CN114656571B - 一种四价SARS-CoV-2嵌合纳米颗粒疫苗及其制备方法与应用 - Google Patents
一种四价SARS-CoV-2嵌合纳米颗粒疫苗及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物学技术领域,公开了一种四价SARS‑CoV‑2嵌合纳米颗粒疫苗及其制备方法与应用,具体公开了一种自组装纳米颗粒,所述纳米颗粒包含:a.至少一种第一纳米颗粒亚基,b.第二纳米颗粒亚基;所述第一纳米颗粒亚基包含HexaPro蛋白和第一载体亚基;所述第二纳米颗粒亚基包含第二载体亚基;所述第一载体亚基为I53‑50A1,所述第二载体亚基为I53‑50B.4PT1,所述HexaPro蛋白与第一载体亚基通过铰链连接。该自组装纳米颗粒首次将SARS‑CoV‑2病毒的HexaPro蛋白展示在纳米颗粒表面,能够诱导更高的抗体滴度,可用于预防SARS‑CoV‑2病毒感染。
Description
技术领域
本发明属于生物学技术领域,具体涉及一种四价SARS-CoV-2嵌合纳米颗粒疫苗及其制备方法与应用。
背景技术
目前,全球出现了5个需要关注变异毒株(Variants of Concerns,VOCs),分别为B.1.1.7 (Alpha)、B.1.351(Beta)、P.1(Gamma)、B.1.617.2(Delta)和B.1.529(Omicron),引起了广泛关注。因为它们增加了病毒传播能力以及减少对疫苗诱导血清和单克隆抗体的中和活性,甚至引起免疫逃逸、再感染以及突破感染。此外,迅速增加的新出现SARS-CoV-2变异的报告给现有疫苗的有效性带来了更多的不确定性,这就需要开发针对VOCs和传播变异株的新候选多价疫苗。
SARS-CoV-2刺突蛋白在病毒附着和宿主细胞融合中起关键作用。因此,大多数中和病毒感染的抗体针对刺突蛋白,使其成为一种理想的抗原,可引发对SARS-CoV-2感染的有效保护性免疫,但是位于刺突蛋白上的SARS-CoV-2变异的突变广泛影响了其抗原性,导致广泛的抗体和疫苗诱导的血清免疫逃逸。第一代上市的疫苗,包括mRNA,腺病毒载体疫苗等,主要是基于S-2P设计和生产,但是S-2P表达产量低、对温度敏感等因素限制了基于S-2P设计的亚单位疫苗疫苗的工业化生产。
发明内容
本发明第一方面的目的,在于提供一种自组装纳米颗粒。
本发明第二方面的目的,在于提供本发明第一方面的自组装纳米颗粒的制备方法。
本发明第三方面的目的,在于提供本发明第一方面的自组装纳米颗粒或本发明第二方面的制备方法在制备用于预防新型冠状病毒感染的药物中的应用。
本发明第四方面的目的,在于提供一种疫苗。
本发明第五方面的目的,在于提供一种试剂盒。
本发明第六方面的目的,在于提供本发明第一方面的自组装纳米颗粒在制备治疗新型冠状病毒感染所引起的疾病的药品中的应用。
为了实现上述目的,本发明所采取的技术方案是:
本发明的第一个方面,提供一种自组装纳米颗粒,所述纳米颗粒包含:
a.至少一种第一纳米颗粒亚基;
b.第二纳米颗粒亚基;
所述第一纳米颗粒亚基包含HexaPro蛋白和第一载体亚基;所述第二纳米颗粒亚基包含第二载体亚基;所述第一载体亚基为I53-50A1,所述第二载体亚基为I53-50B.4PT1,所述HexaPro 蛋白与第一载体亚基通过铰链连接。
优选地,所述HexaPro蛋白为新型冠状病毒SARS-CoV-2的HexaPro蛋白。
优选地,所述HexaPro蛋白为新型冠状病毒SARS-CoV-2野生型病毒株的HexaPro蛋白(SEQ ID NO:1)、新型冠状病毒SARS-CoV-2Alpha型病毒株的HexaPro蛋白(SEQ ID NO:2)、新型冠状病毒SARS-CoV-2Beta型病毒株的HexaPro蛋白(SEQ ID NO:3)和新型冠状病毒SARS-CoV-2Gamma型病毒的HexaPro蛋白(SEQ ID NO:4)中的至少一种。
优选地,所述I53-50A1的氨基酸序列如SEQ ID NO:5所示。
优选地,所述I53-50B.4PT1的氨基酸序列如SEQ ID NO:14所示。
优选地,所述铰链包含柔性序列和刚性接头,铰链用于HexaPro蛋白和载体蛋白(第一载体亚基)的链接,不影响HexaPro蛋白的免疫原性以及蛋白的正确折叠。
优选地,所述柔性序列的氨基酸序列如SEQ ID NO:7所示,所述刚性接头的氨基酸序列为 EKAAKAEEAARK。
优选地,在所述HexaPro蛋白与铰链之间插入稳定蛋白。
优选地,所述稳定蛋白T4噬菌体纤维蛋白原。
优选地,所述第一纳米颗粒亚基为第一纳米颗粒亚基三聚体。
优选的,所述第二纳米颗粒亚基为第二纳米颗粒亚基五聚体。
优选地,所述第一纳米颗粒亚基还包括信号肽。
进一步优选地,所述信号肽为组织纤维溶酶原激活物。
更进一步优选地,所述信号肽的氨基酸序列如SEQ ID NO:9所示。
优选地,所述第一纳米颗粒亚基通过如下方式获得:将表达包含HexaPro蛋白和第一载体亚基的核酸同引入第一宿主细胞;孵育第一宿主细胞表达第一纳米颗粒亚基。
优选地,所述第一宿主细胞为真核细胞。
进一步优选地,所述第一宿主细胞为Expi293F细胞。
优选地,所述第二纳米颗粒亚通过如下方式获得:将表达第二载体亚基的核酸引入第二宿主细胞;孵育第二宿主细胞表达第二纳米颗粒亚基。
优选的,所述第二宿主细胞为原核细胞;更优选为大肠杆菌;最优选为Rosetta(DE3)。
优选地,通过分子筛色谱法对所述第一纳米颗粒亚基和第二纳米颗粒亚基进行纯化。
本发明的第二个方面,在于提供本发明第一方面的自组装纳米颗粒的制备方法,包括以下步骤:将一种第一纳米颗粒亚基与第二纳米颗粒亚基混合孵育,得到自组装纳米颗粒;或
将至少两种第一纳米颗粒亚基混合,混合后与第二纳米颗粒亚基混合孵育,得到自组装纳米颗;或
先单独将一种第一纳米颗粒亚基与第二纳米颗粒亚基混合孵育后,再将孵育后的纳米颗粒混匀,得到自组装纳米颗粒。
优选地,所述第一纳米颗粒亚基和第二纳米颗粒亚基的摩尔浓度比为(1~6):1。
进一步优选地,所述第一纳米颗粒亚基和第二纳米颗粒亚基的摩尔浓度比为(1~4):1。
优选地,所述孵育的条件为在组装缓冲液中20~27℃孵育1~2h或3~5℃孵育8~14h。
优选地,所述组装缓冲液组成为:50mM 4-羟乙基哌嗪乙磺酸pH 8.0,300mM NaCl,5%甘油。
本发明的第三个方面,在于提供一提供本发明第一方面的自组装纳米颗粒或本发明第二方面的制备方法在制备用于预防新型冠状病毒感染的药物中的应用。
本发明的第四个方面,在于提供一种疫苗,包括本发明第一方面的自组装颗粒疫苗。
优选地,所述疫苗还包括佐剂和/或载体。
优选地,所述佐剂为铝佐剂、油乳佐剂(水包油、油包水、双向型乳液等)、微生物来源类佐剂(肽聚糖、革兰氏阴性菌外膜脂多糖、分枝杆菌及其组份、GpG寡核苷酸、霍乱毒素等)、微粒抗原递送体系(脂质体、聚合微球体、惰性纳米微球、纳米铝佐剂、免疫刺激复合物、细胞因子等)、多糖类(菊粉)和天然来源类(如蜂胶、皂苷)中的至少一种;更优选为MF59佐剂。
优选地,所述载体为药学上可接受的载体成分,包括结合剂(糖浆、阿拉伯树胶、明胶、山梨醇、黄芪胶、聚乙烯吡咯烷酮等)、填充剂(乳糖、蔗糖、淀粉、磷酸钙、山梨糖醇、甘氨酸等)、润滑剂(硬脂酸镁、滑石、聚乙二醇等)、崩解剂(淀粉、微晶纤维素等)、湿润剂(十二烷基硫酸钠等)、悬浮剂(山梨糖醇、糖浆、甲基纤维素、葡萄糖浆、明胶、氢化食用脂肪等)、乳化剂(卵磷脂、山梨醇单油酸酯、阿拉伯树胶等)、非水性载体(杏仁油、分馏椰子油或甘油、丙二醇、乙醇等疏水酯等)、防腐剂(对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、山梨酸等)、芳香剂(合成香料、天然香料等)、甜味剂(蔗糖、甜叶菊、木糖醇等)、 pH调节剂(碳酸氢钠、碳酸钾等)、粉剂(色素、染料、树脂等)、增稠剂(阿拉伯树胶、甲基纤维素等)、抗氧化剂(维生素C、维生素E等)等等。
本发明第五个方面,在于提供一种试剂盒,包括本发明第一方面的自组装纳米颗粒或第六方面的纳米颗粒疫苗以及用于接种所述自组装纳米颗粒或所述纳米颗粒疫苗的容器。
优选地,所述容器为医用注射器。
本发明第六个方面,在于提供本发明第一方面的自组装纳米颗粒在制备治疗新型冠状病毒感染所引起的疾病的药品中的应用。
本发明的有益效果是:
本发明提供的自组装纳米颗粒首次将SARS-CoV-2病毒的HexaPro蛋白展示在纳米颗粒表面,能够诱导更高的抗体滴度,可用于预防SARS-CoV-2病毒感染及治疗SARS-CoV-2病毒感染所引起的疾病。
本发明利用SARS-CoV-2的HexaPro作为抗原设计的一价或多价新型嵌合纳米颗粒疫苗,克服SARS-CoV-2抗原的生产产量低和稳定性等因素,保留了刺突蛋白的抗原性,增加了表达产量和对温度的敏感性,其中多价嵌合纳米疫苗还保持了融合前的构象,能展示不同 SARS-CoV-2病毒株的Spike蛋白且不影响其空间结构,能够提升疫苗的免疫原性,增强体液免疫反应,可同时针对野生型和VOCs诱发高滴度的中和性抗体,免受不同病毒株的攻击。
附图说明
图1为基于SARS-CoV-2 HexaPro设计的纳米颗粒疫苗的示意图。
图2为纳米颗粒免疫原的SDS-PAGE电泳的考马斯亮蓝染色图;其中,a为四种SARS-CoV-2 的HexaPro-I53-50A1和纳米颗粒组份在还原和非还原条件的SDS-PAGE电泳的考马斯亮蓝染色图;b为SARS-CoV-2的HexaPro-I53-50 NP、Mosaic HexaPro-I53-50 NP和空纳米颗粒在还原和非还原条件的SDS-PAGE电泳的考马斯亮蓝染色图。
图3为纳米颗粒免疫原的颗粒粒径分布图和分子筛色谱图;其中,a为纳米颗粒免疫原的颗粒粒径分布图;b为纳米颗粒免疫原的分子筛色谱图。
图4为纳米颗粒免疫原的负染透射电镜图。
图5为纳米颗粒免疫原的热稳定性分析结果图;其中,a为纳米颗粒免疫原的热稳定性结果表;b为纳米颗粒免疫原在300~430nm处的固有蛋白荧光的平均重心(BCM)和266nm处的静态光散射强度。
图6为纳米颗粒免疫原与SARS-CoV-2特异性抗体的结合曲线。
图7为纳米颗粒免疫原与SARS-CoV-2抗体S2-E12的Co-IP分析结果图。
图8为纳米颗粒免疫原免疫小鼠后诱导对SARS-CoV-2野生型和流行突变株的体液免疫反应结果图;其中,a为纳米颗粒免疫原免疫接种小鼠1次和2次疫苗后的结合抗体和中和抗体滴度的热图;b为纳米颗粒免疫原免疫接种小鼠第2周和第5周采集的血清的SARS-CoV-2野生型和突变株HexaPro的终点结合抗体滴度结果统计图;c为纳米颗粒免疫原免疫接种小鼠第2周和第5周采集的血清的SARS-CoV-2野生型和突变株的假病毒中和滴度结果统计图;d为纳米颗粒免疫原免疫接种小鼠第2周和第5周采集的血清的SARS-CoV-2野生型和突变株的活病毒中和滴度结果统计图。
图9为纳米颗粒免疫原免疫食蟹猴后诱导对SARS-CoV-2野生型和流行突变株的体液免疫反应结果图;其中,a为纳米颗粒免疫原免疫接种食蟹猴1次、2次和3次疫苗后的结合抗体和中和抗体滴度的热图;b为纳米颗粒免疫原免疫接种食蟹猴后每间隔两周之后采集的血清的 SARS-CoV-2野生型和突变株的HexaPro的终点结合抗体滴度结果统计图;c为纳米颗粒免疫原免疫接种食蟹猴后每间隔两周之后采集的血清的SARS-CoV-2野生型和突变株的假病毒中和滴度结果统计图;d为纳米颗粒免疫原免疫接种食蟹猴后每间隔两周之后采集的血清的 SARS-CoV-2野生型和突变株的活病毒中和滴度结果统计图。
图10为纳米颗粒免疫原免疫接种食蟹猴三剂两周之后的血清对SARS-CoV-2流行毒株的受体结合区的重要突变的假病毒的中和滴度结果图;其中,a为影响疫苗诱导的血清和抗体逃逸的 SARS-CoV-2流行毒株受体结合区的重要突变位点;b食蟹猴接种疫苗三剂之后第二周采集的血清对SARS-CoV-2流行毒株和受体结合区单点/多点的中和潜能;c为血清样本与SARS-CoV-2 受体ACE2的竞争结合分析结果图。
图11为纳米颗粒免疫原接种小鼠之后感染SARS-CoV-2B.1.351突变株的保护作用结果;其中,a为接种SARS-CoV-2B.1.351突变株之后小鼠的体重变化结果图;b为攻毒之后第二天采集的小鼠肺脏的活病毒滴度变化结果图;c为攻毒4天之后肺脏的病理组织学分析结果图,左图为苏木精和伊红染色,右图为免疫组织化学染色。
图12为纳米颗粒免疫原接种小鼠之后感染SARS-CoV-2野生型病毒的保护作用结果;其中, a为接种SARS-CoV-2野生型病毒之后小鼠的体重变化结果图;b为攻毒之后第二天采集的小鼠肺脏的活病毒滴度变化结果图;c为攻毒4天之后肺脏的病理组织学分析结果图,左图为苏木精和伊红染色,右图为免疫组织化学染色。
具体实施方式
现结合具体实施例对本发明进行详细说明,但不限制本发明的范围。
本实施例中所使用的材料、试剂等,如无特别说明,为从商业途径得到的材料和试剂。
本申请的四价嵌合纳米颗粒的制备方法包括以下步骤:
1.通过Sic_axle、Rosetta等计算机辅助设计,确定抗原与纳米颗粒载体的相融间距,同时引入T4噬菌体纤维蛋白的天然三聚体结构域,从而确定序列中用于纳米颗粒设计的铰链(linker) 长度和抗原三聚化,并且基于该长度设计选择纳米颗粒载体。
2.通过第一宿主细胞,利用瞬时转染技术将不同的真核表达载体分别转入第一细胞中表达,获得不同的HexaPro-I53-50A1的纳米颗粒亚基(第一纳米颗粒亚基至第四纳米颗粒亚基),同时利用第二宿主细胞,转化另一个I53-50B.4PT1的表达质粒,在IPTG诱导后表达获得 I53-50B.4PT1这另一纳米颗粒亚基(第五纳米颗粒亚基),各纳米颗粒亚基通过亲和层级以及分子排阻色谱进行进一步纯化后经SDS-PAGE凝胶电泳确定纯度。
3.在组装缓冲液中按一定比例加入等摩尔浓度的第一纳米颗粒亚基至第四纳米颗粒亚基以及第五纳米颗粒亚基,室温下孵育,利用分子排阻色谱分离组装成功的纳米颗粒,并利用负染电镜、动态光散射、热稳定仪和透射电子显微镜评估蛋白的粒径和稳定性,利用ELISA、Co-IP 和生物膜层干涉技术(BLI)评估免疫原的抗原性。
以下为进一步具体阐述本申请的纳米颗粒疫苗。
实施例1嵌合四价SARS-CoV-2 HexaPro纳米颗粒疫苗的构建、表达和纯化
1.1SARS-CoV-2双组份抗原的设计
通过Sic_axle、Rosetta等计算机软件辅助设计,确定SARS-CoV-2野生型和VOCs(英国株、南非株和巴西株,分别对应Alpha型、Beta型和Gamma型)的HexaPro抗原(SARS-CoV-2 野生型、Alpha型、Beta型和Gamma型的HexaPro抗原的氨基酸序依次为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4)与纳米颗粒载体(I53-50A1)融合间距;在HexaPro 抗原和三聚化的I53-50A1亚基(SEQ ID NO:5)之间引入T4噬菌体纤维蛋白的天然三聚体结构域(SEQ ID NO:6)、一段包含16个甘氨酸-丝氨酸残基的柔性linker(SEQ IDNO:7)和一段刚性linker(SEQ ID NO:8);为了后续纯化三聚化的HexaPro-I53-50A1蛋白和去除亲和标签,在目的基因的C端引入8个His-tag和HRV 3C位点;在目的基因的N端引入Kozak序列 (GCCACC)增强目的蛋白的表达,同时引入组织纤溶酶原激活物信号肽(tissueplasminogen activator,TPA)(SEQ ID NO:9)使目的蛋白分泌至细胞上清,便于蛋白纯化,进而得到野生型和3个VOCs的HexaPro-I53-50A1基因(其核酸序列依次为SEQ ID NO:10、SEQ ID NO:11、 SEQ ID NO:12和SEQ ID NO:13)。
1.2SARS-CoV-2双组份抗原的表达和纯化
(1)将野生型和3个VOCs的HexaPro-I53-50A1基因以及纳米颗粒蛋白亚基基因(I53-50B.4PT1基因)(SEQ ID NO:14)通过南京金斯瑞生物有限公司OptimumGeneTM密码子平台优化和合成,分别克隆至哺乳动物表达载体VRC8405(美国国立卫生研究院)和大肠杆菌表达载体pET28a(+)(ThermoFisher),得到四种质粒VRC8405-I53-50A1和 pET28-I53-50B.4PT1。
(2)抽提重组质粒:将VRC8405表达载体携带野生型和3个VOCs的HexaPro-I53-50A1 基因转化DH5α感受态细胞(天根生化科技(北京)有限公司);在包含50ng/mL的卡那抗性的TB琼脂糖固体培养基中生长过夜;挑选单克隆,在TB液体培养基扩大培养,根据质粒大抽试剂盒(德国MN Xtra,货号:740414.50)的说明书分别抽提4种细胞的质粒,利用Nanodrop测量质粒的浓度。
(3)转染Expi293FTM细胞:通过瞬时转染的方法将目的基因的质粒转染至悬浮型Expi293FTM细胞(ThermoFisher)内。具体方法如下:将1mg目的质粒分别加入至50mL新鲜的不含抗生素的Expi293FTM细胞培养基,同时将3mL1mg/mL的转染级线性聚乙烯亚胺盐酸盐(lPEI-MAX)(Polysciences,货号:24765-1)加入至47mL新鲜的不含抗生素的Expi293FTM细胞培养基,两者在室温静置5min;随后将两者轻轻地混匀,并在室温静置15min,使DNA 和PEI通过正负电结合;随后将质粒和PEI-MAX的混合物加入至1L的悬浮型Expi293FTM细胞(1.0×106个/mL)中,在37℃、5%CO2浓度的细胞摇床以120rpm/min震荡培养5天。
(4)纯化HexaPro-I53-50A1重组蛋白:将转染后的细胞及其细胞碎片通过离心(9000rpm/min,2h)和过滤(0.22μm滤膜)去除,得到细胞上清液;将细胞上清通过重力方法流穿含有Ni Sepharose excel琼脂糖珠(Cytiva,货号:17371201)的柱子,重组蛋白由于与Ni树脂有亲和作用,结合至琼脂糖珠;依次通过10倍柱体积低浓度的咪唑洗脱液(50mMHEPES 缓冲液pH 8.0,300mM NaCl,5%甘油,0.5%(w/v)3-[3-(胆酰胺丙基)二甲氨基]丙磺酸内盐 (CHAPS)和30mM咪唑)和10倍柱体积高浓度的咪唑洗脱液(50mM HEPES pH 8.0,300mM NaCl,5%甘油,0.5%(w/v)CHAPS和500mM咪唑)进行洗脱,得到粗提纯的蛋白;通过分子筛色谱柱,纯化得到高纯度的4种重组蛋白,即4种HexaPro-I53-50A1蛋白。
