CN113215178A - 用于2019-nCoV型冠状病毒mRNA疫苗、制备方法及其应用 - Google Patents
用于2019-nCoV型冠状病毒mRNA疫苗、制备方法及其应用 Download PDFInfo
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Abstract
本发明提供了一种mRNA以及包含mRNA的组合物,其中,所述的mRNA包含编码2019‑nCoV型冠状病毒的至少一个抗原肽或蛋白或其片段、变体或衍生物的编码区的mRNA序列。本发明还提供了所述mRNA或组合物在制备预防和/或治疗2019‑nCoV型冠状病毒感染的药物(尤其是疫苗)中的应用。
Description
技术领域
本发明涉及疫苗研制技术领域,具体涉及包含编码2019-nCoV型冠状病毒的至少一个抗原肽或蛋 白或其片段、变体或衍生物的编码区的mRNA序列,本发明涉及包含一个或多个mRNA的组合物。以 及所述mRNA或组合物在制备预防和/或治疗2019-nCoV型冠状病毒感染的药物(尤其是疫苗)中的应 用。
背景技术
冠状病毒为不分节段的单股正链RNA病毒,属于巢病毒(Nidovirales)冠状病毒(Coronaviridae)正冠 状病毒亚科(Orthocoronavirinae),根据血清型和基因组特点冠状病毒亚科被分为α、β、γ和δ四个属。 迄今为止,共有7种冠状病毒可感染人类:包括α属的229E和NL63,β属的OC43和HKU1、中东呼 吸综合征相关冠状病毒(MERSr-CoV)、严重急性呼吸综合征相关冠状病毒(SARSr-CoV)和新型冠状病毒 (2019-nCoV)。其中只有后三种会导致严重的人类疾病甚至死亡。
冠状病毒有包膜,颗粒呈圆形或椭圆形,经常为多形性,直径通常为50~200nm。S蛋白位于病毒 表面形成棒状结构,作为病毒的主要抗原蛋白之一,是用于分型的主要基因。N蛋白包裹病毒基因组, 可用作诊断抗原。对冠状病毒理化特性的认识多来自对SARS-CoV和MERS-CoV的研究。基于 SARS-CoV的全长S蛋白设计的疫苗被报道会诱导大量非中和抗体,在动物模型上攻毒失败且引起等严 重的副反应,比如增加发病率,引起肝部组织强烈炎症反应及肝损伤(“Evaluation of modified vaccinia virus ankara basedrecombinant SARS vaccine in ferrets”,Vaccine 23,2273-2279.)。因此,在疫苗设计中避免暴露能具有免疫优势的非中和表位是保障疫苗安全性的基础。
SARS-CoV和MERS-CoV的RBD都由两部分组成:一个高度相似的核心结构和一段差异极大的受 体结合基序(RBM)。RBM的不同使得SARS-CoV和MERS-CoV分别识别不同的受体:SARS-CoV 识别血管紧张素转化酶2(ACE2),而MERS-CoV识别二肽基肽酶4(DPP4)。
目前SARS-CoV和MERS-CoV疫苗研发所涉及到的疫苗平台有:病毒载体疫苗、DNA疫苗、亚 单位疫苗、类病毒颗粒(VLP)疫苗、全病毒灭活疫苗和减毒疫苗。
虽然全病毒灭活疫苗理论上可以快速生产应对2019-nCoV疫情的爆发,但是一方面病毒的培养需 要生物安全三级实验室,疫苗企业一般很难满足其生产要求;另一方面安全性可能也存在问题,研发中 的SARS-CoV和MERS-CoV的全病毒灭活疫苗均有报道在小鼠模型上攻毒后会在肺部发现过敏型病理 现象(“Immunization with inactivated middleeast respiratory syndrome coronavirus vaccine leads to lung immunopathologyon challenge with live virus”,Hum.Vaccin.Immunother.12,2351-2356.),因此全病毒灭活疫苗的形式并不是研发用于2019-nCoV疫苗的最佳选择。
目前受2019-nCoV感染的患者的年龄绝大部分超过25岁,18岁以下的患者较少,而减毒活苗平台 制备得到的疫苗不适合老年人及免疫力低下个体,因此不适合用于2019-nCoV疫苗的研发。
DNA疫苗和病毒载体疫苗都是将DNA递送至疫苗接种者的细胞内表达,虽然诸如基于腺病毒载 体的疫苗目前并没有整合重组进基因组的报导,但是也不能完全排除此种可能,仍有一定安全风险。亚 单位疫苗和VLP疫苗则是需要建立优化表达、纯化方法,并且一般需要选择搭配适合的佐剂,需要的 研究时间往往以年计算,难以用于应对快速发展的疫情。
近年来RNA分子领域相关技术突破性进展,mRNA疫苗在流感病毒、埃博拉病毒和寨卡病毒等多 种传染病上取得了一定的研究成果,mRNA疫苗将mRNA传递至细胞,表达产生蛋白,从而使机体获 得免疫保护。与传统的重组蛋白疫苗、灭活疫苗和减毒疫苗相比,mRNA疫苗制备步骤简单,对于传 染性疾病的控制有着重大意义。此外,mRNA疫苗比传统重组疫苗更耐高温也更加稳定。同时,mRNA 疫苗能够引起强烈的CD4+或CD8+的T细胞应答,与DNA免疫接种不同,在动物体内mRNA疫苗通 过一两次低剂量接种就能够产生抗体。
因此,本发明提供了一种安全可靠的mRNA疫苗,避免了其他疫苗平台的缺陷。
发明内容
本发明的第一方面,提供了一种mRNA,所述的mRNA包含至少一种编码2019-nCoV型冠状病毒 的至少一个抗原肽或蛋白或其片段、变体或衍生物的编码区的mRNA序列。其中,所述的抗原肽或蛋 白或其片段、变体或衍生物能够在人体中诱发免疫反应,产生中和抗体。
优选的,所述的mRNA包含编码2019-nCoV型冠状病毒S蛋白的mRNA序列。进一步优选的, 所述的mRNA包含编码2019-nCoV型冠状病毒的RBD的mRNA序列。
在本发明的一个具体实施方式中,所述的RBD的氨基酸序列中包含单个位点氨基酸突变并引入N- 连接糖基化。优选的,所述的突变位点为第190位的脯氨酸突变为天冬氨酸。
优选的,所述的mRNA包含编码2019-nCoV型冠状病毒的RBM的mRNA序列。
优选的,所述的mRNA包含编码dS蛋白的mRNA序列。进一步优选的,所述的mRNA包含编码 dS蛋白与RBD或RBM的融合蛋白的mRNA序列。
优选的,所述的mRNA包含编码M蛋白和/或E蛋白的mRNA序列。
进一步优选的,所述的mRNA编码的抗原肽或蛋白或其片段、变体或衍生物选自下列任一种:
A)信号肽和2019-nCoV型冠状病毒的RBD,其中,所述的2019-nCoV型冠状病毒的RBD不包含 信号肽区域;RBD中包含了主要的中和表位,非中和表位相对较少,安全性高。
B)信号肽和氨基酸突变引入N-连接糖基化的2019-nCoV型冠状病毒的RBD,其中,所述的 2019-nCoV型冠状病毒的RBD不包含信号肽区域;为避免脱离全长S蛋白暴露出原本埋在全长S蛋白 中的氨基酸序列,出现免疫优势的非中和表位,则通过氨基酸突变引入N-连接糖基化,以遮蔽非中和 表位,并提高免疫原性。同时,现有技术中公开的部分内容也支持了本发明的技术方案,例如通过对 2019-nCoV的RBD的序列分析,以及对其结构的模拟预测,认为2019-nCoV的S蛋白维持了SARS-CoV 的S蛋白和ACE2相互作用的结构构象。通过比对MERS-CoV的RBD的不同片段,确定蛋白片段377-588 为关键中和域,即可以在小鼠和兔子模型中引起最高的中和抗体滴度;而且此关键中和域仍可以和受体 hDPP4结合,证明其保持了结构构象,不止可以提供线性表位,也可以提供结构表位(见Cuiqing,M等 (2014),Searching for an ideal vaccine candidate among different MERS coronavirusreceptor-binding fragments--the importance of immunofocusing in subunitvaccine design,Vaccine.32(46):6170-6176.)。
C)2019-nCoV型冠状病毒的S蛋白;优选的,还包括2019-nCoV型冠状病毒的M蛋白和/或E蛋 白;具体的为(1)2019-nCoV型冠状病毒的S蛋白和M蛋白的组合;(2)2019-nCoV型冠状病毒的 S蛋白和E蛋白的组合;或(3)2019-nCoV型冠状病毒的S蛋白、M蛋白和E蛋白的组合。其中,在 本发明的一个具体实施方式中,S蛋白、M蛋白与E蛋白的mRNA摩尔比为1:1:1。
同时,现有技术中也有类似的做法支持本技术方案,例如利用杆状病毒表达系统在昆虫细胞内同时 表达MERS-CoV的S、M、E三个结构蛋白,表达出的蛋白会自动形成与冠状病毒这种包膜病毒类似的 约100nm直径的类病毒颗粒(见Wang.C等(2017),MERS-CoVvirus-like particles produced in insect cells induce specific humoural andcellular imminity in rhesus macaques,Oncotarget.8(8):12686-12694.)。然而, 利用此种方法制备的MERS-CoV病毒样颗粒虽然有很好的表现,但是无法纯化,且无法做到性质均一, 不具备疫苗生产的可行性;而如果通过mRNA疫苗来实现对三种抗原的同时表达,则可以完全避开杆 状病毒表达系统的缺陷。
D)信号肽、dS蛋白以及dS蛋白与RBD的融合蛋白的组合,其中,所述的RBD不包含信号肽区 域。其中,在本发明的一个具体实施方式中,dS蛋白与包含信号肽的2019-nCoVRBD-dS融合蛋白的 mRNA的摩尔比为1:1。
同时,现有技术中也有类似的做法支持本技术方案,例如已有研究在酵母中共表达dS和dS融合 蛋白,可形成直径约20nm的类包膜病毒颗粒(见Wetzel.C等(2018),Establishment of a yeast-based VLP platform for antigen presentation,MicrobCell Fact.5;17(1):17.)。然而,利用此方法制备的病毒颗粒无法 纯化,一致性难以保证,但是本发明技术方案采用mRNA疫苗的形式,有效避免了这种情况的发生。
或E)信号肽、dS蛋白以及dS蛋白与RBM的融合蛋白的组合,其中,所述的RBM不包含信号 肽区域。其中,在本发明的一个具体实施方式中,dS蛋白与包含信号肽的2019-nCoVRBM-dS融合蛋 白的mRNA的摩尔比为1:1。
更进一步优选的,所述的mRNA编码的信号肽为编码一个人类细胞可识别分泌信号肽,如组织型 纤溶酶原激活剂(tPA)的信号肽或者血清免疫球蛋白E(lgE)的信号肽等。进一步优选为tPA。
所述的RBD第190位氨基酸为在全长S蛋白中不易接触的位点,但在RBD结构中确实一个突出 的位点,极易接触,将该位点的脯氨酸突变为天冬氨酸,可以引入N-连接糖基化基序:天冬氨酸-非脯 氨酸-苏氨酸。最为优选的,所述B)中突变位点为第190位的脯氨酸突变为天冬氨酸。
在本发明的一个具体实施方式中,所述的B)中氨基酸突变引入N-连接糖基化的2019-nCoV型冠 状病毒的RBD的氨基酸序列如SEQ ID NO:1或与SEQ ID NO:1具有70%、75%、80%、85%、90%、 95%、99%同一性的氨基酸序列。
更进一步优选的,所述的编码C)中S蛋白、M蛋白两种蛋白的mRNA可以有以下几种形式:I) 两条mRNA,一条编码S蛋白,一条编码M蛋白;II)一条mRNA,有两个编码区分别编码S蛋白和 M蛋白。
更进一步优选的,所述的编码C)中S蛋白、E蛋白两种蛋白的mRNA可以有以下几种形式:i) 两条mRNA,一条编码S蛋白,一条编码E蛋白;ii)一条mRNA,有两个编码区分别编码S蛋白和E 蛋白。
更进一步优选的,所述的编码C)中S蛋白、M蛋白和E蛋白三种蛋白的mRNA可以有以下几种 形式:a)三条mRNA,分别编码S蛋白、M蛋白及E蛋白;b)两条mRNA,一条编码S蛋白,第二 条有两个编码区,分别编码M蛋白和E蛋白;c)一条mRNA,有三个编码区分别编码S蛋白,M蛋 白和E蛋白。
在本发明的一个具体实施方式中,所述的dS蛋白的氨基酸序列如SEQ ID NO:2或与SEQ ID NO: 2具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
更进一步优选的,所述的编码D)中信号肽、dS蛋白以及dS蛋白与RBD的融合蛋白的mRNA可 以有以下几种形式:(1)两条mRNA,一条编码dS蛋白,另一条编码信号肽和dS蛋白与RBD的融 合蛋白;(2)一条mRNA,有两个编码区分别编码dS蛋白、信号肽和dS蛋白与RBD的融合蛋白。
在本发明的一个具体实施方式中,所述的dS蛋白与RBD的融合蛋白的氨基酸序列如SEQ ID NO: 3或与SEQ ID NO:3具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
更进一步优选的,所述的编码E)中信号肽、dS蛋白以及dS蛋白与RBM的融合蛋白的mRNA可 以有以下几种形式:1)两条mRNA,一条编码dS蛋白,另一条编码信号肽和dS蛋白与RBM的融合 蛋白;2)一条mRNA,有两个编码区分别编码dS蛋白、信号肽和dS蛋白与RBM的融合蛋白。
在本发明的一个具体实施方式中,所述的dS蛋白与RBM的融合蛋白的氨基酸序列如SEQ ID NO:4或与SEQ ID NO:4具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
在本发明的一个具体实施方式中,所述的S蛋白的氨基酸序列如SEQ ID NO:5或与SEQ ID NO: 5具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
在本发明的一个具体实施方式中,所述的M蛋白的氨基酸序列如SEQ ID NO:6或与SEQ ID NO: 6具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
在本发明的一个具体实施方式中,所述的E蛋白的氨基酸序列如SEQ ID NO:7或与SEQ ID NO: 7具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
