CN112316130A - 一种SARS-CoV2粘膜免疫疫苗及其应用 - Google Patents
一种SARS-CoV2粘膜免疫疫苗及其应用 Download PDFInfo
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- CN112316130A CN112316130A CN202011225947.4A CN202011225947A CN112316130A CN 112316130 A CN112316130 A CN 112316130A CN 202011225947 A CN202011225947 A CN 202011225947A CN 112316130 A CN112316130 A CN 112316130A
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Abstract
本发明涉及一种SARS‑CoV2粘膜免疫疫苗及其应用,采用SARS‑CoV2的Spike蛋白的RBD基因和水解Spike蛋白S1/S2位点基因组成疫苗的基本组分,同时结合CT‑B亚单位基因、能结合人IgA‑Fc的sdAb基因和Furin蛋白酶切位点区域hd,构建在大肠杆菌或酵母表达载体里,表达后的蛋白形成的五聚体纳米颗粒可以引起机体粘膜免疫反应,产生针对SARS‑CoV2的抗体,对机体起到免疫保护作用。
Description
技术领域
本发明涉及疫苗技术领域,尤其涉及一种SARS-CoV2粘膜免疫疫苗及其应用。
背景技术
冠状病毒可引起动物和人类的呼吸道和肠道感染,具有高致病性。SARS冠状病毒利用血管紧张素转化酶2作为受体并主要感染有纤毛的支气管上皮细胞和II型肺泡壁细胞,而MERS-CoV利用二肽基肽酶4作为受体感染无纤毛的支气管上皮细胞和II型肺泡壁细胞。
2019-nCoV是一类新发现的单股正链RNA冠状病毒,与SARS-Cov在基因序列上有高度同源性,其病毒粒子外包脂质双层膜,膜表面有三种糖蛋白:其中刺突糖蛋白Spike是冠状病毒最重要的表面膜蛋白,含有两个亚基,即S1和 S2,其中S1主要包含有受体结合区RBD,负责识别细胞的受体AEC2,S2含有膜融合过程所需的基本元件,S蛋白承担病毒与宿主细胞膜受体结合及膜融合功能,是宿主中和抗体的重要作用位点以及疫苗设计的关键靶点。
传统疫苗研究方案是分离病原微生物,制备死疫苗、减毒活疫苗、病原微生物结构组成成分的亚单位疫苗,其核酸疫苗等。有鉴于2019-nCoV病毒的Spike 蛋白是病毒感染细胞的必需蛋白,阻断其RBD和细胞受体蛋白ACE2结合可以阻断病毒进入细胞,是阻断病毒传播的关键环节。
由于2019-nCov主要通过呼吸道等各种粘膜感染,通过非口服途径的疫苗难以诱导有效的粘膜免疫反应,因此研制粘膜免疫疫苗成为疫苗研究中的重点。
发明内容
有鉴于此,本发明提出了一种刺激机体粘膜能产生较强免疫反应的SARS-CoV2粘膜免疫疫苗。
本发明的技术方案是这样实现的:本发明提供了一种SARS-CoV2粘膜免疫疫苗,所述疫苗基因包括SARS-CoV2的Spike蛋白的RBD基因、水解Spike 蛋白S1/S2位点基因、CT-B亚单位基因、结合人IgA-Fc的sdAb基因和Furin 蛋白酶切位点hd。
在以上技术方案的基础上,优选的,所述疫苗基因构建成 RBD-S1/S2-hd-CT-B-sdAb,在大肠杆菌或酵母表达载体里表达后的蛋白形成五聚体的纳米颗粒。
在以上技术方案的基础上,优选的,所述疫苗基因顺序为 sdAb-linker1-CT-B-linker2-RBD-S1/S2-6His。
在以上技术方案的基础上,优选的,所述SARS-CoV2的Spike蛋白RBD 段来自SARS-CoV2病毒的不同突变株。
在以上技术方案的基础上,优选的,所述SARS-CoV2的Spike蛋白RBD 基因包含SARS-CoV2的Spike蛋白RBD全长基因或部分基因。
在以上技术方案的基础上,优选的,所述水解Spike蛋白S1/S2位点基因包含水解Spike蛋白S1/S2位点全长基因或部分基因。
在以上技术方案的基础上,优选的,所述疫苗的氨基酸序列如SEQNO:1 所示,基因序列如SEQNO:4所示。
在以上技术方案的基础上,优选的,所述RBD-S1/S2的氨基酸序列如SEQ NO:2所示,基因序列如SEQNO:5所示。
在以上技术方案的基础上,优选的,所述CT-B-sdAb的氨基酸序列如SEQ NO:3所示,基因序列如SEQNO:6所示。
更进一步优选的,还提供了一种SARS-CoV2粘膜免疫疫苗在制备治疗和/ 或预防SARS-CoV2的药物中的应用。
本发明提供的一种SARS-CoV2粘膜免疫疫苗及其应用具有以下有益效果:
(1)RBD-S1/S2-hd-CT-B-sdAb在大肠杆菌或酵母表达载体里表达后的蛋白形成五聚体的纳米颗粒,可以引起机体粘膜免疫反应,增加其诱导机体粘膜免疫能力较强。
