CN113325172A - 新型冠状病毒检测试剂盒 - Google Patents
新型冠状病毒检测试剂盒 Download PDFInfo
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- CN113325172A CN113325172A CN202010126712.3A CN202010126712A CN113325172A CN 113325172 A CN113325172 A CN 113325172A CN 202010126712 A CN202010126712 A CN 202010126712A CN 113325172 A CN113325172 A CN 113325172A
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Abstract
本发明涉及一种新型冠状病毒检测试剂盒，包括抗原组分和发光组分；抗原组分中含有新型冠状病毒蛋白‑磁珠复合物，新型冠状病毒蛋白‑磁珠复合物包括S1蛋白‑磁珠复合物、S2蛋白‑磁珠复合物、E蛋白‑磁珠复合物、M蛋白‑磁珠复合物和N蛋白‑磁珠复合物；发光组分中含有抗人IgG抗体，且抗人IgG抗体上标记有发光标记物。本发明的新型冠状病毒检测试剂盒基于直接化学发光的两步间接免疫法原理，利用相应的化学发光测定仪，能够快速判断出待测样品中新型冠状病毒IgG抗体的浓度，且通过将所有可能产生抗体的新型冠状病毒抗原包被至磁珠表面，最大程度上避免了个别患者由于体内产生抗体不同而造成的漏检。
Description
技术领域
本发明涉及病毒检测技术领域，特别是涉及一种新型冠状病毒检测试剂盒。
背景技术
新型冠状病毒(SARS-CoV-2，亦被称为2019-nCoV、HCoV-19)属于β属 的冠状病毒，颗粒呈圆形或椭圆形直径60nm～140nm，基因特征与SARS具有明 显的区别，且相比于SARS具有更高的感染能力。基于流行病学调查，COVID-19 的潜伏期为1～14天，多为3～7天，症状以发热、干咳、乏力为主，重症患者多 在发病一周后出现呼吸困难和/或低氧血症，严重者可快速进展为急性呼吸窘迫 综合征、脓毒症休克、难以纠正的代谢性酸中毒和出现凝血功能障碍及多器官 功能衰竭等。因此，如何快速确诊疑似病例，以及如何有效监控疾病进程，将 为治疗COVID-19，打好疫情攻坚战的重点。
据《新型冠状病毒肺炎诊疗方案(试行第六版)》中规定，目前确诊COVID-19 的方法为使用实时荧光RT-PCR检测新型冠状病毒核酸阳性，或病毒基因测序与已知的新型冠状病毒高度同源。但疫情发展至今，核酸检测试剂的漏检问题一再暴露，阳性检出率只有30％～50％，主要是由于检测方式的局限性造成的。核酸检测，一般是通过收集鼻咽拭子、疑似患者的痰、血液、粪便，提取其中的 RNA片段进行荧光RT-PCR，采样过程中会混入大量人体细胞、细菌，进而造成待测RNA丰度低，检测系统无法检测，最终导致假阴性的产生。同时，除抽血外，其余采样方式均会造成采样人员暴露于可能含有病原体的环境中，有潜在的感染风险。而且核酸检测样品的制备过程，需要步骤多、操作时间长，对检测人员的技术水平要求高。
发明内容
基于此，有必要提供一种检测灵敏度高、检测速度快且漏检率低的新型冠状病毒检测试剂盒。
一种新型冠状病毒检测试剂盒，包括抗原组分和发光组分；所述抗原组分中含有新型冠状病毒蛋白-磁珠复合物，所述新型冠状病毒蛋白-磁珠复合物包括 S1蛋白-磁珠复合物、S2蛋白-磁珠复合物、E蛋白-磁珠复合物、M蛋白-磁珠复合物和N蛋白-磁珠复合物；所述发光组分中含有抗人IgG抗体，且所述抗人 IgG抗体上标记有发光标记物。
在其中一个实施例中，所述抗原组分中，S1蛋白、S2蛋白、E蛋白、M蛋白和N蛋白的摩尔比为(2～5):(1～5):(2～5):(0.1～3):(0.1～3)。
在其中一个实施例中，所述抗原组分中，所述新型冠状病毒蛋白-磁珠复合物的总浓度为0.1mg/mL～0.5mg/mL。
在其中一个实施例中，所述抗人IgG抗体为鼠抗人IgG抗体。
在其中一个实施例中，所述抗人IgG抗体的Fc段为除鼠以外物种来源的Fc 段。
在其中一个实施例中，所述除鼠以外物种选自如下任意种属：马、猪、兔、犬和羊。
在其中一个实施例中，所述抗人IgG抗体的Fc段来源为马Fc段。
在其中一个实施例中，所述发光组分中，所述抗人IgG抗体的浓度为 1μg/mL～400μg/mL。
在其中一个实施例中，还包括样品稀释组分，所述样品稀释组分中含有阻断剂和二硫苏糖醇。
在其中一个实施例中，所述样品稀释组分中还含有PBS、BSA、与所述抗人IgG抗体Fab段同物种来源的IgG、胆固醇、海藻糖、甘露醇、甘氨酸、精氨酸、谷胱甘肽、酪蛋白和表面活性剂中的一种或多种。
在其中一个实施例中，所述样品稀释组分中各物质的浓度分别为：PBS 10mM～100mM、BSA 0.1wt％～5wt％、与所述抗人IgG抗体Fab段同物种来源的 IgG 10μg/mL～200μg/mL、阻断剂40μg/mL～60μg/mL、二硫苏糖醇0.1mM～10mM、胆固醇1mM～10mM、海藻糖1mM～10mM、甘露醇1mM～200mM、甘氨酸 1mM～50mM、精氨酸1mM～50mM、谷胱甘肽1mM～10mM、酪蛋白1mM～50mM、表面活性剂0.1wt％～2wt％。
在其中一个实施例中，所述阻断剂包括MAK33-IgG1/IgG1 poly、 MAK33-IgG1/Fab1 Poly、Poly MAK IgG2b/Fab2a和IEP-Framework中的一种或多种。
在其中一个实施例中，所述新型冠状病毒蛋白-磁珠复合物的制备方法包括以下步骤：使用3mM～7mM的十二烷基硫酸钠溶液处理新型冠状病毒蛋白得到变性抗原，然后使用所述变性抗原包被磁珠。
在其中一个实施例中，所述发光标记物包括吖啶酯、吖啶酯磺酰胺、吖啶酯甲苯磺酰胺、吖啶酯对甲基磺酰胺、吖啶酯三氟甲基磺酰胺中的一种或多种。
本发明的新型冠状病毒检测试剂盒基于直接化学发光的两步间接免疫法原理，利用相应的化学发光测定仪，能够快速判断出待测样品中新型冠状病毒IgG 抗体的浓度。在检测过程中，无需对样品进行RNA提取操作，检测步骤较少，操作时间缩短，可避免因RNA丰度低导致的假阴性结果。而且可配合使用自动的化学发光测定仪，减少了人员与可能携带病原体样本的接触，最大程度上降低感染几率。同时，化学发光技术本身检测灵敏，检测速度快，远远优于核酸检测。
本发明的新型冠状病毒检测试剂盒的抗原组分中，将所有可能产生抗体的新型冠状病毒抗原包被至磁珠表面，最大程度上避免了个别患者由于体内产生抗体不同而造成的漏检。
本发明的新型冠状病毒检测试剂盒的发光组分中，使用抗体Fc段替换为马 Fc段的重组鼠抗人IgG抗体，能够在保证抗体亲和力的前提下，避免可能存在的异噬性抗体HAMA干扰，进一步提高检测的准确度。
本发明的新型冠状病毒检测试剂盒使用含有阻断剂和二硫苏糖醇等物质的样品稀释组分对待测样品进行稀释，能够最大程度上减少可能存在的异噬性抗体HAMA干扰和类风湿因子RF干扰，进一步提高检测的准确度。
本发明的新型冠状病毒检测试剂盒在蛋白-磁珠复合物的制备工艺中，使用一定浓度的SDS处理新型冠状病毒相关抗原，释放抗原表位，增加了与不同样本中新型冠状病毒IgG抗体结合的可能性，提高了检测的灵敏度，进一步减少了假阴性或漏检的可能性。
附图说明
图1为质粒pAc-κ-CH3andpAc-λ-CH3(Progen)的图谱。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
根据研究结果，病人在感染新型冠状病毒后，会于3～7天左右产生IgM抗体，1周后IgG抗体也会上升，IgM抗体是体液免疫反应中最早出现的抗体，检测早期IgM抗体能够缩短病毒感染人体后检测的窗口期，临床上同时检测IgM 抗体和IgG抗体能够辅助诊断、监控病情，对愈后的判断也有重要意义。因而，检测新型冠状病毒IgG抗体时，如何全面地检测感染者血液中全部新型冠状病毒IgG抗体的含量及变化是IgG抗体检测的关键。因此，开展对于新型冠状病毒肺炎血清学的检测，定量疑似患者或确诊病人血液中新型冠状病毒抗体的含量时，抗原的选择和配比非常重要。
化学发光技术主要依据检测体系中待测物浓度与体系的化学发光强度在一定条件下成定量线性惯性的原理，利用专用的仪器对化学发光强度进行检测，从而确定待测物的含量，具有灵敏度高、报告速度快、自动化程度高等突出的优点。根据反应原理，可将化学发光技术分为间接法、捕获法、竞争法和夹心法，其中，间接法是将抗原包被于固相表面，根据抗原-抗体结合的免疫学原理，能够快速富集待测抗体，并通过合适的二抗，就能检测出待测抗体的含量。
