CN111944023A - 一种抗o型口蹄疫的疫苗组合物及其制备方法和应用 - Google Patents
一种抗o型口蹄疫的疫苗组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及兽用生物制品领域，更具体地，公开了三种O型口蹄疫病毒样颗粒以及抗O型口蹄疫的疫苗组合物及其制备方法。本发明筛选的毒株序列制备的病毒样颗粒对于我国流行的O型口蹄疫SEA型、CATHAY型及其变异株有着较好的免疫应答能力，以此制备的疫苗组合物能有效防治三种亚型口蹄疫的感染，是一种新型疫苗。
Description
本申请是申请日为2014年11月7日、申请号为201410624645.2、发明名称为“一种抗O型口蹄疫的疫苗组合物及其制备方法和应用”的中国专利申请的分案申请。
技术领域
本发明涉及兽用生物制品领域。更具体地，本发明涉及一种抗O型口蹄疫的疫苗组合物。
背景技术
口蹄疫(FMD)为一种急性、高度接触传染性和可快速远距离传播的动物疾病，是哺乳类动物中感染性最强的疾病，其中偶蹄类动物染病更会造成全球重大的经济损失。遭受口蹄疫危害的动物包括牛、羊、山羊和猪。致病因子，口蹄疫病毒(FMDV)，是小核糖核酸病毒属家族的一种口疮病毒。该病毒分为7个血清型(A、O、C、Asia 1、SAT1、SAT2、和SAT3型)，其中O型口蹄疫病毒流行最为广泛。疫苗免疫是控制此病、保护家畜免受危害的有效措施。传统的疫苗包括灭活疫苗和减毒疫苗，他们虽然具有较好的免疫原性，也确实在FMD的预防和控制中起到了非常重要的作用。但是也存在以下几个缺点：1.病毒必须在高度密封的设备中生产，以防止污染周围环境；生产过程中，病毒有可能没有完全杀死或充分减毒，会导致疫苗中含有高毒性致病物质，进而导致被免疫动物发病而使疾病大规模流行。2.有效期很短，而且常常需要冷冻保存，这增大了疫苗在农村推广使用的难度。3.灭活苗免疫与感染FMD的动物区分不开，限制了动物出口。4.生产依赖于FMDV，故而不能彻底消灭FMDV。目前使用的灭活疫苗和减毒疫苗防控已不能适应当前畜牧业的健康发展。
基因工程疫苗相比来说安全稳定性比较好，同时能给被免疫的动物提供有效的保护效果。但是仅仅是用抗原决定簇的表达蛋白来做疫苗，由于其分子小，结构简单，往往并不能起到很好的免疫效果；只有将抗原决定簇与大分子物质(如脂质体或者蛋白等)一起免疫才能诱导机体产生有效的免疫反应。
病毒样颗粒(VLPs)是一种在体外和/或体内表达时能够自主包装成病毒外壳结构的类病毒粒子，它们是具有病毒的相似外壳结构但不具有病毒复制能力的假病毒。VLPs疫苗能有效地激发机体产生抗感染，抗肿瘤免疫，基于病毒样颗粒设计的疫苗是一种较为理想的疫苗形式。然而，O型口蹄疫病毒抗原性很弱，尤其是我国流行的CATHAY型变异株，其抗原发生较大变异，原有疫苗对其保护力明显下降，加之自身免疫原性较弱，不能诱导动物机体产生足够的免疫力。因此，筛选理想的毒株序列制备病毒样颗粒是当务之急，也符合国家提出的有效防控重大动物疫病，保障畜牧业健康可持续发展的需要。
此外，O型口蹄疫各亚型之间的抗原性不同，彼此之间不能交互免疫，在我国，O型口蹄疫CATHAY型及其变异株长期流行，加上近年SEA型的流行，使得O型口蹄疫的流行更趋复杂化，迫切需要能同时防治三种亚型感染的新型疫苗。
发明内容
本发明的目的在于克服现有技术缺陷，要解决的第一个技术问题是提供一种O型口蹄疫病毒样颗粒，其中，病毒样颗粒由结构蛋白VP0、VP3和VP1构成。
优选地，本发明提供的O型口蹄疫病毒的结构蛋白VP0氨基酸序列为SEQ ID NO.2，VP3氨基酸序列为SEQ ID NO.4，VP1氨基酸序列为SEQ ID NO.6。
优选地，本发明提供的O型口蹄疫病毒的结构蛋白VP0氨基酸序列为SEQ ID NO.8，VP3氨基酸序列为SEQ ID NO.10，VP1氨基酸序列为SEQ ID NO.12。
优选地，本发明提供的O型口蹄疫病毒的结构蛋白VP0氨基酸序列为SEQ IDNO.14，VP3氨基酸序列为SEQ ID NO.16，VP1氨基酸序列为SEQ ID NO.18。
本发明要解决的第二个技术问题是提供一种预防和/或治疗O型FMDV感染的疫苗组合物，包含O型口蹄疫病毒氨基酸序列为SEQ ID NO.2所示的VP0、SEQ ID NO.4所示的VP3、SEQ ID NO.6所示的VP1组成的病毒样颗粒和/或氨基酸序列为SEQ ID NO.8所示的VP0、SEQ ID NO.10所示的VP3、SEQ ID NO.12所示的VP1组成的病毒样颗粒和/或氨基酸序列为SEQ ID NO.14所示的VP0、SEQ ID NO.16所示的VP3、SEQ ID NO.18所示的VP1组成的病毒样颗粒及佐剂。
优选地，本发明提供的预防和/或治疗O型FMDV感染的疫苗组合物，所述编码O型口蹄疫病毒的结构蛋白VP0的核苷酸序列为SEQ ID NO.1，VP3的核苷酸序列为SEQ ID NO.3，VP1的核苷酸序列为SEQ ID NO.5。
优选地，本发明提供的预防和/或治疗O型FMDV感染的疫苗组合物，所述编码O型口蹄疫病毒的结构蛋白VP0的核苷酸序列为SEQ ID NO.7，VP3的核苷酸序列为SEQ ID NO.9，VP1的核苷酸序列为SEQ ID NO.11。
优选地，本发明提供的预防和/或治疗O型FMDV感染的疫苗组合物，所述编码O型口蹄疫病毒的结构蛋白VP0的核苷酸序列为SEQ ID NO.13，VP3的核苷酸序列为SEQ IDNO.15，VP1的核苷酸序列为SEQ ID NO.17。
作为本发明的另外一种实施方式，本发明提供的预防和/或治疗O型FMDV感染的疫苗组合物包含氨基酸序列为SEQ ID NO.2,4,6,8,10,12,14,16,18及核苷酸序列为SEQ IDNO.1,3,5,7,9,11,13,15,17所示的变体。
“变体”旨在表示基本上类似序列。对于多核苷酸，变体包含在天然多核苷酸之内的一个或更多位点的一个或更多核苷酸的缺失和/或添加，和/或在天然多核苷酸中一个或更多位点的一个或更多核苷酸的取代。如本文所用，“天然”多核苷酸或多肽分别包含天然存在的核苷酸序列或氨基酸序列。本发明的特定多核苷酸(即,参照多核苷酸)的变体也可通过比较由变体多核苷酸编码的多肽和由参照多核苷酸编码的多肽之间的百分率序列同一性来评价。“变体”蛋白旨在表示通过在天然蛋白中的一个或更多位点的一个或更多氨基酸的缺失或添加，和/或天然蛋白中的一个或更多位点的一个或更多氨基酸的取代而源于天然蛋白的蛋白。本发明包括的变体蛋白有生物学活性，即，它们有引发免疫应答的能力，能对O型FMDV攻击具有保护性反应的能力。
变体包括等位基因变体。术语"等位基因变体"指称含有导致蛋白的氨基酸序列变化及在天然的群(例如，病毒物种或变种)之内存在的多态性的多核苷酸或多肽。该天然的等位基因变异可一般导致多核苷酸或多肽的1％～5％变异。等位基因变体可通过在许多不同物种中测序目的核酸序列来鉴定，其可通过使用鉴定那些物种中的相同的遗传座位的杂交探针来容易进行。任何和全部该核酸变异及得到的氨基酸多态性或是天然的等位基因变异的结果且不改变目的基因的功能活性的变异旨在本发明的范围之内。
术语“预防”指通过其与O型FMDV相关的感染或疾病的症状被阻断或延迟；术语“治疗”指通过与O型FMDV相关的感染或疾病的症状被缓和或完全消除的过程。
术语“保护性反应”意为在动物中预防O型FMDV相关疾病或由O型FMDV导致的感染的发作或减轻存在的这样的疾病的严重性。
本发明涉及的O型FMDV蛋白，其有利地激发动物中的保护性反应。具体地，本发明实施方式的蛋白序列包含与其功能衍生物基本相同的氨基酸序列。
“基本上相同”可以理解为本发明的蛋白优选地具有这样的氨基酸序列，其与SEQID NO：2,4,6,8,10,12,14,16,18中所示的序列的部分或全部具有至少70％同源性，或甚至优选地80％同源性，或甚至更优选地90％同源性，或最优选地95％同源性。
在本文中术语“同源性”还包括与参比序列相同或类似，同时提供任何氨基酸的简单替换/修饰。可以用BLAST-P(基本局部排比检索工具)，本领域技术人员公知的程序进行该方面的同源性检索。对于相应的核酸序列，同源性涉及在本领域中已知的BLASTX和BLASTN程序。
术语“佐剂”指加入到本发明的组合物中以增加组合物的免疫原性的物质。已知的佐剂包括，但不限于：(1)氢氧化铝，皂苷(Saponine)(例如QuilA)，阿夫立定，DDA，(2)丙烯酸或甲基丙烯酸的聚合物，顺丁烯二酸酐和链烯基衍生物的聚合物，或(3)疫苗可以以水包油，油包水或水包油包水乳剂形式制成。
尤其是，乳剂可以基于轻液体石蜡油、类异戊二烯油，例如角鲨烷或角鲨烯；烯烃，特别是异丁烯或癸烯低聚化产生的油，带直链烷基的酸或醇形成的酯，更特别是植物油，油酸乙基酯，丙二醇二(辛酸酯/癸酸酯)，甘油三(辛酸酯/癸酸酯)，丙二醇二油酸酯；分支脂肪酸酯或醇的酯，特别是异硬脂酸酯。油与乳化剂一起使用形成乳剂。乳化剂优选非离子表面活性剂，特别是聚氧乙烯化脂肪酸(例如油酸)，脱水山梨糖醇、甘露醇(例如脱水甘露醇油酸酯)、甘油、聚甘油、丙二醇和可选地乙氧基化的油酸、异硬脂酸、蓖麻油酸、羟基硬脂酸形成的酯，脂肪醇和多元醇(例如油醇)的醚，聚氧丙稀-聚氧乙烯嵌段共聚物，特别是PluronicR，尤其是L121(参照Hunter等，1995，“The Theory and Practical ApplicationofAdjuvants”(Steward-Tull，D.E.S主编)John Wiley andSons，NY，51-94；Todd等，Vaccine，1997，15，564-570)。
特别地，丙烯酸或甲基丙烯酸聚合物通过糖或多元醇的聚链烯基醚交联。这些化合物被称作卡波姆。
