CN116693637A - 缺失7个氨基酸的SARS-CoV-2刺突蛋白和/或其编码基因的应用 - Google Patents
缺失7个氨基酸的SARS-CoV-2刺突蛋白和/或其编码基因的应用 Download PDFInfo
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Abstract
本发明涉及生物技术领域,公开了缺失7个氨基酸的SARS‑CoV‑2刺突蛋白和/或其编码基因的应用。本发明提供的缺失型刺突蛋白能够刺激宿主产生SARS‑CoV‑2特异性抗体,且与野生型刺突蛋白相比免疫原性更高。此外,该具有缺失突变的刺突蛋白与野生型刺突蛋白具有类似的抗原特性和群体特异性模式,且能对大鼠提供更强的免疫保护效果,因此在制备新冠疫苗等预防和/或治疗新冠肺炎的产品等方面具有较好的应用前景。
Description
技术领域
本发明涉及生物技术领域,具体涉及缺失7个氨基酸的SARS-CoV-2刺突蛋白和/或其编码基因的应用。
背景技术
SARS-CoV-2与SARS-CoV、MERS-CoV同为冠状病毒科冠状病毒属成员。SARS-CoV-2是一种有包膜的RNA病毒,其基因组全长近30kb,两端为5’和3’非编码区,中间为单一开放读码框,编码4个结构蛋白(刺突蛋白S,膜蛋白E,基质蛋白M和核衣壳蛋白N)和16个非结构蛋白。结构蛋白S位于病毒颗粒的表面,呈刺突状,由S1和S2亚基组成。S1主要负责与细胞表面受体结合,S2则参与后续的病毒膜与细胞膜融合过程。S1和S2之间含有一段蛋白酶识别氨基酸序列,S蛋白经宿主蛋白酶识别并切割为S1和S2是病毒完成侵入的关键步骤。
目前上市的新冠病毒疫苗包括mRNA疫苗、病毒载体疫苗、DNA疫苗和灭活疫苗等多种类型。其中,mRNA疫苗、病毒载体疫苗和DNA疫苗主要以SARS-CoV-2病毒中的(部分)核酸序列或其cDNA分子等作为有效抗原,但是由于核酸(尤其是RNA)较为脆弱,很容易被降解,因此存在制备和保存条件苛刻,容易失活等缺陷。灭活疫苗主要采用灭活的完整SARS-CoV-2病毒为有效抗原,虽然相比于核酸分子而言更易保存,但是由于以活病毒为原料,制作过程中存在接触风险,对于操作人员和设备的要求也更高。
发明内容
本发明的目的是为了克服现有技术存在的现有新冠疫苗制备和保存条件苛刻,容易失活,或对操作人员和设备的要求较高等问题,提供缺失7个氨基酸的SARS-CoV-2刺突蛋白和/或其编码基因的应用,该具有刺突蛋白具有良好的免疫原性,能够刺激宿主产生中和抗体,具备用于研发新型新冠疫苗的潜力。
为了实现上述目的,本发明一方面提供具有缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因在制备治疗和/或预防新冠肺炎的产品中的应用,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
本发明第二方面提供一种疫苗组合物,所述疫苗组合物中含有活性成分和辅料,所述活性成分包括氨基酸序列如SEQ ID NO:1所示的SARS-CoV-2刺突蛋白和/或其编码基因。
本发明第三方面提供如前所述的疫苗组合物或具有缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因在快速诱导SARS-CoV-2特异性抗体产生中的应用,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
通过上述技术方案,本发明能够取得如下有益效果:
(1)本发明提供的具有缺失突变的SARS-CoV-2刺突蛋白(简称“缺失型刺突蛋白”)能够快速有效刺激诱导宿主产生SARS-CoV-2特异性抗体,在免疫大鼠14天时,与不具有缺失突变的野生型SARS-CoV-2刺突蛋白(简称“野生型刺突蛋白”)相比,本发明提供的缺失型刺突蛋白产生的IgG抗体效价超过野生型2倍以上,说明该缺失型刺突蛋白具有更高的免疫原性。
(2)大鼠接种本发明提供的缺失型刺突蛋白后,其免疫血清中的中和抗体效价明显高于接种野生型刺突蛋白的大鼠,说明该缺失型刺突蛋白能够为大鼠提供更强的免疫保护效果。
(3)本发明提供的缺失型刺突蛋白与野生型刺突蛋白的结构相似,且具有与野生型刺突蛋白类似的抗原特性和群体特异性模式,具有很好的疫苗研制前景。
(4)本发明提供的缺失型刺突蛋白能够通过细胞载体进行体外表达,且体外表达的蛋白能够刺激宿主产生中和抗体,具备用于新冠疫苗研制的基础和潜力。
(5)相比于现有的mRNA疫苗、病毒载体疫苗、DNA疫苗和灭活疫苗等,采用本发明提供的缺失型刺突蛋白进行疫苗研制的过程中对于人员和设备的要求更低,极大降低了接触风险,且以该缺失型刺突蛋白作为有效抗原的疫苗不易失活,保存条件也更为宽松。
附图说明
图1是实施例1中获得的缺失型S蛋白与野生型S蛋白的S1/S2连接区序列对比示意图;
图2是(A)实施例2中的缺失型S蛋白凝胶过滤色谱图;(B)实施例2中缺失型S蛋白的SDS-PAGE结果图。
图3是实施例3中野生型S蛋白免疫组、缺失型S蛋白免疫组和安慰剂组小鼠免疫后,小鼠血清中的IgG效价对比示意图。
图4是实施例4中灭活的缺失突变株DEL-7aa对小鼠的免疫保护效果图。
图5是实施例5中缺失型S蛋白和野生型S蛋白与新冠病毒中和抗体的结合能力对比图。
图6是实施例6中野生型S蛋白免疫组、缺失型S蛋白免疫组和安慰剂组大鼠免疫后,大鼠血清中中和抗体效价对比示意图。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
本发明中,“缺失型刺突蛋白”和“缺失型S蛋白”意义相同,可互换使用。未作特殊说明的情况下,指的是在S1/S2切割位点上游缺失了7个氨基酸残基(具体为相较未发生缺失突变的野生型S蛋白而言,缺失第678-685位氨基酸)的S蛋白,其氨基酸序列如SEQ IDNO:1所示。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIRVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGVEHVNNSYECDIPIGAGICASYQTQTSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT(SEQ ID NO:1)
本发明中,“野生型刺突蛋白”和“野生型S蛋白”意义相同,可互换使用。未做特殊说明的情况下,指的是SARS-CoV-2临床分离株的S蛋白,其氨基酸序列如SEQ ID NO:2所示。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGVEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT(SEQ ID NO:2)
本发明的发明人在研究的过程中发现,SARS-CoV-2临床分离株(野生型SARS-CoV-2)在Vero细胞中连续传代过程中,其基因组核苷酸会产生突变,并在其中分离获得一株在多次传代(例如5次以上传代)后具有复制竞争优势的突变株,经全基因组测序发现,该突变株中S蛋白编码区中的S1/S2切割位点上游缺失了21个核苷酸,导致该突变株的S蛋白缺失7个氨基酸残基(也即所述突变株的基因组RNA对应的cDNA编码的S蛋白第678-685位氨基酸缺失)。经过进一步地研究发现,通过真核表达系统体外表达的该缺失型S蛋白免疫小鼠后,相比于野生型S蛋白,能够产生更高水平的IgG抗体,而且通过特异性抗体结合实验还发现,该缺失型S蛋白能够与SARS-CoV-2中和抗体结合,其与野生型S蛋白相比结合能力更强且群体特异性模式类似,表明缺失型S蛋白可能具有较强的刺激宿主产生抗SARS-CoV-2中和抗体的能力(能够提供更强的免疫保护力),从而具有用于研发适用于治疗和/或预防新冠肺炎的产品的潜力。此外,根据研究结果还能推测出采用该缺失型S蛋白制备的产品对于能够与该缺失型S蛋白结合的中和抗体相结合的SARS-CoV-2病毒株均能产生一定的预防和/或治疗效果。
基于上述发现,本发明一方面提供具有缺失突变的SARS-CoV-2刺突蛋白(S蛋白)和/或其编码基因在制备治疗和/或预防新冠肺炎的产品中的应用,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
本发明中,对于所述治疗和/或预防新冠肺炎的产品的具体类型没有特别限制,例如可以为新冠疫苗,用于治疗新冠肺炎的靶向药物,外源性中和抗体等。
本发明中,具有缺失突变的SARS-CoV-2刺突蛋白(简称缺失型S蛋白)的编码基因可以为任意能够编码该S蛋白的基因,其既可以是RNA(例如可以是由表达该缺失型S蛋白的缺失突变株中获得的基因组RNA,也可以是根据该缺失型S蛋白的氨基酸序列,参照本领域公知的密码子表获得的mRNA等),也可以是DNA(例如可以是该缺失型S蛋白的基因组RNA对应的cDNA,也可以是根据该缺失型S蛋白的氨基酸序列,参照本领域公知的密码子表获得的DNA)。根据本发明的优选实施方式,其中,所述编码基因为编码所述缺失型S蛋白的RNA和/或其对应的cDNA。
根据本发明的一种优选实施方式,其中,所述编码基因如SEQ ID NO:3和/或SEQID NO:4所示。