新型冠状病毒基因编码多种结构蛋白，主要有突刺蛋白(spike glycoprotein,S)、包膜蛋白(envelope,E)、膜蛋白(membrane,M)和核衣壳蛋白 (nucleocapsid protein,N)，均可作为人体免疫新型冠状病毒的抗原，市面上所售的抗原多为S蛋白和N蛋白，检测IgG时如仅检测S蛋白和(或)N蛋白所激发的抗体的含量，并不能全面的反映感染者体内特异性IgG抗体的产生和滴度变化。同时，由于病毒感染会引起强烈的免疫反应，可能会产生大量的类风湿因子(rheumatoid factor，RF)，这将会影响人体内特异性IgG和IgM抗体含量的精确测量。因此，如何减小或消除RF干扰，也是准确测量新型冠状病毒肺炎特异性IgG和IgM抗体需要克服的重点问题。
本发明一实施例的新型冠状病毒检测试剂盒，包括抗原组分和发光组分。抗原组分中含有新型冠状病毒蛋白-磁珠复合物，该新型冠状病毒蛋白-磁珠复合物包括S1蛋白-磁珠复合物、S2蛋白-磁珠复合物、E蛋白-磁珠复合物、M蛋白 -磁珠复合物和N蛋白-磁珠复合物。发光组分中含有抗人IgG抗体，且抗人IgG 抗体上标记有发光标记物。其中，S1蛋白即突刺蛋白Spike-S1亚基，S2蛋白即突刺蛋白Spike-S2亚基，N蛋白即核衣壳蛋白，E蛋白即衣壳蛋白，M蛋白即膜蛋白。
本发明的新型冠状病毒检测试剂盒基于直接化学发光的两步间接免疫法原理，利用相应的化学发光测定仪，能够快速判断出待测样品中新型冠状病毒IgG 抗体的浓度。在检测过程中，无需对样品进行RNA提取操作，检测步骤较少，操作时间缩短，可避免因RNA丰度低导致的假阴性结果。而且可配合使用自动的化学发光测定仪，减少了人员与可能携带病原体样本的接触，最大程度上降低感染几率。同时，化学发光技术本身检测灵敏，检测速度快，远远优于核酸检测。本发明的新型冠状病毒检测试剂盒的抗原组分中，将所有可能产生抗体的新型冠状病毒抗原包被至顺磁性磁珠表面，最大程度上避免了个别患者由于体内产生抗体不同而造成的漏检。
在一个具体示例中，上述抗原组分中，S1蛋白、S2蛋白、E蛋白、M蛋白和N蛋白的摩尔比为(2～5):(1～5):(2～5):(0.1～3):(0.1～3)，优选为 (3～4):(1.5～2.5):(3～4):(0.3～0.7):(0.3～0.7)。该比例是通过对不同个体产生针对不同抗原的抗体的时间和丰度的变化研究获得的最优比例，检测的检出率和准确性最佳。
在一个具体示例中，上述抗原组分中，新型冠状病毒蛋白-磁珠复合物(包含不同磁珠大小和表面基团)的总浓度为0.1mg/mL～0.5mg/mL，优选为 0.3mg/mL。可选地，抗原组分中还含有磁珠稀释液，磁珠稀释液含有 10mM～100mM PBS、0.1wt％～5wt％BSA和防腐剂等成分，pH为5.5～8.5。
在一个具体示例中，上述抗人IgG抗体为鼠抗人IgG抗体。优选地，上述抗人IgG抗体的Fc段为除鼠以外物种来源的Fc段。优选地，除鼠以外物种选自如下任意种属：马、猪、兔、犬和羊。更优选地，抗人IgG抗体的Fc段来源为马Fc段。通过使用抗体Fc段被替换的重组鼠抗人IgG抗体，能够在保证抗体亲和力的前提下，避免可能存在的异噬性抗体HAMA干扰，进一步提高检测的准确度。
在一个具体示例中，上述发光组分中，抗人IgG抗体的浓度为 1μg/mL～400μg/mL，优选为200μg/mL。可选地，发光组分中还含有标记物稀释液，标记物稀释液含有10mM～100mM PBS、0.1wt％～5wt％BSA、Mouse IgG和防腐剂等成分，pH为5.5～8.5。
在一个具体示例中，发光标记物包括吖啶酯、吖啶酯磺酰胺、吖啶酯甲苯磺酰胺、吖啶酯对甲基磺酰胺、吖啶酯三氟甲基磺酰胺中的一种或多种，但不限于此。
在一个具体示例中，新型冠状病毒检测试剂盒还包括样品稀释组分，样品稀释组分中含有阻断剂和二硫苏糖醇。优选地，样品稀释组分中还含有PBS、BSA、与抗人IgG抗体Fab段同物种来源的IgG、胆固醇、海藻糖、甘露醇、甘氨酸、精氨酸、谷胱甘肽、酪蛋白、表面活性剂和防腐剂中的一种或多种。通过使用含有阻断剂和二硫苏糖醇等物质的样品稀释组分对待测样品进行稀释，能够最大程度上减少可能存在的异噬性抗体HAMA干扰和类风湿因子RF干扰，进一步提高检测的准确度。
在一个具体示例中，样品稀释组分中各物质的浓度分别为：BS 10mM～100mM、BSA0.1wt％～5wt％、与抗人IgG抗体Fab段同物种来源的IgG 10μg/mL～200μg/mL、阻断剂40μg/mL～60μg/mL、二硫苏糖醇0.1mM～10mM、胆固醇1mM～10mM、海藻糖1mM～10mM、甘露醇1mM～200mM、甘氨酸 1mM～50mM、精氨酸1mM～50mM、谷胱甘肽1mM～10mM、酪蛋白1mM～50mM、表面活性剂0.1wt％～2wt％、防腐剂0.1wt％～0.5wt％。在该浓度范围内，试剂盒具有更好的检测灵敏度和抗干扰能力。
在一个具体示例中，阻断剂包括MAK33-IgG1/IgG1 poly、MAK33-IgG1/Fab1 Poly、Poly MAK IgG2b/Fab2a和IEP-Framework中的一种或多种，但不限于此。可选地，表面活性剂包括但不限于Tween-20、Tween-80等，防腐剂包括但不限于NaN3、ProClin-300等。
在一个具体示例中，新型冠状病毒蛋白-磁珠复合物的制备方法包括以下步骤：使用3mM～7mM的十二烷基硫酸钠溶液处理新型冠状病毒蛋白得到变性抗原，然后使用变性抗原包被磁珠。优选地，SDS浓度为4mM～6mM。由于抗原种类较多且构象复杂，因此在蛋白-磁珠复合物的制备工艺中，通过使用一定浓度的SDS处理重组的新型冠状病毒相关抗原，释放抗原表位，增加了与不同样本中新型冠状病毒IgG抗体结合的可能性，提高了检测的灵敏度，进一步减少了假阴性或漏检的可能性。
本发明针对核酸检测方法的缺陷，以及化学反光检测技术可能会存在的疏漏，依据直接化学发光技术的两步间接免疫法的原理，开发了此款新型冠状病毒检测试剂盒。与相应的化学发光测定仪配套，能够实现对新型冠状病毒肺炎 IgG抗体的自动化(自动取样、自动检测、自动报告)、高通量(200人份/小时)、快速检测(25min出报告)。
以下通过具体实施例对本发明做进一步详细的描述。
实施例1
一、抗原的制备
根据新型冠状病毒基因序列，以及其外壳的组成，应用293表达系统，分别表达纯化组成新型冠状病毒结构蛋白的各蛋白质(突刺蛋白Spike-S1亚基、 Spike-S2亚基、核衣壳蛋白、衣壳蛋白、膜蛋白)作为包被抗原。
例如S1蛋白的表达纯化：
选择新冠病毒刺突蛋白的RBD(受体结合区)蛋白，氨基酸序列为：
NITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFV IRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKST(SEQ ID NO:1)；
信号肽，氨基酸序列为：MFVFLVLLPLVSSQCV(SEQ ID NO:2)；
跨膜结构域，氨基酸序列为：ELWLVLVAVGAGLLLLGLIILLL(SEQ ID NO:3)；
标签肽段，氨基酸序列为：WGQGGTHGQWNKPSKP(SEQ ID NO:4)。
将信号肽、RBD蛋白、跨膜结构域、标签肽段依次连接，融合成RBD重组抗原，完整融合蛋白的DNA序列为：
ATGTTTGTTTTTCTTGTTTTATTGCCACTAGTCTCTAGTCAGTGTGTTAATATTACAAACTTGTGCCCTTT TGGTGAAGTTTTTAACGCCACCAGATTTGCATCTGTTTATGCTTGGAACAGGAAGAGAATCAGCAACT GTGTTGCTGATTATTCTGTCCTATATAATTCCGCATCATTTTCCACTTTTAAGTGTTATGGAGTGTCTCCT ACTAAATTAAATGATCTCTGCTTTACTAATGTCTATGCAGATTCATTTGTAATTAGAGGTGATGAAGTCA GACAAATCGCTCCAGGGCAAACTGGAAAGATTGCTGATTATAATTATAAATTACCAGATGATTTTACAG GCTGCGTTATAGCTTGGAATTCTAACAATCTTGATTCTAAGGTTGGTGGTAATTATAATTACCTGTATAG ATTGTTTAGGAAGTCTAATCTCAAACCTTTTGAGAGAGATATTTCAACTGAAATCTATCAGGCCGGTAG CACACCTTGTAATGGTGTTGAAGGTTTTAATTGTTACTTTCCTTTACAATCATATGGTTTCCAACCCACT AATGGTGTTGGTTACCAACCATACAGAGTAGTAGTACTTTCTTTTGAACTTCTACATGCACCAGCAACT GTTTGTGGACCTAAAAAGTCTACTGAGCTGTGGCTGGTGCTGGTGGCCGTGGGCGCTGGACTGCTGC TGCTGGGACTGATCATCCTGCTGCTGTGGGGTCAAGGCGGTACACATGGTCAATGGAACAAGCCTTC GAAGCCGTGA(SEQ ID NO:5)。
