CN107987136A - Zikv-ns1蛋白及其在制备寨卡病毒传播阻断疫苗中的应用 - Google Patents
Zikv-ns1蛋白及其在制备寨卡病毒传播阻断疫苗中的应用 Download PDFInfo
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- CN107987136A CN107987136A CN201711327739.3A CN201711327739A CN107987136A CN 107987136 A CN107987136 A CN 107987136A CN 201711327739 A CN201711327739 A CN 201711327739A CN 107987136 A CN107987136 A CN 107987136A
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Abstract
本发明公开了ZIKV‑NS1蛋白及其在制备寨卡病毒传播阻断疫苗中的应用。本发明提供了一种蛋白质,命名为ZIKV‑NS1蛋白,为由序列表的序列1所示的氨基酸序列组成的蛋白质。本发明还保护所述ZIKV‑NS1蛋白的应用,为如下(e1)或(e2):(e1)制备寨卡病毒疫苗;(e2)制备寨卡病毒传播阻断疫苗。本发明提供的疫苗可阻断寨卡病毒通过蚊虫在自然界的传播,降低自然环境中蚊虫的感染率,从而保护健康人群不受寨卡病毒感染,预防寨卡病毒突然大暴发。
Description
技术领域
本发明涉及ZIKV-NS1蛋白及其在制备寨卡病毒传播阻断疫苗中的应用。
背景技术
寨卡病毒(zika virus,ZIKV)属于黄病毒科黄病毒属的单股正链RNA病毒,最早在非洲乌干达丛林中被发现。寨卡病毒的天然蚊媒宿主是伊蚊,包括埃及伊蚊和白纹伊蚊。寨卡病毒呈球形,由囊膜、衣壳蛋白及单股正链RNA组成。寨卡病毒在进化过程中,逐渐分成两个世系—非洲世系和亚洲世系。在2007年,寨卡病毒只是在非洲和亚洲热带地区散在流行,直到2013年在法国波利尼西亚群岛暴发,随后在2015年在美洲地区大暴发。寨卡病毒感染后,典型的临床症状有发热、斑丘疹、关节及肌肉酸痛。2013年和2015年的寨卡病毒疫情表明,寨卡病毒也会引起格林巴利综合征和新生儿小头畸形。
寨卡病毒主要由埃及伊蚊(Aedes aegypti)叮咬人体后感染传播。不存在埃及伊蚊的地区,白纹伊蚊(Aedesalbopictus)也被认为是寨卡病毒传播的重要媒介。目前认为,寨卡病毒的天然宿主仅有人、低等灵长类及伊蚊。在自然界中,寨卡病毒主要在两种模式中循环:1)城市循环:在城市型的寨卡病毒流行中,病毒在“人-伊蚊-人”之间传播;2)丛林循环:主要是通过热带丛林中的伊蚊及低等灵长类之间传播,此循环为寨卡病毒的原始循环。城市循环的寨卡病毒严格遵循“人-伊蚊-人”的传播途径,伊蚊是唯一的传播媒介。在病毒传播的过程中,感染的伊蚊通过叮咬将寨卡病毒注射到人体内(传播病毒),病毒在人皮下角质细胞及树突状细胞中增殖;病毒扩散到血液后进一步感染血液中的各类免疫细胞形成病毒血症;在病毒血症期,病毒可通过吸血的方式被吸入到叮咬的蚊虫体内(病毒获取)。病毒感染蚊虫的唾液腺等组织,感染的伊蚊可再次传播病毒。
寨卡病毒虽然从发现至今已有70多年的历史,但是目前仍无特效的治疗方法以及有效的可以应用的疫苗。
发明内容
本发明的目的是提供ZIKV-NS1蛋白及其在制备寨卡病毒传播阻断疫苗中的应用。
本发明提供了一种蛋白质,命名为ZIKV-NS1蛋白,为如下(a1)或(a2)或(a3):
(a1)由序列表的序列1所示的氨基酸序列组成的蛋白质;
(a2)将(a1)经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同功能的由其衍生的蛋白质;
(a3)来源于寨卡病毒的与(a1)具有97%以上同一性且具有相同功能的蛋白质。
本发明还提供了一种融合蛋白,为如下(b1)或(b2)或(b3)或(b4)或(b5)或(b6)或(b7):