AUGUUCGUGUUCCUCGUGCUCCUGCCUCUGGUGUCUAGCCAGUGCGUGAACCUGACCACACGGACCCAGCUCCCUCCCGCCUACACAAACUCUUUCACCCGGGGCGUGUACUACCCCGACAAGGUGUUCCGGUCUAGCGUGCUCCACUCUACACAGGACCUGUUCCUCCCUUUCUUCAGCAACGUGACAUGGUUCCACGCCAUCCACGUGUCUGGCACAAACGGCACAAAGCGGUUCGACAACCCCGUGCUCCCUUUCAACGACGGCGUGUACUUCGCCAGCACCGAGAAGUCUAACAUUAUCCGGGGCUGGAUUUUCGGCACCACACUCGACUCUAAGACACAGUCCCUCCUGAUUGUGAACAACGCCACAAACGUGGUGAUUAAGGUGUGCGAGUUCCAGUUCUGCAACGACCCUUUCCUGGGCGUGUACUACCACAAGAACAACAAGUCUUGGAUGGAGUCUGAGUUCAGAGUGUACUCUAGCGCCAACAACUGCACCUUCGAGUACGUGUCCCAGCCUUUCCUCAUGGACCUGGAGGGCAAGCAGGGCAACUUCAAGAACCUGAGAGAGUUCGUGUUCAAGAACAUUGACGGCUACUUCAAGAUUUACUCUAAGCACACCCCAAUUAACCUCGUGAGGGACCUCCCUCAGGGCUUCUCCGCCUUAGAACCACUGGUGGACCUCCCUAUUGGCAUUAACAUCACACGCUUCCAGACACUGCUCGCCCUCCACCGGUCUUACCUGACCCCAGGCGACUCUAGCUCUGGCUGGACAGCCGGCGCCGCCGCCUACUACGUGGGCUACCUGCAGCCUAGGACCUUCCUCCUGAAGUACAACGAGAACGGCACAAUUACCGACGCCGUGGACUGCGCCCUGGACCCACUGUCCGAGACAAAGUGCACACUGAAGUCCUUCACAGUGGAGAAGGGCAUUUACCAGACAUCUAACUUCCGGGUGCAGCCUACAGAGUCUAUUGUGCGGUUCCCAAACAUCACAAACCUGUGCCCUUUCGGCGAGGUGUUCAACGCCACCCGGUUCGCCUCUGUGUACGCCUGGAACCGGAAGCGGAUCUCUAACUGCGUGGCCGACUACUCCGUGCUGUACAACUCCGCCUCUUUCUCUACAUUCAAGUGCUACGGCGUGUCCCCUACAAAGCUGAACGACCUGUGCUUCACCAACGUGUACGCCGACUCUUUCGUGAUUAGAGGCGACGAGGUGAGGCAGAUUGCCCCCGGCCAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACAGGCUGCGUGAUCGCCUGGAACUCUAACAACCUGGACUCUAAGGUGGGCGGCAACUACAACUACCUGUACAGACUGUUCCGGAAGUCUAACCUGAAGCCAUUCGAGAGGGACAUUAGCACCGAGAUUUACCAGGCCGGCUCUACCCCAUGCAACGGCGUGGAGGGCUUCAACUGCUACUUCCCACUGCAGUCCUACGGCUUCCAGCCUACAAACGGCGUGGGCUACCAGCCUUACCGGGUGGUGGUGCUGUCUUUCGAGCUGCUCCACGCCCCCGCCACAGUGUGCGGCCCAAAGAAGAGCACAAACCUCGUGAAGAACAAGUGCGUGAACUUCAACUUCAACGGCCUCACAGGCACAGGCGUGCUCACCGAGUCUAACAAGAAGUUCCUCCCUUUCCAGCAGUUCGGCCGCGACAUUGCCGACACCACCGACGCCGUGCGGGACCCUCAGACACUGGAAAUUCUCGACAUCACCCCUUGCAGCUUCGGCGGCGUGUCCGUGAUCACCCCAGGCACAAACACAUCUAACCAGGUGGCCGUGCUGUACCAGGACGUGAACUGCACCGAGGUGCCAGUGGCCAUCCACGCCGACCAGCUCACCCCAACAUGGAGGGUGUACAGCACAGGCUCUAACGUGUUCCAGACCCGGGCCGGCUGCCUCAUUGGCGCCGAGCACGUGAACAACUCUUACGAGUGCGACAUCCCUAUUGGCGCCGGCAUUUGCGCCUCUUACCAGACCCAGACAUCUGUGGCCUCUCAGAGCAUUAUUGCCUACACCAUGUCUCUGGGCGCCGAGAACUCUGUGGCCUACUCUAACAACUCUAUUGCCAUCCCUACAAACUUCACAAUUUCUGUGACCACCGAGAUUCUCCCAGUGUCUAUGACCAAGACAUCUGUGGACUGCACCAUGUACAUUUGCGGCGACUCCACCGAGUGCUCUAACCUCCUGCUCCAGUACGGCUCUUUCUGCACCCAGCUCAACCGCGCCCUGACAGGCAUCGCCGUGGAGCAGGACAAGAACACCCAGGAGGUGUUCGCCCAGGUGAAGCAGAUUUACAAGACCCCCCCAAUUAAGGACUUCGGCGGCUUCAACUUCUCUCAGAUUCUCCCCGACCCAUCCAAGCCUAGCAAGCGGUCCUUCAUUGAGGACCUCCUGUUCAACAAGGUGACACUGGCCGACGCCGGCUUCAUUAAGCAGUACGGCGACUGCCUGGGCGACAUUGCCGCCCGGGACCUGAUUUGCGCCCAGAAGUUCAACGGCCUCACAGUGCUCCCCCCACUGCUCACCGACGAGAUGAUUGCCCAGUACACAUCUGCCCUCCUGGCCGGCACAAUUACAUCUGGCUGGACCUUCGGCGCCGGCGCCGCCCUGCAGAUCCCUUUCGCCAUGCAGAUGGCCUACCGCUUCAACGGCAUCGGCGUGACACAGAACGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUUGGCAAGAUUCAGGACUCUCUGAGCAGCACAGCCAGCGCCCUGGGCAAGCUGCAGGACGUGGUGAACCAGAACGCCCAGGCCCUGAACACACUGGUGAAGCAGCUGUCUUCUAACUUCGGCGCCAUUUCUAGCGUGCUGAACGACAUUCUGUCGCGGCUGGACCCACCCGAGGCCGAGGUGCAGAUUGACAGGCUCAUCACAGGCAGACUGCAGUCUCUGCAGACAUACGUGACCCAGCAGCUGAUUAGAGCCGCCGAGAUUAGAGCCUCCGCCAACCUGGCCGCCACCAAGAUGAGCGAGUGCGUGCUCGGCCAGUCUAAGCGGGUGGACUUCUGCGGCAAGGGCUACCACCUCAUGUCUUUCCCUCAGUCCGCCCCUCACGGCGUGGUGUUCCUCCACGUGACAUACGUGCCCGCCCAGGAGAAGAACUUCACCACAGCCCCCGCCAUUUGCCACGACGGCAAGGCCCACUUCCCUAGGGAGGGCGUGUUCGUGUCUAACGGCACCCACUGGUUCGUGACCCAGCGGAACUUCUACGAGCCUCAGAUUAUUACCACAGACAACACAUUCGUGAGCGGCAACUGCGACGUGGUGAUUGGCAUUGUGAACAACACAGUGUACGACCCACUGCAGCCUGAGUUGGACUCUUUCAAGGAGGAACUCGACAAGUACUUCAAGAACCACACAUCUCCUGACGUGGACCUGGGCGACAUUAGCGGCAUUAACGCCUCUGUGGUGAACAUUCAGAAGGAGAUUGACAGACUGAACGAGGUGGCCAAGAACCUGAACGAGUCUCUCAUUGACCUGCAGGAGCUGGGCAAGUACGAGCAGGGCGGCCGCGGCAGCGGAUAUAUUCCCGAAGCACCGAGAGAUGGGCAAGCAUAUGUUAGGAAGGAUGGAGAAUGGGUUUUACUCAGUACCUUUCUAGGCAGAAGCCUGGAAGUGCUGUUCCAGGGCCCCGGCUGGAGUCACCCUCAGUUUGAAAAGGGAGGCGGAUCAGGAGGAGGCUCUGGCGGAAGUUCAGCUUGGUCGCAUCCACAGUUCGAGAAGUAA(SEQ ID NO:3)
ATGTTCGTGTTCCTCGTGCTCCTGCCTCTGGTGTCTAGCCAGTGCGTGAACCTGACCACACGGACCCAGCTCCCTCCCGCCTACACAAACTCTTTCACCCGGGGCGTGTACTACCCCGACAAGGTGTTCCGGTCTAGCGTGCTCCACTCTACACAGGACCTGTTCCTCCCTTTCTTCAGCAACGTGACATGGTTCCACGCCATCCACGTGTCTGGCACAAACGGCACAAAGCGGTTCGACAACCCCGTGCTCCCTTTCAACGACGGCGTGTACTTCGCCAGCACCGAGAAGTCTAACATTATCCGGGGCTGGATTTTCGGCACCACACTCGACTCTAAGACACAGTCCCTCCTGATTGTGAACAACGCCACAAACGTGGTGATTAAGGTGTGCGAGTTCCAGTTCTGCAACGACCCTTTCCTGGGCGTGTACTACCACAAGAACAACAAGTCTTGGATGGAGTCTGAGTTCAGAGTGTACTCTAGCGCCAACAACTGCACCTTCGAGTACGTGTCCCAGCCTTTCCTCATGGACCTGGAGGGCAAGCAGGGCAACTTCAAGAACCTGAGAGAGTTCGTGTTCAAGAACATTGACGGCTACTTCAAGATTTACTCTAAGCACACCCCAATTAACCTCGTGAGGGACCTCCCTCAGGGCTTCTCCGCCTTAGAACCACTGGTGGACCTCCCTATTGGCATTAACATCACACGCTTCCAGACACTGCTCGCCCTCCACCGGTCTTACCTGACCCCAGGCGACTCTAGCTCTGGCTGGACAGCCGGCGCCGCCGCCTACTACGTGGGCTACCTGCAGCCTAGGACCTTCCTCCTGAAGTACAACGAGAACGGCACAATTACCGACGCCGTGGACTGCGCCCTGGACCCACTGTCCGAGACAAAGTGCACACTGAAGTCCTTCACAGTGGAGAAGGGCATTTACCAGACATCTAACTTCCGGGTGCAGCCTACAGAGTCTATTGTGCGGTTCCCAAACATCACAAACCTGTGCCCTTTCGGCGAGGTGTTCAACGCCACCCGGTTCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCTCTAACTGCGTGGCCGACTACTCCGTGCTGTACAACTCCGCCTCTTTCTCTACATTCAAGTGCTACGGCGTGTCCCCTACAAAGCTGAACGACCTGTGCTTCACCAACGTGTACGCCGACTCTTTCGTGATTAGAGGCGACGAGGTGAGGCAGATTGCCCCCGGCCAGACAGGCAAGATCGCCGACTACAACTACAAGCTGCCCGACGACTTCACAGGCTGCGTGATCGCCTGGAACTCTAACAACCTGGACTCTAAGGTGGGCGGCAACTACAACTACCTGTACAGACTGTTCCGGAAGTCTAACCTGAAGCCATTCGAGAGGGACATTAGCACCGAGATTTACCAGGCCGGCTCTACCCCATGCAACGGCGTGGAGGGCTTCAACTGCTACTTCCCACTGCAGTCCTACGGCTTCCAGCCTACAAACGGCGTGGGCTACCAGCCTTACCGGGTGGTGGTGCTGTCTTTCGAGCTGCTCCACGCCCCCGCCACAGTGTGCGGCCCAAAGAAGAGCACAAACCTCGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGCCTCACAGGCACAGGCGTGCTCACCGAGTCTAACAAGAAGTTCCTCCCTTTCCAGCAGTTCGGCCGCGACATTGCCGACACCACCGACGCCGTGCGGGACCCTCAGACACTGGAAATTCTCGACATCACCCCTTGCAGCTTCGGCGGCGTGTCCGTGATCACCCCAGGCACAAACACATCTAACCAGGTGGCCGTGCTGTACCAGGACGTGAACTGCACCGAGGTGCCAGTGGCCATCCACGCCGACCAGCTCACCCCAACATGGAGGGTGTACAGCACAGGCTCTAACGTGTTCCAGACCCGGGCCGGCTGCCTCATTGGCGCCGAGCACGTGAACAACTCTTACGAGTGCGACATCCCTATTGGCGCCGGCATTTGCGCCTCTTACCAGACCCAGACATCTGTGGCCTCTCAGAGCATTATTGCCTACACCATGTCTCTGGGCGCCGAGAACTCTGTGGCCTACTCTAACAACTCTATTGCCATCCCTACAAACTTCACAATTTCTGTGACCACCGAGATTCTCCCAGTGTCTATGACCAAGACATCTGTGGACTGCACCATGTACATTTGCGGCGACTCCACCGAGTGCTCTAACCTCCTGCTCCAGTACGGCTCTTTCTGCACCCAGCTCAACCGCGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAACACCCAGGAGGTGTTCGCCCAGGTGAAGCAGATTTACAAGACCCCCCCAATTAAGGACTTCGGCGGCTTCAACTTCTCTCAGATTCTCCCCGACCCATCCAAGCCTAGCAAGCGGTCCTTCATTGAGGACCTCCTGTTCAACAAGGTGACACTGGCCGACGCCGGCTTCATTAAGCAGTACGGCGACTGCCTGGGCGACATTGCCGCCCGGGACCTGATTTGCGCCCAGAAGTTCAACGGCCTCACAGTGCTCCCCCCACTGCTCACCGACGAGATGATTGCCCAGTACACATCTGCCCTCCTGGCCGGCACAATTACATCTGGCTGGACCTTCGGCGCCGGCGCCGCCCTGCAGATCCCTTTCGCCATGCAGATGGCCTACCGCTTCAACGGCATCGGCGTGACACAGAACGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACAGCGCCATTGGCAAGATTCAGGACTCTCTGAGCAGCACAGCCAGCGCCCTGGGCAAGCTGCAGGACGTGGTGAACCAGAACGCCCAGGCCCTGAACACACTGGTGAAGCAGCTGTCTTCTAACTTCGGCGCCATTTCTAGCGTGCTGAACGACATTCTGTCGCGGCTGGACCCACCCGAGGCCGAGGTGCAGATTGACAGGCTCATCACAGGCAGACTGCAGTCTCTGCAGACATACGTGACCCAGCAGCTGATTAGAGCCGCCGAGATTAGAGCCTCCGCCAACCTGGCCGCCACCAAGATGAGCGAGTGCGTGCTCGGCCAGTCTAAGCGGGTGGACTTCTGCGGCAAGGGCTACCACCTCATGTCTTTCCCTCAGTCCGCCCCTCACGGCGTGGTGTTCCTCCACGTGACATACGTGCCCGCCCAGGAGAAGAACTTCACCACAGCCCCCGCCATTTGCCACGACGGCAAGGCCCACTTCCCTAGGGAGGGCGTGTTCGTGTCTAACGGCACCCACTGGTTCGTGACCCAGCGGAACTTCTACGAGCCTCAGATTATTACCACAGACAACACATTCGTGAGCGGCAACTGCGACGTGGTGATTGGCATTGTGAACAACACAGTGTACGACCCACTGCAGCCTGAGTTGGACTCTTTCAAGGAGGAACTCGACAAGTACTTCAAGAACCACACATCTCCTGACGTGGACCTGGGCGACATTAGCGGCATTAACGCCTCTGTGGTGAACATTCAGAAGGAGATTGACAGACTGAACGAGGTGGCCAAGAACCTGAACGAGTCTCTCATTGACCTGCAGGAGCTGGGCAAGTACGAGCAGGGCGGCCGCGGCAGCGGATATATTCCCGAAGCACCGAGAGATGGGCAAGCATATGTTAGGAAGGATGGAGAATGGGTTTTACTCAGTACCTTTCTAGGCAGAAGCCTGGAAGTGCTGTTCCAGGGCCCCGGCTGGAGTCACCCTCAGTTTGAAAAGGGAGGCGGATCAGGAGGAGGCTCTGGCGGAAGTTCAGCTTGGTCGCATCCACAGTTCGAGAAGTAA(SEQ ID NO:4)
出于便于体外表达,提高体外表达的表达量,或提高体外表达获得的缺失型S蛋白的免疫原性/刺激宿主产生免疫保护的效果等方面的考虑,优选地,所述编码基因还可以经过密码子优化,以获得更适合制备治疗和/或预防新冠肺炎的产品的所述缺失型S蛋白。
本发明第二方面提供一种疫苗组合物,所述疫苗组合物中含有活性成分和辅料,所述活性成分包括缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
本发明提供的疫苗组合物中采用的缺失型刺突蛋白的编码基因特点如前所述,在此不再赘述。
本发明中,所述辅料可以为任意本领域中用于制备治疗和/或预防新冠肺炎的产品(例如新冠疫苗等)时采用的辅料,只要其对于所述缺失型刺突蛋白的活性没有明显影响即可。根据本发明的优选实施方式,其中,所述辅料选自吸附剂、防腐剂、稳定剂和乳化剂中的至少一种。
优选地,所述吸附剂选自铝佐剂,例如氢氧化铝凝胶、磷酸铝、硫酸铝、铵明矾和钾明矾等。
优选地,所述防腐剂选自硫柳汞等。
优选地,所述稳定剂选自明胶、山梨糖醇、糖分子蔗糖和乳糖等。
优选地,所述乳化剂选自泊洛沙姆、聚氧乙烯蓖麻油、吐温等。
本发明的发明人在研究的过程中还发现,相比于野生型S蛋白,本发明中采用的缺失型S蛋白在免疫大鼠后,能在较短时间内(例如免疫后14天内)产生更多的IgG抗体。
基于上述发现,本发明第三方面提供如前所述的疫苗组合物或具有缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因在快速诱导SARS-CoV-2特异性抗体产生中的应用,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
该应用中,所述编码基因的特征如前所述,在此不再赘述。
根据本发明,所述缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因作为主要活性成分(优选作为唯一活性成分)进行施用。
以下将通过具体实施例对本发明进行进一步详细描述。应当能够理解的是,以下实施例仅用于进一步解释和说明本发明,而不用于限制本发明。
以下实施例中,所述新冠病毒临床分离株V34分离自新冠病毒感染的患者的鼻拭子样本。该研究已获得相关人员的知情同意。Vero细胞购自美国生物样本培养物保藏中心(ATCC)。HEK293 F细胞购自Thermo Fisher。SARS-CoV-2的S蛋白的特异抗体均购自SinoBiological公司。BALB/c小鼠由北京维通利华实验动物技术有限公司提供。Wistar大鼠由维通利华提供。以下实施例中采用的其他试剂、材料等均购自正规生物或化学试剂/耗材供应商。