优选地，本发明选用佐剂ISA 206(法国赛比克公司)，制备水包油包水乳剂。
在最终疫苗组合物中，佐剂的浓度范围是从10％到60％V/V，优选从30％到50％V/V，更优选50％V/V。
本发明通过在结构蛋白VP0第178位氨基酸突变为半胱氨酸、VP1第17位氨基酸突变为天冬氨酸，在核苷酸水平上，相当于用编码半胱氨酸和天冬氨酸的密码子置换原来的密码子，提高了病毒样颗粒的稳定性，无论在热环境条件下，还是在酸环境条件下，其稳定性大大增强。不仅如此，意外发现，通过结构优化的病毒样颗粒制备的疫苗组合物在免疫持续期显著长于优化前的病毒样颗粒制备的疫苗组合物。
在一个实施方式中，本发明提供一种预防和/或治疗O型FMDV感染的疫苗组合物，由三种O型口蹄疫病毒样颗粒及佐剂组成；
所述病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中VP0的氨基酸序列为SEQ ID NO.2，VP3氨基酸序列为SEQ ID NO.4，VP1氨基酸序列为SEQ ID NO.6，但SEQ ID NO.2第178位氨基酸突变为半胱氨酸，SEQ ID NO.6第17位氨基酸突变为天冬氨酸；
所述病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中VP0的氨基酸序列为SEQ ID NO.8，VP3氨基酸序列为SEQ ID NO.10，VP1氨基酸序列为SEQ ID NO.12，但SEQ ID NO.8第178位氨基酸突变为半胱氨酸，SEQ ID NO.12第17位氨基酸突变为天冬氨酸；
所述病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中VP0的氨基酸序列为SEQ ID NO.14，VP3氨基酸序列为SEQ ID NO.16，VP1氨基酸序列为SEQ ID NO.18，但SEQ ID NO.14第178位氨基酸突变为半胱氨酸，SEQ ID NO.18第17位氨基酸突变为天冬氨酸。
本发明的另一个目的是提供一种预防和/或治疗O型FMDV感染的疫苗组合物的制备方法，包括：
(1)制备O型口蹄疫病毒样颗粒的步骤；
(2)加入佐剂，乳化的步骤。
本发明疫苗组合物进一步包含亚洲1型口蹄疫病毒样颗粒和/或A型口蹄疫病毒样颗粒。
优选地，本发明所述的亚洲1型口蹄疫病毒样颗粒为亚洲1型口蹄疫病毒JSL株制备。
优选地，本发明所述A型口蹄疫病毒样颗粒为A型口蹄疫病毒WH/09株制备。
本发明疫苗组合物还可以进一步将其他的试剂加入到本发明的组合物。例如，本发明的组合物还可以包含试剂，如：药物，免疫刺激剂(如：α-干扰素、β-干扰素、γ-干扰素、粒细胞巨噬细胞集落刺激因子(GM-CSF)、巨噬细胞集落刺激因子(M-CSF)和白介素2(IL2))，抗氧化剂，表面活性剂，着色剂，挥发性油，缓冲剂，分散剂，推进剂和防腐剂。为了制备这样的组合物，可以使用本领域公知的方法。
本发明的组合物的成分或组分的量优选地是治疗有效量。所述治疗有效量是指在组合物施用的宿主中发挥它们的免疫学作用而不导致过度副作用所必需量。所用的成分和待施用的组合物的精确的量将根据因素如治疗的疾病的类型，待治疗的动物的类型和年龄，施用的方式，以及组合物中的其它成分而变化。
优选地，本发明疫苗组合物每种病毒样颗粒含量为50-150μg/ml。
更优选地，所述疫苗组合物每种病毒样颗粒含量为100μg/ml。
本发明具有以下突出的优点：
(1)本发明提供的疫苗组合物制备安全，无减毒疫苗、灭活疫苗可能引起的致病作用；
(2)本发明提供的病毒样颗粒结构，口蹄疫的表位被有效呈递在病毒样颗粒的表面，可以很好地刺激B、T细胞，引起免疫应答；
(3)本发明提供病毒样颗粒疫苗的结构在体内血清中的半衰期长，稳定性好，有效期长，持续刺激免疫反应，尤其是O型口蹄疫病毒Ⅰ病毒样颗粒，为CATHAY型变异株，解决了CATHAY型变异株一直以来免疫原性较差的问题，能很好地对机体提供免疫保护，可以有效应对CATHAY型变异株的侵袭；
(4)本发明还提供一种优化的病毒样颗粒结构，提高了病毒样颗粒的稳定性，不仅温度稳定性及酸性环境稳定性增加，而且意外发现，优化后的病毒样颗粒的疫苗组合物免疫持续期显著增长，能维持更长时间的免疫保护。
序列表中：
序列1为O型口蹄疫病毒ⅠVP0蛋白核苷酸序列；
序列2为O型口蹄疫病毒ⅠVP0蛋白氨基酸序列；
序列3为O型口蹄疫病毒ⅠVP3蛋白核苷酸序列；
序列4为O型口蹄疫病毒ⅠVP3蛋白氨基酸序列；
序列5为O型口蹄疫病毒ⅠVP1蛋白核苷酸序列；
序列6为O型口蹄疫病毒ⅠVP1蛋白氨基酸序列；
序列7为O型口蹄疫病毒ⅡVP0蛋白核苷酸序列；
序列8为O型口蹄疫病毒ⅡVP0蛋白氨基酸序列；
序列9为O型口蹄疫病毒ⅡVP3蛋白核苷酸序列；
序列10为O型口蹄疫病毒ⅡVP3蛋白氨基酸序列；
序列11为O型口蹄疫病毒ⅡVP1蛋白核苷酸序列；
序列12为O型口蹄疫病毒ⅡVP1蛋白氨基酸序列；
序列13为O型口蹄疫病毒ⅢVP0蛋白核苷酸序列；
序列14为O型口蹄疫病毒ⅢVP0蛋白氨基酸序列；
序列15为O型口蹄疫病毒ⅢVP3蛋白核苷酸序列；
序列16为O型口蹄疫病毒ⅢVP3蛋白氨基酸序列；
序列17为O型口蹄疫病毒ⅢVP1蛋白核苷酸序列；
序列18为O型口蹄疫病毒ⅢVP1蛋白氨基酸序列。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
本发明实施例中所用PBS缓冲液如无特别说明，均采用pH7.4的PBS，配制方法：NaCl 8.0g，KCl 0.2g，KH2PO4 0.24g，Na2HPO4·12H2O 3.628g，溶于800ml蒸馏水中，用盐酸调pH值为7.4，蒸馏水定容至1000ml，121℃高压灭菌20min，室温保存。
实施例1
具有序列SEQ ID NO.1、3、5、7、9、11、13、15、17的口蹄疫的蛋白表达
1.用做模板的口蹄疫基因片段的制备
分别将序列SEQ ID NO.1、3、5所示的O型口蹄疫病毒ⅠVP0、VP3、VP1基因，序列SEQID NO.7、9、11所示的O型口蹄疫病毒ⅡVP0、VP3、VP1基因，序列SEQ ID NO.13、15、17所示的O型口蹄疫病毒ⅢVP0、VP3、VP1基因全长由生工生物工程(上海)股份有限公司合成。所合成的基因片段全长分别为909bp、660bp、639bp，909bp、660bp、639bp，909bp、660bp、639bp。在此人工合成的口蹄疫基因片段的基础上制备本发明的口蹄疫基因的模板。
2.口蹄疫基因表达载体的构建
以前一步骤所合成的口蹄疫基因模板。分别设计引物(见表1)，扩增获得O型口蹄疫病毒ⅠVP0、VP3、VP1基因；O型口蹄疫病毒ⅡVP0、VP3、VP1基因；O型口蹄疫病毒ⅢVP0、VP3、VP1基因。
表1引物表
在PCR仪上按如下条件(见表2)进行PCR反应：
表2 PCR扩增条件
分别将不同血清亚型的O型口蹄疫扩增得到的VP0、VP3、VP1基因DNA片段分别与pBLUE-T Vector载体连接，将连接成功的重组克隆分别经BamH I/EcoR I、Sac I/Sal I、Hind III/Xho I酶切消化后得到的片段，与经过相同的酶切的pET 28a载体连接，得到插入O型口蹄疫病毒ⅠVP0、VP3、VP1基因的阳性克隆pET28a-Ⅰ-VP0-VP3-VP1；插入O型口蹄疫病毒ⅡVP0、VP3、VP1基因的阳性克隆pET28a-Ⅱ-VP0-VP3-VP1以及插入O型口蹄疫病毒ⅢVP0、VP3、VP1基因的阳性克隆pET28a-Ⅲ-VP0-VP3-VP1。将连接好的质粒转化到用CaCl2制备的DH5a感受态细胞中，涂布于卡那霉素抗性的固体LB培养基上，等单克隆菌落清晰可见时，挑取单克隆至含有卡那霉素的LB液体培养基中，37℃230转/分钟，培养12小时过夜，提取质粒。
3.将上述的插入O型口蹄疫病毒ⅠVP0、VP3、VP1基因的阳性克隆pET28a-Ⅰ-VP0-VP3-VP1；插入O型口蹄疫病毒ⅡVP0、VP3、VP1基因的阳性克隆pET28a-Ⅱ-VP0-VP3-VP1以及插入O型口蹄疫病毒ⅢVP0、VP3、VP1基因的阳性克隆pET28a-Ⅲ-VP0-VP3-VP1分别转化40μl以氯化钙法制备的感受态大肠杆菌BL21(DE3)，涂布于卡那霉素抗性的固体LB培养基，37℃静置培养10-12小时至单菌落清晰可见时，挑取单克隆至含4ml卡那霉素抗性的液体LB培养基的试管，37℃，230转/分振荡培养12小时，从中取1ml菌液于-80℃冻干保存。
4.蛋白的大量表达
从-80℃中取出带有重组质粒pET28a-Ⅰ-VP0-VP3-VP1、pET28a-Ⅱ-VP0-VP3-VP1和pET28a-Ⅲ-VP0-VP3-VP1的大肠杆菌菌种分别接种卡那霉素抗性的50ml LB液体培养基，37℃，230转/分振荡培养12小时后，转接入1L LB液体培养基中，37℃大量表达，等OD600值达到0.6后，加入0.1mM的IPTG，诱导蛋白表达，20℃过夜。
使用发酵罐为上海保兴生物公司50L发酵罐，配制30L培养基装入发酵罐，121℃灭菌30分钟。第二天将5L种子液接入发酵罐，培养菌液浓度达到OD600大约10左右时将培养温度降至25℃，加入4gIPTG诱导培养12小时。终浓度大约为40左右(OD600)下罐，离心收集菌体大约2.5kg。
按照1g菌体对应10ml裂解液的比例重悬菌体，采用均质机以800bar压力破碎菌体4次。13500rpm，离心40min，留取上清，通过15％SDS-PAGE电泳检测，此时上清中三个血清亚型中的三个串联表达的蛋白其各自表达量均在20％左右。采用硫酸铵分级沉淀法进行蛋白粗纯，随后进行色谱纯化，纯化后的蛋白经SDS-PAGE电泳，显示目的蛋白均得到了纯化和富集。
