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: 10609822
• 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/10609822
• 关键词: 2019-nCoV; Address; Advanced Development; Affect; Affinity; Animals; Antibodies; Antibody Response; Antigens; Binding; Biology; Blood; Body Fluids; 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; Employee; FDA Emergency Use Authorization; Failure; Glycoproteins; Goals; HIV envelope protein; Hospitalization; Hospitals; Human; IgG1; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunology; Individual; Infection; Inflammatory; Macaca mulatta; Mass Spectrum Analysis; Measures; Mediating; Medical center; Mucous Membrane; Myeloid Cells; Patients; Phagocytosis; Plasma; Polysaccharides; Population; Positioning Attribute; Predisposition; 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; convalescent plasma; cytokine; cytotoxicity; experience; glycosylation; high risk population; 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.

项目总结/摘要 COVID-19大流行是由SARS-CoV-2引起的，SARS-CoV-2是一种新型冠状病毒，首次发现于 2019年11月至12月，全球数百万人死亡。在美国，疫情正在影响 数百万条生命退伍军人医院，包括布朗克斯的詹姆斯·J·彼得斯退伍军人医疗中心（JJP VAMC）， 纽约，已迅速作出反应，为退伍军人和雇员提供照顾。退伍军人通常比 美国普通人群，使他们极易患上严重疾病。COVID-19疫苗也是 最初分发给老年人和其他高危人群。这为VA提供了一个独特的机会， 研究SARS-CoV-2感染和疫苗接种在最脆弱的个人。 本VA Merit申请旨在研究抗体（Abs）的保护作用， SARS-CoV-2刺突蛋白及其受体结合结构域（RBD）。在 特别地，我们将检查尚未很好理解的Ab Fc特性和功能以及 存在于血液和唾液中，作为病毒进入粘膜部位的Ab的替代物。该研究旨在建立 根据我们发表的和初步的结果，显示不同的免疫球蛋白（IG）同种型的检测 恢复期COVID-19患者和疫苗的唾液vs血浆中SARS-CoV-2刺突和RBD 受惠人士有趣的是，我们的初步数据表明，唾液中的刺突特异性IG同种型缺乏相关性 与来自感染和接种疫苗的受试者的血浆相比。数据进一步显示了C1 q的结合，第一个 在经典补体级联反应中，抗体是补体的一个重要组成部分，与来自感染和接种受试者的Ab结合。值得注意的是， 唾液与血浆中Ab的C1 q结合活性相关性较差，为以下结论提供了初步证据： 由感染和疫苗接种引起的粘膜抗刺突抗体与循环抗刺突抗体的不同Fc功能。 为了进一步研究抗SARS-CoV-2抗体的Fc特性和功能，我们假设 Fc同种型和糖基化是Fc依赖性Ab在保护中功能的关键决定因素， 对抗新冠肺炎。一个研究团队，包括在抗体和病毒方面具有专业知识的研究专家 免疫学（主要研究者：卡塔里纳Hioe，JJP VAMC;合作者：Susan Zolla-Pazner，Chitra Upadhyay，Ray Alvarez在西奈山医学院/MSSM），质谱和聚糖生物学专家（惠 约翰霍普金斯大学的Zhang）和传染病临床医生（JJP VAMC的Juan Bandres）将在 一起来检验这个假设。我们将利用我们在抗艾滋病毒抗体方面的广泛专业知识， 糖蛋白和我们在过去一年中研究抗SARS-CoV-2抗体应答的经验。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持久性， 门诊和住院COVID-19患者和健康人不同体液中的峰电位和RBD 未受感染的COVID-19 RNA疫苗接种者。目的2将评价Fc区上的聚糖结构 来自SARS-CoV-2感染和接种受试者的抗刺突抗体。目标3将评估Fc介导的 这些Ab介导的破坏病毒颗粒和病毒感染细胞的活性，即补体 结合/活化和Fc γ R介导的信号传导、细胞毒性和吞噬作用。不同IG同种型的Ab和 还将检查实验修饰的Fc聚糖的Fc依赖性活性。拟议 这项研究将产生关键数据，以推动开发用于诊断的改进的基于抗体的武库， 抗COVID-19药物和治疗药物。