优选的,所述的mRNA为单顺反子、双顺反子或多顺反子mRNA。所述的双顺反子或多顺反子 mRNA即含有两个及以上编码区的mRNA。
在本发明的一个具体实施方式中,所述的双顺反子或多顺反子mRNA的编码区可通过至少一种内 部核糖体进入位点(IRES)序列分开,可使用的IRES序列包括但不限于:小RNA病毒(例如FMDV)、 瘟病毒(例如CFFV)、脊髓灰质炎病毒(例如PV)、脑心肌炎病毒(例如ECMV)、口蹄疫病毒(例如FMDV)、 丙肝病毒(例如HCV)、古典猪瘟病毒(例如CSFV)、小鼠角膜白斑病毒(例如MLV)、猿免疫缺陷病毒(例 如SIV)或蟋蟀麻痹病毒(例如CrPV)。
优选的,所述的mRNA由若干个结构元件组成,即所述的mRNA除包含上述编码区外还包括5’ 帽子结构,5’非编码区,3’非编码区和/或多聚腺苷酸尾的mRNA序列。
优选的,所述的mRNA序列的长度为200-10000个核苷酸。进一步优选的,所述的mRNA序列的 长度为500-8000个核苷酸。
本发明的第二方面,提供了一种包含mRNA的组合物,所述的mRNA包含编码2019-nCoV型冠状 病毒的至少一个抗原肽或蛋白或其片段、变体或衍生物的编码区的mRNA序列。
优选的,所述抗原肽或蛋白或其片段、变体或衍生物选自下列任一种:
A)信号肽和2019-nCoV型冠状病毒的RBD,其中,所述的2019-nCoV型冠状病毒的RBD不包含 信号肽区域;RBD中包含了主要的中和表位,非中和表位相对较少,安全性高。
B)信号肽和氨基酸突变引入N-连接糖基化的2019-nCoV型冠状病毒的RBD,其中,所述的 2019-nCoV型冠状病毒的RBD不包含信号肽区域;为避免脱离全长S蛋白暴露出原本埋在全长S蛋白 中的氨基酸序列,出现免疫优势的非中和表位,则通过氨基酸突变引入N-连接糖基化,以遮蔽非中和 表位,并提高免疫原性。
C)2019-nCoV型冠状病毒的S蛋白;优选的,还包括2019-nCoV型冠状病毒的M蛋白和/或E蛋 白;具体的为(1)2019-nCoV型冠状病毒的S蛋白和M蛋白的组合;(2)2019-nCoV型冠状病毒的 S蛋白和E蛋白的组合;(3)2019-nCoV型冠状病毒的S蛋白、M蛋白和E蛋白的组合;
D)信号肽、dS蛋白以及dS蛋白与RBD的融合蛋白的组合,其中,所述的RBD不包含信号肽区 域;或
E)信号肽、dS蛋白以及dS蛋白与RBM的融合蛋白的组合,其中,所述的RBM不包含信号肽区 域。
优选的,所述的mRNA编码的信号肽为编码一个人类细胞可识别分泌信号肽,如组织型纤溶酶原 激活剂(tPA)的信号肽或者血清免疫球蛋白E(lgE)的信号肽等。进一步优选为tPA。
所述的RBD第190位氨基酸为在全长S蛋白中不易接触的位点,但在RBD结构中确实一个突出 的位点,极易接触,将该位点的脯氨酸突变为天冬氨酸,可以引入N-连接糖基化基序:天冬氨酸-非脯 氨酸-苏氨酸。
优选的,所述B)中突变位点为第190位的脯氨酸突变为天冬氨酸。进一步优选的,所述的B)中 氨基酸突变引入N-连接糖基化的2019-nCoV型冠状病毒的RBD的氨基酸序列如SEQ ID NO:1或与 SEQ ID NO:1具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
更进一步优选的,所述的编码C)中S蛋白、M蛋白两种蛋白的mRNA可以有以下几种形式:I) 两条mRNA,一条编码S蛋白,一条编码M蛋白;II)一条mRNA,有两个编码区分别编码S蛋白和 M蛋白。
更进一步优选的,所述的编码C)中S蛋白、E蛋白两种蛋白的mRNA可以有以下几种形式:i) 两条mRNA,一条编码S蛋白,一条编码E蛋白;ii)一条mRNA,有两个编码区分别编码S蛋白和E 蛋白。
更进一步优选的,所述的编码C)中S蛋白、M蛋白和E蛋白三种蛋白的mRNA可以有以下几种 形式:a)三条mRNA,分别编码S蛋白、M蛋白及E蛋白;b)两条mRNA,一条编码S蛋白,第二 条有两个编码区,分别编码M蛋白和E蛋白;c)一条mRNA,有三个编码区分别编码S蛋白,M蛋 白和E蛋白。
进一步优选的,所述的dS蛋白的氨基酸序列如SEQ ID NO:2或与SEQ ID NO:2具有70%、75%、 80%、85%、90%、95%、99%同一性的氨基酸序列。
更进一步优选的,所述的编码D)中信号肽、dS蛋白以及dS蛋白与RBD的融合蛋白的mRNA可 以有以下几种形式:(1)两条mRNA,一条编码dS蛋白,另一条编码信号肽和dS蛋白与RBD的融 合蛋白;(2)一条mRNA,有两个编码区分别编码dS蛋白、信号肽和dS蛋白与RBD的融合蛋白。
进一步优选的,所述的dS蛋白与RBD的融合蛋白的氨基酸序列如SEQ ID NO:3或与SEQ ID NO: 3具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
更进一步优选的,所述的编码E)中信号肽、dS蛋白以及dS蛋白与RBM的融合蛋白的mRNA可 以有以下几种形式:1)两条mRNA,一条编码dS蛋白,另一条编码信号肽和dS蛋白与RBM的融合 蛋白;2)一条mRNA,有两个编码区分别编码dS蛋白、信号肽和dS蛋白与RBM的融合蛋白。
进一步优选的,所述的dS蛋白与RBM的融合蛋白的氨基酸序列如SEQ ID NO:4或与SEQ ID NO: 4具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
进一步优选的,所述的S蛋白的氨基酸序列如SEQ ID NO:5或与SEQ ID NO:5具有70%、75%、 80%、85%、90%、95%、99%同一性的氨基酸序列。
进一步优选的,所述的M蛋白的氨基酸序列如SEQ ID NO:6或与SEQ ID NO:6具有70%、75%、 80%、85%、90%、95%、99%同一性的氨基酸序列。
进一步优选的,所述的E蛋白的氨基酸序列如SEQ ID NO:7或与SEQ ID NO:7具有70%、75%、 80%、85%、90%、95%、99%同一性的氨基酸序列。
优选的,所述的mRNA为单顺反子、双顺反子或多顺反子mRNA。所述的双顺反子或多顺反子 mRNA即含有两个及以上编码区的mRNA。
在本发明的一个具体实施方式中,所述的双顺反子或多顺反子mRNA的编码区可通过至少一种内 部核糖体进入位点(IRES)序列分开,可使用的IRES序列包括但不限于:小RNA病毒(例如FMDV)、 瘟病毒(例如CFFV)、脊髓灰质炎病毒(例如PV)、脑心肌炎病毒(例如ECMV)、口蹄疫病毒(例如FMDV)、 丙肝病毒(例如HCV)、古典猪瘟病毒(例如CSFV)、小鼠角膜白斑病毒(例如MLV)、猿免疫缺陷病毒(例 如SIV)或蟋蟀麻痹病毒(例如CrPV)。
优选的,所述的mRNA由若干个结构元件组成,即所述的mRNA除包含上述编码区外还包括5’ 帽子结构,5’非编码区,3’非编码区和/或多聚腺苷酸尾的mRNA序列。
优选的,所述的mRNA序列的长度为200-10000个核苷酸。进一步优选的,所述的mRNA序列的 长度为500-8000个核苷酸。
优选的,所述的组合物中还包括阳离子或聚阳离子化合物。其中所述的阳离子或聚阳离子化合物游 离或者与mRNA结合。为了使得所述组合物更稳定选择阳离子或聚阳离子化合物与所述mRNA结合的 形式。
优选的,所述的组合物中还包含脂质。
优选的,所述的脂质包括但不限于能够促进自组装形成病毒大小的颗粒(~100nm)的脂质、使得 mRNA从内涵体中释放到胞内的脂质、支撑磷脂双分子层结构的脂质或用作稳定剂的脂质。
更优选的,为了增加LNP的半衰期,所述的脂质还可以包含PEG化脂质。
在本发明的一个具体实施方式中,所述的脂质包含阳离子脂质、PEG化脂质、胆固醇和/或磷脂。
本发明所述的mRNA或组合物还可以包含药学上可接受的赋形剂。所述药学上可接受的赋形剂可 以是载体、稀释剂、佐剂或编码佐剂核苷酸序列、增溶剂、粘合剂、润滑剂、助悬剂、转染促进剂等。 所述转染促进剂包括但不限于表面活性剂如免疫刺激复合物、费氏(Freunds)不完全佐剂、LPS类似物(例 如单磷酰酯A)、胞壁肽、苯醌类似物、角鲨烯、透明质酸、脂质、脂质、钙离子、病毒蛋白质、阳离 子、聚阳离子(例如聚-L-谷氨酸(LGS))或纳米粒子或其他已知的转染促进剂。所述的编码佐剂的核苷酸 序列为编码如下至少一种佐剂的核苷酸序列:GM-CSF、IL-17、IFNg、IL-15、IL-21、抗PD1/2、乳铁 蛋白、鱼精蛋白、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12、INF-α、INF- γ、Lymphotoxin-α、hGH、MCP-1、MIP-1a、MIP-1p、IL-8、RANTES、L-选择蛋白、P-选择蛋白、 E-选择蛋白、CD34、GlyCAM-1、MadCAM-1、LFA-1、VLA-1、Mac-1、pl50.95、PECAM、ICAM-1、 ICAM-2、ICAM-3、CD2、LFA-3、M-CSF、、CD40、CD40L、血管生长因子、成纤维细胞生长因子、 神经生长因子、血管内皮生长因子、Apo-1、p55、WSL-1、DR3、TRAMP、Apo-3、AIR、LARD、NGRF、 DR4、DR5、KILLER、TRAIL-R2、TRICK2、DR6、半胱天冬酶ICE、Fos、c-jun、Sp-1、Ap-1、Ap-2、 p38、p65Rel、MyD88、IRAK、TRAF6、IkB、无活性的NIK、SAP K、SAP-1、JNK、NFkB、Bax、TRAIL、 TRAILrec、TRAILrecDRC5、TRAIL-R3、TRAIL-R4、RANK、RANK LIGAND、Ox40、Ox40LIGAND、 NKG2D、MICA、MICB、NKG2A、NKG2B、NKG2C、NKG2E、NKG2F、TAP1、TAP2以及其功能 性片段。
本发明所述的组合物可以为脂质、脂质复合物或脂质纳米粒子。所述的脂质可以为以下形式制备得 到的脂质:1,2-二油烯基氧基-N,N-二甲基氨基丙烷(DODMA)脂质、1,2-二亚油基氧基-3-二甲基氨 基丙烷(DLin-DMA)、2,2-二亚油基-4-(2-二甲基氨基乙基)-[1,3]-二氧杂环戊烷(DLin-KC2-DMA)脂质。 所述脂质复合物或脂质纳米粒子可以由选自以下的脂质形成:DLin-DMA、DLin-K-DMA、98N12-5、 C12-200、DLin-MC3-DMA、DLin-KC2-DMA、DODMA、PLGA、PEG、PEG-DMG、聚乙二醇化脂质 和氨基醇脂质。
本发明的第三方面,提供了一种本发明所述的mRNA或组合物编码的蛋白。
本发明的第四方面,提供了一种氨基酸突变引入N-连接糖基化的2019-nCoV型冠状病毒的RBD 的蛋白。优选的,所述的2019-nCoV型冠状病毒的RBD不包含信号肽区域。
本发明的第五方面,提供了一种2019-nCoV型冠状病毒的S蛋白、M蛋白或E蛋白中的两种或三 种蛋白的融合蛋白。
本发明的第六方面,提供了一种dS蛋白与RBD或RBM的融合蛋白。优选的,所述的RBD和RBM 不包含信号肽区域。
本发明的第七方面,提供了一种编码第三至六方面所述蛋白或融合蛋白的核酸。优选的,所述的核 酸的序列为所述蛋白或融合蛋白的表位抗原基因的核苷酸序列。
本发明的第八方面,提供了一种包含本发明第七方面所述核酸的载体。
本发明的第九方面,提供了一种包含本发明所述的mRNA、所述的蛋白或融合蛋白、所述的核酸 和/或所述的载体的细胞。
本发明的第十方面,提供了一种包含mRNA的组合物的制备方法,包括将mRNA与阳离子或聚阳 离子化合物混合后用脂质包装。
优选的,所述的脂质包括但不限于能够促进自组装形成病毒大小的颗粒(~100nm)的脂质、使得 mRNA从内涵体中释放到胞内的脂质、支撑磷脂双分子层结构的脂质或用作稳定剂的脂质。更优选的, 为了增加LNP的半衰期,所述的脂质还可以包含PEG化脂质。
在本发明的一个具体实施方式中,所述的脂质包含阳离子脂质、PEG化脂质、胆固醇和/或磷脂。
本发明的第十一方面,提供了所述mRNA或包含mRNA的组合物在预防和/或治疗2019-nCoV型 冠状病毒感染中的应用。
本发明的第十二方面,提供了所述mRNA或包含mRNA的组合物在制备预防和/或治疗2019-nCoV 型冠状病毒感染的药物中的应用。
优选的,所述的预防包括将本发明所述的mRNA或包含mRNA的组合物用作疫苗。
优选的,所述的治疗包括筛选与本发明所述的mRNA或包含mRNA的组合物结合的抗体,并将其 用于治疗。
本发明的第十三方面,提供了一种预防2019-nCoV型冠状病毒感染的方法,包括向未感染 2019-nCoV型冠状病毒的个体施加有效量的本发明所述的mRNA或包含mRNA的组合物。
本发明的第十四方面,提供了一种治疗2019-nCoV型冠状病毒感染的方法,包括向感染2019-nCoV 型冠状病毒的个体施加有效量的本发明所述的mRNA或包含mRNA的组合物。以使得个体体内产生中 和抗体抵制2019-nCoV型冠状病毒。
本发明的第十五方面,提供了一种抗体筛选的方法,包括向个体施加有效量的本发明所述的mRNA 或包含mRNA的组合物的步骤。
其中,所述的抗体筛选的方法不是治疗方法。该方法用来筛选中和抗体,对抗体的药效进行检测和 比较,以确定哪些抗体可以作为药物,哪些不能作为药物,或者,比较不同药物的药效敏感程度,即治 疗效果不是必然的,只是一种可能性。
本发明的第十六方面,提供了一种诱导个体中和抗原特异性免疫应答的方法,包括向个体施加本发 明所述的mRNA或包含mRNA的组合物。
优选的,所述的抗原特异性免疫应答包括T细胞应答和/或B细胞应答。
本发明所述的mRNA或包含mRNA的组合物具备的优势在于:1、体外合成,无需细胞培养,无 动物源污染的风险;2、研发、生产较快,标准化生产,易于量产和质量控制,同一生产流程适用于多 个不同产品;3、可以在一段时间内持续表达,延长抗原暴露时间从而提高免疫反应的强度和质量;4、 模拟天然感染的过程,在人体细胞内被翻译、修饰,可以被MHCI类分子呈递,诱发更强的细胞免疫; 5、支持多种蛋白形式,包括胞内蛋白、跨膜蛋白、VLP等,且可避开VLP产量低而造成的纯化问题; 6、具有自佐剂效应,无需进行佐剂筛选;7、无感染、基因组整合风险;8、无预存免疫,可多次免疫。