通过磷钨酸负染及电镜观察可见三种口蹄疫蛋白均形成了类病毒样颗粒，并且形成的类病毒样颗粒饱满，组装效率高，没有聚集。通过将这三种口蹄疫病毒样颗粒置于4℃下放置3个月，再通过磷钨酸负染及电镜观察可见病毒样颗粒依旧颗粒饱满，无聚集现象。说明本发明筛选的序列制备的三种口蹄疫蛋白均形成了稳定的类病毒样颗粒。
实施例2
抗O型口蹄疫的疫苗组合物的制备
取实施例1制备的O型口蹄疫病毒Ⅰ病毒样颗粒、O型口蹄疫病毒Ⅱ病毒样颗粒和O型口蹄疫病毒Ⅲ病毒样颗粒，缓缓加入到佐剂中，加的过程不断用转速为800rpm乳化机搅拌12min，混匀，4℃保存，即为抗O型口蹄疫的疫苗组合物。具体配比见表3。适用于本发明的佐剂可以为本领域技术人员公知的佐剂。在本实施例中，选用佐剂ISA 206(法国赛比克公司)。
表3抗O型口蹄疫的疫苗组合物成分配比
| 疫苗1 | 疫苗2 | 疫苗3 | 疫苗4 | 疫苗5 | 疫苗6 | 疫苗7 | |
| Ⅰ(μg/ml) | 100 | 0 | 0 | 100 | 50 | 100 | 150 |
| Ⅱ(μg/ml) | 0 | 100 | 0 | 100 | 50 | 100 | 150 |
| Ⅲ(μg/ml) | 0 | 0 | 100 | 0 | 50 | 100 | 150 |
| 206佐剂(V/V％) | 50％ | 50％ | 50％ | 50％ | 50％ | 50％ | 50％ |
实施例3
抗O型口蹄疫的单价疫苗的免疫原性试验
1.免疫程序
利用口蹄疫O型抗体ELISA检测试剂盒筛选抗体均为阴性的6月龄的健康黄牛20头，随机分为4组，每组5头。1-3组分别为本发明实施例2制备的疫苗1、疫苗2、疫苗3免疫组，第4组为PBS对照组。免疫组免疫途径为颈部肌肉注射1ml，PBS对照组免疫等量的PBS。疫苗免疫前每头牛采血，免疫后每周采血，连续采血至免疫后21日。
2.抗体水平检测
对采集的血清使用口蹄疫O型抗体ELISA检测试剂盒进行相关抗体的检测。结果显示，疫苗免疫前所有牛只的抗体均为阴性，免疫后7天不同疫苗免疫的牛只抗体水平均开始上升，免疫后21天均能达到1：128以上。PBS对照组牛只抗体为阴性，无变化。具体结果见表4。
表4不同疫苗免疫牛只后口蹄疫ELISA抗体水平
证明本发明制备的三种病毒样颗粒均能快速形成高水平的特异性抗体，解决了O型口蹄疫免疫原性较差的问题，尤其是CATHAY型变异株免疫原性较差的问题，能对机体起到很好的免疫保护作用。
实施例4
抗O型口蹄疫的多价疫苗的免疫原性试验
1.免疫程序
利用口蹄疫O型抗体ELISA检测试剂盒筛选抗体均为阴性的6月龄的健康黄牛25头，随机分为5组，每组5头。1-4组分别为本发明实施例2制备的疫苗4、疫苗5、疫苗6、疫苗7免疫组，第5组为PBS对照组。免疫组免疫途径为颈部肌肉注射1ml，PBS对照组免疫等量的PBS。疫苗免疫前每头牛采血，免疫后每周采血，连续采血至免疫后21日。
2.抗体水平检测
对采集的血清使用口蹄疫O型抗体ELISA检测试剂盒进行相关抗体的检测。结果显示，疫苗免疫前所有牛只的抗体均为阴性，免疫后7天不同疫苗免疫的牛只抗体水平均开始上升，免疫后21天均能达到1：128以上。PBS对照组牛只抗体为阴性，无变化。具体结果见表5。
表5多价疫苗免疫牛只后口蹄疫ELISA抗体水平
证明本发明制备的多价疫苗组合物能快速形成高水平的特异性抗体，能对机体起到很好的免疫保护作用。
实施例4
抗O型口蹄疫的疫苗组合物的免疫原性比较试验
1.免疫程序
利用口蹄疫O型抗体ELISA检测试剂盒筛选抗体阴性的6月龄的健康黄牛15头，随机分为3组，每组5头。第1组为本发明实施例2制备的疫苗6免疫组，第2组为市售商品化O型口蹄疫全病毒二价灭活疫苗(金宇保灵生物药品有限公司生产，批号4136011)，第3组为PBS对照组。免疫组免疫途径为颈部肌肉注射，第1组免疫1ml，第2组免疫2ml，PBS对照组免疫2ml的PBS。疫苗免疫前每头牛采血，免疫后每周采血，连续采血至免疫后21日。
2.抗体水平检测
对采集的血清使用口蹄疫O型抗体ELISA检测试剂盒进行相关抗体的检测。结果显示，疫苗免疫前所有牛只的抗体均为阴性，免疫后7天不同疫苗免疫的牛只抗体水平均开始上升，免疫后21天均能达到1：128以上。PBS对照组牛只抗体为阴性，无变化。详细抗体检测情况见表6，表明本发明疫苗组合物能产生更高的抗体水平。
表6不同疫苗免疫牛只后ELISA抗体水平
证明了本发明提供的疫苗组合物，其抗原表位被有效呈递在病毒样颗粒的表面，比全病毒疫苗能更好地刺激B、T细胞，引起免疫应答。与全病毒疫苗相比，本发明提供的疫苗组合物在体内血清中的半衰期长，稳定性好，有效期长，持续刺激免疫反应，其抗体水平远高于全病毒疫苗。
实施例5
抗口蹄疫的疫苗组合物病毒样颗粒结构的优化
将SEQ ID NO.2第178位氨基酸Ser突变为Cys，SEQ ID NO.6第17位氨基酸Asn突变为Asp，SEQ ID NO.8第178位氨基酸Ser突变为Cys，SEQ ID NO.12第17位氨基酸Asn突变为Asp，SEQ ID NO.14第178位氨基酸Ser突变为Cys，SEQ ID NO.18第17位氨基酸Asn突变为Asp。根据突变后的氨基酸序列参考实施例1的方法制备抗O型口蹄疫的病毒样颗粒。
实施例6
优化的抗口蹄疫的疫苗组合物病毒样颗粒结构的稳定性检验
将实施例1及实施例5制备的病毒样颗粒分别置于50℃水浴中1小时及pH6.0条件下处理30分钟，然后在电镜下观察。结果显示优化的病毒样颗粒无论是在热环境下还是在酸性条件下，其病毒样颗粒大小均匀，呈空心形态；而未优化的病毒样颗粒出现聚团，颗粒大小不一。具体结果见表7。
表7口蹄疫病毒样颗粒稳定性检验
证明了本发明提供的优化后的疫苗组合物的病毒样颗粒结构的稳定性进一步增强，其有利地保障了疫苗组合物在不同环境下结构的稳定性，有利于储存与运输，保证了疫苗性状的稳定性。
实施例7
优化的抗口蹄疫的疫苗组合物的制备
取实施例5制备的O型口蹄疫病毒Ⅰ病毒样颗粒、O型口蹄疫病毒Ⅱ病毒样颗粒和O型口蹄疫病毒Ⅲ病毒样颗粒，按照实施例2的制备方法制备抗O型口蹄疫的疫苗组合物。具体配比见表8。
表8优化的抗O型口蹄疫的疫苗组合物的成分配比
| 疫苗8 | |
| Ⅰ(μg/ml) | 100 |
| Ⅱ(μg/ml) | 100 |
| Ⅲ(μg/ml) | 100 |
| 206佐剂(V/V％) | 50％ |
实施例8
优化的抗口蹄疫的疫苗组合物免疫持续期对比试验
1.免疫程序
利用口蹄疫O型抗体ELISA检测试剂盒筛选抗体阴性的6月龄的健康黄牛15头，随机分为3组，每组5头。第1组为本发明实施例2制备的疫苗6免疫组，第2组为本发明实施例7制备的疫苗8免疫组，第3组为PBS对照组。免疫组免疫途径为颈部肌肉注射1ml，PBS对照组免疫等量的PBS。疫苗免疫前每头牛采血，免疫后每月采血，连续采血至免疫后6个月。
2.抗体水平检测
对采集的血清分使用口蹄疫O型抗体ELISA检测试剂盒进行抗体的检测。结果显示，疫苗免疫前所有牛只的抗体均为阴性，免疫后4个月疫苗6免疫的牛只抗体水平均开始下降，而疫苗8依然保持较高的抗体水平。PBS对照组牛只抗体为阴性，无变化。详细抗体检测情况见表9。
表9免疫持续期对比试验ELISA抗体水平
证明了本发明提供的优化的病毒样颗粒结构，提高了病毒样颗粒的稳定性，不仅温度稳定性及酸性环境稳定性增加，而且意外发现，优化后的病毒样颗粒的疫苗组合物免疫持续期显著增长，能维持更长时间的免疫保护。
实施例9
抗口蹄疫的疫苗组合物的功效应用
1.免疫程序
利用田间猪场200头，随机分为10组，每组20头，免疫本发明制备的疫苗6，免疫途径为颈部肌肉注射1ml。疫苗免疫前每头猪采血，免疫后每周采血，连续采血至免疫后21日。
2.抗体水平检测
对采集的血清使用口蹄疫O型抗体ELISA检测试剂盒进行抗体的检测。结果显示，疫苗免疫前所有猪只的抗体均为阴性，免疫后7天疫苗免疫的猪只抗体水平均开始上升，免疫后21天均能达到1：128以上。详细抗体检测情况见表10。
表10疫苗免疫猪只后ELISA抗体平均水平
| 组别 | 免疫0天 | 免疫7天 | 免疫14天 | 免疫21天 |
| 1 | 1:8 | 1:180 | 1:360 | 1:1024 |
| 2 | 1:8 | 1:157.7 | 1:360 | 1:1024 |
| 3 | 1:16 | 1:90 | 1:360 | 1:720 |
| 4 | 1:8 | 1:180 | 1:720 | 1:1024 |
| 5 | 1:8 | 1:135 | 1:360 | 1:1024 |
| 6 | 1:8 | 1:90 | 1:360 | 1:720 |
| 7 | 1:11 | 1:126 | 1:360 | 1:1024 |
| 8 | 1:8 | 1:180 | 1:720 | 1:1024 |
| 9 | 1:11 | 1:144 | 1:360 | 1:948 |
| 10 | 1:16 | 1:180 | 1:360 | 1:1024 |
证明了本发明提供的疫苗组合物能快速形成高水平的特异性抗体，对猪只起到良好的免疫保护作用。
以上所述仅是本发明的优选实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以优选实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案的范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
SEQUENCE LISTING
<110> 普莱柯生物工程股份有限公司斯澳生物科技（苏州）有限公司
<120> 一种抗O型口蹄疫的疫苗组合物及其制备方法和应用
<160> 18
