacgagaa tggcaccatc accgacgccg tggactgtgc tctggatcct 1620
ctgtccgaga caaagtgcac cctgaagtcc ttcaccgtgg aaaagggcat ctaccagacc 1680
tccaacttcc gggtgcagcc caccgagtct atcgtgcggt tccctaacat caccaacctg 1740
tgtcctttcg gcgaggtgtt caatgccacc agattcgcct ctgtgtacgc ctggaaccgg 1800
aagcggatct ctaactgcgt ggccgactac agcgtgctgt acaactccgc ctccttcagc 1860
accttcaagt gctacggcgt gtcccctaca aagctgaacg acctgtgctt cacaaacgtg 1920
tacgccgaca gcttcgtgat ccggggagat gaagtgcggc agatcgctcc tggacagacc 1980
ggcaagatcg ccgattacaa ctacaagctg cccgacgact tcaccggctg tgtgatcgct 2040
tggaactcca acaacctgga ctccaaagtc ggcggcaact acaactacct gtaccggctg 2100
ttccggaagt ctaacctgaa gcctttcgag cgggacatca gcaccgagat ctaccaggct 2160
ggcagcaccc cttgtaacgg cgtggaaggc ttcaactgct acttcccact gcagtcctac 2220
ggctttcagc ctaccaatgg cgtgggctat cagccctaca gagtggtggt gctgtccttc 2280
gagctgctgc atgctcctgc taccgtgtgc ggccctaaga aatctaccaa cctggtcaag 2340
aacaaatgcg tgaacttcaa cttcaacggc ctgaccggca ccggcgtgct gacagagtcc 2400
aacaagaagt tcctgccatt ccagcagttc ggccgggata tcgccgatac cacagatgcc 2460
gtcagggacc ctcagacact ggaaatcctg gacatcaccc cttgctcctt cggcggagtg 2520
tctgtgatca ccccaggcac caacacctct aaccaggtgg ccgtgctgta tcaggacgtg 2580
aactgtaccg aggtgcccgt ggctatccat gccgatcagc tgacccctac atggcgcgtg 2640
tactccaccg gctctaacgt gttccagaca agagctggct gtctgatcgg cgctgagcac 2700
gtgaacaatt cctacgagtg cgacatcccc atcggagccg gaatctgcgc ctcttatcag 2760
acccagacca actctcccag acgggccaga tctgtggcca gccagtctat cattgcttac 2820
accatgagcc tgggcgccga gaactctgtg gcctacagca acaactctat cgctatcccc 2880
accaacttca ccatctccgt gaccacagag atcctgccag tgtccatgac caagaccagc 2940
gtggactgca ccatgtacat ctgcggcgac tctaccgagt gctccaacct gctgctccag 3000
tacggctcct tctgcaccca gctgaataga gccctgaccg gaatcgccgt ggaacaggac 3060
aagaacaccc aagaggtgtt cgcccaagtg aagcagatct acaagacccc tcctatcaag 3120
gacttcggcg gcttcaattt ctcccagatt ctgcccgatc ctagcaagcc ctccaagcgg 3180
tctttcatcg aggacctgct gttcaacaaa gtgacactgg ccgacgccgg cttcatcaag 3240
cagtacggcg actgtctggg cgacattgcc gctagggatc tgatctgcgc ccagaagttt 3300
aacggactga cagtgctgcc tcctctgctg accgatgaga tgatcgccca gtacacctcc 3360
gcactgctgg ctggcacaat cacctctgga tggacatttg gcgctggcgc tgctctgcaa 3420
atcccattcg ctatgcaaat ggcctaccgg ttcaacggca tcggcgtgac ccagaatgtg 3480
ctgtacgaga accagaagct gatcgccaac cagttcaaca gcgccatcgg aaagatccag 3540
gacagcctgt ccagcaccgc ttctgccctg ggaaagctgc aggatgtggt caaccagaac 3600
gctcaggccc tgaacaccct cgtgaagcag ctgtctagca acttcggcgc catctcctct 3660
gtgctgaacg atatcctgag ccggctggac aaggtggaag ccgaggtgca gatcgacaga 3720
ctgatcaccg gacggctgca gtccctgcag acctatgtta cccagcagct gatccgggct 3780
gccgagatta gagcctctgc caatctggcc gcaaccaaga tgtctgagtg tgtgctggga 3840
cagtccaaga gagtggactt ctgcggcaag ggctaccacc tgatgagctt ccctcagtct 3900
gctcctcacg gcgtggtgtt tctgcacgtg acctacgtgc ccgctcaaga gaagaacttt 3960
accaccgctc ctgccatctg ccacgacggc aaggctcact ttcctagaga aggcgtgttc 4020
gtgtctaacg gcacccattg gttcgtgaca cagcggaact tctacgagcc ccagatcatc 4080
accaccgaca acaccttcgt gtccggcaac tgcgacgtcg tgatcggaat tgtgaacaat 4140
accgtgtacg accctctgca gcccgagctg gactccttca aagaggaact ggacaagtac 4200
tttaagaacc acacaagccc cgacgtggac ctgggagaca tctctggcat caacgcctcc 4260
gtggtcaaca tccagaaaga gatcgaccgg ctgaacgagg tggccaagaa tctgaacgag 4320
tccctgatcg acctgcaaga actggggaag tacgagcagt acatcaagtg gccctggtac 4380
atctggctgg gctttatcgc tggcctgatc gctatcgtga tggtcacaat catgctgtgc 4440
tgtatgacct cctgttgctc ctgcctgaag ggctgctgct cttgcggctc ttgctgcaag 4500
