CN116688113A - 核酸疫苗 - Google Patents
核酸疫苗 Download PDFInfo
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- CN116688113A CN116688113A CN202310206287.2A CN202310206287A CN116688113A CN 116688113 A CN116688113 A CN 116688113A CN 202310206287 A CN202310206287 A CN 202310206287A CN 116688113 A CN116688113 A CN 116688113A
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Abstract
本发明提出了一种核酸疫苗，其包括编码下列的核酸序列：信号肽；抗原蛋白；和跨膜结构域，其中，所述信号肽和所述跨膜结构域至少之一独立地衍生自病毒。采用具有上述结构的核酸疫苗，不仅能够提高所述表达抗原的免疫原性，激活较强水平的免疫应答，还能将不可成为疫苗靶点的蛋白成为可能，将低免疫原性的抗原蛋白诱导出更强的免疫应答。
Description
技术领域
本申请属于生物医药领域，具体的，本申请涉及核酸疫苗。
背景技术
核酸疫苗是一种开发疫苗的新途径，核酸疫苗通过向宿主的细胞传递一套特定的指令，使得细胞可以产生能够被免疫系统识别和应答的特定蛋白质。
然而，目前的核酸疫苗仍有待进一步改进。
发明内容
本申请旨在至少在一定程度上解决相关技术中的技术问题之一。
本发明的发明人基于对核酸疫苗的研究，发现抗原的免疫方式对于体液免疫产生抗体的滴度会有巨大的影响，例如通过采用佐剂来提升疫苗中抗原的免疫能力。但是，仍有大量免疫原性差的抗原，难以以核酸疫苗的方式进行呈现。本发明的发明人通过对核酸疫苗的抗原表达序列进行改造修饰，可以使得所表达的抗原能够获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
由此，在本发明的一个方面，本发明提出了一种核酸疫苗。根据本发明的实施例，所述核酸疫苗包括编码下列的核酸序列：信号肽；抗原蛋白；和跨膜结构域，其中，所述信号肽和所述跨膜结构域至少之一独立地衍生自病毒。
由此，发明人意外地发现通过采用具有上述结构的核酸疫苗，能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
根据本发明的实施例，所述抗原蛋白包括自身抗原和/或异源抗原。
根据本发明的实施例，所述自身抗原包括选自HER2，PSA，TRP-2，VEGF,EpCAM，GPC3，MSLN，TNFα，PCSK9，EGFR，EGF，Survivin，ANGPTL3和IgE中的至少之一。
根据本发明的实施例，所述异源抗原包括病原体蛋白。
根据本发明的实施例，所述病原体蛋白为病原体蛋白，所述病原体蛋白包括：Zika病毒蛋白(由prM和E基因编码)，HIV病毒蛋白，HSV病毒蛋白，EBV病毒蛋白，巨细胞病毒蛋白，新型冠状病毒蛋白和柯萨奇病毒蛋白中的至少之一。
根据本发明的实施例，所述信号肽和所述跨膜结构域来自相同或者不同病毒。
根据本发明的实施例，所述信号肽和所述跨膜结构域衍生自弹状病毒糖蛋白(G蛋白)。
根据本发明的实施例，所述信号肽和所跨膜膜结构域分别衍生自相同或者不同的弹状病毒糖蛋白。
根据本发明的实施例，所述弹状病毒包括水疱性病毒属、狂犬病病毒属、短暂热病毒属、非毒粒弹状病毒属，优选水疱性口炎病毒。
根据本发明的实施例，所述信号肽和所跨膜膜结构域分别衍生自相同或者不同血清型的水疱性口炎病毒。
根据本发明的实施例，所述信号肽包括下列氨基酸序列：(a)SEQ ID NO：1-3、45和46任一项所示的氨基酸序列；或者(b)与SEQ ID NO：1-3、45和46任一项所示的氨基酸序列具有至少80％、至少85％、至少90％、至少95％同一性的氨基酸序列。
MGSRPFTKNPAPMMLTIRVALVLSCICPANSIDGRPFAAA(SEQ ID NO：1)。
MVPQALLFVPLLVFPLCFGKFPIYTIPDKL(SEQ ID NO：2)。
MTSSVTISVILLISFIAPSYSSLSIAFPEN(SEQ ID NO：3)。
MKCLLYLAFLFIGVNCKFTIVFPHN(SEQ ID NO：45)。
MLSYLILAIVVSPILGKIEIVFPQHTT(SEQ ID NO：46)。
根据本发明的实施例，编码所述信号肽的核酸包括下列核苷酸序列：(a)SEQ IDNO：4-6、47和48任一项所示的核苷酸序列；或者(b)与SEQ ID NO：4-6、47和48任一项所示的核苷酸序列具有至少80％、至少85％、至少90％、至少95％同一性的核苷酸序列。
atgggctccagaccttttaccaagaacccagcacctatgatgctgactatccgggtcgcgctggtattgagttgcatctgtccggcaaactccattgatggcaggccttttgcagctgca(SEQ ID NO：4)。
atggttcctcaggctctcctgtttgtaccccttctggtttttccattgtgttttgggaaattccctatttacacgataccagacaagctt(SEQ ID NO：5)。
atgacttcttcagtgacaattagtgtgatccttcttatctcctttattgccccatcatactcatctttgagtatagcatttccagaaaac(SEQ ID NO：6)。
atgaagtgccttttgtacttagcctttttattcattggggtgaattgcaagttcaccatagtttttccacacaac(SEQ ID NO：47)。
atgttgtcttatctaattcttgcaattgttgtttcgcctattttaggcaaaattgaaattgtcttccctcagcatactact(SEQ ID NO：48)。
根据本发明的实施例，所述跨膜结构域包括下列氨基酸序列：(a)SEQ ID NO：7-9、49和50任一项所示的氨基酸序列；或者(b)与SEQ ID NO：7-9、49和50任一项所示的氨基酸序列具有至少80％、至少85％、至少90％、至少95％同一性的氨基酸序列。
LEESNRKLDKVNVKLTSTSALITYIVLTIISLVFGILSLILACYLMYKQKAQQKTLLWLGNNTLDQMRATTKM(SEQ ID NO：7)。
HNQVSGVDLGLPNWGKYVLLSAGALTALMLIIFLMTCCRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSG GETRL(SEQ ID NO：8)。
FFGDTGVSKNPVELVTGWFTSWKESLAAGVVLILVVVLIYGVLRCFPVLCTTCRKPKWKKGVERSDSFEMRIFKPN NMRARV(SEQ ID NO：9)。
AASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRL GK(SEQ ID NO：49)。
AAQTYLKKDDTEEVIYYGDTGVSKNPVELVEGWFSGWRSSIMGVVAVIFGFVISILLIRLIGVLSSLFRPKKRPIYKSD VEMAHFR(SEQ ID NO：50)。
根据本发明的实施例，编码所述跨膜结构域的核酸分子包括下列核苷酸序列：(a)SEQ ID NO：10-12、51和52任一项所示的核苷酸序列；或者，(b)与SEQ ID NO：10-12、51和52任一项所示的核苷酸序列具有至少80％、至少85％、至少90％、至少95％同一性的核苷酸序列。
ttagaggaaagcaacagaaaactagacaaagtcaatgtcaaactgaccagcacatctgctctcattacctatatcgttttgactatcatatctcttgtttttggtatacttagcctgattctagc atgctacctaatgtacaagcaaaaggcgcaacaaaagaccttattatggcttgggaataataccctagatcagatgagagccactacaaaaatg(SEQ ID NO：10)。
cacaatcaggtctcaggagttgacttgggtctcccgaactgggggaagtatgtattactgagtgcaggggccctgactgccttgatgttgataattttcctgatgacatgttgtagaagagt caatcgatcagaacctacgcaacacaatctcagagggacagggagggaggtgtcagtcactccccaaagcgggaagatcatatcttcatgggaatcacacaagagtgggggtgagaccag actg(SEQ ID NO：11)。
ttctttggagacactggggtttccaagaatccagtagaactagttacagggtggttcactagctggaaagagagcttagctgccggtgttgttttgatattggtagttgtcctgatttatggtg tcctccgttgtttcccggtgttgtgtactacctgcagaaagcccaaatggaagaaaggggtagagaggtccgatagctttgagatgcggattttcaagcccaacaacatgagagccagagta(SEQ ID NO：12)。
gctgcttcgcaacttcctgatgatgagagtttattttttggtgatactgggctatccaaaaatccaatcgagcttgtagaaggttggttcagtagttggaaaagctctattgcctcttttttctttat catagggttaatcattggactattcttggttctccgagttggtatccatctttgcattaaattaaagcacaccaagaaaagacagatttatacagacatagagatgaaccgacttggaaag(SEQ ID NO：51)。
gccgctcagacatatttaaaaaaagatgatacagaagaagtcatctattatggcgacacaggggtatcaaaaaacccagttgagttagtcgagggctggtttagtggatggaggagctc catcatgggagtggtggctgtgattttcggatttgtgatttcgatacttttaattagactgattggagtcctatccagtctcttcagacctaagaaaaggccaatttataaatcagatgtggagatggct cacttccgt(SEQ ID NO：52)。
根据本发明的实施例，进一步包括胞内段，所述胞内段与所述跨膜结构域相连。
根据本发明的实施例，所述核酸疫苗为任选携带修饰基团的自复制RNA、mRNA、DNA以及病毒载体。
在本发明的另一方面，本发明提出了一种疫苗组合物。根据本发明的实施例，所述疫苗组合物包括：前面所述的核酸疫苗；和药学上可以接受的赋形剂。由此，通过采用疫苗组合物，能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
在本发明的另一方面，本发明提出了一种表达载体。根据本发明的实施例，携带编码分子，所述编码分子编码前面所述的核酸疫苗。由此，利用该表达载体能够有效地通过分子生物学的手段，快速复制、表达、扩增上述核酸疫苗，从而实现了能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
在本发明的另一方面，本发明提出了一种对个体进行免疫的方法。根据本发明的实施例，所述方法包括：为有需要的个体给药前面所述的疫苗组合物或者前面所述的核酸疫苗。由此，能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
在本发明的又一方面，本发明提出了前面所述的疫苗组合物或者前面所述的核酸疫苗在制备药物中的用途。根据本发明的实施例，所述药物用于免疫个体。由此，能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
本申请的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本申请的实践了解到。
附图说明
本申请的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1显示了根据本发明一个实施例的核酸疫苗编码产物结构示意图；
图2显示了根据本发明另一个实施例的核酸疫苗编码产物结构示意图；
图3显示了根据本发明一个实施例的自复制RNA分子(reRNATM)的结构示意图；
图4显示了根据本发明一个实施例的含有自复制RNA分子的蛋白质-RNA复合物的结构示意图；
图5显示了根据本发明实施例1中CVA16病原体疫苗设计示意图；
图6显示了根据本发明实施例1中疫苗抗原特异性结合抗体滴度的柱形图；
图7显示了根据本发明实施例1中V2组不同时间点的抗体亚型的检测结果图；
图8显示了根据本发明实施例2中CVA10病原体疫苗抗原设计示意图；
图9显示了根据本发明实施例3中CVA6病原体疫苗抗原设计示意图；
图10显示了根据本发明实施例4中HER2 B细胞疫苗抗原设计示意图；
图11显示了根据本发明实施例5中CVB3病原体疫苗抗原设计示意图；
图12显示了根据本发明实施例5中疫苗抗原特异性结合抗体滴度的柱形图。
具体实施方式
下面详细描述本申请的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本申请，而不能理解为对本申请的限制。
核酸疫苗
在本发明的一个方面，本发明提出了一种核酸疫苗，根据本申请的实施例，参考图1，该核酸疫苗包括编码下列的核酸序列：信号肽；抗原蛋白；和跨膜结构域，其中，所述信号肽和所述跨膜结构域至少之一独立地衍生自病毒。
由此，发明人意外地发现通过采用具有上述结构的核酸疫苗，能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
需要说明的是，在本文中所使用的术语“核酸疫苗”是指适合在宿主细胞内表达目标核酸序列的核酸分子，其携带适于在宿主细胞内表达的开放阅读框(ORF)，该开放阅读框包括编码信号肽的序列、编码抗原蛋白的序列以及编码跨膜结构域的序列。
根据本申请的实施例，信号肽的长度可以为5～100个氨基酸，例如5～50、5～30个氨基酸，其能够引导新合成的蛋白质向分泌通路转移，从而使得所合成的抗原蛋白展示在细胞外表面。
根据本申请的实施例，跨膜结构域是蛋白质序列中跨越细胞膜的区域，其可以为α-螺旋结构，长度约20～25个氨基酸残基，这些氨基酸残基中主要是疏水性氨基酸。通过采用跨膜结构域可以将抗原蛋白锚定在细胞膜上，从而进一步有利于使得所合成的抗原蛋白展示在细胞外表面。
根据本发明的实施例，所述信号肽和所述跨膜结构域来自相同或者不同病毒。根据本发明的实施例，所述信号肽和所述跨膜结构域衍生自弹状病毒糖蛋白(G蛋白)。根据本发明的实施例，所述信号肽和所跨膜膜结构域分别衍生自相同或者不同的弹状病毒糖蛋白。
根据本发明的实施例，所述弹状病毒包括水疱性病毒属、狂犬病病毒属、短暂热病毒属、非毒粒弹状病毒属，优选水疱性口炎病毒。根据本发明的实施例，所述信号肽和所跨膜膜结构域分别衍生自相同或者不同血清型的水疱性口炎病毒。
水泡性病毒属包括但不限于Vesicular stomatitis New Jersey virus,Marabavirus,Vesicular stomatitis Alagoas virus Indiana3,Cocal virus Indiana 2,Isfahan virus,Chandipura virus,Spring viraemia of carp virus,American batvesiculovirus,Carajas vesiculovirus,Jurona vesiculovirus,Malpais Springvesiculovirus,Morreton vesiculovirus,Perinet vesiculovirus,Piryvesiculovirus,Radi vesiculovirus,Yug Bogdanovac vesiculovirus。狂犬病病毒属包括但不限于West Caucasian bat virus,Aravan lyssavirus,Khujand lyssavirus,Rabies virus,Australian bat lyssavirus,European bat lyssavirus 1,European batlyssavirus 2,Irkut virus,Shimoni bat virus,Lagos bat virus,Mokola virus,Lleida bat lyssavirus,Ikoma lyssavirus，Gannoruwa bat lyssavirus,Bokeloh batlyssavirus,Duvenhage lyssavirus。短暂热病毒属包括但不限于Bovine feverephemerovirus,Adelaide River ephemerovirus,Berrimah ephemerovirus,Kimberleyephemerovirus。
由此，根据本发明的实施例，所述弹状病毒科病毒包括选自水疱性口炎新泽西病毒、马拉巴病毒、水疱性口炎阿拉戈斯病毒印第安纳3号、科卡尔病毒印第安纳2号、伊斯法罕病毒、钱迪普拉病毒、鲤鱼春季病毒血症病毒、美国蝙蝠水疱病毒、卡拉哈斯水疱病毒、朱罗纳水疱病毒、马尔帕斯春季水疱病毒、莫雷顿水疱病毒、佩里特水疱病毒、，皮里水泡病毒、拉迪水泡病毒、尤格·博格达诺瓦克水泡病毒、西高加索蝙蝠病毒、Aravan狂犬病毒、Khujand狂犬病毒、狂犬病病毒、澳大利亚蝙蝠狂犬病毒、欧洲蝙蝠狂犬病毒1、欧洲蝙蝠狂犬病毒2、伊尔库特病毒、希莫尼蝙蝠病毒、拉各斯蝙蝠病毒、莫科拉病毒、莱伊达蝙蝠狂犬病毒、伊科马狂犬病毒、甘诺鲁瓦蝙蝠狂犬病毒、博克洛蝙蝠狂犬病毒、杜文哈格狂犬病毒、热蜉蝣病毒、阿德莱德河蜉蝣病毒、伯里玛蜉蝣病毒、金伯利蜉蝣病毒的至少之一。
本申请的发明人意外发现，通过采用根据本申请实施例的衍生自水疱性口炎病毒的信号肽和所跨膜膜结构域不仅可以通过所合成的抗原蛋白展示在细胞外表面来提高核酸疫苗刺激免疫系统的活性，自身也可以作为免疫激活剂进一步提高核酸疫苗刺激免疫系统的活性。
根据本发明的实施例，所述信号肽包括下列氨基酸序列：(a)SEQ ID NO：1-3、45和46任一项所示的氨基酸序列；或者(b)与SEQ ID NO：1-3、45和46任一项所示的氨基酸序列具有至少80％、至少85％、至少90％、至少95％同一性的氨基酸序列。
MGSRPFTKNPAPMMLTIRVALVLSCICPANSIDGRPFAAA(SEQ ID NO：1)。
MVPQALLFVPLLVFPLCFGKFPIYTIPDKL(SEQ ID NO：2)。
MTSSVTISVILLISFIAPSYSSLSIAFPEN(SEQ ID NO：3)。
MKCLLYLAFLFIGVNCKFTIVFPHN(SEQ ID NO：45)。
MLSYLILAIVVSPILGKIEIVFPQHTT(SEQ ID NO：46)。
根据本发明的实施例，编码所述信号肽的核酸包括下列核苷酸序列：(a)SEQ IDNO：4-6、47和48任一项所示的核苷酸序列；或者(b)与SEQ ID NO：4-6、47和48任一项所示的核苷酸序列具有至少80％、至少85％、至少90％、至少95％同一性的核苷酸序列。
atgggctccagaccttttaccaagaacccagcacctatgatgctgactatccgggtcgcgctggtattgagttgcatctgtccggcaaactccattgatggcaggccttttgcagctgca(SEQ ID NO：4)。
atggttcctcaggctctcctgtttgtaccccttctggtttttccattgtgttttgggaaattccctatttacacgataccagacaagctt(SEQ ID NO：5)。
atgacttcttcagtgacaattagtgtgatccttcttatctcctttattgccccatcatactcatctttgagtatagcatttccagaaaac(SEQ ID NO：6)。
atgaagtgccttttgtacttagcctttttattcattggggtgaattgcaagttcaccatagtttttccacacaac(SEQ ID NO：47)。
atgttgtcttatctaattcttgcaattgttgtttcgcctattttaggcaaaattgaaattgtcttccctcagcatactact(SEQ ID NO：48)。
根据本发明的实施例，所述跨膜结构域包括下列氨基酸序列：(a)SEQ ID NO：7-9、49和50任一项所示的氨基酸序列；或者(b)与SEQ ID NO：7-9、49和50任一项所示的氨基酸序列具有至少80％、至少85％、至少90％、至少95％同一性的氨基酸序列。
LEESNRKLDKVNVKLTSTSALITYIVLTIISLVFGILSLILACYLMYKQKAQQKTLLWLGNNTLDQMRATTKM(SEQ ID NO：7)。
HNQVSGVDLGLPNWGKYVLLSAGALTALMLIIFLMTCCRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGETRL(SEQ ID NO：8)。
FFGDTGVSKNPVELVTGWFTSWKESLAAGVVLILVVVLIYGVLRCFPVLCTTCRKPKWKKGVERSDSFEMRIFKPNNMRARV(SEQ ID NO：9)。
AASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK(SEQ ID NO：49)。
AAQTYLKKDDTEEVIYYGDTGVSKNPVELVEGWFSGWRSSIMGVVAVIFGFVISILLIRLIGVLSSLFRPKKRPIYKSD VEMAHFR(SEQ ID NO：50)。
根据本发明的实施例，编码所述跨膜结构域的核酸分子包括下列核苷酸序列：(a)SEQ ID NO：10-12、51和52任一项所示的核苷酸序列；或者(b)与SEQ ID NO：10-12、51和52任一项所示的核苷酸序列具有至少80％、至少85％、至少90％、至少95％同一性的核苷酸序列。
