CN113481178A - 山羊传染性胸膜肺炎基因工程亚单位疫苗及其制法与应用 - Google Patents
山羊传染性胸膜肺炎基因工程亚单位疫苗及其制法与应用 Download PDFInfo
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Abstract
本发明公开了一种山羊传染性胸膜肺炎基因工程亚单位疫苗及其制法与应用。所述疫苗包含第一重组蛋白和第二重组蛋白以及医药学上可接受的载剂，所述第一重组蛋白、第二重组蛋白分别具有SEQ ID NO：2、SEQ ID NO：6所示序列。本发明提供的所述疫苗无任何毒性，安全性高，免疫原性好，能够在羊体内产生较强的体液免疫，其中的第一重组蛋白、第二重组蛋白表达的抗原具有很好的交叉保护作用，能够同时抵御山羊支原体山羊肺炎亚种、丝状支原体山羊亚种和绵羊肺炎支原体的攻击，免疫后的羊能够抵御强毒攻毒，并且还可以使用生物反应器大规模无血清悬浮培养制备，具有质控容易、批次间稳定、生产成本低等优点。
Description
技术领域
本发明涉及一种基因工程疫苗，具体涉及一种山羊传染性胸膜肺炎基因工程亚单位疫苗、其制备方法及应用，属于动物免疫药物技术领域。
背景技术
山羊传染性胸膜肺炎(Contagious Caprine Pleuropneumonia，CCPP)是由山羊支原体山羊肺炎亚种(Mycoplasma capricolum subsp.capripneumoniae，Mccp)引起的一类严重呼吸道疫病，主要危害山羊及野生羊，在夏末和秋季气温骤变时最常流行，主要的临床症状表现为高热、咳嗽，渐进性消瘦以及肺实质、小叶间质及胸膜发生浆液性和纤维素性炎，肺有明显的肝变等。CCPP传播快、发病率和死亡率高，给多地区山羊产业造成较大经济损失和潜在威胁，被世界动物卫生组织(OIE)列为法定报告动物疫病之一。
Mccp无细胞壁，外层有三层细胞膜组成，呈细小多形性，是丝状支原体簇(Mycoplasma mycoides cluster，Mm Cluster)成员之一。该簇成员还包括：丝状支原体丝状亚种(M.mycoides subsp.Mycoides，Mmm)、丝状支原体山羊亚种(M.mycoidessubsp.capri，Mmc)、山羊支原体山羊亚种(M.capricolum subsp.Capricolum，Mcc)、李奇氏支原体(M.Leachii，M1)。其中Mmc和绵羊肺炎支原体(M.ovipneumoniae，Mo)被认为是CCPP的病原。支原体的主要抗原物质存在于细胞膜，主要成分为膜蛋白与糖脂。膜蛋白成分复杂，是产生免疫反应的主要免疫原之一。甘油激酶(Glycerol Kinase，GK)是Mccp外膜一个重要的膜蛋白，是甘油代谢反应中的关键酶，在Mg2+和ATP的共同参与下，通过催化反应GK将甘油转变成3-磷酸甘油，在磷酸甘油氧化酶作用下氧化生成磷酸二羟丙酮和H2O2，H2O2是ROS的主要成员之一，也是Mccp、Mo、Mmc等菌的主要致病因素(Jacobs N J，VanDemark PJ.Comparison of the mechanism of glycerol oxidation in aerobically andanaerobically grown Streptococcus faecalis，J Bact，1960，79：532-538.)。以上反应过程中，镁离子转运蛋白(Magnesium Transporter，MagT)负责Mg2+的转运，Mg2+是许多酶化反应中不可或缺的辅助因子。
我国目前主要依靠灭活疫苗来预防CCPP，但原疫苗采用强毒气管注射山羊，采集肺组织制成疫苗，不适宜工业化生产，存在散毒风险，由于肺组织中杂菌含量高，所制备的疫苗易出现过敏反应。同时由于该疾病所属支原体簇种类多，菌株间交叉保护并不理想，且抗原质量受培养条件影响较大，限制了其推广应用。
发明内容
本发明的主要目的在于提供一种山羊传染性胸膜肺炎基因工程亚单位疫苗、其制备方法及应用，以克服现有技术中的不足。
为实现前述发明目的，本发明采用的技术方案包括：
本发明实施例提供了一种重组蛋白，其包括第一重组蛋白和第二重组蛋白；所述第一重组蛋白具有SEQ ID NO：2所示序列或者与SEQ ID NO：2的全长序列95％以上相同的序列，所述第二重组蛋白具有SEQ ID NO：6所示序列或者与SEQ ID NO：6的全长序列95％以上相同的序列。
即，本发明实施例提供的所述第一重组蛋白、第二重组蛋白的氨基酸序列可以是原始序列，增加或截短的序列。
优选的，所述重组蛋白包括第一重组蛋白和第二重组蛋白，其中所述第一重组蛋白的序列如SEQ ID NO：2所示，所述第二重组蛋白的序列如SEQ ID NO：6所示。
本发明实施例还提供了用于编码所述重组蛋白的基因。
在一些实施方式中，所述的基因包括第一基因、第二基因，其中第一基因具有SEQID NO：1所示序列或者与SEQ ID NO：1的全长序列95％以上相同的序列，第二基因具有SEQID NO：5所示序列或者与SEQ ID NO：5的全长序列95％以上相同的序列。