<170> PatentIn version 3.3
<210> 1
<211> 909
<212> DNA
<213> O型口蹄疫病毒ⅠVP0蛋白核苷酸序列
<400> 1
ggcgccgggc aatccagccc gaccaccgga tcacaaaacc aatctggcaa caccggtagt 60
atcattaaca attactacat gcagcagtac cagaactcta tggacaccca acttggcgac 120
aacgccatca gtggagggtc caacgagggc tccacggaca ctacatctac tcacaccaac 180
aacacccaga acaacgactg gttttcgaaa ctggccaaca ccgctttcag cggcctcttc 240
ggcgctcttc ttgccgacaa aaagacggag gaaaccaccc tcctcgaaga ccgcatcctc 300
acgacccgta acggacacac gacctcgact acccagtcaa gtgtcggggt gacgtacggg 360
tatgcaacgg ctgaggactt tgtgagcgga cctaacacgt ccggtctcga gaccagagtt 420
gttcaggccg aacggttctt caaaacccac ctgttcgact ggggcaccaa cgactcgttc 480
gggcggtgcc acttgttgga gttaccaact gaccacaaag gtgtctacgg cagcctgacc 540
gactcatatg catacatgag gaacggttgg gacgttgagg tcaccgcagt gggtaaccag 600
ttcaacggag gttgcttgtt ggtggcgatg gtgccggagc tctgctccat caccaagaga 660
gagctgtacc aactcacact cttcccccat cagttcatca acccacggac gaacatgacg 720
gcgcacatca ccgtgcccta tctcggtgtc aacaggtacg accaatacaa ggtacacaaa 780
ccctggactc ttgtggtcat ggttgtggct cccctgacgg tcaacaacga gggcgccccg 840
caaatcaagg tatatgctaa catcgccccc accaacgtcc acgtcgcggg tgagctccct 900
tccaaagag 909
<210> 2
<211> 303
<212> PRT
<213> O型口蹄疫病毒ⅠVP0蛋白氨基酸序列
<400> 2
Gly Ala Gly Gln Ser Ser Pro Thr Thr Gly Ser Gln Asn Gln Ser Gly
1 5 10 15
Asn Thr Gly Ser Ile Ile Asn Asn Tyr Tyr Met Gln Gln Tyr Gln Asn
20 25 30
Ser Met Asp Thr Gln Leu Gly Asp Asn Ala Ile Ser Gly Gly Ser Asn
35 40 45
Glu Gly Ser Thr Asp Thr Thr Ser Thr His Thr Asn Asn Thr Gln Asn
50 55 60
Asn Asp Trp Phe Ser Lys Leu Ala Asn Thr Ala Phe Ser Gly Leu Phe
65 70 75 80
Gly Ala Leu Leu Ala Asp Lys Lys Thr Glu Glu Thr Thr Leu Leu Glu
85 90 95
Asp Arg Ile Leu Thr Thr Arg Asn Gly His Thr Thr Ser Thr Thr Gln
100 105 110
Ser Ser Val Gly Val Thr Tyr Gly Tyr Ala Thr Ala Glu Asp Phe Val
115 120 125
Ser Gly Pro Asn Thr Ser Gly Leu Glu Thr Arg Val Val Gln Ala Glu
130 135 140
Arg Phe Phe Lys Thr His Leu Phe Asp Trp Gly Thr Asn Asp Ser Phe
145 150 155 160
Gly Arg Cys His Leu Leu Glu Leu Pro Thr Asp His Lys Gly Val Tyr
165 170 175
Gly Ser Leu Thr Asp Ser Tyr Ala Tyr Met Arg Asn Gly Trp Asp Val
180 185 190
Glu Val Thr Ala Val Gly Asn Gln Phe Asn Gly Gly Cys Leu Leu Val
195 200 205
Ala Met Val Pro Glu Leu Cys Ser Ile Thr Lys Arg Glu Leu Tyr Gln
210 215 220
Leu Thr Leu Phe Pro His Gln Phe Ile Asn Pro Arg Thr Asn Met Thr
225 230 235 240
Ala His Ile Thr Val Pro Tyr Leu Gly Val Asn Arg Tyr Asp Gln Tyr
245 250 255
Lys Val His Lys Pro Trp Thr Leu Val Val Met Val Val Ala Pro Leu
260 265 270
Thr Val Asn Asn Glu Gly Ala Pro Gln Ile Lys Val Tyr Ala Asn Ile
275 280 285
Ala Pro Thr Asn Val His Val Ala Gly Glu Leu Pro Ser Lys Glu
290 295 300
<210> 3
<211> 660
<212> DNA
<213> O型口蹄疫病毒ⅠVP3蛋白核苷酸序列
<400> 3
gggatcttcc ctgtggcatg cagcgacggt tacggcggtt tggtgaccac ggacccgaag 60
acggcagacc ccgtctacgg gaaagtgttc aacccacccc gcaacctgct gcccgggcgg 120
ttcacaaatc tccttgatgt tgctgaggcg tgtcccacat tcctgcattt cgacggtgac 180
gttccctacg tggtcacgaa gacggattca gacagggtgt tggcccagtt cgacttgtcc 240
cttgcagcaa aacacatgtc gaacaccttt ctcgcgggtc ttgcccagta ctacgcgcag 300
tacagtggca ccattaactt gcacttcatg ttcacgggac ctaccgacgc aaaggcgcgc 360
tacatggttg cttacgcccc tcctggcatg gaaccaccta aaacgcctga ggcggctgca 420
cactgcatcc acgctgagtg ggacactggg ctgaactcga aattcacgtt ttcgatccca 480
tacctttcgg cggcagacta cgcgtacacc gcgtccgacg tcgccgagac gacaaacgtg 540
cagggatggg tctgcctatt ccagataacg cacgggaagg ccgacggcga tgccctggtc 600
gtactggcca gtgccggcaa ggactttgat ttacgcctgc cggttgacgc ccgaacccag 660
<210> 4
<211> 220
<212> PRT
<213> O型口蹄疫病毒ⅠVP3蛋白氨基酸序列
<400> 4
Gly Ile Phe Pro Val Ala Cys Ser Asp Gly Tyr Gly Gly Leu Val Thr
1 5 10 15
Thr Asp Pro Lys Thr Ala Asp Pro Val Tyr Gly Lys Val Phe Asn Pro
20 25 30
Pro Arg Asn Leu Leu Pro Gly Arg Phe Thr Asn Leu Leu Asp Val Ala
35 40 45
Glu Ala Cys Pro Thr Phe Leu His Phe Asp Gly Asp Val Pro Tyr Val
50 55 60
Val Thr Lys Thr Asp Ser Asp Arg Val Leu Ala Gln Phe Asp Leu Ser
65 70 75 80
Leu Ala Ala Lys His Met Ser Asn Thr Phe Leu Ala Gly Leu Ala Gln
85 90 95
Tyr Tyr Ala Gln Tyr Ser Gly Thr Ile Asn Leu His Phe Met Phe Thr
100 105 110
Gly Pro Thr Asp Ala Lys Ala Arg Tyr Met Val Ala Tyr Ala Pro Pro
115 120 125