本发明所述的“S蛋白”为组成2019-nCoV型冠状病毒的结构蛋白,名称为纤突蛋白。
本发明所述的“RBD”为组成2019-nCoV型冠状病毒的结构蛋白,名称为纤突蛋白受体结合域。 所述的RBD包含核心结构和纤突蛋白受体结合基序,所述的纤突蛋白受体结合基序即为本发明所述的 “RBM”。
本发明所述的“M蛋白”为组成2019-nCoV型冠状病毒的结构蛋白,名称为包膜蛋白。
本发明所述的“E蛋白”为组成2019-nCoV型冠状病毒的结构蛋白,名称为小包膜蛋白。
本发明所述的“dS蛋白”为鸭乙肝病毒小表面蛋白。
本发明所述的“LNP”为脂质纳米颗粒。
本发明所述的“同一性”是指在使用氨基酸序列或核苷酸序列的方面,本领域技术人员可以根据实 际工作需要对序列进行调整,使使用序列与现有技术获得的序列相比,具有(包括但不限于)1%,2%, 3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%, 20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%, 36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%, 52%,53%,54%,55%,56%,57%,58%,59%,60%,70%,80%,81%,82%,83%,84%,85%, 86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,99.1%,99.2%, 99.3%,99.4%,99.5%,99.6%,99.7%,99.8%,99.9%的相似度,且依然具有与原氨基酸序列或核苷 酸序列相同的功能。
本发明所述的“个体”包括哺乳动物和人。所述的哺乳动物包括但不限于啮齿类动物(例如小鼠、 大鼠)、猴子、斑马鱼、猪、鸡、兔子等等。
本发明所述的“预防”指在疾病开始发展之前或之后通过施用本发明所述的产品来避免症状或者延 缓特定症状紧张的所有行为。
本发明所述的“治疗”指在疾病已开始发展后改善疾病或病理状态的体征、症状等等的治疗干预。
本发明所述的“有效量”是指在以单个或多个剂量给予至患者或器官之后提供所希望的治疗或预防 的本发明所述产品的量或剂量。
附图说明
以下,结合附图来详细说明本发明的实施例,其中:
图1:通过RaptorX的蛋白结构预测分别对2019-nCoV的RBD部分和S全长蛋白进行模拟,图中 显示预测的蛋白结构中氨基酸的目标突变突变位置。
图2:含有T7启动子,5’UTR,3’UTR,和polyA尾的基础质粒模板序列图。
图3:编码含tPA信号肽的野生型2019-nCoV的RBD的序列测序结果。
图4:编码含tPA信号肽的190位突变的2019-nCoV的RBD的序列测序结果。
图5:编码野生型2019-nCoV M蛋白的序列测序结果。
图6:编码野生型2019-nCoV E蛋白的序列测序结果。
图7:图7A和图7B的拼接为编码野生型2019-nCoV S蛋白的序列测序结果。
图8:编码含tPA信号肽的2019-nCoV RBD-dS融合蛋白的序列测序结果。
图9:编码含tPA信号肽的2019-nCoV RBM-dS融合蛋白的序列测序结果。
图10:编码dS蛋白的序列测序结果。
图11:用含有与基础质粒模板同源的引物对实施例制备的mRNA进行PCR扩增的结果图,其中, RBD-M为编码190位突变引入N-连接糖基化后的mRNA,S-F为编码全长S蛋白的mRNA。
图12:用甲醛变性胶检测加帽纯化后的mRNA,M为Marker,其中1为编码含tPA信号肽的 2019-nCoV RBD-dS融合蛋白的mRNA,2为编码含tPA信号肽的2019-nCoV RBM-dS融合蛋白的 mRNA,3为编码野生型2019-nCoV S蛋白的mRNA,4为编码野生型2019-nCoV M蛋白的mRNA,5 为编码野生型2019-nCoV E蛋白的mRNA,6为编码含tPA信号肽的190位突变的2019-nCoV的RBD 的mRNA,7为编码含tPA信号肽的野生型2019-nCoV的RBD的mRNA,8为编码dS蛋白的mRNA。
图13:WB(Western Blot,蛋白质印迹法)表达检测结果,其中,M为Marker,1为编码含tPA 信号肽的野生型2019-nCoV的RBD的mRNA的表达上清,2为编码含tPA信号肽的190位突变并引入 N-连接糖基化的2019-nCoV的RBD的mRNA的表达上清,3为阴性对照。
图14:抗S蛋白多抗免疫荧光检测S蛋白表达的结果。
图15:DLS(Dynamic Light Scattering,动态光散射)检测mRNA-LNP的粒径和粒径分布(用聚 合物分散性指数PDI(Polymer dispersity index)标征),其中,A为编码野生型2019-nCOV S蛋白的 mRNA-LNP,B为编码含tPA信号肽的野生型2019-nCOV的RBD的mRNA-LNP,C为编码含tPA信 号肽的190位突变并引入N-连接糖基化的2019-nCOV的RBD的mRNA-LNP。
图16:一免、二免后的S蛋白特异性抗体滴度,其中,Negative为阴性对照,S-F为编码野生型 2019-nCOV S蛋白的mRNA-LNP,RBD为编码含tPA信号肽的野生型2019-nCOV的RBD的 mRNA-LNP,RBD-M编码含tPA信号肽的190位突变并引入N-连接糖基化的2019-nCOV的RBD的mRNA-LNP。
图17:ELISpot(酶联免疫斑点法)检测干扰素γ的结果,其中,Negative为阴性对照,S-F为编 码野生型2019-nCOV S蛋白的mRNA-LNP,RBD为编码含tPA信号肽的野生型2019-nCOV的RBD的 mRNA-LNP,RBD-M编码含tPA信号肽的190位突变并引入N-连接糖基化的2019-nCOV的RBD的 mRNA-LNP,纵坐标为每百万脾细胞的点形成单位(spot forming unit,SFU)。
图18:二免后中和抗体滴度,其中,S-F为编码野生型2019-nCOV S蛋白的mRNA-LNP,RBD为 编码含tPA信号肽的野生型2019-nCOV的RBD的mRNA-LNP,RBD-M编码含tPA信号肽的190位突 变并引入N-连接糖基化的2019-nCOV的RBD的mRNA-LNP,sVNT代表替代性病毒中和试验。
图19:对细胞上清进行WB检测,其中1为阴性对照,2为VLP-1的表达上清,3为VLP-2的表 达上清,4为编码野生型2019-nCoV S蛋白的mRNA的表达上清。
图20:DLS检测mRNA-LNP的粒径和粒径分布,其中,A代表VLP-1-LNP,B代表VLP-2-LNP, C代表编码野生型2019-nCOV S蛋白的mRNA-LNP。
图21:甲醛变性胶检测包装后样品的mRNA完整性,其中,M为Marker,1为VLP-1-LNP,2为 VLP-2-LNP,3为编码野生型2019-nCOV S蛋白的mRNA-LNP。
图22:一免、二免后的S蛋白特异性抗体滴度,其中,Negative为阴性对照,S-F为编码野生型 2019-nCOV S蛋白的mRNA-LNP。
图23:ELISpot检测干扰素γ的结果,其中,Negative为阴性对照,S-F为编码野生型2019-nCOV S蛋白的mRNA-LNP,纵坐标为每百万脾细胞的点形成单位(spot formingunit,SFU)。
图24:胞内CK染色法进行了交叉验证结果,其中,Negative为阴性对照,S-F为编码野生型 2019-nCOV S蛋白的mRNA-LNP。
图25:DLS检测mRNA-LNP的粒径和粒径分布,其中,左图代表VLP-3-LNP,中图代表VLP-4-LNP, 右图代表编码野生型2019-nCOV S蛋白的mRNA-LNP。
图26:一免、二免后的S蛋白特异性抗体滴度,其中,Negative为阴性对照,S-F为编码野生型 2019-nCOV S蛋白的mRNA-LNP。
图27:ELISpot检测干扰素γ的结果,其中,Negative为阴性对照,S-F为编码野生型2019-nCOV S蛋白的mRNA-LNP,纵坐标为每百万脾细胞的点形成单位(spot formingunit,SFU)。
图28:胞内CK染色法进行了交叉验证结果,其中,Negative为阴性对照,S-F为编码野生型 2019-nCOV S蛋白的mRNA-LNP。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然, 所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员 在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1mRNA的制备与检测
1、人工合成抗原设计的基因序列。
2、通过固相亚磷酰胺三酯法合成短核苷酸链(引物)。
3、引物互为模板进行PCR扩增。
4、将步骤3扩增的产物连接到pUC57载体上,转化测序。
5、经测序验证,序列与预期一致,结果见图3-10所示。具体的,图3显示了编码含tPA信号肽的 野生型2019-nCoV的RBD的序列测序结果,其核苷酸序列如SEQ ID NO:9所示,氨基酸序列如SEQ ID NO:17所示。图4显示编码含tPA信号肽的190位突变的2019-nCoV的RBD(位置参见图1)的 序列测序结果,其核苷酸序列如SEQ ID NO:10所示,氨基酸序列如SEQ ID NO:18所示。图5显示 编码野生型2019-nCoV M蛋白的序列测序结果,其核苷酸序列如SEQ ID NO:11所示,其氨基酸序列 如SEQ ID NO:6所示。图6显示编码野生型2019-nCoVE蛋白的序列测序结果,其核苷酸序列如SEQ ID NO:12所示,其氨基酸序列如SEQ ID NO:7所示。图7显示编码野生型2019-nCoV S蛋白的序列 测序结果,其核苷酸序列如SEQ ID NO:13所示,其氨基酸序列如SEQ ID NO:5所示。图8显示编 码含tPA信号肽的2019-nCoV RBD-dS融合蛋白的序列测序结果,其核苷酸序列如SEQ ID NO:14所 示,且不含信号肽的RBD-dS融合蛋白的氨基酸序列如SEQ ID NO:3所示。图9显示编码含tPA信号 肽的2019-nCoV RBM-dS融合蛋白的序列测序结果,其核苷酸序列如SEQ ID NO:15所示,且其不含 信号肽的2019-nCoV RBM-dS融合蛋白的氨基酸序列如SEQ ID NO:4所示。图10显示编码dS蛋白的 序列测序结果,其氨基酸序列如SEQ ID NO:2所示,其核苷酸序列如SEQ ID NO:16所示。
6、准备含有T7启动子,5’UTR,3’UTR,和polyA尾的基础质粒模板,序列如图2(SEQID NO: 8)所示。
7、用含有与基础质粒模板同源的引物进行PCR,结果如图11所示。
基础质粒模板用限制性核酸内切酶BsmBI线性化。将PCR产物分别通过同源重组的方式分别连到 基础质粒模板上,分别转化到Xl1-Blue菌株中,并进行测序确认序列正确,转录模板构建成功。用摇 瓶发酵菌株,用无内毒素质粒大提试剂盒纯化获得转录模板。
将转录模板用限制性核酸内切酶BbsI线性化。用T7体外转录试剂盒进行转录,获得SEQ ID NO: 9-16转录的未加帽的mRNA。分别用DNaseI消化转录模板,并用沉淀法纯化mRNA。用Cap1加帽试 剂盒给mRNA加帽,并分别用mRNA纯化试剂盒对加帽后的mRNA进行纯化。将纯化后的mRNA溶 解于酸性柠檬酸钠缓冲液中,待用。
用甲醛变性胶检测加帽纯化后的mRNA,如图12所示,其中1为编码含tPA信号肽的2019-nCoV RBD-dS 融合蛋白的mRNA,2为编码含tPA信号肽的2019-nCoV RBM-dS融合蛋白的mRNA,3为编码野生型 2019-nCoV S蛋白的mRNA,4为编码野生型2019-nCoV M蛋白的mRNA,5为编码野生型2019-nCoV E蛋白的mRNA,6为编码含tPA信号肽的190位突变的2019-nCoV的RBD的mRNA,7为编码含tPA 信号肽的野生型2019-nCoV的RBD的mRNA,8为编码dS蛋白的mRNA。可以看到mRNA的大小正 确且基本无降解。
实施例2mRNA疫苗的制备与免疫
1、原料准备
1)将阳离子脂质D-Lin-MC3-DMA、二硬脂酰基磷脂酰胆碱DSPC、胆固醇、PEG化脂质PEG-DMG 四个组分按摩尔比50:10:38.5:1.5在乙醇中溶解、混合。
2)实施例1制备的编码含tPA信号肽的野生型2019-nCoV的RBD的mRNA,编码含tPA信号肽 的190位突变并引入N-连接糖基化的2019-nCoV的RBD的mRNA,和编码野生型2019-nCoV S蛋白 的mRNA。
2、表达检测
用24孔板铺4个孔的HEK293细胞,其中1、2、3号孔分别用lipofectamine 2000转染0.5μg加 帽纯化后的编码含tPA信号肽的野生型2019-nCoV的RBD的mRNA,编码含tPA信号肽的190位突变 并引入N-连接糖基化的2019-nCoV的RBD的mRNA,和编码野生型2019-nCoV S蛋白的mRNA,4 号孔作为阴性对照加入lipofectamine 2000转染试剂。转染24h后,取1、2、4号孔的细胞上清进行WB 检测,3、4号孔的细胞固定后用抗S蛋白多抗进行免疫荧光检测。WB检测结果如图13所示,其中1 为编码含tPA信号肽的野生型2019-nCoV的RBD的mRNA的表达上清,2为编码含tPA信号肽的190 位突变并引入N-连接糖基化的2019-nCoV的RBD的mRNA的表达上清,3为阴性对照。可以看到表 达出来的蛋白大小正确,引入糖基化的设计比野生型约大5kDa,证明糖基化位点成功引入。免疫荧光 结果如图14所示,证明野生型2019-nCoV S蛋白的mRNA可以正常表达。
3、试验步骤