ttcgacgagg acgactctga gcccgtgctg aaaggcgtga agctgcacta tacctgatga 4560
ctcgag 4566
<210> 33
<211> 1513
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> SITE
<222> (1)..(1513)
<223> HBSAg-(EAAAK)3-全长SARS-CoV-2刺突蛋白
<400> 33
Met Glu Asn Ile Thr Ser Gly Phe Leu Gly Pro Leu Leu Val Leu Gln
1 5 10 15
Ala Gly Phe Phe Leu Leu Thr Arg Ile Leu Thr Ile Pro Gln Ser Leu
20 25 30
Asp Ser Trp Trp Thr Ser Leu Asn Phe Leu Gly Gly Ser Pro Val Cys
35 40 45
Leu Gly Gln Asn Ser Gln Ser Pro Thr Ser Asn His Ser Pro Thr Ser
50 55 60
Cys Pro Pro Ile Cys Pro Gly Tyr Arg Trp Met Cys Leu Arg Arg Phe
65 70 75 80
Ile Ile Phe Leu Phe Ile Leu Leu Leu Cys Leu Ile Phe Leu Leu Val
85 90 95
Leu Leu Asp Tyr Gln Gly Met Leu Pro Val Cys Pro Leu Ile Pro Gly
100 105 110
Ser Thr Thr Thr Asn Thr Gly Pro Cys Lys Thr Cys Thr Thr Pro Ala
115 120 125
Gln Gly Asn Ser Met Phe Pro Ser Cys Cys Cys Thr Lys Pro Thr Asp
130 135 140
Gly Asn Cys Thr Cys Ile Pro Ile Pro Ser Ser Trp Ala Phe Ala Lys
145 150 155 160
Tyr Leu Trp Glu Trp Ala Ser Val Arg Phe Ser Trp Leu Ser Leu Leu
165 170 175
Val Pro Phe Val Gln Trp Phe Val Gly Leu Ser Pro Thr Val Trp Leu
180 185 190
Ser Ala Ile Trp Met Met Trp Tyr Trp Gly Pro Ser Leu Tyr Ser Ile
195 200 205
Val Ser Pro Phe Ile Pro Leu Leu Pro Ile Phe Phe Cys Leu Trp Val
210 215 220
Tyr Ile Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala
225 230 235 240
Lys Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
245 250 255
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
260 265 270
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
275 280 285
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
290 295 300
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
305 310 315 320
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
325 330 335
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
340 345 350
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
355 360 365
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
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Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
385 390 395 400
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
405 410 415
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
420 425 430
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
435 440 445
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
450 455 460
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
465 470 475 480
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
485 490 495
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
500 505 510
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
515 520 525
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
530 535 540
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
545 550 555 560
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
565 570 575
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
580 585 590
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
595 600 605
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
610 615 620
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
625 630 635 640
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
645 650 655
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
660 665 670
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
675 680 685
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
690 695 700
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
