CN114377121A - 含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗及其应用 - Google Patents
含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗及其应用 Download PDFInfo
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Abstract
本发明涉及含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗及其应用,属于生物技术制药领域,所述的“鸡尾酒”疫苗含有OprI‑p30‑modified p54‑TT、OprI‑p72 epitope‑pE248R的N段氨基酸序列‑TT和OprI‑CD2v的N段氨基酸序列‑pEP153R的C段氨基酸序列‑TT 3种重组非洲猪瘟病毒抗原融合蛋白。本发明提供了上述3种重组非洲猪瘟病毒抗原融合蛋白的表达和纯化方法,以及用于配制上述“鸡尾酒”疫苗的组分比例和佐剂配伍。利用本发明制备的“鸡尾酒”疫苗可激发机体产生中和抗体和特异性细胞免疫应答,可作为一种预防非洲猪瘟的亚单位疫苗。
Description
技术领域
本发明属于生物技术制药领域,具体涉及一种含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗及其应用。
背景技术
非洲猪瘟(African swine fever, ASF)是由非洲猪瘟病毒(African swinefever virus, ASFV)引起猪发病的急性烈性传染病,死亡率可达100 %,目前尚无商品化的疫苗。世界动物卫生组织(World Organization for Animal Health, OIE)将其列为将ASF列为必须通报的动物疫病,我国将其列为重点防御的一类动物传染病。ASF疫苗以往的研究经验表明:(1)ASF灭活疫苗不能提供免疫保护;(2)ASF减毒活疫苗虽能提供针对同源毒株的免疫保护,但会引起严重的免疫副反应,且存在毒力返强的风险。(3)一些ASFV抗原亚单位能诱导针对ASFV的保护性免疫应答,为开发安全有效的ASF疫苗提供了条件。随着ASFV功能蛋白的不断发掘和解析,以及疫苗分子内佐剂的发展和应用,采用全新策略研发有效的ASF亚单位疫苗已成为可能。
ASFV 基因组大小为 170-194 kb,编码50多种结构蛋白和100多种非结构蛋白。研究发现p30、p54、p72和CD2v蛋白诱导产生的抗体能够抑制ASFV感染,p54和p30两种蛋白产生的抗体可抑制病毒的对敏感细胞的吸附和病毒内化。p72诱导产生的抗体也能抑制ASFV的吸附,重组CD2v蛋白试制的疫苗可诱导以细胞免疫为主的免疫保护,可能是诱导保护性免疫应答的重要抗原之一,pEP153R能诱导产生特异性抗体,并针对同源毒株提供部分免疫保护,提示这些蛋白可能是ASFV的重要保护性抗原。
铜绿假单胞菌的主要外膜脂蛋白I(OprI)具有强大的免疫刺激能力,其可以通过TLR-2依赖途径刺激刺激树突状细胞的活化,促进抗原提呈分子(例如MHC分子)和共同刺激分子(例如,CD40、CD80、CD86)的表达,以及炎性细胞因子(TNF-α和IL-12p70)的分泌。研究表明:OprI和破伤风类毒素中通用性CD4+ T细胞表位TT-p2(简称TT)联用具有协同增强融合抗原特异性体液和细胞免疫的作用。
发明内容
为采用全新策略研发有效的ASF亚单位疫苗,本发明通过基因融合和串联表达的方式得到OprI-p30-modified p54-TT、OprI-p72 epitope-pE248R的N段氨基酸序列-TT和OprI-CD2v的N段氨基酸序列-pEP153R的C段氨基酸序列-TT 3种重组ASFV抗原融合蛋白,将这3种重组ASFV抗原融合蛋白按一定比例与佐剂配伍成“鸡尾酒”疫苗,免疫动物后诱导产生ASFV中和抗体和细胞免疫应答,是一种具有开发应用前景的ASF亚单位疫苗。
为了实现上述目的,本发明采用的具体方案为:
本发明的目的一是提供一种含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗,以三种重组ASFV抗原融合蛋白OPMT、OPET和OCET中的至少两种为活性成分;
所述OPMT由OprI、ASFV抗原p30、修饰的ASFV抗原p54和TT通过连接肽(Linker)融合而成,通式为OprI-(Linker 1)3-p30-(Linker 1)3-mp54-(Linker 2)-TT;
所述OPET由OprI、ASFV结构蛋白p72的4个已验证抗原表位、pE248R的N段氨基酸序列和TT通过连接肽(Linker)融合而成,通式为:OprI-(Linker 1)3-p72抗原表位1-(Linker1)3-p72抗原表位2-(Linker 1)3-p72抗原表位3-(Linker 1)3-p72抗原表位4-(Linker 1)3-pE248R的N段氨基酸序列-(Linker 2)-TT;
所述OCET由OprI、CD2v的N段氨基酸序列、pEP153R的C段氨基酸序列和TT通过连接肽(Linker)融合而成,通式为:OprI-(Linker 1)3-CD2v的N 段氨基酸序列-(Linker 1)2-pEP153R的C段氨基酸序列-(Linker 2)-TT;
其中,所述Linker 1的氨基酸序列为GGGGS;所述Linker 2的氨基酸序列为PG。