以下实施例中,实时定量RT-PCR通过Roche公司的LightCycler480 Il PCR仪完成。
以下实施例中,所述“室温”在未做特殊说明的情况下指的是25±5℃。
实施例1
本实施例用于说明含有缺失型S蛋白的SARS-CoV-2突变株(缺失突变株)的发现及其基因组特征。
本实施例中,所述空斑试验的方式为:将含有病毒的细胞培养上清用无血清的DMEM培养基进行10倍系列稀释,将各稀释度液体以250μL/孔加入铺于24孔板中的Vero细胞,于37℃,5%CO2条件下培养吸附50min,移去上清,加入含1体积%低熔点琼脂糖和2体积%FBS的DMEM(500uL/孔),于37℃,5%CO2条件下进行培养。感染后第3天,加入4体积%甲醛固定液(1mL/孔),室温固定30min,移除琼脂盖,加入结晶紫,室温染色30min,PBS清洗3次后计数空斑数。
将新冠病毒临床分离株V34(即野生型SARS-CoV-2)以MOI=0.1的接种剂量感染铺于6孔板中的Vero细胞(约2×105个细胞/孔)。于37℃,5%CO2条件下进行培养。感染后第3天收取细胞上清,通过空斑试验确定上清中的病毒滴度,作为第一代毒株,命名为P1。
将P1毒株以MOI=0.1的接种剂量感染6孔板中的Vero细胞(约2×105个细胞/孔),于37℃,5%CO2条件下进行培养。于感染后第3天收取细胞上清,通过空斑试验确定上清中的病毒滴度,作为第二代毒株,命名为P2。
依照上述方式将该病毒连续在Vero细胞中传代5次,获得第五代毒株,命名为P5(即缺失型SARS-CoV-2,其编码S蛋白的基因组RNA如SEQ ID NO:3所示)。
使用病毒核酸提取试剂盒Viral RNA mini(购自Qiagen),按照试剂盒操作说明提取V34和P5毒株的病毒RNA,采用Invitrogen SuperScript III One-Step RT-PCR试剂盒扩增获得其S蛋白基因序列。相关引物名称和序列为:
S22-F(上游引物,SEQ ID NO:5):
5’-GATTACGCCAAGCTTTACAATCTAGTCAAGCGTGGCAACCG-3’;
S22-R(下游引物,SEQ ID NO:6):
5’-GATTACGCCAAGCTTCAATAAGTAGGGACTGGGTCTTC-3’;
S23-F(上游引物,SEQ ID NO:7):
5’-GATTACGCCAAGCTTCTGGGACCAATGGTACTAAGAGG-3’;
S23-R(下游引物,SEQ ID NO:8):
5’-GATTACGCCAAGCTTGCACCAAGTGACATAGTGTAGGC-3’;
S24-F(上游引物,SEQ ID NO:9):
5’-GATTACGCCAAGCTTCCGTGATCCACAGACACTTGAGA-3’;
S24-R(下游引物,SEQ ID NO:10):
5’-GATTACGCCAAGCTTCAGCAACTGGTCATACAGCAAAGC-3’;
S25-F(上游引物,SEQ ID NO:11):
5’-GATTACGCCAAGCTTCGCCTCAATGAGGTTGCCAAGAA-3’;
S25-R(下游引物,SEQ ID NO:12):
5’-GATTACGCCAAGCTTGAGCCACATCAAGCCTACAAGACA-3’。
利用上述引物,采用表1中的反应体系,按照表2中的条件进行RT-PCR扩增。
表1 RT-PCR反应体系
反应体系组成 | 体积(μL) |
2x Taq buffer | 25 |
上游引物 | 1 |
下游引物 | 1 |
病毒RNA | 2 |
Platium mix | 2 |
RNase Free dH2O | 19 |
总体积 | 50 |
表2 RT-PCR反应条件
*该时间根据扩增序列长度,按照1000bp/60s计算获得。
扩增获得的目的片段由北京诺赛基因公司完成测序。利用Lasergen软件对V34和P5病毒的S基因进行序列比对,结果如图1所示。从中可以看出,与V34(WT)相比,P5毒株(DEL-7aa)S蛋白中的S1/S2切割位点上游缺失21个核苷酸,导致缺失7个氨基酸残基(NSPRRAR,SEQ ID NO:13)。V34的S蛋白(野生型S蛋白)和P5的S蛋白(缺失型S蛋白)氨基酸序列分别如SEQ ID NO:2和SEQ ID NO:1所示。
实施例2
本实施例用于说明缺失型S蛋白的获得。
以野生型SARS-CoV-2全长刺突蛋白(残基1-1028)的质粒(GenBank:MN908947)为模板,利用PCR构建表达VAS5(即实施例1中获得的缺失突变株P5)的S蛋白的质粒(其中编码缺失型S蛋白的核苷酸序列如SEQ ID NO:4所示,构建方法可以参考Lv,Z.et al.,Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potenttherapeutic antibody.SCIENCE 369 1505(2020).。全长S基因构建在残基986和987位用两个脯氨酸替换,C端引入T4纤维蛋白折叠域,并且在C端引入双链strep-tag II标签(氨基酸序列为WSHPQFEKGGGSGGGSGGSSAWSHPQFEK,SEQ ID NO:14)用于蛋白纯化。将构建的质粒瞬时转染到HEK293 F细胞中,将细胞悬液放入37℃,8%CO2的震荡培养箱中培养,转速130rpm。孵育72小时后,收集上清,浓缩,用切向流过滤盒(VIVAFLOW 200 100,000MWCOPES)交换到结合缓冲液中。用链霉亲和素树脂亲和层析分离目的蛋白并进一步透析到20mMTris pH 8.0和200mM NaCl的缓冲液中。
亲和纯化得到的缺失型S蛋白凝胶过滤色谱图如图2(A)所示。由图中可以看出,在洗脱体积为~15ml处A280吸收值达到谱峰,收集此处的蛋白缓冲液即为纯化的缺失型S蛋白缓冲液。
将含有目的蛋白的缓冲液用凝胶过滤层析进一步纯化浓缩,得到目的蛋白凝胶过滤色谱图,根据色谱图谱峰位置取目的蛋白缓冲液。取10uL蛋白缓冲液加入2.5uL 5×loading buffer变性,进行SDS-PAGE电泳,电压120V,时间50min。将得到的PAGE胶用考马斯亮蓝G250染色,微波炉高火染色2min,之后用dH2O(加入适量无水乙醇)微波炉高火脱色约15-20min,于照胶仪上观察结果,拍照。
缺失型S蛋白SDS-PAGE结果如图2(B)所示,左边泳道为蛋白Marker,右边泳道为缺失型S蛋白缓冲液,可以观察到在~250kDa处有一单一条带,即为目的蛋白(缺失型S蛋白)。上述结果表明,纯化得到的目的蛋白纯度较高,无杂蛋白。
实施例3
本实施例用于说明缺失型S蛋白在大鼠体内的免疫原性评价结果。
将Wistar大鼠随机分为3组,每组10只。用PBS分别稀释野生型S蛋白(S-WT)和缺失型S蛋白(S-VAS5),获得蛋白稀释液(5μg/50μL)。将铝佐剂分别与蛋白稀释液或等体积PBS(安慰剂)按体积比1:1乳化,肌肉注射进行第一次免疫。初次接种后14天肌肉注射进行第二次免疫。大鼠在第二次免疫后14天、21天放血,分离血清,56℃灭活30min。
将所得的各组大鼠的血清在含2%胎牛血清的PBS中连续3倍稀释,从1:30开始。用野生型S蛋白或缺失型S蛋白包被96孔板(此处设置空白对照-采用PBS作为一抗和阴性对照-采用接种安慰剂组大鼠血清),每孔加入抗原100uL,置于37℃孵育4h后弃去孔中液体。用PBS(含2%的BSA)37℃封闭40min,封闭结束后用洗涤液满孔洗涤3遍,每遍3min。加入稀释血清作为第一抗体,以1:3的比例在PBS中连续稀释共8次,初始浓度为10μg/mL,每孔100uL,37℃孵育1h后洗涤3次。每孔加入100uL酶标二抗(Thermo Fisher Scientific)37℃孵育1h,洗涤3次后每孔加底物溶液(TMB)50μL,置室温避光显色10min。显色后,每孔加入50μL终止液(2mol/L H2SO4)终止反应。使用酶标仪读取450nm的OD值。以吸光度为X轴、靶蛋白浓度为Y轴绘制靶蛋白标准曲线,通过图中各点绘制最佳拟合曲线。计算曲线下面积(AUC)和ELISA半最大值浓度(EC50)(PRISM),以评估抗原结合能力。
图3中示出了野生型S蛋白免疫组、缺失型S蛋白免疫组和安慰剂组在第二次免疫后第14天和21天时的抗原结合能力,从图中可以看出,在第二次免疫后第14天(n=10),缺失型S蛋白免疫组出现SARS-CoV-2特异性IgG抗体,且抗体血清滴度超过野生型S蛋白免疫组的2倍以上。上述结果表明,体外表达的缺失型S蛋白在大鼠体内具有良好的免疫原性。
实施例4
本实施例用于说明灭活的SARS-CoV-2缺失突变株能够为小鼠提供有效的免疫保护。
将β-丙内脂以1:3000的体积比加入含有SARS-CoV-2缺失突变株DEL-7aa的细胞培养上清(其中DEL-7aa的滴度为2×107PFU/mL),置4℃处理16h。再通过分子筛和亲和纯化层析获取灭活病毒颗粒,进一步与铝佐剂(氢氧化铝)混合,制备获得灭活病毒制剂。将灭活病毒以1.25ug/只和2.5ug/只的剂量,经肌肉注射途径免疫4周龄BALB/c雌鼠,免疫后第14天,再以相同剂量加强免疫一次。同时设立PBS组作为对照,以与灭活病毒制剂等量的PBS对该组小鼠进行给药。首次免疫后第30天,经滴鼻途径接种新冠病毒株p6(60000PFU/只)至各组小鼠。于感染后第5天取小鼠肺组织和气管。用1mL DMEM将肺组织(约0.1g)和气管组织(约0.03g)重悬并研磨,7000rpm离心10min,留取组织研磨液上清。使用病毒核酸提取试剂盒Viral RNA mini(购自Qiagen),按照试剂盒操作说明提取上清中的病毒RNA,通过实时定量RT-PCR检测病毒RNA拷贝数。结果如图4所示,从中可以看出,1.25ug和2.5ug组的小鼠肺组织中的病毒核酸分别比PBS组降低约1000倍和3000倍,气管中的病毒核酸分别降低10倍和1000倍,呈现出明显的保护效果。这说明含有缺失型S蛋白的缺失突变株DEL-7aa具有制备用于预防新冠肺炎的疫苗制品的前景。