优选的，所述的基因包括第一基因和第二基因，其中第一基因的序列如SEQ IDNO：1所示，第二基因的序列如SEQ ID NO：5所示。
本发明实施例还提供了包含所述重组蛋白的编码基因的重组载体。
在一些实施方式中，所述重组载体包括但不限于pFastBac 1、pVL1393、pFastBacdual等，例如可以优选采用pFastBac 1。
本发明实施例还提供了包含所述重组蛋白的编码基因的宿主细胞。
在一些实施方式中，所述宿主细胞选自昆虫细胞，例如Sf9细胞系，优选的，所述Sf9细胞系包括但不限于Sf9、High Five或Sf21细胞，更优选为Sf9细胞。
本发明实施例还提供了一种免疫组合物，其特征在于包括：所述的重组蛋白；以及，医药学上可接受的载剂。
在一些实施方式中，所述医药学上可接受的载剂包括但不限于MONTANIDE ISA206 VG、MONTANIDE ISA 201 VG、MONTANIDE ISA 51 VG、液体石蜡、樟脑油、植物细胞凝集素等一种或者两种以上的组合，例如可以优选使用MONTANIDE ISA 201 VG。
本发明实施例还提供了所述重组蛋白的一种制备方法，其包括：
提供第一重组蛋白的编码基因和/或第二重组蛋白的编码基因；
将所述第一重组蛋白的编码基因和/或第二重组蛋白的编码基因克隆到穿梭载体中，获得含有目的基因的重组穿梭载体；
将所述重组穿梭载体转化感受态细胞，并分离获得含有目的基因表达框的重组杆状病毒基因组质粒；
以所述重组杆状病毒基因组质粒转染昆虫细胞，并分离获得重组杆状病毒；
将所述重组杆状病毒接种昆虫细胞并进行培养，之后分离获得所述重组蛋白。
在一些实施方式中，所述制备方法包括：
分别将第一重组蛋白的编码基因、第二重组蛋白的编码基因克隆到穿梭载体中，获得含有第一基因的第一重组穿梭载体、含有第二基因的第二重组穿梭载体；
分别将第一重组穿梭载体、第二重组穿梭载体转化感受态细胞，并分离获得含有第一基因表达框的第一重组杆状病毒基因组质粒、含有第二基因表达框的第二重组杆状病毒基因组质粒；
分别以第一重组杆状病毒基因组质粒、第二重组杆状病毒基因组质粒转染昆虫细胞，并分离获得第一重组杆状病毒、第二重组杆状病毒；
将所述第一重组杆状病毒、第二重组杆状病毒接种昆虫细胞并进行培养，之后分离获得第一重组蛋白、第二重组蛋白。
在一些实施方式中，所述穿梭载体包括但不限于pFastBac 1、pVL1393、pFastBacdual等，例如可以优选采用pFastBac 1。
在一些实施方式中，所述宿主细胞选自昆虫细胞，例如可以包括但不限于Sf9、High Five或Sf21细胞等，优选为Sf9细胞。
本发明实施例还提供了一种山羊传染性胸膜肺炎基因工程亚单位疫苗的制备方法，其包括：采用前述的任一种方法制备重组蛋白，并将所述重组蛋白与医药学上可接受的载剂混合。
本发明实施例还提供了所述重组蛋白或所述免疫组合物在制备山羊传染性胸膜肺炎检测试剂，在生产用于在受试动物中诱导针对山羊传染性胸膜肺炎抗原的免疫反应的药剂，或者，在生产用于预防动物受山羊传染性胸膜肺炎感染的药剂中的用途。
本发明实施例还提供了所述重组蛋白或所述免疫组合物在制备山羊传染性胸膜肺炎基因工程亚单位疫苗中的用途。
本发明实施例提供了一种山羊传染性胸膜肺炎基因工程亚单位疫苗，其包含前述的任一种免疫组合物。进一步的，所述疫苗还可包含医药学上可接受的载剂。
本发明实施例还提供了包含所述重组蛋白的编码基因的重组载体或宿主细胞在生产用于检测动物受山羊传染性胸膜肺炎感染的试剂的用途。
本发明实施例还提供了包含所述重组蛋白的编码基因的重组载体或宿主细胞在生产用于在受试动物中诱导针对山羊传染性胸膜肺炎抗原的免疫反应的药剂的用途。
本发明实施例还提供了包含所述重组蛋白的编码基因的重组载体或宿主细胞在生产用于预防动物受山羊传染性胸膜肺炎感染的药剂的用途。
本发明实施例还提供了一种诱导针对山羊传染性胸膜肺炎抗原的免疫反应的方法，所述方法包括向受试动物施用所述山羊传染性胸膜肺炎基因工程亚单位疫苗。
本发明实施例还提供了一种保护受试动物免受山羊传染性胸膜肺炎感染的方法，所述方法包括向受试动物施用所述山羊传染性胸膜肺炎基因工程亚单位疫苗。
本发明实施例还提供了一种适用于在受试动物中产生针对山羊传染性胸膜肺炎感染的免疫反应的疫苗，所述疫苗包含：本发明的重组蛋白以及佐剂分子。
进一步的，在每毫升所述的疫苗中可以含有100ug左右的第一重组蛋白和80ug左右的第二重组蛋白。
如本说明书所述的“佐剂”意指被添加到本说明书所述的疫苗中来增强由下文所述编码核酸序列的所编码的抗原的免疫原性的任何分子。优选的，所述佐剂可以采用苏州世诺生物技术有限公司生产的相关佐剂，以提高疫苗效果。
较之现有技术，本发明实施例提供的技术方案至少有如下优点：
(1)采用的第一重组蛋白(即重组GK蛋白)、第二重组蛋白(即重组MagT蛋白)是对山羊支原体外膜的重要膜蛋白GK蛋白、MagT蛋白进行优化后获得，该两种重组蛋白具有很好的免疫原性，且这两种重组蛋白在三个支原体(山羊支原体山羊肺炎亚种、丝状支原体山羊亚种和绵羊肺炎支原体)中高度保守，表达的抗原具有很好的交叉保护作用。尤其优选的，经过大量实验证实，若按照100∶80的质量比例将该两种重组蛋白配制为疫苗使用，能够同时抵御前述三种不同支原体的攻击。并且，由于甘油激酶催化甘油转变成3-磷酸甘油过程中需要Mg2+参与，因此该两种重组蛋白同时进行免疫能够达到最好的效果，缺少其中的任一重组蛋白，将无法保证提供有效保护。
