CN110092840A - 一种鸡传染性喉气管炎、减蛋综合征二联多表位疫苗 - Google Patents
一种鸡传染性喉气管炎、减蛋综合征二联多表位疫苗 Download PDFInfo
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Abstract
本发明涉及一种用于预防鸡传染性喉气管炎和减蛋综合征的融合蛋白。具体地，利用基因重组技术，将8段与鸡传染性喉气管炎病毒gB、gD、gE蛋白相关的抗原表位多肽以及6段与减蛋综合征病毒Penton、Fiber蛋白相关的抗原表位多肽，与分子佐剂IL‑8串联，连入载体，转化宿主菌，经过发酵、纯化、乳化工艺制备，得到一种鸡传染性喉气管炎、减蛋综合征二联多表位疫苗。动物实验表明，该疫苗安全性高，使用方便，能诱导机体产生显著的体液免疫和细胞免疫反应，且抗体持续期长，可有效预防鸡传染性喉气管炎病毒和减蛋综合征病毒的感染。
Description
技术领域
本发明属于生物技术基因工程领域，涉及一种用于预防鸡传染性喉气管炎和减蛋综合征的融合蛋白。具体地，利用基因重组技术，将8段与鸡传染性喉气管炎病毒gB、gD、gE蛋白相关的抗原表位多肽以及6段与减蛋综合征病毒Penton、Fiber蛋白相关的抗原表位多肽，与分子佐剂IL-8串联，连入载体，转化宿主菌，经过发酵、纯化、乳化工艺制备，得到一种鸡传染性喉气管炎、减蛋综合征二联多表位疫苗。动物实验表明，该疫苗安全性高，使用方便，能诱导机体产生显著的体液免疫和细胞免疫反应，且抗体持续期长，可有效预防鸡传染性喉气管炎病毒和减蛋综合征病毒的感染。
背景技术
鸡传染性喉气管炎（Infectious laryngotracheitis，ILT）是由鸡传染性喉气管炎病毒（Infectious laryngotracheitis virus，ILTV）引起的一种鸡的急性呼吸道传染病，主要特征为呼吸困难、咳嗽，咳出含有血液的渗出物，喉部和气管黏膜肿胀、出血并形成糜烂。传播快，死亡率较高，且各个年龄的鸡只都易感，尤其蛋鸡处于产蛋高峰期时非常容易感染，能造成产蛋率降低，给养殖业带来巨大经济损失。
目前用于预防传染性喉气管炎病毒的疫苗主要是弱毒苗，弱毒苗一般经点眼、滴鼻免疫，但一般毒力较强，能引起流泪、眼肿或呼吸道症状等不同的反应，甚至成批死亡，且弱毒苗接种后的8-10天内不能接种法氏囊弱毒苗和新城疫弱毒苗，疫苗之间会彼此产生干扰和抑制（王华明.蛋鸡传染性喉气管炎的流行病学、症状与防治措施.现代畜牧科技.2016.7:129）；而强毒苗接种后4～5天后会出现水肿和出血性炎症反应，排毒危险性很大，一般只适用于发病鸡场。目前ILT疫苗一般仅进行一次免疫，于12周左右进行，但临床检测结果表明，一次免疫的效果并不理想，免疫后鸡群仍存在一定比例的阴性样本（张国中.鸡传染性喉气管炎的流行病学特点及防控.兽医导刊.2010.2:27）。
在病毒载体疫苗方面，抗ILTV的重组禽痘病毒载体苗在美国已经商业化生产多年，并广泛用于各品种鸡的免疫。我国也于2004年自主研发了鸡传染性喉气管炎重组鸡痘病毒基因工程疫苗，且取得了不错的临床效果，哈尔滨维科生物技术开发公司对该产品的生产工艺进行优化升级，第二代鸡传染性喉气管炎重组鸡痘病毒基因工程疫苗重返市场，但该疫苗对接种鸡群有严格要求，由于疫苗是以鸡痘病毒作为载体，受鸡痘疫苗干扰，故在接种前，鸡群不能接种其它形式的鸡痘疫苗。此外，该疫苗刺种部位要在鸡翅内侧无毛处翼膜下，不能伤及血管、肌肉和关节，对免疫人员操作要求较高。
目前已有不少关于α-疱疹病毒的基因疫苗相关报道，但对ILTV表位疫苗和DNA疫苗报道较少，且免疫效果不理想。孟松树等（2000）将分别构建的含有鸡传染性喉气管炎病毒王岗株gB、gC和gD基因的重组真核表达质粒肌肉注射雏鸡，攻毒后免疫保护率仅为79%。姬向波等（2006）构建了表达ILTV烟台株gB基因的重组真核表达质粒，并对4周龄非免疫鸡群进行免疫注射，结果表明该重组质粒能够诱导机体产生特异性体液免疫和细胞免疫应答，但保护效果还不能与弱毒苗相比。因而急需一种既能克服传统活疫苗的返毒风险，又能提供很好免疫效果的、安全的、使用方便的鸡传染性喉气管炎疫苗。
鸡减蛋综合征（eggs drop syndrome，EDS）是世界性的商品蛋鸡和母鸡产蛋下降的一种病毒性疾病，自1976年荷兰科学家Van Eck等首次报道以来，许多国家和地区都有流行，已成为当今引起产蛋损失的主要原因之一。群发性产蛋下降、产蛋异常、蛋体畸形、蛋质低劣等症状是本病患鸡的主要表现。该病是由禽腺病毒Ⅲ群中的病毒引起，所有年龄的鸡均可感染，但幼鸡感染后不表现任何临床症状，母鸡只是在产蛋高峰期表现明显，发病期可持续4-10周，在几周内产蛋会快速或大幅度下降，鸡群减蛋可达20%-30%，甚至40%-50%，给蛋鸡饲养带来重大经济损失。目前用于预防减蛋综合征的疫苗主要是油佐剂灭活疫苗，而油佐剂灭活疫苗对免疫剂量要求严格，张云山等（2016）研究发现，以低于推荐剂量50%的剂量免疫油佐剂灭活疫苗会导致破蛋率显著上升（P＜0.05）；以高于推荐剂量50%的剂量免疫会导致产蛋量显著下降（P＜0.05）、破蛋率显著上升（P＜0.05）、料蛋比显著升高（P＜0.05）、蛋黄胆固醇含量显著升高（P＜0.05）。因此，目前急需研究一种免疫效果好，且对产蛋性能影响小的疫苗。
细胞因子（Cytokine）是指由活性细胞分泌的具有生物学活性的多肽或蛋白质，对细胞生长有调节作用，具有明显的免疫佐剂效应，可增强疫苗的保护效应，激发机体对抗原的免疫反应。白细胞介素-8（IL-8）是趋化因子家族的一种细胞因子，在参与和调节生殖生理和病理过程的作用已得到肯定，其作用机制之一就是与其特异性受体结合而发挥作用。
目前尚无国内或国际注册的ILT与EDS二联基因工程疫苗。
为了提供一种可以减少免疫次数的、安全的、有效的、能够同时预防鸡传染性喉气管炎和减蛋综合征的疫苗，本发明通过比对筛选，分别选取多段与ILTV gB、gD、gE蛋白及EDSV Penton、Fiber蛋白相关的抗原表位多肽，串联分子佐剂IL-8，获得具有免疫原性的融合蛋白，制成鸡传染性喉气管炎、减蛋综合征二联多表位疫苗。
发明内容
本发明根据不同结构蛋白在病毒感染过程中的作用，利用生物信息学软件对ILTV和EDSV不同蛋白的亲水性、抗原性、可塑性、表面可及性和 Garnier-Robson 的二级结构进行分析，选择ILTV主要结构蛋白gB、gD、gE的多个抗原表位，以及EDSV Penton、Fiber蛋白的多个抗原表位作为疫苗框架结构，通过柔性Linker连接后，再与分子佐剂IL-8串联，克隆入pRSETB载体后转化大肠杆菌，经过发酵、纯化、乳化等工艺，获得具有理想免疫原性的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗。利用本发明制备的疫苗可以有效预防鸡传染性喉气管炎病毒和减蛋综合征病毒的感染。