RBD重组蛋白的DNA通过基因合成(通用生物系统(安徽)有限公司)获得。该RBD重组抗原的DNA上游带有Hind III位点和Kozak序列，下游带有EcoR I位点。该DNA经过相应的限制性内切酶酶切，连接到用Hind III和EcoR I酶切后的穿梭表达载体pcDNA3.1(+)，得到重组质粒pcDNA3.1(+)-RBD。
将该重组质粒转入大肠杆菌克隆菌株Top 10，挑取单克隆菌落接种至100 mL含有100μg/mL氨苄青霉素的LB培养基中，37℃、200rpm培养过夜，用于提取重组质粒。重组质粒使用无内毒素质粒提取试剂盒(天根生化科技(北京)有限公司，DP120)提取。293T细胞铺皿培养至汇合度约85％时，转染重组质粒pcDNA3.1(+)-RBD。
一皿细胞转染10μg质粒DNA，质粒DNA与PEI质量比为1:5。将质粒 DNA和PEI各自与250μL PBS混匀后，将两种混合物涡旋混匀1min，室温静置15min后，均匀滴加于细胞培养皿中，混匀后置于培养箱培养48h。将转染后的细胞刮下，PBS重悬清洗细胞两次后，一皿细胞使用1mL 10mM Na2HPO4/50mM NaCl/1％Triton X-100，pH7.4缓冲液(缓冲液A)重悬，并置于4℃环境中提取30min；16000g离心15min，上清即为提取的重组RBD抗原，-20℃保存备用。
N蛋白的表达纯化：
选择核衣壳蛋白(N蛋白)，氨基酸序列为：
MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGAL NTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARM AGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRR GPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTAAIKLDDKDPNFK DQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADS TQA(SEQ ID NO:6)；
以及寡聚赖氨酸序列为RRRRR，连接肽的氨基酸序列为GSGS。寡聚赖氨酸、N蛋白、寡聚赖氨酸均通过连接肽连接，融合成N蛋白重组蛋白，其DNA 序列为
ATGCGTCGCAGACGTCGAGGATCTGGCTCGATGAGTGATAACGGCCCGCAGAATCAGCGCAATGCCCCGCGCATTACCTTTGGTGGCCCGAGTGATAGTACCGGTAGTAATCAGAATGGTGAACGCAGCGGCGCC CGCAGTAAACAGCGTCGTCCGCAGGGTCTGCCGAATAATACCGCAAGCTGGTTTACCGCCCTGACCC AGCATGGCAAAGAAGATCTGAAATTTCCGCGCGGTCAGGGTGTTCCGATTAATACCAATAGCAGTCCG GATGATCAGATTGGTTATTATCGTCGTGCCACCCGTCGTATTCGCGGCGGCGATGGTAAAATGAAAGAT CTGAGTCCGCGTTGGTATTTTTATTATCTGGGCACCGGTCCGGAAGCAGGCCTGCCTTATGGTGCCAAT AAGGATGGCATTATTTGGGTGGCAACCGAAGGCGCCCTGAATACCCCGAAAGATCATATTGGTACCCG TAATCCGGCCAATAATGCAGCAATTGTGCTGCAGCTGCCGCAGGGCACCACCCTGCCTAAAGGCTTTT ATGCAGAAGGTAGTCGCGGTGGCAGCCAGGCAAGCAGCCGTAGTAGTAGCCGCAGTCGTAATAGCAG TCGCAATAGCACCCCGGGTAGCAGTCGTGGTACCAGCCCGGCACGCATGGCAGGCAATGGTGGTGAC GCCGCACTGGCACTGCTGCTGCTGGATCGTCTGAATCAGCTGGAAAGCAAAATGAGTGGCAAAGGTC AGCAGCAGCAGGGCCAGACCGTGACCAAAAAATCTGCCGCAGAAGCCAGCAAAAAACCGCGTCAG AAACGTACCGCCACCAAAGCCTATAATGTGACCCAGGCATTTGGCCGTCGCGGCCCGGAACAGACCC AGGGTAATTTTGGTGACCAGGAACTGATTCGCCAGGGCACCGATTATAAACATTGGCCGCAGATTGCA CAGTTTGCACCGAGTGCCAGTGCCTTTTTCGGCATGAGCCGCATTGGCATGGAAGTTACCCCGAGTGG TACCTGGCTGACCTATACCGGTGCCATTAAGCTGGATGATAAAGATCCGAATTTTAAAGATCAGGTTAT TCTGCTGAACAAACATATTGATGCCTATAAAACCTTCCCGCCGACCGAACCGAAAAAAGATAAAAAG AAAAAGGCAGATGAGACCCAGGCACTGCCGCAGCGCCAGAAAAAACAGCAGACCGTGACACTGCT GCCGGCAGCAGATCTGGATGATTTTAGTAAACAGCTGCAGCAGAGCATGAGTAGCGCCGATAGTACCC AGGCCGGATCTGGCTCGCGTCGCAGACGTCGATAA(SEQ ID NO:7)。
N蛋白重组蛋白的DNA通过基因合成(通用生物系统(安徽)有限公司)获得。该N蛋白重组蛋白的DNA上游带有Nco I位点，下游带有Hind III位点。该DNA经过相应的限制性内切酶酶切，连接到用Nco I和Hind III酶切后的表达载体pET-28a(+)，得到重组质粒pET-28a(+)-N。
将该重组质粒转入大肠杆菌表达菌株BL21(DE3)，挑取单克隆菌落接种至 100mL含有50μg/mL卡那霉素的LB培养基中，37℃、200rpm培养过夜。次日吸取1％体积的过夜培养物至1L新鲜的含有50μg/mL卡那霉素的LB培养基中，37℃、200rpm培养至OD600＝0.6左右，用终浓度为1mM的IPTG(异丙基硫代半乳糖苷)于18℃诱导表达20h。4℃、12000g离心3min收集菌体，每升菌液的菌体用冰上预冷的40mL 50mM Na2HPO4，pH 7.4缓冲液(缓冲液A) 悬浮，添加少量RNase，高压均质机破碎，4℃、12000g离心30min，上清液使用0.22μm滤膜过滤，过阳离子交换柱。
用10倍柱体积的缓冲液A平衡阳离子交换柱，加入上清液，用至少10倍柱体积的缓冲液A洗去未结合的蛋白。配制50mM Na2HPO4/500mM NaCl，pH 7.4缓冲液(缓冲液B)，用20个柱体积含有0mM～500mM NaCl的缓冲液线性梯度洗脱目的蛋白。选择纯度达90％的目的蛋白部分合并，在4℃环境下充分透析于10mM Tris 7.5缓冲液(缓冲液C)中。为了进一步去除杂质，将透析后的 N蛋白，上柱于Buffer C预平衡的阴离子交换柱，收集穿透液，充分透析于PBS 缓冲液中。N蛋白超滤浓缩后，-20℃保存备用。
二、抗原-磁珠复合物的制备
取包被抗原0.2mL，加入含有5mM的十二烷基硫酸钠(SDS)的磷酸盐溶液0.02mL，混匀后，于37℃孵育30min，以打开抗原的二级结构，释放抗体结合表位，最终得到经SDS变性后的重组包被抗原。取10mg末端修饰有羧基基团的纳米磁珠悬浮液，用10mM～20mM 2-(N-吗啉基)乙磺酸(MES)缓冲液， pH6.0，清洗数次并重悬为0.3mL。加入0.1mL 20mg/ml的N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺(EDC)水溶液，25℃下混合反应30分钟。磁分离后，磁珠用20mM磷酸盐缓冲液重悬至1.0mL，混匀中加入0.2mg包被抗原，并于 25℃下反应2小时。磁分离，去除未结合的包被抗原，用含1％BSA，pH为7.5 的Tris缓冲液液重悬到10mg/mL，得到重组抗原包被的羧基化的磁微粒，保存于2～8℃备用。
三、重组鼠抗人IgG抗体的制备
(1)在抗体重链可变区基因上游添加Xho1酶切位点，基因下游添加Nhe1 酶切位点，克隆到质粒pAc-κ-CH3andpAc-λ-CH3(Progen)上，图谱如图1 所示，抗体重链可变区基因序列见表1。
(2)在马抗体重链恒定区基因(CH1-CH3)基因(FC段)上游添加Nhe1 酶切位点，基因下游添加BamHI酶切位点，克隆到质粒pAc-κ-CH3andpAc-λ -CH3(Progen)上，马抗体重链恒定区基因(CH1-CH3)基因(FC段)见表1。