(2)新冠病毒主要通过呼吸道等各种粘膜感染,本发明疫苗通过粘膜进行免疫,因粘膜上有IgA,疫苗容易通过此与粘膜结合,达到诱导机体产生粘膜和体液的免疫保护能力,而且疫苗使用方便,采用呼吸道喷雾或吸入免疫。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,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的附图。
图1为实施例1中疫苗基因组成顺序;
图2为实施例1中对照载体基因组成顺序;
图3为实施例1中疫苗基因合成图;
图4为实施例1中疫苗基因蛋白表达纯化后的SDS-PAGE电泳图;
图5为实施例2中疫苗基因纯化蛋白排阻峰图;
图6为实施例2中对照载体基因纯化蛋白排阻峰图;
图7为实施例3中疫苗蛋白免疫小鼠血清ELISA检测图。
具体实施方式
下面将结合本发明实施方式,对本发明实施方式中的技术方案进行清楚、完整地描述,显然,所描述的实施方式仅仅是本发明一部分实施方式,而不是全部的实施方式。基于本发明中的实施方式,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施方式,都属于本发明保护的范围。
实施例1疫苗制备
S1,疫苗基因合成和载体构建:
疫苗基因组成顺序见图1,对照载体的基因组成顺序见图2。
图中WKD-COVID19-M1为本发明疫苗,WKD-sdAb-CT-B为对照载体。
WKD-S-RBD1,1694bp,常规序列合成并克隆到pET28aNcoI/XhoI,获得重组质粒:pET28a-WKD-S-RBD1;
WKD-S-2,746bp,常规序列合成克隆到pET28aNcoI/XhoI,获得重组质粒: pET28a-WKD-S-2;
sdAb来源于北京纽安博生物技术有限公司专利的单域抗体,基因合成由中美泰和生物技术(北京)有限公司完成,基因合成结果见图3。
S1,WKD-COVID19-M1的表达与纯化:
将含有质粒A:WKD-COVID19-M1和B:WKD-sdAb-CTB的菌株分别接种在含卡那霉素的LB培养板上,37℃培养过夜。挑选单个菌落接种于10ml的含卡那霉素的LB培养液中,37℃摇床培养过夜。转种10ml于1L含氨卡那霉素的LB培养液中,37℃摇床培养,220转/分,培养到OD值达0.6~1.0时,加入0.1~0.5MIPTG,继续培养过夜。离心,收菌。加溶菌酶裂解细菌,离心,收上清中表达蛋白。蛋白经Ni+离子亲和层析柱纯化,纯化蛋白SDS-PAGE结果如图4所示,纯化蛋白纯度可达90-95%以上,A:WKD-COVID19-M1有561 个氨基酸残基,分子量约60.95KD。B:WKD-sdAb-CTB对照载体有245个氨基酸残基,分子量约26.48KD。
克隆到酵母表达载体,进行表达和纯化:将上述A:WKD-COVID19基因M1、 B:WKD-sdAb-CTB基因,扩增带有EcoRI/XbaI,克隆于PPiCZα酵母载体,进行表达纯化。
实施例2纯化蛋白WKD-COVID19-M1五聚体验证
用凝胶排阻试验,验证上述表达纯化的A:WKD-COVID19-M1蛋白和蛋白B:WKD-sdAb-CTB在液体状态下,是否能形成五聚体:用GE公司的Superdex 200TM柱层析,用不同分子量的蛋白Marker进行对照,结果见图5、图6。
A:WKD-COVID19-M1蛋白的五聚体分子量理论值为300KD,如图5所示,WKD-COVID19-M1蛋白在相应分子量Marker的位置出现排阻峰,因其分子量大,穿过凝胶筛孔的速度快,在9.20分钟出现峰值。B:WKD-sdAb-CTB 蛋白的五聚体分子量理论值为130KD,如图6所示,WKD-sdAb-CTB蛋白在相应分子量Marker的位置出现排阻峰,其分子量小,穿过凝胶筛孔的速度较A蛋白快,在13.10分钟出现峰值。同时也说明了CT-B分子在液体里可以自动组装成五聚体,从而使得A:WKD-COVID19-M1蛋白具有较强的刺激机体粘膜产生粘膜免疫反应。
实施例3SARS-CoV2粘膜免疫疫苗在小鼠体内及抗体鉴定
S1,6-8周的雌性Balb/c小鼠,分组为A,B,C,3组,A组:WKD-COVID19-M1; B组:WKD-sdAb-CT-B;C组:PBS对照组。
每组20只小鼠,10/组小鼠进行鼻内免疫,分别于1,14,24天10ug/50微升/只,不同的疫苗成分免疫。10/组小鼠进行腹部皮下免疫,10ug/100ul/只。
S2,样品收集:在第35天,2种免疫方案的小鼠,5只/组,安乐死前,收集大便、阴道洗液、鼻腔洗液和血清。
S3,进行ELISA测定特异性IgA和IgG抗体:分别用新冠病毒抗原-Spike1 和受体结合域抗原包被96孔酶免板(Thermo公司),2ug/ml,100ul/孔,4℃,过夜,用4%脱脂牛奶PBST,在37℃,封闭1.5小时;分别加入1:2稀释的大便和鼻腔洗液样品,加入1:20稀释的阴道洗液样品,加入1:1000稀释的血清样品,在37℃,1小时,用PBST洗板3次;分别加入1:3000稀释的羊抗鼠IgA-HRP 和羊抗鼠IgG-HRP,在37℃,1小时,用PBST洗板3次;加入TMB100ul/孔,室温20分钟,加入终止缓冲液50ul/孔,测定OD450值。