(b1)由序列表的序列5自N端第53至410位氨基酸残基组成的蛋白质;
(b2)由序列表的序列5自N端第43至404位氨基酸残基组成的蛋白质;
(b3)由序列表的序列5自N端第43至410位氨基酸残基组成的蛋白质;
(b4)由序列表的序列5自N端第39至410位氨基酸残基组成的蛋白质;
(b5)由序列表的序列5所示的氨基酸序列组成的蛋白质;
(b6)给序列表的序列5自N端第53-404位氨基酸残基组成的蛋白质的末端增加蛋白标签得到的蛋白质;
(b7)将(b1)或(b2)或(b3)或(b4)或(b5)或(b6)经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同功能的由其衍生的蛋白质。
编码所述ZIKV-NS1蛋白的基因也属于本发明的保护范围。
编码所述融合蛋白的基因也属于本发明的保护范围。
编码所述ZIKV-NS1蛋白的基因为如下(c1)或(c2)或(c3)所述的DNA分子:
(c1)编码区如序列表的序列2所示的DNA分子;
(c2)在严格条件下与(c1)限定的DNA序列杂交且编码所述ZIKV-NS1蛋白的DNA分子;
(c3)来源于寨卡病毒的与(c1)限定的DNA序列至少具有97%以上同源性且编码所述ZIKV-NS1蛋白的DNA分子。
编码所述融合蛋白的基因为如下(d1)或(d2)或(d3)或(d4)所述的DNA分子:
(d1)编码区如序列表的序列4第7-1239位核苷酸所示的DNA分子;
(d2)序列表的序列4所示的DNA分子;
(d3)在严格条件下与(d1)或(d2))限定的DNA序列杂交且编码所述融合的DNA分子;
(d4)来源于寨卡病毒的与(d1)或(d2)限定的DNA序列至少具有97%以上同源性且编码所述融合蛋白的DNA分子。
以所述ZIKV-NS1蛋白为免疫原得到的抗体(抗体甲)也属于本发明的保护范围。
以所述融合蛋白为免疫原得到的抗体(抗体乙)也属于本发明的保护范围。
本发明还保护所述ZIKV-NS1蛋白或所述融合蛋白的应用,为如下(e1)或(e2):
(e1)制备寨卡病毒疫苗;
(e2)制备寨卡病毒传播阻断疫苗。
本发明还保护一种疫苗,其活性成分为所述ZIKV-NS1蛋白或所述融合蛋白;所述疫苗为寨卡病毒疫苗或寨卡病毒传播阻断疫苗。
本发明还保护所述抗体甲或所述抗体乙的应用,为如下(e1)或(e2):
(e1)制备寨卡病毒疫苗;
(e2)制备寨卡病毒传播阻断疫苗。
本发明还保护一种疫苗,其活性成分为所述抗体甲或所述抗体乙;所述疫苗为寨卡病毒疫苗或寨卡病毒传播阻断疫苗。
以上任一所述疫苗具有阻断蚊虫从人获取登革热病毒的功能。
以上任一所述疫苗具有阻断蚊虫从哺乳动物获取登革热病毒的功能。
以上任一所述疫苗具有抑制蚊虫获取寨卡病毒的功能。
以上任一所述疫苗具有抑制蚊虫传播寨卡病毒的功能。
以上任一所述疫苗具有阻断蚊虫从人体感染寨卡病毒的功能。
以上任一所述疫苗具有阻断蚊虫从哺乳动物体感染寨卡病毒的功能。
以上任一所述疫苗具有预防寨卡病毒传播的功能。
以上任一所述疫苗具有阻断寨卡病毒传播的功能。
所述哺乳动物具体可为灵长类动物。所述哺乳动物具体可为小鼠。
所述蚊虫可为伊蚊,具体可为埃及伊蚊。
以上任一所述寨卡病毒具体可为PRVABC59毒株。
以上任一所述严格条件可为在6×SSC,0.5%SDS的溶液中,在65℃下杂交,然后用2×SSC,0.1%SDS和1×SSC,0.1%SDS各洗膜一次。
对于虫媒传染病的预防,除了传统的疫苗策略外,还可以阻断媒介病原体在自然界的循环过程,从而降低媒介传染病在自然界的传播。因此,传播阻断疫苗是一种在宿主中免疫某种抗原蛋白阻断病原体传播途径,从而降低虫媒感染率及宿主发病率的免疫策略。本发明提供的疫苗,可以降低媒介蚊虫的感染率,从而作为寨卡病毒防治的效措施,具有重大的应用推广价值。本发明提供的疫苗可阻断寨卡病毒通过蚊虫在自然界的传播,降低自然环境中蚊虫的感染率,从而保护健康人群不受寨卡病毒感染,预防寨卡病毒突然大暴发。
附图说明
图1为实施例2中NS1含量的结果。
图2为实施例2中感染率的结果。
图3为实施例3中NS1含量的结果。