作为对上述“鸡尾酒”疫苗的进一步优化,所述OPMT的氨基酸序列如SEQ ID NO:4所示,所述OPET的氨基酸序列如SEQ ID NO:5所示,所述OCET的氨基酸序列如SEQ ID NO:6所示。优选地,编码所述OPMT的核苷酸序列如SEQ ID NO:1所示,编码所述OPET的核苷酸序列如SEQ ID NO:2所示,编码所述OCET的核苷酸序列如SEQ ID NO:3所示。
作为对上述“鸡尾酒”疫苗的进一步优化,所述“鸡尾酒”疫苗以三种重组ASFV抗原融合蛋白OPMT、OPET和OCET为活性成分。优选地,还包括佐剂,是将OPMT、OPET和OCET混合后与佐剂配伍后制得。
本发明的目的二是提供所述含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗在制备治疗/预防非洲猪瘟病毒感染的药物方面的应用。
由于采用了上述技术方案,本发明具有如下的优点:
1、本发明采用的3种重组蛋白均可在原核表达系统(大肠杆菌)中诱导表达,表达量高、易于纯化;
2、选择pET载体系列时,3种重组蛋白均以融合蛋白形式表达;重组蛋白的C端携带6×His标签,对融合蛋白的功能没有影响,而且经一步纯化得到的重组蛋白的纯度约为90%;
3、由3种重组蛋白制成的鸡尾酒疫苗共含有6种ASFV抗原,包括重要的结构蛋白和非结构蛋白,诱导的体液和细胞免疫应答更加全面;
4、利用本发明制备的ASFV“鸡尾酒”疫苗在接种动物体内诱导产生高水平的特异性抗体和细胞免疫。并经中和试验证实,所述“鸡尾酒”疫苗诱导产生的抗体在体外对ASFV感染具有显著的抑制作用,是一种有应用前景的ASF亚单位疫苗。
附图说明
图1为本发明实施列中3种重组ASFV抗原融合蛋白纯化后的SDS-PAGE检测结果。泳道1:纯化的OPMT;泳道2:纯化的OPET;泳道3:纯化的OCET;泳道4:蛋白分子量标准(Marker)。
图2为本发明实施列中利用6×His单克隆抗体(A)和ASFV阳性血清(B)对3种重组蛋白进行鉴定的Western blotting结果。泳道1:纯化的OPMT;泳道2:纯化的OPET;泳道3:纯化的OCET。
图3本发明实施列中首次免疫猪后不同时间点血清中p30 (A)、p54 (B)、p72 (C)、pE248R (D)、CD2v (E)和pEp153R (F)特异性IgG的消长结果。
图4为本发明实施列中首次免疫猪后35天,外周血单核淋巴细胞经灭活ASFV刺激后淋巴细胞增殖水平检测。
图5为本发明实施列中首次免疫猪后35天,外周血单核淋巴细胞经灭活ASFV刺激后分泌IFN-γ、IL-2和TNF-α 的CD8+ T细胞检测结果。
图6为本发明实施列中首次免疫猪后42天,免疫血清抑制ASFV在猪肺泡巨噬细胞(PAM)内复制的间接免疫荧光结果。
图7为本发明实施列中ASFV与首次免疫后42天的血清孵育后培养的ASFV基因组拷贝数(A)及病毒中和率(B)。
具体实施方式
本发明的发明人在研究中发现,通过基因融合和串联表达的方式得到OprI-p30-modified p54-TT、OprI-p72 epitope-pE248R的N段氨基酸序列-TT和OprI-CD2v的N段氨基酸序列-pEP153R的C段氨基酸序列-TT三种重组ASFV抗原融合蛋白,将这3种重组ASFV抗原融合蛋白按一定比例混合后,与佐剂配伍成“鸡尾酒”疫苗,免疫动物后诱导产生中和抗体和细胞免疫应答,说明该疫苗形式是一种有应用开发前景的ASF亚单位疫苗控。3种重组ASFV抗原融合蛋白具体如下:
(1) 重组ASFV抗原融合蛋白OPMT,所述重组蛋白由OprI、ASFV抗原p30、修饰的ASFV抗原p54和TT通过连接肽(Linker)融合而成,所述重组蛋白的通式为 OprI-(Linker1)3-p30-(Linker 1)3-mp54-(Linker 2)-TT;
(2) 重组ASFV抗原融合蛋白OPET,所述重组蛋白由OprI、ASFV结构蛋白p72的4个抗原表位、pE248R的N段氨基酸序列和TT通过连接肽(Linker)融合而成,所述重组蛋白的通式为:OprI-(Linker 1)3-p72抗原表位1-(Linker 1)3-p72抗原表位2-(Linker 1)3-p72抗原表位3-(Linker 1)3-p72抗原表位4-(Linker 1)3-pE248R的N段氨基酸序列-(Linker2)-TT;
(3) 重组ASFV抗原融合蛋白OCET,所述重组蛋白由OprI、CD2v的N段氨基酸序列、pEP153R的C段氨基酸序列和TT通过连接肽(Linker)融合而成,所述重组蛋白的通式为:OprI-(Linker 1)3-CD2v的N 段氨基酸序列-(Linker 1)2-pEP153R的C段氨基酸序列-(Linker 2)-TT;
其中,所述的Linker 1氨基酸序列为GGGGS;所述的Linker 2氨基酸序列为PG。
根据本发明的实施方案中,所述的重组ASFV抗原融合蛋白OPMT、OPET和OCET的氨基酸序列分别为SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6。
在本发明的实施方案中,所述重组ASFV抗原融合蛋白OPMT、OPET和OCET编码的核苷酸序列分别为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3。
本发明还提供了一种表达载体,所述表达载体由骨架质粒可修饰地连接编码上述重组蛋白的核苷酸序列形成;优选地,所述骨架质粒选自pET系列载体,更优选为pET-30a(+)。
上述重组蛋白的表达、纯化及鉴定方法,所述方法包括:
(1) 载体构建:构建重组表达载体,所述表达载体由骨架质粒可修饰地连接编码上述重组蛋白的核苷酸序列形成;优选地,所述骨架质粒选自pET系列载体,更优选为pET-30a(+);
