CN113908266B - 一种串联表达的口蹄疫病毒vlp亚单位疫苗 - Google Patents
一种串联表达的口蹄疫病毒vlp亚单位疫苗 Download PDFInfo
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Abstract
本发明提供一种串联表达的口蹄疫病毒VLP亚单位疫苗,所述疫苗含有通过SF9真核表达系统表达的串联的口蹄疫病毒A型和O型病毒样颗粒(VLP)。所述方案能表达A‑O‑VLP‑3Cmutant,由于其串联表达的特性,一次可以同时生产两价疫苗,并且两种抗原表达量保持一致;相对于表达口蹄疫病毒单一血清型VLP,串联表达基于使用2A蛋白酶切位点链接并且共用一个3C蛋白酶的特性,减少了3C蛋白酶表达,这使串联表达的总产量更高,大约提升30%左右;安全性高,有效避免了病毒泄漏或灭活不彻底等风险;应用范围较广,只要得到结构蛋白基因序列,就可以开发相应的VLP疫苗以及串联表达多种血清型或流行株的疫苗;成本低,一次生产即可获得双价疫苗,同时本发明不需要高等级的生产设施,采用的SF9昆虫细胞生产成本也远低于哺乳动物细胞。
Description
本申请主张中国在先申请,申请号:202010665408.6,申请日2020年7月11日的优先权;其所有的内容作为本发明的一部分。
技术领域
本发明涉及基因工程技术领域和免疫学领域,具体而言,涉及一种串联表达的口蹄疫病毒VLP亚单位疫苗及其构建方法。
背景技术
口蹄疫(Foot-and-mouth disease,FMD)是由口蹄疫病毒(Foot-and-mouthdisease virus,FMDV)引起的动物急性、烈性传染病,主要危害猪、牛、羊等偶蹄动物,发病率极高,能造成巨大的经济损失。
口蹄疫病毒有O、A、C、SAT1、SAT2、SAT3(即南非1、2、3型)和Asia1(亚洲 1型)7个血清型。各型之间几乎没有免疫保护力,感染了一型口蹄疫的动物仍可感染另一型口蹄疫病毒而发病。
口蹄疫病毒颗粒呈圆形,表面光滑,直径约27~30nm。病毒粒子无囊膜,呈二十面体对称,FMDV的ORF编码一个大的聚合蛋白,在病毒翻译的同时,也伴随着聚合蛋白的剪切、折叠等翻译后的加工。
口蹄疫病毒包括结构蛋白基因P1和非结构蛋白基因P2、P3,其中P1基因编码口蹄疫病毒的抗原结构,是研究口蹄疫免疫机制和新型疫苗的基础,长约2200nt,能在2A和3C蛋白酶的作用下裂解产生4种基因,1A、1B、1C、1D,分别编码VP4、VP3、VP2、VP1四种结构蛋白,并组装成病毒的衣壳,由蛋白衣壳包裹基因组RNA组成核衣壳。
病毒样颗粒(VLP)具有与真实病毒粒子大小相似的结构,能引起免疫应答但不具有感染性,可模拟病毒真实空间结构,又不需要冒险培养真实病毒。VLP疫苗为利用微生物的表面结构成分(抗原)来制成不含核酸、能诱发机体产生抗体的疫苗,又称VLP亚单位疫苗。
口蹄疫病毒是无囊膜的RNA病毒,其结构蛋白可组装成VLP,且具有良好的免疫原性,可以用于生产疫苗,也可用于检测口蹄疫病毒中和抗体,因此制备口蹄疫病毒的VLP 亚单位疫苗具有很好的应用前景。
目前国内流行口蹄疫病毒血清型主要是A型和O型。因此进行口蹄疫防疫工作时,需要免疫两种血清型的疫苗。目前市面上口蹄疫病毒疫苗在A型和O型双价苗选择很有限,价格也较为昂贵,因为双价苗需要培养A型和O型两种病毒,如采用一条生产线存在交叉污染风险,必须采用两条高等级生物安全生产线分别进行生产口蹄疫病毒A型和O型灭活疫苗,生产成本较高。还有一种选择是分别免疫口蹄疫病毒A型和O型两种疫苗,购买两种疫苗成本也不低,而且免疫程序更复杂,不利于降低养殖成本。
基于灭活工艺生产的口蹄疫病毒疫苗,需要特定的高等级生产设施,生产成本高,并且可能存在泄漏或灭活不彻底的散毒风险。再者对于还没有规模培养工艺的口蹄疫病毒或者本地区未发现但已公布序列的毒株无法迅速开发对应的疫苗。因此口蹄疫病毒的VLP亚单位疫苗为目前制备口蹄疫病毒疫苗的最佳选择,能模拟口蹄疫病毒真实空间结构,又不需要冒险培养口蹄疫病毒。
因此急需一种直接通过一条生产链即可完成的,能够完整表达口蹄疫A型和O型两种独立抗原的、更安全的VLP疫苗。
发明内容
为解决上述问题,本发明提供一种串联表达的口蹄疫病毒VLP亚单位疫苗,运用两个 VLP串联共用一个3C蛋白酶,减少3C蛋白酶表达来提高VLP产量,同时运用口蹄疫病毒基因自带的2A来自酶切分离两个VLP和3C蛋白酶,通过SF9真核表达系统串联表达口蹄疫病毒A型和O型两种抗原的VLP,制得的VLP具有与真实病毒粒子大小相似的结构,模拟口蹄疫病毒真实空间结构,能引起免疫应答但不具有感染性,仅需一条生产链即可完成,串联表达的总产量更高,提升30%以上,成本更低,可以激发强大的体液免疫和细胞免疫,具有完整的病毒外壳结构,更多的抗原位点,可以更好地对抗病毒变异。
一方面,本发明提供了一种口蹄疫病毒VLP疫苗,所述疫苗由融合片段 A-O-VLP-3Cmutan在表达体系中表达形成,所述表达系统选自大肠杆菌、酵母、昆虫细胞、植物或者哺乳动物细胞中的任一种。
进一步地,所述融合片段A-O-VLP-3Cmutant具有如序列表中Seq ID NO.3所示的核苷酸序列;A-O-VLP-3Cmutant氨基酸序列推导得到的氨基酸序列如序列表Seq ID NO.7所示;所述表达体系为SF9真核表达系统。
再一方面,本发明提供了一种口蹄疫病毒VLP疫苗的制备方法,通过口蹄疫病毒A型的A-P12A基因和O型的O-P12A3C-mutant基因,制得融合片段A-O-VLP-3Cmutant,再经表达体系中表达形成。
口蹄疫病毒的结构蛋白基因P1基因是编码口蹄疫病毒的抗原结构,在2A和3C蛋白酶作用下可裂解产生VP4、VP3、VP2、VP1四种结构蛋白,并组装成病毒的衣壳,由蛋白衣壳包裹基因组RNA组成核衣壳。
本发明提供的串联表达A型和O型两种抗原的VLP,运用两个VLP串联共用一个3C蛋白酶,减少3C蛋白酶表达来提高VLP产量,同时巧妙地分别运用口蹄疫病毒A型和O型基因自带的2A来自酶切分离两个VLP和3C蛋白酶,是一种非常理想的串联方式,能大幅提升 VLP的产量。如果两个VLP直接简单串联,中间不增加2A,则两个VLP没法分离形成A型和O型两种VLP;而且如果不共用3C蛋白酶,因用于表达蛋白的核酸量较大,容易造成VLP 产量低。
在一些方式中,经串联融合后的融合片段,经表达体系中表达形成重组杆状病毒。
在一些方式中,重组杆状病毒再经扩增,分子筛过柱纯化,去除2A和3C蛋白酶,获得更纯的口蹄疫A型和O型病毒蛋白,可用于制备VLP疫苗。
一些方式中,口蹄疫A型和O型病毒蛋白中可添加佐剂,用于制备VLP疫苗。
由于口蹄疫病毒株的不断变异,还需要及时跟进研制出新变异病毒株的有效疫苗,针对目前流行的A型东南亚97(A/Sea-97)G2株和O型缅甸98(O/Mya-98)毒株 (O/MYA98/BY/2010株),发明人分别研制了针对A型东南亚97(A/Sea-97)G2株和O 型缅甸98(O/Mya-98)毒株(O/MYA98/BY/2010株)的VLP疫苗,同时还进一步研制了可以同时完整表达A型东南亚97(A/Sea-97)G2株和O型缅甸98(O/Mya-98)毒株 (O/MYA98/BY/2010株)的两个独立抗原的口蹄疫外壳蛋白(病毒样颗粒vlp)来提供有效保护。但这不表示本发明提供的制备串联表达的VLP疫苗仅适用于这两株流行株,针对任何流行株,只要得到其结构蛋白基因序列,就可以利用本发明提供的方法开发相应的 VLP疫苗以及串联表达多种血清型或流行株的疫苗。
进一步地,所述O-P12A3C-mutant基因是将O-P12A和O-3C-mutant进行融合PCR而获得,其中的O-P12A和O-3C-mutant分别具有如序列表中Seq ID NO.4、Seq ID NO.5所示的核苷酸序列。
进一步地,所述的O-3C-mutant是由3C基因的一个氨基酸密码子突变而获得,其中的 3C具有如序列表Seq ID NO.6所示的核苷酸序列。
进一步地,所述的O-3C-mutant是由O-3C的第127个氨基酸由L变为P。
进一步地,所述的O-P12A3C-mutant序列是将O-P12A和O-3C-mutant进行融合PCR而获得,其中的O-P12A和O-3C-mutant分别具有如序列表中Seq ID NO.4、Seq ID NO.5所示的核苷酸序列。
进一步地,所述的O-3C-mutant是由3C基因的一个氨基酸密码子突变而获得,其中的 3C具有如序列表6所示的核苷酸序列。
进一步地,所述的O-3C-mutant是由O-3C的第127个氨基酸由L变为P。
本发明中VLP表达所用的基因序列为口蹄疫病毒A型P12A基因序列和O型P12A3C基因序列,长度为5169bp,合1723个氨基酸残基。为了提高表达量,突变了O型VLP第4909-4911核苷酸由CTG变为CCT,对应的第1637个氨基酸残基也由L(亮氨酸)变为P(脯氨酸),该位置对应于O-3C的第127个氨基酸由L变为P。
进一步地,所述A-P12A、O-P12A3C-mutant、A-O-VLP-3Cmutant具有如序列表中SeqID NO.1、Seq ID NO.2、Seq ID NO.3所示的核苷酸序列。
进一步地,所述的A-O-VLP-3Cmutant经表达体系表达制备VLP,是通过 pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,进行重组、筛选、鉴定,得到Bacmid-A-O-VLP-3Cmutant质粒,再转入表达体系,所述表达系统选自大肠杆菌、酵母、昆虫细胞、植物或者哺乳动物细胞中的任一种。
进一步地,所述表达体系为SF9真核表达系统。
在一些方式中,所述的A-O-VLP-3Cmutant表达制备的VLP是通过 pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,进行重组,蓝白斑筛选,PCR鉴定,得到Bacmid-A-O-VLP-3Cmutant质粒。
在一些方式中,所述的pFast-A-O-VLP-3Cmutant的获得方法:先由pFast载体与A-P12A 酶切连接获得pFast-A-P12A,再由pFast-A-P12A与O-P12A3C-mutant序列酶切连接获得 pFast-A-O-VLP-3Cmutant。
进一步地,A-O-VLP-3Cmutant经SF9真核表达系统表达的氨基酸序列如序列表中Seq ID NO.7所示。
进一步地,所述制备方法主要包括以下步骤:
1)制备口蹄疫病毒A型的A-P12A基因和O型的O-P12A3C-mutant基因;
2)pFast载体与A-P12A酶切连接获得pFast-A-P12A;
3)pFast-A-P12A与O-P12A3C-mutant酶切连接获得pFast-A-O-VLP-3Cmutant;
4)pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,得到Bacmid-A-O-VLP-3Cmutant 质粒;
5)Bacmid-A-O-VLP-3Cmutant转入SF9真核表达系统,收获重组杆状病毒。
进一步地,收获的重组杆状病毒还需扩增,裂解,再经过分子筛过柱纯化。
进一步地,所述重组杆状病毒细胞蛋白纯化步骤如下:
1)SF9细胞1.5×106细胞密度(25ml体积),2ml P2代病毒感染,72h后收获。
2)细胞1000×g离心10min,留取细胞沉淀,-80℃冻存备用。