优选地，本发明所述ILTV gB蛋白抗原表位1，选自SEQ ID No.4的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gB蛋白抗原表位2，选自SEQ ID No.6的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gB蛋白抗原表位3，选自SEQ ID No.8的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gD蛋白抗原表位1，选自SEQ ID No.10的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gD蛋白抗原表位2，选自SEQ ID No.12的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gE蛋白抗原表位1，选自SEQ ID No.14的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gE蛋白抗原表位2，选自SEQ ID No.16的氨基酸序列或其功能等价物。
优选地，本发明所述ILTV gE蛋白抗原表位3，选自SEQ ID No.18的氨基酸序列或其功能等价物。
优选地，本发明所述EDSV Penton蛋白抗原表位1，选自SEQ ID No.20的氨基酸序列或其功能等价物。
优选地，本发明所述EDSV Penton蛋白抗原表位2，选自SEQ ID No.22的氨基酸序列或其功能等价物。
优选地，本发明所述EDSV Penton蛋白抗原表位3，选自SEQ ID No.24的氨基酸序列或其功能等价物。
优选地，本发明所述EDSV Fiber蛋白抗原表位1，选自SEQ ID No.26的氨基酸序列或其功能等价物。
优选地，本发明所述EDSV Fiber蛋白抗原表位2，选自SEQ ID No.28的氨基酸序列或其功能等价物。
优选地，本发明所述EDSV Fiber蛋白抗原表位3，选自SEQ ID No.30的氨基酸序列或其功能等价物。
优选地，本发明所述白介素-8，选自SEQ ID No.32的氨基酸序列或其功能等价物。
本发明所述融合蛋白还包含药学上可接受的盐以及表达所需要的载体。
所述疫苗也包括非免疫活性物质，即为各多肽的连接部分，不具有抗原表位的免疫原性，也不具有任何佐剂活性，主要有纯化标签、接头肽、化学修饰部分等。
本发明所提供的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗具有良好的安全性，以低剂量和高剂量免疫时，均对蛋鸡产蛋性能无显著不良影响，临床上有较高免疫原性，能刺激动物体产生高水平细胞免疫和体液免疫，有效预防鸡传染性喉气管炎病毒和减蛋综合征病毒的感染。此外，本疫苗不依托鸡痘病毒为载体，因而不受鸡痘疫苗的干扰，免疫方法简单易操作。
附图说明
下列附图用于说明本发明的具体实施方案，而不用于限定由权利要求书所界定的本发明范围。
图1为含有融合蛋白编码基因的表达载体pRSETB-ILTV/EDSV-IL-8的示意图。
图2显示了重组表达载体pRSETB-ILTV/EDSV-IL-8用BamHⅠ+ EcoRⅠ酶切后的电泳结果，其中泳道1为DNA Marker2000，泳道2为质粒酶切图，泳道3为未酶切对照，泳道4为空质粒。
图3为融合蛋白编码基因表达产物SDS-PAGE鉴定结果，其中泳道M为分子量Marker，泳道1为诱导纯化样品。
图4为纯化样品Western blot印迹结果，其中泳道M为预染Marker，泳道1为纯化样品，泳道2为阴性对照。
图5显示了疫苗免疫后试验鸡ELISA检测血清特异性抗体结果。
图6显示了疫苗免疫后试验鸡外周血CD4+T淋巴细胞亚类数量的变化。
图7显示了疫苗免疫后试验鸡外周血CD8+T淋巴细胞亚类数量的变化。
具体实施方式
实施例中所述的具体试验方法描述仅是示例性描述，用于详细阐明本发明，但并不构成对本发明范围的限制，以下所述实验方法，没有具体说明的，均按照《分子克隆实验指南》（2002年，第三版，科学出版社）所述方法进行。
实施例一 融合蛋白基因的来源
本发明综合分析国内外鸡传染性喉气管炎和减蛋综合征主要流行株的基因序列、抗原结构、流行病学研究进展，根据ILTV主要结构蛋白gB、gD、gE及EDSV Penton、Fiber蛋白的氨基酸序列，利用生物信息学软件对其亲水性、抗原性、可塑性、表面可及性和二级结构进行分析，预测可能的B细胞抗原表位及T细胞抗原表位，从而确定8段ILTV抗原表位多肽和6段EDSV抗原表位多肽。通过柔性Linker连接形成疫苗骨架结构后再与IL-8串联，该疫苗总体结构为：
ILTV-1 - ILTV-2 - ILTV-3 - ILTV-4 - ILTV-5 - ILTV-6 - ILTV-7 - ILTV-8 -EDSV-1 - EDSV-2 - EDSV-3 - EDSV-4 - EDSV-5 - EDSV-6 - IL-8 - Tag
实施例二 大肠杆菌表达载体与表达菌株的构建
将实施例一中设计好的多肽编码核苷酸送上海英俊生物技术公司合成，核苷酸片段两端分别设计了BamHⅠ（5’端）和EcoRⅠ（3’端）限制性酶切位点，将合成好的片段克隆到pMD18T载体上，序列测定证实插入基因片段与涉及序列一致（见序列表）。将重组质粒命名为pMD18T-ILTV/EDSV-IL-8，用相应的限制性内切酶对质粒进行酶切处理，大肠杆菌表达载体选用Invitrogen公司的pRSETB质粒，也使用相同的限制性内切酶处理，酶切条件：10μl反应体系，体系内加入质粒2μl，限制性内切酶5个活性单位（New England biolabs），10×缓冲液1μl，去离子水补齐，37.0℃酶切1.5小时。酶切结束后加入1μl 200mM EDTA终止反应。在1%琼脂糖凝胶电泳中电泳30分钟。紫外灯下将pRSETB质粒和目的片段切下，按照QIAGEN公司凝胶回收试剂盒说明书进行胶回收。按照载体：片段为1:2～3的比例将核苷酸片段与表达载体混合，反应体系15μl，由T4 DNA连接酶进行连接，16℃连接过夜，获得重组质粒命名为pRSETB-ILTV/EDSV-IL-8（见图1），转化感受态大肠杆菌BL21（DE3）pLysS。
转化：将pRSETB-ILTV/EDSV-IL-8置冰上融化，加入1ml连接反应液，再次混匀，冰水浴30分钟，42℃ 30秒钟，然后迅速放回冰水浴90秒钟，加入1ml LB培养液，37.0℃静置培养1小时，4000g低温离心10秒钟弃上清，用200μl LB培养基重悬菌体，将菌液均匀涂布于含有100μl/ml氨苄青霉素的LB琼脂培养板上，倒置于37℃恒温箱中培养12～16小时，直至克隆形成。
鉴定：挑取平板上的单克隆至LB培养基中，37℃，200rpm震荡培养12小时，提取质粒，使用限制性内切酶BamHⅠ和EcoRⅠ进行双酶切，可以切出相应大小片段的克隆为1700bp左右，可初步确定为阳性克隆（见图2），阳性克隆进行DNA序列测定进一步验证其正确性（见序列表）。
诱导表达：将阳性克隆过夜培养，次日早上按照1:100转接，37℃震荡培养3小时候，加入0.5mM IPTG诱导，继续培养3小时，制备样品。常规SDS-PAGE检测目的蛋白的表达情况，可在约61KD分子量处见到特异性条带为正确克隆（见图3）。取正确克隆，放大培养，SDS-PAGE证实表达正确后，使用常规Western blot进一步证实其表达准确性（见图4）。最后筛选得到的高效分泌表达融合蛋白的工程菌，命名为pRSETB-ILTV/EDSV-IL-8/BL21(DE3,PLysS)。