705 710 715 720
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
725 730 735
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
740 745 750
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
755 760 765
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
770 775 780
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
785 790 795 800
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
805 810 815
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
820 825 830
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
835 840 845
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
850 855 860
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
865 870 875 880
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
885 890 895
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
900 905 910
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
915 920 925
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
930 935 940
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
945 950 955 960
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
965 970 975
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
980 985 990
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
995 1000 1005
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
1010 1015 1020
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
1025 1030 1035 1040
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
1045 1050 1055
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
1060 1065 1070
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
1075 1080 1085
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
1090 1095 1100
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
1105 1110 1115 1120
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
1125 1130 1135
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
1140 1145 1150
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
1155 1160 1165
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
1170 1175 1180
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
1185 1190 1195 1200
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
1205 1210 1215
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
1220 1225 1230
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
1235 1240 1245
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1250 1255 1260
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1265 1270 1275 1280
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1285 1290 1295
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1300 1305 1310
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1315 1320 1325
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1330 1335 1340
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1345 1350 1355 1360
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1365 1370 1375
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1380 1385 1390
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1395 1400 1405
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1410 1415 1420
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1425 1430 1435 1440
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1445 1450 1455
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1460 1465 1470
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1475 1480 1485
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1490 1495 1500
Leu Lys Gly Val Lys Leu His Tyr Thr
1505 1510
Claims (28)