(2)通过对Mccp的GK蛋白、MagT蛋白进行优化，并基于杆状病毒昆虫细胞表达系统，使用悬浮培养Sf9细胞等进行表达和大规模无血清悬浮培养制备，大大降低了疫苗生产成本，同时所获产品的抗原性、免疫原性和功能与天然蛋白质相似，表达水平较高，免疫原性强，只需要很少量就能提供很好的免疫效果，对羊没有致病性，适于作为山羊传染性胸膜肺炎重组基因工程亚单位疫苗广泛应用。
附图说明
为了更清楚地说明本发明实施方式的技术方案，下面将对实施方式中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1是实施例1的步骤1中密码子优化的GK基因PCR扩增产物的凝胶电泳图，其中在1.5kbp位置出现目的条带。
图2是实施例1的步骤5中菌落PCR扩增产物的凝胶电泳图，其中在1.5kbp位置出现目的条带。
图3是实施例1中转移载体pF-GK的结构示意图。
图4是实施例1的步骤6中密码子优化的MagT基因PCR扩增产物的凝胶电泳图，其中在1.4kbp位置出现目的条带。
图5是实施例1的步骤6中菌落PCR扩增产物的凝胶电泳图，其中在1.4kbp位置出现目的条带。
图6是实施例1中转移载体pF-MagT的结构示意图。
图7是实施例4所获rBac-GK细胞培养物及rBac-MagT细胞培养物的SDS-PAGE检测图谱。
图8是实施例5所获SDS-PAGE电泳后产物的化学发光成像图。
图9是实施例6中接种重组杆状病毒、空杆状病毒的Sf9细胞的荧光检测图谱。
图10是实施例8所获的纯化后重组蛋白的灰度扫描图。
具体实施方式
应该指出，以下详细说明都是示例性的，旨在对本发明提供进一步的说明。除非另有指明，本说明书使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
如前所述，GK蛋白和MagT蛋白都是山羊支原体外膜的重要膜蛋白，本发明实施例通过对该两种蛋白进行优化，使之形成具有很好免疫原性的重组蛋白(即前述第一重组蛋白、第二重组蛋白)，并且这两种重组蛋白在山羊支原体山羊肺炎亚种、丝状支原体山羊亚种和绵羊肺炎支原体中高度保守，表达的抗原具有很好的交叉保护作用，同时免疫能够抵御比如山羊支原体山羊肺炎亚种、丝状支原体山羊亚种、绵羊肺炎支原体等多种支原体的攻击。
进一步的，前述第一重组蛋白、第二重组蛋白可以基于杆状病毒昆虫细胞表达系统，使用悬浮培养Sf9细胞进行表达，其不仅表达水平较高，而且蛋白免疫原性好。
进一步的，前述重组蛋白可以用于制备山羊传染性胸膜肺炎基因工程亚单位疫苗。
例如，在本发明实施例的一个具体实施方案中，一种山羊传染性胸膜肺炎基因工程亚单位疫苗的制备方法具体可以包括：
(1)制备用于编码前述第一重组蛋白(重组GK蛋白)和前述第二重组蛋白(重组MagT蛋白)的核酸分子；
(2)分别将步骤(1)中制备的编码所述第一、第二重组蛋白的核酸分子克隆到穿梭载体中，得到含有目的基因的重组穿梭载体；
(3)将步骤(2)获得的重组穿梭载体转化DH10Bac菌，挑选重组菌，抽提基因组转染Sf9细胞(或前述的其它昆虫细胞)，获得重组杆状病毒；
(4)培育所述Sf9细胞(或前述的其它昆虫细胞)进而重组表达产生第一重组蛋白、第二重组蛋白；
(5)将所获第一重组蛋白、第二重组蛋白混合加入到佐剂中，得到所述疫苗。
该具体实施方案中，使用Sf9细胞表达重组GK蛋白及重组MagT蛋白，产品的抗原性、免疫原性和功能与天然蛋白质相似，表达水平较高，免疫原性强，对动物(例如山羊、野生羊且不限于此)没有致病性，并且疫苗可以使用生物反应器大规模无血清悬浮培养制备，也大大降低了疫苗生产成本。
本发明实施例提供的山羊传染性胸膜肺炎基因工程亚单位疫苗无任何毒性，安全性高，免疫原性好，能够在动物体内产生较强的体液免疫，免疫后的动物能够抵御强毒攻毒，且还具有可以大规模批量生产、质控容易、批次间稳定、生产成本低等一系列优点。
本发明实施例提供的山羊传染性胸膜肺炎基因工程亚单位疫苗在应用时，只需将有效量接种于动物。如本文中所使用的，术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如，预防疾病有效量是指，足以预防，阻止，或延迟疾病的发生的量；治疗疾病有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中所用试剂和原料均市售可得，而其中未注明具体条件的试验方法，通常按照常规条件，或者按照各制造商所建议的条件。又及，除非另外说明，本发明中所公开的实验方法、检测方法、制备方法均采用本技术领域常规的分子生物学、生物化学、染色质结构和分析、分析化学、细胞培养、重组DNA技术及相关领域的常规技术。这些技术在现有文献中已有完善说明。
实施例1转移载体pF-GK构建与鉴定
1.GK基因扩增与纯化