(2) 转化及阳性克隆的筛选:将步骤(1)中的表达载体转化至宿主菌感受态细胞,经诱导和SDS-PAGE鉴定得到能够表达目的蛋白的重组菌株;
(3) 诱导表达:将步骤(2)中的阳性菌株转接生长到一定浓度时加入IPTG对重组蛋白进行诱导表达;
(4) 蛋白纯化:收集步骤(3)中的菌体,经超声破碎、包涵体溶解、Ni螯合亲和层析纯化和透析得到目的蛋白;
(5)重组蛋白的鉴定:采用SDS-PAGE和Western blotting 对步骤(4)中获得的重组蛋白鉴定。
上述重组蛋白用于制备ASF “鸡尾酒”疫苗的方法,包括:
蛋白浓度测定:采用Bradford法对纯化的重组蛋白进行定量;
抗原的配制:将重组蛋白稀释到相同浓度并按一定比例进行混合;
疫苗的乳化:将(2)中的抗原混合物与等体积ISA206佐剂乳化后制成疫苗。
为了更好的理解本发明的内容,下面结合具体实施方法对本发明内容作进一步说明,但发明的保护内容不局限于以下实施例。
重组质粒的构建
(1)根据GenBank现有ASFVASFV-SY18 (登录号:MH766894.1)选取p30和p54的氨基酸序列,其中p54的跨膜区His30-Phe52替换连接肽(GGGGS)3得到mP54,将OprI(登录号:X13748.1)、p30和mP54通过连接肽(GGGGS)3依次相连,再通过短连接肽PG与TT串联得到重组融合蛋白OPMT的氨基酸序列;
(2)根据The Immune Epitope Database (IEDB) 数据库中已验证的4个ASFV p72表位(表位ID :141844、141941、141989、142069),通过(GGGGS)3柔性Linker依次串联,将OprI、串联后的p72表位以及ASFV-SY18结构蛋白pE248R (蛋白ID:AYW34102.1) N段氨基酸序列(Met1-Lys198)通过(GGGGS)3依次相连,再通过短连接肽PG与TT串联得到重组融合蛋白OPET的氨基酸序列;
(3) 将OprI通过(GGGGS)3与ASFV-SY18 CD2v (蛋白ID:AYW34030.1) 的N段氨基酸序列(Asp17-Tyr206)相连,再通过(GGGGS)2与pEP153R (蛋白ID:AYW34029.1) 的C段氨基酸序列(Asn49-Lys158)相连,最后通过短连接肽PG与TT串联得到重组融合蛋白OCET的氨基酸序列。
将以上3种重组融合蛋白的氨基酸序列按大肠杆菌的密码子偏好分别转换为相应的核苷酸序列,在设计DNA序列的5´端和3´端分别引入特异性酶切位点NdeI和XhoI,委托南京金斯瑞生物科技有限公司合成,并克隆到pET-30a(+)表达载体上,获得重组表达质粒pET-30a(+)-OPMT、pET-30a(+)-OPET、pET-30a(+)-OCET,基因测序结果显示:3种重组质粒上NdeI和XhoI间的序列与设计目的基因的同源性为100%,读码框完全正确。
重组蛋白的诱导表达及纯化
将3种已构建的重组质粒分别转化大肠杆菌BL21(DE3) 感受态细胞,分别挑取阳性克隆接种于5 mL含LB培养基(Kan+)中,37 ℃ 220 rpm培养8 h后按1:100接种到1 L LB培养基(Kan+)中,37 ℃ 220 rpm培养。待菌液的OD600达到0.4-0.6时加入终浓度为1 mMIPTG诱导,37 ℃ 220 rpm继续培养4 h。7000 rpm离心8 min分别收集菌体,向3种收获的菌体中分别加入50 mL 结合缓冲液(300 mM NaCl, 20 mM NaH2PO4, 5 mM咪唑; pH 8.0)重悬菌体,将菌体超声裂解40 min,经10000 rpm离心25min收集包涵体。将3种包涵体分别在含6 M盐酸胍和2 % triton X-100的结合缓冲液中溶解,10000 rpm离心25 min收集的上清与Ni-excel亲和介质在4 ℃条件下旋转结合1.5 h,用20 mL洗涤缓冲液(8 M尿素,300 mMNaCl, 20 mM NaH2PO4, 20 mM咪唑; pH 8.0)淋洗,最后用20 mL洗脱缓冲液(8 M尿素,300mM NaCl, 20 mM NaH2PO4, 500 mM咪唑; pH 8.0)对结合的重组蛋白进行洗脱。洗脱的重组蛋白依次在含8 M、6 M、4 M、2 M和0 M的透析液 (20 mM NaH2PO4, 300 mM NaCl, 2 mMβ-mercaptoethanol, 0.4% arginine, 10% glycerol, pH 7.5)中进行透析复性。每种梯度透析液透析8 h,直到透析至尿素浓度降为0 M,取少量复性的重组蛋白进行SDS-PAGE检测。结果显示,重组蛋白OPMT、OPET和OCET大小分别为64、50和40 kDa,与复性前重组蛋白大小完全一致(图1)。
重组蛋白的Western blotting鉴定
分别取3种重组蛋白80 μL与5×上样缓冲液混合后煮沸10分钟,进行SDS-PAGE(80V 30 min,120V 1 h 10 min),然后电转印于硝酸纤维素膜(PVDF)上,并用5%脱脂奶粉室温封闭2 h;然后将PVDF膜分别与鼠抗6×His单克隆抗体(1:5000倍稀释)和ASFV阳性血清(1:300倍稀释),4 ℃过夜;用1×PBST洗涤6次,将过氧化物酶标记的羊抗鼠IgG(1:5000倍稀释)和抗猪IgG(1:5000倍稀释)分别加入对应的PVDF膜中,室温孵育1 h;用1×PBST洗涤6次,加入ECL发光液,采用多功能成像仪采集图像。
Western blotting结果(图2),3种重组蛋白均能被His单克隆抗体识别,且与ASFV阳性血清反应性良好,具有潜在的应用价值。
疫苗制备及免疫方案