以脂质混合物:mRNA流速比1:3,在Precision Nanosystems的纳米颗粒制备仪器Benchtop中分别 混合包装上述三种mRNA。将包装好的mRNA-LNP透析并超滤浓缩到DPBS中,无菌过滤后获得用于 动物实验的样品。用DLS检测mRNA-LNP的粒径和粒径分布(用聚合物分散性指数PDI标征),检 测结果如图15所示,包装后样品的粒径大小均在80nm左右,PDI均小于0.2,其中,编码野生型 2019-nCOV S蛋白的mRNA-LNP:粒径平均值78.83nm,PDI值0.028,截距(intercept)0.953,具体 见表1;编码含tPA信号肽的野生型2019-nCOV的RBD的mRNA-LNP:粒径平均值83.13nm,PDI值0.013,截距(intercept)0.978,具体见表2;编码含tPA信号肽的190位突变并引入N-连接糖基化的 2019-nCOV的RBD的mRNA-LNP:粒径平均值83.41nm,PDI值0.031,截距(intercept)0.978,具体 见表3。
表1:编码野生型2019-nCOV S蛋白的mRNA-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 82.74 | 100 | 19.35 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
表2:编码含tPA信号肽的野生型2019-nCOV的RBD的mRNA-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 86.64 | 100 | 19.17 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
表3:编码含tPA信号肽的190位突变并引入N-连接糖基化的2019-nCOV的RBD的mRNA-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 87.63 | 100 | 20.5 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
6周龄左右的BALB/c雌性小鼠随机6只一组,分为4组。分别在第0天和第28天免疫后腿肌肉 接种10ug,在第28天和第42天检测S蛋白特异性抗体滴度,在第42天杀鼠检测细胞因子,并用竞争 性ELISA法检测中和抗体滴度。
4、实验结果
一免、二免后的S蛋白特异性抗体滴度如图16所示,可以看到两种RBD设计均可以在一免时就 快速刺激出显著性高于野生型S全长蛋白设计的特异性抗体,二免后三者的特异性抗体滴度没有显著 性差异。用ELISpot检测干扰素γ的结果如图17所示,可以看到两种RBD设计引起的细胞免疫水平显 著高于野生型S全长蛋白设计,而引入糖基化的RBD设计的细胞免疫水平显著高于野生型RBD设计。 二免后中和抗体滴度如图18所示,显示在三种设计的特异性抗体滴度无显著性差异的情况下,两种RBD 设计的中和抗体水平均显著性高于野生型S全长蛋白设计,而引入糖基化的RBD设计的中和抗体水平 显著高于野生型RBD设计。说明RBD设计中包含了主要的中和表位,非中和表位相对较少,引起的 中和抗体占比高,安全性更高;而通过氨基酸突变引入N-连接糖基化的RBD设计遮蔽了暴露出来的可 能产生免疫优势的非中和表位,使得中和抗体占比更高,可在2019-nCoV型冠状病毒感染的预防上取 得更好的效果。
实施例3mRNA疫苗的制备与免疫
1、原料准备
1)将阳离子脂质D-Lin-MC3-DMA、二硬脂酰基磷脂酰胆碱DSPC、胆固醇、PEG化脂质PEG-DMG 四个组分按摩尔比50:10:38.5:1.5在乙醇中溶解、混合。
2)实施例1制备的编码野生型2019-nCoV S、E和M蛋白的mRNA。将这三种mRNA分别按摩 尔比1:1:1和质量比1:1:1进行混合,得到混合后的mRNA,简写为VLP-1和VLP-2。
2、表达检测
用24孔板铺4个孔的HEK293细胞,其中1、2、3号孔分别用lipofectamine 2000转染0.5μg VLP-1、 VLP-2和编码野生型2019-nCoV S蛋白的mRNA,4号孔作为阴性对照加入lipofectamine 2000转染试 剂。转染24h后,取细胞上清进行WB检测。WB检测结果如图19所示,其中1为阴性对照,2为VLP-1 的表达上清,3为VLP-2的表达上清,4为编码野生型2019-nCoV S蛋白的mRNA的表达上清。可以 看到2号泳道有清晰条带,3号泳道有微弱条带,1号和4号泳道无条带。证明编码野生型2019-nCoV S、 E和M三种蛋白的mRNA按一定比例混合后可以形成类病毒颗粒表达到细胞上清;而单一的编码野生 型2019-nCoV S蛋白的mRNA表达后,S蛋白会锚定在细胞膜上,不会进入细胞上清。
3、试验步骤
以脂质混合物:mRNA流速比1:3,在Precision Nanosystems的纳米颗粒制备仪器Benchtop中分别 混合包装VLP-1、VLP-2和编码野生型2019-nCoV S蛋白的mRNA。将包装好的mRNA-LNP透析并超 滤浓缩到DPBS(杜氏磷酸盐缓冲液)中,无菌过滤后获得用于动物实验的样品。用DLS检测mRNA-LNP 的粒径和粒径分布,检测结果如图20所示,包装后样品的粒径大小均在80nm左右,PDI均小于0.2。 其中,VLP-1-LNP:粒径平均值81.44nm,PDI值0.023,截距(intercept)0.978,具体见表4;VLP-2-LNP: 粒径平均值82.59nm,PDI值0.038,截距(intercept)0.977,具体见表5;编码野生型2019-nCOV S蛋 白的mRNA-LNP:粒径平均值84.77nm,PDI值0.030,截距(intercept)0.957,具体见表6。
表4:VLP-1-LNP
表5:VLP-2-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 87.01 | 100 | 20.52 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
表6:编码野生型2019-nCOV S蛋白的mRNA-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 89.19 | 100 | 21.37 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
用甲醛变性胶检测包装后样品的mRNA完整性,结果如图21所示,可见mRNA基本无降解。
6周龄左右的BALB/c雌性小鼠随机6只一组,分为4组。分别在第0天和第28天免疫后腿肌肉 接种10ug,在第28天和第42天检测S蛋白特异性抗体滴度,在第42天杀鼠检测细胞因子。
4、结果显示
一免、二免后的S蛋白特异性抗体滴度如图22所示,可以看到VLP-2没能引起高水平的特异性抗 体滴度,但VLP-1设计和S全长蛋白设计的特异性抗体滴度在一免、二免时均没有显著性差异。用 ELISpot检测干扰素γ的结果如图23所示,可以看到VLP-1设计引起的Th1类细胞免疫水平显著高于 野生型S全长蛋白设计,而此结果也用胞内CK染色法进行了交叉验证,如图24所示。证明编码野生 型2019-nCoV S、E和M蛋白的mRNA按摩尔比1:1:1混合包装后免疫可以获得不低于野生型S全长蛋 白设计的体液免疫反应和显著性高于野生型S全长蛋白设计的细胞免疫反应,可在2019-nCoV型冠状 病毒感染的预防上取得更好的效果。且该mRNA疫苗在动物体内表达出来的蛋白会自动形成与 2019-nCoV型冠状病毒类似的类病毒颗粒,同时,避免了体外表达系统表达产品的性质不均一问题,适 合大批量作为疫苗生产。
实施例-4mRNA疫苗的制备
1、原料准备
1)将阳离子脂质D-Lin-MC3-DMA、二硬脂酰基磷脂酰胆碱DSPC、胆固醇、PEG化脂质PEG-DMG 四个组分按摩尔比50:10:38.5:1.5在乙醇中溶解、混合。
2)实施例1制备的编码dS蛋白、含tPA信号肽的2019-nCoV RBD-dS融合蛋白的mRNA、含tPA 信号肽的2019-nCoV RBM-dS融合蛋白的mRNA和编码野生型2019-nCoV S蛋白的mRNA。将编码dS 蛋白、含tPA信号肽的2019-nCoV RBD-dS融合蛋白的mRNA按摩尔比1:1进行混合,得到混合后的 mRNA,简写为VLP-3。将编码dS蛋白、含tPA信号肽的2019-nCoV RBM-dS融合蛋白的mRNA按摩 尔比1:1进行混合,得到混合后的mRNA,简写为VLP-4。
2、试验步骤
以脂质混合物:mRNA流速比1:3,在Precision Nanosystems的纳米颗粒制备仪器Benchtop中分别 混合包装VLP-3、VLP-4和编码野生型2019-nCoV S蛋白的mRNA。将包装好的mRNA-LNP透析并超 滤浓缩到DPBS中,无菌过滤后获得用于动物实验的样品。用DLS检测mRNA-LNP的粒径和粒径分布, 检测结果如图25所示,包装后样品的粒径大小均在85nm左右,PDI均小于0.2。其中,VLP-3-LNP: 粒径平均值84.19nm,PDI值0.018,截距(intercept)0.954,具体见表7;VLP-4-LNP:粒径平均值82.16nm, PDI值0.018,截距(intercept)0.959,具体见表8;编码野生型2019-nCOV S蛋白的mRNA-LNP:粒 径平均值84.77nm,PDI值0.030,截距(intercept)0.957,具体见表6。
表7:VLP-3-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 87.98 | 100 | 19.99 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
表8:VLP-4-LNP
粒径(nm) | 强度(%) | 标准差 | |
峰1 | 85.95 | 100 | 19.84 |
峰2 | 0 | 0 | 0 |
峰3 | 0 | 0 | 0 |
3、实验结果
一免、二免后的S蛋白特异性抗体滴度如图26所示,可以看到VLP-4没能引起高水平的特异性抗 体滴度,但VLP-3设计和S全长蛋白设计的特异性抗体滴度在一免、二免时均没有显著性差异。用 ELISpot检测干扰素γ的结果如图27所示,可以看到VLP-3设计引起的Th1类细胞免疫水平显著高于 野生型S全长蛋白设计,而此结果也用胞内CK染色法进行了交叉验证,如图28所示。证明编码dS 蛋白、含tPA信号肽的2019-nCoV RBD-dS融合蛋白的mRNA按摩尔比1:1混合包装后免疫可以获得 不低于野生型S全长蛋白设计的体液免疫反应和显著性高于野生型S全长蛋白设计的细胞免疫反应, 可在2019-nCoV型冠状病毒感染的预防上取得更好的效果。且该mRNA疫苗在动物体内表达出来的蛋 白会自动形成类病毒颗粒,同时,避免了体外表达系统表达产品的纯化困难问题,适合大批量作为疫苗 生产。
综上所述,实施例2-4制备的mRNA疫苗可以用于2019-nCoV型冠状病毒感染的预防,且该mRNA 疫苗在动物体内表达出来的蛋白会自动形成与2019-nCoV型冠状病毒类似的类病毒颗粒,诱发更强的 细胞免疫,在体内出现的非中和抗体极少或基本没有。同时,生产周期短,可以纯化做到性质均一,适 合大批量作为疫苗生产。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,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,这些简单变型均属于本发明 的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可 以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说 明。
序列表
<110> 康希诺生物股份公司 苏州吉玛基因股份有限公司
<120> 用于2019-nCoV型冠状病毒mRNA疫苗、制备方法及其应用
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<160> 18
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<211> 198
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Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe
1 5 10 15
Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala
20 25 30
Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys
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Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val
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Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala
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Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp
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Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser
100 105 110
Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser
115 120 125
Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala
130 135 140
Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro
145 150 155 160
Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro
165 170 175
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Asn Ala Thr
180 185 190
Val Cys Gly Pro Lys Lys
195
<210> 2
<211> 167
<212> PRT
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Met Ser Gly Thr Phe Gly Gly Ile Leu Ala Gly Leu Ile Gly Leu Leu
1 5 10 15
Val Ser Phe Phe Leu Leu Ile Lys Ile Leu Glu Ile Leu Arg Arg Leu
20 25 30
Asp Trp Trp Trp Ile Ser Leu Ser Ser Pro Lys Gly Lys Met Gln Cys
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Ala Phe Gln Asp Thr Gly Ala Gln Ile Ser Pro His Tyr Val Gly Ser
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Cys Pro Trp Gly Cys Pro Gly Phe Leu Trp Thr Tyr Leu Arg Leu Phe
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Ile Ile Phe Leu Leu Ile Leu Leu Val Ala Ala Gly Leu Leu Tyr Leu
85 90 95
Thr Asp Asn Gly Ser Thr Ile Leu Gly Lys Leu Gln Trp Ala Ser Val
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Ser Ala Leu Phe Ser Ser Ile Ser Ser Leu Leu Pro Ser Asp Pro Lys
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Ser Leu Val Ala Leu Thr Phe Gly Leu Ser Leu Ile Trp Met Thr Ser
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Ser Ser Ala Thr Gln Thr Leu Val Thr Leu Thr Gln Leu Ala Thr Leu
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Ser Ala Leu Phe Tyr Lys Ser
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Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe
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Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala
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Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys
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Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val
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Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala
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Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp
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Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser
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Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser
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Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala
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Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro
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Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro
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Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr
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Val Met Ser Gly Thr Phe Gly Gly Ile Leu Ala Gly Leu Ile Gly Leu
195 200 205
Leu Val Ser Phe Phe Leu Leu Ile Lys Ile Leu Glu Ile Leu Arg Arg
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Leu Asp Trp Trp Trp Ile Ser Leu Ser Ser Pro Lys Gly Lys Met Gln
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Cys Ala Phe Gln Asp Thr Gly Ala Gln Ile Ser Pro His Tyr Val Gly
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Ser Cys Pro Trp Gly Cys Pro Gly Phe Leu Trp Thr Tyr Leu Arg Leu
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Phe Ile Ile Phe Leu Leu Ile Leu Leu Val Ala Ala Gly Leu Leu Tyr
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Leu Thr Asp Asn Gly Ser Thr Ile Leu Gly Lys Leu Gln Trp Ala Ser
290 295 300
Val Ser Ala Leu Phe Ser Ser Ile Ser Ser Leu Leu Pro Ser Asp Pro
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Lys Ser Leu Val Ala Leu Thr Phe Gly Leu Ser Leu Ile Trp Met Thr
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Ser Ser Ser Ala Thr Gln Thr Leu Val Thr Leu Thr Gln Leu Ala Thr
340 345 350
Leu Ser Ala Leu Phe Tyr Lys Ser
355 360
<210> 4
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<212> PRT
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Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
1 5 10 15
Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
20 25 30
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
35 40 45
Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
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Asn Gly Val Gly Tyr Gln Pro Tyr Met Ser Gly Thr Phe Gly Gly Ile
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Leu Ala Gly Leu Ile Gly Leu Leu Val Ser Phe Phe Leu Leu Ile Lys
85 90 95
Ile Leu Glu Ile Leu Arg Arg Leu Asp Trp Trp Trp Ile Ser Leu Ser
100 105 110
Ser Pro Lys Gly Lys Met Gln Cys Ala Phe Gln Asp Thr Gly Ala Gln
115 120 125
Ile Ser Pro His Tyr Val Gly Ser Cys Pro Trp Gly Cys Pro Gly Phe
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Leu Trp Thr Tyr Leu Arg Leu Phe Ile Ile Phe Leu Leu Ile Leu Leu
145 150 155 160
Val Ala Ala Gly Leu Leu Tyr Leu Thr Asp Asn Gly Ser Thr Ile Leu
165 170 175
Gly Lys Leu Gln Trp Ala Ser Val Ser Ala Leu Phe Ser Ser Ile Ser
180 185 190
Ser Leu Leu Pro Ser Asp Pro Lys Ser Leu Val Ala Leu Thr Phe Gly
195 200 205
Leu Ser Leu Ile Trp Met Thr Ser Ser Ser Ala Thr Gln Thr Leu Val
210 215 220
Thr Leu Thr Gln Leu Ala Thr Leu Ser Ala Leu Phe Tyr Lys Ser
225 230 235
<210> 5
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<212> PRT
<213> 人工序列(Artificial Sequence)
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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
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Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
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Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
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Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
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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
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
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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
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
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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
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Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