(3)在抗体轻链可变区基因上游添加Sac1酶切位点，基因下游添加Hind111 酶切位点，克隆到质粒pAc-κ-CH3andpAc-λ-CH3(Progen)上，抗体轻链可变区基因序列见表1；最终得到完整的构建质粒pAc-κ-CH3andpAc-λ-CH3 (Progen)。
(4)细胞转染
准备处在对数生长期且活率高于90％的HEK293细胞。转染当天，取样计数细胞密度和活率，细胞密度应该在(3～5)×106cells/mL，活率高于90％。调整细胞密度至3×106cells/mL，每瓶细胞液体积为20mL。用150mM的NaCl稀释20μg DNA(10μg克隆构建质粒1#+10μg克隆构建质粒2#)至总体积为0.5mL，温和混匀；用150mM的NaCl稀释100μLSinofection转染试剂至总体积为0.5mL，温和混匀；将稀释好的DNA和转染试剂同时单独静置约5分钟后温和混匀，总体积1mL，之后室温静置10分钟。将转染液逐滴加入到细胞培养液中，滴加的同时轻轻摇动培养瓶，摇匀后放回摇床继续培养，转染48小时后收集细胞上清。
(5)细胞上清抗体纯化
采用proteinG亲和层析法。首先制备proteinG亲和层析柱，用PBS平衡柱子后，取腹水过柱，然后用PBS清洗柱子，以50nmol/L的甘氨酸盐酸盐溶液洗脱，收集洗脱液，测定各收集管的OD值，保留峰值区的洗脱液，洗脱液经透析后收集。
表1抗体基因序列
四、抗原组分的制备
由上述方法制备的抗原-磁珠复合物以及磁珠稀释液组成。其中，S1蛋白、 S2蛋白、N蛋白、E蛋白和M蛋白的摩尔比为3.5:2:3.5:0.5:0.5。抗原-磁珠复合物的总浓度为0.3mg/mL，磁珠稀释液含有10mM PBS、0.5wt％BSA、0.2％Proclin 300等成分，pH为7.4。
五、发光组分的制备
由标记了化学发光标记物的上述重组鼠抗人IgG抗体及标记物稀释液组成。其中，鼠抗人IgG抗体的浓度为200μg/mL，标记物稀释液含有10mM PBS、 0.5wt％BSA、0.5mg/mLMouse IgG、0.2％Proclin 300等成分，pH为7.4。
六、样品稀释组分的制备
各物质的浓度分别为：PBS 10mM、BSA 0.5wt％、Mouse IgG 50μg/mL、阻断剂50μg/mL、二硫苏糖醇1mM、胆固醇1mM、海藻糖5mM、甘露醇50mM、甘氨酸10mM、精氨酸5mM、谷胱甘肽1mM、酪蛋白2mM、表面活性剂2wt％、 0.2％Proclin 300。
实施例2
本实施例与实施例1基本相同，区别仅在于抗原-磁珠复合物的制备工艺中，分别使用不同浓度的SDS(2mM、7mM、10mM)。
使用不同浓度SDS条件得到的试剂盒分别测试了10份阳性标本。从上表中可以看出，在使用2mM SDS时，因为处理时抗原暴露不充分，导致个别样本测试结果为阴性。使用5mM SDS时，处理效果最佳，10份阳性样本均可测出。而采用7mM以及10mM时，因使用浓度较大，导致蛋白完全变性，而使得抗原位点遭到破坏，部分阳性测试结果为阴性。
实施例3
本实施例与实施例1基本相同，区别仅在于抗原组分中，分别使用不同摩尔比的S1蛋白、S2蛋白、E蛋白、M蛋白和N蛋白。
从上表中可以看出，测试了10例阳性(1～10号为阳性)为以及10例阴性样本(10～20号为阴性样本)。增加了E蛋白和M蛋白复合物比例，导致阳性样本出现了漏检以及阴性样本出现假阳的情况，可能是由于检测到了由其他冠状病毒刺激机体产生的抗体；同时增加S1、S2蛋白的含量和M蛋白及N蛋白含量，阳性样本虽然都能检出，但阴性样本也产生了假阳性，可能是由于检测到了由其他冠状病毒刺激机体产生的抗体；单独增加了N蛋白复合物的含量，阳性结果都能检出，但阴性样本出现了假阳性；而选择的3.5:2:3.5:0.5:0.5本次新型冠状病毒与其他冠状病毒抗原位点的差异，同时也兼顾了其他结构蛋白，保证了特异性的同时也提升了检出率。
实施例4
本实施例与实施例1基本相同，区别仅在于发光组分中，抗人IgG抗体为采用其他Fc段进行替换的鼠抗人IgG抗体。
从上表中可以看出，测试了10例阳性(1～10号为阳性)为以及10例阴性样本(10～20号为阴性样本)。鼠抗人IgG本身的Fc端因为样本中可能存在HAMA 抗体而对阴性样本产生干扰，导致检测结果假阳性；将鼠抗人Fc端替换为羊抗人Fc段能够改善假阳性问题，但仍然存在假阳性的结果；替换为马Fc段后能够改善假阳性，同时阳性结果都能检出。
使用上述新型冠状病毒检测试剂盒进行检测的具体步骤如下。可将该试剂盒与本公司生产的iFlash-3000系列化学发光测定仪配套使用，其中清洗液、预激发液、激发液以及相应的清洗和发光读数步骤为测定仪的默认设定，其余步骤由人工设定程序，由测定仪处理完成。
1、样品预稀释：设定程序吸取10μl样品于反应杯中，并加入试剂样品稀释组分，稀释比例优选为1:10(1:1～1:20)，混匀后于37℃孵育5min，以消除或降低异噬性抗体HAMA及类风湿因子RF干扰引起的假阳性或假阴性。
2、添加磁珠：向反应杯中添加50μl上述抗原组分试剂，于37℃孵育5min，使新型冠状病毒IgG抗体充分与固定至磁珠表面的抗原反应，随后执行清洗程序，洗去未结合和吸附的样品。
3、添加吖啶：向反应杯中添加100μl发光组分，并于37℃孵育5min，使带有发光标记物的抗体与待测物充分结合，随后执行清洗程序，洗去未结合的抗体。
4、测定待测物浓度：根据仪器预先设定好的发光程序，激发通过一系列反应结合在磁珠上的化学发光标记物，并由化学发光测定仪读取发光值。
5、产生报告：根据校准曲线和参考区间，报告病人血样中新型冠状病毒IgG 抗体的含量，以辅助临床判断病情。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
序列表
<110> 深圳市亚辉龙生物科技股份有限公司
<120> 新型冠状病毒检测试剂盒
<140> 2020101267123
<141> 2020-02-28
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 201
<212> PRT
<213> Artificial Sequence
<400> 1
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg
1 5 10 15
Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp
100 105 110
Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys
115 120 125
Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
130 135 140
Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe
145 150 155 160
Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln
165 170 175
Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala
180 185 190
Thr Val Cys Gly Pro Lys Lys Ser Thr
195 200
<210> 2
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 2
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
<210> 3
<211> 23
<212> PRT
<213> Artificial Sequence
<400> 3
Glu Leu Trp Leu Val Leu Val Ala Val Gly Ala Gly Leu Leu Leu Leu
1 5 10 15
Gly Leu Ile Ile Leu Leu Leu
20
<210> 4
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 4
Trp Gly Gln Gly Gly Thr His Gly Gln Trp Asn Lys Pro Ser Lys Pro
1 5 10 15
<210> 5
<211> 771
<212> PRT
<213> Artificial Sequence
<400> 5
Ala Thr Gly Thr Thr Thr Gly Thr Thr Thr Thr Thr Cys Thr Thr Gly
1 5 10 15
