Project 3: Defining the antibody landscape after SARS-CoV-2 infection

项目 3：定义 SARS-CoV-2 感染后的抗体格局

基本信息

批准号：
10221910
负责人：
SABRA L. KLEIN
金额：
$ 85.51万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221910
关键词：
2019-nCoV Antibodies Antibody Response Antibody titer measurement Autoimmunity Biological Assay COVID-19 COVID-19 pandemic Cells Characteristics Clinical Complement Complement Activation Complement-Dependent Cytotoxicity Data Disease Enrollment Goals Immune response Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunoglobulins Individual Infection Kinetics Linear Regressions Measures Mediating Methods Modeling Pathogenesis Pathology Patients Phase Plasma Population Positioning Attribute Prospective cohort Proteins Public Health Regression Analysis Research Personnel Research Project Grants Resolution Resources Role Sampling Serological Serum Severity of illness Survivors Time Vaccination Variant Virion Virus Virus Diseases Work antibody-dependent cell cytotoxicity cohort dimer experience influenzavirus male neutralizing antibody pandemic disease prospective receptor binding response sample fixation vaccine development virology

项目摘要

Research Project 3 Summary There are insufficient data regarding the long-term humoral immune responses induced after SARS-CoV-2 infection. Our preliminary data indicate that there is variation in the magnitude and duration of antibody responses following SARS-CoV-2 infection. While IgG and IgA antibodies against spike (S) and the receptor binding domain of S (S-RBD) appear to remain constant over time, neutralizing antibody (nAb) titers wane and are not detected in up to 25% of infected individuals who have detectable anti-S and anti-S-RBD antibodies. We have also observed that during the convalescent phase of SARS-CoV-2 infection, individuals with more severe COVID-19 (i.e., hospitalized, older, and male patients) have significantly greater serological responses to SARS-CoV-2. The antibody responses mediating protection from re-infection are not defined, and neither are responses that may mediate greater pathology. From studies of other viruses, it is clear that a variety of antibody functions contribute to protection from re-infection and modulate disease severity. Both nAbs and non-nAbs can mediate a number of different activities, which include complement activation and antibody- dependent cellular cytotoxicity (ADCC), which may contribute to pathogenesis as well as protections from SARS-CoV-2. The overarching goal of JH-EPICS Research Project 3 is to analyze the magnitude and duration of the total as well as functional antibody responses after SARS-CoV-2 infection. We have developed a core set of serological assays to be applied to a prospective, demographically diverse cohort of hospitalized patients presenting with mild, moderate, and severe COVID-19 disease. Plasma samples have and will continue to be collected at multiple timepoints from enrollment through one year post-enrollment. Aim 1 will systematically evaluate antibody isotype switching and the subclasses and quality of the immunoglobulins (IgG, IgM, and IgA [monomeric and dimeric]) that recognize the SARS-CoV-2 S and S-RBD. Aim 2 will characterize the kinetics and duration of the neutralizing antibody response against SARS-CoV-2 and the ability of viruses to escape from nAbs. Finally, Aim 3 will analyze the function of non-neutralizing SARS-CoV-2-specific serological response by assessing ADCC, complement-mediated cytotoxicity, and complement fixation activity toward SARS-CoV-2 virus particles and virus-infected cells. Using linear regression analyses and modeling of these data in the context of clinical and demographic information, we are uniquely positioned to determine the modifiers that drive a protective antibody response following SARS-CoV-2 infection or, eventually, vaccination.

研究项目3概要关于 SARS-CoV-2 后诱导的长期体液免疫反应的数据不足感染。我们的初步数据表明抗体的强度和持续时间存在差异 SARS-CoV-2 感染后的反应。而针对刺突 (S) 和受体的 IgG 和 IgA 抗体 S (S-RBD) 的结合域似乎随着时间的推移保持恒定，中和抗体 (nAb) 滴度下降并且在高达 25% 的具有可检测到的抗 S 和抗 S-RBD 抗体的感染者中未检测到。我们还观察到，在 SARS-CoV-2 感染的恢复期，患有更多疾病的个体重症 COVID-19（即住院患者、老年患者和男性患者）的血清学反应明显更高 SARS-CoV-2。介导防止再次感染的抗体反应尚未定义，也没有定义是可能介导更大病理学的反应。从对其他病毒的研究来看，很明显，多种病毒抗体功能有助于防止再次感染并调节疾病的严重程度。 nAb 和非 nAb 可以介导许多不同的活性，其中包括补体激活和抗体- 依赖性细胞毒性（ADCC），可能有助于发病机制以及保护免受 SARS-CoV-2。 JH-EPICS 研究项目 3 的总体目标是分析影响的幅度和持续时间 SARS-CoV-2 感染后的总抗体反应和功能性抗体反应。我们开发了一个核心一组血清学检测，适用于前瞻性、人口多样化的住院患者队列患有轻度、中度和重度 COVID-19 疾病。血浆样本已经并将继续从注册到注册后一年的多个时间点收集。目标1将系统地评估抗体同种型转换以及免疫球蛋白（IgG、IgM 和 IgA）的亚类和质量 [单体和二聚体]）可识别 SARS-CoV-2 S 和 S-RBD。目标 2 将表征动力学针对 SARS-CoV-2 的中和抗体反应的持续时间以及病毒逃逸的能力来自 nAb。最后，目标 3 将分析非中和 SARS-CoV-2 特异性血清学的功能通过评估 ADCC、补体介导的细胞毒性和补体结合活性来评估反应 SARS-CoV-2 病毒颗粒和病毒感染的细胞。使用线性回归分析和建模临床和人口统计信息背景下的数据，我们具有独特的优势来确定在 SARS-CoV-2 感染或最终接种疫苗后驱动保护性抗体反应的修饰剂。