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

• 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
• 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

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 SARS-CoV-2 感染或最终疫苗接种后驱动保护性抗体反应的修饰剂。