图4为实施例3中感染率的结果。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。以下实施例中的定量试验,均设置三次重复实验,结果取平均值。
pFastBac-dual载体和大肠杆菌DH10Bac感受态:赛默飞世尔,货号10359-016。
ZIKV病毒PRVABC59毒株,简称PRVABC59毒株:参考文献:Liu Y,Liu J,Du S,etal.Evolutionary enhancement of Zika virus infectivity in Aedes aegyptimosquitoes.[J].Nature,2017,545(7655):482。
AG6小鼠(即文献中的AG6mice)(IFN-alpha/gamma receptor double knock-outB6mouse):参考文献:Liu J,Liu Y,Nie K,et al.Flavivirus NS1protein in infectedhost sera enhances viral acquisition by mosquitoes:[J].Nature Microbiology,2016,1(9):16087。在普通小鼠、猴子等模式动物中,寨卡病毒感染后不表现典型的临床症状,或仅有轻微的病毒血症。AG6小鼠的背景为B6小鼠。AG6小鼠为干扰素双受体缺陷型小鼠,是目前寨卡病毒致病机制研究及药物研发的主要动物模型,可以产生超过106pfu/ml的病毒血症并导致动物死亡。AG6小鼠对寨卡病毒非常敏感,接种寨卡病毒后,病毒在AG6小鼠体内快速扩增,埃及伊蚊叮咬寨卡病毒感染的AG6小鼠后,可以获取病毒被感染。
埃及伊蚊(Aedes aegypti):参考文献:Liu J,Liu Y,Nie K,et al.FlavivirusNS1protein in infected host sera enhances viral acquisition by mosquitoes:[J].Nature Microbiology,2016,1(9):16087。
实施例中所用的昆虫细胞培养基为SFX-INSECT培养基。
ZIKV-NS1蛋白如序列表的序列1所示,其编码基因如序列表的序列2所示。
实施例1、蛋白的制备
一、构建重组质粒
以pFastBac-dual载体为出发载体,构建重组质粒pFastBac-dual-ZIKV-NS1。
与pFastBac-dual载体相比,重组质粒pFastBac-dual-ZIKV-NS1的差异仅在于:用序列表的序列4所示的双链DNA分子取代了出发载体中序列表的序列3所示的双链DNA分子。
序列表的序列4中,第7-1239位核苷酸为开放阅读框,编码序列表的序列5所示的蛋白质。
序列表的序列4中,第7-9位核苷酸为起始密码子,第7-120位核苷酸编码gp67信号肽,第133-162位核苷酸编码Myc标签,第163-1218位核苷酸编码ZIKV-NS1蛋白,第1219-1236位核苷酸编码His6标签,第1237-1239位核苷酸编码终止密码子。
序列表的序列5中,第1-38位氨基酸残基组成gp67信号肽,第43-52位氨基酸残基组成Myc标签,第53-404位氨基酸残基组成ZIKV-NS1蛋白,第405-410位氨基酸残基组成His6标签。在细胞中,首先表达得到序列表的序列5所示的蛋白质,然后信号肽被切除,形成序列表的序列5第39-410位氨基酸残基组成的蛋白质,将其命名为Myc-ZIKV-NS1-His6蛋白。
二、重组Bacmid的制备
1、将重组质粒pFastBac-dual-ZIKV-NS1加入大肠杆菌DH10Bac感受态细胞中,冰上放置30min;然后42℃热激90s,放回冰上5min;然后加入500μl SOC液体培养基,于37℃复苏4h;然后吸取100μl涂布于含50μg/ml卡那霉素、7μg/ml庆大霉素、10μg/ml四环素、40μg/mlIPTG和100μg/ml X-gal的LB固体培养基平板,避光培养48小时。