采用Bradford法对3种重组蛋白进行浓度测定,分别量取600 µg OPMT、600 µgOPET和1200 µg OCET,混合后将总体积稀释到4 mL,与ISA206佐剂(50g:50g)混合,乳化成水/油/水剂型的疫苗。设置PBS作为对照组。将7头6周龄雌性小猪随机分为2组(实验组4头,对照组3头),将制备好的疫苗以肌肉注射的方式,按照下列表中的免疫分组以及免疫剂量,初免后21天加强免疫1次。
结果及分析:根据不同浓度的蛋白标准品与Bradford溶液反应在592 nm处的OD值所建立的标准曲线为y=0.00049964x+0.28323,R2=0.993,线性良好,重组蛋白OPMT、OPET和OCET与等量Bradford反应的吸光度分别为0.637、0.741和0.539,3种重组蛋白的浓度分别为707.2μg/mL、915.2 μg/mL和512.1 μg/mL。
抗原特异性IgG检测采集免疫前及免疫后14、21、35和42天血样,分离血清,用实验室建立的p30、p54、p72、pE248R、CD2v和pEP153R间接ELISA检测血清中特异性IgG含量。具体程序如下:包被:分别用纯化重组p30(0.125 µg/mL)、p54(0.5 µg/mL)、p72(1 µg/mL)、pE248R(1 µg/mL)、CD2v(2 µg/mL)和pEP153R(2 µg/mL)包被96孔酶标板,每孔100 μL,4 ℃过夜;封闭:弃掉包被液,加入封闭液(5%脱脂奶粉,200 μL/孔), 37 ℃孵育2 h;孵育一抗:弃掉封闭液,用1×PBST洗板5次并拍干,将免疫猪血清经1∶100稀释后分别加入酶标板中,100 µL/孔,37 ℃孵育1小时;孵育二抗:弃掉液体,用1×PBST洗板5次后拍干。加入1∶10000稀释的HRP标记羊抗猪IgG,100 µL/孔,37 ℃孵育1 h;显色:弃掉液体,用1×PBST洗5次,加入底物显色液,100 μL/孔,室温避光反应10 min;检测:加入终止液(2 M H2SO4),每孔100μL,测定OD450 nm处吸光度值。
如图3所示,所有实验动物免疫前和PBS组,血清中均未检测到p30、p54、p72、pE248R、CD2v和pEP153R的特异性IgG抗体。“鸡尾酒”疫苗免疫后7天,已经产生p30、p54、p72、pE248R、CD2v和pEP153R的特异性IgG抗体,加强免疫后抗体滴度明显升高,其中p30和p54特异性IgG抗体水平最高,p72和pE248R特异性IgG水平次之,CD2v和pEP153R 特异性IgG最低,但均显著高于对照组(p < 0.001)。该结果说明该“鸡尾酒”疫苗具有良好的免疫原性,免疫猪后能诱导产生较高水平的特异性IgG。
淋巴细胞增殖实验
免疫42后天,采集抗凝血5 mL,用等体积灭菌的PBS稀释后;加入含有10 mL分离液的离心管,保持两液面界面清晰;采用水平转子离心机800×g离心30 min(室温);小心吸取中间的白膜层到另一离心管,加入20 mL无菌PBS重悬细胞,250×g离心10 min.弃上清,重复该步骤1次;将收集的外周血单核淋巴细胞(PBMC)用0.5 mL PBS重悬,加入0.5 mL 2.5 µM CFSE工作液迅速混合均匀;将细胞悬液放置于37 ℃水浴10 min,每隔2 min轻摇一次;向细胞悬液中加入5 mL RPMI-1640,1500 rpm离心5min弃上清,重复该步骤1次;用含10% FBS的RPMI-1640重悬PBMC并调整细胞密度至1×106/mL,接种24孔板,每孔1 mL。向实验组各孔中加入105 HAD50灭活的ASFV,同时设未染色组、未加刺激剂组和5 µg/mL ConA刺激组分别作为空白对照、阴性对照和阳性对照,37 ℃培养72 h;1500 rpm离心5min收集细胞,用PBS洗涤2次后重悬至100 µL PBS中,采用流式细胞仪测定细胞中FITC的荧光强度,计算活化淋巴细胞百分比。
如图4所示,“鸡尾酒”疫苗免疫组的PBMC经灭活ASFV刺激后,低荧光强度FITC细胞群的比例显著高于空白对照和PBS组(p < 0.01),即实验组的淋巴细胞刺激后增殖明显。实验结果表明:“鸡尾酒”疫苗能激活细胞免疫,诱导良好的免疫记忆。
抗原特异性CD8+ T淋巴细胞检测
PBMC分离如2.6所述,调整细胞密度1×106/mL并铺至24孔板中,每孔1mL;向实验组各孔中加入105 HAD50灭活的ASFV,将不加刺激剂的孔作为阴性对照,加入25 μg/mL 佛波酯和1 μg/mL离子霉素的孔作为阳性对照,37 ℃5 % CO2培养40 h;向各孔加入1.7 μg/mL莫能霉素,37 ℃5% CO2继续孵育8 h;分别收集各孔的细胞,用PBS洗涤2次后,重悬至100µL PBS中,加入PerCP-Cy5.5标记的抗CD3单克隆抗体和PE标记的抗CD8单克隆抗体各1 μL,4 ℃染色30 min;加入PBS洗涤2次,1500 rpm离心5 min收集细胞,按照固定剂及破膜试剂使用说明书,样本中加500 µL固定剂涡旋混匀并在室温黑暗条件下作用20min,用1mL 1×Perm/Wash 洗涤1次,1500 rpm离心5 min收集细胞,加入1.5mL 1×Perm/Wash重悬细胞并在室温黑暗条件下作用5 min;1500 rpm离心5 min收集细胞,用100 µL 1×Perm/Wash重悬细胞,加入AF700标记的抗IL-2,Pecy7标记的抗TNF-α和AF647标记的抗IFN-γ单克隆抗体,4度避光染色30 min;用1×Perm/Wash洗涤2次,将细胞重悬至100 µL含2% FBS的PBS中进行流式细胞仪检测分析,确定IFN-γ、IL-2和TNF-α阳性的CD8+ T细胞占T淋巴细胞的百分比。
