CN116514930A - 中国人群中新型冠状病毒的t细胞优势表位的鉴定和应用 - Google Patents
中国人群中新型冠状病毒的t细胞优势表位的鉴定和应用 Download PDFInfo
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Abstract
本发明公开了本发明涉及中国人群中新型冠状病毒的T细胞优势表位的鉴定和应用,属于免疫检测和疫苗研发领域。本发明首先鉴定了中国人群来源的PBMC细胞的HLA分型,主要为HLA‑A2/A11/A24/A3/A1,HLA‑B27/B62/B46/B60/B44/B61/B35等,将271条多肽序列一一进行ELISpot验证,筛选得到85条覆盖中国人群主要HLA分型的新冠病毒阳性表位,其中位于S蛋白53条,位于M蛋白的13条,位于N蛋白的19条。本发明鉴定得到15条CD8+T阳性表位,这些序列为今后新型冠状病毒疫苗研发、新型治疗药物研发和诊断检测试剂盒的的开发提供了基础。
Description
技术领域
本发明涉及中国人群中新型冠状病毒的T细胞优势表位的鉴定和应用,属于免疫检测和疫苗研发领域。
背景技术
新型冠状病毒的持续传播及突变病毒的不断出现,对全球人民的健康及生活产生重大影响。当前的新冠疫苗主要推广接种的有灭活疫苗、多肽蛋白疫苗及mRNA疫苗等。新冠突变株不仅改变其致病性、传播力,同时也影响到其免疫原性,对目前应用的检测试剂和疫苗的效果造成重要影响。因而探索更有效的能够应对变异株的检测试剂和疫苗迫在眉睫。在抗病毒免疫反应中,细胞免疫和体液免疫同样发挥重要的作用,而在细胞免疫中,表位多肽激发的细胞免疫反应受到人群白细胞抗原(HLA)限制性的影响,基于这一现象,可筛选适用于中国人群的免疫优势的T细胞表位,以用于T细胞免疫检测技术和相关疫苗的研发。
T细胞优势表位的筛选基于酶联免疫斑点检测(Enzyme-linked ImmunospotAssay,ELISpot),该技术结合了细胞培养技术与酶联免疫吸附技术,能够检测到单个细胞分泌的细胞因子情况。其原理是:用PVDF膜为底的96孔板包被上特异性的单克隆抗体以捕获细胞分泌的细胞因子,在培养板的孔内加入待检测的抗原刺激物和细胞进行培养。在刺激物的刺激下,T细胞就会在对应的时间段分泌对应的细胞因子,此时细胞因子就被包被在膜上的抗体所捕获。洗去细胞后,被捕获的细胞因子可以与生物素标记的第二抗体结合,然后用酶标亲和素与生物素结合,进行化学酶联显色,就可以在膜的局部形成一个个圆形的斑点,每一个斑点就对应了当初一个分泌细胞因子的细胞。
T细胞识别多肽受到个体HLA分型的限制,不同地区的人群具有不同的HLA分型特点,在中国人群中,占主要比例的HLA-A分型包括HLA-A2/A11/A24/A3/A1,HLA-B分型包括B27/B62/B46/B60/B44/B61/B35等。当前,国内外在新冠病毒T细胞表位鉴定中,多数采用软件直接预测特定HLA分型的8-10个氨基端的短肽,利用特定HLA分型的COVID-19康复者来鉴定是否是阳性表位。这种方法鉴定的表位局限于个别HLA分型,不够全面,且缺乏适用于中国人群的较为优势表位系统而全面的筛选。
发明内容
为了解决现有技术方法鉴定的表位局限于个别HLA分型,不够全面的问题,本发明鉴定了覆盖新冠病毒结构蛋白S/M/N的所有阳性长肽,筛选所用的样本HLA分型覆盖中国人群占比较高的HLA分型。并且依据该发明中的鉴定方法,筛选出新冠病毒阳性表位85条,其中位于S蛋白53条,位于M蛋白的13条,位于N蛋白的19条。其中鉴定出优势T细胞表位35条,包括位于S蛋白的优势表位17条,位于M蛋白的优势表位7条,位于N蛋白的优势表位11条。本发明鉴定出的优势表位可用于T细胞免疫检测技术和疫苗的研发。
本发明提供了氨基酸序列如SEQ ID NO.1~SEQ ID NO.85所示的长肽中的任意一条或多条组成的肽库在制备中国人群HLA特异新型冠状病毒疫苗中的应用。
在一种实施方式中,所述肽库覆盖9个HLA-A等位基因和17个HLA-B等位基因。