在南京金斯瑞生物科技有限公司合成了密码子优化后的GK基因(SEQ ID NO：1)并克隆到pUC17载体上，得到pUC-GK质粒载体。以pUC-GK质粒作为模板，GK-F、GK-R作为上下游引物进行PCR扩增(GK-F、GK-R的基因序列如SEQ ID NO：3、4所示)，扩增体系见表1。
表1 GK基因扩增体系
反应条件为：95℃预变性5分钟；94℃变性45秒，54℃退火45秒，72℃延伸1分钟，35个循环；72℃延伸10分钟。
将PCR产物进行凝胶电泳验证目的基因大小，如图1所示，在1.5kbp的位置出现目的条带，目的基因扩增成功，用凝胶回收纯化试剂盒进行回收纯化。
2.酶切与纯化
将pFastBac 1质粒和GK基因PCR扩增产物使用BamH I、Hind III 37℃双酶切3小时，具体酶切反应体系见表2、表3。
将酶切产物进行凝胶电泳，分别使用凝胶回收纯化试剂盒纯化酶切的pFastBac 1质粒以及GK基因片段。
表2 GK基因酶切反应体系
表3 pFastBac 1质粒酶切反应体系
3.连接
将酶切过的pFastBac 1质粒和GK基因酶切产物使用T4 DNA连接酶16℃水浴连接过夜，连接体系见表4。
表4 GK基因与pFastBac 1质粒连接体系
4.转化
取10μl连接产物加入100μl的DH5α感受态细胞，混匀，42℃热休克90秒，冰浴2分钟，加入900μl不含Amp的LB培养基，37℃培养1小时。取1.0mL菌液离心浓缩成100μl涂布于含有Amp的LB固体培养基上，37℃培养16小时。
5.菌落PCR和测序鉴定
挑取平板上的单菌落分别接种LB液体培养基，37℃培养2小时，以菌液作为模板，GK-F和GK-R作为引物进行菌落PCR。将PCR产物进行凝胶电泳验证目的基因大小，如图2所示，出现1.5kbp附近条带的样品为阳性样品。将菌落PCR鉴定阳性的菌液送测序公司测序，选择测序正确的菌液进行保存。构建的含有目的基因的转移载体pF-GK，其示意图如图3。
6.以同样的方式构建含有目的基因的转移载体pF-MagT，如图4、图5所示，在1.4kbp附近出现目的条带，转移载体pF-MagT其示意图如图6所示。
实施例2重组杆状病毒基因组Bac-GK和Bac-MagT构建
1.DH10Bac菌转化
取实施例1中1μl pF-GK质粒和1μl pF-MagT质粒分别加入100μl的DH10Bac感受态细胞中混匀，冰浴30分钟，42℃水浴热休克90秒，再冰浴2分钟，加入900μl不含Amp的LB液体培养基，37℃培养5小时。取100μl菌液稀释81倍后，取100μl稀释的菌液涂布到含有庆大霉素、卡那霉素、四环素、X-gal以及IPTG的LB固体培养基上，37℃培养48小时。
2.挑选单克隆
使用接种针挑取大的白色菌落，然后在含有庆大霉素、卡那霉素、四环素、X-gal以及IPTG的LB固体培养基上划线，37℃培养48小时，然后挑取单菌落接种含有庆大霉素、卡那霉素、四环素的LB液体培养基培养，保存菌种，抽提质粒。获得重组质粒Bacmid-GK和Bacmid-MagT。
实施例3重组杆状病毒转染
六孔板中每个孔接种0.8×106个Sf9细胞，细胞汇合度为50～70％。对于每一个孔制备以下的复合物：用100μl转染培养基T1稀释4μl的Cellfectin转染试剂，短暂的漩涡震荡；用100μl转染培养T1基分别稀释3μg实施例2中的重组Bacmid-GK质粒和重组Bacmid-MagT质粒，分别将稀释的转染试剂和质粒混合，轻轻吹匀，制备转染混合物。待细胞贴壁后加入上述的转染复合物，27℃孵育5小时，移除上清，添加2mLSF-SFM新鲜培养基，27℃培养4～5日收获上清。获得重组杆状病毒rBac-GK和rBac-MagT，对收获的P1代重组杆状病毒使用间接免疫荧光法检测病毒滴度，rBac-GK种毒病毒滴度为6.8×108.0pfu/mL，rBac-MagT种毒病毒滴度为7.3×108.0pfu/mL。扩增重组杆状病毒rBac-GK和rBac-MagT作为种毒备用。
实施例4 SDS-PAGE检测
将实施例3中收获的rBac-GK和rBac-MagT细胞培养物进行SDS-PAGE检测，同时使用感染空杆状病毒的Sf9细胞作为阴性对照。具体操作如下：取40μl收获的细胞培养物，加入10μl的5×loading buffer，沸水浴5分钟，12000r/min离心1分钟，取上清进行SDS-PAGE凝胶(12％浓度凝胶)电泳，电泳后取凝胶经染色、脱色后观察目的条带。结果如图7所示，rBac-GK细胞培养物在分子量约57kDa处出现目的条带，rBac-MagT细胞培养物在分子量约53kDa处出现目的条带，阴性对照在对应位置没有条带。
实施例5 Western Blot检测
将实施例4中SDS-PAGE电泳后的产物转印到NC(硝酸纤维素)膜上，用5％脱脂牛奶封闭2小时，兔源抗Mccp阳性血清孵育2小时，漂洗，HRP标记的羊抗兔多克隆抗体孵育2小时，漂洗，然后滴加增强型化学发光荧光底物，使用化学发光成像仪拍照。结果如图8所示，重组杆状病毒表达样品出现目的条带，阴性对照没有条带，说明目的蛋白在Sf9细胞中得到正确表达。
实施例6间接免疫荧光检测
