COVID-19: Significance of Fc properties and functions in antibody responses against SARS-CoV-2

COVID-19：Fc 特性和功能在针对 SARS-CoV-2 的抗体反应中的重要性

• 批准号: 10365140
• 负责人: Catarina E Hioe
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365140
• 关键词: 2019-nCoV; Address; Advanced Development; Affect; Affinity; Animals; Antibodies; Antibody Response; Antigens; Binding; Biology; Blood; COVID-19; COVID-19 diagnostic; COVID-19 intervention; COVID-19 pandemic; COVID-19 patient; COVID-19 therapeutics; COVID-19 vaccine; Caring; Cells; Cessation of life; China; Chitra; Communicable Diseases; Complement; Complement 1q; DNA Vaccines; Data; Death Records; Deposition; Detection; Development; Diagnostic; Disease; Disease Outbreaks; Disease Outcome; Elderly; Emergency Situation; Employee; Failure; Glycoproteins; Goals; HIV; Hospitals; Human; IgG1; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunology; Individual; Infection; Inflammatory; Lead; Liquid substance; Macaca mulatta; Mass Spectrum Analysis; Measures; Mediating; Medical center; Mucous Membrane; Myeloid Cells; Patients; Phagocytosis; Plasma; Polysaccharides; Population; Positioning Attribute; Production; Property; Proxy; Publishing; RNA vaccine; Reporting; Research; Risk Factors; Role; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Saliva; Signal Transduction; Specialist; Specimen; Structure; Symptoms; Testing; Time; Vaccination; Vaccinee; Vaccines; Veterans; Viral; Virion; Virus; Vulnerable Populations; Work; antibody-dependent cellular phagocytosis; base; convalescent plasma; cytokine; cytotoxicity; experience; glycosylation; high risk; improved; male; medical schools; mucosal site; neutralizing antibody; neutrophil; novel coronavirus; pandemic disease; preclinical study; prophylactic; receptor binding; response; saliva sample; severe COVID-19; vector

Project Summary/Abstract The COVID-19 pandemic, which is caused by SARS-CoV-2, a novel coronavirus first detected in November-December 2019, has inflicted millions of deaths worldwide. In the US, the outbreak is affecting millions of lives. The VA hospitals, including the James J. Peters VA Medical Center (JJP VAMC) in the Bronx, NY, have responded promptly to provide care to Veterans and employees. Veterans are typically older than the general US population, making them highly susceptible to severe disease. COVID-19 vaccines are also distributed initially to the elderly and other high-risk individuals. This provides the VA a unique opportunity to study SARS-CoV-2 infection and vaccination in the most vulnerable individuals. This VA Merit application proposes to investigate the protective role of antibodies (Abs) elicited against the SARS-CoV-2 spike protein and its receptor-binding domain (RBD) following vaccination or infection. In particular, we will examine the Ab Fc properties and functions that are not well understood and the Abs that are present in blood and in saliva as a proxy of Abs at the mucosal site of virus entry. The proposed study is built upon our published and preliminary results showing the detection of different immunoglobulin (Ig) isotypes against SARS-CoV-2 spike and RBD in saliva vs plasma of convalescent COVID-19 patients and vaccine recipients. Interestingly, our preliminary data indicate a lack of correlation of spike-specific Ig isotypes in saliva vs plasma from infected and vaccinated subjects. The data further show the binding of C1q, the first component in the classical complement cascade, to Abs from both infected and vaccinated subjects. Notably, the C1q binding activities of Abs in saliva vs plasma correlated poorly, offering the initial evidence for differential Fc functions of mucosal vs circulating anti-spike Abs elicited by infection and vaccination. To investigate further the Fc properties and functions of Abs against SARS-CoV-2, we hypothesize that Fc isotype and glycosylation are the key determinants of Fc-dependent Ab functions in protection against COVID-19. A research team that include research specialists with expertise in Abs and viral immunology (PI: Catarina Hioe at JJP VAMC; collaborators: Susan Zolla-Pazner, Chitra Upadhyay, Ray Alvarez at Mount Sinai School of Medicine/MSSM), an expert in mass spectrometry and glycan biology (Hui Zhang at Johns Hopkins Univ), and an infectious disease clinician (Co-I: Juan Bandres at JJP VAMC) will work together to test this hypothesis. We will leverage our extensive expertise in Abs against HIV envelope glycoprotein and our experience investigating Ab responses against SARS-CoV-2 in the past year. In Aim 1, we will collect longitudinal plasma and saliva samples to determine the isotypes and durability of Abs against spike and RBD in different bodily fluids of ambulatory and hospitalized COVID-19 patients and healthy uninfected recipients of COVID-19 RNA vaccines. Aim 2 will evaluate the glycan structures on the Fc regions of Abs against spike from SARS-CoV-2-infected and vaccinated subjects. Aim 3 will assess the Fc-mediated activities that these Abs mediate to destroy virus particles and virus-infected cells, i.e. complement binding/activation and FcɣR-mediated signaling, cytotoxicity, and phagocytosis. Abs of different Ig isotypes and with experimentally modified Fc glycans will also be examined for their Fc-dependent activities. The proposed study will produce data critical to advance the development of improved Ab-based arsenals for diagnostics, prophylactics, and therapeutics against COVID-19.