3)细胞加入5ml细胞裂解液(20mM Tris-HCl pH 8.0,1mM EDTA,1mMTCEP,1mMPMSF,1%Triton X-100)冰上30min,10000×g离心取上清用GE厂商的HiPrep 16/60Sephacryl S-500HR的预装柱进行分子筛过柱,用缓冲液PBS洗脱。
4)进行进样环进样,尽可能减小体积的稀释。
本发明提供的串联表达A型和O型口蹄疫病毒抗体的VLP疫苗,具有很多优点:
(1)产量高:串联表达过程中,两个VLP串联共用一个3C蛋白酶,相对于表达口蹄疫病毒单一血清型VLP,串联表达的总产量更高,大约提升30%左右;
(2)同时表达两种血清型抗原:通过串联表达,可以实现在同一反应器同一生产线同时表达两种口蹄疫病毒血清型的抗原VLP,并且由于其串联表达的特性,两种表达量保持一致;甚至可以通过在两个启动子各插入一组双抗原,来实现同时表达生产4个血清型 (流行株)抗原的目标;
(3)安全性高:本发明通过表达制备口蹄疫病毒A型和O型VLP代替口蹄疫病毒A 型或O型生产,有效避免了病毒泄漏或灭活不彻底等风险;
(4)适应性强:目前口蹄疫病毒有7个血清型及很多流行株,部分未传入我国或还没有规模培养工艺,无法开发常规灭活疫苗。但只要得到结构蛋白基因序列,就可以开发相应的VLP疫苗以及串联表达多种血清型或流行株的疫苗;
(5)成本低:相对于基于灭活病毒的疫苗,本发明不需要高等级的生物安全生产设施,采样的SF9昆虫细胞生产成本也远低于哺乳动物细胞。
附图说明
图1为实施例2的质粒Bacmid-A-VLP-3Cmutant转入DH10bac感受态细胞,进行Western Bolting检测,其中泳道1:口蹄疫病毒O型灭活病毒液,泳道2:O-VLP-3Cmutant,泳道3、 4为A-O-VLP-3Cmutant,M为MARKER。
图2为实施例3的串联表达的VLP经过分子筛过柱纯化结果图。
图3为实施例5的以A-O-VLP口蹄疫A型抗原浓度为纵坐标,OD450值为横坐标建立标准曲线。
图4为实施例5的以A-O-VLP口蹄疫O型抗原浓度为纵坐标,OD450值为横坐标建立标准曲线。
图5为实施例6的A-O VLP诱导的CD8+T细胞反应结果示意图。
图6为实施例6的A-O VLP诱导的CD4+T细胞反应结果示意图。
图7为实施例6的A-O VLP诱导的CD8+T细胞免疫反应代表图。
图8为实施例6的A-O VLP诱导的CD4+T细胞免疫反应代表图。
具体实施方式
下面结合附图对本发明的优选实施例作进一步详细描述,需要指出的是,以下所述实施例旨在便于对本发明的理解,而对其不起任何限定作用。
实施例1融合片段A-O-VLP-3Cmutant的构建
本实施例针对目前流行的A型东南亚97(A/Sea-97)G2株和O型缅甸98(O/Mya-98)毒株(O/MYA98/BY/2010株),构建融合片段A-O-VLP-3Cmutant。
本实施例中VLP表达所用的基因序列为口蹄疫病毒A型东南亚97(A/Sea-97)G2株的A 型P12A基因序列和O型缅甸98(O/Mya-98)毒株(O/MYA98/BY/2010株)的O型P12A3C 基因序列,长度为5169bp,合1723个氨基酸残基。为了提高表达量,突变了O型VLP第 4909-4911核苷酸由CTG变为CCT,对应的第1637个氨基酸残基也由L(亮氨酸)变为P(脯氨酸)。
根据文献(GenBank:JN998085.1),并进行序列优化,合成的含口蹄疫病毒O型cDNA的pMD18-FMDO-BY质粒作为O-P12A3C基因扩增模板,使用融合PCR的方法实现P12A基因和3C基因的融合,并实现3C基因一个氨基酸密码子的突变,位置是O-3C的第127个氨基酸由L变为P,以便更好的表达。
设计特异性引物O-P12A-EcoRI-F/O-P12A-R,O-3C-F/O-3C-Mu-R, O-3C-Mu-F/O-3C-HindIII-R。先用Q5 PCR MasterMix高保真酶(NEB)分别扩增O-3C mutant up和O-3Cmutant down序列,具体操作参照Q5 PCR MasterMix高保真酶(NEB)的使用说明书进行。
PCR反应条件如下(以下PCR反应条件除72℃延伸根据1min/2kb变化外其余不变):
将片段凝胶电泳胶回收后,使用Ultra-Sep Gel Extraction胶回收试剂盒(OMEGA)纯化,使用O-3C-F和O-3C-HindIII-R引物将两个片段作为模版进行融合PCR,得到O-3C-mutant。
扩增P12A序列:使用O-P12A-EcoRI-F/O-P12A-R引物扩增O-P12A序列。将O-P12A和O-3C-mutant片段凝胶电泳胶回收后,使用胶回收试剂盒纯化,使用O-P12A-EcoRI-F 和O-3C-HindIII-R引物将两个片段作为模版进行融合PCR,得到O-P12A3C-mutant。
根据文献《口蹄疫病毒A型AF_72株VLPs的构筑及其免疫效果研究》,并进行序列优化,合成的含口蹄疫病毒A型cDNA的pUC57-TEH116质粒作为A-P12A基因扩增模板,使用引物A-P12A-EcoRI-F/A-2Ap-XhoI-R扩增A-P12A序列。
pFast载体(四正柏)与A-P12A序列均用EcoRI与XhoI(NEB)双酶切,胶回收纯化后,用T4连接酶(NEB)连接,并转化大肠杆菌,筛选后提取质粒pFast-A-P12A。
将质粒pFast-A-P12A与O-P12A3C-mutant序列均用HindIII与XhoI(NEB)双酶切,胶回收纯化后,用T4连接酶(NEB)连接,并转化大肠杆菌,筛选后提取质粒 pFast-A-O-VLP-3Cmutant。
引物序列如下:
O-P12A序列:
O-P12A-EcoRI-F:CCGCTCGAGAGGGGAGCTGGACAGTCTAGCC(Seq ID NO.8)
O-P12A-R:GTCGGTAGGGGGAGCGCCGCTGCCAGGGTTGCTTTCCACAT(Seq ID NO.9)
O-3C mutant up序列:
O-3C-F:AGCGGCGCTCCCCCTACCG(Seq ID NO.10)
O-3C-Mu-R:AGGCCGGCCCACGTCGGCGTTGT(Seq ID NO.11)
O-3C mutant down序列:
O-3C-Mu-F:ACAACGCCGACGTGGGCCGGCCTATCTTTTCTGGCGAGGCCCTGAC(Seq IDNO.12)
O-3C-HindIII-R:CCCAAGCTTTCATTCATGGTGAGCTCGGGGTC(Seq ID NO.13)
A-P12A序列:
A-P12A-EcoRI-F:CCGGAATTCATGGGAGCCGGACAATCTTCT(Seq ID NO.14)
A-2Ap-XhoI-R:CCGCTCGAGAGGTCCGGGGTTGCTTTCCA(Seq ID NO.15)
将质粒pFast-A-P12A与O-P12A3C-mutant转入DH10bac感受态细胞(四正柏),进行重组,蓝白斑筛选,PCR鉴定,得到Bacmid-A-O-VLP-3Cmutant质粒。
DH10bac感受态细胞中有Bacmid载体,能与我们构建的pfast载体进行重组,筛选后就可以得到重组后的质粒Bacmid-A-VLP-3Cmutant。
同时制备口蹄疫Bacmid-O-VLP-3Cmutant与Bacmid-A-VLP-3Cmutant质粒作为对照。
实施例2串联表达的口蹄疫病毒VLP亚单位疫苗的构建
取实施例1获得的质粒Bacmid-A-VLP-3Cmutant、及用于对照的 Bacmid-O-VLP-3Cmutant与Bacmid-A-VLP-3Cmutant质粒,提取质粒进行SF9细胞(购自四正柏)的转染。转染后,取样细胞离心上清使用口蹄疫病毒O型豚鼠抗体进行Western Bolting检测,结果如图1所示,其中泳道1:口蹄疫病毒O型灭活病毒液,泳道2:O-VLP-3Cmutant,泳道3、4为A-O-VLP-3Cmutant,M为MARKER。由图1可以看到与对照类似的明显的条带,分别是VLP裂解后形成的约24kDa的VP1和VP3以及约31kDa 的VP0,表明表达A-O-VLP-3Cmutant的VLP构建成功。
实施例3VLP的纯化
实施例2制备的串联表达的VLP还需经过分子筛过柱,再用缓冲液PBS洗脱进行纯化。
VLP纯化步骤如下:
1)SF9细胞1.5×106细胞密度(25ml体积),2ml P2代病毒感染,72h后收获。
2)细胞1000×g离心10min,留取细胞沉淀,-80℃冻存备用。
3)细胞加入5ml细胞裂解液(20mM Tris-HCl pH 8.0,1mM EDTA,1mMTCEP,1mMPMSF,1%Triton X-100)冰上30min,10000×g离心取上清用GE厂商的HiPrep 16/60Sephacryl S-500HR的预装柱进行分子筛过柱,用缓冲液PBS洗脱。
4)进行进样环进样,尽可能减小体积的稀释。结果如图2所示,通道8为纯化获得的VLP。
经分子筛过柱纯化后,能去除2A和3C蛋白酶,获得更纯的口蹄疫A型和O型病毒蛋白。
实施例4抗原效价的测定
用双抗夹心ELISA方法检测实施例3制得的口蹄疫A型和O型病毒蛋白的表达,具体方法为:将待检蛋白、口蹄疫A型灭活病毒用PBS进行倍比稀释。稀释的样品依次加入口蹄疫A型兔抗血清(使用中农威特口蹄疫A型AF72株灭活疫苗免疫兔,每间隔1周免疫一次,共4次)包被好的96孔板中(50μL/孔),稍微震荡后,封板,37℃孵育1h。用PBST洗板5 次,甩干。每孔加入50μL的A型口蹄疫豚鼠抗血清工作液(使用中农威特口蹄疫A型AF72 株灭活疫苗免疫兔,每间隔1周免疫一次,共4次),封板,37℃孵育30min。同上洗板5次,甩干。每孔加入50μL羊抗豚鼠血清IgG-辣根过氧化物酶结合物工作液,封板,37℃孵育 30min。同上洗板5次,甩干。每孔加入50μL底物溶液,37℃孵育15min。每孔加50μL终止液终止反应,读取OD450nm值。结果如表1和表2所示,其中表1为串联表达VLP(A-O VLP) 与单独A型VLP、以及灭活口蹄疫A型病毒(中农威特)进行抗原效价比较;表2为串联表达VLP(A-O VLP)与单独O型VLP、以及灭活口蹄疫O型病毒(中农威特)进行抗原效价比较。
表1、A-O VLP与A型VLP、灭活口蹄疫A型病毒抗原效价比较
表2、A-O VLP与O型VLP、灭活口蹄疫O型病毒抗原效价比较
由表1可见,串联表达的A-O VLP的A型抗原效价虽然比单独A型VLP的A型抗原效价稍低,但由于A-O VLP能同时表达A型和O型抗原,而且由表2可见,A-O VLP的O型抗原效价与单独O型VLP的O型抗原效价较为接近,因此串联表达的A-O VLP的A型和O型抗原效价总和,与单独A型VLP和单独O型VLP相比,总产量大约提升了30%左右。
串联表达的A-O VLP的A型抗原效价与市购的灭活口蹄疫A型病毒抗原效价相比大幅提升,串联表达的A-O VLP经800倍~102400倍稀释,其A型抗原效价与市购的灭活口蹄疫A 型病毒20倍~2560倍稀释的抗原效价相当。
同样,比较串联表达的A-O VLP的O型抗原效价与市购的灭活口蹄疫O型病毒抗原效价,也是出现大幅提升,串联表达的A-O VLP经800倍~102400倍稀释,其O型抗原效价与市购的灭活口蹄疫O型病毒25倍~3200倍稀释的抗原效价相当。
可见,本发明提供的串联表达的A-O VLP的能明显提升A型和O型抗原的总产量,提升了30%左右,而且仅需一条生产线即可同时产出,成本大幅降低。
实施例5、串联表达VLP和A型、O型VLP的抗原浓度比较