向96孔细胞培养板中加入转染过rBac-GK的Sf9细胞悬液，100μl/孔(细胞浓度为2.5×105～4.0×105个/ml)，接种4孔，27℃静置15分钟，使Sf9细胞贴于培养板底壁，然后每孔加入10μl稀释10倍的毒种。同时设空白细胞对照。接种后细胞置27℃恒温培养箱中培养72～96小时，弃培养液，冷甲醇/丙酮(1∶1)固定。首先与兔源抗Mccp多抗血清反应，然后与FITC标记的羊抗兔IgG反应，倒置荧光显微镜观察结果。以同样的方法对rBac-MagT进行间接免疫荧光检测。结果如图9所示，接种空杆状病毒Sf9细胞不能观察到荧光，而接种了重组杆状病毒Sf9细胞能够观察到荧光，说明目的抗原蛋白在Sf9细胞中得到正确表达，重组杆状病毒构建正确。
实施例7昆虫细胞的生物反应器无血清悬浮培养
在1000mL摇瓶中无菌培养Sf9昆虫细胞3-4天，待浓度长到3-5×106cell/mL，活力大于95％时，将细胞接种到5L的生物反应器中，接种浓度为3-8×105cell/mL。当细胞浓度达到3-55×106cell/mL时，将细胞接种到50L生物反应器中，待细胞长至浓度为3-55×106cell/mL，接种到500L生物反应器中，待细胞浓度达到2-85×106cell/mL时，接种rBac-GK，反应器培养条件为pH值6.0-6.5、温度25-27℃、溶氧30-80％、搅拌速度100-180rpm。考虑到细胞培养的最适条件，优选的pH6.2、细胞培养阶段温度设定27℃、溶氧50％、搅拌速度100-180rpm。在感染之后继续培养5-9天后，加入千分之一终浓度BEI，37℃作用48h后，加千分之二终浓度Na2S2O3终止灭活。通过离心或中空纤维过滤的方法收获细胞培养上清，置2-8℃保存GK蛋白原液。以同样的方法制备表达MagT的蛋白原液。
实施例8蛋白纯化
1.将收获的原液使用阳离子交换层析法进行纯化
使用强阳粒子层析填料POROS 50HS进行粒子交换层析，填料使用前使用0.5MNaOH进行消毒。然后用微滤缓冲液在室温平衡，然后将疫苗原液以125mL/min的速率上柱，然后用漂洗bufferA(0.05M MOPS(钠盐)，pH＝7.0，0.5M NaCl)洗脱8个柱体积。然后线性梯度进行洗脱，从0％bufferA到100％buffer B(0.05M MOPS(钠盐)，pH＝7.0，1.5M NaCl)，其中线性洗脱一共洗脱了10个柱体积，然后平均分别收获这10个柱体积的洗脱物。线性洗脱完后，再用buffer B洗脱2个柱体积，并分别收集。将收集的样品放在2L的无菌的塑料瓶中放置在4℃。然后将最后一个洗脱峰(A280)下收集的组份无菌过滤储存在4℃。
2.羟基磷灰石疏水层析
使用预装羟基磷灰石柱(CHTTM Ceramic Hydroxyapatite Type II Media)，首先使用50mM MOPS(钠盐)，pH＝7.0，1.25M NaCl进行平衡，然后将上面初步纯化的样品以90cm/hour进行上样，上完样后使用8体积的平衡液进行洗脱直至UV值为零。然后使用洗脱液(0.2M磷酸盐，pH＝7.0，1.25M NaCl)进行梯度洗脱，洗脱液浓度从0％到100％，速度仍然是90cm/h，洗脱体积是4个柱体积。纯化得到目的蛋白。
将纯化的目的蛋白使用BCA总蛋白定量，然后结合灰度扫描确定目的蛋白纯度，纯化后的蛋白如图10所示，重组GK蛋白浓度为2.5g/L，纯度为98％；重组MagT蛋白浓度为2.2g/L，纯度为96％。
实施例9疫苗制备
将实施例8中所收获的重组GK蛋白原液和重组MagT蛋白原液按一定比例混合后加入到MONTANIDE ISA 201 VG佐剂中(体积比为46∶54)，使得最终乳化好的疫苗中GK蛋白浓度为50μg/ml、MagT蛋白浓度为40μg/ml，质检合格后置于4℃保存。以相同的方法将重组GK蛋白原液、重组MagT蛋白原液分别制备成疫苗并保存，将制备的两种疫苗设为对照组1、对照组2。
实施例10免疫实验
试验一：安全检验
取3～6月龄的健康易感山羊6只，随机分为3组，每组2只。分别于颈部两侧肌肉注射免疫组、对照组1和对照组2疫苗，每侧5.0ml，连续观察14天，均不出现由疫苗引起的局部或全身不良反应。
试验二：攻毒保护试验
上述各组羊免疫21d采血完成后，各气管注射山羊支原体山羊肺炎亚种强毒C87002株、绵羊肺炎支原体MoGH3-3株和丝状支原体山羊亚种M87-1株混合病毒液4.0ml，观察30日。观察山羊发病情况并进行剖检，结果见表10。
表10
注：(1)体温反应：体温超过40.5℃、呈稽留热，且持续至少3日。(2)①：肺部可见明显浸润和肝样病变，病灶切面呈大理石样；②：胸腔有淡黄色积液，肺部形成纤维素性肺炎；③：胸膜附着纤维素层，甚至与肺和心包发生粘连。
应当理解，以上所描述的实施例是本发明一部分实施例，而不是全部的实施例。本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示本发明的选定实施例。基于本发明中的实施例，本领域普通技术人员在没有作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。
序列表
<110> 苏州米迪生物技术有限公司