在一种实施方式中,所述肽库覆盖HLA-A2、HLA-A11、HLA-A24、HLA-A3、HLA-A1、HLA-A31、HLA-A33、HLA-A30、HLA-A2,HLA-B27、HLA-B62、HLA-B46、HLA-B60、HLA-B44、HLA-B61、HLA-B35、HLA-B51、HLA-B67、HLA-B75、HLA-B55、HLA-B58、HLA-B13、HLA-B54、HLA-B5102、HLA-B52、HLA-B39。
在一种实施方式中,所述疫苗包括表位疫苗。
在一种实施方式中,所述疫苗还包括载体,所述载体包括脂质、热激活蛋白、卵清蛋白、牛血清蛋白、钥孔血蓝蛋白。
在一种实施方式中,所述疫苗还包括佐剂,所述佐剂包括弗氏佐剂和氢氧化铝佐剂。
本发明还提供了氨基酸序列如SEQ ID NO.1~SEQ ID NO.85所示的长肽组成的肽库在制备中国人群HLA特异新型冠状病毒T细胞免疫检测试剂盒中的应用。
在一种实施方式中,所述肽库覆盖9个HLA-A等位基因和17个HLA-B等位基因。
在一种实施方式中,所述肽库覆盖HLA-A2、HLA-A11、HLA-A24、HLA-A3、HLA-A1、HLA-A31、HLA-A33、HLA-A30、HLA-A2,HLA-B27、HLA-B62、HLA-B46、HLA-B60、HLA-B44、HLA-B61、HLA-B35、HLA-B51、HLA-B67、HLA-B75、HLA-B55、HLA-B58、HLA-B13、HLA-B54、HLA-B5102、HLA-B52、HLA-B39。
在一种实施方式中,所述试剂盒中还含有IFN-γ单克隆抗体。
在一种实施方式中,所述试剂盒中还设置有ELISpot反应板,ELISpot上预包被捕获T细胞分泌的IFN-γ的单克隆抗体。
在一种实施方式中,所述ELISpot板上预包被有捕获IFN-γ的单克隆抗体。
本发明还提供了氨基酸序列如SEQ ID NO.1~SEQ ID NO.85所示的长肽组成的肽库在制备细胞疗法或过继疗法试剂盒中的应用。
本发明还提供了新型冠状病毒CD8+T细胞表位肽,其氨基酸序列如SEQ ID NO.86~SEQ ID NO.91,SEQ ID NO.94~SEQ ID NO.100所示。
本发明还提供了编码上述新型冠状病毒CD8+T细胞表位肽的核酸。
本发明还提供了携带上述核酸的重组载体。
在一种实施方式中,所述重组载体包括腺病毒载体、慢病毒载体或原核表达载体。
本发明还提供了携带上述核酸或上述重组载体的宿主细胞。
在一种实施方式中,所述宿主细胞包括哺乳动物细胞或原核细胞。
本发明还提供了氨基酸序列如SEQ ID NO.86~SEQ ID NO.100所示的新型冠状病毒CD8+T细胞表位肽或上述核酸或上述重组载体或上述宿主细胞在制备新型冠状病毒疫苗中的应用或抗体或检测试剂盒。
在一种实施方式中,氨基酸序列如SEQ ID NO.86~SEQ ID NO.100所示的新型冠状病毒CD8+T细胞表位肽能够与MHC-I类分子结合,其中,当多肽与MHC-I类分子结合时能被CD8+T细胞识别。
有益效果:
本发明技术方案通过PeptGen软件设计了271条由10个氨基酸重叠而成的15-18个氨基酸的SARS-CoV-2肽段,这些肽段覆盖了整个S、M和N蛋白,根据SARS-CoV-2S蛋白S1区和S2区的裂解位点,将S蛋白的多肽分为S1和S2,分别包含92和93条肽,M和N蛋白肽库分别包含29和57条肽,肽段作为抗原刺激物用于复苏后的新冠康复者PBMC的刺激培养;期间加入白介素2(IL-2)和白介素7(IL-7)等生物因子,培养9天后进行ELISpot检测,为了量化抗原特异性反应,从实验孔中减去阴性对照孔中的斑点数量,结果以每105个PBMCs表达斑点形成细胞(SFC)来计数。评价标准如下:阴性对照SFC<5个/105个,阳性反应定义为SFC>10个/105个;否则,阳性反应被定义为结果至少是阴性对照组的两倍。
本发明首先鉴定了中国人群来源的PBMC细胞的HLA分型,主要为HLA-A2/A11/A24/A3/A1,HLA-B27/B62/B46/B60/B44/B61/B35等,将271条多肽序列一一进行ELISpot验证,筛选得到85条覆盖中国人群主要HLA分型的新冠病毒阳性表位,其中位于S蛋白53条,位于M蛋白的13条,位于N蛋白的19条。并鉴定出优势T细胞表位35条,包括位于S蛋白的优势表位17条,位于M蛋白的优势表位7条,位于N蛋白的优势表位11条。