本实施例采用实施例4提供的双抗夹心ELISA方法,检测实施例3制得的串联VLP和A 型、O型VLP病毒蛋白的表达,比较其抗原浓度。检测结果如表3、表4所示,其中表3为A-OVLP的A型抗原浓度与A型VLP的A型、O型抗原浓度列表,表4为A-O VLP的O型抗原浓度与O型VLP的O型、A型抗原浓度列表。
表3、A-O VLP的A型抗原浓度与A型VLP的A型、O型抗原浓度
A-O VLP浓度 | 稀释比 | A-O VLP | A型VLP | O型VLP |
128a | 1:800 | 0.3836 | 0.6273 | 0.0773 |
64a | 1:1600 | 0.2401 | 0.4399 | 0.0680 |
32a | 1:3200 | 0.1638 | 0.3915 | 0.0679 |
16a | 1:6400 | 0.1169 | 0.2636 | 0.0581 |
8a | 1:12800 | 0.0965 | 0.2043 | 0.0591 |
4a | 1:25600 | 0.0813 | 0.1405 | 0.0590 |
2a | 1:51200 | 0.0767 | 0.1087 | 0.0550 |
1a | 1:102400 | 0.0654 | 0.0825 | 0.0541 |
假定A-O-VLP在1:102400稀释比时口蹄疫A型抗原浓度为a,依照稀释关系可得表3的A-O-VLP口蹄疫A型抗原浓度值为128a~1a。以A-O-VLP口蹄疫A型抗原浓度为纵坐标,OD450值为横坐标建立标准曲线如图3所示。
根据图3的标准曲线计算可得A型VLP在1:800稀释时的口蹄疫A型抗原浓度为223.08a,O型VLP在1:800稀释时的口蹄疫A型抗原浓度为1.34a。
以相同条件下,生产两次A-O-VLP和分别生产一次A型VLP和O型VLP相比, A-O-VLP口蹄疫A型抗原产量增加14.07%。
表4、A-O VLP的O型抗原浓度与O型VLP的O型、A型抗原浓度
A-O VLP浓度 | 稀释比 | A-O VLP | O型VLP | A型VLP |
128a | 1:800 | 0.4022 | 0.5638 | 0.0754 |
64a | 1:1600 | 0.2954 | 0.3331 | 0.0685 |
32a | 1:3200 | 0.1811 | 0.2127 | 0.0605 |
16a | 1:6400 | 0.1616 | 0.1675 | 0.0553 |
8a | 1:12800 | 0.1177 | 0.1270 | 0.0588 |
4a | 1:25600 | 0.1173 | 0.1093 | 0.0602 |
2a | 1:51200 | 0.0963 | 0.0974 | 0.0600 |
1a | 1:102400 | 0.0984 | 0.0991 | 0.0570 |
同理,假定A-O-VLP在1:102400稀释比时口蹄疫OO型抗原浓度为b,依照稀释关系可得表4的A-O-VLP口蹄疫O型抗原浓度值为128b~1b。以A-O-VLP口蹄疫O型抗原浓度为纵坐标,OD450值为横坐标建立标准曲线。
根据图4的标准曲线计算可得O型VLP在1:800稀释时的口蹄疫O型抗原浓度为183.22b,A型VLP在1:800稀释时的口蹄疫O型抗原浓度为0.57a。
以相同条件下,生产两次A-O-VLP和分别生产一次A型VLP和O型VLP相比, A-O-VLP口蹄疫A型抗原产量增加39.29%。
综上,相同条件下,生产两次A-O-VLP对比分别生产一次A型VLP和O型VLP相比,A-O-VLP口蹄疫抗原产量综合平均增加26.68%,约在30%左右。
实施例6、疫苗免疫效力实验
分别用实施例3制备的A-O VLP疫苗免疫8周龄balb/c小鼠(n=5)和6周龄三元猪(n=5),同时设置对照组(空白细胞上清对照,n=5),检测小鼠细胞免疫水平和猪体内抗体水平。
免疫4周后采集猪血清,使用中国农业科学院兰州兽医研究所生产的口蹄疫抗体液相阻断检测试剂盒检测,根据说明书操作:效价≥1:64为99%保护,效价小于1:8为不保护,其余为50%保护。结果如表5所示。
表5、A-O VLP疫苗免疫三元猪
判定标准:以4孔病毒抗原对照孔的除去最大值和最小值之后的平均值的一半为临界值,通过临界值判读口蹄疫病毒抗体效价,其中表5上的临界值是1.14455,表5下的临界值是1.17005,低于临界值为受到免疫保护。
由表5结果显示:A-O VLP疫苗免疫三元猪后,A型和O型免疫组抗体效价均达到99%保护,与对照组差异很显著(p<0.01)。
免疫4周后脱颈椎处死小鼠,无菌采集脾细胞,与转染表达FMDA/O蛋白的293细胞共培养4~6h,同时加入蛋白分泌阻断剂阻断细胞因子分泌。对细胞表面标志物包括CD4、CD8分子,固定破膜后对细胞内细胞因子包括IFNγ、TNFα和IL2进行染色,使用流式细胞仪读取数据。结果如图5和图6所示,其中图5为A-O VLP诱导的CD8+T细胞反应结果示意图,图6为A-O VLP诱导的CD4+T细胞反应结果示意图;代表性结果如图7至图 8所示,其中图7为A-OVLP诱导的CD8+T细胞免疫反应代表图,图8为A-O VLP诱导的CD4+T细胞免疫反应代表图。显示不论是CD8+T细胞还是CD4+T细胞,其表达的IFNγ、 TNFα和IL2水平均显著高于空白细胞上清对照组(p<0.01)。
虽然本发明披露如上,但本发明并非限定于此。任何本领域技术人员,在不脱离本发明的精神和范围内,均可作各种更动与修改,因此本发明的保护范围应当以权利要求所限定的范围为准。
序列表
<110> 嘉兴安宇生物科技有限公司
<120> 一种串联表达的口蹄疫病毒VLP亚单位疫苗
<150> 2020106654086
<151> 2020-07-11
<160> 15
<170> SIPOSequenceListing 1.0
<210> 1
<211> 2262
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
atgggagccg gacaatcttc tcctgccacc ggctctcaga accagtctgg caataccggc 60
agcatcatca acaactacta catgcagcag taccagaaca gcatggacac acagctgggc 120
gacaatgcca tcagcggcgg ctctaatgag ggcagcaccg ataccaccag cacacacacc 180
aacaacaccc agaacaacga ctggttcagc aagctggcct ccagcgcctt taccggactg 240
tttggagcac tgctggccga caagaaaacc gaggaaacca cactgctgga agatcggatc 300
ctgaccacca gaaacggcca caccacaagc accacacagt ctagcgtggg cgtgacctac 360
ggctactcta caggcgagga tcacgtgtca ggccccaata cctctggcct ggaaaccaga 420
gtgacccagg ccgagcggtt cttcaagaag cacctgttcg actggaccac cgacaaggcc 480
tttggccacc tggaaaagct ggaactgccc accgatcaca agggcgtgta cggacacctg 540
gtggacagct tcgcctacat gagaaacggc tgggacgttg aggtgtccgc cgtgggcaat 600
cagttcaatg gcggatgtct gctggtggcc atggtgcccg agtacaagga cttcaccctg 660
agagagaagt accagctgac cctgtttcct caccagttca tcagccccag gaccaacatg 720
acagcccaca tcaccgtgcc ttacctgggc gtgaacagat acgaccagta taagaagcac 780
aagccctgga cactggtcgt gatggtggtg tctcctctga ccgtgaacaa ctctggcgcc 840
gagcagatca aggtgtacgc caatatcgcc cctacctatg tgcacgtggc aggcgagctg 900
cctagcaaag agggcatcgt tcctgtcgcc tgctctgatg gatatggcgg cctggtcacc 960
accgatccta agaccgccga tcctatctac ggcatggtgt acaaccctcc acggacaaac 1020
taccccggca gattcaccaa cctgctggat gtggctgagg cctgtcctac cttcctgtgc 1080
ttcgacgacg gcaagcccta cgtggtcaca agagccgatg gacagaggct gctggccaag 1140
ttcgatgtgt ctctggccgc caagcacatg agcaacacct acctgtctgg aatcgcccag 1200
tactacgccc agtatagcgg caccatcaac ctgcacttca tgttcactgg ccccaccgat 1260
agcaaggccc ggtacatggt ggcttatgtg ccacctggca tggaaacacc tccagacaca 1320
cctgaggaag ccgctcactg tattcacgcc gagtgggaca caggcctgaa cagcaagttt 1380
accttcagca tcccctacgt gtcagccgcc gattacgcct acacagcctc tgatgtggcc 1440
gaaaccacca acgtgcaagg ctgggtctgc atctaccaga tcacacacgg caaggccgag 1500
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atggaccgct tcgtgaagat ccccagccag tctcctactc acgtgatcga cctgatgcag 1740
actcaccagc acggacttgt tggcgccctg ctgagagctg ccacctacta cttcagcgac 1800
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acagccctgc acaacacctc taatcccacc gcctaccaca agggcccctt cacaagactg 1920
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gctcagctgc ccgccagctt caattttggc gctatcagag ccaccgtgat ccacgaactg 2100
ctcgtgcgga tgaagagagc cgagctgtac tgccctagac ctctgctggc tgtggaagtg 2160
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<210> 2
<211> 2898
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gacaacgcca tcagcggcgg ctctaatgag ggcagcaccg acaccacctc cacccacacc 180