<120> 山羊传染性胸膜肺炎基因工程亚单位疫苗及其制法与应用
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atgaccgata gcaaaaaata tattctgacc ctggatgaag gcaccaccag cgcgcgcgcg 60
ctgattaccg ataaacaggg caacattatt gcggtggaac agagcgaatt tacccagtat 120
tttccgaaag aaggctgggt ggaacatgat gcgattgaaa tttggaacac ccagcgcagc 180
gcgctggtgc aggtgctgaa caaaagcggc attgatccga gccagattga agcgattggc 240
attaccaacc agcgcgaaac cgcggtgatt tggaacaaag aaaccggcct gccgatttat 300
aacgcgattg tgtggcagga tcagcgcacc gcggattatt gccagacctt tgataaagat 360
accctggaaa tggtgaaaga acgcagcggc ctgattatta acccgtattt tagcggcacc 420
aaagtgaaat ggattctgga taacgtgccg aacgcgcgcc agctggcgaa agatggcaaa 480
ctgatgtttg gcaccattaa cacctggctg atttatcgcc tgaccggcgg cgaagtgttt 540
gtgaccgatc ataccaacgc gcagcgcacc ctgctgtata acattcatac caacgattgg 600
gatgatgaac tgctgaaact gtttgatatt ccgcgcaaca ttctgccgga aattaaaagc 660
tgcagcgaag tgtatggcta tacctttaaa ggcctgttta gcaaaggcaa cgaacagcgc 720
attaaaattg cgagcagcat tggcgatcag cagagcgcgc tgtttggcca gctgtgcctg 780
gaaaaaggcc aggtgaaagt gacctatggc accggctgct ttattctgac caacaccggc 840
gaagaaattg tgaaaagcaa ccatggcctg ctgaccaccg tggcgtatag ctttaaagat 900
aaagtgtatt atgcgctgga aggcagcgtg atgattgcgg gcgcggcggt gcagtggctg 960
cgcgataacc tgcgcattgt gtataacgcg attgaaaccg aatggtatgc gggccaggtg 1020
aaagatgatc gccgcgtgta tgtggtgccg agctttaccg gcctgggcag cccgtattgg 1080
gatagcttta gccgcggcgc gatttttggc ctggatcgcg gcacccgccg cgaacatatt 1140
gtgcgcgcga ccctggaagc gattgcgtat caggcgaacg atgtggtgga tgcgatgggc 1200
aaagatatga aaaaaccgat tgaaattttt aaagtggatg gcggcgcggc gaacaacaaa 1260
tttctgatgc agtttcagag caacattagc cagagcaaag tgattaaacc gaccaacgtg 1320
gaaaccaccg cgatgggcgc ggcgtttatg gcgggcctgg cggtgggcta ttgggaaaac 1380
gtggaagaac tgaaaaaaac ctataaagtg cattttgaac tgaccccgga actgagcaaa 1440
ccggaagtgg ataaactgat taaaggctgg aaagtggcgg tgcagcgcac ctttaaatgg 1500
gtggaagaaa ttgaataa 1518
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Tyr Cys Gln Thr Phe Asp Lys Asp Thr Leu Glu Met Val Lys Glu Arg
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Gln Leu Cys Leu Glu Lys Gly Gln Val Lys Val Thr Tyr Gly Thr Gly
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Cys Phe Ile Leu Thr Asn Thr Gly Glu Glu Ile Val Lys Ser Asn His