(5)纯化I53-50B.4PT1蛋白:质粒pET28-I53-50B.4PT1转至化Rosseta(DE3)感受态细胞(天根生化科技(北京)有限公司),将转化后的细胞在含有50μg/mL卡那霉素和30μg/mL 氯霉素筛的TB固体培养基过夜培养过夜,筛选阳性单克隆细胞;挑选单克隆细胞进行测序,验证是否转化成功;序列验证正确之后,将单克隆细胞在37℃,150rpm/min的细菌摇床扩大培养;当细菌的OD600=0.6至0.8时,将细菌摇床降温至18℃,并且在培养基中加入终浓度为0.1mM 的异丙基硫代半乳糖苷(IPTG),诱导目的蛋白的表达;当培养16~20h之后,细菌通过离心收集菌体,高压破碎,离心收取蛋白上清,并且用0.22μm滤膜进行过滤,得到粗提存的蛋白;进一步通过亲和层析和分子筛纯化得到高纯度的目的蛋白,即I53-50B.4PT1蛋白。
1.3制备嵌合四价SARS-CoV-2纳米颗粒疫苗
利用BCA方法测定纯化后的SARS-CoV-2野生型和3种VOCs的HexaPro-I53-50A1蛋白与I53-50B.4PT1蛋白的蛋白浓度。
分别取等摩尔浓度(50μM)的四种HexaPro-I53-50A1蛋白预先加入至600μL组装缓冲液中(50mM 4-羟乙基哌嗪乙磺酸pH 8.0,300mM NaCl,5%甘油),随后加入等摩尔浓度的I53-50B.4PT1蛋白,在室温(25℃)组装1h或者在4℃组装过夜。通过分子筛 Superose6Increase 10/300GL凝胶柱去除未组装的组份(I53-50B.4PT1),分离获得嵌合四种 SARS-CoV-2变种的HexaPro的四价嵌合纳米颗粒疫苗(Mosaic HexaPro-I53-50 NP,记为MosaicNP)。同时分别制备四种不同SARS-CoV-2来源的一价纳米颗粒疫苗(HexaPro-I53-50 NP,分别记为WT NP、Alpha NP、Beta NP和Gamma NP)和混合纳米颗粒疫苗(Cocktai HexaPro-I53-50 NP,记为Cocktail NP),其中HexaPro-I53-50 NP的制备方法为:将等摩尔浓度的SARS-CoV-2 野生型、Alpha型、Gamma型和Beta型的四种HexaPro-I53-50A1分别与I53-50B.4PT1在体外独立组装,即得到相应毒株的HexaPro-I53-50 NP。Cocktail NP的制备方法为将WT NP、Alpha NP、 Beta NP和Gamma NP混合在一起,即得到Cocktail NP。
将得到的HexaPro-I53-50A1蛋白进行SDS-PAGE电泳实验,所获得的SARS-CoV-2野生型以及3种VOCs的HexaPro-I53-50A1蛋白的纯度较高,在还原条件或者非还原条件下,四种 HexaPro-I53-50A1蛋白都为单一条带,并且在还原条件下,分子量较非还原条件大(图2中a)。
四种HexaPro-I53-50A1蛋白与I53-50B.4PT1组装之后,形成正二十面体的纳米颗粒, SARS-CoV-2HexaPro抗原颗粒化分子量要显著大于空颗粒,表明双组份I53-50纳米颗粒表面展示SARS-CoV-2HexaPro抗原。同时,由SDS-PAGE和分子筛色谱图显示四种SARS-CoV-2的HexaPro-I53-50A1蛋白与I53-50B.4PT1共组装成嵌合颗粒与只展示其中一种毒株的HexaPro颗粒分子量几乎完全相等(图2中b和图3中b),表明I53-50颗粒能够展示SARS-CoV-2四种病毒株的Spike蛋白而不影响其空间结构。
实施例2嵌合四价纳米颗粒免疫原的生物物理特性
2.1纳米颗粒免疫原的粒径大小和分布
将实施例1中得到的四种SARS-CoV-2的HexaPro-I53-50 NP,Mosaic NP以及空颗粒(I53-50 NP)分别用PBS溶液稀释至浓度为0.5mg/mL;分别取50μL稀释后的样品加入至一次性耐溶剂微型试管,25℃静置2min,使用Zetasizer Ultra动态光散射仪(MalvernPanalytical)检测纳米颗粒的粒径,设置测量角度为173°,通过测量散射光的强度来确定蛋白的尺寸分布,每个样品测量5次,取平均值得到颗粒粒径大小。
如图3中a所示,各纳米颗粒免疫原均为单峰,四种SARS-CoV-2的HexaPro-I53-50NP和 Mosaic HexaPro-I53-50 NP的分布图几乎重叠,颗粒直径大小约为70nm,显著大于空颗粒(直径约为25nm),表明HexaPro成功展示在纳米颗粒的表面。
2.2纳米颗粒免疫原的结构特性
将实施例1中得到的四种SARS-CoV-2的HexaPro-I53-50 NP、Mosaic NP以及空颗粒(I53-50 NP)分别用PBS溶液稀释至浓度为0.25mg/mL;分别吸取10μL稀释后的样品滴于塑料膜上;将放电之后的碳涂层铜网放于蛋白溶液中,孵育2min;用滤纸轻轻地吸干铜网表面的溶液,用双蒸水轻轻地清洗2次,滤纸吸干;再与2%乙酸铀孵育染色2min,在自然条件下风干;染色后的蛋白样品在120KV透射电镜显微镜(FEI,USA)下观察纳米颗粒的大小和形态。
如图4所示,在120KV透射电镜显微镜下可以清晰地看到四种SARS-CoV-2的HexaPro-I53-50 NP和Mosaic NP样品的表面较空颗粒(I53-50 NP)有刺突状突起,并且颗粒的表面均一的分布抗原,表明抗原成功的展示在颗粒表面。
2.3检测纳米颗粒免疫原的热稳定性
将实施例1中SARS-CoV-2野生型HexaPro、四种SARS-CoV-2的HexaPro-I53-50 NP以及 Mosaic NP分别用PBS溶液稀释至浓度为0.5mg/mL;取9μL稀释后的样品至微量毛细管中,随后利用UNcle高通量蛋白质稳定性分析仪(Unchained Labs)测定样品的静态光散射266nm的强度和荧光强度的平均重心(图5中b)得到其熔解温度(melting temperature,Tm)以及聚集温度(aggregation temperature onset,Tagg)。设置参数如下:温度以0.6℃/min的速率从25℃上升到95℃。
结果如图5所示,图5中a总结了各样品的熔解温度和聚集温度,可以看到所有的纳米颗粒疫苗的Tm1值相近。其中,WT NP、Alpha NP和Beta NP三种纳米颗粒疫苗中Tm2值和Tm3值比WT HexaPro的Tm2和Tm3值大,Gamma NP和Mosaic NP增加了一个Tm4值并且具有聚集现象,表明HexaPro在与纳米颗粒结合后化可增强其热稳定性。
实施例3嵌合四价纳米颗粒免疫原的抗原性分析
3.1酶联免疫吸附实验(Enzyme-Linked Immunosorbent Assay,ELISA)
(1)SARS-CoV-2 Spike特异性抗体的表达和纯化
SARS-CoV-2 Spike特异性抗体(REGN-10933,Regdanvimab,S2-E12,COVA1-16,S2-H14, S2-M11,CB6,IgG1-ab1,P2B-2F6,CR3022,COV2-2196,4A8,Fab 2-15和REGN-10987)的VH和VL基因序列来源于冠状病毒抗体数据库(http://opig.stats.ox.ac.uk/webapps/covabdab),分别合成上述基因并插入至抗体表达载体(哺乳动物表达载体VRC8405)中进行表达,提取质粒,转染至Expi293FTM细胞,利用Protein A亲和层析色谱柱和分子筛对所得到的SARS-CoV-2 抗体进行纯化,获得了高纯度的抗体。
(2)嵌合四价纳米颗粒免疫原抗原特征的检测
将浓度为1μg/mL四种SARS-CoV-2的HexaPro-I53-50 NP和Mosaic NP分别包被于96孔 ELISA板,100μL/孔,4℃孵育过夜;PBST(PBS+0.05%Tween 20)清洗一次,加入350μL封闭液(含有5%(w/v)酪蛋白和2%(w/v)明胶的PBS),4℃孵育过夜;用PBST清洗一次,加入100μLSARS-CoV-2Spike特异性抗体(起始浓度为10μg/mL的SARS-CoV-2Spike特异性抗体,以10倍为梯度,PBS为稀释液,连续稀释8个梯度),并设置EBV gH-gL特异性抗体AMMOI 为抗体对照,BAS为蛋白对照,37℃孵育1h;用PBST清洗5次,加入100μL 1:5000稀释的辣根过氧化物酶共轭的山羊抗人IgG二抗(Promega,货号W4031),37℃孵育45min;PBST清洗5次,加入100μLTMB显色液,37℃孵育15min后加入50μL终止液(用蒸馏水1:12稀释的浓盐酸);置于酶标仪上读取OD450和OD630处的吸光值,在GraphPad Prism 8软件绘制抗原和受体亲和曲线。每个样品设置3个重复。
结果如图6所示,抗体S2-H14,S2-M11,CB6,IgG1-ab1,P2B-2F6和Fab 2-15轻微结合或不结合SARS-CoV-2巴西株的HexaPro-I53-50 NP,抗体S2-H14和4A8不结合SARS-CoV-2英国株的HexaPro-I53-50 NP,抗体S2-H14,S2-M11,CB6,IgG1-ab1,P2B-2F6,4A8和Fab 2-15 不结合或者轻微地结合SARS-CoV-2南非株的HexaPro-I53-50 NP。而四价嵌合纳米颗粒疫苗能够结合所有的SARS-CoV-2 Spike特异性抗体,表明嵌合疫苗保留了四种SARS-CoV-2HexaPro 的抗原性。
3.2免疫共沉淀(Co-Immunoprecipitation,CO-IP)
取5μg 1mg/mL的SARS-CoV-2Spike特异性抗体S2-E12加入至含有20μL的proteinA琼脂糖中,室温孵育30min;抗体结合至protein A之后,将5μg四种SARS-CoV-2HexaPro、HexaPro-I53-50A1和HexaPro-I53-50 NP以及Cocktai NP和Mosaic NP加到S2-E12抗体结合的琼脂糖上,在PCR反应管中轻轻摇摆孵育1h;用PBS清洗3次,去掉未结合的抗体和抗原;加入15μL 2×SDS loading样品缓冲液(天根生化科技(北京)有限公司,货号为:RT209),进行 SDS-PAGE电泳和考马斯亮蓝染色。
S2-E12为一种超高效靶向Spike蛋白RBM区域的和对SARS-CoV-2相关的冠状病毒具有广谱中和作用的中和性抗体。使用S2-E12抗体进行Co-IP分析纳米颗粒免疫原的抗原性,结果如图7所示,嵌合纳米颗粒(Mosaic NP)、混合纳米颗粒(Cocktail NP)、四种SARS-CoV-2 HexaPro 和HexaPro-I53-50 NP都能等价结合S2-E12抗体,表明设计的嵌合纳米免疫原保留了四种SARS-CoV-2 HexaPro的抗原性。
3.3生物膜层干涉技术(Biolayer Interferometry,BLI)
将protein A生物传感器(Fortebio)或者SA生物传感器(Fortebio)在预湿板上加入150μL PBST,30℃孵育10min;将SARS-CoV-2RBD特异性抗体(REGN10933和P2B-2F6)、NTD特异性抗体(4A8)和ACE2受体(KANG.et al;Rapid Development of SARS-CoV-2SpikeProtein Receptor-Binding Domain Self-Assembled Nanoparticle VaccineCandidates.ACS Nano.2021 Feb23;15(2):2738-2752)分别用PBS溶液稀释至浓度为10μg/mL;将上述稀释后的抗体或受体分别与传感器进行偶联;四种SARS-CoV-2 HexaPro和HexaPro-I53-50 NP以及Mosaic NP以起始浓度为200nM,以2倍为梯度,PBS为稀释液,连续稀释6个梯度(200nM,100nM,50nM,25nM, 12.5nM,6.25nM),将稀释后的SARS-CoV-2HexaPro、HexaPro-I53-50 NP和Mosaic NP加入至传感器中,总体积为200μL,结合180s,随后使用动力学缓冲液(PBST溶液)将传感器平衡 300s,记录其结合信号和解离信号。结合信号利用1:1的结合模型进行拟合,以计算其动力学参数。
使用BLI分析基于HexaPro设计的免疫原的亲和动力学变化,结果如表1所示,HexaPro 纳米颗粒(HexaPro-I53-50 NP)与抗体的结合能力要高于三聚化的HexaPro,并且抗原很难从抗体上解离下来,表明多聚化的纳米颗粒疫苗的免疫原性较三聚化的HexaPro的抗原性更高。另外,我们还发现SARS-CoV-2不同变种的HexaPro-I53-50 NP和嵌合四价纳米颗粒的亲和参数差异不大,可能的原因为抗原多聚化之后从抗体解离下来之后又重新结合抗体,暗示纳米颗粒疫苗免疫受试动物能够长时间在淋巴组织B细胞受体中驻留,刺激体液免疫反应。
表1 BLI动力学参数表
注:Kon为结合动力学常数;Koff为解离动力学常数;KD为亲和常数,由Koff/Kon计算得到。
实施例4嵌合四价纳米颗粒疫苗对BALB/c小鼠的免疫原性
利用实施例1制得的纳米颗粒疫苗免疫小鼠,考察纳米颗粒疫苗对小鼠的免疫原性。
4.1免疫小鼠
具体实验步骤如下:
(1)BALB/c小鼠分组:120只小鼠(浙江维通利华有限公司)随机分成6组,每组20只,分别为阴性处理组、WT HexaPro处理组、WT NP处理组、Cocktail NP处理组、Mosaic NP处理组和PBS处理组饲养于中山大学肿瘤防治中心实验动物中心。
(2)配制和免疫疫苗:将实施例1制得的WT HexaPro、WT NP、Cocktail NP和MosaicNP 用PBS溶液稀释至终浓度为1mg/mL;加入等体积的MF59佐剂(0.5%(v/v)Tween 80、0.5%(v/v)Span 85、4.3%(v/v)角鲨烯和10mM柠檬酸钠缓冲液,用0.22μm滤膜过滤除菌)轻轻混匀,在4℃孵育过夜,孵育过程中轻轻摇转使抗原充分粘附于佐剂;经皮下免疫的方式免疫小鼠, WT HexaPro的免疫剂量为5μg/只,纳米颗粒免疫原(WT NP、Cocktail NP和Mosaic NP)的免疫剂量为6.5μg/只(等摩尔质量于5μg WT HexaPro),PBS作为阴性对照。间隔三周加强一次免疫,共免疫2次。每次免疫间隔2周后,采集小鼠眼眶静脉血,分离血清,56℃灭活30min,使补体因子和病原体失活,-20℃保存,用于后续血清学和免疫学试验。
4.2总IgG滴度的测定
将分离得到的血清通过ELISA试验测定小鼠血清抗SARS-CoV-2HexaPro结合的总IgG滴度。
具体试验过程如下:将1μg/mL的SARS-CoV-2野生型(包括 SARS-CoV-2/human/CHN/IQTC01/2020,GenBank accession ID:MT123290.1和2020XN4276,GISAID accessionID:EPI_ISL_413859)、Alpha(2021A-XG02292,Lineage:B.1.1.7)、Beta (20SF18530,Lineage:B.1.351,GISAID accession ID:EPI_ISL_2536954)、Gamma(2021A-XG04123,Lineage:P1)、Delta(2021K-XG0186,Lineage:B.1.617.2)和Eta (2021A-XG02275,Lineage:B.1.525)变异株的HexaPro分别包被于96孔ELISA板,每孔30ng, 4℃孵育过夜;PBST清洗1次(350μL/孔),每孔加入350μL封闭液(含有5%(w/v)酪蛋白和2%(w/v)明胶的PBS),4℃孵育过夜;PBST清洗1次(350μL/孔),每孔加入100μL血清 (血清以起始浓度1:100稀释,以10倍为梯度,以PBS为稀释液,连续稀释8个梯度),37℃孵育1h;PBST清洗5次(350μL/孔),每孔加入100μL 1:5000稀释的辣根过氧化物酶共轭的山羊抗鼠的总IgG抗体(Abcam公司,货号:ab6789),37℃孵育45min;PBST洗5次(350μL/ 孔),每孔加入100μL TMB显色液,37℃孵育15min;加入50μL终止液(用蒸馏水1:12稀释的浓盐酸)终止反应;用EpochTM 2微孔板分光光度计(BioTek)测定450nm和630nm处的吸光度值。ELISA结合终点滴度定义为吸光度超过0.2的血清最高稀释度的倒数。
4.3血清中和抗体滴度的测定
采用假病毒建立的中和试验和细胞病变建立的活病毒中和试验测定血清中和抗体滴度。
假病毒建立的中和试验的具体试验过程如下:
(1)制备SARS-CoV-2假病毒:使用基于HIV慢病毒方法(pNL4-3.Luc.R-E-系统,具体方法参考XIA S,LIU M et al,Inhibition of SARS-CoV-2(previously 2019-nCoV)infection by a highly potent pan-coronavirus fusion inhibitor targeting itsspike protein that harbors a high capacity to mediate membrane fusion.CellRes,2020,30(4):343-355)制备SARS-CoV-2野生型和突变株 (包括Alpha,Beta,Gamma,Delta和Eta)的假病毒;