ttagaggaaagcaacagaaaactagacaaagtcaatgtcaaactgaccagcacatctgctctcattacctatatcgttttgactatcatatctcttgtttttggtatacttagcctgattctagc atgctacctaatgtacaagcaaaaggcgcaacaaaagaccttattatggcttgggaataataccctagatcagatgagagccactacaaaaatg(SEQ ID NO：10)。
cacaatcaggtctcaggagttgacttgggtctcccgaactgggggaagtatgtattactgagtgcaggggccctgactgccttgatgttgataattttcctgatgacatgttgtagaagagt caatcgatcagaacctacgcaacacaatctcagagggacagggagggaggtgtcagtcactccccaaagcgggaagatcatatcttcatgggaatcacacaagagtgggggtgagaccag actg(SEQ ID NO：11)。
ttctttggagacactggggtttccaagaatccagtagaactagttacagggtggttcactagctggaaagagagcttagctgccggtgttgttttgatattggtagttgtcctgatttatggtg tcctccgttgtttcccggtgttgtgtactacctgcagaaagcccaaatggaagaaaggggtagagaggtccgatagctttgagatgcggattttcaagcccaacaacatgagagccagagta(SEQ ID NO：12)。
gctgcttcgcaacttcctgatgatgagagtttattttttggtgatactgggctatccaaaaatccaatcgagcttgtagaaggttggttcagtagttggaaaagctctattgcctcttttttctttat catagggttaatcattggactattcttggttctccgagttggtatccatctttgcattaaattaaagcacaccaagaaaagacagatttatacagacatagagatgaaccgacttggaaag(SEQ ID NO：51)。
gccgctcagacatatttaaaaaaagatgatacagaagaagtcatctattatggcgacacaggggtatcaaaaaacccagttgagttagtcgagggctggtttagtggatggaggagctc catcatgggagtggtggctgtgattttcggatttgtgatttcgatacttttaattagactgattggagtcctatccagtctcttcagacctaagaaaaggccaatttataaatcagatgtggagatggct cacttccgt(SEQ ID NO：52)。
参考图2，根据本发明的实施例，进一步包括胞内段，所述胞内段与所述跨膜结构域相连。
另外，根据本发明的实施例，所述抗原蛋白包括自身抗原和/或异源抗原。根据本发明的实施例，所述自身抗原包括选自HER2，PSA，TRP-2，VEGF，EpCAM，GPC3，MSLN，TNFα，PCSK9，EGFR，EGF，Survivin，ANGPTL3和IgE的至少之一。根据本发明的实施例，所述异源抗原包括病原体蛋白。根据本发明的实施例，所述病原体蛋白为病原体蛋白，所述病原体蛋白包括：Zika病毒蛋白(由prM和E基因编码)，HIV病毒蛋白，HSV病毒蛋白，EBV病毒蛋白，巨细胞病毒蛋白，新型冠状病毒蛋白和柯萨奇病毒蛋白中的至少之一。
在本文中所使用的术语“核酸”是指具有开放阅读框(ORF)的核酸分子，其能够编码蛋白质，可以为DNA也可以是RNA。需要说明的是，除非特别说明，否则在本申请中所描述的核酸序列有时是以DNA序列列举的，在表述RNA序列时，只需要将T替换为U即可。根据本发明的实施例，所述核酸疫苗为任选携带修饰基团的自复制RNA、mRNA或DNA。
在本文中，优选所述核酸疫苗为RNA疫苗，RNA疫苗具有相对于DNA疫苗的显著的优点：(i)RNA疫苗含有变应原的纯的遗传信息但没有通常存在于用于DNA疫苗的质粒骨架中的附加的外源序列，例如病毒启动子、抗生素抗性基因或病毒/细菌调节序列。(ii)RNA不能整合入宿主基因组，因此去除了恶性风险。(iii)RNA可以在细胞的细胞质中被翻译，因此不需要细胞核的转录机制，这使得RNA疫苗不依赖于转运入细胞核和转运出细胞核，以及不依赖于核的阶段。(iv)由于RNA的迅速降解，外源转基因的表达寿命短，这避免了不可控制的长期抗原表达。
在本文中所使用的术语“自复制RNA分子”也可以称为“自我扩增RNA”，与普通mRNA相比，自复制RNA分子的重要的区别在于它可以使用自己的RNA序列作为模板进行自我复制。根据本申请的实施例，自复制RNA分子还可以在细胞质进行翻译和复制工作，不进入细胞核，可以避免与基因组发生整合所带来的潜在风险。通常mRNA编码需要表达的蛋白质，细胞内的核糖体用来完成翻译和蛋白质生产。根据本申请的实施例，自复制RNA分子会携带一个能够表达RNA聚合酶(RNA依赖RNA聚合酶)的序列，在该RNA分子在细胞质中通过翻译产生RNA聚合酶产生后，它可以用该自复制RNA分子作为模板来产生更多的自复制RNA分子。
参考图3和图4，自复制RNA分子的结构包括：第一RNA序列，所述第一RNA序列编码N蛋白或其功能片段；第二RNA序列，所述第二RNA序列编码P蛋白或其功能片段；和第三RNA序列，所述第三RNA序列编码L蛋白或其功能片段，其中，所述自复制RNA分子在动物细胞内适于产生所述N蛋白、所述P蛋白、所述L蛋白或其功能片段。由此，这些第一、第二和第三RNA序列构成了自复制RNA分子的核心区区域，也称为“核心生命区”，可以作为能够在动物细胞内实现自我复制和翻译的最小区域，进一步可以搭载其他的编码序列来表达或者复制靶分子，从而发挥疫苗的功能。
在本文中所使用的术语“功能片段”是指蛋白质的全长序列的一部分，但仍能够发挥与RNA分子自我复制相关的功能，例如可以是全长序列的截断型的，也可以是蛋白质全长序列的氨基酸序列发生替换、突变或者删除等改变后的蛋白质。根据本申请的实施例，对于N蛋白的功能片段，可以结合RNA分子，保护RNA不受核酸酶的影响，对于P蛋白的功能片段，能够结合N蛋白，在模板上定位L聚合酶，同时也能够作为RNA聚合酶转录和复制复合体的基本组成部分，进一步L蛋白的功能片段能够发挥RNA聚合酶的功能，与RNA的转录及复制有关。
根据本发明的实施例，所述N蛋白、所述P蛋白、所述L蛋白的至少之一分别独立地来自弹状病毒科病毒。
根据本发明的实施例，N蛋白、P蛋白和L蛋白也可以分别独立地来自相同病毒种的不同的病毒血清型，例如包括但不限于水泡性口炎病毒(VSV)印第安那株、新泽西株和可卡尔株。
根据本发明实施例，自复制核心序列包括5种序列组合。
组合1：所述N蛋白的序列包括SEQ ID NO：13所示的氨基酸序列，所述P蛋白的序列包括SEQ ID NO：14所示的氨基酸序列，所述L蛋白的序列包括SEQ ID NO：15所示的氨基酸序列。
相应地，所述自复制核心序列(核心区区域的序列)包括：
第一RNA序列，所述第一RNA序列编码N蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：16所示的核苷酸序列；
第二RNA序列，所述第二RNA序列编码P蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：17所示的核苷酸序列；
第三RNA序列，所述第三RNA序列编码L蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：18所示的核苷酸序列。
N蛋白
MSVTVKRIIDNTVIVPKLPANEDPVEYPADYFRKSKEIPLYINTTKSLSDLRGYVYQGLKSGNVSIIHVNSYLYGALKDIRGKLDKDWSSFGINIGKAGDTIGIFDLVSLKALDGVLPDGVSDASRTSADDKWLPLYLLGLYRVGRTQMPEYRKKLMDGLTNQCKMINEQFEPLVPEGRDIFDVWGNDSNYTKIVAAVDMFFHMFKKHECASFRYGTIVSRFKDCAALATFGHLCKITGMSTEDVTTWILNREVADEMVQMMLPGQEIDKADSYMPYLIDFGLSSKSPYSSVKNPAFHFWGQLTALLLRSTRARNARQPDDIEYTSLTTAGLLYAYAVGSSADLAQQFCVGDNKYTPDDSTGGLTTNAPPQGRDVVEWLGWFEDQNRKPTPDMMQYAKRAVMSLQGLREKTIGKYAKSEFDK*(SEQ ID NO：13)
atgtctgttacagtcaagagaatcattgacaacacagtcatagttccaaaacttcctgcaaatgaggatccagtggaatacccggcagattacttcagaaaatcaaaggagattcctctttacatcaatactacaaaaagtttgtcagatctaagaggatatgtctaccaaggcctcaaatccggaaatgtatcaatcatacatgtcaacagctacttgtatggagcattaaaggacatccggggtaagttggataaagattggtcaagtttcggaataaacatcgggaaagcaggggatacaatcggaatatttgaccttgtatccttgaaagccctggacggcgtacttccagatggagtatcggatgcttccagaaccagcgcagatgacaaatggttgcctttgtatctacttggcttatacagagtgggcagaacacaaatgcctgaatacagaaaaaagctcatggatgggctgacaaatcaatgcaaaatgatcaatgaacagtttgaacctcttgtgccagaaggtcgtgacatttttgatgtgtggggaaatgacagtaattacacaaaaattgtcgctgcagtggacatgttcttccacatgttcaaaaaacatgaatgtgcctcgttcagatacggaactattgtttccagattcaaagattgtgctgcattggcaacatttggacacctctgcaaaataaccggaatgtctacagaagatgtaacgacctggatcttgaaccgagaagttgcagatgaaatggtccaaatgatgcttccaggccaagaaattgacaaggccgattcatacatgccttatttgatcgactttggattgtcttctaagtctccatattcttccgtcaaaaaccctgccttccacttctgggggcaattgacagctcttctgctcagatccaccagagcaaggaatgcccgacagcctgatgacattgagtatacatctcttactacagcaggtttgttgtacgcttatgcagtaggatcctctgccgacttggcacaacagttttgtgttggagataacaaatacactccagatgatagtaccggaggattgacgactaatgcaccgccacaaggcagagatgtggtcgaatggctcggatggtttgaagatcaaaacagaaaaccgactcctgatatgatgcagtatgcgaaaagagcagtcatgtcactgcaaggcctaagagagaagacaattggcaagtatgctaagtcagaatttgacaaatga(SEQ ID NO：16)
P蛋白
MDNLTKVREYLKSYSRLDQAVGEIDEIEAQRAEKSNYELFQEDGVEEHTKPSYFQAADDSDTESEPEIEDNQGLYAQDPEAEQVEGFIQGPLDDYADEEVDVVFTSDWKPPELESDEHGKTLRLTSPEGLSGEQKSQWLSTIKAVVQSAKYWNLAECTFEASGEGVIMKERQITPDVYKVTPVMNTHPSQSEAVSDVWSLSKTSMTFQPKKASLQPLTISLDELFSSRGEFISVGGDGRMSHKEAILLGLRYKKLYNQARVKYSL*(SEQ ID NO：14)
atggataatctcacaaaagttcgtgagtatctcaagtcctattctcgtctggatcaggcggtaggagagatagatgagatcgaagcacaacgagctgaaaagtccaattatgagttgttccaagaggatggagtggaagagcatactaagccctcttattttcaggcagcagatgattctgacacagaatctgaaccagaaattgaagacaatcaaggtttgtatgcacaggatccagaagctgagcaagttgaaggctttatacaggggcctttagatgactatgcagatgaggaagtggatgttgtatttacttcggactggaaaccacctgagcttgaatctgacgagcatggaaagaccttacggttgacatcgccagagggtttaagtggagagcagaaatcccagtggctttcgacgattaaagcagtcgtgcaaagtgccaaatactggaatctggcagagtgcacatttgaagcatcgggagaaggggtcattatgaaggagcgccagataactccggatgtatataaggtcactccagtgatgaacacacatccgtcccaatcagaagcagtatcagatgtttggtctctctcaaagacatccatgactttccaacccaagaaagcaagtcttcagcctctcaccatatccttggatgaattgttctcatctagaggagagttcatctctgtcggaggtgacggacgaatgtctcataaagaggccatcctgctcggcctgagatacaaaaagttgtacaatcaggcgagagtcaaatattctctgtag(SEQ ID NO：17)
L蛋白
MEVHDFETDEFNDFNEDDYATREFLNPDERMTYLNHADYNLNSPLISDDIDNLIRKFNSLPIPSMWDSKNWDGVLEMLTSCQANPISTSQMHKWMGSWLMSDNHDASQGYSFLHEVDKEAEITFDVVETFIRGWGNKPIEYIKKERWTDSFKILAYLCQKFLDLHKLTLILNAVSEVELLNLARTFKGKVRRSSHGTNICRIRVPSLGPTFISEGWAYFKKLDILMDRNFLLMVKDVIIGRMQTVLSMVCRIDNLFSEQDIFSLLNIYRIGDKIVERQGNFSYDLIKMVEPICNLKLMKLARESRPLVPQFPHFENHIKTSVDEGAKIDRGIRFLHDQIMSVKTVDLTLVIYGSFRHWGHPFIDYYTGLEKLHSQVTMKKDIDVSYAKALASDLARIVLFQQFNDHKKWFVNGDLLPHDHPFKSHVKENTWPTAAQVQDFGDKWHELPLIKCFEIPDLLDPSIIYSDKSHSMNRSEVLKHVRMNPNTPIPSKKVLQTMLDTKATNWKEFLKEIDEKGLDDDDLIIGLKGKERELKLAGRFFSLMSWKLREYFVITEYLIKTHFVPMFKGLTMADDLTAVIKKMLDSSSGQGLKSYEAICIANHIDYEKWNNHQRKLSNGPVFRVMGQFLGYPSLIERTHEFFEKSLIYYNGRPDLMRVHNNTLINSTSQRVCWQGQEGGLEGLRQKGWTILNLLVIQREAKIRNTAVKVLAQGDNQVICTQYKTKKSRNVVELQGALNQMVSNNEKIMTAIKIGTGKLGLLINDDETMQSADYLNYGKIPIFRGVIRGLETKRWSRVTCVTNDQIPTCANIMSSVSTNALTVAHFAENPINAMIQYNYFGTFARLLLMMHDPALRQSLYEVQDKIPGLHSSTFKYAMLYLDPSIGGVSGMSLSRFLIRAFPDPVTESLSFWRFIHVHARSEHLKEMSAVFGNPEIAKFRITHIDKLVEDPTSLNIAMGMSPANLLKTEVKKCLIESRQTIRNQVIKDATIYLYHEEDRLRSFLWSINPLFPRFLSEFKSGTFLGVADGLISLFQNSRTIRNSFKKKYHRELDDLIVRSEVSSLTHLGKLHLRRGSCKMWTCSATHADTLRYKSWGRTVIGTTVPHPLEMLGPQHRKETPCAPCNTSGFNYVSVHCPDGIHDVFSSRGPLPAYLGSKTSESTSILQPWERESKVPLIKRATRLRDAISWFVEPDSKLAMTILSNIHSLTGEEWTKRQHGFKRTGSALHRFSTSRMSHGGFASQSTAALTRLMATTDTMRDLGDQNFDFLFQATLLYAQITTTVARDGWITSCTDHYHIACKSCLRPIEEITLDSSMDYTPPDVSHVLKTWRNGEGSWGQEIKQIYPLEGNWKNLAPAEQSYQVGRCIGFLYGDLAYRKSTHAEDSSLFPLSIQGRIRGRGFLKGLLDGLMRASCCQVIHRRSLAHLKRPANAVYGGLIYLIDKLSVSPPFLSLTRSGPIRDELETIPHKIPTSYPTSNRDMGVIVRNYFKYQCRLIEKGKYRSHYSQLWLFSDVLSIDFIGPFSISTTLLQILYKPFLSGKDKNELRELANLSSLLRSGEGWEDIHVKFFTKDILLCPEEIRHACKFGIAKDNNKDMSYPPWGRESRGTITTIPVYYTTTPYPKMLEMPPRIQNPLLSGIRLGQLPTGAHYKIRSILHGMGIHYRDFLSCGDGSGGMTAALLRENVHSRGIFNSLLELSGSVMRGASPEPPSALETLGGDKSRCVNGETCWEYPSDLCDPRTWDYFLRLKAGLGLQIDLIVMDMEVRDSSTSLKIETNVRNYVHRILDEQGVLIYKTYGTYICESEKNAVTILGPMFKTVDLVQTEFSSSQTSEVYMVCKGLKKLIDEPNPDWSSINESWKNLYAFQSSEQEFARAKKVSTYFTLTGIPSQFIPDPFVNIETMLQIFGVPTGVSHAAALKSSDRPADLLTISLFYMAIISYYNINHIRVGPIPPNPPSDGIAQNVGIAITGISFWLSLMEKDIPLYQQCLAVIQQSFPIRWEAVSVKGGYKQKWSTRGDGLPKDTRTSDSLAPIGNWIRSLELVRNQVRLNPFNEILFNQLCRTVDNHLKWSNLRRNTGMIEWINRRISKEDRSILMLKSDLHEENSWRD*(SEQ ID NO：15)