Thr Thr Thr Thr Ala Thr Thr Gly Cys Cys Ala Cys Thr Ala Gly Thr
20 25 30
Cys Thr Cys Thr Ala Gly Thr Cys Ala Gly Thr Gly Thr Gly Thr Thr
35 40 45
Ala Ala Thr Ala Thr Thr Ala Cys Ala Ala Ala Cys Thr Thr Gly Thr
50 55 60
Gly Cys Cys Cys Thr Thr Thr Thr Gly Gly Thr Gly Ala Ala Gly Thr
65 70 75 80
Thr Thr Thr Thr Ala Ala Cys Gly Cys Cys Ala Cys Cys Ala Gly Ala
85 90 95
Thr Thr Thr Gly Cys Ala Thr Cys Thr Gly Thr Thr Thr Ala Thr Gly
100 105 110
Cys Thr Thr Gly Gly Ala Ala Cys Ala Gly Gly Ala Ala Gly Ala Gly
115 120 125
Ala Ala Thr Cys Ala Gly Cys Ala Ala Cys Thr Gly Thr Gly Thr Thr
130 135 140
Gly Cys Thr Gly Ala Thr Thr Ala Thr Thr Cys Thr Gly Thr Cys Cys
145 150 155 160
Thr Ala Thr Ala Thr Ala Ala Thr Thr Cys Cys Gly Cys Ala Thr Cys
165 170 175
Ala Thr Thr Thr Thr Cys Cys Ala Cys Thr Thr Thr Thr Ala Ala Gly
180 185 190
Thr Gly Thr Thr Ala Thr Gly Gly Ala Gly Thr Gly Thr Cys Thr Cys
195 200 205
Cys Thr Ala Cys Thr Ala Ala Ala Thr Thr Ala Ala Ala Thr Gly Ala
210 215 220
Thr Cys Thr Cys Thr Gly Cys Thr Thr Thr Ala Cys Thr Ala Ala Thr
225 230 235 240
Gly Thr Cys Thr Ala Thr Gly Cys Ala Gly Ala Thr Thr Cys Ala Thr
245 250 255
Thr Thr Gly Thr Ala Ala Thr Thr Ala Gly Ala Gly Gly Thr Gly Ala
260 265 270
Thr Gly Ala Ala Gly Thr Cys Ala Gly Ala Cys Ala Ala Ala Thr Cys
275 280 285
Gly Cys Thr Cys Cys Ala Gly Gly Gly Cys Ala Ala Ala Cys Thr Gly
290 295 300
Gly Ala Ala Ala Gly Ala Thr Thr Gly Cys Thr Gly Ala Thr Thr Ala
305 310 315 320
Thr Ala Ala Thr Thr Ala Thr Ala Ala Ala Thr Thr Ala Cys Cys Ala
325 330 335
Gly Ala Thr Gly Ala Thr Thr Thr Thr Ala Cys Ala Gly Gly Cys Thr
340 345 350
Gly Cys Gly Thr Thr Ala Thr Ala Gly Cys Thr Thr Gly Gly Ala Ala
355 360 365
Thr Thr Cys Thr Ala Ala Cys Ala Ala Thr Cys Thr Thr Gly Ala Thr
370 375 380
Thr Cys Thr Ala Ala Gly Gly Thr Thr Gly Gly Thr Gly Gly Thr Ala
385 390 395 400
Ala Thr Thr Ala Thr Ala Ala Thr Thr Ala Cys Cys Thr Gly Thr Ala
405 410 415
Thr Ala Gly Ala Thr Thr Gly Thr Thr Thr Ala Gly Gly Ala Ala Gly
420 425 430
Thr Cys Thr Ala Ala Thr Cys Thr Cys Ala Ala Ala Cys Cys Thr Thr
435 440 445
Thr Thr Gly Ala Gly Ala Gly Ala Gly Ala Thr Ala Thr Thr Thr Cys
450 455 460
Ala Ala Cys Thr Gly Ala Ala Ala Thr Cys Thr Ala Thr Cys Ala Gly
465 470 475 480
Gly Cys Cys Gly Gly Thr Ala Gly Cys Ala Cys Ala Cys Cys Thr Thr
485 490 495
Gly Thr Ala Ala Thr Gly Gly Thr Gly Thr Thr Gly Ala Ala Gly Gly
500 505 510
Thr Thr Thr Thr Ala Ala Thr Thr Gly Thr Thr Ala Cys Thr Thr Thr
515 520 525
Cys Cys Thr Thr Thr Ala Cys Ala Ala Thr Cys Ala Thr Ala Thr Gly
530 535 540
Gly Thr Thr Thr Cys Cys Ala Ala Cys Cys Cys Ala Cys Thr Ala Ala
545 550 555 560
Thr Gly Gly Thr Gly Thr Thr Gly Gly Thr Thr Ala Cys Cys Ala Ala
565 570 575
Cys Cys Ala Thr Ala Cys Ala Gly Ala Gly Thr Ala Gly Thr Ala Gly
580 585 590
Thr Ala Cys Thr Thr Thr Cys Thr Thr Thr Thr Gly Ala Ala Cys Thr
595 600 605
Thr Cys Thr Ala Cys Ala Thr Gly Cys Ala Cys Cys Ala Gly Cys Ala
610 615 620
Ala Cys Thr Gly Thr Thr Thr Gly Thr Gly Gly Ala Cys Cys Thr Ala
625 630 635 640
Ala Ala Ala Ala Gly Thr Cys Thr Ala Cys Thr Gly Ala Gly Cys Thr
645 650 655
Gly Thr Gly Gly Cys Thr Gly Gly Thr Gly Cys Thr Gly Gly Thr Gly
660 665 670
Gly Cys Cys Gly Thr Gly Gly Gly Cys Gly Cys Thr Gly Gly Ala Cys
675 680 685
Thr Gly Cys Thr Gly Cys Thr Gly Cys Thr Gly Gly Gly Ala Cys Thr
690 695 700
Gly Ala Thr Cys Ala Thr Cys Cys Thr Gly Cys Thr Gly Cys Thr Gly
705 710 715 720
Thr Gly Gly Gly Gly Thr Cys Ala Ala Gly Gly Cys Gly Gly Thr Ala
725 730 735
Cys Ala Cys Ala Thr Gly Gly Thr Cys Ala Ala Thr Gly Gly Ala Ala
740 745 750
Cys Ala Ala Gly Cys Cys Thr Thr Cys Gly Ala Ala Gly Cys Cys Gly
755 760 765
Thr Gly Ala
770
<210> 6
<211> 419
<212> PRT
<213> Artificial Sequence
<400> 6
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
1 5 10 15
Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg
20 25 30
Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn
35 40 45
Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu
50 55 60
Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro
65 70 75 80
Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly
85 90 95
Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr
100 105 110
Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp
115 120 125
Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp
130 135 140
His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
145 150 155 160
Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
165 170 175
Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn
180 185 190
Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala
195 200 205
Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu
210 215 220
Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln
225 230 235 240
Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys
245 250 255
Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln
260 265 270
Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp
275 280 285
Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile
290 295 300
Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile
305 310 315 320
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Ala Ala
325 330 335
Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu
340 345 350
Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro
355 360 365
Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln
370 375 380
Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu
385 390 395 400
Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser
405 410 415
Thr Gln Ala
<210> 7
<211> 1317
<212> PRT
<213> Artificial Sequence
<400> 7
Ala Thr Gly Cys Gly Thr Cys Gly Cys Ala Gly Ala Cys Gly Thr Cys
1 5 10 15
Gly Ala Gly Gly Ala Thr Cys Thr Gly Gly Cys Thr Cys Gly Ala Thr
20 25 30
Gly Ala Gly Thr Gly Ala Thr Ala Ala Cys Gly Gly Cys Cys Cys Gly
35 40 45
Cys Ala Gly Ala Ala Thr Cys Ala Gly Cys Gly Cys Ala Ala Thr Gly
50 55 60
Cys Cys Cys Cys Gly Cys Gly Cys Ala Thr Thr Ala Cys Cys Thr Thr
65 70 75 80
Thr Gly Gly Thr Gly Gly Cys Cys Cys Gly Ala Gly Thr Gly Ala Thr
85 90 95
Ala Gly Thr Ala Cys Cys Gly Gly Thr Ala Gly Thr Ala Ala Thr Cys
100 105 110
Ala Gly Ala Ala Thr Gly Gly Thr Gly Ala Ala Cys Gly Cys Ala Gly
115 120 125
Cys Gly Gly Cys Gly Cys Cys Cys Gly Cys Ala Gly Thr Ala Ala Ala
130 135 140
Cys Ala Gly Cys Gly Thr Cys Gly Thr Cys Cys Gly Cys Ala Gly Gly
145 150 155 160
Gly Thr Cys Thr Gly Cys Cys Gly Ala Ala Thr Ala Ala Thr Ala Cys
165 170 175
Cys Gly Cys Ala Ala Gly Cys Thr Gly Gly Thr Thr Thr Ala Cys Cys
180 185 190
Gly Cys Cys Cys Thr Gly Ala Cys Cys Cys Ala Gly Cys Ala Thr Gly
195 200 205
Gly Cys Ala Ala Ala Gly Ala Ala Gly Ala Thr Cys Thr Gly Ala Ala
210 215 220
Ala Thr Thr Thr Cys Cys Gly Cys Gly Cys Gly Gly Thr Cys Ala Gly
225 230 235 240
Gly Gly Thr Gly Thr Thr Cys Cys Gly Ala Thr Thr Ala Ala Thr Ala
245 250 255
Cys Cys Ala Ala Thr Ala Gly Cys Ala Gly Thr Cys Cys Gly Gly Ala
260 265 270
Thr Gly Ala Thr Cys Ala Gly Ala Thr Thr Gly Gly Thr Thr Ala Thr
275 280 285
Thr Ala Thr Cys Gly Thr Cys Gly Thr Gly Cys Cys Ala Cys Cys Cys
290 295 300
Gly Thr Cys Gly Thr Ala Thr Thr Cys Gly Cys Gly Gly Cys Gly Gly
305 310 315 320
Cys Gly Ala Thr Gly Gly Thr Ala Ala Ala Ala Thr Gly Ala Ala Ala
325 330 335
Gly Ala Thr Cys Thr Gly Ala Gly Thr Cys Cys Gly Cys Gly Thr Thr
340 345 350
Gly Gly Thr Ala Thr Thr Thr Thr Thr Ala Thr Thr Ala Thr Cys Thr
355 360 365
Gly Gly Gly Cys Ala Cys Cys Gly Gly Thr Cys Cys Gly Gly Ala Ala
370 375 380
Gly Cys Ala Gly Gly Cys Cys Thr Gly Cys Cys Thr Thr Ala Thr Gly
385 390 395 400
Gly Thr Gly Cys Cys Ala Ala Thr Ala Ala Gly Gly Ala Thr Gly Gly
405 410 415
Cys Ala Thr Thr Ala Thr Thr Thr Gly Gly Gly Thr Gly Gly Cys Ala
420 425 430