如图5所示,“鸡尾酒”疫苗免疫组的PBMC经灭活ASFV刺激后,分泌IFN-γ、IL-2和TNF-α的CD8+ T细胞的比例显著高于阴性对照和PBS组,其中IL-2+ CD8+ T细胞比例最高。该实验结果证明:“鸡尾酒”疫苗免疫后能够显著激活T淋巴细胞,产生记忆性T淋巴细胞,在诱导抗原特异性细胞免疫应答方面具有优势。
间接免疫荧光实验
取首次免疫42天后的血样,分离血清并将其按1:5稀释,置于56 ℃灭活30 min,加入24孔板中,每孔200 μL,并按MOI=0.01(按待接种的PAM细胞计算)加入ASFV CN/SC/2019,37 ℃ 孵育过夜。取血清/病毒混合物接种单层PAM细胞(24孔板),每孔200 μL,37 ℃ 5 %CO2吸附1 h,每隔10 min轻轻摇动1次细胞培养板;弃掉血清/病毒混合物,并用PBS洗3遍,加入0.5 mL含5 % FBS的RPMI-1640,37 ℃ 5 % CO2培养48 h;用PBS洗3遍,每孔加入1 mL4 %多聚甲醛,4 ℃固定1 h;弃掉多聚甲醛,每孔加入0.5 mL 0.25 % triton X-100,室温通透10 min;每孔用1 mL PBS清洗3次,每次3 min并在微量振荡器上混匀;每孔加入1 mL5% BSA封闭60 min;弃掉封闭液,向每孔加入0.5 mL以1:2000稀释的抗p30单克隆抗体,37℃孵育60 min;弃掉孔中的液体并用PBS洗3遍,在避光条件下每孔加入0.5 mL 1:500稀释的TRITC标记的羊抗猪IgG,37 ℃孵育60 min;每孔加入两滴DAPI并补加0.5 mL PBS,室温静置5 min, 每孔用1 mL PBS清洗3次;最后每孔加入0.5 mL的PBS,用Leica DM16000B倒置荧光显微镜观察并拍照。
如图6所示,与阴性对照相比,“鸡尾酒”疫苗免疫组血清与ASFV孵育后,明显降低TRITC荧光强度和阳性细胞的数量,而PBS免疫组的TRITC荧光强度和阳性细胞数量均无明显改变,结果证明:“鸡尾酒”疫苗诱导产生的抗体在体外能够抑制ASFV感染PAM细胞。
病毒中和实验将免疫前和免疫后42天的血清按1:5稀释,置于56 ℃灭活30 min,加入24孔板中(200 μL/孔),并按MOI=0.01(按待接种的PAM细胞计算)加入ASFV CN/SC/2019,37 ℃ 孵育过夜。取血清/病毒混合物接种单层PAM细胞(24孔板),每孔200 μL,37 ℃5 % CO2吸附1 h,每隔10 min轻轻摇动1次细胞培养板;弃掉血清/病毒混合物,并用PBS洗3遍,加入0.5 mL含5 % FBS的RPMI-1640,37 ℃ 5% CO2培养48 h;,收集细胞,利用DNA基因组提取试剂盒,分别提取各实验组ASFV基因组,采用ASFV qPCR试剂盒扩增,计算样品ASFV的拷贝数,间接计算病毒中和率:病毒中和率(%)=100-100*免疫血清孵育后ASFV拷贝数/免疫前血清孵育后ASFV拷贝数。
如图7A所示,与免疫前血清(对照组)相比,“鸡尾酒”疫苗免疫组血清与ASFV孵育后,接种PAM细胞的ASFV基因组拷贝数显著降低(p < 0.001),而PBS免疫组血清与ASFV孵育后接种PAM细胞的ASFV拷贝数并无明显下降,根据ASFV基因拷贝数计算出这两种免疫血清在体外对ASFV的平均中和率分别为82.8%和3.2%(图7B)。说明本发明制备的“鸡尾酒”疫苗诱导了中和抗体,且体外能够显著抑制ASFV感染PAM细胞,是一种非常又前景的疫苗配伍形式。
需要说明的是,以上所述的实施方案应理解为说明性的,而非限制本发明的保护范围,本发明的保护范围以权利要求书为准。对于本领域技术人员而言,在不背离本发明实质和范围的前提下,对本发明作出的一些非本质的改进和调整仍属于本发明的保护范围。
SEQUENCE LISTING
<110> 中国农业科学院兰州兽医研究所
<120> 含分子内佐剂的重组非洲猪瘟抗原"鸡尾酒"疫苗及其应用
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catatgaaca acgttctgaa atttagcgcg ctggcgctgg cggcggtgct ggcgaccggt 60
tgcagcagcc acagcaagga aaccgaggcg cgtctgaccg cgaccgagga tgcggcggcg 120
cgtgcgcaag cgcgtgcgga cgaagcgtat cgtaaagcgg atgaagcgct gggtgcggcg 180
cagaaagcgc agcaaaccgc ggatgaagcg aacgagcgtg cgctgcgtat gctggaaaaa 240
gcgagccgta aaggtggcgg tggcagcggt ggcggtggca gcggtggcgg tggcagcatg 300
gacttcattc tgaacatcag catgaagatg gaagttatct tcaagaccga cctgcgtagc 360
agcagccaag tggttttcca cgcgggtagc ctgtacaact ggtttagcgt tgagatcatt 420
aacagcggcc gtattgtgac caccgcgatc aaaaccctgc tgagcaccgt gaagtatgac 480
attgttaaaa gcgcgcgtat ctacgcgggt cagggctata ccgaacacca ggcgcaagag 540
gaatggaaca tgattctgca cgtgctgttc gaggaagaga ccgagagcag cgcgagcagc 600