atggaagtccacgattttgagaccgacgagttcaatgatttcaatgaagatgactatgccacaagagaattcctgaatcccgatgagcgcatgacgtacttgaatcatgctgattacaatttgaattctcctctaattagtgatgatattgacaatttgatcaggaaattcaattctcttccgattccctcgatgtgggatagtaagaactgggatggagttcttgagatgttaacatcatgtcaagccaatcccatctcaacatctcagatgcataaatggatgggaagttggttaatgtctgataatcatgatgccagtcaagggtatagttttttacatgaagtggacaaagaggcagaaataacatttgacgtggtggagaccttcatccgcggctggggcaacaaaccaattgaatacatcaaaaaggaaagatggactgactcattcaaaattctcgcttatttgtgtcaaaagtttttggacttacacaagttgacattaatcttaaatgctgtctctgaggtggaattgctcaacttggcgaggactttcaaaggcaaagtcagaagaagttctcatggaacgaacatatgcaggattagggttcccagcttgggtcctacttttatttcagaaggatgggcttacttcaagaaacttgatattctaatggaccgaaactttctgttaatggtcaaagatgtgattatagggaggatgcaaacggtgctatccatggtatgtagaatagacaacctgttctcagagcaagacatcttctcccttctaaatatctacagaattggagataaaattgtggagaggcagggaaatttttcttatgacttgattaaaatggtggaaccgatatgcaacttgaagctgatgaaattagcaagagaatcaaggcctttagtcccacaattccctcattttgaaaatcatatcaagacttctgttgatgaaggggcaaaaattgaccgaggtataagattcctccatgatcagataatgagtgtgaaaacagtggatctcacactggtgatttatggatcgttcagacattggggtcatccttttatagattattacactggactagaaaaattacattcccaagtaaccatgaagaaagatattgatgtgtcatatgcaaaagcacttgcaagtgatttagctcggattgttctatttcaacagttcaatgatcataaaaagtggttcgtgaatggagacttgctccctcatgatcatccctttaaaagtcatgttaaagaaaatacatggcccacagctgctcaagttcaagattttggagataaatggcatgaacttccgctgattaaatgttttgaaatacccgacttactagacccatcgataatatactctgacaaaagtcattcaatgaataggtcagaggtgttgaaacatgtccgaatgaatccgaacactcctatccctagtaaaaaggtgttgcagactatgttggacacaaaggctaccaattggaaagaatttcttaaagagattgatgagaagggcttagatgatgatgatctaattattggtcttaaaggaaaggagagggaactgaagttggcaggtagatttttctccctaatgtcttggaaattgcgagaatactttgtaattaccgaatatttgataaagactcatttcgtccctatgtttaaaggcctgacaatggcggacgatctaactgcagtcattaaaaagatgttagattcctcatccggccaaggattgaagtcatatgaggcaatttgcatagccaatcacattgattacgaaaaatggaataaccaccaaaggaagttatcaaacggcccagtgttccgagttatgggccagttcttaggttatccatccttaatcgagagaactcatgaattttttgagaaaagtcttatatactacaatggaagaccagacttgatgcgtgttcacaacaacacactgatcaattcaacctcccaacgagtttgttggcaaggacaagagggtggactggaaggtctacggcaaaaaggatggactatcctcaatctactggttattcaaagagaggctaaaatcagaaacactgctgtcaaagtcttggcacaaggtgataatcaagttatttgcacacagtataaaacgaagaaatcgagaaacgttgtagaattacagggtgctctcaatcaaatggtttctaataatgagaaaattatgactgcaatcaaaatagggacagggaagttaggacttttgataaatgacgatgagactatgcaatctgcagattacttgaattatggaaaaataccgattttccgtggagtgattagagggttagagaccaagagatggtcacgagtgacttgtgtcaccaatgaccaaatacccacttgtgctaatataatgagctcagtttccacaaatgctctcaccgtagctcattttgctgagaacccaatcaatgccatgatacagtacaattattttgggacatttgctagactcttgttgatgatgcatgatcctgctcttcgtcaatcattgtatgaagttcaagataagataccgggcttgcacagttctactttcaaatacgccatgttgtatttggacccttccattggaggagtgtcgggcatgtctttgtccaggtttttgattagagccttcccagatcccgtaacagaaagtctctcattctggagattcatccatgtacatgctcgaagtgagcatctgaaggagatgagtgcagtatttggaaaccccgagatagccaagtttcgaataactcacatagacaagctagtagaagatccaacctctctgaacatcgctatgggaatgagtccagcgaacttgttaaagactgaggttaaaaaatgcttaatcgaatcaagacaaaccatcaggaaccaggtgattaaggatgcaaccatatatttgtatcatgaagaggatcggctcagaagtttcttatggtcaataaatcctctgttccctagatttttaagtgaattcaaatcaggcacttttttgggagtcgcagacgggctcatcagtctatttcaaaattctcgtactattcggaactcctttaagaaaaagtatcatagggaattggatgatttgattgtgaggagtgaggtatcctctttgacacatttagggaaacttcatttgagaaggggatcatgtaaaatgtggacatgttcagctactcatgctgacacattaagatacaaatcctggggccgtacagttattgggacaactgtaccccatccattagaaatgttgggtccacaacatcgaaaagagactccttgtgcaccatgtaacacatcagggttcaattatgtttctgtgcattgtccagacgggatccatgacgtctttagttcacggggaccattgcctgcttatctagggtctaaaacatctgaatctacatctattttgcagccttgggaaagggaaagcaaagtcccactgattaaaagagctacacgtcttagagatgctatctcttggtttgttgaacccgactctaaactagcaatgactatactttctaacatccactctttaacaggcgaagaatggaccaaaaggcagcatgggttcaaaagaacagggtctgcccttcataggttttcgacatctcggatgagccatggtgggttcgcatctcagagcactgcagcattgaccaggttgatggcaactacagacaccatgagggatctgggagatcagaatttcgactttttattccaagcaacgttgctctatgctcaaattaccaccactgttgcaagagacggatggatcaccagttgtacagatcattatcatattgcctgtaagtcctgtttgagacccatagaagagatcaccctggactcaagtatggactacacgcccccagatgtatcccatgtgctgaagacatggaggaatggggaaggttcgtggggacaagagataaaacagatctatcctttagaagggaattggaagaatttagcacctgctgagcaatcctatcaagtcggcagatgtataggttttctatatggagacttggcgtatagaaaatctactcatgccgaggacagttctctatttcctctatctatacaaggtcgtattagaggtcgaggtttcttaaaagggttgctagacggattaatgagagcaagttgctgccaagtaatacaccggagaagtctggctcatttgaagaggccggccaacgcagtgtacggaggtttgatttacttgattgataaattgagtgtatcacctccattcctttctcttactagatcaggacctattagagacgaattagaaacgattccccacaagatcccaacctcctatccgacaagcaaccgtgatatgggggtgattgtcagaaattacttcaaataccaatgccgtctaattgaaaagggaaaatacagatcacattattcacaattatggttattctcagatgtcttatccatagacttcattggaccattctctatttccaccaccctcttgcaaatcctatacaagccatttttatctgggaaagataagaatgagttgagagagctggcaaatctttcttcattgctaagatcaggagaggggtgggaagacatacatgtgaaattcttcaccaaggacatattattgtgtccagaggaaatcagacatgcttgcaagttcgggattgctaaggataataataaagacatgagctatcccccttggggaagggaatccagagggacaattacaacaatccctgtttattatacgaccaccccttacccaaagatgctagagatgcctccaagaatccaaaatcccctgctgtccggaatcaggttgggccaattaccaactggcgctcattataaaattcggagtatattacatggaatgggaatccattacagggacttcttgagttgtggagacggctccggagggatgactgctgcattactacgagaaaatgtgcatagcagaggaatattcaatagtctgttagaattatcagggtcagtcatgcgaggcgcctctcctgagccccccagtgccctagaaactttaggaggagataaatcgagatgtgtaaatggtgaaacatgttgggaatatccatctgacttatgtgacccaaggacttgggactatttcctccgactcaaagcaggcttggggcttcaaattgatttaattgtaatggatatggaagttcgggattcttctactagcctgaaaattgagacgaatgttagaaattatgtgcaccggattttggatgagcaaggagttttaatctacaagacttatggaacatatatttgtgagagcgaaaagaatgcagtaacaatccttggtcccatgttcaagacggtcgacttagttcaaacagaatttagtagttctcaaacgtctgaagtatatatggtatgtaaaggtttgaagaaattaatcgatgaacccaatcccgattggtcttccatcaatgaatcctggaaaaacctgtacgcattccagtcatcagaacaggaatttgccagagcaaagaaggttagtacatactttaccttgacaggtattccctcccaattcattcctgatccttttgtaaacattgagactatgctacaaatattcggagtacccacgggtgtgtctcatgcggctgccttaaaatcatctgatagacctgcagatttattgaccattagccttttttatatggcgattatatcgtattataacatcaatcatatcagagtaggaccgatacctccgaaccccccatcagatggaattgcacaaaatgtggggatcgctataactggtataagcttttggctgagtttgatggagaaagacattccactatatcaacagtgtttagcagttatccagcaatcattcccgattaggtgggaggctgtttcagtaaaaggaggatacaagcagaagtggagtactagaggtgatgggctcccaaaagatacccgaacttcagactccttggccccaatcgggaactggatcagatctctggaattggtccgaaaccaagttcgtctaaatccattcaatgagatcttgttcaatcagctatgtcgtacagtggataatcatttgaaatggtcaaatttgcgaagaaacacaggaatgattgaatggatcaatagacgaatttcaaaagaagaccggtctatactgatgttgaagagtgacctacacgaggaaaactcttggagagattaa(SEQ ID NO：18)
组合2：所述N蛋白的序列包括SEQ ID NO：19所示的氨基酸序列，所述P蛋白的序列包括SEQ ID NO：20所示的氨基酸序列，所述L蛋白的序列包括SEQ ID NO：21所示的氨基酸序列。
相应地，所述自复制核心序列包括：
第一RNA序列，所述第一RNA序列编码N蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：22所示的核苷酸序列；
第二RNA序列，所述第二RNA序列编码P蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：23所示的核苷酸序列；
第三RNA序列，所述第三RNA序列编码L蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：24所示的核苷酸序列。
N蛋白
MAPTVKRIINDSIIQPKLPANEDPVEYPADYFKNNTNIVLYVSTKVALNDLRAYVYQGIKSGNPSILHINAYLYAALKGVEGTLDRDWVSFGRTIGKREENVKIFDLVKVEELKTALPDGKSDPDRSAEDDKWLPIYILGLYRVGRSKVTDYRKKLLDGLENQCRVASTRFESLVEDGLDFFDIWENDPNFTKIVAAVDMFFHMFKKHERAPIRYGTIVSRFKDCAALATFGHLSKVSGLSIEDLTTWVLNREVADELCQMMYPGQEIDKADSYMPYMIDFGLSQKSPYSSVKNPAFHFWGQLAALLLRSTRAKNARQPDDIEYTSLTCASLLLSFAVGSSADIEQQFYIGEDKYTTEKDDSLKKSDVPPKGRNVVDWLGWYDDNGGKPTPDMLNFARRAVSSLQSLREKTIGKYAKVEFDK*(SEQ ID NO：19)。
atggctcctacagttaagagaatcattaatgactccataattcagcctaaactaccggccaatgaggatccggtagagtatccagctgattacttcaaaaataacaccaacatagtattatatgtgagcactaaagtagccctaaatgatttaagggcctatgtctaccagggaatcaaatccggtaatccatcaatactccacataaatgcttatctttatgccgcgttaaagggagtagaaggaacattagacagagactgggttagctttggaagaacgatcggaaagagggaagagaatgtcaaaatcttcgatctagtcaaagttgaggaactgaagacagctcttcctgatgggaaatcggatccagatcgatcagctgaagatgataaatggcttcctatttacatcctaggcctatatcgagtgggtagatccaaagttacagattacagaaagaaactcctggacggtctagaaaatcagtgtagagtggcatcaaccagatttgaaagccttgttgaagatggtcttgacttctttgacatctgggaaaatgatcccaacttcaccaaaatagttgctgcagtggatatgttttttcacatgttcaagaagcatgaacgtgctccaatcagatatggaaccatagtctcacgattcaaagactgtgcagcacttgctacatttggacatctcagcaaggttagcggactttcaattgaagacctaacaacatgggttctgaatcgagaagtcgcagacgaactatgccaaatgatgtacccaggccaagaaattgacaaggcagattcatacatgccatatatgattgatttcgggttatcccaaaaatctccttattcatcagtgaagaatccagctttccacttctggggtcaactggccgcactcttgctaagatcaactcgagcaaaaaatgctcggcaacccgatgacattgagtacacttcgctgacttgtgcaagtttactactgtcatttgcagttggatcttcagcagacattgaacaacaattctacatcggagaggacaaatacacaacagagaaagatgacagtctcaagaaatctgatgtcccaccgaaaggaagaaatgttgtagactggctcggttggtatgatgacaatggagggaaacccacaccggatatgctcaacttcgcacgaagagcagtcagttcgttgcagtcactccgcgagaaaacaattggcaaatacgcaaaagtagaatttgacaaatga(SEQ ID NO：22)
P蛋白
MDSVDRLKTYLATYDNLDSALQDANESEERREDKYLQDLFIEDQGDKPTPSYYQEEESSDSDTDYNAEHLTMLSPDERIDKWEEDLPELEKIDDDIPVTFSDWTQPVMKENGGEKSLSLFPPVGLTKIQTEQWKKTIEAVCESSKYWNLSECQILNLEDSLTLKGRLMTPDCSSSVKSQNSVRRSEPLYSSHSPGPPLKVSESINLWDLKSTEVQLISKRAGVKDMTVKLTDFFGSEEEYYSVCPEGAPDLMGAIIMGLKYKKLFNQARMKYRL*(SEQ ID NO：20)。
atggacagtgttgataggctcaagacttacttagccacttatgataatttggattctgccttgcaggatgccaatgaatctgaggaaagacgagaggataaatatctccaagacctcttcatcgaagatcaaggagataaaccaactccgtcatattatcaggaagaagaatcgtcagattcagatactgattataatgctgaacatcttacgatgctgtcaccggatgaaagaatagacaagtgggaagaagatttgcctgaattagaaaagattgatgatgatataccggtgaccttttctgattggacacagcctgtaatgaaggaaaatgggggagagaaatcattgtctctgttccctccagtcgggttaacaaagattcaaacagaacaatggaaaaaaaccattgaggcggtttgtgagagttcaaaatattggaatttatcagaatgccaaattcttaacttggaagacagcctcactctcaaaggccgattgatgactcctgattgtagttcttcagtaaaatctcaaaattctgtccggaggtcagaacctctctactcctctcattctccaggtcccccactcaaggtatcagagtccatcaatttatgggatttaaagtccactgaagtacaattgatctccaagagagccggagttaaggacatgacagtcaaattgacagacttctttggaagtgaggaagagtattattcagtatgcccagaaggggcgccagacttgatgggagctatcatcatgggactgaagtacaagaaactcttcaatcaggcaagaatgaaatatcgtctttaa(SEQID NO：23)
L蛋白
MDFDLIEDSANWEDDESDFFLRDILSQEDQMSYLNTADYNLNSPLISDDMVYIIKRMNHEEVPPIWRSKEWDSPLDMLRGCQAQPMSHQEMHNWFGTWIQNVQHDSAQPFTFLKEVDKESEMTYDLVSTFLKGWVGKDYPFKSKNKEIDSMALVGPLCQKFLDLHKITLILNAVSLGETKELLTTFKGKYRMSCENIPIARLRLPSLGPVFMCKGWTYIHKERVLMDRTSFSCVKDVIIGRMQTFLSMIGRSDNKFSPDQIYTLANVYRIGDKILEQCGNKAYDLIKMIEPICNLKMMELARLHRPKIPKFPHFEEHVKGSVQELTQRSNRIQTLYDLIMSMKDVDLVLVVYGSFRHWGHPFIDYFQGLEKLHTQVNMEKHIDKEYPQQLASDLARLVLNKQFSESKKWFVDPSKMSPKHPFYEHVINKTWPTAAKIQDFGDNWHKLPLIQCFEIPDLIDPSVIYSDKSHSMNKKEVIQHVRSKPNIPIPSNKVLQTMLTNRATNWKAFLKDIDENGLDDDDLIIGLKGKERELKIAGRFFSLMSWRLREYFVITEYLIKTYYVPLFKGLTMADDLTSVIKKMMDSSSGQGLDDYSSVCLANHIDYEKWNNHQRKESNGPIFRVMGQFLGYPSLIERTHEFFEKSLIYYNGRPDLMTIRNGTLCNSTKHRVCWNGQKGGLEGLRQKGWSIVNLLVIQREAKIRNTAVKVLAQGDNQVICTQYKTKKTRSELELRAVLHQMAGNNNKIMEEIKRGTEKLGLIINDDETMQSADYLNYGKIPIFRGVIRGLETKRWSRVTCVTNDQIPTCANLMSSVSTNALTVAHFAENPINAMIQYNYFGTFARLLLFMHDPAIRQSLYKVQEKIPGLHTRTFKYAMLYLDPSIGGVCGMALSRFLIRAFPDPVTESLSFWKFIYEHASEPHLKKMEVMFETPQGAKFRIEHINKLLEDPTSLNISMGMSPANLLKSEVKKCLIESRSSIKNEIIKDATIYMHQEEEKLRGFLWSIKPLFPRFLSEFKAGTFLGVSEGFINLFQNSRTIRNSFKKRYHKDLDELIIKREISSLSHLGSMHYRLGDNQIWSCSASRADILRYKSWTRKVVGTTVPHPLEMHGPPSKKERPCQLCNSSGLTYISVHCPKGIIDVFNRRGPLPAYLGSNTSESTSILQPWEKESKIPIIKRATRLRDAISWFIPPESPLSTCILNNIQALTGEDWSSKQHGFKRTGSALHRFSTSRMSNGGFASQSPATLTRMIATTDTMRDFGTKNYDFMFQASLLYGQMTTSISRYGTPGSCTDHYHIRCKGCIREIEEVELNTSLEYKTPDVSHILEKWRNNTGSWGHQIKQLKPAEGNWESLSPVEQSYQVARCIGFLYGELTHKKSRQADDSSLFPLSIQLKVRGRGFLRGLLDGLMRSSCCQVIHRRSVSTLKRPANAVYGGLIYLIDKLSASSPFLSLVRTGPIRQELEQVPHKMSTSYPTNIRDLGSIVRNYFKYQCRPVERGNYKTYYNQIWLFSDVLSTEFIGPMRISSSLLRLLYRPSLTKKDREELRELAALSSNLRSGEDWDDLHIKFFSNDLLFCSQEIRHACKFGIKKDNEDITFYPNWGTEYIGNVTDIPVFYRAQNVKKDIRVPPRIQNPLMSGLRLGQLPTGAHYKMRAIVFRLKIPYHDFLDCGDGSGGMTAALLRYNRTSRGIFNSLLDLSDTMLRGSSPEPPSALETLGGERVRCVNGDSCWEHPSDLSDENTWKYFLHLKKGCGMSINLITMDMEVQDSVISYKIESLVRQYVPVLLESDGCLIYKTYGTYIATQEDNSLTLIGSLFHSVQLVQTDLSSSNTSELYLVCRRLKDYVDTPFVDWIELYDNWEKQYAFRSFKDEFQRAQSLTPETTLIGIPPQFVPDPGVNLETLFQIAGVPTGVAHGITHHILQSKDKLISNAIGSMCVISHFHINTIRTTDSMPGPPSDGDVNKMCSALIGACFWLDWMESDLNLYKHCLRSIMKSMPVRWFRTLKNEKWSQKWDCKGDAIPKDSRLGDSLANIGNWIRAWELIRNGNKSEPFDSMVAEALTKSVDKSLSWRKISKSTGIPRLLNSDIDLVDQSILNVQIDIVENQAWQN*(SEQ ID NO：21)