本发明鉴定得到15条CD8+T阳性表位,这些序列为今后新型冠状病毒疫苗研发、新型治疗药物研发和诊断检测试剂盒的的开发提供了基础。
附图说明
图1新冠病毒S蛋白阳性表位。
图2新冠病毒M蛋白和N蛋白阳性表位。
具体实施方式
以下结合具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市售商品或者可以通过已知方法制备。
鉴定PBMC的HLA分型:
1、样品处理
血样体积是200μL时,向离心管中加入血样后直接进行下一步操作;
血样体积少于200μL时,加入Buffer GR补足至200μL,进行下一步;
血样体积大于200μL时,加入1-2.5倍体积的Buffer RCL,轻轻颠倒混匀,12000rpm离心1min,弃掉上清,如果沉淀中还有红色,可重复上述步骤一次。然后向沉淀中加入200μLBuffer GR,震荡混匀然后进行下一步操作。
2、向上述溶液中加入20μL蛋白酶K,混匀。
3、加入200μL Buffer GL,震荡混匀。
4、56℃水浴10min,期间颠倒混匀数次。
5、加入200μL无水乙醇,颠倒混匀,瞬离,使管壁液体集中到管底。
6、将步骤5中的液体全部转移至已装入收集管的吸附柱中,液体较多可分多次加入。12000rpm离心1min,弃掉收集管中废液,吸附柱重新放回。
7、向吸附柱中加入500μLBuffer GW1(使用前确认已加入相应体积的无水乙醇),12000rpm离心1min,弃掉收集管中废液,吸附柱重新放回。
8、向吸附柱中加入500μLBuffer GW2(使用前确认已加入相应体积的无水乙醇),12000rpm离心1min,弃掉收集管中废液,吸附柱重新放回。
9、12000rpm离心2min,弃掉收集管中废液,吸附柱置于室温数分钟,彻底晾干。
10、将吸附柱放置于一个新的离心管中,悬空滴入50μL灭菌水,室温放置5min,12000rpm离心1min,收集DNA溶液。
将提取的研究对象的血液DNA送至北京曼泰里生物技术有限公司,公司采用美国ONE LAMBDA公司的流式SSO分型技术测定HLA分型。每个样本均进行了HLA-A和HLA-B两个基因位点的测序。
实施例1多肽的制备
通过PeptGen软件设计了271条由10个氨基酸重叠而成的15-18聚体SARS-CoV-2肽段,这些肽段覆盖了整个S、M和N蛋白,根据SARS-CoV-2S蛋白S1和S2的裂解位点,将S蛋白的多肽分为S1和S2,分别包含92和93条肽,M和N蛋白肽库包含29和57条肽。将肽段混合成为肽库,分别为S1、S2、M和N四个肽库,并作为抗原刺激物用于复苏后的PBMC的刺激培养。
实施例2阳性多肽的免疫原性强弱谱的鉴定
(1)外周血PBMCs分离
(a)主要试剂耗材
10mL抗凝管与促凝管(BD)、10mL移液管、淋巴细胞分离管(Cat#DKW-LST-24015SK)、1640培养基、DMSO、15mL离心管、50mL离心管、细胞冻存盒、细胞冻存管(Thermo)、国产细胞冻存管(江苏海门,黄盖/蓝盖)、液氮冻存盒、电动移液器、异丙醇、胎牛血清(FBS)、巴斯德吸管,具有升降加速度配有15mL离心管吊桶的水平离心机。
(b)样本处理
采用达科为人外周血淋巴细胞分离管Cat#DKW-LST-24015SK。
(c)步骤
1)预处理:取出淋巴细胞分离管,用离心机800g,20℃,离心1min。将存储有抗凝血的试管400g离心5min,吸取上层血浆2mL,分2管(蓝盖国产细胞冻存管)冻存,或经过长时间放置后直接吸取。
2)样本离心:向含有抗凝血的试管中补加1640培养基至10mL,颠倒混匀后,缓缓倒入淋巴细胞分离管中,800g,离心25min,20℃。
3)吸取PBMCs:离心后管底是红细胞,中间层是分离液,最上层是血浆,血浆和分离液中间是致密的白膜,含单个核细胞(包括淋巴细胞和单核粒细胞)。在生物安全柜中,用巴斯德吸管吸取中间的白色细胞层,转移至新的15mL离心管内,补加1640培养液至12mL。400g离心10min。
4)PBMCs清洗:离心完毕,在生物安全柜中,倒掉上清,晃动离心管,利用残余的约200微升的液体重悬细胞。补加1640培养基10mL,400g,10min清洗细胞。