gaaaacatcc acgagaagaa cgataacgaa accaacgagt gcaccagcag cttcgaaacc 660
ctgtttgaac aagagccgag cagcgaggtt ccgaaggaca gcaaactgta catgctggcg 720
cagaaaaccg tgcaacacat tgaacagtat ggcaaggcgc cggatttcaa caaagttatc 780
cgtgcgcaca actttattca gaccatctac ggcaccccgc tgaaggaaga ggaaaaagag 840
gtggttcgtc tgatggtgat caagctgctg aagaaaaagg gtggcggtgg cagcggtggc 900
ggtggcagcg gtggcggtgg cagcatggat agcgaattca tggatagtga atttttccag 960
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cgtgcgcaag cgcgtgcgga cgaagcgtat cgtaaagcgg atgaagcgct gggtgcggcg 180
cagaaagcgc agcaaaccgc ggatgaagcg aacgagcgtg cgctgcgtat gctggaaaaa 240
gcgagccgta aaggtggcgg tggcagcggt ggcggtggca gcggtggcgg tggcagcatg 300
cagaaagacc tggttaacga attcccgggt ctgttcgttc gtcagtctcg tttcatcgcg 360
ggtcgtccgt ctcgtcgtaa catccgtttc aaaccgggtg gtggtggttc tggtggtggt 420
ggttctggtg gtggtggttc tgcgtgctct tctatctctg acatctctcc ggttacctac 480
ccgatcaccc tgccgatcat caaaaacatc tctgttaccg cgcacggtat caacctgatc 540
gacaaaggtg gtggtggttc tggtggtggt ggttctggtg gtggtggttc ttactgcgaa 600
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gaatactctt ctgacgttac caccctgccg ggtctgaaac cgcgtgaaga ataccagccg 720
tctggtggtg gtggttctgg tggtggtggt tctggtggtg gtggttctct gtgcaacatc 780
cacgacctgc acaaaccgca ccagtctaaa ccgatcctga ccgacgaaaa cgacacccag 840
cgtacctgct ctcacaccaa cccgggtggt ggtggttctg gtggtggtgg ttctggtggt 900
ggtggttcta tgggtggttc tacctctaaa aactctttca aaaacaccac caacatcatc 960
tctaactcta tcttcaacca gatgcagtct tgcatctcta tgctggacgg taaaaactac 1020
atcggtgttt tcggtgacgg taacatcctg aaccacgttt tccaggacct gaacctgtct 1080
ctgaacacct cttgcgttca gaaacacgtt aacgaagaaa acttcatcac caacctgtct 1140
aaccagatca cccagaacct gaaagaccag gaagttgcgc tgacccagtg gatggacgcg 1200
ggtacccacg accagaaaac cgacatcgaa gaaaacatca aagttaacct gaccaccacc 1260
ctgatccaga actgcgtttc ttctctgtct ggtatgaacg ttctggttgt taaaggtaac 1320
ggtaacatcg ttgaaaacgc gacccagaaa cagtctcagc agatcatctc taactgcctg 1380
cagggttcta aacaggcgat cgacaccacc accggtatca ccaacaccgt taaccagtac 1440
tctcactaca cctctaaaaa cttcttcgac ttcatcgcgg acgcgatctc tgcggttttc 1500
aaaccgggtc agtacatcaa agcgaactct aaattcatcg gtatcaccga actgctcgag 1560
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tgcagcagcc acagcaagga aaccgaggcg cgtctgaccg cgaccgagga tgcggcggcg 120
cgtgcgcaag cgcgtgcgga cgaagcgtat cgtaaagcgg atgaagcgct gggtgcggcg 180
cagaaagcgc agcaaaccgc ggatgaagcg aacgagcgtg cgctgcgtat gctggaaaaa 240