accaacaccc agaacaacga ctggttcagc aagctggcct ccagcgcctt cagcggcctg 240
tttggagcac tgctggccga caagaaaacc gaggaaacca ccctgctgga agatcggatc 300
ctgaccaccc ggaacggcca caccacaagc accacacaga gcagcgtggg catcacccac 360
ggctatgcca ccgccgagga cttcgtgaac ggccccaata cctccggcct ggaaaccaga 420
gtggtgcagg ccgagcggtt cttcaagacc cacctgttcg actgggtcac cagcgacccc 480
ttcggcagat gctatctgct ggaactgccc accgaccaca agggcgtgta cggcagcctg 540
accgacagct acgcctacat gagaaacggc tgggacgtgg aagtgaccgc cgtgggcaac 600
cagttcaatg gcggctgtct gctggtggcc atggtgcctg agctgtgcag catcgagcgg 660
agagagctgt tccagctgac cctgttcccc caccagttca tcaacccccg gaccaacatg 720
accgcccaca tcaaggtgcc cttcgtgggc gtgaacagat acgaccagta caaggtgcac 780
aagccctgga ccctggtcgt gatggtggtg gcccctctga ccgtgaatac cgaaggcgcc 840
cctcagatca aggtgtacgc caatatcgcc cccaccaatg tgcacgtggc cggcgagttc 900
cctagcaaag agggcatctt ccccgtggcc tgctccgatg gatatggcgg cctcgtgacc 960
accgacccta agaccgccga tcccgtgtat ggcaaggtgt tcaacccccc cagaaacatg 1020
ctgcccggca gattcacaaa cctgctggac gtggccgagg cctgccctac cttcctgcac 1080
tttgatggcg acgtgcccta cgtgaccaca aagaccgact ccgacagagt gctggcccag 1140
ttcgatctga gcctggccgc caagcacatg agcaacacct ttctggccgg cctggctcag 1200
tactacaccc agtacagcgg caccgtgaac ctgcacttca tgttcaccgg ccccaccgat 1260
gccaaggccc ggtacatgat tgcctacgcc cctcccggca tggaaccccc aaagacacct 1320
gaagccgctg cccactgtat ccacgccgag tgggataccg gcctgaacag caagtttacc 1380
ttcagcatcc cctacctgtc tgccgccgac tacgcctata ccgcctctga tgccgccgaa 1440
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gacgcactgg tggtgctggc tagcgccggc aaggacttcg agctgagact gcccgtggac 1560
gccagacagc agacaaccag cacaggcgag agcgccgatc ctgtgaccgc caccgtggaa 1620
aactacggcg gcgagacaca ggtgcagcgg agacaccaca ccgacgtgtc cttcatcctg 1680
gacagattcg tgaaagtgac ccccaaggac agcatcaacg tgctggacct gatgcagacc 1740
cccagccaca cactcgtggg agccctgctg agaaccgcca cctactactt cgccgacctg 1800
gaagtggccg tgaagcacga gggcgatctg acatgggtgc ccaatggcgc ccctgaggcc 1860
gccctggaca ataccacaaa ccccaccgcc taccacaagg cccccctgac aagactggcc 1920
ctgccttaca cagcccccca tagggtgctg gccaccgtgt acaacggcaa ctgcaaatac 1980
gctggcggct ccctgcctaa cgtgcgcgga gatctgcagg tgctggcaca gaaagccgcc 2040
agacctctgc ccaccagctt caattacggc gccatcaagg ccaccagagt gaccgagctg 2100
ctgtaccgga tgaagcgggc cgagacatac tgccccagac ccctgctggc tgtgcaccct 2160
tctgccgctc ggcacaagca gaaaatcgtg gcccctgtga agcagagcct gaacttcgac 2220
ctgctgaagc tggccgggga tgtggaaagc aaccctggca gcggcgctcc ccctaccgac 2280
ctgcagaaaa tggtcatggg caacaccaag cctgtggaac tgatcctgga cggcaagacc 2340
gtggccatct gctgtgccac aggcgtgttc ggcacagcct acctggtgcc cagacacctg 2400
tttgccgaga agtacgacaa gattatgctg gacggccgga ccatgaccga tagcgactac 2460
cgggtgttcg agttcgagat caaagtgaag ggccaggaca tgctgagcga cgccgctctg 2520
atggtgctgc accggggaaa cagagtgcgg gacatcacaa agcacttccg ggacaccgcc 2580
agaatgaaga aaggcacccc cgtcgtggga gtgatcaaca acgccgacgt gggccggcct 2640
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cccgagcctc accatgaa 2898
<210> 3
<211> 5169
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
atgggagccg gacaatcttc tcctgccacc ggctctcaga accagtctgg caataccggc 60
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gacaatgcca tcagcggcgg ctctaatgag ggcagcaccg ataccaccag cacacacacc 180
aacaacaccc agaacaacga ctggttcagc aagctggcct ccagcgcctt taccggactg 240
tttggagcac tgctggccga caagaaaacc gaggaaacca cactgctgga agatcggatc 300
ctgaccacca gaaacggcca caccacaagc accacacagt ctagcgtggg cgtgacctac 360
ggctactcta caggcgagga tcacgtgtca ggccccaata cctctggcct ggaaaccaga 420
gtgacccagg ccgagcggtt cttcaagaag cacctgttcg actggaccac cgacaaggcc 480
tttggccacc tggaaaagct ggaactgccc accgatcaca agggcgtgta cggacacctg 540
gtggacagct tcgcctacat gagaaacggc tgggacgttg aggtgtccgc cgtgggcaat 600
cagttcaatg gcggatgtct gctggtggcc atggtgcccg agtacaagga cttcaccctg 660
agagagaagt accagctgac cctgtttcct caccagttca tcagccccag gaccaacatg 720
acagcccaca tcaccgtgcc ttacctgggc gtgaacagat acgaccagta taagaagcac 780
aagccctgga cactggtcgt gatggtggtg tctcctctga ccgtgaacaa ctctggcgcc 840
gagcagatca aggtgtacgc caatatcgcc cctacctatg tgcacgtggc aggcgagctg 900
cctagcaaag agggcatcgt tcctgtcgcc tgctctgatg gatatggcgg cctggtcacc 960
accgatccta agaccgccga tcctatctac ggcatggtgt acaaccctcc acggacaaac 1020
taccccggca gattcaccaa cctgctggat gtggctgagg cctgtcctac cttcctgtgc 1080
ttcgacgacg gcaagcccta cgtggtcaca agagccgatg gacagaggct gctggccaag 1140
ttcgatgtgt ctctggccgc caagcacatg agcaacacct acctgtctgg aatcgcccag 1200
tactacgccc agtatagcgg caccatcaac ctgcacttca tgttcactgg ccccaccgat 1260
agcaaggccc ggtacatggt ggcttatgtg ccacctggca tggaaacacc tccagacaca 1320
cctgaggaag ccgctcactg tattcacgcc gagtgggaca caggcctgaa cagcaagttt 1380
accttcagca tcccctacgt gtcagccgcc gattacgcct acacagcctc tgatgtggcc 1440
gaaaccacca acgtgcaagg ctgggtctgc atctaccaga tcacacacgg caaggccgag 1500
gacgataccc tggtcgttag cctgtctgcc ggcaaggatt tcgagctgag actgcctatc 1560
gaccccagaa gccagaccac cacaacaggc gagtctgctg atcctgtgac caccaccgtg 1620