实施例5
本实施例用于说明缺失型S蛋白的抗原性及其与野生型S蛋白的群体特异性比较。
采用实施例2中的方法获得体外表达并纯化的缺失型S蛋白和野生型S蛋白,通过ELISA检测高度纯化的缺失型S蛋白(VAS5)和野生型S蛋白(WT)的中和抗体(NAb)结合。共检测了43个RBD-和27个NTD靶向的NAbs(包括一些临床应用的治疗性的NAbs或研究充分的Nabs,具体参考图5),分别识别RBD和NTD上所有6个和4个目前确定的表位组。在RBD靶向的NAbs中,可以分为两种类型:1)只与“上”RBD结合;2)与RBD结合,而不管它们的“上”和“下”构象。
本实施例中,ELISA检测方法如下:用野生型S蛋白或缺失型S蛋白包被96孔板(此处设置空白对照和阴性对照),每孔加入抗原100ul,置于37℃孵育4h后弃去孔中液体。用PBS(含2重量%的BSA)37℃封闭40min,封闭结束后用洗涤液满孔洗涤3遍,每遍3min。加入不同类型的中和抗体NAbs作为第一抗体,以1:3的比例在PBS中连续稀释共8次,初始浓度为10μg/mL,每孔100uL,37℃孵育1h后洗涤3次。每孔加入100uL酶标二抗(Thermo FisherScientific)37℃孵育1h,洗涤3次后每孔加底物溶液(TMB)50μl,置室温避光显色10min。显色后,每孔加入50μL终止液(2mol/L H2SO4)终止反应。使用酶标仪读取450nm的OD值。以吸光度为X轴、靶蛋白浓度为Y轴绘制靶蛋白标准曲线,通过图中各点绘制最佳拟合曲线。计算曲线下面积(AUC)和ELISA半最大值浓度(EC50)(PRISM),以评估缺失型S蛋白和野生型S蛋白与不同Nabs的结合能力。
最终得到的6类针对缺失型S蛋白(VAS5)和野生型S蛋白(WT)的靶向RBD单克隆抗体和NTD单克隆抗体的EC50值热图如图5所示。从图中可以看出,这两个S蛋白表现出很大程度上相似的特性与群体特异性模式。缺失型S蛋白的抗原特性在一定程度上反映了其与野生型的免疫原性。上述结果表明,缺失型S蛋白的抗原性良好,且其与野生型S蛋白在结构上的相似性赋予他们相似的群体特异性,表明该缺失型S蛋白在疫苗研制具有很好的前景。
实施例6
本实施例用于说明缺失型S蛋白对于大鼠的免疫保护效果。
采用实施例2中的方法获得体外表达并纯化的缺失型S蛋白和野生型S蛋白,按照以下方法进行实验:Wistar(维通利华)大鼠被随机分为3组,每组10只。使用PBS稀释野生型S蛋白(S-WT)和缺失型S蛋白(S-VAS5)(5μg/50μL),铝佐剂(氢氧化铝)与稀释后的蛋白质或等体积PBS以1:1的体积比乳化作为铝佐剂疫苗用于第一次免疫(5μg/只)。通过肌肉注射初次接种疫苗后,使用铝佐剂疫苗对大鼠进行加强免疫,每隔两周肌肉注射S-WT或S-VAS5。分别于初免后14天、21天、28天对大鼠取血,分离血清,56℃灭活30min。通过标准空斑减少中和试验(PRNT)确定血清中针对WT病毒的中和抗体滴度。将Vero细胞接种在24孔板(200,000个细胞/孔)中并孵育约16小时,直至90%–100%融合。在含有2%FBS的DMEM中制备从1:30开始的连续3倍稀释的血清。然后将稀释的血清与滴定病毒以1:1(v/v)的比例混合以产生含有大约200PFU/mL病毒的混合物,然后在37℃下孵育1小时。将病毒/血清混合物一式两份地添加到Vero细胞单层的24孔板的孔中(250μL/孔)。然后将板在37℃,每20分钟间歇摇动(约120rpm,1min/次)的条件下孵育1小时。除去混合物,用含有2%FBS的DMEM中的1%低熔点琼脂糖(Promega)覆盖细胞。在37℃下进一步培养2天后,将细胞用4%甲醛固定并用0.2%结晶紫染色。在用去离子水冲洗板后记录斑块数。50%中和效价(NT50)通过Spearman-Karber方法计算(Hamilton et al.,1977)。
图6中示出了缺失型S蛋白(S-VAS5)、野生型S蛋白(S-WT)和安慰剂(PBS)处理组的大鼠血浆中产生的中和抗体的14天、21天和28天半最大中和效价(NT50)。从图中可以看出,缺失型S蛋白不仅能够刺激大鼠产生中和抗体,而且相比于野生型S蛋白产生的抗体量更多,能够为大鼠提供更强的免疫保护效果。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
SEQUENCE LISTING
<110> 中国人民解放军军事科学院军事医学研究院
中国科学院生物物理研究所
<120> 缺失7个氨基酸的SARS-CoV-2刺突蛋白和/或其编码基因的应用
<130> I74772JSY
<160> 14
<170> PatentIn version 3.5
<210> 1
<211> 1266
<212> PRT
<213> 缺失型S蛋白
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Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
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Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
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Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
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Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
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Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
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Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
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Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
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Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
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Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
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Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
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Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Val Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr
675 680 685
Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser
690 695 700
Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu
705 710 715 720
Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys
725 730 735
Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe
740 745 750
Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp
755 760 765
Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr
770 775 780
Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro
785 790 795 800
Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe
805 810 815
Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp
820 825 830
Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe
835 840 845
Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala
850 855 860
Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr
865 870 875 880
Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala
885 890 895
Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn
900 905 910
Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln
915 920 925
Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val
930 935 940
Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser
945 950 955 960
Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg
965 970 975
Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly
980 985 990
Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala
995 1000 1005
Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser
1010 1015 1020
Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys
1025 1030 1035
Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val
1040 1045 1050
Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe
1055 1060 1065
Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro
1070 1075 1080
Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val Thr
1085 1090 1095
Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1100 1105 1110
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn
1115 1120 1125
Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu
1130 1135 1140
Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp
1145 1150 1155
Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln
1160 1165 1170
Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu
1175 1180 1185
Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile
1190 1195 1200
Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile
1205 1210 1215
Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys
1220 1225 1230
Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys
1235 1240 1245
Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu
1250 1255 1260
His Tyr Thr
1265
<210> 2
<211> 1273
<212> PRT
<213> 野生型S蛋白
<400> 2
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Val Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 3
<211> 3825
<212> RNA
<213> 缺失型S蛋白编码基因
<400> 3
auguucgugu uccucgugcu ccugccucug gugucuagcc agugcgugaa ccugaccaca 60
cggacccagc ucccucccgc cuacacaaac ucuuucaccc ggggcgugua cuaccccgac 120
aagguguucc ggucuagcgu gcuccacucu acacaggacc uguuccuccc uuucuucagc 180
aacgugacau gguuccacgc cauccacgug ucuggcacaa acggcacaaa gcgguucgac 240
aaccccgugc ucccuuucaa cgacggcgug uacuucgcca gcaccgagaa gucuaacauu 300
auccggggcu ggauuuucgg caccacacuc gacucuaaga cacagucccu ccugauugug 360
aacaacgcca caaacguggu gauuaaggug ugcgaguucc aguucugcaa cgacccuuuc 420
cugggcgugu acuaccacaa gaacaacaag ucuuggaugg agucugaguu cagaguguac 480
ucuagcgcca acaacugcac cuucgaguac gugucccagc cuuuccucau ggaccuggag 540
ggcaagcagg gcaacuucaa gaaccugaga gaguucgugu ucaagaacau ugacggcuac 600
uucaagauuu acucuaagca caccccaauu aaccucguga gggaccuccc ucagggcuuc 660
uccgccuuag aaccacuggu ggaccucccu auuggcauua acaucacacg cuuccagaca 720
cugcucgccc uccaccgguc uuaccugacc ccaggcgacu cuagcucugg cuggacagcc 780
ggcgccgccg ccuacuacgu gggcuaccug cagccuagga ccuuccuccu gaaguacaac 840
gagaacggca caauuaccga cgccguggac ugcgcccugg acccacuguc cgagacaaag 900
ugcacacuga aguccuucac aguggagaag ggcauuuacc agacaucuaa cuuccgggug 960
cagccuacag agucuauugu gcgguuccca aacaucacaa accugugccc uuucggcgag 1020
guguucaacg ccacccgguu cgccucugug uacgccugga accggaagcg gaucucuaac 1080
ugcguggccg acuacuccgu gcuguacaac uccgccucuu ucucuacauu caagugcuac 1140
ggcguguccc cuacaaagcu gaacgaccug ugcuucacca acguguacgc cgacucuuuc 1200
gugauuagag gcgacgaggu gaggcagauu gcccccggcc agacaggcaa gaucgccgac 1260
uacaacuaca agcugcccga cgacuucaca ggcugcguga ucgccuggaa cucuaacaac 1320
cuggacucua aggugggcgg caacuacaac uaccuguaca gacuguuccg gaagucuaac 1380
cugaagccau ucgagaggga cauuagcacc gagauuuacc aggccggcuc uaccccaugc 1440
aacggcgugg agggcuucaa cugcuacuuc ccacugcagu ccuacggcuu ccagccuaca 1500
aacggcgugg gcuaccagcc uuaccgggug guggugcugu cuuucgagcu gcuccacgcc 1560
cccgccacag ugugcggccc aaagaagagc acaaaccucg ugaagaacaa gugcgugaac 1620
uucaacuuca acggccucac aggcacaggc gugcucaccg agucuaacaa gaaguuccuc 1680
ccuuuccagc aguucggccg cgacauugcc gacaccaccg acgccgugcg ggacccucag 1740
acacuggaaa uucucgacau caccccuugc agcuucggcg gcguguccgu gaucacccca 1800
ggcacaaaca caucuaacca gguggccgug cuguaccagg acgugaacug caccgaggug 1860
ccaguggcca uccacgccga ccagcucacc ccaacaugga ggguguacag cacaggcucu 1920
aacguguucc agacccgggc cggcugccuc auuggcgccg agcacgugaa caacucuuac 1980
