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: 10688368
• 负责人: SABRA L. KLEIN
• 金额: $ 43.22万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688368
• 关键词: 2019-nCoV; Antibodies; Antibody Response; Antibody titer measurement; Autoimmunity; COVID-19 pandemic; COVID-19 patient; COVID-19 survivors; 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; SARS-CoV-2 antibody; SARS-CoV-2 immune response; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Sampling; Serology; Serology test; Serum; Severity of illness; Time; Vaccination; Variant; Virion; Virus; Work; antibody-dependent cell cytotoxicity; cohort; convalescent plasma; dimer; experience; influenza infection; male; neutralizing antibody; pandemic disease; post SARS-CoV-2 infection; prospective; receptor binding; response; sample fixation; severe COVID-19; 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总结 关于SARS-CoV-2诱导的长期体液免疫应答的数据不足 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和伊加抗体 S（S-RBD）的结合结构域似乎随着时间的推移保持恒定，中和抗体（nAb）滴度减弱， 在高达25%的具有可检测的抗S和抗S-RBD抗体的感染个体中未检测到。 我们还观察到，在SARS-CoV-2感染的恢复期， 严重的COVID-19（即，住院患者、老年患者和男性患者）的血清学应答显著更高 SARS-CoV-2。介导防止再感染的抗体应答尚未确定， 可能会导致更严重的疾病从对其他病毒的研究来看，很明显， 抗体功能有助于防止再感染和调节疾病的严重程度。nAb和 非nAb可以介导许多不同的活性，包括补体激活和抗体- 依赖性细胞毒性（ADCC），这可能有助于发病机制以及保护 SARS-CoV-2. JH-EPICS研究项目3的首要目标是分析 SARS-CoV-2感染后的总抗体应答和功能性抗体应答。我们开发了一个核心 一组血清学检测，用于前瞻性、人口统计学多样性的住院患者队列 出现轻度、中度和重度COVID-19疾病。血浆样本已经并将继续 在从入组到入组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和免疫球蛋白（IgG、IgM和伊加）的亚类和质量 [单体和二聚体]）识别SARS-CoV-2 S和S-RBD。目标2将描述动力学特征 中和抗体对SARS-CoV-2的反应时间和病毒逃逸的能力 nAbs的。最后，目的3将分析非中和SARS-CoV-2特异性血清学抗体的功能， 通过评估ADCC、补体介导的细胞毒性和补体结合活性， SARS-CoV-2病毒颗粒和病毒感染细胞。使用线性回归分析和建模这些 在临床和人口统计信息的背景下，我们处于独特的地位，以确定 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。