项目概要/摘要 COVID-19 大流行是由 SARS-CoV-2 引起的，这是一种在 2019 年首次发现的新型冠状病毒 2019年11月至12月，美国疫情已造成全球数百万人死亡。 退伍军人管理局医院，包括布朗克斯区的詹姆斯·J·彼得斯退伍军人管理局医疗中心 (JJP VAMC)， 纽约州迅速做出反应，为退伍军人和雇员提供护理，退伍军人的年龄通常比老年人要大。 美国普通民众也极易感染 COVID-19 疫苗。 最初分发给老年人和其他高危人群，这为 VA 提供了独特的机会。 研究最脆弱人群的 SARS-CoV-2 感染和疫苗接种。 该 VA Merit 申请旨在研究抗体 (Abs) 的保护作用 疫苗接种或感染后的 SARS-CoV-2 刺突蛋白及其受体结合域 (RBD)。 特别是，我们将检查尚未被充分理解的 Ab Fc 特性和功能，以及尚未被充分理解的 Ab。 存在于血液和唾液中，作为病毒进入粘膜部位的抗体的代表。 根据我们已发表的初步结果显示不同免疫球蛋白 (Ig) 同种型的检测 恢复期 COVID-19 患者唾液与血浆中的 SARS-CoV-2 尖峰和 RBD 及疫苗的对抗 recipients.symbolic，我们的初步数据表明唾液中尖峰特异性 Ig 同种型缺乏相关性 与来自感染者和肺炎受试者的血浆相比，数据进一步显示了 C1q 的结合，这是第一个。 经典补体级联的组成部分，针对感染者和肺炎受试者的抗体。 唾液与血浆中 Abs 的 C1q 结合活性相关性较差，为 感染和疫苗接种引起的粘膜与循环抗尖峰抗体的不同 Fc 功能。 为了进一步研究针对 SARS-CoV-2 的抗体的 Fc 特性和功能，我们 Fc 同种型和糖基化是 Fc 依赖性抗体保护功能的关键决定因素 针对 COVID-19 的研究团队，包括具有抗体和病毒专业知识的研究专家。 免疫学（PI：JJP VAMC 的 Catarina Hioe；合作者：Susan Zolla-Pazner、Chitra Upadhyay、Ray 西奈山医学院/MSSM 的 Alvarez），质谱和聚糖生物学专家（Hui 约翰·霍普金斯大学的张）和传染病临床医生（Co-I：JJP VAMC 的胡安·班德雷斯）将工作 我们将利用我们在抗 HIV 包膜抗体方面的丰富专业知识来共同检验这一假设。 糖蛋白以及我们在过去一年中研究针对 SARS-CoV-2 的抗体反应的经验 在目标 1 中， 我们将收集纵向血浆和唾液样本，以确定抗体的同种型和耐久性 门诊和住院 COVID-19 患者和健康人不同体液中的峰值和 RBD 目标 2 将评估 Fc 区域的聚糖结构。 目标 3 将评估 Fc 介导的抗体。 这些抗体介导的破坏病毒颗粒和病毒感染细胞的活动，即补体 不同 Ig 同种型和抗体的结合/激活和 FcɣR 介导的信号传导、细胞毒性和吞噬作用。 还将检查经过实验修饰的 Fc 聚糖的 Fc 依赖性活性。 研究将产生对于推进改进的基于抗体的诊断工具库的开发至关重要的数据， 针对 COVID-19 的预防和治疗。