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Gly Leu Leu Thr Thr Val Ala Tyr Ser Phe Lys Asp Lys Val Tyr Tyr
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Ala Leu Glu Gly Ser Val Met Ile Ala Gly Ala Ala Val Gln Trp Leu
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Arg Asp Asn Leu Arg Ile Val Tyr Asn Ala Ile Glu Thr Glu Trp Tyr
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Ala Gly Gln Val Lys Asp Asp Arg Arg Val Tyr Val Val Pro Ser Phe
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Thr Gly Leu Gly Ser Pro Tyr Trp Asp Ser Phe Ser Arg Gly Ala Ile
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ataggatcca tgaccgatag caaaaaatat attctgac 38
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ataaagcttt tattcaattt cttccaccca tttaaagg 38
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atggtggatc tggaaaacaa agaacaggaa attctggaat tttataacaa caaagaattt 60
gataaatgca ttgaaattat taaaaaactg cgctatgcgg atgtgggcga aattctgaac 120
tatctggatg aaaaaattgc gtttaacctg tataaaaaac tggaaattaa caaagcgagc 180
gaaattttta actatctgag ctttgatctg aaagaatata ttctgaccaa cctgagccag 240
accaaaatta aacagctgat taacgatctg tataccgatg atgtgattaa cgcggtggaa 300
aacatgccgg tggaagtggt gaaacgcgtg tttaacgcgg cgagcaaaga acagaaaaaa 360
gaaattgcga gcattctgaa atatgatatt gataccgcgg gcagcattat gagcgtgaac 420
tttctgagcg tgaaacagac caccaccgtg agcaaaacca ttaaagaaat tcagaaaaac 480
catgatgatt atgatgaaat tgatgatgtg tttgtggtga acaaactgaa ccagctggtg 540
ggcagcattg aagtgaaaga tctgattctg aacgatatga acaccaaaat tgaagatatt 600
atgaacacca aagtgattag cattaacagc aaccagagcc aggaagatgc gagcaacgcg 660
ctgaaaaaat atgatattag caccctggcg gtggtggata acaacaacgt gctggtgggc 720
attattacca gcgatgatat tattgatgtg ctgattgaag aaaccaacga agatatgcag 780
aaatataccg gcattcgcac caacgaaacc aactattttg ataccagcat ttttaaaatg 840
tttattagcc gcatttggag cctggtgctg atgctgggcc tgaccattat taccaacagc 900
ctgctgctga ttatttttca gaaatataac tggaccccgg cgattaaaac caaagaagaa 960
ctgctgttta tgctgattcc gctgagcatt attctgagca ccgtgattat ttgctgcgcg 1020
aaccagaccc tggtgatgat tcgccgcgcg attagcctgg aacagattaa caaaaaaagc 1080
ctgaaaacca ttgcgctgaa agaactggtg attagcctga tgattagctt tgtgctggtg 1140