gaaaactacg gcggagagac acaggtgcag cggagacagc acaccaatgt gggctttatc 1680
atggaccgct tcgtgaagat ccccagccag tctcctactc acgtgatcga cctgatgcag 1740
actcaccagc acggacttgt tggcgccctg ctgagagctg ccacctacta cttcagcgac 1800
ctggaaatcg tcgtgcggca cgatgacaac ctgacctggg ttccaaatgg cgcccctgaa 1860
acagccctgc acaacacctc taatcccacc gcctaccaca agggcccctt cacaagactg 1920
gccctgcctt atacagcccc tcacagagtg ctggccaccg tgtacaatgg caccaccaag 1980
tacagcaccg gcaacgccgg aagaagaggc gatcctggat ctctggctgc tagagtggct 2040
gctcagctgc ccgccagctt caattttggc gctatcagag ccaccgtgat ccacgaactg 2100
ctcgtgcgga tgaagagagc cgagctgtac tgccctagac ctctgctggc tgtggaagtg 2160
accagccagg acagacacaa gcagcggatt atcgccccag ccaaacagct gctgaacttc 2220
gatctgctga aactggccgg cgacgtggaa agcaaccccg gacctctcga gatgggagct 2280
ggacagtcta gccctgccac cggcagccag aaccagtctg gcaataccgg cagcatcatc 2340
aacaactact acatgcagca gtaccagaac agcatggaca cacagctggg cgacaacgcc 2400
atcagcggcg gctctaatga gggcagcacc gacaccacct ccacccacac caccaacacc 2460
cagaacaacg actggttcag caagctggcc tccagcgcct tcagcggcct gtttggagca 2520
ctgctggccg acaagaaaac cgaggaaacc accctgctgg aagatcggat cctgaccacc 2580
cggaacggcc acaccacaag caccacacag agcagcgtgg gcatcaccca cggctatgcc 2640
accgccgagg acttcgtgaa cggccccaat acctccggcc tggaaaccag agtggtgcag 2700
gccgagcggt tcttcaagac ccacctgttc gactgggtca ccagcgaccc cttcggcaga 2760
tgctatctgc tggaactgcc caccgaccac aagggcgtgt acggcagcct gaccgacagc 2820
tacgcctaca tgagaaacgg ctgggacgtg gaagtgaccg ccgtgggcaa ccagttcaat 2880
ggcggctgtc tgctggtggc catggtgcct gagctgtgca gcatcgagcg gagagagctg 2940
ttccagctga ccctgttccc ccaccagttc atcaaccccc ggaccaacat gaccgcccac 3000
atcaaggtgc ccttcgtggg cgtgaacaga tacgaccagt acaaggtgca caagccctgg 3060
accctggtcg tgatggtggt ggcccctctg accgtgaata ccgaaggcgc ccctcagatc 3120
aaggtgtacg ccaatatcgc ccccaccaat gtgcacgtgg ccggcgagtt ccctagcaaa 3180
gagggcatct tccccgtggc ctgctccgat ggatatggcg gcctcgtgac caccgaccct 3240
aagaccgccg atcccgtgta tggcaaggtg ttcaaccccc ccagaaacat gctgcccggc 3300
agattcacaa acctgctgga cgtggccgag gcctgcccta ccttcctgca ctttgatggc 3360
gacgtgccct acgtgaccac aaagaccgac tccgacagag tgctggccca gttcgatctg 3420
agcctggccg ccaagcacat gagcaacacc tttctggccg gcctggctca gtactacacc 3480
cagtacagcg gcaccgtgaa cctgcacttc atgttcaccg gccccaccga tgccaaggcc 3540
cggtacatga ttgcctacgc ccctcccggc atggaacccc caaagacacc tgaagccgct 3600
gcccactgta tccacgccga gtgggatacc ggcctgaaca gcaagtttac cttcagcatc 3660
ccctacctgt ctgccgccga ctacgcctat accgcctctg atgccgccga aaccaccaac 3720
gtgcagggct gggtgtgcct gttccagatc acacacggaa aggccgaggg cgacgcactg 3780
gtggtgctgg ctagcgccgg caaggacttc gagctgagac tgcccgtgga cgccagacag 3840
cagacaacca gcacaggcga gagcgccgat cctgtgaccg ccaccgtgga aaactacggc 3900
ggcgagacac aggtgcagcg gagacaccac accgacgtgt ccttcatcct ggacagattc 3960
gtgaaagtga cccccaagga cagcatcaac gtgctggacc tgatgcagac ccccagccac 4020
acactcgtgg gagccctgct gagaaccgcc acctactact tcgccgacct ggaagtggcc 4080
gtgaagcacg agggcgatct gacatgggtg cccaatggcg cccctgaggc cgccctggac 4140
aataccacaa accccaccgc ctaccacaag gcccccctga caagactggc cctgccttac 4200
acagcccccc atagggtgct ggccaccgtg tacaacggca actgcaaata cgctggcggc 4260
tccctgccta acgtgcgcgg agatctgcag gtgctggcac agaaagccgc cagacctctg 4320
cccaccagct tcaattacgg cgccatcaag gccaccagag tgaccgagct gctgtaccgg 4380
atgaagcggg ccgagacata ctgccccaga cccctgctgg ctgtgcaccc ttctgccgct 4440
cggcacaagc agaaaatcgt ggcccctgtg aagcagagcc tgaacttcga cctgctgaag 4500
ctggccgggg atgtggaaag caaccctggc agcggcgctc cccctaccga cctgcagaaa 4560
atggtcatgg gcaacaccaa gcctgtggaa ctgatcctgg acggcaagac cgtggccatc 4620
tgctgtgcca caggcgtgtt cggcacagcc tacctggtgc ccagacacct gtttgccgag 4680
aagtacgaca agattatgct ggacggccgg accatgaccg atagcgacta ccgggtgttc 4740
gagttcgaga tcaaagtgaa gggccaggac atgctgagcg acgccgctct gatggtgctg 4800
caccggggaa acagagtgcg ggacatcaca aagcacttcc gggacaccgc cagaatgaag 4860
aaaggcaccc ccgtcgtggg agtgatcaac aacgccgacg tgggccggcc tatcttttct 4920
ggcgaggccc tgacctacaa ggatatcgtc gtgtgcatgg acggcgacac catgcctggc 4980
ctgttcgcct ataaggccgc caccaaggcc ggctattgtg gcggagctgt gctggcaaaa 5040
gacggcgccg acaccttcat cgtgggcaca cattctgccg gcggaaacgg cgtgggctac 5100
tgctcttgcg tgtccagatc catgctgcag aagatgaagg cccacatcga ccccgagcct 5160
caccatgaa 5169
<210> 4
<211> 2259
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
atgggagctg gacagtctag ccctgccacc ggcagccaga accagtctgg caataccggc 60
agcatcatca acaactacta catgcagcag taccagaaca gcatggacac acagctgggc 120
gacaacgcca tcagcggcgg ctctaatgag ggcagcaccg acaccacctc cacccacacc 180
accaacaccc agaacaacga ctggttcagc aagctggcct ccagcgcctt cagcggcctg 240
tttggagcac tgctggccga caagaaaacc gaggaaacca ccctgctgga agatcggatc 300
ctgaccaccc ggaacggcca caccacaagc accacacaga gcagcgtggg catcacccac 360
ggctatgcca ccgccgagga cttcgtgaac ggccccaata cctccggcct ggaaaccaga 420
gtggtgcagg ccgagcggtt cttcaagacc cacctgttcg actgggtcac cagcgacccc 480
ttcggcagat gctatctgct ggaactgccc accgaccaca agggcgtgta cggcagcctg 540
accgacagct acgcctacat gagaaacggc tgggacgtgg aagtgaccgc cgtgggcaac 600
