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.

项目摘要/摘要 由SARS-COV-2引起的COVID-19大流行，这是一种新的冠状病毒，最初检测到 2019年11月至12月，在全球造成数百万次死亡。在美国，爆发正在影响 数百万的生命。 VA医院，包括Bronx的James J. Peters VA医疗中心（JJP VAMC） 纽约，已迅速做出回应，以向退伍军人和雇员提供照顾。退伍军人通常比 美国普通人群，使其非常容易受到严重疾病的影响。 Covid-19疫苗也是 最初分配给老年人和其他高风险个体。这为VA提供了一个独特的机会 研究最脆弱的个体中的SARS-COV-2感染和疫苗接种。 这项VA值得应用的提案，以调查引起的抗体（ABS）的保护作用 疫苗接种或感染后，SARS-COV-2尖峰蛋白及其接收器结合结构域（RBD）。在 特别是，我们将检查AB FC的属性和功能，这些属性和功能尚未很好地理解，ABS是 在病毒进入的粘膜部位中存在于血液和唾液中作为ABS的代理。拟议的研究是建立的 根据我们发表的初步结果，显示了不同免疫球蛋白（IG）同种型的检测 反对唾液与康复盐联合19例患者和疫苗的SARS-COV-2尖峰和RBD 收件人。有趣的是，我们的初步数据表明唾液中缺乏峰值特异性Ig同种型的相关性 与感染和疫苗接种受试者的血浆。数据进一步显示了C1Q的结合，第一个 经典补体级联反应中的成分，来自感染和接种受试者的ABS。尤其， 唾液与等离子体中ABS的C1Q结合活性的相关性很差，提供了初始证据 粘膜与循环抗尖峰的差异FC功能通过感染和疫苗接种引起。 为了进一步研究ABS对SARS-COV-2的FC特性和功能，我们假设 FC同种型和糖基化是Provestion FC依赖性AB功能的关键决定剂 反对COVID-19。一个研究团队，包括具有ABS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 质谱和聚糖生物学专家（HUI） 张在约翰·霍普金斯大学（Johns Hopkins Univ）和传染病临床（Co-I：JJP VAMC的Juan Bandres）将起作用 共同检验这一假设。我们将利用我们在针对HIV信封的ABS方面的广泛专业知识 在过去的一年中，糖蛋白和我们调查针对SARS-COV-2的AB反应的经验。在AIM 1中， 我们将收集纵向血浆和唾液样品，以确定ABS的同种型和耐用性 在不同的体液和住院的Covid-19患者和健康的体液中的尖峰和RBD 未感染的Covid-19 RNA疫苗的接收者。 AIM 2将评估FC区域的聚糖结构 来自SARS-COV-2感染和接种疫苗的受试者的ABS针对尖峰。 AIM 3将评估FC介导的 这些ABS介导的活动以破坏病毒颗粒和病毒感染的细胞，即完成 结合/激活和FCɣR介导的信号传导，细胞毒性和吞噬作用。不同的Ig同种型和 通过实验修改的FC聚糖，还将检查其FC依赖性活动。提议 研究将产生至关重要的数据，以促进改进基于AB的砷的诊断， 预防药物和针对COVID-19的治疗。