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Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
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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
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Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
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Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
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Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
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Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
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Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
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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
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Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
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Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
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Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
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Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
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Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
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Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
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Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
<210> 6
<211> 222
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Ala Asp Ser Asn Gly Thr Ile Thr Val Glu Glu Leu Lys Lys Leu
1 5 10 15
Leu Glu Gln Trp Asn Leu Val Ile Gly Phe Leu Phe Leu Thr Trp Ile
20 25 30
Cys Leu Leu Gln Phe Ala Tyr Ala Asn Arg Asn Arg Phe Leu Tyr Ile
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Ile Lys Leu Ile Phe Leu Trp Leu Leu Trp Pro Val Thr Leu Ala Cys
50 55 60
Phe Val Leu Ala Ala Val Tyr Arg Ile Asn Trp Ile Thr Gly Gly Ile
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Ala Ile Ala Met Ala Cys Leu Val Gly Leu Met Trp Leu Ser Tyr Phe
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Ile Ala Ser Phe Arg Leu Phe Ala Arg Thr Arg Ser Met Trp Ser Phe
100 105 110
Asn Pro Glu Thr Asn Ile Leu Leu Asn Val Pro Leu His Gly Thr Ile
115 120 125
Leu Thr Arg Pro Leu Leu Glu Ser Glu Leu Val Ile Gly Ala Val Ile
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Leu Arg Gly His Leu Arg Ile Ala Gly His His Leu Gly Arg Cys Asp
145 150 155 160
Ile Lys Asp Leu Pro Lys Glu Ile Thr Val Ala Thr Ser Arg Thr Leu
165 170 175
Ser Tyr Tyr Lys Leu Gly Ala Ser Gln Arg Val Ala Gly Asp Ser Gly
180 185 190
Phe Ala Ala Tyr Ser Arg Tyr Arg Ile Gly Asn Tyr Lys Leu Asn Thr
195 200 205
Asp His Ser Ser Ser Ser Asp Asn Ile Ala Leu Leu Val Gln
210 215 220
<210> 7
<211> 75
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Tyr Ser Phe Val Ser Glu Glu Thr Gly Thr Leu Ile Val Asn Ser
1 5 10 15
Val Leu Leu Phe Leu Ala Phe Val Val Phe Leu Leu Val Thr Leu Ala
20 25 30
Ile Leu Thr Ala Leu Arg Leu Cys Ala Tyr Cys Cys Asn Ile Val Asn
35 40 45
Val Ser Leu Val Lys Pro Ser Phe Tyr Val Tyr Ser Arg Val Lys Asn
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Leu Asn Ser Ser Arg Val Pro Asp Leu Leu Val
65 70 75
<210> 8
<211> 319
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (308)..(312)
<223> n is a, c, g, t or u
<400> 8
taatacgact cactataggg aaataagaga gaaaagaaga gtaagaagaa atataagagc 60
caccggagac ggattgattg ccgtctcctg ataataggct ggagcctcgg tggccatgct 120
tcttgcccct tgggcctccc cccagcccct cctccccttc ctgcacccgt acccccgtgg 180
tctttgaata aagtctgagt gggcggcaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 240
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 300
aaaaaaannn nnggtcttc 319
<210> 9
<211> 672
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 9
atggacgcca tgaagagggg actgtgctgc gtgctgctgc tgtgcggagc cgtgttcgtg 60
agcaactcca tcaccaacct gtgccccttc ggcgaggtgt ttaacgccac acgctttgcc 120
tccgtgtatg cctggaaccg gaagagaatc tccaattgcg tggccgacta ttctgtgctg 180
tacaattctg ccagcttctc cacctttaag tgctatggcg tgtctcctac caagctgaac 240
gacctgtgct tcacaaacgt gtacgccgac agctttgtga tccggggcga tgaggtgaga 300
cagatcgcac caggacagac cggcaagatc gcagactaca actataagct gcccgacgat 360
ttcacaggct gcgtgatcgc ctggaattct aacaatctgg atagcaaagt gggcggcaac 420
tacaattatc tgtacaggct gttccgcaag agcaacctga agccttttga gcgggacatc 480
agcaccgaga tctaccaggc cggctccaca ccatgcaacg gcgtggaggg cttcaattgt 540
tattttccac tgcagtccta cggcttccag cccaccaatg gcgtgggcta tcagccttac 600
cgggtggtgg tgctgtcttt tgagctgctg cacgcaccag caacagtgtg cggacctaag 660
aagtgataat ag 672
<210> 10
<211> 672
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 10
atggacgcca tgaagagggg actgtgctgc gtgctgctgc tgtgcggagc cgtgttcgtg 60
agcaactcca tcaccaacct gtgccctttc ggcgaggtgt ttaacgccac acgctttgcc 120
tccgtgtatg cctggaaccg gaagagaatc tccaattgcg tggccgacta ttctgtgctg 180
tacaattctg ccagcttctc cacctttaag tgctatggcg tgtctccaac caagctgaac 240
gacctgtgct tcacaaacgt gtacgccgac agctttgtga tccggggcga tgaggtgaga 300
cagatcgcac caggacagac cggcaagatc gcagactaca actataagct gcctgacgat 360
ttcacaggct gcgtgatcgc ctggaattct aacaatctgg atagcaaagt gggcggcaac 420
tacaattatc tgtacaggct gttccgcaag agcaacctga agccatttga gcgggacatc 480
agcaccgaga tctaccaggc aggatccaca ccatgcaacg gagtggaggg cttcaattgt 540
tattttcccc tgcagtccta cggcttccag cctaccaacg gcgtgggcta tcagccatac 600
cgggtggtgg tgctgtcttt tgagctgctg cacgccaatg ccacagtgtg cggccccaag 660
aagtgataat ag 672
<210> 11
<211> 675
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 11
atggccgact ctaatggcac catcacagtg gaggagctga agaagctgct ggagcagtgg 60
aacctggtca tcggcttcct gtttctgaca tggatctgcc tgctgcagtt cgcctacgcc 120
aaccggaata gatttctgta tatcatcaag ctgatcttcc tgtggctgct gtggcccgtg 180
acactggcct gctttgtgct ggccgccgtg taccggatca attggatcac cggaggaatc 240
gcaatcgcaa tggcatgtct ggtgggcctg atgtggctgt cttacttcat cgccagcttc 300
agactgtttg ccaggacacg ctccatgtgg tctttcaacc ccgagaccaa tatcctgctg 360
aacgtgcctc tgcacggcac catcctgaca aggccactgc tggagagcga gctggtcatc 420