atggatttcgatctaatagaagattctgctaactgggaagatgatgagtcggacttttttttgcgagacattctatctcaagaagatcagatgtcttacttaaacaccgcagactataatttgaattctccactcatttccgatgacatggtttatataattaaaagaatgaatcacgaggaggttccccccatttggagatctaaggagtgggattctcctcttgatatgcttagaggttgtcaagctcaacccatgtctcaccaagagatgcacaattggtttggaacttggattcaaaatgttcagcatgattccgcccaacccttcacattcttaaaagaggtggacaaagagtcagaaatgacctatgacttggtctccacttttctgaaggggtgggtggggaaagattacccattcaagtcaaagaacaaagaaattgatagtatggcattagtcggtcctctttgtcaaaaattccttgatttgcataaaatcactctgatattaaatgcagtttctttgggggaaactaaagaactcctaaccactttcaagggtaaataccgcatgagttgtgaaaacattcctattgctcgcttaagacttccaagtctaggccctgtattcatgtgcaaaggttggacttatatccacaaagaaagagtgctaatggatcgaacttccttctcatgtgtaaaagatgtgataataggacgaatgcagacatttttgtctatgatcggacgatcggataacaagtttagtcctgatcaaatctatactctggcaaatgtatacagaattggagataaaattttagaacaatgcggcaataaggcttatgatttgattaaaatgattgaacccatctgcaatctgaaaatgatggaattagctagattgcatcgtcccaagattccgaagttccctcattttgaagagcatgtcaaaggctcagtgcaagaattgacacaaaggtccaatagaatacaaacattgtatgatctgattatgtctatgaaggatgttgacctcgtattagtggtttacggatctttccgtcattggggtcacccattcatcgattattttcagggattggaaaaattgcacactcaagtgaatatggaaaagcatattgacaaggagtacccacagcaattggccagtgacttagccagactagtattaaataaacaattcagcgaatcaaaaaaatggtttgtagacccttcaaaaatgtctcccaaacaccctttttatgaacatgttatcaataagacatggcctacagcagctaaaattcaagactttggagacaattggcacaagctcccattgattcaatgttttgaaataccagacttgatagatccatcagtgatttattcagacaaaagtcattccatgaacaaaaaggaggtgatacagcatgttcggtctaagccaaatattcccatcccaagcaacaaagttctgcaaacaatgcttaccaatagagcaacaaattggaaagcctttctgaaagatattgacgaaaatggactggatgatgacgatttaataatcggattaaagggaaaagaaagagaattgaaaatagctgggagattcttctcattaatgtcatggagattaagggaatattttgtgatcacagagtacctaatcaagacatactacgttcccttgtttaaggggttaactatggcagatgacctcacatcggtgatcaagaagatgatggacagttcatcaggtcaagggcttgatgattattcatctgtttgtttagccaaccatatcgattatgagaagtggaataaccatcagagaaaggaatcgaatggtcccatcttcagagtcatgggacagtttctaggttatccatcacttatagagagaactcatgagttttttgagaagagcttaatttactataacgggcgtccagatttgatgacaattcgaaatggtacattgtgtaattccacgaagcaccgagtttgctggaatgggcagaaaggaggattggaaggactaagacaaaagggatggagtattgtgaatctcttggttattcaaagggaagctaagatccgaaacacagcagtgaaggtcttagcacagggagataatcaggttatatgcactcaatacaagacaaagaagactagatcagagttagagttgagagcagtcttacatcagatggccgggaataataacaaaattatggaagaaattaagagaggtacagaaaagttgggcctaatcataaatgatgatgagactatgcaatcagcagactatttgaactatgggaaaattccaattttccgaggagtcatcagaggactagaaacaaagagatggtcacgggtgacatgcgtcacaaatgatcaaatcccgacgtgtgccaatttgatgtcctcagtctctactaatgccttgactgttgctcattttgctgaaaatcctataaatgcaatgattcaatacaattactttggaacctttgcacgattattgctttttatgcatgaccccgcaatccggcaatccttgtataaggtccaagaaaaaatacctggtttgcacaccagaacattcaaatacgccatgttgtacctagatccttcaatcggaggagtatgtggtatggcattatctcgttttttaattagagcatttccagatccagtaacagagagtctctcattctggaagtttatctatgaacatgcttctgagcctcatctaaaaaagatggaagtgatgttcgagaccccccaaggtgccaaattcagaatagaacacatcaacaaattgttagaggaccctacctctctaaacatctcaatgggtatgagtcccgcaaatttgttaaagagtgaggtcaaaaaatgtttaatagaatcaagatcatccatcaagaatgaaatcataaaagatgctactatctacatgcatcaagaagaagagaagcttagaggatttttgtggtccatcaaaccattattccctcgtttcttgagtgaattcaaagctggaacttttttgggagtatctgagggctttataaatttatttcaaaactcacgtaccataagaaactcatttaaaaagagatatcacaaggatcttgatgaattaataatcaagagagaaatatcgtccttgagtcatctcggatctatgcattatcgattaggggataatcagatatggtcctgttctgcatctcgagccgacatattaagatacaagtcatggaccaggaaagttgtgggaactacagtgcctcatcctttggaaatgcacggaccaccctcaaagaaggaaagaccttgccaattgtgtaattcatccggtctcacatatatttcggtacattgtccaaaaggaattattgatgtattcaatagaaggggacctttgccggcttacttggggtccaatacatctgagtctacatctattttacagccgtgggaaaaagagagtaaaataccaataattaaaagagcaactagattaagggacgccatttcttggttcatcccacccgagtctcctctgtctacatgcattttgaataatattcaggctttaacaggagaagattggagctctaaacaacatggctttaagaggacaggatcagcattacatagattttccacctcccggatgagcaatggaggatttgcctcacaaagcccggccaccttaactcgcatgattgcaactacagacacaatgagagactttggtacaaaaaattatgatttcatgttccaagcatctttgttatatggacagatgacaacaagtatttcaagatatggaaccccagggtcttgcacggatcattaccatatcagatgtaaaggatgcattagagagattgaagaagtagaactgaacactagtctagaatacaagacgcccgatgtttctcacatattggaaaaatggaggaacaatactggatcttggggtcatcaaatcaaacaattgaaacctgccgagggaaactgggaatcattgtctcctgtagagcaatcatatcaagttgcaagatgtattggatttctttatggtgaactgacacacaagaaatcgagacaggctgatgatagttctctattccccttgagcatccaactaaaagtgagagggagaggtttcttgcgaggccttctagacggtttgatgagatccagttgctgtcaggtaattcatagacgaagtgtttctaccttaaagagacctgcaaatgcagtttacggtggcctcatatacctcattgataaactaagtgcctcaagtcccttcttatcacttgtaagaaccggacctattcgacaagaattagaacaggtgccacacaagatgtctacatcgtatccaacgaacattagggacttgggctccattgtgagaaattattttaaatatcagtgtcgaccagttgagagaggaaactataaaacttattataatcaaatatggttattttctgatgttttgtccactgaatttatagggccaatgcgtatatccagctctctccttagactcctttatcgaccttctctgacaaagaaggatagagaagaattgagggagttagcagcactatcatctaatttacgaagtggagaagattgggatgatttacatatcaaatttttctcaaacgatctcctcttttgctcacaagagataagacatgcttgcaaatttgggattaaaaaagataatgaagatatcactttttacccgaattggggaacagagtacattgggaatgtcactgatattcctgtgttttaccgagctcaaaatgtcaaaaaggatattagagtaccccctcggatccaaaatcctttaatgtcaggactcaggcttggacaactgccaactggggctcattacaaaatgagagccattgtatttcgtcttaaaattccgtatcatgactttctggattgcggagatgggtcaggaggaatgactgcagcattactccggtataataggacatccagaggaatctttaacagtttgttggatctgtcagacacaatgctaagaggatcctcaccagaacctcccagtgcccttgagaccctggggggagagagagtaagatgtgtgaatggagacagttgctgggaacatccttccgatctcagcgatgagaacacatggaagtattttctccatttaaaaaagggatgtggaatgagtatcaatcttattaccatggatatggaagtccaggattctgttatatcatacaaaatcgagtcattggtcagacagtatgttccggttctattggaatccgacggttgccttatttataaaacatatggaacatatattgccacacaagaagacaattccctgactcttataggatcactttttcactctgtccaacttgtccaaacggatttaagctctagtaatacatccgaattgtacttggtatgcaggagattgaaggattatgtagacactccctttgttgattggatagaattatacgacaactgggagaaacagtatgctttcagaagcttcaaagatgaatttcaaagagctcaatcacttaccccagagacaaccctaataggaatacctcctcaatttgtaccggatcctggagtcaatctagagaccctgtttcaaatagcaggggttcccaccggagttgcgcatggaatcacacatcacatattgcagtctaaggataaattaatatcaaatgccatcggaagcatgtgtgttatctctcatttccacattaacacaatacggaccacagatagtatgcctggacccccatcagatggggatgtcaacaaaatgtgttcagcattgattggggcatgtttctggctggactggatggaatctgatcttaacttatacaaacattgtctaagatcaataatgaagtctatgcctgtgagatggtttagaacattaaaaaatgaaaaatggtcgcaaaaatgggattgtaaaggagatgcaatcccaaaagattccagattaggagacagccttgctaatatcggcaattggataagagcttgggaattaattagaaatggaaataagtctgagccttttgattcaatggtagcagaagcattgacaaaatctgtggataaatcacttagttggaggaaaatctcaaagtcaactggaattccgagacttctaaacagtgatatcgatttggttgatcaatctatactaaatgttcagatcgacatcgtagaaaatcaagcttggcaaaattga(SEQ ID NO：24)
组合3：所述N蛋白的序列包括SEQ ID NO：25所示的氨基酸序列，所述P蛋白的序列包括SEQ ID NO：26所示的氨基酸序列，所述L蛋白的序列包括SEQ ID NO：27所示的氨基酸序列。
相应地：所述自复制核心序列包括：
第一RNA序列，所述第一RNA序列编码N蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：28所示的核苷酸序列；
第二RNA序列，所述第二RNA序列编码P蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：29所示的核苷酸序列；
第三RNA序列，所述第三RNA序列编码L蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：30所示的核苷酸序列。
N蛋白
MSSQVFCISTGQTVSVCLPANEDPVEFPGAFFTPNARKPTVYIKKETDLSLLRSHVYDGIKDGSVTVSQINSYLYMVLKDIREKPDKNWTSFGVELGKKNEPMGIFDLLNVEDVKGKELDKKGQDTRLPGDDLWLPTLILGLYRVSRATQVEYKKTLMTNLYAQCKLRTKDAEEIVDETAEFFNAWANDSNFTKIVAAVDMYFHHFKKSDHAPIRFGTIVSRFKDCAALSTLSHLQKVTGLPIEEVFTWVFNKSVQDDLLRMMTPGQEIDQADSYMPYLIDMGLSTKSPYSSTKNPSFHFWGQLTAFLVKSARAKNALVPVDIAYHELTTAALLFAYAIGRSSELEQRFVLNGKKFTKEKDSRDDNDTTPPSERNVVVWLAWWEDIKHEITPDMKAFAKRAVERVGDIRVNSVAEYARKLFA*(SEQ ID NO：25)
atgagttctcaagtattctgcatttctacaggtcaaacagtctccgtatgccttccagcaaatgaagacccagtagagtttccaggggcgttcttcactccaaatgctaggaaaccgacggtgtacataaagaaggagacagatctgagtcttttgaggagtcatgtttatgacgggattaaggatggttctgtgacagtgtcccagataaattcttatctatacatggttttgaaagatatccgggagaaaccagataaaaattggacttctttcggagtcgaattgggaaaaaagaatgagccaatgggaattttcgatctgttgaatgttgaagatgttaaggggaaagaattggacaaaaaagggcaagacacccgactgcccggagatgatctatggcttccaacgctgatcctcggtctttatcgcgtgtccagggcgacacaggtcgaatacaagaagactctgatgaccaatctatatgctcagtgtaaattgcgcacgaaggatgcagaggagattgtggatgaaacagcagaattcttcaatgcttgggcaaatgactccaacttcacaaaaatcgtagctgctgtggatatgtacttccaccacttcaagaagagtgatcatgctcctattcgtttcggaacaattgtgtctagattcaaagactgtgcagcattgtccactctgtcgcacctccaaaaggtcacagggctccccattgaggaggtcttcacctgggttttcaataaatcagtacaggatgatttgttgcggatgatgactcctggccaggaaattgaccaagctgattcctatatgccctatctgatcgacatgggcttgtccacgaagtctccttactcttcaacaaaaaatcccagtttccatttctgggggcaactgaccgcattcttggtaaaatccgcaagagcaaagaatgcgttagtcccagttgacatcgcataccatgaactgaccactgctgcactgctttttgcctatgcaattggcagatcgtctgagctggagcagagattcgtgcttaacgggaagaagttcaccaaggagaaggactctcgagatgacaatgacactactccgccatcggagagaaatgttgttgtttggctggcctggtgggaggacattaagcatgaaattactccggacatgaaggcctttgccaagagagcagtggaaagggtaggagatattcgagtgaactcagttgcagagtatgccaggaaactctttgcatga(SEQ ID NO：28)
P蛋白
MEDSQLYQALKNYPKLQDTLDSIENLEDDTKSEPSECGSPTERGIPSYYLAEELDECEEEDSEDDDDNLPTEIPDPPTVDMLEAIMEDEIDDTAYQVHFEAKQTWKPVIETGGNERGKFTLSVPQNLSALQLLQWETGIHALAERLGGCRLLQISTRGTRDGIEFTVRETPCVSPASDPIPSTSRSSSIASNVSTRQTESPGSKSNTSLGIPEVPANLIDIGAIDKEFILAAISPSDPPYKNTLRNLFGSGDSFEQYNQTGIYSLKELVVAGLKRKGIYNRIRIRCHLEPQFN*(SEQ ID NO：26)