实施例三 工程菌的发酵、纯化与乳化
发酵 将生产菌种接种到2ml 含有100μl/ml氨苄青霉素的LB液体培养基中，37℃，180rpm震荡培养12小时活化菌种。将活化好的菌种以1:100的接种量接入摇瓶，37℃震荡培养至OD600=3，可按10%比例接种入发酵罐。发酵用培养基为半合成培养基，用蒸馏水配制，其中不含有任何抗生素。校正溶氧和pH值电极，开启罐体搅拌，转数为300rpm，罐体在线灭菌，待罐内培养液温度降至37℃时，标定pH及溶氧（OD）零点。发酵温度为37.0℃±0.1℃，溶氧控制在20%左右，pH控制在7.0，接种后培养菌体OD600=1.0～1.2时流加补料500ml，补料后1小时加入IPTG（终浓度为0.5mM）诱导表达，连续诱导6个小时后发酵结束，取样做SDS-PAGE检测表达情况。
纯化 将收集的菌体，用包涵体洗液Ⅰ（1% Triton X-100，20Mm Tris-cl pH 8.0）混悬后进行超声，2000W超声裂解1小时。4℃，12000rpm离心收集包涵体，并用包涵体洗液Ⅱ（1% DOC,4M尿素，20mM Tris-cl pH 8.0）混悬二次超声洗涤包涵体，二次低温离心收集包涵体。包涵体沉淀用8M尿素，0.3%β-ME，20mM Tris-cl（pH=8.0）混匀，室温搅拌4小时，8000rpm低温离心30分钟，弃去沉淀。变性蛋白1:100稀释，复性液用Tris（pH=8.0）缓冲体系，加入0.3M精氨酸，4℃搅拌复性24小时。复性液用pH=8.0的20mM磷酸缓冲液，0.5M氯化钠，20mM咪唑，平衡上亲和层析柱，用pH=8.0的20mM磷酸缓冲液，0.5M氯化钠，0.5M咪唑洗脱。再用1.5M硫酸铵、100mM EDTA、pH=8.5的10mM磷酸氢二钠平衡上疏水层析柱，再平衡，用pH=8.5的10mM 磷酸氢二钠洗脱，即得鸡传染性喉气管炎、减蛋综合征二联多表位疫苗半成品原液，进行SDS-PAGE以及Western blot印记检定纯化产物是否为目的蛋白。
乳化 将纯化的半成品原液用灭菌PBS稀释至200μg/ml。取进口白油佐剂DUOPRIME(医药级)经121℃灭菌15分钟，备用。按油相:水相=50:50的比例配制，先将油相加入乳化缸内，开动搅拌机以80～100rpm的速度缓慢搅拌，缓缓加入水相，加完后再搅拌2分钟，然后以5500rpm高速循环乳化9分钟，制成油包水单相疫苗。按照现行版《中国兽药典》附录进行无菌检验、粘度测定、稳定性测定合格，置于2～8℃保存备用。
实施例四 鸡传染性喉气管炎、减蛋综合征二联多表位疫苗安全性实验
疫苗：鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，批号20171011、20171012、20171013，由公司研发中心提供。
方法
疫苗对雏鸡的安全性
将40只1日龄SPF雏鸡随机分为3个疫苗组和1个对照组，10只/组。疫苗组分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，0.5ml/只。对照组肌肉注射生理盐水白油乳剂0.5ml/只。连续观察14天，记录雏鸡的健康状况。
疫苗对产蛋鸡的安全性
将40只150日龄健康蛋鸡随机分为3个疫苗组和1个对照组，10只/组。疫苗组分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，0.5ml/只。对照组肌肉注射生理盐水白油乳剂0.5ml/只。连续观察14天，记录蛋鸡的健康状况及产蛋状况。
试验结果
疫苗对雏鸡的安全性试验
结果见表1，免疫后，三个疫苗组雏鸡均未出现任何过敏反应或中毒症状，精神状态良好，采食、饮水等一切正常，未出现明显局部炎症等临床副反应，无死亡发生，与对照组一致，表明鸡传染性喉气管炎、减蛋综合征二联多表位疫苗对雏鸡是安全的。
表1 疫苗对雏鸡的安全性试验结果
| 组别 | 数量（只） | 采食 | 饮水 | 精神 | 健康状况 | 炎症反应 | 死亡数量 |
| 20171011 | 10 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
| 20171012 | 10 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
| 20171013 | 10 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
| 对照组 | 10 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
疫苗对蛋鸡的安全性试验
结果如表2，整个观察期内，所有疫苗组的蛋鸡采食、饮水、产蛋等均正常，精神状态良好，未出现任何临床异常现象，免疫部位未发现过敏或炎症反应，无死亡发生，与对照组一致，表明鸡传染性喉气管炎、减蛋综合征二联多表位疫苗对蛋鸡是安全的。
表2 疫苗对蛋鸡的安全性试验结果
| 组别 | 数量（只） | 采食 | 饮水 | 精神 | 产蛋 | 健康状况 | 炎症反应 | 死亡数量 |
| 20171011 | 10 | 正常 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
| 20171012 | 10 | 正常 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
| 20171013 | 10 | 正常 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
| 对照组 | 10 | 正常 | 正常 | 正常 | 正常 | 良好 | 无 | 0 |
实施例五 低剂量或高剂量免疫对蛋鸡产蛋性能的影响
疫苗：鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，批号20171011、20171012、20171013，由公司研发中心提供。
方法
将70只25周龄健康蛋鸡随机分为6个疫苗组和1个对照组，10只/组。疫苗组1～3组为低剂量组，分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，0.25ml/只。疫苗组4～6组为高剂量组，分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，1ml/只。同时设空白对照组。于免前7天至免后60天，持续观察蛋鸡的健康状况，并记录产蛋量、总蛋重、破壳蛋数，统计平均蛋重、产蛋率和破蛋率。
试验结果