gcgagccgta aaggtggcgg tggcagcggt ggcggtggca gcggtggcgg tggcagcatg 300
gactactggg tttctttcaa caaaaccatc atcctggact ctaacatcac caacgacaac 360
aacgacatca acggtgtttc ttggaacttc ttcaacaact ctttcaacac cctggcgacc 420
tgcggtaaag cgggtaactt ctgcgaatgc tctaactact ctacctctat ctacaacatc 480
accaacaact gctctctgac catcttcccg cacaacgacg ttttcgacac cacctaccag 540
gttgtttgga accagatcat caactacacc atcaaactgc tgaccccggc gaccccgccg 600
aacatcacct acaactgcac caacttcctg atcacctgca aaaaaaacaa cggcaccaac 660
accaacatct acctgaacat caacgacacc ttcgttaaat acaccaacga atctatcctg 720
gaatacaact ggaacaactc taacatcaac aacttcaccg cgacctgcat catcaacaac 780
accatctcta cctctaacga aaccaccctg atcaactgca cctacctgac cctgtcttct 840
aactacttct acaccttctt caaactgtac gagctcggtg gtggtggttc tggtggtggt 900
ggttctcata tgaacaaacc gatctgctac cagaacgacg acaaaatctt ctactgcccg 960
aaagactggg ttggttacaa caacgtttgc tactacttcg gtaacgaaga aaaaaactac 1020
aacaacgcgt ctaactactg caaacagctg aactctaccc tgaccaacaa caacaccatc 1080
ctggttaacc tgaccaaaac cctgaacctg accaaaacct acaaccacga atctaactac 1140
tgggttaact actctctgat caaaaacgaa tctgttctgc tgcgtgactc tggttactac 1200
aaaaaacaga aacacgtttc tctgctgtac atctgctcta aaccgggtca gtacatcaaa 1260
gcgaactcta aattcatcgg tatcaccgaa ctgctcgag 1299
<210> 4
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Gln Ala Gln Glu Glu Trp Asn Met Ile Leu His Val Leu Phe Glu Glu
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Gln Lys Thr Val Gln His Ile Glu Gln Tyr Gly Lys Ala Pro Asp Phe
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Asn Lys Val Ile Arg Ala His Asn Phe Ile Gln Thr Ile Tyr Gly Thr
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Ala Ser Val Gly Lys Pro Val Thr Gly Arg Pro Ala Thr Asn Arg Pro
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Ala Thr Asn Lys Pro Val Thr Asp Asn Pro Val Thr Asp Arg Leu Val
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Ser Gln Thr Met Ser Ala Ile Glu Asn Leu Arg Gln Arg Asn Thr Tyr
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Thr His Lys Asp Leu Glu Asn Ser Leu Pro Gly Gln Tyr Ile Lys Ala
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Ala Tyr Arg Lys Ala Asp Glu Ala Leu Gly Ala Ala Gln Lys Ala Gln
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Leu Thr Asp Glu Asn Asp Thr Gln Arg Thr Cys Ser His Thr Asn Pro
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met
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Gly Gly Ser Thr Ser Lys Asn Ser Phe Lys Asn Thr Thr Asn Ile Ile