cagttcaatg gcggctgtct gctggtggcc atggtgcctg agctgtgcag catcgagcgg 660
agagagctgt tccagctgac cctgttcccc caccagttca tcaacccccg gaccaacatg 720
accgcccaca tcaaggtgcc cttcgtgggc gtgaacagat acgaccagta caaggtgcac 780
aagccctgga ccctggtcgt gatggtggtg gcccctctga ccgtgaatac cgaaggcgcc 840
cctcagatca aggtgtacgc caatatcgcc cccaccaatg tgcacgtggc cggcgagttc 900
cctagcaaag agggcatctt ccccgtggcc tgctccgatg gatatggcgg cctcgtgacc 960
accgacccta agaccgccga tcccgtgtat ggcaaggtgt tcaacccccc cagaaacatg 1020
ctgcccggca gattcacaaa cctgctggac gtggccgagg cctgccctac cttcctgcac 1080
tttgatggcg acgtgcccta cgtgaccaca aagaccgact ccgacagagt gctggcccag 1140
ttcgatctga gcctggccgc caagcacatg agcaacacct ttctggccgg cctggctcag 1200
tactacaccc agtacagcgg caccgtgaac ctgcacttca tgttcaccgg ccccaccgat 1260
gccaaggccc ggtacatgat tgcctacgcc cctcccggca tggaaccccc aaagacacct 1320
gaagccgctg cccactgtat ccacgccgag tgggataccg gcctgaacag caagtttacc 1380
ttcagcatcc cctacctgtc tgccgccgac tacgcctata ccgcctctga tgccgccgaa 1440
accaccaacg tgcagggctg ggtgtgcctg ttccagatca cacacggaaa ggccgagggc 1500
gacgcactgg tggtgctggc tagcgccggc aaggacttcg agctgagact gcccgtggac 1560
gccagacagc agacaaccag cacaggcgag agcgccgatc ctgtgaccgc caccgtggaa 1620
aactacggcg gcgagacaca ggtgcagcgg agacaccaca ccgacgtgtc cttcatcctg 1680
gacagattcg tgaaagtgac ccccaaggac agcatcaacg tgctggacct gatgcagacc 1740
cccagccaca cactcgtggg agccctgctg agaaccgcca cctactactt cgccgacctg 1800
gaagtggccg tgaagcacga gggcgatctg acatgggtgc ccaatggcgc ccctgaggcc 1860
gccctggaca ataccacaaa ccccaccgcc taccacaagg cccccctgac aagactggcc 1920
ctgccttaca cagcccccca tagggtgctg gccaccgtgt acaacggcaa ctgcaaatac 1980
gctggcggct ccctgcctaa cgtgcgcgga gatctgcagg tgctggcaca gaaagccgcc 2040
agacctctgc ccaccagctt caattacggc gccatcaagg ccaccagagt gaccgagctg 2100
ctgtaccgga tgaagcgggc cgagacatac tgccccagac ccctgctggc tgtgcaccct 2160
tctgccgctc ggcacaagca gaaaatcgtg gcccctgtga agcagagcct gaacttcgac 2220
ctgctgaagc tggccgggga tgtggaaagc aaccctggc 2259
<210> 5
<211> 639
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
agcggcgctc cccctaccga cctgcagaaa atggtcatgg gcaacaccaa gcctgtggaa 60
ctgatcctgg acggcaagac cgtggccatc tgctgtgcca caggcgtgtt cggcacagcc 120
tacctggtgc ccagacacct gtttgccgag aagtacgaca agattatgct ggacggccgg 180
accatgaccg atagcgacta ccgggtgttc gagttcgaga tcaaagtgaa gggccaggac 240
atgctgagcg acgccgctct gatggtgctg caccggggaa acagagtgcg ggacatcaca 300
aagcacttcc gggacaccgc cagaatgaag aaaggcaccc ccgtcgtggg agtgatcaac 360
aacgccgacg tgggccggcc tatcttttct ggcgaggccc tgacctacaa ggatatcgtc 420
gtgtgcatgg acggcgacac catgcctggc ctgttcgcct ataaggccgc caccaaggcc 480
ggctattgtg gcggagctgt gctggcaaaa gacggcgccg acaccttcat cgtgggcaca 540
cattctgccg gcggaaacgg cgtgggctac tgctcttgcg tgtccagatc catgctgcag 600
aagatgaagg cccacatcga ccccgagcct caccatgaa 639
<210> 6
<211> 639
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
agcggcgctc cccctaccga cctgcagaaa atggtcatgg gcaacaccaa gcctgtggaa 60
ctgatcctgg acggcaagac cgtggccatc tgctgtgcca caggcgtgtt cggcacagcc 120
tacctggtgc ccagacacct gtttgccgag aagtacgaca agattatgct ggacggccgg 180
accatgaccg atagcgacta ccgggtgttc gagttcgaga tcaaagtgaa gggccaggac 240
atgctgagcg acgccgctct gatggtgctg caccggggaa acagagtgcg ggacatcaca 300
aagcacttcc gggacaccgc cagaatgaag aaaggcaccc ccgtcgtggg agtgatcaac 360
aacgccgacg tgggccggct gatcttttct ggcgaggccc tgacctacaa ggatatcgtc 420
gtgtgcatgg acggcgacac catgcctggc ctgttcgcct ataaggccgc caccaaggcc 480
ggctattgtg gcggagctgt gctggcaaaa gacggcgccg acaccttcat cgtgggcaca 540
cattctgccg gcggaaacgg cgtgggctac tgctcttgcg tgtccagatc catgctgcag 600
aagatgaagg cccacatcga ccccgagcct caccatgaa 639
<210> 7
<211> 1723
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Gly Ala Gly Gln Ser Ser Pro Ala Thr Gly Ser Gln Asn Gln Ser
1 5 10 15
Gly Asn Thr Gly Ser Ile Ile Asn Asn Tyr Tyr Met Gln Gln Tyr Gln
20 25 30
Asn Ser Met Asp Thr Gln Leu Gly Asp Asn Ala Ile Ser Gly Gly Ser
35 40 45
Asn Glu Gly Ser Thr Asp Thr Thr Ser Thr His Thr Asn Asn Thr Gln
50 55 60
Asn Asn Asp Trp Phe Ser Lys Leu Ala Ser Ser Ala Phe Thr Gly Leu
65 70 75 80
Phe Gly Ala Leu Leu Ala Asp Lys Lys Thr Glu Glu Thr Thr Leu Leu
85 90 95
Glu Asp Arg Ile Leu Thr Thr Arg Asn Gly His Thr Thr Ser Thr Thr
100 105 110
Gln Ser Ser Val Gly Val Thr Tyr Gly Tyr Ser Thr Gly Glu Asp His
115 120 125
Val Ser Gly Pro Asn Thr Ser Gly Leu Glu Thr Arg Val Thr Gln Ala
130 135 140
Glu Arg Phe Phe Lys Lys His Leu Phe Asp Trp Thr Thr Asp Lys Ala
145 150 155 160
Phe Gly His Leu Glu Lys Leu Glu Leu Pro Thr Asp His Lys Gly Val
165 170 175
Tyr Gly His Leu Val Asp Ser Phe Ala Tyr Met Arg Asn Gly Trp Asp
180 185 190
Val Glu Val Ser Ala Val Gly Asn Gln Phe Asn Gly Gly Cys Leu Leu
195 200 205
Val Ala Met Val Pro Glu Tyr Lys Asp Phe Thr Leu Arg Glu Lys Tyr
210 215 220
Gln Leu Thr Leu Phe Pro His Gln Phe Ile Ser Pro Arg Thr Asn Met
225 230 235 240
Thr Ala His Ile Thr Val Pro Tyr Leu Gly Val Asn Arg Tyr Asp Gln
245 250 255
Tyr Lys Lys His Lys Pro Trp Thr Leu Val Val Met Val Val Ser Pro
260 265 270
Leu Thr Val Asn Asn Ser Gly Ala Glu Gln Ile Lys Val Tyr Ala Asn