Ala Cys Cys Gly Ala Ala Gly Gly Cys Gly Cys Cys Cys Thr Gly Ala
435 440 445
Ala Thr Ala Cys Cys Cys Cys Gly Ala Ala Ala Gly Ala Thr Cys Ala
450 455 460
Thr Ala Thr Thr Gly Gly Thr Ala Cys Cys Cys Gly Thr Ala Ala Thr
465 470 475 480
Cys Cys Gly Gly Cys Cys Ala Ala Thr Ala Ala Thr Gly Cys Ala Gly
485 490 495
Cys Ala Ala Thr Thr Gly Thr Gly Cys Thr Gly Cys Ala Gly Cys Thr
500 505 510
Gly Cys Cys Gly Cys Ala Gly Gly Gly Cys Ala Cys Cys Ala Cys Cys
515 520 525
Cys Thr Gly Cys Cys Thr Ala Ala Ala Gly Gly Cys Thr Thr Thr Thr
530 535 540
Ala Thr Gly Cys Ala Gly Ala Ala Gly Gly Thr Ala Gly Thr Cys Gly
545 550 555 560
Cys Gly Gly Thr Gly Gly Cys Ala Gly Cys Cys Ala Gly Gly Cys Ala
565 570 575
Ala Gly Cys Ala Gly Cys Cys Gly Thr Ala Gly Thr Ala Gly Thr Ala
580 585 590
Gly Cys Cys Gly Cys Ala Gly Thr Cys Gly Thr Ala Ala Thr Ala Gly
595 600 605
Cys Ala Gly Thr Cys Gly Cys Ala Ala Thr Ala Gly Cys Ala Cys Cys
610 615 620
Cys Cys Gly Gly Gly Thr Ala Gly Cys Ala Gly Thr Cys Gly Thr Gly
625 630 635 640
Gly Thr Ala Cys Cys Ala Gly Cys Cys Cys Gly Gly Cys Ala Cys Gly
645 650 655
Cys Ala Thr Gly Gly Cys Ala Gly Gly Cys Ala Ala Thr Gly Gly Thr
660 665 670
Gly Gly Thr Gly Ala Cys Gly Cys Cys Gly Cys Ala Cys Thr Gly Gly
675 680 685
Cys Ala Cys Thr Gly Cys Thr Gly Cys Thr Gly Cys Thr Gly Gly Ala
690 695 700
Thr Cys Gly Thr Cys Thr Gly Ala Ala Thr Cys Ala Gly Cys Thr Gly
705 710 715 720
Gly Ala Ala Ala Gly Cys Ala Ala Ala Ala Thr Gly Ala Gly Thr Gly
725 730 735
Gly Cys Ala Ala Ala Gly Gly Thr Cys Ala Gly Cys Ala Gly Cys Ala
740 745 750
Gly Cys Ala Gly Gly Gly Cys Cys Ala Gly Ala Cys Cys Gly Thr Gly
755 760 765
Ala Cys Cys Ala Ala Ala Ala Ala Ala Thr Cys Thr Gly Cys Cys Gly
770 775 780
Cys Ala Gly Ala Ala Gly Cys Cys Ala Gly Cys Ala Ala Ala Ala Ala
785 790 795 800
Ala Cys Cys Gly Cys Gly Thr Cys Ala Gly Ala Ala Ala Cys Gly Thr
805 810 815
Ala Cys Cys Gly Cys Cys Ala Cys Cys Ala Ala Ala Gly Cys Cys Thr
820 825 830
Ala Thr Ala Ala Thr Gly Thr Gly Ala Cys Cys Cys Ala Gly Gly Cys
835 840 845
Ala Thr Thr Thr Gly Gly Cys Cys Gly Thr Cys Gly Cys Gly Gly Cys
850 855 860
Cys Cys Gly Gly Ala Ala Cys Ala Gly Ala Cys Cys Cys Ala Gly Gly
865 870 875 880
Gly Thr Ala Ala Thr Thr Thr Thr Gly Gly Thr Gly Ala Cys Cys Ala
885 890 895
Gly Gly Ala Ala Cys Thr Gly Ala Thr Thr Cys Gly Cys Cys Ala Gly
900 905 910
Gly Gly Cys Ala Cys Cys Gly Ala Thr Thr Ala Thr Ala Ala Ala Cys
915 920 925
Ala Thr Thr Gly Gly Cys Cys Gly Cys Ala Gly Ala Thr Thr Gly Cys
930 935 940
Ala Cys Ala Gly Thr Thr Thr Gly Cys Ala Cys Cys Gly Ala Gly Thr
945 950 955 960
Gly Cys Cys Ala Gly Thr Gly Cys Cys Thr Thr Thr Thr Thr Cys Gly
965 970 975
Gly Cys Ala Thr Gly Ala Gly Cys Cys Gly Cys Ala Thr Thr Gly Gly
980 985 990
Cys Ala Thr Gly Gly Ala Ala Gly Thr Thr Ala Cys Cys Cys Cys Gly
995 1000 1005
Ala Gly Thr Gly Gly Thr Ala Cys Cys Thr Gly Gly Cys Thr Gly Ala
1010 1015 1020
Cys Cys Thr Ala Thr Ala Cys Cys Gly Gly Thr Gly Cys Cys Ala Thr
1025 1030 1035 1040
Thr Ala Ala Gly Cys Thr Gly Gly Ala Thr Gly Ala Thr Ala Ala Ala
1045 1050 1055
Gly Ala Thr Cys Cys Gly Ala Ala Thr Thr Thr Thr Ala Ala Ala Gly
1060 1065 1070
Ala Thr Cys Ala Gly Gly Thr Thr Ala Thr Thr Cys Thr Gly Cys Thr
1075 1080 1085
Gly Ala Ala Cys Ala Ala Ala Cys Ala Thr Ala Thr Thr Gly Ala Thr
1090 1095 1100
Gly Cys Cys Thr Ala Thr Ala Ala Ala Ala Cys Cys Thr Thr Cys Cys
1105 1110 1115 1120
Cys Gly Cys Cys Gly Ala Cys Cys Gly Ala Ala Cys Cys Gly Ala Ala
1125 1130 1135
Ala Ala Ala Ala Gly Ala Thr Ala Ala Ala Ala Ala Gly Ala Ala Ala
1140 1145 1150
Ala Ala Gly Gly Cys Ala Gly Ala Thr Gly Ala Gly Ala Cys Cys Cys
1155 1160 1165
Ala Gly Gly Cys Ala Cys Thr Gly Cys Cys Gly Cys Ala Gly Cys Gly
1170 1175 1180
Cys Cys Ala Gly Ala Ala Ala Ala Ala Ala Cys Ala Gly Cys Ala Gly
1185 1190 1195 1200
Ala Cys Cys Gly Thr Gly Ala Cys Ala Cys Thr Gly Cys Thr Gly Cys