(2)假病毒中和实验:小鼠血清以起始浓度为1:40,以4倍为梯度梯度,DMEM减血清培养基为稀释液,连续稀释8个梯度,每个处理平行3次;将稀释后的血清加入等体积的假病毒,共100μL,于37℃孵育2h;随后将100μL假病毒-血清混合物加入至预先铺好的1.5×104个/孔的hACE2-HEK293T细胞中,感染48h,弃去细胞上清,加入50μL预混好Steady-Gloluciferase底物的1×裂解液(Promega公司,货号E2520),室温裂解10min,使用GloMaxNavigator GM2010光度计(Promega)测量样品的荧光素酶活性。采用GraphPad Prismv.8.0软件进行4 参数非线性回归拟合的S型曲线计算。每个血清样品重复两次。IC50定义为感染后能够中和50%的假病毒的血清最大倍稀释数的倒数。
细胞病变建立的活病毒中和试验的具体过程如下:
小鼠血清以起始浓度为1:40稀释,以4倍为梯度,DMEM减血清培养基为稀释液,连续稀释6个梯度,将稀释的血清样本中加入等体积的100组织培养感染剂量(median tissueculture infective dose,TCID50)SARS-CoV-2活病毒(分别为SARS-CoV-2野生型和突变株(Alpha、 Beta、Gamma、Delta和Eta)),共100μL,在37℃孵育2h,随后将100μL病毒-血清混合物加至预铺好的Vero-E6细胞(15000个/孔)中,在37℃,5%CO2的条件下孵育,在3~5天内连续观察细胞病变情况,计算中和抗体滴度(NT50)。每个血清样品重复两次。NT50被定义为感染后能够中和50%的活病毒的血清最大稀释倍数的倒数。
通过ELISA、假病毒建立的中和试验和细胞病变建立的活病毒中和试验测定各疫苗免疫小鼠后对SARS-CoV-2病毒的免疫原性,结果如图8所示,在第一次和第二次免疫接种之后,WT NP对SARS-CoV-2野生型和突变株(Alpha,Beta,Gamma,Delta和Eta)的Spike特异性总 IgG滴度、假病毒中和抗体滴度和活病毒中和抗体滴度相等或者略高于WT HexaPro。随着免疫次数的增加,WT NP、Cocktail NP和Mosaic NP结合抗体滴度和中和抗体滴度随之增加。另外,我们发现接种Mosaic NP和Cocktail NP对SARS-CoV-2突变株(Alpha,Beta,Gamma,Delta和 Eta)的Spike特异性总IgG滴度、假病毒中和抗体滴度和活病毒中和抗体滴度相等或略高于与 WT NP对SARS-CoV-2突变株的Spike特异性总IgG滴度、假病毒中和抗体滴度和活病毒中和抗体滴度,尽管两者之间没有显著的统计学差异,表明纳米颗粒嵌合多种SARS-CoV-2Spike抗原制备成的多价疫苗能够提升疫苗的免疫原性,增强体液免疫反应,特别是对突变株。
实施例5嵌合四价纳米颗粒疫苗对食蟹猴的免疫原性
基于BALB/C鼠免疫原性实验结果,选择WT NP和Mosaic NP两种纳米颗粒疫苗对食蟹猴的免疫原性做进一步的研究。
5.1免疫食蟹猴
具体实验步骤如下:
(1)食蟹猴分组:将8只14个月大的食蟹猴(6只雌性和2只雄性,体重在1.5到1.8公斤之间,购买于康瑞泰(湛江)生物技术有限公司)随机分成2组,每组4只,单笼饲养于广东省科学院动物研究所灵长类动物研究中心,动物伦理审查编号为GZZ20201201。
(2)配制和免疫疫苗:将实施例1制得的WT NP和Mosaic NP用PBS溶液稀释至终浓度为1mg/mL;加入等体积的MF59佐剂(0.5%(v/v)Tween 80、0.5%(v/v)Span 85、4.3%(v/v)角鲨烯和10mM柠檬酸钠缓冲液,用0.22μm滤膜过滤除菌)轻轻混匀,在4℃孵育过夜,孵育过程中轻轻摇转使抗原充分粘附于佐剂;经皮下免疫的方式免疫食蟹猴,每只食蟹猴在第0、第4 和第8周免疫65μg的WT NP或Mosaic NP(等摩尔质量的50μg HexaPro),每次免疫后间隔 2周采集静脉血,分离得到血清,-20℃保存备用。
5.2总IgG滴度和中和抗体滴度的测定
具体测定方法同实施例4.2和4.3,唯一不同的是,食蟹猴血清以起始浓度为1:40开始稀释。
基于SARS-CoV-2纳米颗粒疫苗在小鼠的潜在交叉中和抗体和效力和广度,我们进一步评估了WT NP和Mosaic NP在食蟹猴体内的免疫原性。结果如图9所示,Mosaic NP对突变株 (Alpha,Beta,Gamma,Delta和Eta)的Spike特异性总IgG滴度、假病毒中和抗体滴度和活病毒中和抗体滴度相等或略高于WT NP,Mosaic NP对SARS-CoV-2野生型菌株的Spike特异性总IgG滴度、假病毒中和抗体滴度和活病毒中和抗体滴度相等或略低于WT NP。
同时本研究也评估了Mosaic NP免疫食蟹猴三剂之后第2周,评估了疫苗诱导的血清对新流行株(如Kappa,Lambda和Omicron变异株)以及影响抗体/疫苗血清中和的RBD单个或组合关键残基突变(K417N/T、L452R、T478K、E484K/Q、N501Y)的变异株的中和抗体活性,结果如图10所示,相对于WT NP,通过假病毒中和实验确证了嵌合疫苗能够诱导的更高的中和抗体水平,ID50保持在103.9~105.2左右。
实施例6嵌合四价纳米颗粒疫苗保护BALB/c免受SARS-CoV-2野生型和南非变异株感染 6.1嵌合四价纳米颗粒疫苗对SARS-CoV-2南非变种的免疫保护效果
按实施例4.1中的方法免疫BALB/c小鼠(共60只,每组10只,包括阴性处理组、WTHexaPro 处理组、WT NP处理组、Cocktail NP处理组、Mosaic NP处理组和PBS处理组),在第二次加强免疫4周之后,转移至广州海关技术中心BSL-3级实验室进行SARS-CoV-2南非变种感染实验;小鼠经过异氟烷轻度麻醉,滴鼻接种50μL 1×105噬菌斑形成单位(plaque-forming units,PFU) 的SARS-CoV-2 B.1.351变种活病毒;小鼠感染病毒之后,每天监测体重,直至第8天。在感染病毒第二天,每组小鼠安乐死4只小鼠,收集肺脏,通过病毒蚀斑减少实验测定病毒滴度测定。在感染病毒第四天,将小鼠麻醉后经腹腔灌流30mL PBS后进行安乐死,收集肺脏;室温(25℃) 下,将肺脏用25mL新鲜福尔马林固定7天,进行HE染色和免疫组织化学检查。
为了评估嵌合四价纳米颗粒疫苗诱导血清中和潜能,对小鼠免疫疫苗四周之后通过滴鼻接种鼠适应的SARS-CoV-2 B.1.351活病毒(南非株)。PBS免疫的小鼠在病毒感染之后第1天,体重逐渐下降,在第4天下降至最低,下降了14.6%,随后又逐渐恢复。而所有接种疫苗的小鼠组在8天观察期几乎完全阻止体重下降(图11中a)。攻毒两天之后,采集肺脏进行活病毒滴度的滴定,结果如图11中b所示,基于HexaPro设计的疫苗免疫小鼠肺脏没有检测到感染性病毒。攻毒4天之后,采集肺脏,经福尔马林固定用于HE染色和免疫组织化学检查,结果如图11中c所示,PBS处理的小鼠肺脏的毛细血管积聚大量的炎症细胞,导致肺泡损伤,肺泡间隙塌陷,并滞留大量病毒抗原;相反,基于HexaPro的疫苗组的肺脏含有少量的病毒抗原和炎症细胞,特别是Mosaic NP疫苗组,其肺脏与正常小鼠的肺脏无明显差异,表明四价嵌合纳米颗粒疫苗能够完全保护鼠免受南非株的攻击。
6.2嵌合四价纳米颗粒疫苗对SARS-CoV-2野生型毒株的免疫保护效果
按照实施例4.1中的方法免疫BALB/c小鼠(共60只,每组10只,包括阴性处理组、WTHexaPro处理组、WT NP处理组、Cocktail NP处理组、Mosaic NP处理组和PBS处理组),在第二次免疫加强3周之后,以异氟烷轻度麻醉,滴鼻接种75μL含有2.5×108PFU的Ad5-ACE2 腺病毒的DMEM培养基;感染5天之后,将小鼠转移至广州海关技术中心BSL-3级实验室进行SARS-CoV-2野生型活病毒感染实验;小鼠经过异氟烷轻度麻醉,滴鼻接种50μL 1×105PFU的SARS-CoV-2 B.1.351野生型活病毒;小鼠感染病毒之后,每天监测体重,直至第8天。在感染病毒第二天,每组小鼠安乐死4只小鼠,收集肺脏,通过病毒蚀斑减少实验测定病毒滴度测定。在感染病毒第4天,将小鼠麻醉后经腹腔灌流30mL PBS后进行安乐死,收集肺脏;室温下,将肺脏用25mL新鲜福尔马林固定7天,进行HE染色和免疫组织化学检查。
我们将小鼠第二次接种疫苗4周之后,转导Ad5-ACE2腺病毒,并在转导之后5天接种 SARS-CoV-2野生型活病毒,从图12可以看出,PBS免疫的小鼠在病毒感染之后第1天,体重逐渐下降,在第4天下降至最低,随后又逐渐恢复;而免疫WT NP、Cocktail NP和MosaicNP 的小鼠组在病毒感染1天后体重逐渐下降,但在第3天体重逐渐恢复(图12中a)。攻毒两天之后,采集肺脏进行活病毒滴度的滴定,结果如图12中b所示,免疫WT NP、Cocktail NP和Mosaic NP的小鼠肺脏没有检测到感染性病毒。攻毒四天之后,采集肺脏,经福尔马林固定用于 HE染色和免疫组织化学检查,结果如图12中c所示,PBS处理的小鼠肺脏的毛细血管积聚大量的炎症细胞,肺泡间隙塌陷,并滞留大量病毒抗原;相反,疫苗免疫的小鼠的肺脏含有少量的病毒抗原和炎症细胞,特别是Mosaic NP疫苗组,其肺脏与正常小鼠的肺脏无明显差异,表明四价嵌合纳米颗粒疫苗能够完全保护鼠免受SARS-CoV-2野生型活病毒的攻击。上述结果与感染南非株的保护效率一致。
上面结合附图对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
SEQUENCE LISTING
<110> 中山大学肿瘤防治中心(中山大学附属肿瘤医院、中山大学肿瘤研究所)
<120> 一种四价SARS-CoV-2嵌合纳米颗粒疫苗及其制备方法与应用
<130>
<160> 14
<170> PatentIn version 3.5
<210> 1
<211> 1123
<212> PRT
<213> Wild type HexaPro
<400> 1
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
1 5 10 15
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
20 25 30
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
35 40 45
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
50 55 60
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
65 70 75 80
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
85 90 95
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
100 105 110
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
115 120 125
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
130 135 140
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
145 150 155 160
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
165 170 175
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
180 185 190
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
195 200 205
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
210 215 220
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
225 230 235 240
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
245 250 255
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
260 265 270
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
275 280 285
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
290 295 300
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
305 310 315 320
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
325 330 335
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
340 345 350
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
355 360 365
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
370 375 380
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
385 390 395 400
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
405 410 415
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
420 425 430
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
435 440 445
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
450 455 460
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
465 470 475 480
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
485 490 495
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
500 505 510
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
515 520 525
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
530 535 540
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
545 550 555 560
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
565 570 575
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
580 585 590
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
595 600 605
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
610 615 620
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
625 630 635 640
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
645 650 655
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Gly Ser Ala Ser Ser Val
660 665 670
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
675 680 685
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
690 695 700
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
705 710 715 720
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
725 730 735
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
740 745 750
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
755 760 765
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
770 775 780
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
785 790 795 800
Ser Pro Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
805 810 815
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
820 825 830
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
835 840 845