5)细胞冻存:最后尽量吸弃上清,按照上述操作重悬细胞,先加入1mL的FBS,然后再补加1mL 20%DMSO的血清冻存液,分装两管,放入冻存盒内,置-80度冻存过夜。促凝血3000rpm离心10min,血清分装3管(黄盖国产冻存管),-80℃冻存。
(2)肽库刺激和PBMCs培养
(a)主要试剂耗材
15mL离心管、1.5mL离心管、1mL移液枪、10μL移液枪、细胞计数板、细胞计数器、24孔细胞培养板、1640培养基、白介素-2、白介素-7、胎牛血清(FBS)、青链霉素、台盼蓝染液、水浴箱、配有15mL离心管吊桶的水平离心机、细胞培养箱。
生长培养基:1640培养基,含10%FBS和1%青链霉素。
(b)步骤
1、PBMCs复苏:复苏细胞混匀在10mL 1640培养基里,1500r离心10min,弃掉液体加x mL的生长培养基重悬。
2、细胞计数:离心管内加10μL台盼蓝,10μL混匀后的细胞,读两个九宫格的细胞数y。
细胞浓度为z=(y个÷2格*2倍*104)/mL
细胞数为w=z*x=(y个÷2格*2倍*104)/mL*x mL
根据具体细胞浓度要求计算所需毫升数并定容(24孔板:2mL/孔,细胞3×106/孔)。
3、PBMCs刺激:将24孔板放入培养箱静置沉淀3-5h后,先吸去1mL上清,再加入实施例1中的肽库(肽库:条数×0.2μL+100μL培养基/孔),刺激45min,随后加入900μL含有白介素7(IL-7,20μg/mL)的生长培养基。
4、细胞培养:细胞每天观察,培养9天。每隔两天进行半量换液(吸出上清1mL弃掉,贴壁转圈慢慢补加新鲜培养基)。换液配比为:1mL/孔的1640培养基(含10%FBS),含终浓度为200U/mL白介素2(IL-2),1%青链霉素。
(3)ELISpot检测
(a)主要试剂耗材
PVDF膜为底的96孔板、1.5mL离心管、1mL移液枪、10μL移液枪、细胞计数板、细胞计数器、分液槽、包被抗体(purified anti-IFN-γ)、1×PBS、1640培养基、胎牛血清(FBS)、DMSO、PMA、去离子水、吐温20、检测抗体(Biotinylated anti-IFN-γ)、亲和素-HRP结合物(streptavidin-HRP)、AEC底物溶液(AEC substrate)、AEC染料(AEC chromogen)、细胞培养箱、冰箱、ELISpot读板仪ELISpot Reader System(CTL-Immunospot S5 Versa)等。
(b)步骤
1.包被抗体:准备包被抗体(purified anti-IFN-γ)与1×PBS混合,比例1:200,加入PVDF膜为底的96孔板(100μL/孔)。
2.孵育:盖盖平放,4℃过夜。
3.封闭:轻倒出溶液,1640培养基洗2次(180μL/孔)后,加入每孔180μL生长培养基(1640培养基+10%胎牛血清+1%青链霉素)封闭。
4.孵育:室温孵育2h。
5.多肽和细胞:
5.1多肽:化学合成实施例1中设计的271条肽段,将125μLDMSO加入2.5mg的合成多肽中溶解(20μg/μL);单条肽刺激:每孔添加的单条多肽的终浓度10μg/mL,每孔2μg;
5.2细胞:轻吸出1mL上清,使用剩余液体吹起细胞混匀并加入10mL生长培养基,1500r离心10min,弃上清并重悬,加入生长培养基计数,每孔1×105个细胞。
6.加入多肽并接种:轻倒出封闭液,实验组设2个复孔,并设无刺激物的阴性对照组(mock)及PMA阳性对照组(PMA)(a、实验组:单肽+细胞;b、阴性对照组(mock):生长培养基+细胞;c、阳性对照组:细胞+PMA)。
依次加入多肽(0.1μL+100μL生长培养基/孔)、mock(100μL培养基/孔)、细胞(1×105/孔)、PMA(10μLPMA+90μL培养基/孔,粉末PMA每瓶用500μLPBS溶解)。
7.孵育:37℃,5%CO2,平放孵育18h。
8.洗板:去除细胞,常温去离子水洗3次,每次5分钟,PBST洗3次,每次2分钟,每次清洗后用力甩掉清洗液后在吸水纸上用力扣干。