275 280 285
Ile Ala Pro Thr Tyr Val His Val Ala Gly Glu Leu Pro Ser Lys Glu
290 295 300
Gly Ile Val Pro Val Ala Cys Ser Asp Gly Tyr Gly Gly Leu Val Thr
305 310 315 320
Thr Asp Pro Lys Thr Ala Asp Pro Ile Tyr Gly Met Val Tyr Asn Pro
325 330 335
Pro Arg Thr Asn Tyr Pro Gly Arg Phe Thr Asn Leu Leu Asp Val Ala
340 345 350
Glu Ala Cys Pro Thr Phe Leu Cys Phe Asp Asp Gly Lys Pro Tyr Val
355 360 365
Val Thr Arg Ala Asp Gly Gln Arg Leu Leu Ala Lys Phe Asp Val Ser
370 375 380
Leu Ala Ala Lys His Met Ser Asn Thr Tyr Leu Ser Gly Ile Ala Gln
385 390 395 400
Tyr Tyr Ala Gln Tyr Ser Gly Thr Ile Asn Leu His Phe Met Phe Thr
405 410 415
Gly Pro Thr Asp Ser Lys Ala Arg Tyr Met Val Ala Tyr Val Pro Pro
420 425 430
Gly Met Glu Thr Pro Pro Asp Thr Pro Glu Glu Ala Ala His Cys Ile
435 440 445
His Ala Glu Trp Asp Thr Gly Leu Asn Ser Lys Phe Thr Phe Ser Ile
450 455 460
Pro Tyr Val Ser Ala Ala Asp Tyr Ala Tyr Thr Ala Ser Asp Val Ala
465 470 475 480
Glu Thr Thr Asn Val Gln Gly Trp Val Cys Ile Tyr Gln Ile Thr His
485 490 495
Gly Lys Ala Glu Asp Asp Thr Leu Val Val Ser Leu Ser Ala Gly Lys
500 505 510
Asp Phe Glu Leu Arg Leu Pro Ile Asp Pro Arg Ser Gln Thr Thr Thr
515 520 525
Thr Gly Glu Ser Ala Asp Pro Val Thr Thr Thr Val Glu Asn Tyr Gly
530 535 540
Gly Glu Thr Gln Val Gln Arg Arg Gln His Thr Asn Val Gly Phe Ile
545 550 555 560
Met Asp Arg Phe Val Lys Ile Pro Ser Gln Ser Pro Thr His Val Ile
565 570 575
Asp Leu Met Gln Thr His Gln His Gly Leu Val Gly Ala Leu Leu Arg
580 585 590
Ala Ala Thr Tyr Tyr Phe Ser Asp Leu Glu Ile Val Val Arg His Asp
595 600 605
Asp Asn Leu Thr Trp Val Pro Asn Gly Ala Pro Glu Thr Ala Leu His
610 615 620
Asn Thr Ser Asn Pro Thr Ala Tyr His Lys Gly Pro Phe Thr Arg Leu
625 630 635 640
Ala Leu Pro Tyr Thr Ala Pro His Arg Val Leu Ala Thr Val Tyr Asn
645 650 655
Gly Thr Thr Lys Tyr Ser Thr Gly Asn Ala Gly Arg Arg Gly Asp Pro
660 665 670
Gly Ser Leu Ala Ala Arg Val Ala Ala Gln Leu Pro Ala Ser Phe Asn
675 680 685
Phe Gly Ala Ile Arg Ala Thr Val Ile His Glu Leu Leu Val Arg Met
690 695 700
Lys Arg Ala Glu Leu Tyr Cys Pro Arg Pro Leu Leu Ala Val Glu Val
705 710 715 720
Thr Ser Gln Asp Arg His Lys Gln Arg Ile Ile Ala Pro Ala Lys Gln
725 730 735
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
740 745 750
Pro Gly Pro Leu Glu Met Gly Ala Gly Gln Ser Ser Pro Ala Thr Gly
755 760 765
Ser Gln Asn Gln Ser Gly Asn Thr Gly Ser Ile Ile Asn Asn Tyr Tyr
770 775 780
Met Gln Gln Tyr Gln Asn Ser Met Asp Thr Gln Leu Gly Asp Asn Ala
785 790 795 800
Ile Ser Gly Gly Ser Asn Glu Gly Ser Thr Asp Thr Thr Ser Thr His
805 810 815
Thr Thr Asn Thr Gln Asn Asn Asp Trp Phe Ser Lys Leu Ala Ser Ser
820 825 830
Ala Phe Ser Gly Leu Phe Gly Ala Leu Leu Ala Asp Lys Lys Thr Glu
835 840 845
Glu Thr Thr Leu Leu Glu Asp Arg Ile Leu Thr Thr Arg Asn Gly His
850 855 860
Thr Thr Ser Thr Thr Gln Ser Ser Val Gly Ile Thr His Gly Tyr Ala
865 870 875 880
Thr Ala Glu Asp Phe Val Asn Gly Pro Asn Thr Ser Gly Leu Glu Thr
885 890 895
Arg Val Val Gln Ala Glu Arg Phe Phe Lys Thr His Leu Phe Asp Trp
900 905 910
Val Thr Ser Asp Pro Phe Gly Arg Cys Tyr Leu Leu Glu Leu Pro Thr
915 920 925
Asp His Lys Gly Val Tyr Gly Ser Leu Thr Asp Ser Tyr Ala Tyr Met
930 935 940
Arg Asn Gly Trp Asp Val Glu Val Thr Ala Val Gly Asn Gln Phe Asn
945 950 955 960
Gly Gly Cys Leu Leu Val Ala Met Val Pro Glu Leu Cys Ser Ile Glu
965 970 975
Arg Arg Glu Leu Phe Gln Leu Thr Leu Phe Pro His Gln Phe Ile Asn
980 985 990
Pro Arg Thr Asn Met Thr Ala His Ile Lys Val Pro Phe Val Gly Val
995 1000 1005
Asn Arg Tyr Asp Gln Tyr Lys Val His Lys Pro Trp Thr Leu Val Val
1010 1015 1020
Met Val Val Ala Pro Leu Thr Val Asn Thr Glu Gly Ala Pro Gln Ile
1025 1030 1035 1040
Lys Val Tyr Ala Asn Ile Ala Pro Thr Asn Val His Val Ala Gly Glu
1045 1050 1055
Phe Pro Ser Lys Glu Gly Ile Phe Pro Val Ala Cys Ser Asp Gly Tyr
1060 1065 1070
Gly Gly Leu Val Thr Thr Asp Pro Lys Thr Ala Asp Pro Val Tyr Gly
1075 1080 1085
Lys Val Phe Asn Pro Pro Arg Asn Met Leu Pro Gly Arg Phe Thr Asn
1090 1095 1100
Leu Leu Asp Val Ala Glu Ala Cys Pro Thr Phe Leu His Phe Asp Gly
1105 1110 1115 1120
Asp Val Pro Tyr Val Thr Thr Lys Thr Asp Ser Asp Arg Val Leu Ala
1125 1130 1135
Gln Phe Asp Leu Ser Leu Ala Ala Lys His Met Ser Asn Thr Phe Leu
1140 1145 1150
Ala Gly Leu Ala Gln Tyr Tyr Thr Gln Tyr Ser Gly Thr Val Asn Leu
1155 1160 1165
His Phe Met Phe Thr Gly Pro Thr Asp Ala Lys Ala Arg Tyr Met Ile
1170 1175 1180
Ala Tyr Ala Pro Pro Gly Met Glu Pro Pro Lys Thr Pro Glu Ala Ala
1185 1190 1195 1200
Ala His Cys Ile His Ala Glu Trp Asp Thr Gly Leu Asn Ser Lys Phe
1205 1210 1215
Thr Phe Ser Ile Pro Tyr Leu Ser Ala Ala Asp Tyr Ala Tyr Thr Ala
1220 1225 1230
Ser Asp Ala Ala Glu Thr Thr Asn Val Gln Gly Trp Val Cys Leu Phe
1235 1240 1245
Gln Ile Thr His Gly Lys Ala Glu Gly Asp Ala Leu Val Val Leu Ala
1250 1255 1260
Ser Ala Gly Lys Asp Phe Glu Leu Arg Leu Pro Val Asp Ala Arg Gln
1265 1270 1275 1280
Gln Thr Thr Ser Thr Gly Glu Ser Ala Asp Pro Val Thr Ala Thr Val
1285 1290 1295
Glu Asn Tyr Gly Gly Glu Thr Gln Val Gln Arg Arg His His Thr Asp