Gly Met Glu Pro Pro Lys Thr Pro Glu Ala Ala Ala His Cys Ile His
130 135 140
Ala Glu Trp Asp Thr Gly Leu Asn Ser Lys Phe Thr Phe Ser Ile Pro
145 150 155 160
Tyr Leu Ser Ala Ala Asp Tyr Ala Tyr Thr Ala Ser Asp Val Ala Glu
165 170 175
Thr Thr Asn Val Gln Gly Trp Val Cys Leu Phe Gln Ile Thr His Gly
180 185 190
Lys Ala Asp Gly Asp Ala Leu Val Val Leu Ala Ser Ala Gly Lys Asp
195 200 205
Phe Asp Leu Arg Leu Pro Val Asp Ala Arg Thr Gln
210 215 220
<210> 5
<211> 639
<212> DNA
<213> O型口蹄疫病毒ⅠVP1蛋白核苷酸序列
<400> 5
accacctctg cgggtgagtc tgcggacccc gtgaccacta ccgttgagaa ctacggtggt 60
gagacacaag ttcagaggcg ccaacacacg gacgtcgcgt tcatactgga caggttcgtg 120
aaagtcaaac cacaggaaca ggttaacgtg ttggatctga tgcagatccc tgcccacacc 180
ttggtagggg cactcctgcg gacggccacc tactacttct ctgacctaga gctggctgtc 240
aagcatgagg gcgatctcac ttgggttccg aacggtgccc ccgagacagc gctggacaac 300
accaccaacc caacagccta ccacaaggaa ccgctcacac ggctggcgct accttatacg 360
gctccacacc gtgtcttagc taccgtctac aacgggagca gcaagtacgg tgatgccagc 420
actaacaacg tgagaggcga ccttcaagtg ttggttaaga aggcagaaag agctctgcct 480
acctccttca actatggtgc catcaaggca gcccgcgtga ctgaactact ctacagaatg 540
aaaagagctg agacgtactg tcccaggccc cttcttgcca tccaaccgag tactgccaga 600
cgcaagcaga agattgtggc acccgcaaaa cagcttctg 639
<210> 6
<211> 213
<212> PRT
<213> O型口蹄疫病毒ⅠVP1蛋白氨基酸序列
<400> 6
Thr Thr Ser Ala Gly Glu Ser Ala Asp Pro Val Thr Thr Thr Val Glu
1 5 10 15
Asn Tyr Gly Gly Glu Thr Gln Val Gln Arg Arg Gln His Thr Asp Val
20 25 30
Ala Phe Ile Leu Asp Arg Phe Val Lys Val Lys Pro Gln Glu Gln Val
35 40 45
Asn Val Leu Asp Leu Met Gln Ile Pro Ala His Thr Leu Val Gly Ala
50 55 60
Leu Leu Arg Thr Ala Thr Tyr Tyr Phe Ser Asp Leu Glu Leu Ala Val
65 70 75 80
Lys His Glu Gly Asp Leu Thr Trp Val Pro Asn Gly Ala Pro Glu Thr
85 90 95
Ala Leu Asp Asn Thr Thr Asn Pro Thr Ala Tyr His Lys Glu Pro Leu
100 105 110
Thr Arg Leu Ala Leu Pro Tyr Thr Ala Pro His Arg Val Leu Ala Thr
115 120 125
Val Tyr Asn Gly Ser Ser Lys Tyr Gly Asp Ala Ser Thr Asn Asn Val
130 135 140
Arg Gly Asp Leu Gln Val Leu Val Lys Lys Ala Glu Arg Ala Leu Pro
145 150 155 160
Thr Ser Phe Asn Tyr Gly Ala Ile Lys Ala Ala Arg Val Thr Glu Leu
165 170 175
Leu Tyr Arg Met Lys Arg Ala Glu Thr Tyr Cys Pro Arg Pro Leu Leu
180 185 190
Ala Ile Gln Pro Ser Thr Ala Arg Arg Lys Gln Lys Ile Val Ala Pro
195 200 205
Ala Lys Gln Leu Leu
210
<210> 7
<211> 909
<212> DNA
<213> O型口蹄疫病毒Ⅱ VP0蛋白核苷酸序列
<400> 7
ggagccggac aatccagtcc ggctactggg tcacagaacc aatcaggcaa caccgggagt 60
atcatcaaca attactacat gcagcagtac cagaactcca tggacaccca acttggtgac 120
aatgctatca gcggaggctc caacgaggga tccacagaca caacctccac ccacacaacc 180
aacactcaga acaatgactg gttttcaaag ttggccagct ctgccttcag cggtcttttc 240
ggcgccctcc tcgccgataa gaaaaccgag gagaccactc ttctcgagga ccgcatcctc 300
accacccgaa acggacacac cacctcgaca acccagtcga gtgttggcat aacgcacggg 360
tacgcaacag ctgaggattt tgtgaacggg ccaaacacct ctggtcttga gaccagagtt 420
gtccaggcgg aacggttctt taaaacccac ctgttcgact gggtcaccag tgatccgttc 480
ggacggtgct acttgttgga gctcccgact gaccacaaag gtgtctacgg cagcctgacc 540
gactcatacg cctacatgag aaacggttgg gatgttgagg tcaccgctgt ggggaatcag 600
ttcaacggag gctgcctact ggtggccatg gtgcctgaac tttgttccat cgagcggaga 660
gagctgttcc agcttacgct cttcccccac cagttcatca acccccggac gaacatgaca 720
gcccacatca aggtgccctt tgttggcgtc aaccgttacg atcagtacaa ggtacacaag 780
ccgtggaccc ttgtggttat ggtcgtagcc ccactgactg tcaacaccga aggcgctccg 840
cagatcaagg tgtatgccaa catcgcaccc accaacgtgc acgtcgcggg tgagttccct 900
tccaaagag 909
<210> 8
<211> 303
<212> PRT
<213> O型口蹄疫病毒Ⅱ VP0蛋白氨基酸序列
<400> 8
Gly Ala Gly Gln Ser Ser Pro Ala Thr Gly Ser Gln Asn Gln Ser Gly
1 5 10 15
Asn Thr Gly Ser Ile Ile Asn Asn Tyr Tyr Met Gln Gln Tyr Gln Asn
20 25 30
Ser Met Asp Thr Gln Leu Gly Asp Asn Ala Ile Ser Gly Gly Ser Asn
35 40 45
Glu Gly Ser Thr Asp Thr Thr Ser Thr His Thr Thr Asn Thr Gln Asn
50 55 60
Asn Asp Trp Phe Ser Lys Leu Ala Ser Ser Ala Phe Ser Gly Leu Phe
65 70 75 80
Gly Ala Leu Leu Ala Asp Lys Lys Thr Glu Glu Thr Thr Leu Leu Glu
85 90 95
Asp Arg Ile Leu Thr Thr Arg Asn Gly His Thr Thr Ser Thr Thr Gln
100 105 110
Ser Ser Val Gly Ile Thr His Gly Tyr Ala Thr Ala Glu Asp Phe Val
115 120 125
Asn Gly Pro Asn Thr Ser Gly Leu Glu Thr Arg Val Val Gln Ala Glu
130 135 140