结果如表3，低剂量组和高剂量组的蛋鸡采食和饮水等均正常，精神状态良好，与对照组无差异；低剂量组和高剂量组蛋鸡免疫后的平均蛋重和产蛋率比免疫前略高，但差异不显著（P＞0.05），破蛋率显著降低（P＜0.05）；低剂量组和高剂量组蛋鸡的平均蛋重和产蛋率比对照组略高，但差异不显著（P＞0.05），破蛋率显著降低（P＜0.05），表明鸡传染性喉气管炎、减蛋综合征二联多表位疫苗以低于或高于推荐剂量免疫，对蛋鸡的平均蛋重、产蛋率无显著影响，能明显降低破蛋率。
表3 不同剂量免疫对蛋鸡生产性能的影响
实施例六 鸡传染性喉气管炎、减蛋综合征二联多表位疫苗免疫效力试验
疫苗：鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，批号20171011、20171012、20171013，由公司研发中心提供。
方法
将40只30日龄SPF鸡随机分为4组，3个疫苗组和1个空白对照组，10只/组。按照分组情况对试验鸡进行免疫，肌肉注射0.5ml/只。分别在免前和免后14、28、42、56、90、120、180天翅静脉采血，分离血清，用ELISA法检测特异性抗体。具体方法是：将纯化的重组蛋白抗原用50mmol/L的CBS（pH9.6）稀释成1μg/ml，加入酶标板中，100μl/孔，4℃静置包被过夜；去掉液体，用PBST（含0.05% Tween-20，pH7.4）洗板三次，加入封闭液（含5%小马血清的PBST），100μl/孔，37℃封闭1小时；洗板三次，用血清稀释液（含5%小马血清的PBST）将待检样品1:25、1:50、1:100、1:200、1:400、1:800、1:1600倍稀释，加入酶标板，100μl/孔，同时设阴性对照，37℃孵育1小时；洗板三次，加入1:500稀释的HRP标记兔抗鸡IgG，100μl/孔，37℃孵育1小时；洗板四次，加入TMB底物70μl/孔，避光显色15分钟；加入2M H2SO4终止反应，于450nm波长下检测吸光度值（BIORAD 680酶标仪）。同时参照现行《中国兽药典》方法对28天、42天血清进行血凝抑制试验测定HI抗体滴度。
试验结果：
如图5，免后14天，疫苗组的试验鸡血清中开始检测到特异性抗体，然后抗体水平不断升高，并在免后42天达到高峰，随后稳定下降，至试验观察期结束时，疫苗组的试验鸡血清中平均抗体滴度仍不低于1:500；三个批次的疫苗组之间无显著差异；空白对照组未检测到抗体。
如表4，免后28天，三个疫苗组平均血凝抑制抗体效价均高于8log2；免后42天，三个疫苗组平均血凝抑制抗体效价均高于9log2；对照组未检测到血凝抑制抗体效价。
表4 鸡传染性喉气管炎、减蛋综合征二联多表位疫苗血凝抑制抗体效价检测结果
实施例七 外周血CD4+、CD8+T淋巴细胞含量检测
疫苗：鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，批号20171011、20171012、20171013，由公司研发中心提供。
方法
将40只1日龄SPF雏鸡随机分为3个疫苗组和1个对照组，10只/组。疫苗组分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，0.5ml/只。分别在免前和免后14、28、42、56日采集1ml肝素抗凝血用于外周血T淋巴细胞亚类的检测。取抗凝血0.5mL与Hank’s液1:1混匀，轻轻加在淋巴细胞分层页面上。2000rpm离心15分钟，小心收集中间的淋巴细胞，用Hank’s液洗涤沉淀两次，再以RPMI-1640培养基将细胞稀释成1×107个/ml，分装后离心抽干备用。将已制备好的淋巴细胞分为三组，一、二组分别用10倍稀释的CD4+、CD8+单抗重悬，三组用PBS重悬作为对照，冰水浴30分钟；1500rpm/min离心5分钟，弃上清；PBS洗三遍，最后用不含血清的PBS重悬沉淀并检测。
试验结果
图6可以看出，3个疫苗免疫组的试验鸡CD4+T淋巴细胞百分比在免后14天开始有所升高，并在免后28天达到高峰，随后缓慢下降，直至观察期结束；疫苗免疫组显著高于对照组（P＜0.05）；三个批次的疫苗组之间无显著差异（P＞0.05）。
图7可以看出，免疫后，疫苗免疫组的试验鸡CD84+T淋巴细胞百分比随着免疫时间的增加而增加，直至观察期结束，未出现下降趋势，疫苗免疫组显著高于对照组（P＜0.05）；三个批次的疫苗组之间无显著差异（P＞0.05）。
实施例八 攻毒保护试验
疫苗：鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，批号20171011、20171012、20171013，由公司研发中心提供。
方法
鸡传染性喉气管炎攻毒保护试验
将60只12周龄健康鸡随机分为3个多表位疫苗组、1个弱毒苗组、1个未免攻毒对照组和1个未免未攻毒对照组，10只/组。按照分组情况对试验鸡进行免疫，其中3个多表位疫苗组分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，0.5ml/只。弱毒苗组按说明书点眼方式接种商品化弱毒苗，1羽份/只。未免攻毒对照组和未免未攻毒对照组不免疫。免后28天用105EID50/鸡的王岗株强毒对多表位疫苗组、弱毒苗组和未免攻毒对照组进行攻毒。攻毒后连续观察10天，记录各组鸡的临床症状。观察期结束时剖检所有试验鸡，采集喉头分泌物，进行PCR检测，PCR检测结果为阳性的即判定为发病，统计发病率和死亡情况。
保护率=［（攻毒对照组发病率-疫苗免疫组发病率）/攻毒对照组发病率］×100%。
减蛋综合征攻毒保护试验
将60只150日龄健康蛋鸡随机分为3个多表位疫苗组、1个油佐剂灭活苗组、1个未免攻毒对照组和1个未免未攻毒对照组，10只/组。按照分组情况对试验鸡进行免疫，其中3个多表位疫苗组分别肌肉注射3个不同批次的鸡传染性喉气管炎、减蛋综合征二联多表位疫苗，0.5ml/只。油佐剂灭活苗组按说明书点眼方式接种商品化弱毒苗，1羽份/只。未免攻毒对照组和未免未攻毒对照组不免疫。免后28天用107EID50/鸡的AV-127株对多表位疫苗组、弱毒苗组和未免攻毒对照组进行攻毒。攻毒后连续观察10天，记录各组鸡的临床症状、产蛋情况、发病和死亡情况。观察期结束时，剖检所有试验鸡，采集输卵管狭部，进行PCR检测，PCR检测结果为阳性的即判定为发病，统计发病率并计算保护率。
保护率=［（攻毒对照组发病率-疫苗免疫组发病率）/攻毒对照组发病率］×100%。
试验结果：
鸡传染性喉气管炎攻毒保护试验结果
结果如表5，未免攻毒对照组10只试验鸡全部发病，其中7只死亡；未免未攻毒对照组均未发病，无死亡；多表位疫苗20171011组一只鸡发病，无死亡，保护率为90%；20171012组和20171013组试验鸡均未发病，无死亡，保护率达到100%；弱毒苗组3只鸡发病，其中1只死亡，保护率为70%。
表5 鸡传染性喉气管炎毒株攻毒保护试验结果
| 组别 | 数量（只） | 发病数 | 死亡数 | 保护率 |
| 20171011 | 10 | 1 | 0 | 90% |
| 20171012 | 10 | 0 | 0 | 100% |
| 20171013 | 10 | 0 | 0 | 100% |
| 弱毒苗组 | 10 | 3 | 1 | 70% |
| 未免攻毒对照组 | 10 | 10 | 7 | — |