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
850 855 860
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Pro Ala Leu Gln
865 870 875 880
Ile Pro Phe Pro Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
885 890 895
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
900 905 910
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Pro Ser
915 920 925
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
930 935 940
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
945 950 955 960
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val
965 970 975
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
980 985 990
Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
995 1000 1005
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1010 1015 1020
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1025 1030 1035
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1040 1045 1050
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1055 1060 1065
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1070 1075 1080
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1085 1090 1095
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1100 1105 1110
Val Ile Gly Ile Val Asn Asn Thr Val Tyr
1115 1120
<210> 2
<211> 1120
<212> PRT
<213> Alpha HexaPro
<400> 2
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
1 5 10 15
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
20 25 30
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
35 40 45
Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn
50 55 60
Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys
65 70 75 80
Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys
85 90 95
Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys
100 105 110
Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr His
115 120 125
Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser Ser
130 135 140
Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp
145 150 155 160
Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe
165 170 175
Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile
180 185 190
Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu
195 200 205
Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu
210 215 220
Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp
225 230 235 240
Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr
245 250 255
Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp
260 265 270
Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe
275 280 285
Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro
290 295 300
Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe
305 310 315 320
Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn
325 330 335
Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn
340 345 350
Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys
355 360 365
Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile
370 375 380
Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile
385 390 395 400
Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile
405 410 415
Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn
420 425 430
Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg
435 440 445
Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly
450 455 460
Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln
465 470 475 480
Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser
485 490 495
Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser
500 505 510
Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu
515 520 525
Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe
530 535 540
Gln Gln Phe Gly Arg Asp Ile Asp Asp Thr Thr Asp Ala Val Arg Asp
545 550 555 560
Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly
565 570 575
Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val
580 585 590
Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala
595 600 605
Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val
610 615 620
Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn
625 630 635 640
Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr
645 650 655
Gln Thr Gln Thr Asn Ser His Gly Ser Ala Ser Ser Val Ala Ser Gln
660 665 670
Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala
675 680 685
Tyr Ser Asn Asn Ser Ile Ala Ile Pro Ile Asn Phe Thr Ile Ser Val
690 695 700
Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys
705 710 715 720
Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu
725 730 735
Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile
740 745 750
Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys
755 760 765
Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe
770 775 780
Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Pro Ile
785 790 795 800
Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile
805 810 815
Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile
820 825 830
Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr
835 840 845
Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile
850 855 860
Thr Ser Gly Trp Thr Phe Gly Ala Gly Pro Ala Leu Gln Ile Pro Phe
865 870 875 880
Pro Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn
885 890 895
Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala
900 905 910
Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Pro Ser Ala Leu Gly
915 920 925
Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu
930 935 940
Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn
945 950 955 960
Asp Ile Leu Ala Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp
965 970 975
Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln
980 985 990
Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala
995 1000 1005
Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp
1010 1015 1020
Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1025 1030 1035
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
1040 1045 1050
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys
1055 1060 1065
Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His
1070 1075 1080
Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr
1085 1090 1095
Thr His Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly
1100 1105 1110
Ile Val Asn Asn Thr Val Tyr
1115 1120
<210> 3
<211> 1120
<212> PRT
<213> Beta HexaPro
<400> 3
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
1 5 10 15
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
20 25 30
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
35 40 45
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
50 55 60
Ala Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
65 70 75 80
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
85 90 95
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
100 105 110
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
115 120 125
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
130 135 140
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
145 150 155 160
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
165 170 175
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
180 185 190
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
195 200 205
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
210 215 220
Thr Leu His Ile Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp
225 230 235 240
Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr
245 250 255
Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp
260 265 270
Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe
275 280 285
Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro
290 295 300
Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe
305 310 315 320
Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn
325 330 335
Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn
340 345 350
Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys
355 360 365
Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile
370 375 380
Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Asn Ile
385 390 395 400
Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile
405 410 415
Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn
420 425 430
Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg
435 440 445
Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly
450 455 460
Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln
465 470 475 480
Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser
485 490 495
Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser
500 505 510
Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu
515 520 525
Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe
530 535 540
Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp
545 550 555 560
Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly
565 570 575
Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val
580 585 590
Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala
595 600 605
Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val
610 615 620
Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn
625 630 635 640
Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr
645 650 655
Gln Thr Gln Thr Asn Ser Pro Gly Ser Ala Ser Ser Val Ala Ser Gln
660 665 670
Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Val Glu Asn Ser Val Ala
675 680 685
Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val
690 695 700
Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys
705 710 715 720
Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu
725 730 735
Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile
740 745 750
Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys
755 760 765
Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe
770 775 780
Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Pro Ile
785 790 795 800
Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile
805 810 815
Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile
820 825 830
Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr
835 840 845
Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile
850 855 860
Thr Ser Gly Trp Thr Phe Gly Ala Gly Pro Ala Leu Gln Ile Pro Phe
865 870 875 880
Pro Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn
885 890 895
Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala
900 905 910
Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Pro Ser Ala Leu Gly
915 920 925
Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu
930 935 940
Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn
945 950 955 960
Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp
965 970 975
Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln
980 985 990
Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala
995 1000 1005
Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp
1010 1015 1020
Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1025 1030 1035
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
1040 1045 1050
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys
1055 1060 1065
Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His
1070 1075 1080
Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr
1085 1090 1095
Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly
1100 1105 1110
Ile Val Asn Asn Thr Val Tyr
1115 1120
<210> 4
<211> 1123
<212> PRT
<213> Gamma HexaPro
<400> 4
Val Asn Phe Thr Asn Arg Thr Gln Leu Pro Ser Ala Tyr Thr Asn Ser
1 5 10 15
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
20 25 30
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
35 40 45
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
50 55 60
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
65 70 75 80
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
85 90 95
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
100 105 110
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Tyr Pro Phe Leu Gly Val
115 120 125
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
130 135 140
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
145 150 155 160
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Ser Glu
165 170 175
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
180 185 190
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
195 200 205
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
210 215 220
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
225 230 235 240
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
245 250 255
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
260 265 270
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
275 280 285
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
290 295 300
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
305 310 315 320
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
325 330 335
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
340 345 350
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
355 360 365
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
370 375 380
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
385 390 395 400
Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
405 410 415
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
420 425 430
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
435 440 445
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
450 455 460
Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
465 470 475 480
Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
485 490 495
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
500 505 510
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
515 520 525
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
530 535 540
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
545 550 555 560
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
565 570 575
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
580 585 590
Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala
595 600 605
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
610 615 620
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu Tyr
625 630 635 640
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
645 650 655
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Gly Ser Ala Ser Ser Val
660 665 670
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
675 680 685
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
690 695 700
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
705 710 715 720
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
725 730 735
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
740 745 750
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
755 760 765
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
770 775 780
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
785 790 795 800
Ser Pro Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
805 810 815
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
820 825 830
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
835 840 845
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
850 855 860
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Pro Ala Leu Gln
865 870 875 880
Ile Pro Phe Pro Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
885 890 895
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
900 905 910
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Pro Ser
915 920 925
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
930 935 940
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
945 950 955 960
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val
965 970 975
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
980 985 990
Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
995 1000 1005
Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1010 1015 1020