gagugcgaca ucccuauugg cgccggcauu ugcgccucuu accagaccca gacaucugug 2040
gccucucaga gcauuauugc cuacaccaug ucucugggcg ccgagaacuc uguggccuac 2100
ucuaacaacu cuauugccau cccuacaaac uucacaauuu cugugaccac cgagauucuc 2160
ccagugucua ugaccaagac aucuguggac ugcaccaugu acauuugcgg cgacuccacc 2220
gagugcucua accuccugcu ccaguacggc ucuuucugca cccagcucaa ccgcgcccug 2280
acaggcaucg ccguggagca ggacaagaac acccaggagg uguucgccca ggugaagcag 2340
auuuacaaga cccccccaau uaaggacuuc ggcggcuuca acuucucuca gauucucccc 2400
gacccaucca agccuagcaa gcgguccuuc auugaggacc uccuguucaa caaggugaca 2460
cuggccgacg ccggcuucau uaagcaguac ggcgacugcc ugggcgacau ugccgcccgg 2520
gaccugauuu gcgcccagaa guucaacggc cucacagugc uccccccacu gcucaccgac 2580
gagaugauug cccaguacac aucugcccuc cuggccggca caauuacauc uggcuggacc 2640
uucggcgccg gcgccgcccu gcagaucccu uucgccaugc agauggccua ccgcuucaac 2700
ggcaucggcg ugacacagaa cgugcuguac gagaaccaga agcugaucgc caaccaguuc 2760
aacagcgcca uuggcaagau ucaggacucu cugagcagca cagccagcgc ccugggcaag 2820
cugcaggacg uggugaacca gaacgcccag gcccugaaca cacuggugaa gcagcugucu 2880
ucuaacuucg gcgccauuuc uagcgugcug aacgacauuc ugucgcggcu ggacccaccc 2940
gaggccgagg ugcagauuga caggcucauc acaggcagac ugcagucucu gcagacauac 3000
gugacccagc agcugauuag agccgccgag auuagagccu ccgccaaccu ggccgccacc 3060
aagaugagcg agugcgugcu cggccagucu aagcgggugg acuucugcgg caagggcuac 3120
caccucaugu cuuucccuca guccgccccu cacggcgugg uguuccucca cgugacauac 3180
gugcccgccc aggagaagaa cuucaccaca gcccccgcca uuugccacga cggcaaggcc 3240
cacuucccua gggagggcgu guucgugucu aacggcaccc acugguucgu gacccagcgg 3300
aacuucuacg agccucagau uauuaccaca gacaacacau ucgugagcgg caacugcgac 3360
guggugauug gcauugugaa caacacagug uacgacccac ugcagccuga guuggacucu 3420
uucaaggagg aacucgacaa guacuucaag aaccacacau cuccugacgu ggaccugggc 3480
gacauuagcg gcauuaacgc cucuguggug aacauucaga aggagauuga cagacugaac 3540
gagguggcca agaaccugaa cgagucucuc auugaccugc aggagcuggg caaguacgag 3600
cagggcggcc gcggcagcgg auauauuccc gaagcaccga gagaugggca agcauauguu 3660
aggaaggaug gagaaugggu uuuacucagu accuuucuag gcagaagccu ggaagugcug 3720
uuccagggcc ccggcuggag ucacccucag uuugaaaagg gaggcggauc aggaggaggc 3780
ucuggcggaa guucagcuug gucgcaucca caguucgaga aguaa 3825
<210> 4
<211> 3825
<212> DNA
<213> 缺失型S蛋白编码基因
<400> 4
atgttcgtgt tcctcgtgct cctgcctctg gtgtctagcc agtgcgtgaa cctgaccaca 60
cggacccagc tccctcccgc ctacacaaac tctttcaccc ggggcgtgta ctaccccgac 120
aaggtgttcc ggtctagcgt gctccactct acacaggacc tgttcctccc tttcttcagc 180
aacgtgacat ggttccacgc catccacgtg tctggcacaa acggcacaaa gcggttcgac 240
aaccccgtgc tccctttcaa cgacggcgtg tacttcgcca gcaccgagaa gtctaacatt 300
atccggggct ggattttcgg caccacactc gactctaaga cacagtccct cctgattgtg 360
aacaacgcca caaacgtggt gattaaggtg tgcgagttcc agttctgcaa cgaccctttc 420
ctgggcgtgt actaccacaa gaacaacaag tcttggatgg agtctgagtt cagagtgtac 480
tctagcgcca acaactgcac cttcgagtac gtgtcccagc ctttcctcat ggacctggag 540
ggcaagcagg gcaacttcaa gaacctgaga gagttcgtgt tcaagaacat tgacggctac 600
ttcaagattt actctaagca caccccaatt aacctcgtga gggacctccc tcagggcttc 660
tccgccttag aaccactggt ggacctccct attggcatta acatcacacg cttccagaca 720
ctgctcgccc tccaccggtc ttacctgacc ccaggcgact ctagctctgg ctggacagcc 780
ggcgccgccg cctactacgt gggctacctg cagcctagga ccttcctcct gaagtacaac 840
gagaacggca caattaccga cgccgtggac tgcgccctgg acccactgtc cgagacaaag 900
tgcacactga agtccttcac agtggagaag ggcatttacc agacatctaa cttccgggtg 960
cagcctacag agtctattgt gcggttccca aacatcacaa acctgtgccc tttcggcgag 1020
gtgttcaacg ccacccggtt cgcctctgtg tacgcctgga accggaagcg gatctctaac 1080
tgcgtggccg actactccgt gctgtacaac tccgcctctt tctctacatt caagtgctac 1140
ggcgtgtccc ctacaaagct gaacgacctg tgcttcacca acgtgtacgc cgactctttc 1200
gtgattagag gcgacgaggt gaggcagatt gcccccggcc agacaggcaa gatcgccgac 1260
tacaactaca agctgcccga cgacttcaca ggctgcgtga tcgcctggaa ctctaacaac 1320
ctggactcta aggtgggcgg caactacaac tacctgtaca gactgttccg gaagtctaac 1380
ctgaagccat tcgagaggga cattagcacc gagatttacc aggccggctc taccccatgc 1440
aacggcgtgg agggcttcaa ctgctacttc ccactgcagt cctacggctt ccagcctaca 1500
aacggcgtgg gctaccagcc ttaccgggtg gtggtgctgt ctttcgagct gctccacgcc 1560
cccgccacag tgtgcggccc aaagaagagc acaaacctcg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggcctcac aggcacaggc gtgctcaccg agtctaacaa gaagttcctc 1680
cctttccagc agttcggccg cgacattgcc gacaccaccg acgccgtgcg ggaccctcag 1740