| 未免未攻毒对照组 | 10 | 0 | 0 | — |
减蛋综合征攻毒保护试验结果
结果如表6，三个多表位疫苗组均未发病，无死亡，产蛋正常，保护率达到100%；油佐剂灭活苗组1只发病，攻毒后3日产蛋率下降，至攻毒后10日下降至82.28%，无死亡，保护率为90%；未免攻毒对照组10只均发病，其中4只死亡，产蛋率明显下降，畸形蛋和破壳蛋增多；未免未攻毒对照组均未发病，无死亡，产蛋正常。
表6减蛋综合征毒株攻毒保护试验结果
序列表
<110> 青岛明勤生物科技有限公司
<120> 一种鸡传染性喉气管炎、减蛋综合征二联多表位疫苗
<160> 34
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1722
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
actaacttta ctaagcgaca tcaaaccctg ggataccgaa cgtctacatc ggtcgactgt 60
gttggttctg gtgaagaggc acaaagacaa aatcatctcc cgagagggag agagcgtcgc 120
caagccgcag gtcgccgcac ggcgtcgctg cagggttctg gttttcgcag aaaaccccga 180
accaaggaag atgactaccc cggttctggt aagggcgacg acggcgagga caagtactgt 240
ggttctggta ggaaaaagaa tcctagcgcg ccagaccctc gtccagatag cgtcccgcaa 300
gaaattcccg ctgtaaccaa gaaagcggaa gggcgcaccc cggacgcaga aagcagtgaa 360
aagaaggccc ctccagaaga ctcggaggac gacatgcagg cagaggcttc tggagaaaat 420
cctgccgccc tccccgaaga cgacgaagtc cccgaggaca ccgagcacga tgatccaaac 480
tcggatggtt ctggtgaaga tgatcccaga aacgttccgg aagggggttc tggttacgac 540
ggaggaaaga aagactgccc gcccgcgggt tctggttccc gcgatactct agaagactgc 600
cacgaaaatc gcgtgccgaa cctacggttc gattcgcgac tctccgagtc acgcggttct 660
ggtgtgtctc cgacagaatc ggcaactcaa gacatcaaat tagatgagcg gtctaggtgg 720
tcaggaaatt tggttacttt gttaaaaaca aattgcccta atgttactga atacaataat 780
agtaataagg tacgcgttcg cctaatgact gataagactg atcctcagaa tcctgttggt 840
tctggtatat ctactgatcc cccggcttgg cagactgaat atcggtcatg ggctcttgct 900
tatcataata agggtcctat acgcacgggt tctggtaatg tcccttctgt tgcagatcac 960
ggccagcagc cgttgaaaaa cagcctgccg ggtgttcaaa gaataactct gaccgacgat 1020
aggcggcgca cttgcggttc tggtatcaat ggtgaagggg ctgtggcggt agaatcccct 1080
gtggacccca ttacacttga tacggctggt agaattactt taaattatgg cacaggttta 1140
aatgtgagtg atggaaaatt acgactagta agtcctgaaa gtccgctcac aggttctggt 1200
gttgagaccc gtggcggctt agaaaaaagt gacactggtt taaaaattaa acgtgcgggt 1260
tctggtaact tttacaagga ggaaaccgaa ttgccgggtt acactcgtca ttctttctgc 1320
cctaccggga ccaccggagg ttctggtatg aacggcaagc ttggagctgt cctggccctc 1380
ctcctggttt cagctgctct gtcgcaaggt aggacgctgg taaagatggg gaatgagctg 1440
cggtgccagt gcattagcac tcattctaag ttcatccacc ctaaatccat tcaagatgtg 1500
aagctgacgc caagcggccc ccactgcaag aatgttgaaa tcatagctac tctaaaggat 1560
ggaagagagg tgtgcttgga ccccactgct ccctgggtac agctgatcgt aaaggcactt 1620
atggccaagg ctcagctcaa ttctgatgca ccactgctag aacaaaaact catctcagaa 1680
gaggatctga atagcgccgt cgaccatcat catcatcatc at 1722
<210> 2
<211> 574
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Thr Asn Phe Thr Lys Arg His Gln Thr Leu Gly Tyr Arg Thr Ser Thr
1 5 10 15
Ser Val Asp Cys Val Gly Ser Gly Glu Glu Ala Gln Arg Gln Asn His
20 25 30
Leu Pro Arg Gly Arg Glu Arg Arg Gln Ala Ala Gly Arg Arg Thr Ala
35 40 45
Ser Leu Gln Gly Ser Gly Phe Arg Arg Lys Pro Arg Thr Lys Glu Asp
50 55 60
Asp Tyr Pro Gly Ser Gly Lys Gly Asp Asp Gly Glu Asp Lys Tyr Cys
65 70 75 80
Gly Ser Gly Arg Lys Lys Asn Pro Ser Ala Pro Asp Pro Arg Pro Asp
85 90 95
Ser Val Pro Gln Glu Ile Pro Ala Val Thr Lys Lys Ala Glu Gly Arg
100 105 110
Thr Pro Asp Ala Glu Ser Ser Glu Lys Lys Ala Pro Pro Glu Asp Ser