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Ser Asn Ser Ile Phe Asn Gln Met Gln Ser Cys Ile Ser Met Leu Asp
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Gly Lys Asn Tyr Ile Gly Val Phe Gly Asp Gly Asn Ile Leu Asn His
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Val Phe Gln Asp Leu Asn Leu Ser Leu Asn Thr Ser Cys Val Gln Lys
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His Val Asn Glu Glu Asn Phe Ile Thr Asn Leu Ser Asn Gln Ile Thr
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Gln Asn Leu Lys Asp Gln Glu Val Ala Leu Thr Gln Trp Met Asp Ala
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<213> 大肠杆菌
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Thr Ala Thr Glu Asp Ala Ala Ala Arg Ala Gln Ala Arg Ala Asp Glu
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Ala Tyr Arg Lys Ala Asp Glu Ala Leu Gly Ala Ala Gln Lys Ala Gln
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Gln Thr Ala Asp Glu Ala Asn Glu Arg Ala Leu Arg Met Leu Glu Lys
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Glu
Claims (6)
1.一种含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗,其特征在于:以三种重组ASFV抗原融合蛋白OPMT、OPET和OCET中的至少两种为活性成分;
所述OPMT由OprI、ASFV抗原p30、修饰的ASFV抗原p54和TT通过连接肽(Linker)融合而成,通式为 OprI-(Linker 1)3-p30-(Linker 1)3-mp54-(Linker 2)-TT;
所述OPET由OprI、ASFV结构蛋白p72的4个已验证抗原表位、pE248R的N段氨基酸序列和TT通过连接肽(Linker)融合而成,通式为:OprI-(Linker 1)3-p72抗原表位1-(Linker 1)3-p72抗原表位2-(Linker 1)3-p72抗原表位3-(Linker 1)3-p72抗原表位4-(Linker 1)3-pE248R的N段氨基酸序列-(Linker 2)-TT;
所述OCET由OprI、CD2v的N段氨基酸序列、pEP153R的C段氨基酸序列和TT通过连接肽(Linker)融合而成,通式为:OprI-(Linker 1)3-CD2v的N段氨基酸序列-(Linker 1)2-pEP153R的C段氨基酸序列-(Linker 2)-TT;
其中,所述Linker 1的氨基酸序列为GGGGS;所述Linker 2的氨基酸序列为PG。
2.根据权利要求1所述的“鸡尾酒”疫苗,其特征在于:所述OPMT的氨基酸序列如SEQ IDNO:4所示,所述OPET的氨基酸序列如SEQ ID NO:5所示,所述OCET的氨基酸序列如SEQ IDNO:6所示。
3.根据权利要求2所述的“鸡尾酒”疫苗,其特征在于:编码所述OPMT的核苷酸序列如SEQ ID NO:1所示,编码所述OPET的核苷酸序列如SEQ ID NO:2所示,编码所述OCET的核苷酸序列如SEQ ID NO:3所示。
4.根据权利要求1-3任意一种所述的“鸡尾酒”疫苗,其特征在于:所述“鸡尾酒”疫苗以三种重组ASFV抗原融合蛋白OPMT、OPET和OCET为活性成分。
5.根据权利要求4所述的“鸡尾酒”疫苗,其特征在于:还包括佐剂,是将OPMT、OPET和OCET混合后与佐剂配伍后制得。
6.根据权利要求1所述的含分子内佐剂的重组非洲猪瘟抗原“鸡尾酒”疫苗在制备治疗/预防非洲猪瘟病毒感染的药物方面的应用。
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IRENE RODRÍGUEZ ET AL: "The African Swine Fever Virus Virion Membrane Protein pE248R Is Required for Virus Infectivity and an Early Postentry Event", JOURNAL OF VIROLOGY, vol. 83, no. 23, pages 12290 - 12300 * |
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