atggaagactctcaactatatcaagctctcaagaattacccaaagcttcaggacactctcgactcaattgagaatcttgaagatgacacaaagtcagagccatctgagtgtggttcccccacagagagaggaattcccagctattacctggctgaagaattggatgaatgtgaggaagaagattcggaagatgatgatgacaatttacctactgagataccggatcctcctactgttgacatgctggaggcaattatggaagatgagattgatgatacggcttaccaggtacattttgaggccaaacagacttggaaaccggtgatagagacagggggaaatgaaagaggtaagttcaccctttcagtccctcagaatctgagcgctctacaacttctccagtgggagacagggattcatgcattggcggagagacttgggggatgcagactgctgcagatcagcacacggggaacgagggatgggatagagttcactgtaagagaaacgccttgcgtttcacctgcttctgatccaatcccttccacatccagatccagttcaattgcttccaatgtctctaccagacaaaccgaatcacctggctccaaatccaatacaagtctcgggataccagaagtcccggctaatttgatcgacataggagcaattgataaagaattcatcctggcagctatctctccgtctgacccaccttataagaacactctgagaaacctcttcgggtccggagattcctttgaacagtacaaccagacaggaatttactctcttaaggaactcgtcgttgctggattgaagagaaaaggaatttataatagaatcagaatcagatgtcatcttgagccccagttcaattga(SEQ ID NO：29)
L蛋白
MDLNPVDDAAELSEENFFSGKLSKECRIRGLNSVDYNLNSPLVSDDLTYLLNKFKGKPVPIRWKMKKWDSILDQLRKHDLEYLRPSDLHQWFAEWMLYSKHGSKQGEDFLKTVDEEASDTFEVVRSFIRGWTGGEINFVRKSGKHMGYCAELCQKFLDLHKLTLLGNAATDNELLQLSKTFGDDKIYKKRLIKLPSLGRVIFDSGFFIVLDQRVLMDRNFMLMMKDVIIGRMQTVLSMISRCDDKFSSKDIDFLLKVYSTGDKIIRKLGNDGYELIKTVEPMCNLRLSDLARRFRPLVPPFPHFRRHIESTVDELSAKTPLIRELFSLIDTSPNVDSTLVVYGSFRHWGHPFINYFEGLEKLHKQVTMEKEIDTNYSEALASDLARIVLTKEFNEKKQWAVDYHRVPTSHPFKNHIRDNTWPTAAVIQDFGDHWHELPLIQCFDIPDLIDPSIIYSDKSHSMNRSEVLNHVRTKPHTPIPSKKVLESMIDKPATNWLEFLEEIDKNGLSDEDLVIGLKGKERELKIAGRFFSLMSWKLREYFVVTEYLIKTHFVPLFHGLTMADDMTAVIKKMLESSSGQGLTNYDSVCIANHIDYEKWNNHQRKLSNGPVFKVMGQFLGYPNLIYRTHEFFEKSLIYYNERPDLMKVRNGILENSTHQRVCWNGQAGGLEGLRQKGWSILNLLVIQREAKIRNTAVKVLAQGDNQVICTQYKTKQYRNDIELRQALNQMAANNDVIMKAIESGTNKLGLLINQDETMQSADYLNYGKVPIFRGVIRGLETKRWSRVTCVTNDQLPTCANLMSSVSTNALTVAHFDVHPLNAMIQFNFFGNFARLLLIMHDPAIRQSLNQLKGPNINVHSYGFKVAMLYLDPSIGGVCGTALSRFLIRSFPDPVTESLSFWKLIHHSTSDIRLKNLSEQFGNPKIAVFRESHIEKLLEDPTSLNISMGMSAANLLKTEIKKNLLQKKSSIGNQIVKDAVYYIHSEDEKLRTFLWSITPLFPRFLSEFKAGTFMGVASSIVSLFQNSRTIRNVFRDYMSQTIDDLIVKSELTSLEHLSNYTDRKGSGGIWSCSAEQADKLRRMSWKRPVLGTTVPHPLEMHGRGTLKSPLSKCCKESRMDYISVHIPEGLNKVLDGRGSLPAYLGSKTSESTSILQPWEKESKIPIIRRATRLRDAIHWFVDPDSNLARSILNNIESLTGEKWEGALKGYKRTGSALHRFSTSRVSHGGFSSQSPACLTRMMATTDTMRDYAQLNYDFMFQASLLYSQMTSSVILMGTTVSNTIHFHVTCRKCIREITEPMLESPREYRGKDVHLVLAKWKNSSNGWGETLQLLKPVEGDWDTIPPVEKSYHVGRILGFLYGDLKSQNSSRADDSSIFPLSIQMRLRGRGFLRGILDGLVRASACQVIHRRSVALLSKPANAIYGGLIYLIDKISASTSFTTLCRDGPIREELSSIPHKIPTSYPTSNSDMGLHIRNYLKFQCKTVELGKYQSDIKDLWLFSDVMTSNIAGPFALSTKILKCLYKPALSQKDRNNIRKISNFSKMMRSQLSWDPTSSEFITSQILVCNEEIRHACKFGIPKLSLKFDDPVWGPEDYGLIWSIPVDYSSQSVPKNLKPCPRIQNPSISGFRLGQLPTGAHYKLRSILRKKNIHYRDALCGGDGSGGMTAAVLRYNLKARAIFNSILDFDGSTMKGASPDPPSALETVVNGRTRCVNAESCWENPSDLSEQRTWDYFKFLKTHHGLKIDLIVLDMEVRDFAISASIEKCVRNNVSSILEEDGVLIYKTYGSTIAAESSNAVVNIGVLFESVELIQTEYSSTSTSEVYMYCRKIKKFVDAPHPDWISLDYYWSKLFCFRSYKEEFFRSYEVSRKESLKGIPNSFIPDPLVNLETLLQIAGVPSGISHQLAIDIKESQLTQITAAMVLCGMIANYTLDVTKKRDSYNPPSDGRLIRMSAALVGISFWISVKYYDKELNFELEQILSRSFPIRWMLSRNYLFWTTKKGFRNAKDVRLSGNMANIGNWIRCMELLHLPPGSLSKDEVTTTCGKYIRSLKYSVILQQTGIIDLWKSRVASDDRSLMEVKTEFIESEHWVD*(SEQ ID NO：27)
atggatctcaacccggtcgatgatgctgcagagttatcagaggagaacttcttctctgggaaattgtccaaggaatgccgaattagaggattgaattcagttgattacaatctgaactccccgttggtgtccgacgatttgacatacttgctgaacaaatttaagggaaaacctgtgcctatccgatggaagatgaagaaatgggactctattctagaccaactgcgtaaacatgatctggagtatctgagaccctcggatctacaccaatggtttgcagaatggatgttgtactcaaagcatggcagtaagcagggagaagacttcttaaagacagtagacgaagaggctagtgatacgtttgaggttgtaaggtcgttcataaggggatggactggtggagaaatcaactttgtcaggaagagcggaaagcatatggggtattgtgcggagttgtgccagaaattcttggatttgcataaattgaccctccttggaaatgccgccaccgataatgagttgttacaactgagcaaaactttcggggatgacaagatttacaagaaacggctaatcaaacttccaagtcttggtcgcgtcatctttgattctggattcttcattgtcctggatcagcgagttctaatggatcgtaattttatgttgatgatgaaagacgtaataattggaagaatgcaaacagttctgtccatgattagcagatgtgatgataaattcagttccaaggatattgattttctattaaaggtctactcaacaggcgataagatcataagaaagttgggtaacgatgggtatgagttgatcaagaccgtagaacctatgtgcaatcttcgtctatcagacctggccagaaggttccgtccactcgtacctcctttccctcatttcaggagacatattgaatcgactgtagatgaactgagtgcgaagactccattgatcagggaattgttctcattgattgatacttctcctaatgtagattcaacgttggtcgtttacggttcatttcgtcattggggtcatccttttattaattattttgaaggcctggagaaattgcataagcaagtgacaatggaaaaagaaattgataccaattattcggaagcgttggccagtgatctggctaggatagtcttgactaaagagttcaatgagaaaaaacaatgggctgtagattaccacagagtgcctacaagccatccctttaaaaaccacatccgagacaacacatggccaacagctgcagtgatccaagattttggagatcactggcatgagctcccattaattcaatgcttcgacatacctgatctgattgatccatccattatctactcagacaagagccattccatgaatcgatcagaggtgttaaatcatgtaagaaccaagcctcatacaccgattccaagcaagaaagttttagagagtatgatcgacaaaccagcgacaaattggcttgagtttcttgaagagatcgacaaaaatggattatctgatgaggatttggtgatcggattaaaaggaaaagaaagagaactgaagattgcaggtagatttttctcattgatgtcttggaagcttagggaatactttgttgtcacagagtatttgatcaagactcactttgtgccattgttccatgggctgaccatggctgatgatatgacagcagtgatcaaaaagatgctggaaagctcgtctggtcaagggctaacaaactacgacagcgtttgtattgcaaatcatattgactatgaaaaatggaataatcatcaacgaaaattgtccaatggacctgtgtttaaagtcatgggacaattcttgggttatccaaatttgatataccggacacatgagttttttgagaaaagtttaatttactataatgaaagaccggatctcatgaaagtcagaaatgggatcttagaaaatagcacacatcagagggtttgctggaatggacaggcaggtggtttagaaggtttgagacagaaaggatggagtattcttaatttgctggtcatacagagagaagcgaaaatccggaataccgcagttaaagtgctagcacaaggcgacaatcaagtcatatgtacacagtacaagaccaaacagtatcgaaacgatatcgagttgagacaagccttaaaccaaatggcagcaaacaatgatgtcatcatgaaggccatagagtcaggaaccaataagttgggtttgttgatcaatcaggatgagacgatgcaatctgctgattatctgaactatgggaaggtacctatctttagaggagtaatcagagggctggaaacaaagcgatggtcccgagtcacttgtgtgacaaatgaccaattaccaacgtgtgcaaatctcatgtcatctgtatctacaaatgctttgacagtggcacatttcgatgtacacccattaaatgcaatgatccaatttaacttcttcgggaattttgctcgccttctcttgattatgcacgatccggcgattcgacaatcattaaatcagttgaaaggaccaaacatcaatgtccattcatacgggttcaaagttgcgatgttgtacttggacccttcaataggaggagtgtgtggtacagccctttctcgatttttgattaggagtttccctgaccctgtgacggagagtctctcattttggaagcttatccatcatagcaccagtgatatcagattaaaaaatctctcagaacagtttggcaatcctaagatagcagtttttagagaatctcacatagaaaagttgttggaagatcctactagtttgaatatatcgatgggaatgagtgctgcaaatttgttgaaaacagagataaagaaaaatctcctacaaaagaaatcaagcatagggaatcagatagtcaaagacgccgtatactacatacactcggaagatgagaaattgagaacttttttgtggtccattactccattgtttcctcggtttctgagcgaatttaaagcagggacgttcatgggagtagcgagcagcattgtatctttgttccaaaactctcgaaccattcgaaatgttttcagagactatatgagtcaaacaattgatgacttgattgtcaagagtgaactaacatctctggagcatttgtctaactatactgacaggaaagggagtggtgggatctggagttgctctgcggaacaggctgacaaacttagaagaatgtcctggaagcgtccagtgctagggacaacagtccctcacccgttggaaatgcacggaaggggaacactgaaatccccgctatccaagtgttgcaaggagtcccgaatggattatatttctgtccatattcctgaaggattgaacaaagttttggacggccgaggaagcctaccagcatatttgggttcaaaaacatcagagtctacctcaattcttcagccttgggagaaggaaagcaaaattcccatcataagaagagctactagattacgagatgcaattcattggtttgtggatccggacagtaacttagcccgaagcatattgaacaatattgaatccttaactggagaaaagtgggaaggggctttaaaaggatataagagaacgggttctgccctccatagattttccacctcgcgggtaagccatggtggtttttcttcacaaagtcctgcatgtctcaccagaatgatggcaaccacagacaccatgcgcgattatgctcagctcaattatgacttcatgttccaagcaagtcttctctactctcaaatgaccagttccgtcattttaatgggaaccactgtctcaaacactattcatttccatgttacctgtcgaaaatgtatccgagaaataacagaaccgatgttagaaagtcctagggagtacagagggaaggacgttcatttagtcctggcaaaatggaagaattcttcaaatggttggggagaaaccctccaactactaaagccagttgagggagattgggacactatccctcctgttgaaaaatcttatcatgtgggtaggatcttgggttttctttatggtgacctaaagagtcaaaattccagtcgtgcagacgacagttcaatcttccccctcagcattcaaatgagattaagaggtcgaggctttttacgaggaatccttgacggattagtccgagctagtgcttgtcaggttatccacaggagaagtgttgctttgctttcaaaaccagcaaatgcaatttatggaggattgatttacttgatagacaagataagtgcatccacctcgtttacgacactgtgtagggacggacccattagagaagaactatcatctatacctcacaaaattcctacttcgtatccaacttcaaattcagatatgggactccacattagaaattatttgaagtttcagtgcaagacagtcgaattgggaaaatatcaatctgatataaaggatttatggttgttctcggatgtgatgacgtcgaatattgcaggaccctttgcattgtctacgaaaattttgaagtgcttatacaagcctgctttgtcccagaaagatcgaaacaatatcaggaagatcagcaatttctccaagatgatgcgatcacaattgagctgggaccccacaagctctgaatttattacatctcaaatcctagtatgcaatgaggaaattaggcatgcctgcaagtttggaattccaaaattatcacttaagtttgatgatccagtctggggacccgaggattatggattgatctggtccattccagttgattattccagtcaatcagttccaaagaacttgaagccctgtcctagaattcaaaaccctagcatatctggttttaggttaggacaacttccaacaggagctcactacaagctgagatcaatcctaaggaagaaaaatatacattacagggatgcactgtgtgggggtgatgggtcaggaggtatgacagcggcagtcctacgttataatctaaaggccagggccatatttaatagcatccttgattttgatggatcaacaatgaagggagcttcaccagatccacctagtgcattggaaacagtggtgaatggccggactcggtgcgtcaacgcggagagttgttgggagaacccgtcagatctgagtgaacagagaacatgggattatttcaaattcttgaaaacccatcacggattaaagatagacctgattgtattggacatggaagtgagagactttgcaatctcggcatccatagagaagtgtgtccgaaacaatgtatcgtcaatattggaagaagacggagtcctaatatacaagacctatggatcaacaattgcagcagaaagtagcaatgcagttgtaaatattggagtattgtttgagagcgtagagttgattcagacggagtatagcagtacatccacttcagaagtgtacatgtattgccgaaagattaagaagtttgtggacgctcctcacccagattggatatcacttgattattattggagcaaattattttgctttaggagttacaaagaagaattcttccgatcctacgaagtgtctcgtaaagaatccctaaaaggaatacccaattccttcatccctgacccattggtcaatctagagacattacttcagatagcaggagttccttctgggatatcacaccagttggcaattgatattaaggaatcacagctgactcagatcaccgctgcaatggtgctttgcggaatgatcgcaaactacactttggatgtgacaaaaaagagagattcatacaatcctccttccgacggaagattaattcgaatgagtgctgctttagtcggaataagtttctggatttccgtcaagtattatgacaaagagttgaatttcgaattggaacagatattatccagatcatttcccataaggtggatgctttcacgcaactatttattctggacaacaaaaaagggttttaggaatgcaaaagacgtaagactatctgggaatatggctaatatagggaattggattcgatgcatggagctccttcatctccccccgggatccctgtccaaggatgaggtcacgaccacttgtgggaaatacattagaagcttgaagtattctgtcatactccaacagaccgggatcattgatttgtggaaatcaagggtcgcaagtgatgatcgatcattgatggaggttaagaccgaattcattgaatctgagcattgggtagattaa(SEQ ID NO：30)
组合4：所述N蛋白的序列包括SEQ ID NO：31所示的氨基酸序列，所述P蛋白的序列包括SEQ ID NO：32所示的氨基酸序列，所述L蛋白的序列包括SEQ ID NO：33所示的氨基酸序列。
相应地，所述自复制核心序列包括：
第一RNA序列，所述第一RNA序列编码N蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：34所示的核苷酸序列；
第二RNA序列，所述第二RNA序列编码P蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：35所示的核苷酸序列；
第三RNA序列，所述第三RNA序列编码L蛋白或其功能片段，所述第一RNA序列具有如SEQ ID NO：36所示的核苷酸序列。
N蛋白
MDADKIVFKVNNQVVSLKPEIIVDQYEYKYPAIKDLKKPCITLGKAPDLNKAYKSVLSGMSAAKLNPDDVCSYLAAAMQFFEGTCPEDWTSYGIVIARKGDKITPGSLVEIKRTDVEGNWALTGGMELTRDPTVPEHASLVGLLLSLYRLSKISGQNTGNYKTNIADRIEQIFETAPFVKIVEHHTLMTTHKMCANWSTIPNFRFLAGTYDMFFSRIEHLYSAIRVGTVVTAYEDCSGLVSFTGFIKQINLTAREAILYFFHKNFEEEIRRMFEPGQETAVPHSYFIHFRSLGLSGKSPYSSNAVGHVFNLIHFVGCYMGQVRSLNATVIAACAPHEMSVLGGYLGEEFFGKGTFERRFFRDEKELQEYEAAELTKTDVALADDGTVNSDDEDYFSGETRSPEAVYTRIMMNGGRLKRSHIRRYVSVSSNHQARPNSFAEFLNKTYSSDS*(SEQ ID NO：31)