9.孵抗体:检测抗体(Biotinylated anti-IFN-γ)1:250稀释到含10%FBS的PBS中充分混匀。每孔100μL,室温孵育2h。去除原液体,常温去离子水洗3次,每次5分钟,PBST清洗3次,每次间隔2分钟,吸水纸上用力扣干。亲和素-HRP结合物(streptavidin-HRP)1:100稀释到含10%FBS的PBS中充分混匀。每孔100μL,室温孵育1h。去除原液体,PBST清洗3次,PBS清洗2次,每次间隔2min,吸水纸上用力扣干。
10.显色:体系:100μL/孔AEC底物溶液(AEC substrate)+1滴/mLAEC染料(AECchromogen)避光混匀,每孔加100μL。
11.洗板:避光孵育7.5min后看到清晰的斑点,用水冲洗膜的双面以中止反应,室温下晾干(开盖并解开底膜反扣过夜)、使用ELISpot Reader System(CTL-Immunospot S5Versa)计数斑点。
为了量化抗原特异性反应,从实验组中减去阴性对照组中的斑点数量,结果以每105个PBMCs表达斑点形成细胞(SFC)来计数。评价标准如下:阴性对照SFC<5个/105个,阳性反应定义为SFC>10个/105个;否则,阳性反应被定义为结果至少是阴性对照组的两倍。
结果如图1和图2所示,最终筛选出新冠病毒阳性表位85条,其中位于S蛋白53条,位于M蛋白的13条,位于N蛋白的19条,覆盖了HLA-A2/A11/A24/A3/A1/A31/A33/A30/A2,HLA-B27/B62/B46/B60/B44/B61/B35/B51/B67/B75/B55/B58/B13/B54/B5102/B52/B39。综合针对ELISpot检测结果中IFN-γ的分泌强弱以及针对不同表位的存在阳性反应的人数,鉴定出优势T细胞表位35条,包括位于S蛋白的优势表位17条,位于M蛋白的优势表位7条,位于N蛋白的优势表位11条。
表1新冠病毒阳性表位
*标记为免疫优势表位
实施例3预测CD8+T阳性表位
对于筛选出的85条阳性多肽,根据阳性康复个体的HLA分型,进行CD8+T表位的预测。在预测中,通常将%Rank和Affinity作为NetMHC网站预测结果判定的指标,当Affinity<50和%Rank<0.5定义为高亲和力,Affinity<500和%Rank<2定义为弱亲和力。
本次鉴定选用的标准:Affinity<500和%Rank<2,最终鉴定出15条阳性CD8+T阳性表位,如表2所示。
表2 CD8+T阳性表位
实施例4多肽在细胞免疫检测中的应用
将实施例2中提供的新冠病毒阳性表位多肽序列对应的合成多肽、核酸表达多肽或其它形式的能够产生免疫原的相关组分,应用于新冠病人、康复者、动物实验等的新冠细胞免疫水平检测。
实施例5多肽在制备疫苗中的应用
将实施例2中提供的新冠病毒阳性表位多肽对应的序列,以合成多肽,或核酸序列合成RNA或DNA片段在体内或体外多肽的表达,用于提供新冠的免疫原,将多肽与一定的疫苗载体(脂质、热激活蛋白、卵清蛋白、牛血清蛋白或钥孔血蓝蛋白)连接获得疫苗。
实施例6多肽在细胞疗法中的应用
根据实施例2中的方法,分离单个患者的PBMCs,将细胞与实施例2中提供的多肽在培养基中进行体外刺激,诱导完成后检测T细胞针对新冠病毒的杀伤能力,通过分选获得特异性T细胞,用于患者的新冠治疗。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
SEQUENCE LISTING
<110> 中国疾病预防控制中心病毒病预防控制所
<120> 中国人群中新型冠状病毒的T细胞优势表位的鉴定和应用
<130> BAA220012A
<160> 100
<170> PatentIn version 3.3
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<211> 16
<212> PRT
<213> 人工序列
<400> 74
Gly Ala Asn Lys Asp Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu
1 5 10 15
<210> 75
<211> 17
<212> PRT
<213> 人工序列
<400> 75
Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp His
1 5 10 15
Ile
<210> 76
<211> 18
<212> PRT
<213> 人工序列
<400> 76
Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly
1 5 10 15
Ser Gln
<210> 77
<211> 18
<212> PRT
<213> 人工序列
<400> 77
Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala Arg
1 5 10 15
Met Ala
<210> 78
<211> 18
<212> PRT
<213> 人工序列
<400> 78
Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu Asp
1 5 10 15
Arg Leu
<210> 79
<211> 18
<212> PRT
<213> 人工序列
<400> 79
Glu Ala Ser Lys Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr
1 5 10 15
Asn Val
<210> 80
<211> 17
<212> PRT
<213> 人工序列
<400> 80
Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln Ala Phe Gly Arg
1 5 10 15
Arg
<210> 81
<211> 18
<212> PRT
<213> 人工序列
<400> 81
Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile
1 5 10 15
Gly Met
<210> 82
<211> 18
<212> PRT
<213> 人工序列
<400> 82
Ala Phe Phe Gly Met Ser Arg Ile Gly Met Glu Val Thr Pro Ser Gly
1 5 10 15
Thr Trp
<210> 83
<211> 18
<212> PRT
<213> 人工序列
<400> 83
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Gly Ala
1 5 10 15
Ile Lys
<210> 84
<211> 18
<212> PRT
<213> 人工序列
<400> 84
Thr Trp Leu Thr Tyr Thr Gly Ala Ile Lys Leu Asp Asp Lys Asp Pro
1 5 10 15
Asn Phe
<210> 85
<211> 18
<212> PRT
<213> 人工序列
<400> 85
Pro Asn Phe Lys Asp Gln Val Ile Leu Leu Asn Lys His Ile Asp Ala
1 5 10 15
Tyr Lys
<210> 86
<211> 10
<212> PRT
<213> 人工序列
<400> 86
Thr Lys Ala Tyr Asn Val Thr Gln Ala Phe
1 5 10
<210> 87
<211> 9
<212> PRT
<213> 人工序列
<400> 87
Lys Ala Tyr Asn Val Thr Gln Ala Phe
1 5
<210> 88
<211> 8
<212> PRT
<213> 人工序列
<400> 88
Ala Tyr Asn Val Thr Gln Ala Phe
1 5
<210> 89
<211> 9
<212> PRT
<213> 人工序列
<400> 89
Leu Ala Leu Leu Leu Leu Asp Arg Leu
1 5
<210> 90
<211> 9
<212> PRT
<213> 人工序列
<400> 90
Gly Met Ser Arg Ile Gly Met Glu Val
1 5
<210> 91