结果见图7,疫苗免疫A组动物的大便、阴道洗液、鼻腔洗液和血清样品的针对SpikeS1和RBD特异性IgA与对照组B,C相比较,升高3-10倍,其特异性血清IgG升高10倍,表示该疫苗免疫能诱导动物机体针对新冠病毒SpikeS1 和RBD蛋白的特异性粘膜免疫抗体反应和体液抗体反应,可用于预防或治疗新型冠状病毒COVID-19感染。
以上所述仅为本发明的较佳实施方式而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 武汉科技大学
<120> 一种SARS-CoV2粘膜免疫疫苗及其应用
<130> 2020
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gtcctatata attccgcatc attttccact tttaagtgtt atggagtgtc tcctactaaa 960
ttaaatgatc tctgctttac taatgtctat gcagattcat ttgtaattag aggtgatgaa 1020
gtcagacaaa tcgctccagg gcaaactgga aagattgctg attataatta taaattacca 1080
gatgatttta caggctgcgt tatagcttgg aattctaaca atcttgattc taaggttggt 1140
ggtaattata attacctgta tagattgttt aggaagtcta atctcaaacc ttttgagaga 1200
gatatttcaa ctgaaatcta tcaggccggt agcacacctt gtaatggtgt tgaaggtttt 1260
aattgttact ttcctttaca atcatatggt ttccaaccca ctaatggtgt tggttaccaa 1320
ccatacagag tagtagtact ttcttttgaa cttctacatg caccagcaac tgtttgtgga 1380
cctaaaaagt ctactaattt ggttaaaaac aaatgtgtca atttcaactt caatggttta 1440
acaggcacag gtgttcttac tgagtctaac aaaaagtttc tgcctttcca acaatttggc 1500
agagacattg ctgacactac tgatgctgtc cgtgatccac agacacttga gattcttgac 1560
attacaccat gcgctagtta tcagactcag actaattctc ctcggcgggc acgtagtgta 1620
gctagtcaat ccatcattgc ctacactatg tcacttggtg cagaacacca ccaccaccac 1680
cactga 1686
<210> 5
<211> 903
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
caaccaacag aatctattgt tagatttcct aatattacaa acttgtgccc ttttggtgaa 60
gtttttaacg ccaccagatt tgcatctgtt tatgcttgga acaggaagag aatcagcaac 120
tgtgttgctg attattctgt cctatataat tccgcatcat tttccacttt taagtgttat 180
ggagtgtctc ctactaaatt aaatgatctc tgctttacta atgtctatgc agattcattt 240
gtaattagag gtgatgaagt cagacaaatc gctccagggc aaactggaaa gattgctgat 300
tataattata aattaccaga tgattttaca ggctgcgtta tagcttggaa ttctaacaat 360
cttgattcta aggttggtgg taattataat tacctgtata gattgtttag gaagtctaat 420
ctcaaacctt ttgagagaga tatttcaact gaaatctatc aggccggtag cacaccttgt 480
aatggtgttg aaggttttaa ttgttacttt cctttacaat catatggttt ccaacccact 540
aatggtgttg gttaccaacc atacagagta gtagtacttt cttttgaact tctacatgca 600
ccagcaactg tttgtggacc taaaaagtct actaatttgg ttaaaaacaa atgtgtcaat 660
ttcaacttca atggtttaac aggcacaggt gttcttactg agtctaacaa aaagtttctg 720
