The role of multiple SARS-CoV-2 viral antigens in a vaccine-induced integrated immune response.
The role of multiple SARS-CoV-2 viral antigens in a vaccine-induced integrated immune response.
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DOI：
10.1016/j.vaccine.2021.03.067
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发表时间：
2021-04-28
期刊：
影响因子：
5.5
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Zhang Y;Li D;Zhao H;Wang L;Liao Y;Li X;Mou T;Li Q
2019年底出现的新型冠状病毒严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的全球大流行，已导致超过3000万人感染、100万人死亡的公共卫生危机[1，2]。加速不同国家和地区的疫苗和药物开发（访问ClinicalTrials。gov截至2020年10月10日）导致几种不同类型的疫苗迅速进入临床试验[3]。此后不久，获得了一系列临床数据，特别是免疫原性数据[4-6]。这些研究为开发有效的疫苗提供了基础，但同时也提出了一系列关于SARS-CoV-2感染免疫应答机制的问题，不同类型疫苗的免疫原性差异以及它们诱导的不同免疫应答[7]。我们对SARS-CoV-2的理解仅基于对冠状病毒家族其他成员的有限研究[7]。因此，SARS-CoV-2感染后的免疫应答特性可作为筛选合适疫苗抗原的理论基础。SARS-CoV-2包含四种主要结构蛋白，即刺突蛋白（S）、膜蛋白（M）、包膜蛋白（E）和核衣壳蛋白（N）。在这四种蛋白中，S被用作疫苗开发中的主要靶抗原，因为它负责识别宿主细胞受体以启动病毒进入。相比之下，N蛋白包装病毒RNA以形成螺旋衣壳，并且对于病毒存活是必需的。虽然N蛋白具有高度免疫原性，并且在许多冠状病毒家族成员感染期间大量表达[8]，但其在诱导免疫应答中的复杂作用无法判断其作为疫苗的主要靶抗原的意义。对SARS-CoV和禽冠状病毒传染性支气管炎病毒的研究表明，N抗体既不中和也不保护[9-11];然而，也有报道称N抗体或N特异性T细胞表位可以保护动物免受小鼠肝炎病毒、IBV、SARS-CoV和MERS-CoV的感染[12-15]。也有报道显示，尽管SARS-CoV-2 N蛋白的晶体结构与SARS-CoV N蛋白相似，但它们的表面静电势特征不同[16]。这些发现可能表明N蛋白在不同冠状病毒感染中的复杂作用。通过使用SARS-CoV-2活病毒的微量中和试验和包被有重组S蛋白、N蛋白和天然纯化病毒抗原的ELISA试剂盒，我们不仅能够检测到不同滴度的中和抗体（1：16-1：256），而且能够检测到高滴度的抗S、抗N和抗全病毒体抗体（图1ab）。这些抗体在COVID-19患者恢复期血清中的存在表明，SARS-CoV-2的各种抗原成分在整个病程中刺激了免疫系统。这就提出了一个问题，即针对其他病毒抗原的抗体，特别是作为主要核衣壳蛋白的N蛋白，是否在抗病毒免疫应答中起作用。在恒河猴免疫激发试验中，使用含有暴露的SARS-CoV-2结构蛋白组分的特别制备的灭活疫苗，进一步观察了抗N抗体的抗病毒作用。用200、100和20 EU（ELISA单位，ELISA测定的病毒抗原浓度）灭活疫苗免疫恒河猴，间隔14天，中和抗体反应呈剂量依赖性。
The global pandemic caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged at the end of 2019, has led to a public health crisis in which more than 30 million people have been infected and 1 million have died [1, 2]. Accelerated vaccine and drug development in different countries and regions (accessed at ClinicalTrials. gov as of Oct. 10, 2020) resulted in the rapid entry of several different types of vaccines into clinical trials [3]. Shortly thereafter, a series of clinical data were obtained, especially immunogenic data [4–6]. These studies provide a basis for the development of effective vaccines, but at the same time, they have raised a series of questions regarding the mechanism underlying the immunological response to infection with SARS-CoV-2, the differences in immunogenicity among various types of vaccines and the different immune responses they induce [7]. Our understanding of SARS-CoV-2 is based solely on the limited studies on other members of the coronavirus family [7]. Therefore, the characteristics of the immune response to infection with SARS-CoV-2 should serve as the theoretical basis for the identification of a suitable vaccine antigen. SARS-CoV-2 contains four major structural proteins, namely, spike (S), membrane (M), envelope (E) and nucleocapsid (N). Among these four proteins, S is being used as the leading target antigen in vaccine development because it is responsible for recognition of the host cellular receptor to initiate virus entry. In contrast, N protein packages the viral RNA to form a helical capsid and is essential for virus viability. Although N proteins are highly immunogenic and are expressed abundantly during infection of many coronaviruses family members [8], their complicated role in inducing an immune response is unable to judge its significance as a major target antigen for vaccine. Studies of SARS-CoV and avian coronavirus infectious bronchitis virus showed that N antibodies are not neutralizing nor protecting [9–11]; however, N antibodies or N-specific T cell epitopes have also been reported to protect animals from infection by mouse hepatitis virus, IBV, SARS-CoV and MERS-CoV [12–15]. There are also reports showing that although the crystal structure of the SARS-CoV-2 N protein is similar to that of the SARS-CoV N protein, their surface electrostatic potential characteristics are distinct [16]. These findings might suggest a complicated role of N proteins in different coronavirus infections. With a microneutralization assay using SARS-CoV-2 live virus and an ELISA kit coated with recombinant S protein, N protein and native purified viral antigen, we were able to detect not only varied titers of neutralizing antibodies (1: 16–1: 256) but also high titers of anti-S, anti-N and anti-whole-virion antibodies (Fig. 1 ab). The presence of these antibodies in the convalescent sera of COVID-19 patients suggests the stimulation of the immune system by various antigen components of SARS-CoV-2 throughout the disease course. This raises the question of whether the antibodies against other viral antigens, especially the N protein as the major nucleocapsid protein, function in the antiviral immune response. The antiviral effect of the anti-N antibody was further observed in a rhesus monkey immunization challenge test using a specially prepared inactivated vaccine containing exposed structural protein components of SARS-CoV-2. In rhesus macaques immunized with two doses of 200, 100 and 20 EUs (ELISA units, the viral antigen concentration determined by ELISA) inactivated vaccine with a 14-day interval, the neutralizing antibody reaction showed a dose-dependent …
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影响因子：
64.8
作者：
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