1.一种分离的多核苷酸,其编码来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中针对重组表达对所述多核苷酸进行优化。
2.权利要求1的多核苷酸,针对在选自以下的宿主细胞中表达对其进行优化:
(a)大肠杆菌,
(b)酵母,优选Komagataella或酵母属(Saccharomyces)和/或
(c)哺乳动物细胞,优选人细胞。
3.权利要求1或2的多核苷酸,其中省略了一个或多个顺式作用序列基序,所述一个或多个顺式作用序列基序独立地选自:
(a)内部TATA盒;
(b)chi-位点;
(c)核糖体进入位点;
(d)富含AT和/或富含GC的序列段;
(e)RNA不稳定性基序;
(f)重复序列和/或RNA二级结构;
(g)隐蔽剪接供体位点;
(h)隐蔽剪接接受位点;和/或
(i)(a)至(i)的任何组合。
4.权利要求1至3任一项的多核苷酸,其中多核苷酸整合到宿主细胞基因组中。
5.权利要求1至4任一项的多核苷酸,其具有至少约0.80,优选至少约0.9,更优选至少约0.93的密码子适应指数(CAI)。
6.权利要求1至5任一项的多核苷酸,其包含具有以下的核酸序列或由具有以下的核酸序列组成:
(a)与SEQ ID NO:2具有至少90%同一性;
(b)与SEQ ID NO:3具有至少90%同一性;
(c)与SEQ ID NO:4具有至少90%同一性;
(d)与SEQ ID NO:5具有至少90%同一性;
(e)与SEQ ID NO:6具有至少90%同一性;
(f)与SEQ ID NO:7具有至少90%同一性;
(g)与SEQ ID NO:8具有至少90%同一性
(h)与SEQ ID NO:13具有至少90%同一性
(i)与SEQ ID NO:14具有至少90%序列同一性
(j)与SEQ ID NO:26具有至少90%同一性
(k)与SEQ ID NO:27具有至少90%同一性
(l)与SEQ ID NO:29具有至少90%同一性;
(m)与SEQ ID NO:30具有至少90%同一性;或
(n)与SEQ ID NO:32具有至少90%同一性。
7.权利要求1至6任一项的多核苷酸,其中编码的刺突蛋白或其片段:
(a)保留天然2019-nCoV刺突蛋白中存在的构象表位;
(b)当将核酸或编码的刺突蛋白或其片段施用于受试者时,导致产生对刺突蛋白或其片段特异性的中和抗体;和/或
(c)包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:15具有至少90%同一性。
8.一种表达构建体,其包含与启动子可操作地连接的权利要求1至7任一项的多核苷酸。
9.一种疫苗组合物,其包含来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白,或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:15具有至少90%同一性。
10.权利要求9的组合物,当施用于受试者时,其导致产生对所述刺突蛋白或其片段特异性的中和抗体。
11.一种病毒载体、RNA疫苗或DNA质粒,其表达来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ IDNO:15具有至少90%同一性。
12.权利要求11的病毒载体、RNA疫苗或DNA质粒,其表达刺突蛋白或其片段,还包含信号肽。
13.权利要求12的病毒载体、RNA疫苗或DNA质粒,其中信号肽指导从人细胞分泌。
14.权利要求11至13任一项的病毒载体、RNA疫苗或DNA质粒,其中病毒载体、RNA疫苗或DNA质粒还表达一种或多种另外的抗原或其片段,优选来自2019-nCoV的一种或多种另外的抗原,或其片段。
15.权利要求14的病毒载体、RNA疫苗或DNA质粒,其中刺突蛋白或其片段和一种或多种另外的抗原或其片段如下表达:
(a)作为融合蛋白表达;或
(b)在分开的病毒载体、RNA疫苗或DNA质粒中表达,以供组合使用。
16.权利要求11至15任一项的病毒载体、RNA疫苗或DNA质粒,其包含一个或多个如权利要求1至7任一项中限定的多核苷酸或权利要求8的表达构建体。
17.一种融合蛋白,其包含来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:15具有至少90%同一性。
18.权利要求17的融合蛋白,其进一步包含:
(a)乙型肝炎表面抗原,或其与所述乙型肝炎表面抗原具有共同抗原交叉反应性的片段;
(b)HPV 18LI蛋白,或其与所述HPV 18LI蛋白具有共同抗原交叉反应性的片段;
(c)戊型肝炎P239蛋白,或其与所述戊型肝炎P239蛋白具有共同抗原交叉反应性的片段;和/或
(d)HPV 16LI蛋白,或其与所述HPV 16LI蛋白具有共同抗原交叉反应性的片段;
其中任选地:
(i)所述融合蛋白由多核苷酸编码,所述多核苷酸包含与SEQ ID NO:3、5、6、8、26、27、29、30或32中的任一个具有至少90%同一性的核酸序列或由其组成;和/或
(ii)所述融合蛋白包含与SEQ ID NO:9、10、11、12、28、31或33中的任一个具有至少90%同一性的氨基酸序列或由其组成。
19.一种病毒样颗粒(VLP),其包含来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白或其与所述刺突蛋白具有共同抗原交叉反应性的片段,其中任选地所述片段包含2019-nCoV刺突蛋白的受体结合结构域(RBD)或由其组成,优选与SEQ ID NO:15具有至少90%同一性;
其中任选地,所述VLP包含如权利要求17或18中限定的融合蛋白或由其组成。
20.一种抗体,或其结合片段,其特异性地结合如权利要求1中限定的2091-nCoV刺突蛋白抗原或其片段。
21.权利要求20的抗体,或其结合片段,其中所述抗体是单克隆抗体或多克隆抗体。
22.权利要求20或21的抗体,或其结合片段,其中所述抗体是Fab、F(ab')2、Fv、scFv、Fd或dAb。
23.一种寡核苷酸适配体,其特异性地结合如权利要求1中限定的2019-nCoV刺突蛋白或其片段。
24.一种疫苗组合物,其包含权利要求11至16任一项的病毒载体和/或RNA疫苗和/或DNA质粒。
25.权利要求1至7任一项的多核苷酸,和/或权利要求8的表达构建体,和/或权利要求9、10和/或24中任一项的疫苗组合物,和/或权利要求11至16中任一项的病毒载体和/或RNA疫苗和/或DNA质粒,和/或权利要求19的病毒样颗粒,和/或权利要求17或18的融合蛋白,和/或权利要求20至22中任一项的抗体,和/或权利要求23的适配体,其用于治疗和/或预防2019-nCoV感染。
26.权利要求1至7任一项的多核苷酸,和/或权利要求8的表达构建体,和/或权利要求9、10和/或24中任一项的疫苗组合物,和/或权利要求11至16中任一项的病毒载体和/或RNA疫苗和/或DNA质粒,和/或权利要求19的病毒样颗粒,和/或权利要求17或18的融合蛋白,和/或权利要求20至22中任一项的抗体,和/或权利要求23的适配体在制备用于预防和/或治疗2019-nCoV感染的药物中的用途。
27.一种生产来自2019-nCoV的与SEQ ID NO:1具有至少90%同一性的刺突蛋白或其片段的方法,包括在宿主细胞中表达如权利要求1至7任一项中限定的多核苷酸,并任选地纯化刺突蛋白或片段。
28.权利要求27所述的方法,其还包括将所述刺突蛋白或其片段与药学上可接受的载体或稀释剂一起配制。
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GB202002166D0 (en) | 2020-04-01 |
MX2022010027A (es) | 2023-01-24 |
WO2021165667A1 (en) | 2021-08-26 |
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