Arg Phe Phe Lys Thr His Leu Phe Asp Trp Val Thr Ser Asp Pro Phe
145 150 155 160
Gly Arg Cys Tyr Leu Leu Glu Leu Pro Thr Asp His Lys Gly Val Tyr
165 170 175
Gly Ser Leu Thr Asp Ser Tyr Ala Tyr Met Arg Asn Gly Trp Asp Val
180 185 190
Glu Val Thr Ala Val Gly Asn Gln Phe Asn Gly Gly Cys Leu Leu Val
195 200 205
Ala Met Val Pro Glu Leu Cys Ser Ile Glu Arg Arg Glu Leu Phe Gln
210 215 220
Leu Thr Leu Phe Pro His Gln Phe Ile Asn Pro Arg Thr Asn Met Thr
225 230 235 240
Ala His Ile Lys Val Pro Phe Val Gly Val Asn Arg Tyr Asp Gln Tyr
245 250 255
Lys Val His Lys Pro Trp Thr Leu Val Val Met Val Val Ala Pro Leu
260 265 270
Thr Val Asn Thr Glu Gly Ala Pro Gln Ile Lys Val Tyr Ala Asn Ile
275 280 285
Ala Pro Thr Asn Val His Val Ala Gly Glu Phe Pro Ser Lys Glu
290 295 300
<210> 9
<211> 660
<212> DNA
<213> O型口蹄疫病毒Ⅱ VP3蛋白核苷酸序列
<400> 9
gggattttcc ctgtggcctg tagcgacggt tatggcggct tggtgacaac tgacccaaag 60
acggctgacc ccgtttacgg caaagtgttc aacccccccc gcaacatgtt gccggggcgg 120
ttcaccaacc tcctggacgt ggctgaggct tgccccacgt ttctgcactt cgatggtgac 180
gtaccgtatg tgaccactaa gacggattcg gacagggtgc tcgcacaatt tgacttgtct 240
ttggcagcaa aacacatgtc aaacaccttc cttgcaggtc ttgcccagta ctacacgcag 300
tacagcggca ccgtcaacct gcacttcatg ttcacaggtc ccactgacgc gaaagcgcgt 360
tacatgattg cgtatgcccc tccgggcatg gagccgccca aaacacctga ggctgctgct 420
cactgcattc acgcagagtg ggacacgggt ctgaactcaa agtttacctt ttccatcccc 480
tacctctcgg cggctgatta cgcgtacacc gcgtctgacg ctgctgagac cacaaatgtt 540
cagggatggg tctgcttatt tcaaataaca cacgggaaag ctgagggtga cgctcttgtc 600
gtgctggcca gtgctggcaa agactttgag ctgcgcctgc ctgtggacgc tcggcaacag 660
<210> 10
<211> 220
<212> PRT
<213> O型口蹄疫病毒Ⅱ VP3蛋白氨基酸序列
<400> 10
Gly Ile Phe Pro Val Ala Cys Ser Asp Gly Tyr Gly Gly Leu Val Thr
1 5 10 15
Thr Asp Pro Lys Thr Ala Asp Pro Val Tyr Gly Lys Val Phe Asn Pro
20 25 30
Pro Arg Asn Met Leu Pro Gly Arg Phe Thr Asn Leu Leu Asp Val Ala
35 40 45
Glu Ala Cys Pro Thr Phe Leu His Phe Asp Gly Asp Val Pro Tyr Val
50 55 60
Thr Thr Lys Thr Asp Ser Asp Arg Val Leu Ala Gln Phe Asp Leu Ser
65 70 75 80
Leu Ala Ala Lys His Met Ser Asn Thr Phe Leu Ala Gly Leu Ala Gln
85 90 95
Tyr Tyr Thr Gln Tyr Ser Gly Thr Val Asn Leu His Phe Met Phe Thr
100 105 110
Gly Pro Thr Asp Ala Lys Ala Arg Tyr Met Ile Ala Tyr Ala Pro Pro
115 120 125
Gly Met Glu Pro Pro Lys Thr Pro Glu Ala Ala Ala His Cys Ile His
130 135 140
Ala Glu Trp Asp Thr Gly Leu Asn Ser Lys Phe Thr Phe Ser Ile Pro
145 150 155 160
Tyr Leu Ser Ala Ala Asp Tyr Ala Tyr Thr Ala Ser Asp Ala Ala Glu
165 170 175
Thr Thr Asn Val Gln Gly Trp Val Cys Leu Phe Gln Ile Thr His Gly
180 185 190
Lys Ala Glu Gly Asp Ala Leu Val Val Leu Ala Ser Ala Gly Lys Asp
195 200 205
Phe Glu Leu Arg Leu Pro Val Asp Ala Arg Gln Gln
210 215 220
<210> 11
<211> 639
<212> DNA
<213> O型口蹄疫病毒Ⅱ VP1蛋白核苷酸序列
<400> 11
accacttcga cgggcgagtc ggctgacccc gtgactgcca ccgttgagaa ttacggtggc 60
gagacacagg tccagaggcg ccaccacaca gacgtctcat tcatattgga cagatttgtg 120
aaagtcacac caaaagactc aataaatgta ttggacctga tgcagacccc ctcccacacc 180
ctagtagggg cgctcctccg cactgccact tactatttcg ctgatctaga ggtggcagtg 240
aaacacgagg gggaccttac ctgggtgcca aatggagcac ctgaagcagc cttggacaac 300
accaccaacc caacggcgta ccataaggcg ccgcttactc ggcttgcatt gccctacacg 360
gcaccacacc gtgttttggc caccgtttac aacgggaact gcaaatacgc cgggggctca 420
ctgcccaacg tgagaggcga tctccaagtg ctggctcaga aggcagcgag gccgctgcct 480
acttctttca actacggtgc catcaaagcc actcgggtga cagaactgct gtaccgcatg 540
aagagggccg agacgtactg tcctcggccc ctcttggctg ttcacccgag tgcggccaga 600
cacaaacaga aaatagtggc gcctgtaaag cagtccttg 639
<210> 12
<211> 213
<212> PRT
<213> O型口蹄疫病毒Ⅱ VP1蛋白氨基酸序列
<400> 12
Thr Thr Ser Thr Gly Glu Ser Ala Asp Pro Val Thr Ala Thr Val Glu
1 5 10 15
Asn Tyr Gly Gly Glu Thr Gln Val Gln Arg Arg His His Thr Asp Val
20 25 30
Ser Phe Ile Leu Asp Arg Phe Val Lys Val Thr Pro Lys Asp Ser Ile
35 40 45
Asn Val Leu Asp Leu Met Gln Thr Pro Ser His Thr Leu Val Gly Ala
50 55 60
Leu Leu Arg Thr Ala Thr Tyr Tyr Phe Ala Asp Leu Glu Val Ala Val
65 70 75 80
Lys His Glu Gly Asp Leu Thr Trp Val Pro Asn Gly Ala Pro Glu Ala
85 90 95
Ala Leu Asp Asn Thr Thr Asn Pro Thr Ala Tyr His Lys Ala Pro Leu
100 105 110
Thr Arg Leu Ala Leu Pro Tyr Thr Ala Pro His Arg Val Leu Ala Thr
115 120 125