ggagccgtga tcctgagggg acacctgagg atcgcaggac accacctggg ccgctgtgac 480
atcaaggatc tgcccaagga gatcaccgtg gccacaagcc ggaccctgtc ctactataag 540
ctgggagcat cccagagagt ggcaggcgat tccggattcg cagcatactc tcggtataga 600
atcggcaatt acaagctgaa caccgaccac agctcctcta gcgataacat cgccctgctg 660
gtgcagtgat aatag 675
<210> 12
<211> 234
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgtactctt ttgtgagcga ggagaccggc acactgatcg tgaactccgt gctgctgttc 60
ctggcctttg tggtgttcct gctggtgacc ctggcaatcc tgacagccct gaggctgtgc 120
gcctattgct gtaacatcgt gaacgtgagc ctggtgaagc cctctttcta cgtgtatagc 180
cgggtgaaga acctgaatag ctccagagtg cctgacctgc tggtgtgata atag 234
<210> 13
<211> 3828
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 13
atgttcgtgt ttctggtgct gctgcctctg gtgagctccc agtgcgtgaa cctgaccaca 60
aggacccagc tgccccctgc ctataccaat tccttcacac ggggcgtgta ctatcccgac 120
aaggtgttta gatctagcgt gctgcactcc acacaggatc tgtttctgcc tttcttttct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca atggcacaaa gcggttcgac 240
aatccagtgc tgccctttaa cgatggcgtg tacttcgcct ccaccgagaa gtctaacatc 300
atcagaggct ggatctttgg caccacactg gacagcaaga cacagtccct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa tgatccattc 420
ctgggcgtgt actatcacaa gaacaataag tcttggatgg agagcgagtt tcgcgtgtat 480
tcctctgcca acaattgcac atttgagtac gtgtcccagc ccttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgagg gagttcgtgt ttaagaatat cgatggctac 600
ttcaagatct actccaagca caccccaatc aacctggtgc gcgacctgcc acagggcttc 660
tctgccctgg agccactggt ggatctgccc atcggcatca acatcacccg gtttcagaca 720
ctgctggccc tgcacagaag ctacctgaca ccaggcgaca gctcctctgg atggaccgca 780
ggagcagcag cctactatgt gggctatctg cagcccagga ccttcctgct gaagtacaac 840
gagaatggca ccatcacaga cgccgtggat tgcgccctgg atcccctgtc tgagaccaag 900
tgtacactga agagctttac cgtggagaag ggcatctatc agacaagcaa tttcagggtg 960
cagcctaccg agtccatcgt gcgctttccc aatatcacaa acctgtgccc ttttggcgag 1020
gtgttcaacg caaccaggtt cgcaagcgtg tacgcatgga ataggaagcg catctccaac 1080
tgcgtggccg actattctgt gctgtacaac agcgcctcct tctctacctt taagtgctat 1140
ggcgtgagcc ccacaaagct gaatgacctg tgctttacca acgtgtacgc cgattccttc 1200
gtgatcaggg gcgacgaggt gcgccagatc gcaccaggac agacaggcaa gatcgcagac 1260
tacaattata agctgcctga cgatttcacc ggctgcgtga tcgcctggaa ctctaacaat 1320
ctggatagca aagtgggcgg caactacaat tatctgtacc ggctgtttag aaagtctaat 1380
ctgaagccat tcgagaggga catctccaca gagatctacc aggccggctc taccccctgc 1440
aatggcgtgg agggctttaa ctgttatttc cctctgcaga gctacggctt ccagccaaca 1500
aacggcgtgg gctatcagcc ctaccgcgtg gtggtgctgt cttttgagct gctgcacgca 1560
cctgcaacag tgtgcggacc aaagaagagc accaatctgg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggactgac cggaacaggc gtgctgaccg agtccaacaa gaagttcctg 1680
ccttttcagc agttcggcag ggacatcgca gataccacag acgccgtgcg cgaccctcag 1740
accctggaga tcctggacat cacaccatgc tccttcggcg gcgtgtctgt gatcacacca 1800
ggcaccaata caagcaacca ggtggccgtg ctgtatcagg acgtgaattg taccgaggtg 1860
ccagtggcaa tccacgcaga tcagctgacc cctacatggc gggtgtactc taccggcagc 1920
aacgtgttcc agacaagagc aggatgcctg atcggagcag agcacgtgaa caatagctat 1980
gagtgcgaca tccctatcgg cgccggcatc tgtgcctcct accagaccca gacaaactcc 2040
ccaaggagag cacggtctgt ggcaagccag tccatcatcg cctataccat gagcctgggc 2100
gccgagaatt ccgtggccta ctccaacaat tctatcgcca tccctaccaa cttcacaatc 2160
tccgtgacca cagagatcct gccagtgagc atgaccaaga catccgtgga ctgcacaatg 2220
tatatctgtg gcgattccac cgagtgctct aacctgctgc tgcagtacgg ctctttttgt 2280
acccagctga atagagccct gacaggcatc gccgtggagc aggacaagaa cacacaggag 2340
gtgttcgccc aggtgaagca gatctacaag accccaccca tcaaggactt tggcggcttc 2400
aacttcagcc agatcctgcc cgatcctagc aagccatcca agcggtcttt tatcgaggac 2460
ctgctgttca acaaggtgac cctggccgat gccggcttca tcaagcagta tggcgattgc 2520
ctgggcgaca tcgccgccag agacctgatc tgtgcccaga agtttaatgg cctgaccgtg 2580
ctgcctccac tgctgacaga tgagatgatc gcccagtaca catctgccct gctggcagga 2640
accatcacaa gcggatggac cttcggcgca ggagccgccc tgcagatccc ctttgccatg 2700
cagatggcct atcggttcaa cggcatcggc gtgacccaga atgtgctgta cgagaaccag 2760
aagctgatcg ccaatcagtt taactccgcc atcggcaaga tccaggactc tctgagctcc 2820
acagcaagcg ccctgggcaa gctgcaggat gtggtgaatc agaacgccca ggccctgaat 2880
accctggtga agcagctgtc tagcaacttc ggcgccatct cctctgtgct gaatgacatc 2940
ctgagcaggc tggacaaggt ggaggcagag gtgcagatcg accggctgat cacaggcaga 3000
ctgcagtccc tgcagaccta cgtgacacag cagctgatca gggcagcaga gatcagggca 3060
tctgccaatc tggccgccac caagatgagc gagtgcgtgc tgggccagtc caagagagtg 3120
gacttttgtg gcaagggcta tcacctgatg agcttcccac agtccgcccc tcacggagtg 3180
gtgtttctgc acgtgaccta cgtgccagcc caggagaaga acttcaccac agcaccagca 3240
atctgccacg atggcaaggc acactttcct agggagggcg tgttcgtgag caacggcacc 3300
cactggtttg tgacacagcg caatttctac gagccacaga tcatcaccac agacaataca 3360
ttcgtgtccg gcaactgtga cgtggtcatc ggcatcgtga acaataccgt gtatgatcct 3420
ctgcagccag agctggactc ttttaaggag gagctggata agtacttcaa gaatcacacc 3480
agccccgacg tggatctggg cgacatctct ggcatcaatg ccagcgtggt gaacatccag 3540
aaggagatcg acaggctgaa cgaggtggcc aagaatctga acgagtccct gatcgatctg 3600
caggagctgg gcaagtatga gcagtacatc aagtggccct ggtatatctg gctgggcttc 3660
atcgccggcc tgatcgccat cgtgatggtg accatcatgc tgtgctgtat gacaagctgc 3720
tgttcctgcc tgaagggctg ctgttcttgt ggcagctgct gtaagtttga tgaggacgat 3780
agcgagcctg tgctgaaggg cgtgaagctg cactacacct gataatag 3828
<210> 14
<211> 1158
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 14
atggacgcca tgaagagggg actgtgctgc gtgctgctgc tgtgcggagc cgtgttcgtg 60
agcaactcca tcaccaacct gtgccctttc ggcgaggtgt ttaacgccac aagatttgcc 120
agcgtgtatg cctggaacag gaagcgcatc agcaattgcg tggccgacta ttccgtgctg 180
tacaattctg ccagcttctc cacctttaag tgctatggcg tgagcccaac caagctgaac 240
gacctgtgct tcacaaacgt gtacgccgac tcctttgtga tcaggggcga tgaggtgcgc 300
cagatcgcac ctggacagac cggcaagatc gcagactaca actataagct gccagacgat 360
ttcacaggct gcgtgatcgc ctggaatagc aacaatctgg attccaaagt gggcggcaac 420
tacaattatc tgtaccggct gttcagaaag tccaacctga agccctttga gagggacatc 480
tctaccgaga tctaccaggc cggcagcaca ccttgcaacg gcgtggaggg cttcaattgt 540
tattttcctc tgcagtctta cggctttcag ccaacaaatg gcgtgggcta tcagccctac 600
cgcgtggtgg tgctgtcctt cgagctgctg cacgcacctg caaccgtgat gtctggcaca 660