115 120 125
Glu Asp Asp Met Gln Ala Glu Ala Ser Gly Glu Asn Pro Ala Ala Leu
130 135 140
Pro Glu Asp Asp Glu Val Pro Glu Asp Thr Glu His Asp Asp Pro Asn
145 150 155 160
Ser Asp Gly Ser Gly Glu Asp Asp Pro Arg Asn Val Pro Glu Gly Gly
165 170 175
Ser Gly Tyr Asp Gly Gly Lys Lys Asp Cys Pro Pro Ala Gly Ser Gly
180 185 190
Ser Arg Asp Thr Leu Glu Asp Cys His Glu Asn Arg Val Pro Asn Leu
195 200 205
Arg Phe Asp Ser Arg Leu Ser Glu Ser Arg Gly Ser Gly Val Ser Pro
210 215 220
Thr Glu Ser Ala Thr Gln Asp Ile Lys Leu Asp Glu Arg Ser Arg Trp
225 230 235 240
Ser Gly Asn Leu Val Thr Leu Leu Lys Thr Asn Cys Pro Asn Val Thr
245 250 255
Glu Tyr Asn Asn Ser Asn Lys Val Arg Val Arg Leu Met Thr Asp Lys
260 265 270
Thr Asp Pro Gln Asn Pro Val Gly Ser Gly Ile Ser Thr Asp Pro Pro
275 280 285
Ala Trp Gln Thr Glu Tyr Arg Ser Trp Ala Leu Ala Tyr His Asn Lys
290 295 300
Gly Pro Ile Arg Thr Gly Ser Gly Asn Val Pro Ser Val Ala Asp His
305 310 315 320
Gly Gln Gln Pro Leu Lys Asn Ser Leu Pro Gly Val Gln Arg Ile Thr
325 330 335
Leu Thr Asp Asp Arg Arg Arg Thr Cys Gly Ser Gly Ile Asn Gly Glu
340 345 350
Gly Ala Val Ala Val Glu Ser Pro Val Asp Pro Ile Thr Leu Asp Thr
355 360 365
Ala Gly Arg Ile Thr Leu Asn Tyr Gly Thr Gly Leu Asn Val Ser Asp
370 375 380
Gly Lys Leu Arg Leu Val Ser Pro Glu Ser Pro Leu Thr Gly Ser Gly
385 390 395 400
Val Glu Thr Arg Gly Gly Leu Glu Lys Ser Asp Thr Gly Leu Lys Ile
405 410 415
Lys Arg Ala Gly Ser Gly Asn Phe Tyr Lys Glu Glu Thr Glu Leu Pro
420 425 430
Gly Tyr Thr Arg His Ser Phe Cys Pro Thr Gly Thr Thr Gly Gly Ser
435 440 445
Gly Met Asn Gly Lys Leu Gly Ala Val Leu Ala Leu Leu Leu Val Ser
450 455 460
Ala Ala Leu Ser Gln Gly Arg Thr Leu Val Lys Met Gly Asn Glu Leu
465 470 475 480
Arg Cys Gln Cys Ile Ser Thr His Ser Lys Phe Ile His Pro Lys Ser
485 490 495
Ile Gln Asp Val Lys Leu Thr Pro Ser Gly Pro His Cys Lys Asn Val
500 505 510
Glu Ile Ile Ala Thr Leu Lys Asp Gly Arg Glu Val Cys Leu Asp Pro
515 520 525
Thr Ala Pro Trp Val Gln Leu Ile Val Lys Ala Leu Met Ala Lys Ala
530 535 540
Gln Leu Asn Ser Asp Ala Pro Leu Leu Glu Gln Lys Leu Ile Ser Glu
545 550 555 560
Glu Asp Leu Asn Ser Ala Val Asp His His His His His His
565 570
<210> 3
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
actaacttta ctaagcgaca tcaaaccctg ggataccgaa cgtctacatc ggtcgactgt 60
gtt 63
<210> 4
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Thr Asn Phe Thr Lys Arg His Gln Thr Leu Gly Tyr Arg Thr Ser Thr
1 5 10 15
Ser Val Asp Cys Val
20
<210> 5
<211> 81
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
gaagaggcac aaagacaaaa tcatctcccg agagggagag agcgtcgcca agccgcaggt 60
cgccgcacgg cgtcgctgca g 81
<210> 6
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Glu Glu Ala Gln Arg Gln Asn His Leu Pro Arg Gly Arg Glu Arg Arg
1 5 10 15
Gln Ala Ala Gly Arg Arg Thr Ala Ser Leu Gln
20 25
<210> 7
<211> 39
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
tttcgcagaa aaccccgaac caaggaagat gactacccc 39
<210> 8
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Phe Arg Arg Lys Pro Arg Thr Lys Glu Asp Asp Tyr Pro
1 5 10
<210> 9