atggatgccgacaagattgtattcaaagtcaataatcaggtggtctctttgaagcctgagattatcgtggatcaatatgagtacaagtaccctgccatcaaagatttgaaaaagccctgtataaccctaggaaaggctcccgatttaaataaagcatacaagtcagttttgtcaggcatgagcgccgccaaacttaatcctgacgatgtatgttcctatttggcagcggcaatgcagttttttgaggggacatgtccggaagactggaccagctatggaattgtgattgcacgaaaaggagataagatcaccccaggttctctggtggagataaaacgtactgatgtagaagggaattgggctctgacaggaggcatggaactgacaagagaccccactgtccctgagcatgcgtccttagtcggtcttctcttgagtctgtataggttgagcaaaatatccgggcaaaacactggtaactataagacaaacattgcagacaggatagagcagatttttgagacagccccttttgttaaaatcgtggaacaccatactctaatgacaactcacaaaatgtgtgctaattggagtactataccaaacttcagatttttggccggaacctatgacatgtttttctcccggattgagcatctatattcagcaatcagagtgggcacagttgtcactgcttatgaagactgttcaggactggtatcatttactgggttcataaaacaaatcaatctcaccgctagagaggcaatactatatttcttccacaagaactttgaggaagagataagaagaatgtttgagccagggcaggagacagctgttcctcactcttatttcatccacttccgttcactaggcttgagtgggaaatctccttattcatcaaatgctgttggtcacgtgttcaatctcattcactttgtaggatgctatatgggtcaagtcagatccctaaatgcaacggttattgctgcatgtgctcctcatgaaatgtctgttctagggggctatctgggagaggaattcttcgggaaagggacatttgaaagaagattcttcagagatgagaaagaacttcaagaatacgaggcggctgaactgacaaagactgacgtagcactggcagatgatggaactgtcaactctgacgacgaggactacttttcaggtgaaaccagaagtccggaggctgtttatactcgaatcatgatgaatggaggtcgactaaagagatctcacatacggagatatgtctcagtcagttccaatcatcaagcccgtccaaactcattcgccgagtttctaaacaagacatattcgagtgactcataa(SEQ IDNO：34)
P蛋白
MSKIFVNPSAIRAGLADLEMAEETVDLINRNIEDNQAHLQGEPIEVDNLPEDMGRLHLDDGKSPNHGEIAKVGEGKYREDFQMDEGEDPSFLFQSYLENVGVQIVRQMRSGERFLKIWSQTVEEIISYVAVNFPNPPGKSSEDKSTQTTGRELKKETTPTPSQRESQSSKARMAAQIASGPPALEWSATNEEDDLSVEAEIAHQIAESFSKKYKFPSRSSGILLYNFEQLKMNLDDIVKEAKNVPGVTRLAHDGSKLPLRCVLGWVALANSKKFQLLVESDKLSKIMQDDLNRYTSC*(SEQ ID NO：32)
atgagcaagatctttgtcaatcctagtgctattagagccggtctggccgatcttgagatggctgaagaaactgttgatctgatcaatagaaatatcgaagacaatcaggctcatctccaaggggaacccatagaggtggacaatctccctgaggatatggggcgacttcacctggatgatggaaaatcgcccaaccatggtgagatagccaaggtgggagaaggcaagtatcgagaggactttcagatggatgaaggagaggatcctagcttcctgttccagtcatacctggaaaatgttggagtccaaatagtcagacaaatgaggtcaggagagagatttctcaagatatggtcacagaccgtagaagagattatatcctatgtcgcggtcaactttcccaaccctccaggaaagtcttcagaggataaatcaacccagactactggccgagagctcaagaaggagacaacacccactccttctcagagagaaagccaatcatcgaaagccaggatggcggctcaaattgcttctggccctccagcccttgaatggtcggctaccaatgaagaggatgatctatcagtggaggctgagatcgctcaccagattgcagaaagtttctccaaaaaatataagtttccctctcgatcctcagggatactcttgtataattttgagcaattgaaaatgaaccttgatgatatagttaaagaggcaaaaaatgtaccaggtgtgacccgtttagcccatgacgggtccaaactccccctaagatgtgtactgggatgggtcgctttggccaactctaagaaattccagttgttagtcgaatccgacaagctgagtaaaatcatgcaagatgacttgaatcgctatacatcttgctaa(SEQ ID NO：35)。
L蛋白
MLDPGEVYDDPIDPIELEAEPRGTPIVPNILRNSDYNLNSPLIEDPARLMLEWLKTGNRPYRMTLTDNCSRSFRVLKDYFKKVDLGSLKVGGMAAQSMISLWLYGAHSESNRSRRCITDLAHFYSKSSPIEKLLNLTLGNRGLRIPPEGVLSCLERVDYDNAFGRYLANTYSSYLFFHVITLYMNALDWDEEKTILALWKDLTSVDIGKDLVKFKDQIWGLLIVTKDFVYSQSSNCLFDRNYTLMLKDLFLSRFNSLMVLLSPPEPRYSDDLISQLCQLYIAGDQVLSMCGNSGYEVIKILEPYVVNSLVQRAEKFRPLIHSLGDFPVFIKDKVSQLEETFGPCARRFFRALDQFDNIHDLVFVFGCYRHWGHPYIDYRKGLSKLYDQVHLKKVIDKSYQECLASDLARRILRWGFDKYSKWYLDSRFLARDHPLTPYIKTQTWPPKHIVDLVGDTWHKLPITQIFEIPESMDPSEILDDKSHSFTRTRLASWLSENRGGPVPSEKVIITALSKPPVNPREFLRSIDLGGLPDEDLIIGLKPKERELKIEGRFFALMSWNLRLYFVITEKLLANYILPLFDALTMTDNLNKVFKKLIDRVTGQGLLDYSRVTYAFHLDYEKWNNHQRLESTEDVFSVLDQVFGLKRVFSRTHEFFQKAWIYYSDRSDLIGLREDQIYCLDASNGPTCWNGQDGGLEGLRQKGWSLVSLLMIDRESQIRNTRTKILAQGDNQVLCPTYMLSPGLSQEGLLYELERISRNALSIYRAVEEGASKLGLIIKKEETMCSYDFLIYGKTPLFRGNILVPESKRWARVSCVSNDQIVNLANIMSTVSTNALTVAQHSQSLIKPMRDFLLMSVQAVFHYLLFSPILKGRVYKILSAEGESFLLAMSRIIYLDPSLGGISGMSLGRFHIRQFSDPVSEGLSFWREIWLSSQESWIHALCQEAGNPDLGERTLESFTRLLEDPTTLNIRGGASPTILLKDAIRKALYDEVDKVENSEFREAILLSKTHRDNFILFLISVEPLFPRFLSELFSSSFLGIPESIIGLIQNSRTIRRQFRKSLSKTLEESFYNSEIHGISRMTQTPQRVGGVWPCSSERADQLREISWGRKVVGTTVPHPSEMLGLLPKSSISCTCGATGGGNPRVSVSVLPSFDQSFFSRGPLKGYLGSSTSMSTQLFHAWEKVTNVHVVKRALSLKESINWFITRDSNLAQALIRNIMSLTGPDFPLEEAPVFKRTGSALHRFKSARYSEGGYSSVCPNLLSHISVSTDTMSDLTQDGKNYDFMFQPLMLYAQTWTSELVQRDTRLRDSTFHWHLRCNRCVRPIDDVTLETSQIFEFPDVSKRISRMVSGAVPHFQRLPDIRLRPGDFESLSGREKSHHIGSAQGLLYSILVAIHDSGYNDGTIFPVNIYGKVSPRDYLRGLARGVLIGSSICFLTRMTNININRPLELVSGVISYILLRLDNHPSLYIMLREPSLRGEIFSIPQKIPAAYPTTMKEGNRSILCYLQHVLRYEREIITASPENDWLWIFSDFRSAKMTYLSLITYQSHLLLQRVERNLSKSMRDNLRQLSSLMRQVLGGHGEDTLESDDNIQRLLKDSLRRTRWVDQEVRHAARTMTGDYSPNKKVSRKVGCSEWVCSAQQVAVSTSANPAPVSELDIRALSKRFQNPLISGLRVVQWATGAHYKLKPILDDLNVFPSLCLVVGDGSGGISRAVLNMFPDAKLVFNSLLEVNDLMASGTHPLPPSAIMRGGNDIVSRVIDLDSIWEKPSDLRNLATWKYFQSVQKQVNMSYDLIICDAEVTDIASINRITLLMSDFALSIDGPLYLVFKTYGTMLVNPNYKAIQHLSRAFPSVTGFITQVTSSFSSELYLRFSKRGKFFRDAEYLTSSTLREMSLVLFNCSSPKSEMQRARSLNYQDLVRGFPEEIISNPYNEMIITLIDSDVESFLVHKMVDDLELQRGTLSKVAIIIAIMIVFSNRVFNVSKPLTDPSFYPPSDPKILRHFNICCSTMMYLSTALGDVPSFARLHDLYNRPITYYFRKQVIRGNVYLSWSWSNDTSVFKRVACNSSLSLSSHWIRLIYKIVKTTRLVGSIKDLSREVERHLHRYNRWITLEDIRSRSSLLDYSCL*(SEQ ID NO：33)
atgctcgatcctggagaggtctatgatgaccctattgacccaatcgagttagaggctgaacccagaggaacccccattgtccccaacatcttgaggaactctgactacaatctcaactctcctttgatagaagatcctgctagactaatgttagaatggttaaaaacagggaatagaccttatcggatgactctaacagacaattgctccaggtctttcagagttttgaaagattatttcaagaaggtagatttgggttctctcaaggtgggcggaatggctgcacagtcaatgatttctctctggttatatggtgcccactctgaatccaacaggagccggagatgtataacagacttggcccatttctattccaagtcgtcccccatagagaagctgttgaatctcacgctaggaaatagagggctgagaatccccccagagggagtgttaagttgccttgagagggttgattatgataatgcatttggaaggtatcttgccaacacgtattcctcttacttgttcttccatgtaatcaccttatacatgaacgccctagactgggatgaggaaaagaccatcctagcattatggaaagatttaacctcagtggacatcgggaaggacttggtaaagttcaaagaccaaatatggggactgctgatcgtgacaaaggactttgtttactcccaaagttccaattgtctttttgacagaaactacacacttatgctaaaagatcttttcttgtctcgcttcaactccttaatggtcttgctctctcccccagagccccgatactcagatgacttgatatctcaactatgccagctgtacattgctggggatcaagtcttgtctatgtgtggaaactccggctatgaagtcatcaaaatattggagccatatgtcgtgaatagtttagtccagagagcagaaaagtttaggcctctcattcattccttgggagactttcctgtatttataaaagacaaggtaagtcaacttgaagagacgttcggtccctgtgcaagaaggttctttagggctctggatcaattcgacaacatacatgacttggtttttgtgtttggctgttacaggcattgggggcacccatatatagattatcgaaagggtctgtcaaaactatatgatcaggttcaccttaaaaaagtgatagataagtcctaccaggagtgcttagcaagcgacctagccaggaggatccttagatggggttttgataagtactccaagtggtatctggattcaagattcctagcccgagaccaccccttgactccttatatcaaaacccaaacatggccacccaaacatattgtagacttggtgggggatacatggcacaagctcccgatcacgcagatctttgagattcctgaatcaatggatccgtcagaaatattggatgacaaatcacattctttcaccagaacgagactagcttcttggctgtcagaaaaccgaggggggcctgttcctagcgaaaaagttattatcacggccctgtctaagccgcctgtcaatccccgagagtttctgaggtctatagacctcggaggattgccagatgaagacttgataattggcctcaagccaaaggaacgggaattgaagattgaaggtcgattctttgctctaatgtcatggaatctaagattgtattttgtcatcactgaaaaactcttggccaactacatcttgccactttttgacgcgctgactatgacagacaacctgaacaaggtgtttaaaaagctgatcgacagggtcaccgggcaagggcttttggactattcaagggtcacatatgcatttcacctggactatgaaaagtggaacaaccatcaaagattagagtcaacagaggatgtattttctgtcctagatcaagtgtttggattgaagagagtgttttctagaacacacgagttttttcaaaaggcctggatctattattcagacagatcagacctcatcgggttacgggaggatcaaatatactgcttagatgcgtccaacggcccaacctgttggaatggccaggatggcgggctagaaggcttacggcagaagggctggagtctagtcagcttattgatgatagatagagaatctcaaatcaggaacacaagaaccaaaatactagctcaaggagacaaccaggttttatgtccgacatacatgttgtcgccagggctatctcaagaggggctcctctatgaattggagagaatatcaaggaatgcactttcgatatacagagccgtcgaggaaggggcatctaagctagggctgatcatcaagaaagaagagaccatgtgtagttatgacttcctcatctatggaaaaacccctttgtttagaggtaacatattggtgcctgagtccaaaagatgggccagagtctcttgcgtctctaatgaccaaatagtcaacctcgccaatataatgtcgacagtgtccaccaatgcgctaacagtggcacaacactctcaatctttgatcaaaccgatgagggattttctgctcatgtcagtacaggcagtctttcactacctgctatttagcccaatcttaaagggaagagtttacaagattctgagcgctgaaggggagagctttctcctagccatgtcaaggataatctatctagatccttctttgggagggatatctggaatgtccctcggaagattccatatacgacagttctcagaccctgtctctgaagggttatccttctggagagagatctggttaagctcccaagagtcctggattcacgcgttgtgtcaagaggctggaaacccagatcttggagagagaacactcgagagcttcactcgccttctagaagatccgaccaccttaaatatcagaggaggggccagtcctaccattctactcaaggatgcaatcagaaaggctttatatgacgaggtggacaaggtggaaaattcagagtttcgagaggcaatcctgttgtccaagacccatagagataattttatactcttcttaatatctgttgagcctctgtttcctcgatttctcagtgagctattcagttcgtcttttttgggaatccccgagtcaatcattggattgatacaaaactcccgaacgataagaaggcagtttagaaagagtctctcaaaaactttagaagaatccttctacaactcagagatccacgggattagtcggatgacccagacacctcagagggttgggggggtgtggccttgctcttcagagagggcagatcaacttagggagatctcttggggaagaaaagtggtaggcacgacagttcctcacccttctgagatgttgggattacttcccaagtcctctatttcttgcacttgtggagcaacaggaggaggcaatcctagagtttctgtatcagtactcccgtcctttgatcagtcatttttttcacgaggccccctaaagggatacttgggctcgtccacctctatgtcgacccagctattccatgcatgggaaaaagtcactaatgttcatgtggtgaagagagctctatcgttaaaagaatctataaactggttcattactagagattccaacttggctcaagctctaattaggaacattatgtctctgacaggccctgatttccctctagaggaggcccctgtcttcaaaaggacggggtcagccttgcataggttcaagtctgccagatacagcgaaggagggtattcttctgtctgcccgaacctcctctctcatatttctgttagtacagacaccatgtctgatttgacccaagacgggaagaactacgatttcatgttccagccattgatgctttatgcacagacatggacatcagagctggtacagagagacacaaggctaagagactctacgtttcattggcacctccgatgcaacaggtgtgtgagacccattgacgacgtgaccctggagacctctcagatcttcgagtttccggatgtgtcgaaaagaatatccagaatggtttctggggctgtgcctcacttccagaggcttcccgatatccgtctgagaccaggagattttgaatctctaagcggtagagaaaagtctcaccatatcggatcagctcaggggctcttatactcaatcttagtggcaattcacgactcaggatacaatgatggaaccatcttccctgtcaacatatacggcaaggtttcccctagagactatttgagagggctcgcaaggggagtattgataggatcctcgatttgcttcttgacaagaatgacaaatatcaatattaatagacctcttgaattggtctcaggggtaatctcatatattctcctgaggctagataaccatccctccttgtacataatgctcagagaaccgtctcttagaggagagatattttctatccctcagaaaatccccgccgcttatccaaccactatgaaagaaggcaacagatcaatcttgtgttatctccaacatgtgctacgctatgagcgagagataatcacggcgtctccagagaatgactggctatggatcttttcagactttagaagtgccaaaatgacgtacctatccctcattacttaccagtctcatcttctactccagagggttgagagaaacctatctaagagtatgagagataacctgcgacaattgagttctttgatgaggcaggtgctgggcgggcacggagaagataccttagagtcagacgacaacattcaacgactgctaaaagactctttacgaaggacaagatgggtggatcaagaggtgcgccatgcagctagaaccatgactggagattacagccccaacaagaaggtgtcccgtaaggtaggatgttcagaatgggtctgctctgctcaacaggttgcagtctctacctcagcaaacccggcccctgtctcggagcttgacataagggccctctctaagaggttccagaaccctttgatctcgggcttgagagtggttcagtgggcaaccggtgctcattataagcttaagcctattctagatgatctcaatgttttcccatctctctgccttgtagttggggacgggtcaggggggatatcaagggcagtcctcaacatgtttccagatgccaagcttgtgttcaacagtcttttagaggtgaatgacctgatggcttccggaacacatccactgcctccttcagcaatcatgaggggaggaaatgatatcgtctccagagtgatagatcttgactcaatctgggaaaaaccgtccgacttgagaaacttggcaacctggaaatacttccagtcagtccaaaagcaggtcaacatgtcctatgacctcattatttgcgatgcagaagttactgacattgcatctatcaaccggatcaccctgttaatgtccgattttgcattgtctatagatggaccactctatttggtcttcaaaacttatgggactatgctagtaaatccaaactacaaggctattcaacacctgtcaagagcgttcccctcggtcacagggtttatcacccaagtaacttcgtctttttcatctgagctctacctccgattctccaaacgagggaagtttttcagagatgctgagtacttgacctcttccacccttcgagaaatgagccttgtgttattcaattgtagcagccccaagagtgagatgcagagagctcgttccttgaactatcaggatcttgtgagaggatttcctgaagaaatcatatcaaatccttacaatgagatgatcataactctgattgacagtgatgtagaatcttttctagtccacaagatggttgatgatcttgagttacagaggggaactctgtctaaagtggctatcattatagccatcatgatagttttctccaacagagtcttcaacgtttccaaacccctaactgacccctcgttctatccaccgtctgatcccaaaatcctgaggcacttcaacatatgttgcagtactatgatgtatctatctactgctttaggtgacgtccctagcttcgcaagacttcacgacctgtataacagacctataacttattacttcagaaagcaagtcattcgagggaacgtttatctatcttggagttggtccaacgacacctcagtgttcaaaagggtagcctgtaattctagcctgagtctgtcatctcactggatcaggttgatttacaagatagtgaagactaccagactcgttggcagcatcaaggatctatccagagaagtggaaagacaccttcataggtacaacaggtggatcaccctagaggatatcagatctagatcatccctactagactacagttgcctgtga(SEQ ID NO：36)。