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1025 1030 1035
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1040 1045 1050
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1055 1060 1065
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1070 1075 1080
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1085 1090 1095
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1100 1105 1110
Val Ile Gly Ile Val Asn Asn Thr Val Tyr
1115 1120
<210> 5
<211> 203
<212> PRT
<213> I53-50A1
<400> 5
Met Glu Glu Leu Phe Lys Lys His Lys Ile Val Ala Val Leu Arg Ala
1 5 10 15
Asn Ser Val Glu Glu Ala Ile Glu Lys Ala Val Ala Val Phe Ala Gly
20 25 30
Gly Val His Leu Ile Glu Ile Thr Phe Thr Val Pro Asp Ala Asp Thr
35 40 45
Val Ile Lys Ala Leu Ser Val Leu Lys Glu Lys Gly Ala Ile Ile Gly
50 55 60
Ala Gly Thr Val Thr Ser Val Glu Gln Cys Arg Lys Ala Val Glu Ser
65 70 75 80
Gly Ala Glu Phe Ile Val Ser Pro His Leu Asp Glu Glu Ile Ser Gln
85 90 95
Phe Cys Lys Glu Lys Gly Val Phe Tyr Met Pro Gly Val Met Thr Pro
100 105 110
Thr Glu Leu Val Lys Ala Met Lys Leu Gly His Asp Ile Leu Lys Leu
115 120 125
Phe Pro Gly Glu Val Val Gly Pro Gln Phe Val Lys Ala Met Lys Gly
130 135 140
Pro Phe Pro Asn Val Lys Phe Val Pro Thr Gly Gly Val Asn Leu Asp
145 150 155 160
Asn Val Cys Lys Trp Phe Lys Ala Gly Val Leu Ala Val Gly Val Gly
165 170 175
Lys Ala Leu Val Lys Gly Lys Pro Asp Glu Val Arg Glu Lys Ala Lys
180 185 190
Lys Phe Val Lys Lys Ile Arg Gly Cys Thr Glu
195 200
<210> 6
<211> 27
<212> PRT
<213> 三聚体结构域
<400> 6
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
1 5 10 15
Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25
<210> 7
<211> 16
<212> PRT
<213> 柔性lingker
<400> 7
Gly Gly Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly Gly Ser Gly Ser
1 5 10 15
<210> 8
<211> 12
<212> PRT
<213> 刚性lingker
<400> 8
Glu Lys Ala Ala Lys Ala Glu Glu Ala Ala Arg Lys
1 5 10
<210> 9
<211> 25
<212> PRT
<213> TPA信号肽
<400> 9
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ala Ser
20 25
<210> 10
<211> 4155
<212> DNA
<213> Wild type HexaPro-I53-50A
<400> 10
gtgaacctaa caactagaac ccagttgccg cctgcttaca ccaactcctt cacccgaggc 60
gtgtactacc ccgataaggt gttccggagc agcgtgctgc acagcacaca ggatctgttc 120
ctccctttct tctccaacgt gacctggttc cacgccatcc acgtgtctgg caccaatggt 180
accaagagat tcgacaaccc tgtgctgccc ttcaacgatg gcgtgtactt cgccagcacc 240
gagaagagca acataatccg gggctggatc ttcggaacaa ccctggactc taagacccag 300
agccttctga tagtgaacaa cgccaccaac gtcgtaatca aggtgtgtga attccaattt 360
tgcaacgacc ccttcctggg agtgtactac cacaagaaca acaagagttg gatggaaagc 420
gagttcagag tgtacagctc tgccaacaac tgtacattcg agtacgtcag ccagcccttc 480
ctgatggacc tcgagggcaa gcaggggaac ttcaaaaatc tgcgggagtt cgttttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacaccc ctatcaatct ggtgcgggac 600
ctgcctcagg gctttagcgc cctggaaccc ctggtggatc tgcctatcgg gatcaacatc 660
actagattcc agaccctgct tgccctgcac agaagctacc tgacccctgg cgacagctcc 720
agcggctgga cagccggcgc cgccgcctat tatgtgggct acctgcagcc taggaccttc 780
ctcctgaagt acaacgagaa cggcacaatc accgatgccg tggattgtgc cctggaccct 840
ctgagcgaga ctaagtgtac gctgaagagc ttcaccgtgg agaagggcat ctaccaaacc 900
agcaacttcc gggtgcagcc tacagagagc atcgtgcgat tcccgaacat caccaacctc 960
tgtccttttg gagaggtgtt caacgccacc cggtttgctt ctgtgtacgc ctggaaccgc 1020
aagcgcatct ctaattgcgt ggccgactac agcgtgctgt acaatagcgc cagcttcagc 1080
accttcaagt gctacggagt cagccccacc aagctgaacg atctgtgctt caccaatgtg 1140
tacgccgact ctttcgtgat tagaggcgac gaggttcgcc agatcgctcc cggccagaca 1200
ggcaaaatcg ccgactacaa ctacaagctg cccgacgact tcaccggctg cgtgatcgcc 1260
tggaattcta acaatctgga ttctaaggtg ggcggtaact acaactacct gtacagactg 1320
tttagaaaga gcaacctgaa gcctttcgag cgggacatca gtaccgagat ctaccaggcc 1380
ggtagcacac cttgtaacgg cgttgagggc ttcaactgct actttccact gcagtcatac 1440
ggcttccagc caacaaatgg cgtgggatac cagccttaca gagtggtggt cctgagcttt 1500
gagctgctgc acgcccctgc cacagtgtgc ggacccaaga aaagcacaaa cctggtgaag 1560
aacaagtgcg tcaacttcaa cttcaacggc ctgacaggca ccggcgtact gaccgagtcc 1620
aataaaaagt tcctcccctt tcagcagttc ggcagagata tcgccgacac gaccgacgct 1680
gtgcgggacc cccagaccct ggaaatcctg gacatcaccc cctgctcctt cggcggcgtg 1740
agcgtgatca ccccaggcac caacacaagc aatcaggtgg cagtgctgta ccaggacgtc 1800
aactgcactg aggtgccagt ggccatccat gccgaccagc tgacccctac ttggcgggtg 1860
tattctacag gcagcaacgt gttccagacc agagccggct gtctgatcgg cgctgaacac 1920
gtgaacaata gctacgagtg cgatatccct atcggcgccg gcatctgcgc ctcttatcag 1980
actcagacca acagccccgg aagcgccagc tccgtggcca gccagagcat catcgcctac 2040
accatgtccc tgggcgctga aaactctgtg gcttactcta acaacagcat cgccatcccc 2100
accaacttca caatcagcgt cacaacagag attctgcctg tgagcatgac caagacctct 2160
gtggactgca cgatgtacat ctgcggcgat agcaccgaat gcagcaacct gctgctgcaa 2220
tacggcagct tctgcaccca gctgaatcgg gccctgaccg gaatcgccgt ggagcaggac 2280
aagaacaccc aagaggtgtt cgcccaagtg aagcagatct acaagacacc ccccattaag 2340
gactttggcg gatttaactt cagtcaaatc ctgcctgatc ctagcaaacc tagcaagaga 2400
tctccaatcg aggacctgct ctttaacaag gtgacactgg ccgacgccgg cttcatcaag 2460
cagtacggcg actgcctggg cgacatcgcc gccagagatc tcatctgtgc tcaaaaattc 2520
aacggactga ccgtcctgcc tccactgctg acagacgaga tgatcgccca gtacacctca 2580
gccctgttgg ctggcacaat cactagcgga tggaccttcg gcgccggccc cgccctgcag 2640
atcccctttc ccatgcagat ggcctacaga ttcaacggca ttggcgttac ccagaacgtg 2700
ctgtatgaaa accagaagct gatcgctaac cagttcaaca gcgccatcgg caagatccag 2760
gacagcctgt cttctacccc ttctgccctt ggcaagctgc aggacgtggt caatcaaaat 2820
gcccaggccc tgaacactct ggtgaagcag ctgagcagca acttcggcgc tataagctcc 2880
gtgctgaacg atatcctgag tagactggac cctcctgagg ccgaggtcca gatcgacaga 2940
ctgattacag gcagactgca gagcctacag acctacgtga cccagcagct catccgggcg 3000
gcagagatcc gggccagcgc caacctggct gccacaaaga tgagcgaatg tgttctggga 3060
caaagcaagc gcgtggactt ctgcggcaaa ggctatcacc tgatgtcttt tcctcagtcc 3120
gccccgcacg gcgtggtgtt cctgcatgtg acatacgtgc ctgcccagga gaagaacttc 3180
actaccgccc ctgctatttg tcacgatggc aaggcccact tccctagaga aggcgtgttt 3240
gtgtctaacg gaacacactg gttcgtcaca caaagaaact tctacgagcc tcaaatcatc 3300
accaccgaca acacctttgt gtccggcaat tgcgatgtgg tgatcggaat tgtgaacaac 3360
accgtgtacg gcagcggcgg cggctacatc cctgaggccc ctagagatgg ccaggcgtac 3420
gtgcggaaag acggagaatg ggtgctgctg agcacctttc tgggcggctc cggaggcagc 3480
ggctccgggg gaagcggcgg cagcggcagc gagaaggccg ctaaagccga ggaagccgct 3540
agaaagatgg aggaactgtt caagaaacac aaaatcgtgg cggttctgcg tgcgaacagc 3600
gttgaggaag cgattgagaa agcggtggcg gtttttgcgg gtggcgtgca cctgatcgaa 3660
attaccttta ccgtgccgga cgcggatacc gttatcaagg cgctgagcgt gctgaaggag 3720
aaaggtgcga tcattggtgc gggcaccgtg accagcgttg aacagtgccg taaagcggtt 3780
gagagcggcg cggaatttat cgtgagcccg cacctggacg aggaaattag ccaattctgc 3840
aaggagaagg gtgtgttcta catgccgggc gtgatgaccc cgaccgaact ggttaaggcg 3900
atgaaactgg gtcacgatat cctgaagctg ttcccgggtg aggtggttgg cccgcagttt 3960
gtgaaggcga tgaaaggccc gttcccgaac gtgaaatttg ttccgaccgg tggcgtgaac 4020
ctggacaacg tttgcaagtg gttcaaagcg ggtgttctgg cggtgggtgt tggcaaggcg 4080
ctggttaagg gcaaaccgga tgaagtgcgt gaaaaggcga agaaattcgt gaagaaaatt 4140
cgtggttgca ccgag 4155
<210> 11
<211> 4146
<212> DNA
<213> Alpha HexaPro-I53-50A
<400> 11
gtgaacctga caacaagaac ccagctcccg cctgcctaca ccaacagctt tacaagaggc 60
gtgtactacc ccgacaaggt gttcagatcc tccgtgctgc acagcactca agacctgttc 120
ctgcctttct tcagcaacgt gacatggttc cacgccatca gcggcaccaa cggcaccaag 180
aggttcgaca accccgtgct ccctttcaat gacggcgtgt acttcgcctc tacagagaag 240
agcaacatca tccggggatg gatcttcggc acaacactgg actctaagac ccagagtctg 300
ctgattgtga acaatgccac gaacgtggtc atcaaggtgt gcgaattcca gttctgcaac 360
gaccccttcc tgggcgtgta ccacaagaac aataaatcct ggatggaatc tgaatttcgg 420
gtgtatagca gcgccaataa ctgcaccttc gagtacgtgt cccagccgtt cctgatggac 480
ctggaaggca aacagggaaa cttcaagaat ctgcgggagt ttgtgtttaa gaacattgac 540
ggctacttca agatctactc taaacatact cctatcaacc tcgtgcggga tctgccgcag 600
ggctttagcg ccctggaacc tctggtggac ctgcctatcg gcatcaacat tactagattc 660