2、挑取白色单菌落,接种于5mL含50μg/ml卡那霉素、7μg/ml庆大霉素、10μg/ml四环素的LB液体培养基,37℃、220rpm振荡培养15小时。
3、取步骤2得到的培养体系,提取质粒,得到含有重组Bacmid的溶液,简称Bacmid溶液。
三、重组病毒的制备
1、取生长良好的Sf9细胞,加入10cm培养皿中,静置10min,细胞贴壁,显微镜下观察,保证培养皿底部约有70%-80%被细胞覆盖。
2、取Cellfectin II Reagent15μl,用100μl昆虫细胞培养基稀释。
3、取15-20μl步骤二制备的Bacmid溶液,用100μl昆虫细胞培养基稀释。
4、将步骤2得到的液相缓慢加入步骤3得到的液相中,缓慢吹打均匀,室温静置30min,用昆虫细胞培养基稀释至2ml。
5、取完成步骤1的培养皿,弃去上清,缓慢均匀的将步骤4得到的液相滴加至培养皿中,27℃静置培养5h后吸弃上清,加入7ml新鲜的昆虫细胞培养基,用封口膜密封后27℃静置培养7天,收集培养液,600g离心6min,取上清液,即为P0代重组病毒的病毒液。
四、蛋白的表达和纯化
1、取P0代重组病毒的病毒液,按照1:1000的体积比加入摇瓶培养的细胞浓度为2×106个细胞/mL的Sf9细胞液中,27℃、110rpm培养5天,收集培养液,600g离心6min,取上清液,即为P1代重组病毒的病毒液。
2、取P1代重组病毒的病毒液,按照1:1000的体积比加入摇瓶培养的细胞浓度为2×106个细胞/mL的Sf9细胞液中,27℃、110rpm培养2天,收集培养液,600g离心6min,取上清液。
3、取步骤2得到的上清液,采用TALON purification Kit(Clontech公司,货号635515)并按说明书操作,获得过柱后溶液,即为含有Myc-ZIKV-NS1-His6蛋白的溶液,简称Myc-ZIKV-NS1-His6蛋白溶液。
Myc-ZIKV-NS1-His6蛋白溶液中,总蛋白浓度大于0.5mg/ml,Myc-ZIKV-NS1-His6蛋白的纯度大于95%。Myc-ZIKV-NS1-His6蛋白溶液进行蛋白电泳,回收目的蛋白并测序,测序结果表明,N末端20个氨基酸残基如序列表的序列5第39-58位氨基酸残基所示。
实施例2、蛋白在被动免疫阻碍寨卡病毒获取中的应用
一、以蛋白为免疫原制备鼠源抗血清
试验动物为8周龄的Balb/c雌鼠。
以Myc-ZIKV-NS1-His6蛋白为免疫原。免疫原溶液是将实施例1制备的Myc-ZIKV-NS1-His6蛋白溶液采用PBS缓冲液进行稀释得到的。
第1天(初次免疫):试验动物皮下注射免疫原溶液与弗氏完全佐剂的等体积混合物,每只试验动物给予免疫原的剂量为40μg(以总蛋白计);
第14天(第一次加强免疫):试验动物皮下注射免疫原溶液与弗氏不完全佐剂的等体积混合物,每只试验动物给予免疫原的剂量为40μg(以总蛋白计);
第28天(第二次加强免疫):试验动物皮下注射免疫原溶液与弗氏不完全佐剂的等体积混合物,每只试验动物给予免疫原的剂量为40μg(以总蛋白计)。
第42天:试验动物采集500μl血清,即为鼠源抗血清,简称抗ZIKV-NS1抗体。
6只试验动物制备的抗ZIKV-NS1抗体依次命名为抗ZIKV-NS1抗体Ⅰ、抗ZIKV-NS1抗体Ⅱ、抗ZIKV-NS1抗体Ⅲ、抗ZIKV-NS1抗体Ⅳ、抗ZIKV-NS1抗体Ⅴ和抗ZIKV-NS1抗体Ⅵ。
二、制备抗Pre-immune对照抗体
8周龄的Balb/c雌鼠与步骤一的试验动物进行平行饲养,但不进行三次免疫(初次免疫、第一次加强免疫和第二次加强免疫),第42天,采集500μl血清,即为抗Pre-immune对照抗体。
3只试验动物制备的抗Pre-immune对照抗体依次命名为抗Pre-immune对照抗体Ⅰ、抗Pre-immune对照抗体Ⅱ和抗Pre-immune对照抗体Ⅲ。
三、检测抗体效价
待测抗体为步骤一制备的抗ZIKV-NS1抗体。
1、取96孔板,加入实施例1制备的Myc-ZIKV-NS1-His6蛋白溶液进行包被,每孔包被1μgMyc-ZIKV-NS1-His6蛋白(以总蛋白计),4℃静置孵育过夜。