组合5：正链RNA病毒来源的自复制RNA序列的核心复合物为:NSP1、NSP2、NSP3和NSP4，其中，所述NSP1蛋白的序列包括SEQ ID NO：37所示的氨基酸序列，所述NSP2蛋白的序列包括SEQ ID NO：38所示的氨基酸序列，所述NSP3蛋白的序列包括SEQ ID NO：39所示的氨基酸序列，所述NSP4蛋白的序列包括SEQ ID NO：40所示的氨基酸序列。
编码所述自复制核心复合物序列包括：
编码NSP1蛋白的核酸序列具有如SEQ ID NO：41所示的核苷酸序列；
编码NSP2蛋白的核酸序列具有如SEQ ID NO：42所示的核苷酸序列；
编码NSP3蛋白的核酸序列具有如SEQ ID NO：43所示的核苷酸序列；
编码NSP4蛋白的核酸序列具有如SEQ ID NO：44所示的核苷酸序列。
NSP1蛋白：
MEKPVVNVDVDPQSPFVVQLQKSFPQFEVVAQQVTPNDHANARAFSHLASKLIELEVPTTATILDIGSAPARRMFSEHQYHCVCPMRSPEDPDRMMKYASKLAEKACKITNKNLHEKIKDLRTVLDTPDAETPSLCFHNDVTCNMRAEYSVMQDVYINAPGTIYHQAMKGVRTLYWIGFDTTQFMFSAMAGSYPAYNTNWADEKVLEARNIGLCSTKLSEGRTGKLSIMRKKELKPGSRVYFSVGSTLYPEHRASLQSWHLPSVFHLNGKQSYTCRCDTVVSCEGYVVKKITISPGITGETVGYAVTHNSEGFLLCKVTDTVKGERVSFPVCTYIPATICDQMTGIMATDISPDDAQKLLVGLNQRIVINGRTNRNTNTMQNYLLPIIAQGFSKWAKERKDDLDNEKMLGTRERKLTYGCLWAFRTKKVHSFYRPPGTQTCVKVPASFSAFPMSSVWTTSLPMSLRQKLKLALQPKKEEKLLQVSEELVMEAKAAFEDAQEEARAEKLREALPPLVADKGIEAAAEVVCEVEGLQADIGA(SEQ ID NO：37)。
编码NSP1蛋白的核酸序列:
ATGGAGAAGCCAGTAGTAAACGTAGACGTAGACCCCCAGAGTCCGTTTGTCGTGCAACTGCAAAAAAGCTTCCCGCAATTTGAGGTAGTAGCACAGCAGGTCACTCCAAATGACCATGCTAATGCCAGAGCATTTTCGCATCTGGCCAGTAAACTAATCGAGCTGGAGGTTCCTACCACAGCGACGATCTTGGACATAGGCAGCGCACCGGCTCGTAGAATGTTTTCCGAGCACCAGTATCATTGTGTCTGCCCCATGCGTAGTCCAGAAGACCCGGACCGCATGATGAAATACGCCAGTAAACTGGCGGAAAAAGCGTGCAAGATTACAAACAAGAACTTGCATGAGAAGATTAAGGATCTCCGGACCGTACTTGATACGCCGGATGCTGAAACACCATCGCTCTGCTTTCACAACGATGTTACCTGCAACATGCGTGCCGAATATTCCGTCATGCAGGACGTGTATATCAACGCTCCCGGAACTATCTATCATCAGGCTATGAAAGGCGTGCGGACCCTGTACTGGATTGGCTTCGACACCACCCAGTTCATGTTCTCGGCTATGGCAGGTTCGTACCCTGCGTACAACACCAACTGGGCCGACGAGAAAGTCCTTGAAGCGCGTAACATCGGACTTTGCAGCACAAAGCTGAGTGAAGGTAGGACAGGAAAATTGTCGATAATGAGGAAGAAGGAGTTGAAGCCCGGGTCGCGGGTTTATTTCTCCGTAGGATCGACACTTTATCCAGAACACAGAGCCAGCTTGCAGAGCTGGCATCTTCCATCGGTGTTCCACTTGAATGGAAAGCAGTCGTACACTTGCCGCTGTGATACAGTGGTGAGTTGCGAAGGCTACGTAGTGAAGAAAATCACCATCAGTCCCGGGATCACGGGAGAAACCGTGGGATACGCGGTTACACACAATAGCGAGGGCTTCTTGCTATGCAAAGTTACTGACACAGTAAAAGGAGAACGGGTATCGTTCCCTGTGTGCACGTACATCCCGGCCACCATATGCGATCAGATGACTGGTATAATGGCCACGGATATATCACCTGACGATGCACAAAAACTTCTGGTTGGGCTCAACCAGCGAATTGTCATTAACGGTAGGACTAACAGGAACACCAACACCATGCAAAATTACCTTCTGCCGATCATAGCACAAGGGTTCAGCAAATGGGCTAAGGAGCGCAAGGATGATCTTGATAACGAGAAAATGCTGGGTACTAGAGAACGCAAGCTTACGTATGGCTGCTTGTGGGCGTTTCGCACTAAGAAAGTACATTCGTTTTATCGCCCACCTGGAACGCAGACCTGCGTAAAAGTCCCAGCCTCTTTTAGCGCTTTTCCCATGTCGTCCGTATGGACGACCTCTTTGCCCATGTCGCTGAGGCAGAAATTGAAACTGGCATTGCAACCAAAGAAGGAGGAAAAACTGCTGCAGGTCTCGGAGGAATTAGTCATGGAGGCCAAGGCTGCTTTTGAGGATGCTCAGGAGGAAGCCAGAGCGGAGAAGCTCCGAGAAGCACTTCCACCATTAGTGGCAGACAAAGGCATCGAGGCAGCCGCAGAAGTTGTCTGCGAAGTGGAGGGGCTCCAGGCGGACATCGGAGCA(SEQ ID NO：41)。
NSP2蛋白：
ALVETPRGHVRIIPQANDRMIGQYIVVSPNSVLKNAKLAPAHPLADQVKIITHSGRSGRYAVEPYDAKVLMPAGGAVPWPEFLALSESATLVYNEREFVNRKLYHIAMHGPAKNTEEEQYKVTKAELAETEYVFDVDKKRCVKKEEASGLVLSGELTNPPYHELALEGLKTRPAVPYKVETIGVIGTPGSGKSAIIKSTVTARDLVTSGKKENCREIEADVLRLRGMQITSKTVDSVMLNGCHKAVEVLYVDEAFACHAGALLALIAIVRPRKKVVLCGDPMQCGFFNMMQLKVHFNHPEKDICTKTFYKYISRRCTQPVTAIVSTLHYDGKMKTTNPCKKNIEIDITGATKPKPGDIILTCFRGWVKQLQIDYPGHEVMTAAASQGLTRKGVYAVRQKVNENPLYAITSEHVNVLLTRTEDRLVWKTLQGDPWIKQPTNIPKGNFQATIEDWEAEHKGIIAAINSPTPRANPFSCKTNVCWAKALEPILATAGIVLTGCQWSELFPQFADDKPHSAIYALDVICIKFFGMDLTSGLFSKQSIPLTYHPADSARPVAHWDNSPGTRKYGYDHAIAAELSRRFPVFQLAGKGTQLDLQTGRTRVISAQHNLVPVNRNLPHALVPEYKEKQPGPVKKFLNQFKHHSVLVVSEEKIEAPRKRIEWIAPIGIAGADKNYNLAFGFPPQARYDLVFINIGTKYRNHHFQQCEDHAATLKTLSRSALNCLNPGGTLVVKSYGYADRNSEDVVTALARKFVRVSAARPDCVSSNTEMYLIFRQLDNSRTRQFTPHHLNCVISSVYEGTRDGVGA(SEQ ID NO：38)。
编码NSP2蛋白的核酸序列:
GCATTAGTTGAAACCCCGCGCGGTCACGTAAGGATAATACCTCAAGCAAATGACCGTATGATCGGACAGTATATCGTTGTCTCGCCAAACTCTGTGCTGAAGAATGCCAAACTCGCACCAGCGCACCCGCTAGCAGATCAGGTTAAGATCATAACACACTCCGGAAGATCAGGAAGGTACGCGGTCGAACCATACGACGCTAAAGTACTGATGCCAGCAGGAGGTGCCGTACCATGGCCAGAATTCCTAGCACTGAGTGAGAGCGCCACGTTAGTGTACAACGAAAGAGAGTTTGTGAACCGCAAACTATACCACATTGCCATGCATGGCCCCGCCAAGAATACAGAAGAGGAGCAGTACAAGGTTACAAAGGCAGAGCTTGCAGAAACAGAGTACGTGTTTGACGTGGACAAGAAGCGTTGCGTTAAGAAGGAAGAAGCCTCAGGTCTGGTCCTCTCGGGAGAACTGACCAACCCTCCCTATCATGAGCTAGCTCTGGAGGGACTGAAGACCCGACCTGCGGTCCCGTACAAGGTCGAAACAATAGGAGTGATAGGCACACCGGGGTCGGGCAAGTCAGCTATTATCAAGTCAACTGTCACGGCACGAGATCTTGTTACCAGCGGAAAGAAAGAAAATTGTCGCGAAATTGAGGCCGACGTGCTAAGACTGAGGGGTATGCAGATTACGTCGAAGACAGTAGATTCGGTTATGCTCAACGGATGCCACAAAGCCGTAGAAGTGCTGTACGTTGACGAAGCGTTCGCGTGCCACGCAGGAGCACTACTTGCCTTGATTGCTATCGTCAGGCCCCGCAAGAAGGTAGTACTATGCGGAGACCCCATGCAATGCGGATTCTTCAACATGATGCAACTAAAGGTACATTTCAATCACCCTGAAAAAGACATATGCACCAAGACATTCTACAAGTATATCTCCCGGCGTTGCACACAGCCAGTTACAGCTATTGTATCGACACTGCATTACGATGGAAAGATGAAAACCACGAACCCGTGCAAGAAGAACATTGAAATCGATATTACAGGGGCCACAAAGCCGAAGCCAGGGGATATCATCCTGACATGTTTCCGCGGGTGGGTTAAGCAATTGCAAATCGACTATCCCGGACATGAAGTAATGACAGCCGCGGCCTCACAAGGGCTAACCAGAAAAGGAGTGTATGCCGTCCGGCAAAAAGTCAATGAAAACCCACTGTACGCGATCACATCAGAGCATGTGAACGTGTTGCTCACCCGCACTGAGGACAGGCTAGTGTGGAAAACCTTGCAGGGCGACCCATGGATTAAGCAGCCCACTAACATACCTAAAGGAAACTTTCAGGCTACTATAGAGGACTGGGAAGCTGAACACAAGGGAATAATTGCTGCAATAAACAGCCCCACTCCCCGTGCCAATCCGTTCAGCTGCAAGACCAACGTTTGCTGGGCGAAAGCATTGGAACCGATACTAGCCACGGCCGGTATCGTACTTACCGGTTGCCAGTGGAGCGAACTGTTCCCACAGTTTGCGGATGACAAACCACATTCGGCCATTTACGCCTTAGACGTAATTTGCATTAAGTTTTTCGGCATGGACTTGACAAGCGGACTGTTTTCTAAACAGAGCATCCCACTAACGTACCATCCCGCCGATTCAGCGAGGCCGGTAGCTCATTGGGACAACAGCCCAGGAACCCGCAAGTATGGGTACGATCACGCCATTGCCGCCGAACTCTCCCGTAGATTTCCGGTGTTCCAGCTAGCTGGGAAGGGCACACAACTTGATTTGCAGACGGGGAGAACCAGAGTTATCTCTGCACAGCATAACCTGGTCCCGGTGAACCGCAATCTTCCTCACGCCTTAGTCCCCGAGTACAAGGAGAAGCAACCCGGCCCGGTCAAAAAATTCTTGAACCAGTTCAAACACCACTCAGTACTTGTGGTATCAGAGGAAAAAATTGAAGCTCCCCGTAAGAGAATCGAATGGATCGCCCCGATTGGCATAGCCGGTGCAGATAAGAACTACAACCTGGCTTTCGGGTTTCCGCCGCAGGCACGGTACGACCTGGTGTTCATCAACATTGGAACTAAATACAGAAACCACCACTTTCAGCAGTGCGAAGACCATGCGGCGACCTTAAAAACCCTTTCGCGTTCGGCCCTGAATTGCCTTAACCCAGGAGGCACCCTCGTGGTGAAGTCCTATGGCTACGCCGACCGCAACAGTGAGGACGTAGTCACCGCTCTTGCCAGAAAGTTTGTCAGGGTGTCTGCAGCGAGACCAGATTGTGTCTCAAGCAATACAGAAATGTACCTGATTTTCCGACAACTAGACAACAGCCGTACACGGCAATTCACCCCGCACCATCTGAATTGCGTGATTTCGTCCGTGTATGAGGGTACAAGAGATGGAGTTGGAGCC(SEQID NO：42)。
NSP3蛋白：
APSYRTKRENIADCQEEAVVNAANPLGRPGEGVCRAIYKRWPTSFTDSATETGTARMTVCLGKKVIHAVGPDFRKHPEAEALKLLQNAYHAVADLVNEHNIKSVAIPLLSTGIYAAGKDRLEVSLNCLTTALDRTDADVTIYCLDKKWKERIDAALQLKESVTELKDEDMEIDDELVWIHPDSCLKGRKGFSTTKGKLYSYFEGTKFHQAAKDMAEIKVLFPNDQESNEQLCAYILGETMEAIREKCPVDHNPSSSPPKTLPCLCMYAMTPERVHRLRSNNVKEVTVCSSTPLPKHKIKNVQKVQCTKVVLFNPHTPAFVPARKYIEVPEQPTAPPAQAEEAPEVVATPSPSTADNTSLDVTDISLDMDDSSEGSLFSSFSGSDNSITSMDSWSSGPSSLEIVDRRQVVVADVHAVQEPAPIPPPRLKKMARLAAARKEPTPPASNSSESLHLSFGGVSMSLGSIFDGETARQAAVQPLATGPTDVPMSFGSFSDGEIDELSRRVTESEPVLFGSFEPGEVNSIISSRSAVSFPLRKQRRRRRSRRTEY(SEQ ID NO：39)。
编码NSP3蛋白的核酸序列:
GCGCCGTCATACCGCACCAAAAGGGAGAATATTGCTGACTGTCAAGAGGAAGCAGTTGTCAACGCAGCCAATCCGCTGGGTAGACCAGGCGAAGGAGTCTGCCGTGCCATCTATAAACGTTGGCCGACCAGTTTTACCGATTCAGCCACGGAGACAGGCACCGCAAGAATGACTGTGTGCCTAGGAAAGAAAGTGATCCACGCGGTCGGCCCTGATTTCCGGAAGCACCCAGAAGCAGAAGCCTTGAAATTGCTACAAAACGCCTACCATGCAGTGGCAGACTTAGTAAATGAACATAACATCAAGTCTGTCGCCATTCCACTGCTATCTACAGGCATTTACGCAGCCGGAAAAGACCGCCTTGAAGTATCACTTAACTGCTTGACAACCGCGCTAGACAGAACTGACGCGGACGTAACCATCTATTGCCTGGATAAGAAGTGGAAGGAAAGAATCGACGCGGCACTCCAACTTAAGGAGTCTGTAACAGAGCTGAAGGATGAAGATATGGAGATCGACGATGAGTTAGTATGGATCCATCCAGACAGTTGCTTGAAGGGAAGAAAGGGATTCAGTACTACAAAAGGAAAATTGTATTCGTACTTCGAAGGCACCAAATTCCATCAAGCAGCAAAAGACATGGCGGAGATAAAGGTCCTGTTCCCTAATGACCAGGAAAGTAATGAACAACTGTGTGCCTACATATTGGGTGAGACCATGGAAGCAATCCGCGAAAAGTGCCCGGTCGACCATAACCCGTCGTCTAGCCCGCCCAAAACGTTGCCGTGCCTTTGCATGTATGCCATGACGCCAGAAAGGGTCCACAGACTTAGAAGCAATAACGTCAAAGAAGTTACAGTATGCTCCTCCACCCCCCTTCCTAAGCACAAAATTAAGAATGTTCAGAAGGTTCAGTGCACGAAAGTAGTCCTGTTTAATCCGCACACTCCCGCATTCGTTCCCGCCCGTAAGTACATAGAAGTGCCAGAACAGCCTACCGCTCCTCCTGCACAGGCCGAGGAGGCCCCCGAAGTTGTAGCGACACCGTCACCATCTACAGCTGATAACACCTCGCTTGATGTCACAGACATCTCACTGGATATGGATGACAGTAGCGAAGGCTCACTTTTTTCGAGCTTTAGCGGATCGGACAACTCTATTACTAGTATGGACAGTTGGTCGTCAGGACCTAGTTCACTAGAGATAGTAGACCGAAGGCAGGTGGTGGTGGCTGACGTTCATGCCGTCCAAGAGCCTGCCCCTATTCCACCGCCAAGGCTAAAGAAGATGGCCCGCCTGGCAGCGGCAAGAAAAGAGCCCACTCCACCGGCAAGCAATAGCTCTGAGTCCCTCCACCTCTCTTTTGGTGGGGTATCCATGTCCCTCGGATCAATTTTCGACGGAGAGACGGCCCGCCAGGCAGCGGTACAACCCCTGGCAACAGGCCCCACGGATGTGCCTATGTCTTTCGGATCGTTTTCCGACGGAGAGATTGATGAGCTGAGCCGCAGAGTAACTGAGTCCGAACCCGTCCTGTTTGGATCATTTGAACCGGGCGAAGTGAACTCAATTATATCGTCCCGATCAGCCGTATCTTTTCCACTACGCAAGCAGAGACGTAGACGCAGGAGCAGGAGGACTGAATAC(SEQ ID NO：43)。
NSP4蛋白：