cagaccctcc tggcgctgca tagatcttat ctgacccccg gcgattctag ctctggctgg 720
accgccggtg ctgcagccta ttacgtcgga tacctgcaac cccggacctt cctgcttaag 780
tacaacgaga acggcaccat cacagatgcc gtggactgcg ccctggaccc tctgagtgaa 840
accaagtgca ccctgaagag cttcaccgtg gaaaaaggca tctaccagac ctccaacttc 900
cgggtgcagc ctaccgagag catcgtgcga ttccccaata tcaccaacct gtgccctttc 960
ggagaggtgt tcaacgccac cagattcgcc agcgtgtacg cctggaacag aaagcggatc 1020
agcaattgtg ttgctgacta cagcgttctg tacaacagcg ccagcttcag cacgttcaag 1080
tgctacggcg taagccccac aaagctgaac gacctgtgtt ttaccaacgt gtacgccgat 1140
tccttcgtga tcaggggcga cgaggtgaga cagatcgccc ctggtcagac cgggaagatc 1200
gccgactaca actacaagct gccagacgac ttcaccggct gtgtgatcgc ctggaacagc 1260
aacaacctgg atagcaaagt gggcggcaac tataactacc tgtacagact gttcagaaag 1320
tctaacctca aacctttcga gagagatatc tccacagaaa tctaccaggc cggcagcaca 1380
ccatgcaacg gcgtggaggg cttcaattgt tacttccccc tccagagcta cggcttccaa 1440
cctacctacg gcgtgggcta ccagccttac cgggtcgtcg tgctctcttt cgagctgctg 1500
cacgcccctg ctacagtgtg cggccctaag aagagcacca acctggtgaa aaacaaatgc 1560
gtgaacttca acttcaacgg cctgaccgga acaggagtac tgaccgagag caacaagaag 1620
ttcctgccct ttcagcagtt cggcagagat atcgatgata ccaccgacgc cgtgcgcgac 1680
ccccaaacac tggaaatcct ggatataacc ccctgtagct tcggcggcgt gtcggttatc 1740
acccctggaa ccaatacctc caaccaggtt gccgtgctat accagggcgt gaactgcaca 1800
gaagtccccg tggccatcca cgccgatcag ctgactccta cctggcgggt gtactctaca 1860
ggctccaatg tgtttcaaac acgagccggc tgtctgatcg gcgctgagca cgtgaacaac 1920
agctatgagt gcgacatccc catcggcgct ggaatctgcg cctcttatca gactcagacc 1980
aatagccacg gcagcgccag cagcgtcgcc agccagagca tcatcgccta caccatgagc 2040
ctcggcgccg aaaactcagt ggcttacagc aacaactcca ttgctatacc tatcaatttt 2100
acgatcagtg tgactaccga gatcctgcca gttagcatga caaagaccag cgtggactgc 2160
accatgtata tctgcggcga cagtacagag tgcagcaacc tgctgctgca gtacggcagc 2220
ttctgtaccc agctgaacag agccctgacc ggcatcgccg tggaacagga caagaacacc 2280
caggaggtgt ttgcccaggt gaaacagata tacaagacac cgcctattaa ggacttcggc 2340
ggattcaact tcagccaaat tctgcctgat cctagcaagc ccagcaagag aagccctatc 2400
gaggacctgc tctttaacaa ggtcaccctg gctgacgccg gattcatcaa gcagtacgga 2460
gattgcctgg gcgacatcgc cgcccgggac ctgatctgcg cccagaaatt caatggactg 2520
accgtgctgc cacctctgct tacagatgag atgatcgccc aatacacatc tgcactgctg 2580
gctggcacca tcaccagcgg atggacattt ggcgctggcc ctgccctgca gatccctttt 2640
cctatgcaga tggcctacag attcaacggc ataggcgtga cccagaatgt gctgtacgag 2700
aaccaaaaac tgatcgccaa ccagttcaac tcggccattg gaaagatcca ggatagcctc 2760
agctctacac ccagcgccct gggcaagctg caggacgtgg tgaaccagaa cgcccaggcc 2820
ctgaacaccc tggtgaagca gctgtccagt aactttggcg ctatcagcag cgtcctgaac 2880
gatatcttag ctcggctgga cccccctgag gccgaggtcc agatcgacag actgatcacc 2940
ggcagactgc agagcctgca aacatacgtc acacagcagc tgatccgtgc tgctgagatc 3000
agagcctcag ctaacctggc cgctacaaag atgagtgagt gtgtgctggg ccagtctaaa 3060
agagtggact tctgcggcaa gggctaccac ctgatgagct tccctcaatc agctcctcac 3120
ggcgtggtgt ttctgcacgt gacctacgtg cctgcccagg agaagaactt caccacggcc 3180
cctgccattt gccacgatgg aaaagcccac ttccctagag agggcgtgtt cgtgtctaac 3240
ggcacccact ggttcgtgac ccagagaaac ttctacgagc cccagatcat caccacacac 3300
aacacctttg tgtctggcaa ttgtgatgtg gtgatcggca tcgtgaacaa caccgtgtac 3360
ggctccggcg gcgggtatat ccctgaggcc cctagagacg gccaggccta cgtgcggaag 3420
gacggcgagt gggtgttact gagcaccttt ctgggcggaa gcggcggcag tggctctggc 3480
ggctccggtg gcagcggctc cgagaaggcg gccaaggccg aggaggccgc tagaaagatg 3540
gaggaactgt tcaagaaaca caaaatcgtg gcggttctgc gtgcgaacag cgttgaggaa 3600
gcgattgaga aagcggtggc ggtttttgcg ggtggcgtgc acctgatcga aattaccttt 3660
accgtgccgg acgcggatac cgttatcaag gcgctgagcg tgctgaagga gaaaggtgcg 3720
atcattggtg cgggcaccgt gaccagcgtt gaacagtgcc gtaaagcggt tgagagcggc 3780
gcggaattta tcgtgagccc gcacctggac gaggaaatta gccaattctg caaggagaag 3840
ggtgtgttct acatgccggg cgtgatgacc ccgaccgaac tggttaaggc gatgaaactg 3900
ggtcacgata tcctgaagct gttcccgggt gaggtggttg gcccgcagtt tgtgaaggcg 3960
atgaaaggcc cgttcccgaa cgtgaaattt gttccgaccg gtggcgtgaa cctggacaac 4020
gtttgcaagt ggttcaaagc gggtgttctg gcggtgggtg ttggcaaggc gctggttaag 4080
ggcaaaccgg atgaagtgcg tgaaaaggcg aagaaattcg tgaagaaaat tcgtggttgc 4140
accgag 4146
<210> 12
<211> 4146
<212> DNA
<213> Beta HexaPro-I53-50A
<400> 12
gtgaacctga caaccaggac ccaactgcct cctgcctaca ccaatagctt caccagaggt 60
gtgtactacc ctgataaggt gttccggagc agcgtgctgc attctacaca ggacctcttc 120
ctgcctttct tcagcaacgt gacctggttt cacgccatcc acgttagcgg caccaacggc 180
accaagcggt ttgccaaccc cgtgctgcct ttcaacgacg gcgtatactt tgcgagcacc 240
gagaagagca atatcatcag aggctggatc ttcggcacaa cactggactc caagacccaa 300
agcctgctga tcgtgaacaa cgctactaat gtggtgatca aggtatgcga attccagttc 360
tgcaacgatc ctttcctggg tgtgtattac cacaagaaca acaagagctg gatggaatct 420
gagttccggg tatactcctc tgccaacaac tgtaccttcg agtacgtgag ccaacctttt 480
ctaatggacc tggaaggcaa gcaaggcaat ttcaagaacc ttcgggaatt cgtgttcaag 540
aacatcgacg gctacttcaa gatctacagc aagcacacac ccatcaacct ggtgcgggac 600
ctgcctcaag gcttcagcgc cctggagcct ctggtggacc tgcctatcgg cattaacatc 660
accagattcc agactctgca catctcttac ctgacaccag gcgatagctc ctctggctgg 720
accgccggag ccgccgctta ctacgtgggc tacctgcagc ctcggacctt cctgctgaag 780
tacaacgaga acggcaccat aacagatgcc gtggactgcg ccctcgatcc cctgtctgaa 840
accaagtgca cactgaagag ttttaccgtg gagaaaggca tctaccagac cagcaacttc 900
agagtccagc ctactgagag tatcgtgcgc tttccaaaca tcaccaacct gtgtcctttc 960
ggcgaagtgt tcaacgccac cagatttgcc agcgtgtacg cctggaatag aaagagaatc 1020
agcaactgtg tggccgacta cagcgtgcta tacaactctg cctccttttc taccttcaag 1080
tgctacgggg tgtcccctac caaactgaac gacctctgct tcacaaacgt gtacgccgac 1140
agcttcgtga ttagaggcga tgaggtgaga cagatcgcac ccggccagac cggaaacatt 1200
gccgactaca actacaagct gcccgatgac ttcacaggct gcgtgattgc ttggaattcc 1260
aacaacctgg acagcaaagt gggcggcaac tacaattatc tgtaccggct cttcaggaaa 1320
agcaacctga agcctttcga gagagacatc agcaccgaga tttaccaggc cggctccaca 1380
ccctgtaatg gagtgaaagg attcaactgc tactttcctc tgcagagcta cggcttccag 1440
cctacctacg gcgtgggcta tcagccctac agagtggtgg ttctcagctt cgagctgctg 1500
cacgcccccg ccaccgtgtg cggccctaag aagagcacaa acctggtgaa gaacaaatgc 1560
gtgaatttca acttcaatgg cctgaccggc accggagttc tgacggagag caacaagaag 1620
ttcctgcctt tccagcagtt cggcagagat atcgccgata caaccgatgc cgtgagagat 1680
ccccagacac tggagatcct ggatatcacc ccttgcagct tcggaggcgt gtctgtgatc 1740
accccaggaa ccaacaccag caaccaggtc gccgtgctgt atcagggcgt caattgtaca 1800
gaagtgccgg tggctatcca cgccgaccag ctgacgccga cctggcgggt gtactctaca 1860
ggcagcaacg tgtttcagac cagagccggc tgtctgatcg gcgcagaaca cgtgaacaac 1920
tcctacgaat gtgacatccc tatcggcgct ggcatctgcg ccagttacca gacccagacc 1980
aacagccccg gcagcgccag cagcgtagcc agccagtcta tcatcgccta caccatgagc 2040
ctgggagtgg agaactccgt ggcctacagc aacaattcaa tcgctatccc tacaaacttc 2100
accatcagcg tgaccacaga gatcctgccc gtgtctatga ctaagaccag cgtagactgc 2160
acaatgtaca tctgtggcga ctctaccgaa tgtagcaact tactgcttca gtacggctca 2220
ttctgcaccc aactgaaccg ggccctgact ggcatcgccg tagagcagga caagaataca 2280
caggaagtgt tcgcccaggt gaagcagatc tataagaccc ctccaatcaa ggacttcggc 2340
ggctttaatt tcagccagat cctgccagac cctagcaaac ccagcaagag aagccctatt 2400
gaggacctgc tgttcaacaa ggtgacgctg gccgacgccg gcttcatcaa gcagtacggc 2460
gactgcctgg gcgacatcgc cgctagagac ctgatctgcg cccagaaatt caacggcctg 2520
acagtcctgc cgccactgct gaccgacgag atgatcgccc agtatacaag cgccctgctg 2580
gccggcacca tcaccagcgg ctggacattt ggcgcaggcc ccgccctgca gatccccttt 2640
cctatgcaga tggcctatag attcaacggc atcggagtga cacagaacgt gctctacgaa 2700
aaccagaagc tgatcgctaa tcagttcaac tctgcaatcg gcaagatcca ggatagcctg 2760
agcagcacgc cgagcgccct aggcaagctg caggatgtgg tgaaccagaa cgcccaggct 2820
ctgaataccc tagtgaagca actgtccagc aattttggag ctatcagcag cgtgcttaat 2880
gacatcctgt ctagactgga ccctccagaa gccgaggtgc agatcgatag actgatcacc 2940
ggcagactgc agagcctcca gacatacgtg acgcagcagc tgatccgcgc cgccgagatc 3000
cgggcttctg ctaacctggc cgccacaaag atgagcgagt gcgtgctggg acagtctaag 3060