<211> 10
<212> PRT
<213> 人工序列
<400> 91
Met Glu Val Thr Pro Ser Gly Thr Trp Leu
1 5 10
<210> 92
<211> 9
<212> PRT
<213> 人工序列
<400> 92
Lys Thr Phe Pro Pro Thr Glu Pro Lys
1 5
<210> 93
<211> 10
<212> PRT
<213> 人工序列
<400> 93
Ala Thr Ser Arg Thr Leu Ser Tyr Tyr Lys
1 5 10
<210> 94
<211> 9
<212> PRT
<213> 人工序列
<400> 94
Ala Thr Ser Arg Thr Leu Ser Tyr Tyr
1 5
<210> 95
<211> 9
<212> PRT
<213> 人工序列
<400> 95
Phe Arg Lys Ser Asn Leu Lys Pro Phe
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列
<400> 96
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
1 5
<210> 97
<211> 9
<212> PRT
<213> 人工序列
<400> 97
Val Ala Ser Gln Ser Ile Ile Ala Tyr
1 5
<210> 98
<211> 9
<212> PRT
<213> 人工序列
<400> 98
Leu Val Lys Gln Leu Ser Ser Asn Phe
1 5
<210> 99
<211> 9
<212> PRT
<213> 人工序列
<400> 99
Leu Leu Gln Tyr Gly Ser Phe Cys Thr
1 5
<210> 100
<211> 9
<212> PRT
<213> 人工序列
<400> 100
Val Val Phe Leu His Val Thr Tyr Val
1 5
Claims (10)
1.氨基酸序列如SEQ ID NO.1~SEQ ID NO.85所示的长肽中的任意一条或多条组成的肽库在制备中国人群HLA特异新型冠状病毒疫苗中的应用。
所述肽库覆盖9个HLA-A等位基因和17个HLA-B等位基因。
2.根据权利要求1所述的应用,其特征在于,所述肽库覆盖HLA-A2、HLA-A11、HLA-A24、HLA-A3、HLA-A1、HLA-A31、HLA-A33、HLA-A30、HLA-A2,HLA-B27、HLA-B62、HLA-B46、HLA-B60、HLA-B44、HLA-B61、HLA-B35、HLA-B51、HLA-B67、HLA-B75、HLA-B55、HLA-B58、HLA-B13、HLA-B54、HLA-B5102、HLA-B52和HLA-B39。
3.根据权利要求1所述的应用,其特征在于,所述疫苗包括表位疫苗。
4.根据权利要求1或3所述的应用,其特征在于,所述疫苗还包括载体,所述载体包括脂质、热激活蛋白、卵清蛋白、牛血清蛋白、钥孔血蓝蛋白。
5.氨基酸序列如SEQ ID NO.1~SEQ ID NO.85所示的长肽组成的肽库在制备中国人群HLA特异新型冠状病毒T细胞免疫检测试剂盒中的应用。
6.氨基酸序列如SEQ ID NO.1~SEQ ID NO.85所示的长肽组成的肽库在制备细胞疗法或过继疗法试剂盒中的应用。
7.新型冠状病毒CD8+T细胞表位肽,其特征在于,其氨基酸序列如SEQ ID NO.86~SEQID NO.91,SEQ ID NO.94~SEQ ID NO.100所示。
8.编码权利要求7所述新型冠状病毒CD8+T细胞表位肽的核酸。
9.携带权利要求8所述核酸的重组载体。
10.氨基酸序列如SEQ ID NO.86~SEQ ID NO.100所示的新型冠状病毒CD8+T细胞表位肽或权利要求8所述的核酸或权利要求9所述的重组载体在制备新型冠状病毒疫苗或抗体或检测试剂盒中的应用。
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