2、取完成步骤1的96孔板,每孔加入300μl 1g/100ml BSA水溶液,室温静置孵育1小时。
3、取待测抗体,用BSA溶液梯度稀释,稀释倍数为250-1000000,得到各个稀释液。将10g BSA溶于水并用水定容至1500mL,得到BSA溶液。
4、将步骤3得到的稀释液加入完成步骤2的96孔板(每孔100μl,每种稀释液设置3个重复孔),室温静置孵育2小时。
5、完成步骤4后,取所述96孔板,用PBST溶液洗涤5次,然后加入5000倍稀释的鼠二抗(JM-6402-05,MBL,Japan),每孔100μl,室温静置孵育1小时。
6、完成步骤5后,取所述96孔板,用PBST溶液洗涤6次,加入TMB显色液(52-00-01and 50-85-04,Kirkegaard&Perry Laboratories)进行显色,每孔100μl,然后加入2M硫酸溶液以终止显色,读取OD450nm。
抗ZIKV-NS1抗体Ⅰ、抗ZIKV-NS1抗体Ⅱ、抗ZIKV-NS1抗体Ⅲ、抗ZIKV-NS1抗体Ⅳ、抗ZIKV-NS1抗体Ⅴ和抗ZIKV-NS1抗体Ⅵ的效价依次为:1×106、1×106、1×106、5×105、1×106、1×106。
四、抗体在阻断伊蚊获取寨卡病毒中的应用
待测抗体为待测抗体甲或待测抗体乙。待测抗体甲为步骤一制备的抗ZIKV-NS1抗体Ⅰ、抗ZIKV-NS1抗体Ⅱ、抗ZIKV-NS1抗体Ⅲ、抗ZIKV-NS1抗体Ⅳ、抗ZIKV-NS1抗体Ⅴ和抗ZIKV-NS1抗体Ⅵ的等体积混合物。待测抗体乙为步骤二制备的抗Pre-immune对照抗体Ⅰ、抗Pre-immune对照抗体Ⅱ和抗Pre-immune对照抗体Ⅲ的等体积混合物。
试验动物为6周龄的AG6小鼠。
1、被动免疫抗体并验证其对NS1的阻断效果。
每只试验动物分别进行如下操作:腹腔注射剂量为1×103pfu的PRVABC59毒株进行攻毒,攻毒12小时后两点腹腔注射100μl待测抗体,分别于攻毒1天后、2天后、3天后、4天后、5天后和6天后,静脉取血,并收集血清样品。
试验组包括4只试验动物,采用待测抗体甲。
对照组包括4只试验动物,采用待测抗体乙。
使用NS1检测试剂盒(BioFront Mono Trace Zika NS1ELISA Kit;ZIKV-NS1-EK-96)检测血清样品中的NS1的含量,来鉴定在小鼠体内的NS1的阻断效果。
结果如图1所示(各组均为平均值)。试验组小鼠中NS1的含量几乎检测不到。对照组小鼠中NS1的含量正常,NS1随着寨卡病毒感染逐渐上升。
上述结果表明,被动免疫抗ZIKV-NS1抗体可以成功中和AG6小鼠体内ZIKV病毒产生的NS1,达到阻断NS1蛋白作用的效果。
2、埃及伊蚊通过叮咬感染小鼠获取登革病毒
(1)取试验动物,每只脚掌皮内注射1×103pfu PRVABC59毒株进行攻毒,攻毒12小时后每只腹腔注射100μl待测抗体。
(2)分别于攻毒1天后、2天后、3天后、4天后和5天后,检测感染率。
试验组包括4只试验动物,采用待测抗体甲。
对照组包括4只试验动物,采用待测抗体乙。
检测感染率的步骤如下:
①腹腔注射戊巴比妥钠麻醉小鼠,将麻醉后的小鼠放置在饲养埃及伊蚊的容器中,让伊蚊吸血30分钟;
②将吸血的伊蚊放置在4℃冰上10分钟进行麻醉,从麻醉的蚊子中取a只充分吸血的伊蚊转移至新的容器中饲养8天;
③完成步骤②的伊蚊,-80℃冷冻5分钟,将每个伊蚊分别如下操作:研磨并匀浆,提取总RNA并反转录为cDNA,以cDNA为模板,采用Actin基因作为内参,利用TaqmanRT-QPCR检测伊蚊是否发生了寨卡病毒感染。
用于检测寨卡病毒的引物对如下:
上游引物:5’-CCGCTGCCCAACACAAG-3’;
下游引物:5’-CCACTAACGTTCTTTTGCAGACAT-3’。
用于检测寨卡病毒的探针如下:
5’-FAM-AGCCTACCTTGACAAGCARTCAGACACTCAA-TRAMA-3’。
用于检测Actin基因的引物对如下:
上游引物:5’-GAACACCCAGTCCTGCTGACA-3’;
下游引物:5’-TGCGTCATCTTCTCACGGTTAG-3’。
用于检测Actin基因的探针如下:
5’-FAM-AGGCCCCGCTCAACCCGAAG-TRAMA-3’。
通过RT-QPCR检测得到的△Ct值进行计算,当2-△Ct的值大于0.001时,该伊蚊被认定为ZIKV感染阳性。
b只伊蚊为ZIKV感染阳性。
感染率=b÷a×100%。
结果见图2(各组均为平均值)。与对照组相比,试验组的感染率显著性的降低。结果表明,抗ZIKV-NS1抗体可以阻断伊蚊从AG6小鼠体内获取病毒。
实施例3、ZIKV NS1在作为寨卡传播阻断疫苗中的应用
免疫原为Myc-ZIKV-NS1-His6蛋白或OVA蛋白。免疫原溶液是将实施例1制备的Myc-ZIKV-NS1-His6蛋白溶液采用PBS缓冲液进行稀释得到的或者免疫原溶液是将OVA蛋白用PBS缓冲液进行稀释得到的。
试验动物为6周龄的AG6小鼠。
一、蛋白主动免疫AG6小鼠
试验动物分成两组(对照组采用OVA蛋白作为免疫原,试验组采用Myc-ZIKV-NS1-His6蛋白作为免疫原),每组10只,免疫方法如下:
第1天(初次免疫):试验动物皮下注射免疫原溶液与弗氏完全佐剂的等体积混合物,每只试验动物给予免疫原的剂量为40μg(以总蛋白计);
第14天(第一次加强免疫):实验动物皮下注射免疫原溶液与弗氏不完全佐剂的等体积混合物,每只试验动物给予免疫原的剂量为40μg(以总蛋白计);
第28天(第二次加强免疫):实验动物皮下注射免疫原溶液与弗氏不完全佐剂的等体积混合物,每只试验动物给予免疫原的剂量为40μg(以总蛋白计)。
第42天:通过脚掌皮内注射剂量为1×103pfu的PRVABC59毒株进行攻毒。
二、主动免疫对NS1的阻断效果
分别在步骤一中攻毒1天后、2天后、3天后、4天后、5天后、6天后,通过小鼠尾静脉取血,并收集血清样品。
使用NS1检测试剂盒(BioFront Mono Trace Zika NS1ELISA Kit;ZIKV-NS1-EK-96)检测血清样品中的NS1的含量,来鉴定在小鼠体内的NS1的阻断效果。
结果如图3所示(各组均为平均值)。试验组小鼠中NS1的含量几乎检测不到。对照组小鼠中NS1的含量正常,NS1随着寨卡病毒感染逐渐上升。
二、ZIKV NS1蛋白阻断埃及伊蚊从动物体内获取登革病毒
分别在步骤一中攻毒1天后、2天后、3天后、4天后、5天后、6天后,检测感染率,方法同实施例2的步骤四的2。
结果如图4所示(各组均为平均值)。与对照组相比,试验组的感染率显著性降低,证明主动免疫Myc-ZIKV-NS1-His6蛋白可以阻断伊蚊从AG6小鼠体内获取病毒。
上述结果均表明,Myc-ZIKV-NS1-His6蛋白可作为寨卡病毒传播阻断疫苗,用于预防寨卡病毒传播,阻断伊蚊从动物体感染寨卡病毒。
SEQUENCE LISTING
<110> 清华大学
<120> ZIKV-NS1蛋白及其在制备寨卡病毒传播阻断疫苗中的应用
<130> CGGNQAYX-176146
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 352
<212> PRT
<213> zika virus
<400> 1
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gatgtggggt gctcggtgga cttctcaaag aaggagacga gatgcggtac aggggtgttt 60
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agattggcag cagcagtcaa gcaagcctgg gaagatggta tctgcgggat ctcctctgtt 180
tcaagaatgg aaaacatcat gtggagatca gtagaagggg agctcaacgc aatcctggaa 240
