Project-002

项目-002

• 批准号: 10169069
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 87.39万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10169069
• 关键词: 2019-nCoV; Adult Respiratory Distress Syndrome; Antibodies; Antibody Diversity; Antibody Response; Antibody Specificity; Antibody Therapy; Antigens; B-Cell Activation; B-Lymphocytes; Biological Assay; COVID-19; COVID-19 pandemic; Characteristics; Clinical; Clinical Data; Clonality; Development; Disease; Disease susceptibility; Fc domain; Heterogeneity; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologics; Individual; Infection; Life; Mediating; Memory B-Lymphocyte; Pathogenesis; Pathogenicity; Patient Recruitments; Patients; Phenotype; Pneumonia; Polysaccharides; Population; Predisposition; Property; Public Health; Receptors, Antigen, B-Cell; Research; Serological; Severity of illness; Specificity; Symptoms; Therapeutic Intervention; Virus; Virus Diseases; antiviral immunity; cohort; cross reactivity; disorder control; disorder prevention; epidemiologic data; follow-up; high risk population; insight; novel; novel therapeutics; parent grant; recruit; response; socioeconomics; transcriptome; transcriptomics; vaccine development

Abstract Extensive research on the basic immunological mechanisms that drive human immunity has provided the general framework by which the human immune system responds to foreign antigens. However, it is well-appreciated that each viral infection poses unique challenges to the immune system and the elicited immune responses are characterized by substantial heterogeneity that impacts disease susceptibility and pathogenesis, by conferring either protective or disease-enhancing activities. The ongoing COVID-19 pandemic represents a significant threat for global public health with tremendous socio-economic consequences. Early clinical and epidemiological data from COVID-19 patients suggest that while for the majority of the population, SARS-CoV-2 infection causes mild symptoms that usually resolve within a few weeks, a substantial fraction of patients develops severe, often life-threatening, clinical complications, including acute respiratory distress syndrome and pneumonia. Differences in the induction of protective antiviral immunity likely accounts for the differential susceptibility to severe disease upon SARS-CoV-2 infection. Understanding the heterogeneity of immune responses elicited upon SARS-CoV-2 infection is therefore critical for characterizing the immune mechanisms that confer protection against COVID-19 disease, guiding the development of novel therapeutics for disease control, as well as, determining disease susceptibility in high-risk populations. The proposed studies aim to characterize the antibody responses that are elicited upon infection with SARS-CoV-2, determining the breadth of antibody specificities, neutralization potency, as well as Fc domain heterogeneity of anti-SARS-CoV-2 IgG antibodies. More specifically, we plan to recruit recovered COVID-19 patients and systematically analyze their B-cell responses to determine their transcriptomic profile, as well as the functional properties of their B-cell receptors. In parallel, serologic studies from these individuals aim to characterize the breadth and potency of their neutralization activity and determine the subclass and Fc glycan distribution of anti-SARS-CoV-2 antibodies. Additionally, Fc domain function will be assessed in well-established ADCC, ADCP, and ADE assays to evaluate the capacity of anti-SARS-CoV-2 IgG antibodies to confer protective or pathogenic activities. Follow-up serologic studies will be performed in a large cohort of patients with variable disease severity, ranging from asymptomatic to severe symptomatic cases, to determine the functional activity of elicited anti-SARS-CoV-2 antibodies and assess their Fc domain heterogeneity and effector function. These studies are within the scope of our parent grant, as they are focused on the understanding of the immune responses that are elicited during viral infection. We anticipate that the findings of these studies will provide novel insights into the immunological mechanisms that confer protection or susceptibility to COVID-19 disease, accelerating our efforts for the development of vaccine or therapeutic interventions for the control of SARS-CoV-2 infection.

摘要 对驱动人类免疫的基本免疫机制的广泛研究提供了一般的 人类免疫系统对外来抗原作出反应的框架。然而， 每种病毒感染都会对免疫系统提出独特的挑战， 其特征在于影响疾病易感性和发病机制的实质性异质性， 保护性或增强疾病的活动。持续的COVID-19大流行是一个重大的 对全球公共卫生构成威胁，并带来巨大的社会经济后果。早期临床和流行病学 来自COVID-19患者的数据表明，虽然对大多数人来说，SARS-CoV-2感染导致 轻度症状通常在几周内消退，但相当一部分患者发展为严重症状， 危及生命的临床并发症，包括急性呼吸窘迫综合征和肺炎。 诱导保护性抗病毒免疫的差异可能解释了对 严重的疾病在SARS-CoV-2感染。了解免疫反应的异质性 因此，在SARS-CoV-2感染后， 针对COVID-19疾病，指导疾病控制新疗法的开发，以及， 确定高危人群的疾病易感性。拟议的研究旨在表征 在感染SARS-CoV-2后引发的抗体应答，决定了抗体的宽度 特异性、中和效力以及抗SARS-CoV-2 IgG抗体的Fc结构域异质性。 更具体地说，我们计划招募康复的COVID-19患者，并系统地分析他们的B细胞 反应，以确定其转录谱，以及其B细胞受体的功能特性。 与此同时，对这些个体的血清学研究旨在表征其感染的广度和效力。 中和活性并确定抗SARS-CoV-2抗体的亚类和Fc聚糖分布。 此外，将在成熟的ADCC、ADCP和ADE试验中评估Fc结构域功能，以评价 抗SARS-CoV-2 IgG抗体赋予保护或致病活性的能力。随访血清学 研究将在一个大的疾病严重程度不同的患者队列中进行，从无症状到无症状， 严重症状病例，以确定引发的抗SARS-CoV-2抗体的功能活性， 评估其Fc结构域异质性和效应子功能。这些研究属于我们母公司的范围。 格兰特，因为他们专注于理解病毒感染期间引起的免疫反应。 我们预期这些研究的发现将为免疫学机制提供新的见解 保护或易感COVID-19疾病，加快我们的努力， 控制SARS-CoV-2感染的疫苗或治疗干预措施。