1205 1210 1215
Cys Gly Gly Cys Ala Gly Cys Ala Gly Ala Thr Cys Thr Gly Gly Ala
1220 1225 1230
Thr Gly Ala Thr Thr Thr Thr Ala Gly Thr Ala Ala Ala Cys Ala Gly
1235 1240 1245
Cys Thr Gly Cys Ala Gly Cys Ala Gly Ala Gly Cys Ala Thr Gly Ala
1250 1255 1260
Gly Thr Ala Gly Cys Gly Cys Cys Gly Ala Thr Ala Gly Thr Ala Cys
1265 1270 1275 1280
Cys Cys Ala Gly Gly Cys Cys Gly Gly Ala Thr Cys Thr Gly Gly Cys
1285 1290 1295
Thr Cys Gly Cys Gly Thr Cys Gly Cys Ala Gly Ala Cys Gly Thr Cys
1300 1305 1310
Gly Ala Thr Ala Ala
1315
<210> 8
<211> 420
<212> DNA
<213> Artificial Sequence
<400> 8
atggctcctg cccaattttt aggtttgctt ctcctatgtt tccagggcac tcgttgcgaa 60
gttcaactgg tcgagtctgg agggggtgta gtgcagcccg gccgctcctt acgattgtca 120
tgtgcagcgt cgggatttac cttcagtgat tatccaatga attgggttcg gcaagctccg 180
gggaaaggtc ttgaatgggt cagctctatt tccggctcag gagggtcgac atactatgcc 240
gacagtgtaa agggtagatt tacgatcagc agggataact ctaaaaatac tctctaccta 300
cagatgaact ccctgcgtgc agaggacacc gcggtgtatt actgcgctaa gggcttattc 360
atggttacaa cgtatgcctt tgattactgg ggacaaggga ctaccgtcac agtatcatcg 420
<210> 9
<211> 1065
<212> DNA
<213> Artificial Sequence
<400> 9
gcctccacca ccgccccgaa ggtcttccct ctggctccca gctgtgggac cacatctgac 60
tccacggtgg ccctgggctg cctggtctcc agctacttcc cagagccagt gacagtgtcc 120
tggaactcgg gcacgctgac cagcggtgtg cgcaccttcc cgtccgtcct gcagtcctcg 180
gggctctact ccctcagcag catggtgact gtgcctgcca gcagcttgga gagcaagacc 240
tacatctgca acgtagccca cccggccagc agcaccaagg tggacaagag aatcgagccc 300
gtcctcccaa agcctacgac acctgcacct acagtgccgc taacaaccac agttccagtt 360
gagacgacta caccaccctg tccctgcgag tgtcccaaat gcccagctcc tgagctgcta 420
ggagggcctt ccgtgttcat cttcccccca aaaccgaagg acgtcctcat gatcacccga 480
acgcctgagg tcacctgcct ggttgtggac gtgagccatg acagctccga tgtcctgttc 540
acctggtatg tggacggcac agaggtgaag actgccaaga caatgccgaa cgaggaacag 600
aacaacagca cttaccgcgt ggtcagcgtc ctccgcatcc agcaccagga ctggctgaac 660
ggaaagaagt tcaagtgtaa ggtcaacaac caagccctcc cagcccctgt agagaggacc 720
atctccaagg ccacagggca aacccgggtg ccgcaggtgt atgtcctggc cccgcaccca 780
gatgagctgt ccaagaacaa ggtcagcgtg acctgcctgg tcaaggactt cttaccaacc 840
gacatcaccg tcgagtggca gagcaatgag catccagagc cagagggcaa gtacagaacc 900
actgaagccc agaaggacag cgacgggtcc tacttcctgt acagcaagct cactgtggag 960
acggacaggt ggcagcaggg aacgacattc acgtgtgtgg tgatgcatga ggctctccac 1020
aatcacgtca tgcagaagaa cgtctcccac tctccgggta aatga 1065
<210> 10
<211> 339
<212> DNA
<213> Artificial Sequence
<400> 10
atggctcctg cccaattttt aggtttgctt ctcctatgtt tccagggcac tcgttgcgaa 60
ctgacccaat ctccctcctc attatcggca agtgttggag atcgcgtcac aattacgtgt 120
cgagcgagcc agtctatctc ctcatatttg aattggtacc aacagaaacc agggaaggct 180
ccgaaacttc tcatatatgc cgcatcgagt ctacaaagcg gtgtaccttc tcggttttcc 240
ggctcaggat cggggactga cttcaccctg acaattagta gcttacagcc cgaggatttt 300
gcgacgtact attgccaaca gtcttactcc actccaccg 339
Claims (10)
1.一种新型冠状病毒检测试剂盒，其特征在于，包括抗原组分和发光组分；所述抗原组分中含有新型冠状病毒蛋白-磁珠复合物，所述新型冠状病毒蛋白-磁珠复合物包括S1蛋白-磁珠复合物、S2蛋白-磁珠复合物、E蛋白-磁珠复合物、M蛋白-磁珠复合物和N蛋白-磁珠复合物；所述发光组分中含有抗人IgG抗体，且所述抗人IgG抗体上标记有发光标记物。
2.根据权利要求1所述的新型冠状病毒检测试剂盒，其特征在于，所述抗原组分中，S1蛋白、S2蛋白、E蛋白、M蛋白和N蛋白的摩尔比为(2～5):(1～5):(2～5):(0.1～3):(0.1～3)。
3.根据权利要求2所述的新型冠状病毒检测试剂盒，其特征在于，所述抗原组分中，所述新型冠状病毒蛋白-磁珠复合物的总浓度为0.1mg/mL～0.5mg/mL。
4.根据权利要求1所述的新型冠状病毒检测试剂盒，其特征在于，所述抗人IgG抗体为鼠抗人IgG抗体。
5.根据权利要求4所述的新型冠状病毒检测试剂盒，其特征在于，所述抗人IgG抗体的Fc段为除鼠以外物种来源的Fc段。
6.根据权利要求5所述的新型冠状病毒检测试剂盒，其特征在于，所述抗人IgG抗体的Fc段来源为马Fc段。
7.根据权利要求1所述的新型冠状病毒检测试剂盒，其特征在于，还包括样品稀释组分，所述样品稀释组分中含有阻断剂和二硫苏糖醇。
8.根据权利要求7所述的新型冠状病毒检测试剂盒，其特征在于，所述阻断剂包括MAK33-IgG1/IgG1 poly、MAK33-IgG1/Fab1 Poly、Poly MAK IgG2b/Fab2a和IEP-Framework中的一种或多种。
9.根据权利要求1所述的新型冠状病毒检测试剂盒，其特征在于，所述新型冠状病毒蛋白-磁珠复合物的制备方法包括以下步骤：使用3mM～7mM的十二烷基硫酸钠溶液处理新型冠状病毒蛋白得到变性抗原，然后使用所述变性抗原包被磁珠。
10.根据权利要求1～9任一项所述的新型冠状病毒检测试剂盒，其特征在于，所述发光标记物包括吖啶酯、吖啶酯磺酰胺、吖啶酯甲苯磺酰胺、吖啶酯对甲基磺酰胺、吖啶酯三氟甲基磺酰胺中的一种或多种。
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