acactggaaa ttctcgacat caccccttgc agcttcggcg gcgtgtccgt gatcacccca 1800
ggcacaaaca catctaacca ggtggccgtg ctgtaccagg acgtgaactg caccgaggtg 1860
ccagtggcca tccacgccga ccagctcacc ccaacatgga gggtgtacag cacaggctct 1920
aacgtgttcc agacccgggc cggctgcctc attggcgccg agcacgtgaa caactcttac 1980
gagtgcgaca tccctattgg cgccggcatt tgcgcctctt accagaccca gacatctgtg 2040
gcctctcaga gcattattgc ctacaccatg tctctgggcg ccgagaactc tgtggcctac 2100
tctaacaact ctattgccat ccctacaaac ttcacaattt ctgtgaccac cgagattctc 2160
ccagtgtcta tgaccaagac atctgtggac tgcaccatgt acatttgcgg cgactccacc 2220
gagtgctcta acctcctgct ccagtacggc tctttctgca cccagctcaa ccgcgccctg 2280
acaggcatcg ccgtggagca ggacaagaac acccaggagg tgttcgccca ggtgaagcag 2340
atttacaaga cccccccaat taaggacttc ggcggcttca acttctctca gattctcccc 2400
gacccatcca agcctagcaa gcggtccttc attgaggacc tcctgttcaa caaggtgaca 2460
ctggccgacg ccggcttcat taagcagtac ggcgactgcc tgggcgacat tgccgcccgg 2520
gacctgattt gcgcccagaa gttcaacggc ctcacagtgc tccccccact gctcaccgac 2580
gagatgattg cccagtacac atctgccctc ctggccggca caattacatc tggctggacc 2640
ttcggcgccg gcgccgccct gcagatccct ttcgccatgc agatggccta ccgcttcaac 2700
ggcatcggcg tgacacagaa cgtgctgtac gagaaccaga agctgatcgc caaccagttc 2760
aacagcgcca ttggcaagat tcaggactct ctgagcagca cagccagcgc cctgggcaag 2820
ctgcaggacg tggtgaacca gaacgcccag gccctgaaca cactggtgaa gcagctgtct 2880
tctaacttcg gcgccatttc tagcgtgctg aacgacattc tgtcgcggct ggacccaccc 2940
gaggccgagg tgcagattga caggctcatc acaggcagac tgcagtctct gcagacatac 3000
gtgacccagc agctgattag agccgccgag attagagcct ccgccaacct ggccgccacc 3060
aagatgagcg agtgcgtgct cggccagtct aagcgggtgg acttctgcgg caagggctac 3120
cacctcatgt ctttccctca gtccgcccct cacggcgtgg tgttcctcca cgtgacatac 3180
gtgcccgccc aggagaagaa cttcaccaca gcccccgcca tttgccacga cggcaaggcc 3240
cacttcccta gggagggcgt gttcgtgtct aacggcaccc actggttcgt gacccagcgg 3300
aacttctacg agcctcagat tattaccaca gacaacacat tcgtgagcgg caactgcgac 3360
gtggtgattg gcattgtgaa caacacagtg tacgacccac tgcagcctga gttggactct 3420
ttcaaggagg aactcgacaa gtacttcaag aaccacacat ctcctgacgt ggacctgggc 3480
gacattagcg gcattaacgc ctctgtggtg aacattcaga aggagattga cagactgaac 3540
gaggtggcca agaacctgaa cgagtctctc attgacctgc aggagctggg caagtacgag 3600
cagggcggcc gcggcagcgg atatattccc gaagcaccga gagatgggca agcatatgtt 3660
aggaaggatg gagaatgggt tttactcagt acctttctag gcagaagcct ggaagtgctg 3720
ttccagggcc ccggctggag tcaccctcag tttgaaaagg gaggcggatc aggaggaggc 3780
tctggcggaa gttcagcttg gtcgcatcca cagttcgaga agtaa 3825
<210> 5
<211> 41
<212> DNA
<213> S22-F
<400> 5
gattacgcca agctttacaa tctagtcaag cgtggcaacc g 41
<210> 6
<211> 38
<212> DNA
<213> S22-R
<400> 6
gattacgcca agcttcaata agtagggact gggtcttc 38
<210> 7
<211> 38
<212> DNA
<213> S23-F
<400> 7
gattacgcca agcttctggg accaatggta ctaagagg 38
<210> 8
<211> 38
<212> DNA
<213> S23-R
<400> 8
gattacgcca agcttgcacc aagtgacata gtgtaggc 38
<210> 9
<211> 38
<212> DNA
<213> S24-F
<400> 9
gattacgcca agcttccgtg atccacagac acttgaga 38
<210> 10
<211> 39
<212> DNA
<213> S24-R
<400> 10
gattacgcca agcttcagca actggtcata cagcaaagc 39
<210> 11
<211> 38
<212> DNA
<213> S25-F
<400> 11
gattacgcca agcttcgcct caatgaggtt gccaagaa 38
<210> 12
<211> 39
<212> DNA
<213> S25-R
<400> 12
gattacgcca agcttgagcc acatcaagcc tacaagaca 39
<210> 13
<211> 7
<212> PRT
<213> 缺失型S蛋白中缺失的氨基酸序列
<400> 13
Asn Ser Pro Arg Arg Ala Arg
1 5
<210> 14
<211> 29
<212> PRT
<213> strep-tag II标签
<400> 14
Trp Ser His Pro Gln Phe Glu Lys Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Ser Ser Ala Trp Ser His Pro Gln Phe Glu Lys
20 25
Claims (10)
1.具有缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因在制备治疗和/或预防新冠肺炎的产品中的应用,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
2.根据权利要求1所述的应用,其中,所述编码基因为编码所述刺突蛋白的RNA和/或其对应的cDNA。
3.根据权利要求2所述的应用,其中,所述编码基因如SEQ ID NO:3和/或SEQ ID NO:4所示。
4.一种疫苗组合物,其特征在于,所述疫苗组合物中含有活性成分和辅料,所述活性成分包括缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
5.根据权利要求4所述的疫苗组合物,其中,所述编码基因为编码所述刺突蛋白的RNA和/或其对应的cDNA。
6.根据权利要求5所述的疫苗组合物,其中,所述编码基因如SEQ ID NO:3和/或SEQ IDNO:4所示。
7.根据权利要求4所述的疫苗组合物,其中,所述辅料选自吸附剂、防腐剂、稳定剂和乳化剂中的至少一种。
8.权利要求4-7中任意一项所述的疫苗组合物或具有缺失突变的SARS-CoV-2刺突蛋白和/或其编码基因在快速诱导SARS-CoV-2特异性抗体产生中的应用,所述刺突蛋白的氨基酸序列如SEQ ID NO:1所示。
9.根据权利要求8所述的应用,其中,所述编码基因为编码所述刺突蛋白的RNA和/或其对应的cDNA。
10.根据权利要求9所述的应用,其中,所述编码基因如SEQ ID NO:3和/或SEQ ID NO:4所示。
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