MMPTEANKSRYQSRKVENQKAITTERLLSGLRLYNSATDQPECYKITYPKPLYSSSVPANYSDPQFAVAVCNNYLHENYPTVASYQITDEYDAYLDMVDGTVACLDTATFCPAKLRSYPKKHEYRAPNIRSAVPSAMQNTLQNVLIAATKRNCNVTQMRELPTLDSATFNVECFRKYACNDEYWEEFARKPIRITTEFVTAYVARLKGPKAAALFAKTYNLVPLQEVPMDRFVMDMKRDVKVTPGTKHTEERPKVQVIQAAEPLATAYLCGIHRELVRRLTAVLLPNIHTLFDMSAEDFDAIIAEHFKQGDPVLETDIASFDKSQDDAMALTGLMILEDLGVDQPLLDLIECAFGEISSTHLPTGTRFKFGAMMKSGMFLTLFVNTVLNVVIASRVLEERLKTSRCAAFIGDDNIIHGVVSDKEMAERCATWLNMEVKIIDAVIGERPPYFCGGFILQDSVTSTACRVADPLKRLFKLGKPLPADDEQDEDRRRALLDETKAWFRVGITGTLAVAVTTRYEVDNITPVLLALRTFAQSKRAFQAIRGEIKHLYGGPK(SEQ ID NO：40)。
编码NSP4蛋白的核酸序列:
ATGATGCCCACCGAAGCCAACAAAAGTAGGTACCAGTCTCGTAAAGTAGAAAATCAGAAAGCCATAACCACTGAGCGACTACTGTCAGGACTACGACTGTATAACTCTGCCACAGATCAGCCAGAATGCTATAAGATCACCTATCCGAAACCATTGTACTCCAGTAGCGTACCGGCGAACTACTCCGATCCACAGTTCGCTGTAGCTGTCTGTAACAACTATCTGCATGAGAACTATCCGACAGTAGCATCTTATCAGATTACTGACGAGTACGATGCTTACTTGGATATGGTAGACGGGACAGTCGCCTGCCTGGATACTGCAACCTTCTGCCCCGCTAAGCTTAGAAGTTACCCGAAAAAACATGAGTATAGAGCCCCGAATATCCGCAGTGCGGTTCCATCAGCGATGCAGAACACGCTACAAAATGTGCTCATTGCCGCAACTAAAAGAAATTGCAACGTCACGCAGATGCGTGAACTGCCAACACTGGACTCAGCGACATTCAATGTCGAATGCTTTCGAAAATATGCATGTAATGACGAGTATTGGGAGGAGTTCGCTCGGAAGCCAATTAGGATTACCACTGAGTTTGTCACCGCATATGTAGCTAGACTGAAAGGCCCTAAGGCCGCCGCACTATTTGCAAAGACGTATAATTTGGTCCCATTGCAAGAAGTGCCTATGGATAGATTCGTCATGGACATGAAAAGAGACGTGAAAGTTACACCAGGCACGAAACACACAGAAGAAAGACCGAAAGTACAAGTGATACAAGCCGCAGAACCCCTGGCGACTGCTTACTTATGCGGGATTCACCGGGAATTAGTGCGTAGGCTTACGGCCGTCTTGCTTCCAAACATTCACACGCTTTTTGACATGTCGGCGGAGGATTTTGATGCAATCATAGCAGAACACTTCAAGCAAGGCGACCCGGTACTGGAGACGGATATCGCATCATTCGACAAAAGCCAAGACGACGCTATGGCGTTAACCGGTCTGATGATCTTGGAGGACCTGGGTGTGGATCAACCACTACTCGACTTGATCGAGTGCGCCTTTGGAGAAATATCATCCACCCATCTACCTACGGGTACTCGTTTTAAATTCGGGGCGATGATGAAATCCGGAATGTTCCTCACACTTTTTGTCAACACAGTTTTGAATGTCGTTATCGCCAGCAGAGTACTAGAAGAGCGGCTTAAAACGTCCAGATGTGCAGCGTTCATTGGCGACGACAACATCATACATGGAGTAGTATCTGACAAAGAAATGGCTGAGAGGTGCGCCACCTGGCTCAACATGGAGGTTAAGATCATCGACGCAGTCATCGGTGAGAGACCACCTTACTTCTGCGGCGGATTTATCTTGCAAGATTCGGTTACTTCCACAGCGTGCCGCGTGGCGGATCCCCTGAAAAGGCTGTTTAAGTTGGGTAAACCGCTCCCAGCCGACGACGAGCAAGACGAAGACAGAAGACGCGCTCTGCTAGATGAAACAAAGGCGTGGTTTAGAGTAGGTATAACAGGCACTTTAGCAGTGGCCGTGACGACCCGGTATGAGGTAGACAATATTACACCTGTCCTACTGGCATTGAGAACTTTTGCCCAGAGCAAAAGAGCATTCCAAGCCATCAGAGGGGAAATAAAGCATCTCTACGGTGGTCCTAAATAG(SEQ ID NO：44)。
根据本发明的实施例，进一步包括：靶分子编码区，所述靶蛋白编码前面所述的信号肽、抗原蛋白和跨膜结构域。
本发明所述自复制RNA分子还可含有一种或多种修饰核苷酸，并因此具有改善的稳定性，在体内耐降解和清除，以及其它优点。这些修饰核苷酸的类型包括但不限于m5C(5-甲基胞苷)、m5U(5-甲基尿苷)、m6A(N6-甲基腺苷)、s2U(2-硫代尿苷)、Um(2'-O-甲基尿苷)、m1A(l-甲基腺苷)；m2A(2-甲基腺苷)；Am(2-1-O-甲基腺苷)；ms2m6A(2-甲硫基-N6-甲基腺苷)；i6A(N6-异戊烯基腺苷)；ms2i6A(2-甲硫基-N6异戊烯基腺苷)；io6A(N6-(顺-羟基异戊烯基)腺苷)；ms2io6A(2-甲硫基-N6-(顺-羟基异戊烯基)腺苷)；g6A(N6-甘氨酰氨甲酰基腺苷)；t6A(N6-苏氨酰氨甲酰基腺苷)；ms2t6A(2-甲硫基-N6-苏氨酰氨甲酰基腺苷)；m6t6A(N6-甲基-N6-苏氨酰氨甲酰基腺苷)；hn6A(N6-羟基正缬氨酰(norvalyl)氨甲酰基腺苷)；ms2hn6A(2-甲硫基-N6-羟基正缬氨酰氨甲酰基腺苷)；Ar(p)(2'-O-核糖基腺苷(磷酸盐))；I(肌苷)；m1I(1-甲基肌苷)；m'Im(1,2'-O-二甲基肌苷)；m3C(3-甲基胞苷)；Cm(2T-O-甲基胞苷)；s2C(2-硫胞苷)；ac4C(N4-乙酰胞苷)；f5C(5-甲酰基(fonnyl)胞苷)；m5Cm(5,2-O-二甲基胞苷)；ac4Cm(N4乙酰基2TO甲基胞苷)；k2C(赖西丁)；m1G(1-甲基鸟苷)；m2G(N2-甲基鸟苷)；m7G(7-甲基鸟苷)；Gm(2'-O-甲基鸟苷)；m22G(N2,N2-二甲基鸟苷)；m2Gm(N2,2'-O-二甲基鸟苷)；m22Gm(N2,N2,2'-O-三甲基鸟苷)；Gr(p)(2'-O-核糖基鸟苷(磷酸盐))；yW(怀丁苷)；o2yW(过氧化怀丁苷)；OHyW(羟基怀丁苷)；OHyW*(改性不足的羟基怀丁苷)；imG(怀俄苷)；mimG(甲基鸟苷)；Q(辫苷)；oQ(环氧辫苷)；galQ(半乳糖基-辫苷)；manQ(甘露糖-辫苷)；preQo(7-氰基-7-脱氮(deaza)鸟苷)；preQi(7-氨甲基-7-脱氮鸟苷)；G*(古嘌苷)；D(二氢尿苷)；m5Um(5,2'-O-二甲基尿苷)；s4U(4-硫代尿苷)；m5s2U(5-甲基-2-硫代尿苷)；s2Um(2-硫-2'-O-甲基尿苷)；acp3U(3-(3-氨基-3-羧基丙基)尿苷)；ho5U(5-羟基尿苷)；mo5U(5-甲氧基尿苷)；cmo5U(尿苷5-氧乙酸)；mcmo5U(尿苷5-氧乙酸甲酯)；chm5U(5-(羧基羟基甲基)尿苷))；mchm5U(5-(羧基羟基甲基)尿苷甲酯)；mcm5U(5-甲氧基羰基甲基尿苷)；mcm5Um(S-甲氧基羰基甲基-2-O-甲基尿苷)；mcm5s2U(5-甲氧基羰基甲基-2-硫代尿苷)；nm5s2U(5-氨基甲基-2-硫代尿苷)；mnm5U(5-甲基氨基甲基尿苷)；mnm5s2U(5-甲基氨甲基-2-硫代尿苷)；mnm5se2U(5-甲基氨甲基-2硒基尿苷)；ncm5U(5-氨甲酰基甲基尿苷)；ncm5Um(5-氨甲酰基甲基-2'-O-甲基尿苷)；cmnm5U(5-羧基甲基氨甲基尿苷)；cnmm5Um(5-羧甲基氨甲基-2-L-O甲基尿苷)；cmnm5s2U(5-羧基甲基氨甲基-2-硫代尿苷)；m62A(N6,N6-二甲基腺苷)；Tm(2'-O-甲基肌苷)；m4C(N4-甲基胞苷)；m4Cm(N4,2-O-二甲基胞苷)；hm5C(5-羟基甲基胞苷)；m3U(3-甲基尿苷)；cm5U(5-羧基甲基尿苷)；m6Am(N6,T-O-二甲基腺苷)；rn62Am(N6,N6,O-2-三甲基腺苷)；m2'7G(N2,7-二甲基鸟苷)；m2'2'7G(N2,N2,7-三甲基鸟苷)；m3Um(3,2T-O-二甲基尿苷)；m5D(5-甲基二氢尿苷)；f5Cm(5-甲酰基-2'-O-甲基胞苷)；m1Gm(1,2'-O-二甲基鸟苷)；m'Am(1,2-O-二甲基腺苷)虹膜甲基尿苷(irinomethyluridine))；tm5s2U(S-牛磺酸(taurino)甲基-2-硫代尿苷))；imG-14(4-去甲基鸟苷)；imG2(异鸟苷)；ac6A(N6-乙酰腺苷)、次黄嘌呤、肌苷、8-氧代-腺嘌呤、其7-取代的衍生物、二氢尿嘧啶、假尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-氨基尿嘧啶、5-(C1-C6)-烷基尿嘧啶、5-甲基尿嘧啶、5-(C2-C6)-烯基尿嘧啶、5-(C2-C6)-炔基尿嘧啶、5-(羟基甲基)尿嘧啶、5-氯尿嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、5-羟基胞嘧啶、5-(C1-C6)-烷基胞嘧啶、5-甲基胞嘧啶、5-(C2-C6)-烯基胞嘧啶、5-(C2-C6)-炔基胞嘧啶、5-氯胞嘧啶、5-氟胞嘧啶、5-溴胞嘧啶、N2-二甲基鸟嘌呤、7-脱氮鸟嘌呤、8-氮杂鸟嘌呤、7-脱氮-7-取代鸟嘌呤、7-脱氮-7-(C2-C6)炔基鸟嘌呤、7-脱氮-8-取代鸟嘌呤、8-羟基鸟嘌呤、6-硫代鸟嘌呤、8-氧代鸟嘌呤、2-氨基嘌呤、2-氨基-6-氯嘌呤、2,4-二氨基嘌呤、2,6-二氨基嘌呤、8-氮杂嘌呤、取代的7-脱氮嘌呤、7-氮杂-7-取代嘌呤、7-氮杂-8-取代嘌呤、氢(脱碱基残基)、m5C、m5U、m6A、s2U、W、或2'-O-甲基-U。
其他
在本发明的另一方面，本发明提出了一种表达载体，其特征在于，携带编码分子，所述编码分子编码前面所述的核酸疫苗。由此，利用该表达载体能够有效地通过分子生物学的手段，快速复制、表达、扩增上述核酸疫苗，从而实现了能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
在本发明的另一方面，本发明提出了一种对个体进行免疫的方法，其特征在于，包括：为有需要的个体给药前面所述的疫苗组合物或者前面所述的核酸疫苗。由此，能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体。
在本发明的又一方面，本发明提出了前面所述的疫苗组合物或者前面所述的核酸疫苗在制备药物中的用途。根据本发明的实施例，所述药物用于免疫个体。利用本发明的药物能够使得所述表达的抗原获得更好的抗原呈递，从而具有更强的免疫活性，产生更多的抗体，从而达到预防或治疗疾病的作用。具体地，疾病可以为细菌或病毒感染所引发的疾病，例如肺炎、水泡性口炎(如手足口、疱疹性咽颊炎)、狂犬病等。
本申请的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本申请的实践了解到。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1：CVA16病原体疫苗抗原修饰
本实施例选取柯萨奇病毒A16(CVA16)壳蛋白抗原VP1作为抗原进行疫苗的设计。疫苗设计有两个分组，具体分组如图5所示：包括V1和V2，其中V1是传统的抗原表达方案，直接将病毒抗原插入表达载体pcDNA3.1上；V2是将抗原的N端加上信号肽序列(SEQ ID NO：3)，C端加上跨膜结构域序列(SEQ ID NO：9)，得到修饰后的VP1抗原，使其能够进行胞膜定位。疫苗抗原表达使用自扩增RNA(reRNATM)核心复合体。具体方法为：将序列SEQ ID NO：16，SEQ ID NO：17，SEQ ID NO：18以及修饰后的VP1抗原核苷酸序列构建到pcDNA3.1载体上，得到reRNATM疫苗质粒。构建好的reRNATM疫苗质粒与辅助质粒(pCI-VSVG质粒以及T7RNA聚合酶质粒pCAG-T7pol)共转入293T细胞，48小时后收获上清进行纯化，即可获得reRNATM疫苗。
用小鼠验证体系对构建好的reRNATMCVA16疫苗进行相关实验验证。具体地，通过肌肉注射，将reRNATMCVA16疫苗以每只BabLc小鼠15ng的剂量注入小鼠体内，在给药后7天和14天分别采集小鼠的血液，用ELISA检测给药后14天小鼠的结合抗体浓度，具体的实验结果如图6所示，抗原设计插入信号肽及跨膜区的V2组，有更高的结合抗体滴度。
根据14天结合抗体的结果，发明人又进行了V2组不同时间点的抗体亚型的检测，如图7所示，结果显示，reRNATMCVA16疫苗更倾向于激活机体内IgG2a为主的体液免疫应答。
实施例2：CVA10病原体疫苗抗原修饰
本实施例选取柯萨奇病毒A10(CVA10)壳蛋白抗原VP1作为抗原进行疫苗的设计。疫苗设计有两个分组(如图8)：V1和V2，其中V1是传统的抗原表达方案，直接将病毒抗原插入表达载体pcDNA3.1上；V2是将抗原的N端加上信号肽序列(SEQ ID NO：3)，C端加上跨膜结构域序列(SEQ ID NO：9)，得到修饰后的VP1抗原，使其能够进行胞膜定位。疫苗抗原表达使用自扩增RNA(reRNATM)核心复合体。具体方法为：将序列SEQ ID NO：16，SEQ ID NO：17，SEQID NO：18以及修饰后的VP1抗原核苷酸序列构建到pcDNA3.1载体上，得到reRNATM疫苗质粒。构建好的reRNATM疫苗质粒与辅助质粒(pCI-VSVG质粒以及T7RNA聚合酶质粒pCAG-T7pol)共转入293T细胞，48小时后收获上清进行纯化，即可获得reRNATM疫苗药物。
用小鼠验证体系对构建好的reRNATMCVA10疫苗对进行相关实验验证。具体地，通过肌肉注射，将reRNATMCVA10疫苗以每只BabLc小鼠15ng的剂量注入小鼠体内，给药后14天采集小鼠的血液，用ELISA检测给药后14天小鼠的结合抗体浓度，抗原设计插入信号肽及跨膜区的V2组，有更高的结合抗体滴度。
实施例3：CVA6病原体疫苗抗原修饰
本实施选取柯萨奇病毒A6(CVA6)壳蛋白抗原VP1作为抗原进行疫苗的设计。疫苗设计有两个分组(如图9)：V1和V2，其中V1是传统的抗原表达方案，直接将病毒抗原插入表达载体pcDNA3.1上；V2是将抗原的N端加上信号肽序列(SEQ ID NO：45)，C端加上跨膜结构域序列(SEQ ID NO：49)，得到修饰后的VP1抗原，使其能够进行胞膜定位。疫苗抗原表达使用自扩增RNA(reRNATM)核心复合体。具体方法为：将序列SEQ ID NO：16，SEQ ID NO：17，SEQID NO：18以及修饰后的VP1抗原核苷酸序列构建到pcDNA3.1载体上，得到reRNATM疫苗质粒。构建好的reRNATM疫苗质粒与辅助质粒(pCI-VSVG质粒以及T7RNA聚合酶质粒pCAG-T7pol)共转入293T细胞，48小时后收获上清进行纯化，即可获得reRNATM疫苗。
用小鼠验证体系对构建好的reRNATMCVA6疫苗对进行相关实验验证。具体地，通过肌肉注射，将reRNATMCVA6疫苗以每只BabLc小鼠15ng的剂量注入小鼠体内，给药后14天采集小鼠的血液，用ELISA检测给药后14天小鼠的结合抗体浓度，抗原设计插入信号肽及跨膜区的V2组，有更高的结合抗体滴度。
实施例4：HER2 B细胞疫苗抗原修饰
B细胞抗原是指可以直接递呈给B细胞的抗原分子，而B细胞疫苗是将可以递呈给B细胞抗原进行修饰，使其能够产生更多的抗体。HER2作为一个内源性蛋白，其B细胞抗原的免疫原性低，不易产生抗体，发明人设计了基于自扩增RNA技术的小鼠Her2 B细胞疫苗，设计了两种试验方案(图10)：V1和V2，其中V1是传统的抗原表达方案，直接将病毒抗原插入表达载体pcDNA3.1上；V2是将抗原的N端加上信号肽序列(SEQ ID NO：3)，C端加上跨膜结构域序列(SEQ ID NO：9)，得到修饰后的VP1抗原，使其能够进行胞膜定位。具体方法为：将序列SEQ ID NO：22，SEQ IDNO：23，SEQ ID NO：24以及修饰后的和HER2抗原核苷酸序列构建到pcDNA3.1载体上，得到reRNATM疫苗质粒。构建好的reRNATM疫苗质粒与辅助质粒(pCI-VSVG质粒以及T7RNA聚合酶质粒pCAG-T7pol)共转入293T细胞，48小时后收获上清进行纯化，即可获得reRNATM疫苗。
用小鼠验证体系对构建好的reRNATMHER2 B细胞疫苗对进行相关实验验证。具体地，通过静脉注射，将reRNATMHER2 B疫苗以每只小鼠15ng的剂量注入小鼠体内，给药后21天采集小鼠的血液，检测给药后21天小鼠的HER2抗体的滴度，抗原设计插入信号肽及跨膜区的V2组，有更高的结合抗体滴度。
实施例5：慢病毒载体表达CVB3病原体疫苗抗原修饰
发明人使用慢病毒载体进行了CVB3疫苗的验证，同样设计了两种疫苗方案(图11)：V1和V2，其中V1是传统的抗原表达方案，直接将病毒抗原插入慢病毒载体上；V2是将抗原的N端加上信号肽序列(SEQ ID NO：2)，C端加上跨膜结构域序列(SEQ ID NO：8)，得到修饰后的VP1抗原，使其能够进行胞膜定位。具体方法为：将序列SEQ ID NO：28，SEQ ID NO：29，SEQ ID NO：30以及修饰后的CVB3 VP1抗原核苷酸序列构建到慢病毒载体上，得到reRNATM疫苗质粒。构建好的reRNATM疫苗质粒与辅助质粒(pCI-VSVG质粒以及T7RNA聚合酶质粒pCAG-T7pol)共转入293T细胞，48小时后收获上清进行纯化，即可获得reRNATM疫苗。
利用小鼠验证体系对构建好的reRNATM疫苗进行相关实验验证。具体地，使用肌肉注射方式将CVB3疫苗注射至小鼠体内，并在给药后第14天对小鼠血浆内抗原特异性结合抗体进行检测，相关结果如图12所示，进行了抗原修饰的V2组，有更高的结合抗体滴度。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本申请的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本申请的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本申请的限制，本领域的普通技术人员在本申请的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (17)
1.一种核酸疫苗，其特征在于，包括编码下列的核酸序列：
信号肽；
抗原蛋白；和
跨膜结构域；
其中，所述信号肽和所述跨膜结构域至少之一独立地衍生自病毒。
2.根据权利要求1所述的核酸疫苗，其特征在于，所述抗原蛋白包括自身抗原和/或异源抗原。
3.根据权利要求2所述的核酸疫苗，其特征在于，所述自身抗原包括选自HER2，PSA，TRP-2，VEGF,EpCAM，GPC3，MSLN，TNFα，PCSK9，EGFR，EGF，Survivin，ANGPTL3和IgE中的至少之一。
4.根据权利要求2所述的核酸疫苗，其特征在于，所述异源抗原包括病原体蛋白。
5.根据权利要求4所述的核酸疫苗，其特征在于，所述病原体蛋白包括：Zika病毒蛋白，HIV病毒蛋白，HSV病毒蛋白，EBV病毒蛋白，巨细胞病毒蛋白，新型冠状病毒蛋白，柯萨奇病毒蛋白中的至少之一。
6.根据权利要求1所述的核酸疫苗，其特征在于，所述信号肽和所述跨膜结构域来自相同或者不同病毒。
7.根据权利要求1所述的核酸疫苗，其特征在于，所述信号肽和所述跨膜结构域衍生自弹状病毒糖蛋白。
8.根据权利要求7所述的核酸疫苗，其特征在于，所述信号肽和所跨膜膜结构域分别衍生自相同或者不同的弹状病毒糖蛋白。
9.根据权利要求8所述的核酸疫苗，其特征在于，所述弹状病毒包括水疱性病毒属、狂犬病病毒属、短暂热病毒属、非毒粒弹状病毒属，优选水疱性口炎病毒。
10.根据权利要求8所述的核酸疫苗，其特征在于，所述信号肽和所述跨膜膜结构域分别衍生自相同或者不同血清型的水疱性口炎病毒。
11.根据权利要求1所述的核酸疫苗，其特征在于，所述信号肽包括下列氨基酸序列：
(a)SEQ ID NO：1-3、45和46任一项所示的氨基酸序列；或
(b)与SEQ ID NO：1-3、45和46任一项所示的氨基酸序列具有至少80％、至少85％、至少90％、至少95％同一性的氨基酸序列；
任选地，编码所述信号肽的核酸分子包括下列核苷酸序列：
(a)SEQ ID NO：4-6、47和48任一项所示的核苷酸序列；或
(b)与SEQ ID NO：4-6、47和48任一项所示的核苷酸序列具有至少80％、至少85％、至少90％、至少95％同一性的核苷酸序列。
12.根据权利要求1所述的核酸疫苗，其特征在于，所述跨膜结构域包括下列氨基酸序列：
(a)SEQ ID NO：7-9、49和50任一项所示的氨基酸序列；或
(b)与SEQ ID NO：7-9、49和50任一项所示的氨基酸序列具有至少80％、至少85％、至少90％、至少95％同一性的氨基酸序列；
任选地，编码所述跨膜结构域的核酸分子包括下列核苷酸序列：
(a)SEQ ID NO：10-12、51和52任一项所示的核苷酸序列；或
(b)与SEQ ID NO：10-12、51和52任一项所示的核苷酸序列具有至少80％、至少85％、至少90％、至少95％同一性的核苷酸序列。
13.根据权利要求1所述的核酸疫苗，其特征在于，进一步包括胞内段，所述胞内段与所述跨膜结构域相连。
14.根据权利要求1所述的核酸疫苗，其特征在于，所述核酸疫苗为任选携带修饰基团的自复制RNA、mRNA、DNA以及病毒载体。
15.一种疫苗组合物，其特征在于，包括：
权利要求1～14任一项所述的核酸疫苗；和
药学上可以接受的赋形剂。
16.一种表达载体，其特征在于，携带编码分子，所述编码分子编码权利要求1～14任一项所述的核酸疫苗。
17.权利要求1～14任一项所述的核酸疫苗或者权利要求15所述的疫苗组合物在制备药物中的用途，其特征在于，所述药物用于免疫个体。
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