cgggtagact tctgtggcaa gggctaccac ctgatgtcct tcccacagtc cgctccccac 3120
ggcgtggttt tcctgcacgt gacctacgtg cctgcccagg agaagaactt taccacagcc 3180
cctgccatct gtcacgacgg aaaggcccac ttccccagag agggcgtgtt cgtgagcaac 3240
ggcacacact ggttcgtgac ccaaagaaac ttctatgaac cccaaatcat caccaccgac 3300
aacaccttcg tgagcggcaa ctgcgatgtt gtgatcggca tcgtgaacaa cacggtttac 3360
ggctctggcg gaggctacat ccccgaggcc cctagagacg gtcaggccta cgtcagaaaa 3420
gacggagaat gggtgctgct gagcacattt ctcggcggaa gcggcggcag cggttctggt 3480
ggcagcggag gttctggcag tgaaaaggcc gctaaggcgg aagaagccgc cagaaagatg 3540
gaggaactgt tcaagaaaca caaaatcgtg gcggttctgc gtgcgaacag cgttgaggaa 3600
gcgattgaga aagcggtggc ggtttttgcg ggtggcgtgc acctgatcga aattaccttt 3660
accgtgccgg acgcggatac cgttatcaag gcgctgagcg tgctgaagga gaaaggtgcg 3720
atcattggtg cgggcaccgt gaccagcgtt gaacagtgcc gtaaagcggt tgagagcggc 3780
gcggaattta tcgtgagccc gcacctggac gaggaaatta gccaattctg caaggagaag 3840
ggtgtgttct acatgccggg cgtgatgacc ccgaccgaac tggttaaggc gatgaaactg 3900
ggtcacgata tcctgaagct gttcccgggt gaggtggttg gcccgcagtt tgtgaaggcg 3960
atgaaaggcc cgttcccgaa cgtgaaattt gttccgaccg gtggcgtgaa cctggacaac 4020
gtttgcaagt ggttcaaagc gggtgttctg gcggtgggtg ttggcaaggc gctggttaag 4080
ggcaaaccgg atgaagtgcg tgaaaaggcg aagaaattcg tgaagaaaat tcgtggttgc 4140
accgag 4146
<210> 13
<211> 4155
<212> DNA
<213> Gamma HexaPro-I53-50A
<400> 13
gtgaacttta caaatagaac ccagctgcca agcgcctaca ccaacagttt caccagagga 60
gtgtactacc ctgacaaggt ctttagaagc agcgttctgc acagcacaca ggacctgttc 120
ctgcccttct tctccaacgt gacctggttc cacgccatcc acgtgagtgg taccaacggc 180
accaaacggt tcgacaaccc tgtgctgccc tttaatgacg gcgtgtactt cgccagcacc 240
gagaaatcca atatcatccg gggctggatc ttcggaacta ccctcgacag caaaacacag 300
agcttactga tcgtgaacaa cgcaaccaac gtggtgatca aggtgtgtga attccagttc 360
tgcaactacc cctttttagg agtgtattac cacaagaaca ataagtcttg gatggaaagc 420
gagttcagag tgtacagcag cgccaacaat tgcaccttcg agtacgtgtc ccagcccttc 480
ctgatggact tggaaggcaa acagggcaac tttaaaaacc tgagcgaatt cgtgttcaag 540
aacattgacg gctatttcaa gatctacagc aagcacacac ctataaacct ggtgagagat 600
ctgcctcagg gcttcagcgc cctggagcct ctggtggacc tgcctatcgg catcaacatc 660
acaagattcc agacgctcct ggccctgcac agatcttacc tgacgcccgg cgattccagc 720
agcggctgga ccgccggcgc cgccgcctac tacgtgggat acctgcaacc tcggacattt 780
ctgctgaagt acaacgagaa cggcaccatc acagacgccg tggattgcgc cctggaccca 840
ctgtctgaga caaagtgtac actgaagtct ttcacagtcg agaagggaat ctaccagacg 900
agcaatttta gagtccagcc taccgaatca atcgtgcggt tccctaacat caccaacctg 960
tgcccctttg gcgaggtctt caatgccact agatttgcct ctgtgtatgc ctggaaccga 1020
aagagaatca gcaactgcgt ggccgattac agcgtcctgt acaatagcgc ctcctttagc 1080
accttcaaat gctacggcgt gtctcctacc aagctgaatg acctgtgctt cacgaacgtg 1140
tacgccgaca gcttcgtgat cagaggcgac gaggtgcggc agatcgctcc tggacaaaca 1200
ggcaccatcg ccgactacaa ctacaagctg cctgatgact tcaccggatg tgtgattgcc 1260
tggaacagca acaacctgga tagcaaggtc ggtggcaatt acaactacct gtaccggctg 1320
ttcagaaaga gcaatctgaa gcctttcgag cgggacatca gcaccgagat ctaccaggcc 1380
ggctctacac cttgcaatgg cgtgaagggc ttcaactgct acttcccact gcagagctac 1440
ggctttcagc ccacctacgg cgtggggtac cagccctatc gcgtggtggt gttgtccttc 1500
gaactgctgc acgccccagc tacagtgtgc ggcccgaaga agagcaccaa tctggtgaag 1560
aacaagtgcg tgaacttcaa tttcaacggc ctgacaggca cgggcgtgct caccgaatct 1620
aacaaaaagt tcctgccttt tcagcagttc ggcagagata tcgccgacac caccgatgct 1680
gtgagagacc ctcaaacact ggaaatcctg gacatcaccc cctgtagctt cgggggcgtt 1740
tccgtgatca cacctggcac taacacctct aatcaagtgg ccgtgctgta ccagggcgtg 1800
aactgcaccg aggtgcctgt ggccatccac gccgaccagc tgacacctac atggcgggtg 1860
tacagcactg gcagcaacgt gttccagaca agagccggct gtctgatcgg agccgagtac 1920
gtgaataata gctacgagtg tgacatccct attggcgctg gaatctgcgc ctcctaccag 1980
acacagacaa acagtcctgg cagcgcctcc tctgtagcca gccaaagcat catcgcttat 2040
actatgtctc tgggcgccga aaacagcgtg gcttattcga acaacagcat cgccattccc 2100
accaatttta ccatatctgt gacaacagag atcctgcccg tgtctatgac caagaccagc 2160
gttgactgca ccatgtacat ctgtggcgac agcaccgagt gcagcaacct gctgctgcag 2220
tacggcagtt tctgtaccca gctgaaccgg gcactgaccg gcatcgctgt ggaacaggat 2280
aagaacaccc aggaggtgtt cgcccaggtg aagcagatct acaagacccc acctatcaaa 2340
gatttcggcg gcttcaattt ttctcagatc ctgccagacc cttctaaacc tagtaagcgc 2400
agccctatcg aggacctgct cttcaacaag gtgaccctgg ccgacgccgg cttcatcaag 2460
cagtacggcg actgcctggg cgacatcgcc gctagagacc ttatttgtgc ccaaaagttc 2520
aacggcctga ccgtgcttcc ccccctgctg accgacgaga tgatcgccca gtacaccagc 2580
gccctgctgg ccggcaccat caccagcgga tggaccttcg gagccggccc tgcgctgcag 2640
attcctttcc ccatgcagat ggcctaccgg ttcaacggca tcggtgtcac ccaaaacgta 2700
ctctacgaga atcagaaact catagctaat cagttcaaca gcgcaatcgg aaagattcag 2760
gactccctgt ccagcacccc aagcgccctg ggcaagctgc aggacgttgt gaaccagaac 2820
gcccaggctc tgaacaccct ggtgaaacaa ctgagctcca acttcggcgc catcagctcc 2880
gttctgaacg acatcctgtc tagactggac cctccagagg ccgaggtcca gatcgatagg 2940
ctgatcaccg gcagactgca gagcctgcaa acctatgtga cccagcagct gattagagcc 3000
gccgaaatca gagccagcgc caaccttgct gccattaaga tgtctgaatg cgtactgggc 3060
cagagcaaga gagtggattt ctgcggcaag ggctaccacc tgatgtcttt tcctcagtcc 3120
gctccacacg gcgttgtgtt cctgcacgtg acttacgtgc cagcccagga gaaaaacttt 3180
accacagccc ctgctatctg ccacgacggt aaggcccact tccccagaga aggcgttttc 3240
gttagcaacg gcacccactg gttcgtgacc caaagaaact tctacgagcc tcagatcatc 3300
accaccgata acaccttcgt gtctggaaac tgcgacgtgg tgatcggcat cgtgaacaat 3360
accgtgtacg gaagcggcgg aggctatatc cccgaggccc ctagagatgg ccaggcctat 3420
gtgcggaagg acggcgagtg ggtgctgctg agcacattcc tgggcggctc tggcggcagc 3480
ggcagcggcg gcagcggcgg gagcggctct gaaaaggccg ccaaggctga agaagccgca 3540
agaaagatgg aggaactgtt caagaaacac aaaatcgtgg cggttctgcg tgcgaacagc 3600
gttgaggaag cgattgagaa agcggtggcg gtttttgcgg gtggcgtgca cctgatcgaa 3660
attaccttta ccgtgccgga cgcggatacc gttatcaagg cgctgagcgt gctgaaggag 3720
aaaggtgcga tcattggtgc gggcaccgtg accagcgttg aacagtgccg taaagcggtt 3780
gagagcggcg cggaatttat cgtgagcccg cacctggacg aggaaattag ccaattctgc 3840
aaggagaagg gtgtgttcta catgccgggc gtgatgaccc cgaccgaact ggttaaggcg 3900
atgaaactgg gtcacgatat cctgaagctg ttcccgggtg aggtggttgg cccgcagttt 3960
gtgaaggcga tgaaaggccc gttcccgaac gtgaaatttg ttccgaccgg tggcgtgaac 4020
ctggacaacg tttgcaagtg gttcaaagcg ggtgttctgg cggtgggtgt tggcaaggcg 4080
ctggttaagg gcaaaccgga tgaagtgcgt gaaaaggcga agaaattcgt gaagaaaatt 4140
cgtggttgca ccgag 4155
<210> 14
<211> 161
<212> PRT
<213> I53-50B.4PT1
<400> 14
Met Asn Gln His Ser His Lys Asp His Glu Thr Val Arg Ile Ala Val
1 5 10 15
Val Arg Ala Arg Trp His Ala Glu Ile Val Asp Ala Cys Val Ser Ala
20 25 30
Phe Glu Ala Ala Met Arg Asp Ile Gly Gly Asp Arg Phe Ala Val Asp
35 40 45
Val Phe Asp Val Pro Gly Ala Tyr Glu Ile Pro Leu His Ala Arg Thr
50 55 60
Leu Ala Glu Thr Gly Arg Tyr Gly Ala Val Leu Gly Thr Ala Phe Val
65 70 75 80
Val Asn Gly Gly Ile Tyr Arg His Glu Phe Val Ala Ser Ala Val Ile
85 90 95
Asn Gly Met Met Asn Val Gln Leu Asn Thr Gly Val Pro Val Leu Ser
100 105 110
Ala Val Leu Thr Pro His Asn Tyr Asp Lys Ser Lys Ala His Thr Leu
115 120 125
Leu Phe Leu Ala Leu Phe Ala Val Lys Gly Met Glu Ala Ala Arg Ala
130 135 140
Cys Val Glu Ile Leu Ala Ala Arg Glu Lys Ile Ala Ala Gly Ser Leu
145 150 155 160
Glu
Claims (6)
1.一种自组装纳米颗粒,其特征在于,所述纳米颗粒包含:
所述第一纳米颗粒亚基包含HexaPro蛋白和第一载体亚基;所述第二纳米颗粒亚基包含第二载体亚基;所述第一载体亚基为I53-50A1,所述第二载体亚基为I53-50B.4PT1,所述HexaPro蛋白与第一载体亚基通过铰链连接;
所述I53-50A1的氨基酸序列如SEQ ID NO:5所示;所述I53-50B.4PT1的氨基酸序列如SEQ ID NO:14所示;
在所述HexaPro蛋白与铰链之间插入稳定蛋白,所述稳定蛋白为T4噬菌体纤维蛋白原;
所述四种第一纳米颗粒亚基的HexaPro蛋白的氨基酸序列如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示;
所述铰链包含柔性序列和刚性接头,所述柔性序列的氨基酸序列如SEQ ID NO:7所示,所述刚性接头的氨基酸序列为EKAAKAEEAARK。
2.权利要求1所述的自组装纳米颗粒的制备方法,包括以下步骤:
将四种第一纳米颗粒亚基混合,混合后与第二纳米颗粒亚基混合孵育,得到自组装纳米颗。
3.权利要求1所述的自组装纳米颗粒或权利要求2所述的制备方法制备得到的自组装纳米颗粒在制备用于预防新型冠状病毒感染的药物中的应用。
4.一种疫苗,包含权利要求1所述的自组装纳米颗粒。
5.根据权利要求4所述的疫苗,其特征在于,所述疫苗还包括佐剂和/或载体。
6.一种试剂盒,包含权利要求1所述的自组装纳米颗粒或权利要求4或5所述的纳米颗粒疫苗以及用于接种所述自组装纳米颗粒或所述纳米颗粒疫苗的容器。
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