Val Tyr Asn Gly Asn Cys Lys Tyr Ala Gly Gly Ser Leu Pro Asn Val
130 135 140
Arg Gly Asp Leu Gln Val Leu Ala Gln Lys Ala Ala Arg Pro Leu Pro
145 150 155 160
Thr Ser Phe Asn Tyr Gly Ala Ile Lys Ala Thr Arg Val Thr Glu Leu
165 170 175
Leu Tyr Arg Met Lys Arg Ala Glu Thr Tyr Cys Pro Arg Pro Leu Leu
180 185 190
Ala Val His Pro Ser Ala Ala Arg His Lys Gln Lys Ile Val Ala Pro
195 200 205
Val Lys Gln Ser Leu
210
<210> 13
<211> 909
<212> DNA
<213> O型口蹄疫病毒ⅢVP0蛋白核苷酸序列
<400> 13
ggcgccgggc aatccagccc gacgaccggg tcacagaacc aatcaggcaa cactggaagc 60
atcattaaca actactacat gcagcaatac cagaactcca tggacacaca gcttggtgac 120
aacgccatta gcggaggctc caacgagggt tctacggata ccacctccac ccacacgaac 180
aacacccaga acaacgactg gttttcaaaa ctggccaact ccgctctcag cggtctcttc 240
ggtgctcttc tcgccgacaa aaagacagag gaaactaccc tcctcgagga ccgcattctc 300
accacccgca acggacacac gacctcgaca acccagtcga gcgtcggggt gacgtacggg 360
tatgcaacag ctgaggactt cgtgagcggg cccaacacct ctggtcttga gaccagggtt 420
gtccaggccg aacggttctt caaaacccac ttgttcgact gggtcaccag tgacccgttt 480
ggacggtgcc acatgttgga gctcccgact gaccacaaag gcgtctacgg cagcctaacc 540
gactcgtacg cgtatatgag gaacggttgg gacgttgaag tcaccgcggt gggaaaccag 600
ttcaacggag gctgcttgtt ggtggcaatg gtaccagagc tttgttccat caacaagaga 660
gagctgtacc agctcacact tttcccccac cagttcatta acccacggac gaacatgacg 720
gcacacatca ctgtgcccta cgttggcgtc aacaggtacg accaatacaa ggtgcataaa 780
ccctggaccc ttgttgtcat ggtcgtggcc cccttgacgg tcaacaatga gggtgctccg 840
caaatcaagg tgtatgccaa catcgccccc accaacgttt acgttgcggg tgaattccct 900
tccaaggag 909
<210> 14
<211> 303
<212> PRT
<213> O型口蹄疫病毒ⅢVP0蛋白氨基酸序列
<400> 14
Gly Ala Gly Gln Ser Ser Pro Thr Thr Gly Ser Gln Asn Gln Ser Gly
1 5 10 15
Asn Thr Gly Ser Ile Ile Asn Asn Tyr Tyr Met Gln Gln Tyr Gln Asn
20 25 30
Ser Met Asp Thr Gln Leu Gly Asp Asn Ala Ile Ser Gly Gly Ser Asn
35 40 45
Glu Gly Ser Thr Asp Thr Thr Ser Thr His Thr Asn Asn Thr Gln Asn
50 55 60
Asn Asp Trp Phe Ser Lys Leu Ala Asn Ser Ala Leu Ser Gly Leu Phe
65 70 75 80
Gly Ala Leu Leu Ala Asp Lys Lys Thr Glu Glu Thr Thr Leu Leu Glu
85 90 95
Asp Arg Ile Leu Thr Thr Arg Asn Gly His Thr Thr Ser Thr Thr Gln
100 105 110
Ser Ser Val Gly Val Thr Tyr Gly Tyr Ala Thr Ala Glu Asp Phe Val
115 120 125
Ser Gly Pro Asn Thr Ser Gly Leu Glu Thr Arg Val Val Gln Ala Glu
130 135 140
Arg Phe Phe Lys Thr His Leu Phe Asp Trp Val Thr Ser Asp Pro Phe
145 150 155 160
Gly Arg Cys His Met Leu Glu Leu Pro Thr Asp His Lys Gly Val Tyr
165 170 175
Gly Ser Leu Thr Asp Ser Tyr Ala Tyr Met Arg Asn Gly Trp Asp Val
180 185 190
Glu Val Thr Ala Val Gly Asn Gln Phe Asn Gly Gly Cys Leu Leu Val
195 200 205
Ala Met Val Pro Glu Leu Cys Ser Ile Asn Lys Arg Glu Leu Tyr Gln
210 215 220
Leu Thr Leu Phe Pro His Gln Phe Ile Asn Pro Arg Thr Asn Met Thr
225 230 235 240
Ala His Ile Thr Val Pro Tyr Val Gly Val Asn Arg Tyr Asp Gln Tyr
245 250 255
Lys Val His Lys Pro Trp Thr Leu Val Val Met Val Val Ala Pro Leu
260 265 270
Thr Val Asn Asn Glu Gly Ala Pro Gln Ile Lys Val Tyr Ala Asn Ile
275 280 285
Ala Pro Thr Asn Val Tyr Val Ala Gly Glu Phe Pro Ser Lys Glu
290 295 300
<210> 15
<211> 660
<212> DNA
<213> O型口蹄疫病毒ⅢVP3蛋白核苷酸序列
<400> 15
gggatcttcc ccgtggcatg cagcgacggt tacggcggtt tggtgaccac ggacccaaag 60
acggcggacc ccgtgtacgg gaaagtgttc aacccccccc gtaacttgtt gccagggcgg 120
tttacaaacc tccttgatgt ggccgaggcg tgtcccacgt tcctacactt cgaaggtgac 180
gtaccgtacg tgaccacgaa gacggactca gacagggtgt tggcccaatt cgacctgtct 240
ctggcagcaa agcacatgtc gaacactttc ctcgcgggtc ttgcccagta ttacacacag 300
tacagcggca ccatcaacct acacttcatg ttcacagggc ccaccgatgc gaaggcgcgc 360
tacatgattg cgtatgcccc tcctggcatg gaaccgccga aaacgcctga ggccgccgca 420
cactgcattc acgctgagtg ggacacaggg ctgaattcaa agttcacatt ttcaattccc 480
tacctttcgg ccgctgacta cgcgtacacc gcgtccgacg tcgccgaaac cacaaacgtg 540
cagggatggg tctgcttgtt ccagataaca cacgggaaag ccgacggcga tgctctgatt 600
gttctagcta gtgctggcaa agactttgac ctacgcctac cggttgacgc ccgcacgcag 660
<210> 16
<211> 220
<212> PRT
<213> O型口蹄疫病毒ⅢVP3蛋白氨基酸序列
<400> 16
Gly Ile Phe Pro Val Ala Cys Ser Asp Gly Tyr Gly Gly Leu Val Thr
1 5 10 15
Thr Asp Pro Lys Thr Ala Asp Pro Val Tyr Gly Lys Val Phe Asn Pro
20 25 30
Pro Arg Asn Leu Leu Pro Gly Arg Phe Thr Asn Leu Leu Asp Val Ala
35 40 45