gagaatggag ttcaactgac ggtcgttgtg ggatctgtaa aaaaccccat gtggagaggt 300
ccacagagat tgcccgtgcc tgtgaacgag ctgccccacg gctggaaggc ttgggggaaa 360
tcgtacttcg tcagagcagc aaagacaaat aacagctttg tcgtggatgg tgacacactg 420
aaggaatgcc cactcaaaca tagagcatgg aacagctttc ttgtggagga tcatgggttc 480
ggggtatttc acactagtgt ctggctcaag gttagagaag actattcatt agagtgtgat 540
ccagccgtta ttggaacagc tgttaaggga aaggaggctg tacacagtga tctaggctac 600
tggattgaga gtgagaagaa tgacacatgg aggctgaaga gggcccatct gatcgagatg 660
aaaacatgtg aatggccaaa gtcccacaca ttgtggacag atggaataga agagagtgat 720
ctgatcatac ccaagtcttt agctgggcca ctcagccatc acaataccag agagggctac 780
aggacccaaa tgaaagggcc atggcacagt gaggagcttg aaattcggtt tgaggaatgc 840
ccaggcacta aggtccacgt ggaggaaaca tgtggaacaa gaggaccatc tctgagatca 900
accactgcaa gcggaagggt gatcgaggaa tggtgctgca gggagtgcac aatgccccca 960
ctgtcgttcc gggctaaaga tggctgttgg tatggaatgg agataaggcc caggaaagaa 1020
ccagaaagca acttagtaag gtcaatggtg actgca 1056
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gcggatccca tggaacaaaa actcatctca gaagaggatc tggatgtggg gtgctcggtg 180
gacttctcaa agaaggagac gagatgcggt acaggggtgt ttgtctataa cgacgttgaa 240
gcctggaggg acaggtacaa gtaccatcct gactcccccc gtagattggc agcagcagtc 300
aagcaagcct gggaagatgg tatctgcggg atctcctctg tttcaagaat ggaaaacatc 360
atgtggagat cagtagaagg ggagctcaac gcaatcctgg aagagaatgg agttcaactg 420
acggtcgttg tgggatctgt aaaaaacccc atgtggagag gtccacagag attgcccgtg 480
cctgtgaacg agctgcccca cggctggaag gcttggggga aatcgtactt cgtcagagca 540
gcaaagacaa ataacagctt tgtcgtggat ggtgacacac tgaaggaatg cccactcaaa 600
catagagcat ggaacagctt tcttgtggag gatcatgggt tcggggtatt tcacactagt 660
gtctggctca aggttagaga agactattca ttagagtgtg atccagccgt tattggaaca 720