tttggcggaa tcctggcagg actgatcgga ctgctggtgt ctttctttct gctgatcaag 720
atcctggaga tcctgcggag actggactgg tggtggatca gcctgagctc cccaaagggc 780
aagatgcagt gcgccttcca ggataccggc gcccagatct ctccccacta tgtgggaagc 840
tgcccatggg gatgtccagg ctttctgtgg acatacctgc ggctgttcat catctttctg 900
ctgatcctgc tggtggcagc aggactgctg tatctgaccg acaacggcag cacaatcctg 960
ggcaagctgc agtgggcctc tgtgagcgcc ctgttctcta gcatctcctc tctgctgccc 1020
tccgatccta agtctctggt ggccctgacc tttggcctgt ccctgatctg gatgacaagc 1080
tcctctgcca cccagacact ggtgaccctg acacagctgg ccaccctgtc cgccctgttc 1140
tacaagtctt gataatag 1158
<210> 15
<211> 795
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 15
atggacgcca tgaagagggg actgtgctgc gtgctgctgc tgtgcggagc cgtgttcgtg 60
agcaactcca attctaacaa tctggactcc aaagtgggcg gcaactacaa ttatctgtac 120
aggctgttcc gcaagtctaa cctgaagcct tttgagaggg acatctctac cgagatctat 180
caggccggca gcacaccatg caacggcgtg gagggcttca attgttattt tcctctgcag 240
agctacggct tccagccaac caatggcgtg ggctatcagc cctacatgtc cggcacattt 300
ggcggaatcc tggcaggact gatcggactg ctggtgtctt tctttctgct gatcaagatc 360
ctggagatcc tgcggagact ggactggtgg tggatctccc tgagctcccc caagggcaag 420
atgcagtgtg ccttccagga taccggcgcc cagatctccc ctcactatgt gggatcttgc 480
ccatggggat gtccaggctt tctgtggaca tacctgcggc tgttcatcat ctttctgctg 540
atcctgctgg tggcagcagg actgctgtat ctgaccgaca acggctccac aatcctgggc 600
aagctgcagt gggcaagcgt gtccgccctg ttctctagca tctcctctct gctgccctct 660
gatcctaaga gcctggtggc cctgaccttt ggcctgagcc tgatctggat gacaagctcc 720
tctgccaccc agacactggt gaccctgaca cagctggcca ccctgagcgc cctgttttac 780
aagtcctgat aatag 795
<210> 16
<211> 510
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 16
atgtctggca ccttcggcgg aatcctggca ggactgatcg gactgctggt gagcttcttt 60
ctgctgatca agatcctgga gatcctgcgg agactggact ggtggtggat ctccctgagc 120
tcccctaagg gcaagatgca gtgcgccttc caggataccg gagcacagat ctccccacac 180
tacgtgggat cttgcccatg gggatgtcca ggctttctgt ggacatatct gcggctgttc 240
atcatctttc tgctgatcct gctggtggca gcaggactgc tgtacctgac cgacaacggc 300
tccacaatcc tgggcaagct gcagtgggca agcgtgtccg ccctgttctc tagcatctcc 360
tctctgctgc cctctgatcc taagagcctg gtggccctga cctttggcct gtctctgatc 420
tggatgacaa gctcctctgc cacccagaca ctggtgaccc tgacacagct ggccacactg 480
agcgccctgt tttataagtc ctgataatag 510
<210> 17
<211> 221
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Asn Ser Ile Thr Asn Leu Cys Pro Phe Gly Glu
20 25 30
Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
35 40 45
Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
50 55 60
Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
65 70 75 80
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
85 90 95
Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
100 105 110
Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
115 120 125
Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
130 135 140
Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
145 150 155 160
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
165 170 175
Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
180 185 190
Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
195 200 205
Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys
210 215 220
<210> 18
<211> 221
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Asn Ser Ile Thr Asn Leu Cys Pro Phe Gly Glu
20 25 30
Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
35 40 45
Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
50 55 60
Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
65 70 75 80
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
85 90 95
Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
100 105 110
Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
115 120 125
Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
130 135 140
Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
145 150 155 160
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
165 170 175
Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
180 185 190
Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
195 200 205
Leu Leu His Ala Asn Ala Thr Val Cys Gly Pro Lys Lys
210 215 220
Claims (16)
1.一种mRNA,其特征在于,所述的mRNA包含编码2019-nCoV型冠状病毒的至少一个抗原肽或其片段、变体或衍生物的编码区的mRNA序列;优选的,所述抗原肽或其片段、变体或衍生物选自下列任一种:
A)信号肽和2019-nCoV型冠状病毒的RBD,其中,所述的2019-nCoV型冠状病毒的RBD不包含信号肽区域;
B)信号肽和氨基酸突变引入N-连接糖基化的2019-nCoV型冠状病毒的RBD,其中,所述的2019-nCoV型冠状病毒的RBD不包含信号肽区域;
C)2019-nCoV型冠状病毒的S蛋白;优选的,还包括2019-nCoV型冠状病毒的M蛋白和E蛋白;或,
D)信号肽、dS蛋白以及dS蛋白与RBD的融合蛋白的组合,其中,所述的RBD不包含信号肽区域。
2.根据权利要求1所述的mRNA,其特征在于,所述B)中突变位点为第190位的脯氨酸突变为天冬氨酸,优选的,所述的B)中氨基酸突变引入N-连接糖基化的2019-nCoV型冠状病毒的RBD的氨基酸序列如SEQ ID NO:1或与SEQ ID NO:1具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
3.根据权利要求1所述的mRNA,其特征在于,所述的dS蛋白的氨基酸序列如SEQ ID NO:2或与SEQ ID NO:2具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
4.根据权利要求1所述的mRNA,其特征在于,所述的dS蛋白与RBD的融合蛋白的氨基酸序列如SEQ ID NO:3或与SEQ ID NO:3具有70%、75%、80%、85%、90%、95%、99%同一性的氨基酸序列。
5.根据权利要求1所述的mRNA,其特征在于,所述C)中S蛋白、M蛋白与E蛋白的mRNA摩尔比为1:1:1。
6.根据权利要求1-5任一所述的mRNA,其特征在于,所述的mRNA为单顺反子、双顺反子或多顺反子mRNA。
7.根据权利要求1-6任一所述的mRNA,其特征在于,所述的信号肽为tPA或lgE,优选的,所述的mRNA还包括5’帽子结构,5’非编码区,3’非编码区和/或多聚腺苷酸尾的mRNA序列。
8.一种包含mRNA的组合物,其特征在于,所述的mRNA包含编码2019-nCoV型冠状病毒的至少一个抗原肽或其片段、变体或衍生物的编码区的mRNA序列;优选的,所述的mRNA选自权利要求1-7任一所述的mRNA。
9.根据权利要求8所述的组合物,其特征在于,所述的组合物中还包括阳离子或聚阳离子化合物,优选的,所述的组合物中还包含脂质。
10.一种权利要求1-7任一所述的mRNA编码的蛋白。
11.一种编码权利要求10所述蛋白的核酸。
12.一种包含权利要求11所述核酸的载体。
13.一种包含权利要求10所述的蛋白、权利要求11所述的核酸和/或权利要求12所述的载体的细胞。
14.一种包含mRNA的组合物的制备方法,其特征在于,所述的制备方法包括将权利要求1-7任一所述的mRNA与阳离子或聚阳离子化合物混合后用脂质包装。
15.一种权利要求1-7任一所述的mRNA或权利要求8-9任一所述的包含mRNA的组合物在制备预防和/或治疗2019-nCoV型冠状病毒感染的药物中的应用。
16.一种诱导个体中和抗原特异性免疫应答的方法,其特征在于,所述的方法包括向个体施加权利要求1-7任一所述的mRNA或权利要求8-9任一所述的包含mRNA的组合物。
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CN111494616A (zh) * | 2020-04-27 | 2020-08-07 | 重庆医科大学附属永川医院 | 一种新冠病毒免疫增强型基因疫苗及其制备方法 |
CN113769080A (zh) * | 2021-09-17 | 2021-12-10 | 清华大学 | 多肽免疫偶联物及其应用 |
CN115335390A (zh) * | 2022-01-10 | 2022-11-11 | 广州市锐博生物科技有限公司 | 基于SARS-CoV-2的S蛋白的疫苗和组合物 |
CN116474083A (zh) * | 2023-02-20 | 2023-07-25 | 上海君拓生物医药科技有限公司 | 一种VLP-mRNA复合多价病毒疫苗及其制备方法和应用 |
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WO2024055272A1 (zh) * | 2022-09-16 | 2024-03-21 | 复旦大学附属中山医院 | 能高效表达目的基因的mRNA载体系统、其构建及应用 |
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