attgtgaacc tgctgaaaat gattctgatt tatgcggtga aatataacgc gaacctgacc 1200
aacattaaca tttggaacag cattctgatt agcagcattg gcatttttat tagcattatt 1260
tttgcgaacc tgctgagcct gtttctgccg ctgattgtga aaaaaattgg caaagatagc 1320
agcagcgtga gcctgccgct gtttgcgctg attattgata ttctgtgcgt gggcgtgttt 1380
ctgggcattg gcctgctggt gtaa 1404
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Met Val Asp Leu Glu Asn Lys Glu Gln Glu Ile Leu Glu Phe Tyr Asn
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Asn Ala Val Glu Asn Met Pro Val Glu Val Val Lys Arg Val Phe Asn
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Ala Ala Ser Lys Glu Gln Lys Lys Glu Ile Ala Ser Ile Leu Lys Tyr
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Asp Ile Asp Thr Ala Gly Ser Ile Met Ser Val Asn Phe Leu Ser Val
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Lys Gln Thr Thr Thr Val Ser Lys Thr Ile Lys Glu Ile Gln Lys Asn
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Asn Gln Leu Val Gly Ser Ile Glu Val Lys Asp Leu Ile Leu Asn Asp
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ataaagcttt tacaccagca ggccaatgcc cagaaac 37
Claims (11)
1.重组蛋白，其特征在于包括第一重组蛋白和第二重组蛋白；所述第一重组蛋白具有SEQ ID NO：2所示序列或其增加或截短的序列，所述第二重组蛋白具有SEQ ID NO：6所示序列或其增加或截短的序列。
2.用于编码权利要求1所述重组蛋白的基因。
3.如权利要求2所述的基因，其特征在于包括第一基因、第二基因；所述第一基因具有SEQ ID NO：1所示序列或其增加或截短的序列；所述第二基因具有SEQ ID NO：5所示序列或其增加或截短的序列。
4.包含权利要求1所述重组蛋白的编码基因的重组载体或宿主细胞。
5.一种免疫组合物，其特征在于包括：权利要求1所述的重组蛋白；以及，医药学上可接受的载剂。
6.如权利要求5所述的免疫组合物，其特征在于：所述免疫组合物所含第一重组蛋白与第二重组蛋白的质量比例为5：4；和/或，所述医药学上可接受的载剂包括MONTANIDE ISA206 VG、MONTANIDE ISA 201 VG、MONTANIDE ISA 51 VG、液体石蜡、樟脑油、植物细胞凝集素之中的任意一种或者两种以上的组合。
7.权利要求1所述重组蛋白的制备方法，其特征在于包括：
提供第一重组蛋白的编码基因和/或第二重组蛋白的编码基因；
将所述第一重组蛋白的编码基因和/或第二重组蛋白的编码基因克隆到穿梭载体中，获得含有目的基因的重组穿梭载体；
将所述重组穿梭载体转化感受态细胞，并分离获得含有目的基因表达框的重组杆状病毒基因组质粒；
以所述重组杆状病毒基因组质粒转染昆虫细胞，并分离获得重组杆状病毒；
将所述重组杆状病毒接种昆虫细胞并进行培养，之后分离获得所述重组蛋白。
8.如权利要求7所述的制备方法，其特征在于：所述穿梭载体包括pFastBac 1、pVL1393或pFastBac dual；和/或，所述昆虫细胞包括Sf9、High Five或Sf21细胞。
9.一种山羊传染性胸膜肺炎基因工程亚单位疫苗的制备方法，其特征在于包括：采用权利要求7-8中任一项所述的方法制备重组蛋白，并将所述重组蛋白与医药学上可接受的载剂混合。
10.如权利要求1所述重组蛋白或权利要求5或6所述免疫组合物在制备山羊传染性胸膜肺炎检测试剂，在生产用于在受试动物中诱导针对山羊传染性胸膜肺炎抗原的免疫反应的药剂，或者，在生产用于预防动物受山羊传染性胸膜肺炎感染的药剂中的用途。
11.如权利要求1所述重组蛋白或权利要求5或6所述免疫组合物在制备山羊传染性胸膜肺炎基因工程亚单位疫苗中的用途。
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