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aatgacacat ggaggctgaa gagggcccat ctgatcgaga tgaaaacatg tgaatggcca 840
aagtcccaca cattgtggac agatggaata gaagagagtg atctgatcat acccaagtct 900
ttagctgggc cactcagcca tcacaatacc agagagggct acaggaccca aatgaaaggg 960
ccatggcaca gtgaggagct tgaaattcgg tttgaggaat gcccaggcac taaggtccac 1020
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Claims (10)
1.ZIKV-NS1蛋白或具有所述ZIKV-NS1蛋白的融合蛋白;所述ZIKV-NS1蛋白为如下(a1)或(a2)或(a3):
(a1)由序列表的序列1所示的氨基酸序列组成的蛋白质;
(a2)将(a1)经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同功能的由其衍生的蛋白质;
(a3)来源于寨卡病毒的与(a1)具有97%以上同一性且具有相同功能的蛋白质。
2.如权利要求1所述的融合蛋白,其特征在于:所述融合蛋白为如下(b1)或(b2)或(b3)或(b4)或(b5)或(b6)或(b7):
(b1)由序列表的序列5自N端第53至410位氨基酸残基组成的蛋白质;
(b2)由序列表的序列5自N端第43至404位氨基酸残基组成的蛋白质;
(b3)由序列表的序列5自N端第43至410位氨基酸残基组成的蛋白质;
(b4)由序列表的序列5自N端第39至410位氨基酸残基组成的蛋白质;
(b5)由序列表的序列5所示的氨基酸序列组成的蛋白质;
(b6)给序列表的序列5自N端第53-404位氨基酸残基组成的蛋白质的末端增加蛋白标签得到的蛋白质;
(b7)将(b1)或(b2)或(b3)或(b4)或(b5)或(b6)经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同功能的由其衍生的蛋白质。
3.编码权利要求1所述ZIKV-NS1蛋白的基因或编码权利要求1所述融合蛋白的基因。
4.如权利要求3所述的基因,其特征在于:编码权利要求1所述ZIKV-NS1蛋白的基因为如下(c1)或(c2)或(c3)所述的DNA分子:
(c1)编码区如序列表的序列2所示的DNA分子;
(c2)在严格条件下与(c1)限定的DNA序列杂交且编码所述ZIKV-NS1蛋白的DNA分子;
(c3)来源于寨卡病毒的与(c1)限定的DNA序列至少具有97%以上同源性且编码所述ZIKV-NS1蛋白的DNA分子。
5.如权利要求3所述的基因,其特征在于:编码权利要求1所述融合蛋白的基因为如下(d1)或(d2)或(d3)或(d4)所述的DNA分子:
(d1)编码区如序列表的序列4第7-1239位核苷酸所示的DNA分子;
(d2)序列表的序列4所示的DNA分子;
(d3)在严格条件下与(d1)或(d2))限定的DNA序列杂交且编码所述融合的DNA分子;
(d4)来源于寨卡病毒的与(d1)或(d2)限定的DNA序列至少具有97%以上同源性且编码所述融合蛋白的DNA分子。
6.以权利要求1或2所述蛋白或融合蛋白为免疫原得到的抗体。
7.权利要求1或2所述蛋白或融合蛋白的应用,为如下(e1)或(e2):
(e1)制备寨卡病毒疫苗;
(e2)制备寨卡病毒传播阻断疫苗。
8.一种疫苗,其活性成分为权利要求1或2所述蛋白或融合蛋白;所述疫苗为寨卡病毒疫苗或寨卡病毒传播阻断疫苗。
9.权利要求6所述抗体的应用,为如下(e1)或(e2):
(e1)制备寨卡病毒疫苗;
(e2)制备寨卡病毒传播阻断疫苗。
10.一种疫苗,其活性成分为权利要求6所述抗体;所述疫苗为寨卡病毒疫苗或寨卡病毒传播阻断疫苗。
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