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
aagggcgacg acggcgagga caagtactgt 30
<210> 10
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Lys Gly Asp Asp Gly Glu Asp Lys Tyr Cys
1 5 10
<210> 11
<211> 237
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
aggaaaaaga atcctagcgc gccagaccct cgtccagata gcgtcccgca agaaattccc 60
gctgtaacca agaaagcgga agggcgcacc ccggacgcag aaagcagtga aaagaaggcc 120
cctccagaag actcggagga cgacatgcag gcagaggctt ctggagaaaa tcctgccgcc 180
ctccccgaag acgacgaagt ccccgaggac accgagcacg atgatccaaa ctcggat 237
<210> 12
<211> 79
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Arg Lys Lys Asn Pro Ser Ala Pro Asp Pro Arg Pro Asp Ser Val Pro
1 5 10 15
Gln Glu Ile Pro Ala Val Thr Lys Lys Ala Glu Gly Arg Thr Pro Asp
20 25 30
Ala Glu Ser Ser Glu Lys Lys Ala Pro Pro Glu Asp Ser Glu Asp Asp
35 40 45
Met Gln Ala Glu Ala Ser Gly Glu Asn Pro Ala Ala Leu Pro Glu Asp
50 55 60
Asp Glu Val Pro Glu Asp Thr Glu His Asp Asp Pro Asn Ser Asp
65 70 75
<210> 13
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gaagatgatc ccagaaacgt tccggaaggg 30
<210> 14
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Glu Asp Asp Pro Arg Asn Val Pro Glu Gly
1 5 10
<210> 15
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
tacgacggag gaaagaaaga ctgcccgccc gcg 33
<210> 16
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Tyr Asp Gly Gly Lys Lys Asp Cys Pro Pro Ala
1 5 10
<210> 17
<211> 78
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
tcccgcgata ctctagaaga ctgccacgaa aatcgcgtgc cgaacctacg gttcgattcg 60
cgactctccg agtcacgc 78
<210> 18
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Ser Arg Asp Thr Leu Glu Asp Cys His Glu Asn Arg Val Pro Asn Leu
1 5 10 15
Arg Phe Asp Ser Arg Leu Ser Glu Ser Arg
20 25
<210> 19
<211> 174
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
gtgtctccga cagaatcggc aactcaagac atcaaattag atgagcggtc taggtggtca 60
ggaaatttgg ttactttgtt aaaaacaaat tgccctaatg ttactgaata caataatagt 120
aataaggtac gcgttcgcct aatgactgat aagactgatc ctcagaatcc tgtt 174
<210> 20
<211> 58
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Val Ser Pro Thr Glu Ser Ala Thr Gln Asp Ile Lys Leu Asp Glu Arg
1 5 10 15
Ser Arg Trp Ser Gly Asn Leu Val Thr Leu Leu Lys Thr Asn Cys Pro
20 25 30
Asn Val Thr Glu Tyr Asn Asn Ser Asn Lys Val Arg Val Arg Leu Met
35 40 45
Thr Asp Lys Thr Asp Pro Gln Asn Pro Val
50 55
<210> 21
<211> 81
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
atatctactg atcccccggc ttggcagact gaatatcggt catgggctct tgcttatcat 60
aataagggtc ctatacgcac g 81
<210> 22
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Ile Ser Thr Asp Pro Pro Ala Trp Gln Thr Glu Tyr Arg Ser Trp Ala
1 5 10 15
Leu Ala Tyr His Asn Lys Gly Pro Ile Arg Thr
20 25
<210> 23
<211> 99
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
aatgtccctt ctgttgcaga tcacggccag cagccgttga aaaacagcct gccgggtgtt 60
caaagaataa ctctgaccga cgataggcgg cgcacttgc 99
<210> 24
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Asn Val Pro Ser Val Ala Asp His Gly Gln Gln Pro Leu Lys Asn Ser
1 5 10 15