1300 1305 1310
Val Ser Phe Ile Leu Asp Arg Phe Val Lys Val Thr Pro Lys Asp Ser
1315 1320 1325
Ile Asn Val Leu Asp Leu Met Gln Thr Pro Ser His Thr Leu Val Gly
1330 1335 1340
Ala Leu Leu Arg Thr Ala Thr Tyr Tyr Phe Ala Asp Leu Glu Val Ala
1345 1350 1355 1360
Val Lys His Glu Gly Asp Leu Thr Trp Val Pro Asn Gly Ala Pro Glu
1365 1370 1375
Ala Ala Leu Asp Asn Thr Thr Asn Pro Thr Ala Tyr His Lys Ala Pro
1380 1385 1390
Leu Thr Arg Leu Ala Leu Pro Tyr Thr Ala Pro His Arg Val Leu Ala
1395 1400 1405
Thr Val Tyr Asn Gly Asn Cys Lys Tyr Ala Gly Gly Ser Leu Pro Asn
1410 1415 1420
Val Arg Gly Asp Leu Gln Val Leu Ala Gln Lys Ala Ala Arg Pro Leu
1425 1430 1435 1440
Pro Thr Ser Phe Asn Tyr Gly Ala Ile Lys Ala Thr Arg Val Thr Glu
1445 1450 1455
Leu Leu Tyr Arg Met Lys Arg Ala Glu Thr Tyr Cys Pro Arg Pro Leu
1460 1465 1470
Leu Ala Val His Pro Ser Ala Ala Arg His Lys Gln Lys Ile Val Ala
1475 1480 1485
Pro Val Lys Gln Ser Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp
1490 1495 1500
Val Glu Ser Asn Pro Gly Ser Gly Ala Pro Pro Thr Asp Leu Gln Lys
1505 1510 1515 1520
Met Val Met Gly Asn Thr Lys Pro Val Glu Leu Ile Leu Asp Gly Lys
1525 1530 1535
Thr Val Ala Ile Cys Cys Ala Thr Gly Val Phe Gly Thr Ala Tyr Leu
1540 1545 1550
Val Pro Arg His Leu Phe Ala Glu Lys Tyr Asp Lys Ile Met Leu Asp
1555 1560 1565
Gly Arg Thr Met Thr Asp Ser Asp Tyr Arg Val Phe Glu Phe Glu Ile
1570 1575 1580
Lys Val Lys Gly Gln Asp Met Leu Ser Asp Ala Ala Leu Met Val Leu
1585 1590 1595 1600
His Arg Gly Asn Arg Val Arg Asp Ile Thr Lys His Phe Arg Asp Thr
1605 1610 1615
Ala Arg Met Lys Lys Gly Thr Pro Val Val Gly Val Ile Asn Asn Ala
1620 1625 1630
Asp Val Gly Arg Pro Ile Phe Ser Gly Glu Ala Leu Thr Tyr Lys Asp
1635 1640 1645
Ile Val Val Cys Met Asp Gly Asp Thr Met Pro Gly Leu Phe Ala Tyr
1650 1655 1660
Lys Ala Ala Thr Lys Ala Gly Tyr Cys Gly Gly Ala Val Leu Ala Lys
1665 1670 1675 1680
Asp Gly Ala Asp Thr Phe Ile Val Gly Thr His Ser Ala Gly Gly Asn
1685 1690 1695
Gly Val Gly Tyr Cys Ser Cys Val Ser Arg Ser Met Leu Gln Lys Met
1700 1705 1710
Lys Ala His Ile Asp Pro Glu Pro His His Glu
1715 1720
<210> 8
<211> 31
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
ccgctcgaga ggggagctgg acagtctagc c 31
<210> 9
<211> 41
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
gtcggtaggg ggagcgccgc tgccagggtt gctttccaca t 41
<210> 10
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
agcggcgctc cccctaccg 19
<210> 11
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
aggccggccc acgtcggcgt tgt 23
<210> 12
<211> 46
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
acaacgccga cgtgggccgg cctatctttt ctggcgaggc cctgac 46
<210> 13
<211> 32
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
cccaagcttt cattcatggt gagctcgggg tc 32
<210> 14
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
ccggaattca tgggagccgg acaatcttct 30
<210> 15
<211> 29
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
ccgctcgaga ggtccggggt tgctttcca 29
Claims (2)
1.一种口蹄疫病毒VLP疫苗,其特征在于,由融合片段A-O-VLP-3Cmutant在表达体系中表达形成;所述融合片段A-O-VLP-3Cmutant的核苷酸序列如序列表中Seq ID NO.3所示,氨基酸序列如序列表Seq ID NO.7所示;所述口蹄疫病毒VLP疫苗通过口蹄疫病毒A型的A-P12A基因和O型的O-P12A3C-mutant基因,制得融合片段A-O-VLP-3Cmutant,再经SF9表达体系中表达形成;所述O-P12A3C-mutant基因是将O-P12A和O-3C-mutant进行融合PCR而获得,其中的O-P12A和O-3C-mutant的核苷酸序列如序列表中Seq IDNO.4、Seq ID NO.5所示;所述的O-3C-mutant是由O-3C的第127个氨基酸由L变为P而获得,其中的3C的核苷酸序列如序列表Seq ID NO.6所示;所述A-P12A、O-P12A3C-mutant的核苷酸序列如序列表中Seq IDNO.1、Seq ID NO.2所示;所述的A-O-VLP-3Cmutant经表达体系表达制备VLP,是通过pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,进行重组、筛选、鉴定,得到Bacmid-A-O-VLP-3Cmutant质粒,再转入表达体系;其A型结构蛋白P1和O型结构蛋白P1以及3C蛋白酶中间均使用来自口蹄疫病毒的顺式裂解元件2A蛋白酶进行分离,共用一个3C蛋白酶进行酶切形成VP4、VP3、VP2、VP1四种结构蛋白,并组装成VLP;所述口蹄疫病毒VLP疫苗的制备方法由以下步骤组成:
1)制备口蹄疫病毒A型的A-P12A基因和O型的O-P12A3C-mutant基因;
2)pFast载体与A-P12A酶切连接获得pFast-A-P12A;
3)pFast-A-P12A与O-P12A3C-mutant酶切连接获得pFast-A-O-VLP-3Cmutant;
4)pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,得到Bacmid-A-O-VLP-3Cmutant质粒;
5)Bacmid-A-O-VLP-3Cmutant转入SF9真核表达系统,收获重组杆状病毒;收获的重组杆状病毒还需扩增,裂解,再经过分子筛过柱纯化。
2.一种口蹄疫病毒VLP疫苗的制备方法,其特征在于,所述口蹄疫病毒VLP疫苗通过融合片段A-O-VLP-3Cmutant经SF9表达体系中表达形成;所述融合片段A-O-VLP-3Cmutant是由口蹄疫病毒A型的A-P12A基因和O型的O-P12A3C-mutant基因串联制得,核苷酸序列如序列表中Seq ID NO.3所示,氨基酸序列如序列表Seq ID NO.7所示;所述O-P12A3C-mutant基因是将O-P12A和O-3C-mutant进行融合PCR而获得,其中的O-P12A和O-3C-mutant的核苷酸序列如序列表中Seq IDNO.4、Seq ID NO.5所示;所述的O-3C-mutant是由O-3C的第127个氨基酸由L变为P而获得,其中的3C的核苷酸序列如序列表Seq ID NO.6所示;所述A-P12A、O-P12A3C-mutant的核苷酸序列如序列表中Seq ID NO.1、Seq ID NO.2所示;所述的A-O-VLP-3Cmutant经表达体系表达制备VLP,是通过pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,进行重组、筛选、鉴定,得到Bacmid-A-O-VLP-3Cmutant质粒,再转入表达体系;其A型结构蛋白P1和O型结构蛋白P1以及3C蛋白酶中间均使用来自口蹄疫病毒的顺式裂解元件2A蛋白酶进行分离,共用一个3C蛋白酶进行酶切形成VP4、VP3、VP2、VP1四种结构蛋白,并组装成VLP;所述口蹄疫病毒VLP疫苗的制备方法由以下步骤组成:
1)制备口蹄疫病毒A型的A-P12A基因和O型的O-P12A3C-mutant基因;
2)pFast载体与A-P12A酶切连接获得pFast-A-P12A;
3)pFast-A-P12A与O-P12A3C-mutant酶切连接获得pFast-A-O-VLP-3Cmutant;
4)pFast-A-O-VLP-3Cmutant转入DH10bac感受态细胞,得到Bacmid-A-O-VLP-3Cmutant质粒;
5)Bacmid-A-O-VLP-3Cmutant转入SF9真核表达系统,收获重组杆状病毒;收获的重组杆状病毒还需扩增,裂解,再经过分子筛过柱纯化。
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