Glu Ala Cys Pro Thr Phe Leu His Phe Glu Gly Asp Val Pro Tyr Val
50 55 60
Thr Thr Lys Thr Asp Ser Asp Arg Val Leu Ala Gln Phe Asp Leu Ser
65 70 75 80
Leu Ala Ala Lys His Met Ser Asn Thr Phe Leu Ala Gly Leu Ala Gln
85 90 95
Tyr Tyr Thr Gln Tyr Ser Gly Thr Ile Asn Leu His Phe Met Phe Thr
100 105 110
Gly Pro Thr Asp Ala Lys Ala Arg Tyr Met Ile Ala Tyr Ala Pro Pro
115 120 125
Gly Met Glu Pro Pro Lys Thr Pro Glu Ala Ala Ala His Cys Ile His
130 135 140
Ala Glu Trp Asp Thr Gly Leu Asn Ser Lys Phe Thr Phe Ser Ile Pro
145 150 155 160
Tyr Leu Ser Ala Ala Asp Tyr Ala Tyr Thr Ala Ser Asp Val Ala Glu
165 170 175
Thr Thr Asn Val Gln Gly Trp Val Cys Leu Phe Gln Ile Thr His Gly
180 185 190
Lys Ala Asp Gly Asp Ala Leu Ile Val Leu Ala Ser Ala Gly Lys Asp
195 200 205
Phe Asp Leu Arg Leu Pro Val Asp Ala Arg Thr Gln
210 215 220
<210> 17
<211> 639
<212> DNA
<213> O型口蹄疫病毒ⅢVP1蛋白核苷酸序列
<400> 17
accacctctg cgggcgagtc cgcggacccc gttaccgcca ccgttgagaa ttacggtggt 60
gagacacagg tccagagacg ccagcacacg gatatctcgt ttatactaga cagatttgtg 120
aaagtcacac caaaagacca aatcaatgtg ctggacctga tgcagatccc tgcccacact 180
ttagtagggg ccctcctgcg gacggccacc tactacttct ccgacttgga gttggctgtc 240
aaacacaagg gtgatctcac ctgggttccg aacggggccc ctgagacagc tttggacaac 300
accaccaacc caacagctta ccacaaagca ccactcacgc gactggcctt gccttacacg 360
gccccacacc gcgtcttagc gaccgtctac aacggaagtt gtaagtacag tgacgcccgc 420
gtgagcaacg tgaggggtga ccttcaagtg ttggctcaga aggcagaaag agctctgccc 480
acctccttta actatggtgc cattaaggca acccgggtga ctgagttact ctaccgaatg 540
aagagagccg agacatactg ccccaggccc cttcttgcca ttcaaccgag tgacgctaga 600
cacaagcaga agatcgtggc acccgcaaaa cagcttctg 639
<210> 18
<211> 213
<212> PRT
<213> O型口蹄疫病毒ⅢVP1蛋白氨基酸序列
<400> 18
Thr Thr Ser Ala Gly Glu Ser Ala Asp Pro Val Thr Ala Thr Val Glu
1 5 10 15
Asn Tyr Gly Gly Glu Thr Gln Val Gln Arg Arg Gln His Thr Asp Ile
20 25 30
Ser Phe Ile Leu Asp Arg Phe Val Lys Val Thr Pro Lys Asp Gln Ile
35 40 45
Asn Val Leu Asp Leu Met Gln Ile Pro Ala His Thr Leu Val Gly Ala
50 55 60
Leu Leu Arg Thr Ala Thr Tyr Tyr Phe Ser Asp Leu Glu Leu Ala Val
65 70 75 80
Lys His Lys Gly Asp Leu Thr Trp Val Pro Asn Gly Ala Pro Glu Thr
85 90 95
Ala Leu Asp Asn Thr Thr Asn Pro Thr Ala Tyr His Lys Ala Pro Leu
100 105 110
Thr Arg Leu Ala Leu Pro Tyr Thr Ala Pro His Arg Val Leu Ala Thr
115 120 125
Val Tyr Asn Gly Ser Cys Lys Tyr Ser Asp Ala Arg Val Ser Asn Val
130 135 140
Arg Gly Asp Leu Gln Val Leu Ala Gln Lys Ala Glu Arg Ala Leu Pro
145 150 155 160
Thr Ser Phe Asn Tyr Gly Ala Ile Lys Ala Thr Arg Val Thr Glu Leu
165 170 175
Leu Tyr Arg Met Lys Arg Ala Glu Thr Tyr Cys Pro Arg Pro Leu Leu
180 185 190
Ala Ile Gln Pro Ser Asp Ala Arg His Lys Gln Lys Ile Val Ala Pro
195 200 205
Ala Lys Gln Leu Leu
210
Claims (10)
1.一种O型口蹄疫病毒样颗粒，其特征在于，所述病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中，所述的结构蛋白VP0氨基酸序列为SEQ ID NO.8，VP3氨基酸序列为SEQ ID NO.10，VP1氨基酸序列为SEQ ID NO.12。
2.一种抗O型口蹄疫的疫苗组合物，其特征在于，所述组合物包含权利要求权利要求1所述的O型口蹄疫病毒样颗粒及佐剂。
3.根据权利要求2所述的疫苗组合物，其特征在于，所述组合物还包含一种由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成的O型口蹄疫病毒样颗粒，其中，所述结构蛋白VP0氨基酸序列为SEQ ID NO.2，VP3氨基酸序列为SEQ ID NO.4，VP1氨基酸序列为SEQ ID NO.6。
4.根据权利要求3所述的疫苗组合物，其特征在于，所述组合物进一步包含一种由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成的O型口蹄疫病毒样颗粒，其中，所述的结构蛋白VP0氨基酸序列为SEQ ID NO.14，VP3氨基酸序列为SEQ ID NO.16，VP1氨基酸序列为SEQ IDNO.18。
5.根据权利要求2-4中任一项所述的疫苗组合物，其特征在于，所述组合物中每种病毒样颗粒含量为50-150μg/ml。
6.根据权利要求5所述的疫苗组合物，其特征在于，所述组合物中每种病毒样颗粒含量为100μg/ml。
7.根据权利要求2所述的疫苗组合物，其特征在于，所述组合物进一步包含亚洲1型口蹄疫病毒样颗粒和/或A型口蹄疫病毒样颗粒。
8.一种抗O型口蹄疫的疫苗组合物，其特征在于，
所述疫苗组合物由三种O型口蹄疫病毒样颗粒及佐剂组成；
所述第一种病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中VP0的氨基酸序列为SEQ ID NO.2，VP3氨基酸序列为SEQ ID NO.4，VP1氨基酸序列为SEQ ID NO.6，但SEQ ID NO.2第178位氨基酸突变为半胱氨酸，SEQ ID NO.6第17位氨基酸突变为天冬氨酸；
所述第二种病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中VP0的氨基酸序列为SEQ ID NO.8，VP3氨基酸序列为SEQ ID NO.10，VP1氨基酸序列为SEQ IDNO.12，但SEQ ID NO.8第178位氨基酸突变为半胱氨酸，SEQ ID NO.12第17位氨基酸突变为天冬氨酸；
所述第三种病毒样颗粒由O型口蹄疫病毒的结构蛋白VP0、VP3和VP1构成，其中VP0的氨基酸序列为SEQ ID NO.14，VP3氨基酸序列为SEQ ID NO.16，VP1氨基酸序列为SEQ IDNO.18，但SEQ ID NO.14第178位氨基酸突变为半胱氨酸，SEQ ID NO.18第17位氨基酸突变为天冬氨酸。
9.一种制备权利要求2-8任一项所述疫苗组合物的方法，其中，所述的制备方法包括：
1)制备口蹄疫病毒样颗粒的步骤；
2)加入佐剂，乳化的步骤。
10.权利要求1所述的病毒样颗粒以及权利要求2-8任一项所述的疫苗组合物在制备抗O型口蹄疫相关的药物中的应用。
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