Leu Pro Gly Val Gln Arg Ile Thr Leu Thr Asp Asp Arg Arg Arg Thr
20 25 30
Cys
<210> 25
<211> 147
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
atcaatggtg aaggggctgt ggcggtagaa tcccctgtgg accccattac acttgatacg 60
gctggtagaa ttactttaaa ttatggcaca ggtttaaatg tgagtgatgg aaaattacga 120
ctagtaagtc ctgaaagtcc gctcaca 147
<210> 26
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Ile Asn Gly Glu Gly Ala Val Ala Val Glu Ser Pro Val Asp Pro Ile
1 5 10 15
Thr Leu Asp Thr Ala Gly Arg Ile Thr Leu Asn Tyr Gly Thr Gly Leu
20 25 30
Asn Val Ser Asp Gly Lys Leu Arg Leu Val Ser Pro Glu Ser Pro Leu
35 40 45
Thr
<210> 27
<211> 57
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 27
gttgagaccc gtggcggctt agaaaaaagt gacactggtt taaaaattaa acgtgcg 57
<210> 28
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Val Glu Thr Arg Gly Gly Leu Glu Lys Ser Asp Thr Gly Leu Lys Ile
1 5 10 15
Lys Arg Ala
<210> 29
<211> 72
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
aacttttaca aggaggaaac cgaattgccg ggttacactc gtcattcttt ctgccctacc 60
gggaccaccg ga 72
<210> 30
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Asn Phe Tyr Lys Glu Glu Thr Glu Leu Pro Gly Tyr Thr Arg His Ser
1 5 10 15
Phe Cys Pro Thr Gly Thr Thr Gly
20
<210> 31
<211> 309
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
atgaacggca agcttggagc tgtcctggcc ctcctcctgg tttcagctgc tctgtcgcaa 60
ggtaggacgc tggtaaagat ggggaatgag ctgcggtgcc agtgcattag cactcattct 120
aagttcatcc accctaaatc cattcaagat gtgaagctga cgccaagcgg cccccactgc 180
aagaatgttg aaatcatagc tactctaaag gatggaagag aggtgtgctt ggaccccact 240
gctccctggg tacagctgat cgtaaaggca cttatggcca aggctcagct caattctgat 300
gcaccactg 309
<210> 32
<211> 103
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Met Asn Gly Lys Leu Gly Ala Val Leu Ala Leu Leu Leu Val Ser Ala
1 5 10 15
Ala Leu Ser Gln Gly Arg Thr Leu Val Lys Met Gly Asn Glu Leu Arg
20 25 30
Cys Gln Cys Ile Ser Thr His Ser Lys Phe Ile His Pro Lys Ser Ile
35 40 45
Gln Asp Val Lys Leu Thr Pro Ser Gly Pro His Cys Lys Asn Val Glu
50 55 60
Ile Ile Ala Thr Leu Lys Asp Gly Arg Glu Val Cys Leu Asp Pro Thr
65 70 75 80
Ala Pro Trp Val Gln Leu Ile Val Lys Ala Leu Met Ala Lys Ala Gln
85 90 95
Leu Asn Ser Asp Ala Pro Leu
100
<210> 33
<211> 66
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
ctagaacaaa aactcatctc agaagaggat ctgaatagcg ccgtcgacca tcatcatcat 60
catcat 66
<210> 34
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Leu Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Ser Ala Val Asp
1 5 10 15
His His His His His His
20
Claims (5)
1.一种融合蛋白，其氨基酸序列如SEQ ID No.2所示。
2.一种核酸分子，其编码权利要求1所述的融合蛋白，核苷酸序列如SEQ ID No.1所示。
3.一种载体，其含有权利要求2所述的核酸分子。
4.一种宿主细胞，其含有权利要求3所述的载体。
5.一种用于预防鸡传染性喉气管炎和减蛋综合征的疫苗，其包括权利要求1所述的蛋白以及药学上可接受的载体。
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| CN112708637A (zh) * | 2019-10-25 | 2021-04-27 | 苏州世诺生物技术有限公司 | 禽减蛋综合症病毒新型基因工程疫苗、其制备方法与应用 |
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| CN112708637A (zh) * | 2019-10-25 | 2021-04-27 | 苏州世诺生物技术有限公司 | 禽减蛋综合症病毒新型基因工程疫苗、其制备方法与应用 |
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