cctttccaac aatttggcag agacattgct gacactactg atgctgtccg tgatccacag 780
acacttgaga ttcttgacat tacaccatgc gctagttatc agactcagac taattctcct 840
cggcgggcac gtagtgtagc tagtcaatcc atcattgcct acactatgtc acttggtgca 900
gaa 903
<210> 6
<211> 738
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atggaggtgc agctggtgga gtctggggga ggattggtgc agcctggggg ctctctgaga 60
ctctcctgtg cagcgtctgg tggcaccttc agtagttatg gcatggcctg gttccggcag 120
gctccaggga aggggcttga gtttgtagca gctattacgt ggagtggttc tgctacagac 180
tatacagact ccgtgaaggg ccgattcacc atctccagag acgtcgccaa gaacacgctg 240
tatctgcaaa tgaacagtct gagggctgag gacacggccg tttattattg tgcagcaggt 300
ggtggttata gaactatcgc gaaatcggag agattgtata ccctgtgggg ccaggggacc 360
caggtcaccg tctcctcagg tggaggcggg tccggtggag gcgggtccac acctcaaaat 420
attactgatt tgtgtgcaga ataccacaac acacaaatat atacgctaaa tgataagata 480
ttttcgtata cagaatctct agctggaaaa agagagatgg ctatcattac ttttaagaat 540
ggtgcaattt ttcaagtaga agtaccaggt agtcaacata tagattcaca aaaaaaagcg 600
attgaaagga tgaaggatac cctgaggatt gcatatctta ctgaagctaa agtcgaaaag 660
ttatgtgtat ggaataataa aacgcctcat gcgattgccg caattagtat ggcaaaccag 720
caccaccacc accactga 738
Claims (9)
1.一种SARS-CoV2粘膜免疫疫苗,其特征在于疫苗基因包括SARS-CoV2的Spike蛋白的RBD基因、水解Spike蛋白S1/S2位点基因、CT-B亚单位基因,能结合人IgA-Fc的sdAb基因和Spike蛋白的Furin蛋白酶切位点hd;
所述疫苗基因构建成RBD-S1/S2-hd-CT-B-sdAb,在大肠杆菌或酵母表达载体里表达后的蛋白形成五聚体的纳米颗粒。
2.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述疫苗基因顺序为sdAb-linker1-CT-B-linker2-RBD-S1/S2-6His。
3.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述SARS-CoV2的Spike蛋白RBD片段来自SARS-CoV2病毒的不同突变株。
4.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述SARS-CoV2的Spike蛋白RBD基因包含SARS-CoV2的Spike蛋白RBD全长基因或部分基因。
5.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述水解Spike蛋白S1/S2位点基因包含水解Spike蛋白S1/S2位点全长基因或部分基因。
6.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述疫苗的氨基酸序列如SEQ NO:1所示,基因序列如SEQ NO:4所示。
7.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述RBD-S1/S2的氨基酸序列如SEQ NO:2所示,基因序列如SEQ NO:5所示。
8.如权利要求1所述的一种SARS-CoV2粘膜免疫疫苗,其特征在于,所述CT-B-sdAb的氨基酸如SEQ NO:3所示,基因序列如SEQ NO:6所示。
9.权利要求1-8任一所述一种SARS-CoV2粘膜免疫疫苗在制备治疗和/或预防SARS-CoV2的药物中的应用。
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