Antibody display libraries for precision screening of antibody immune responses to SARS-CoV-2

用于精确筛选针对 SARS-CoV-2 的抗体免疫反应的抗体展示文库

• 批准号: 10649740
• 负责人: Brandon James DeKosky
• 金额: $ 11.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-09 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649740
• 关键词: 2019-nCoV; Address; Antibodies; Antibody titer measurement; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Burkitt Lymphoma; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical; Clinical Research; Convalescence; Cost Effectiveness Analysis; Cryopreservation; Data; Data Analyses; Data Set; Development; Disease; EBV-associated disease; Ensure; Epstein-Barr Virus Infections; Exhibits; Fatigue; Future; Goals; Herpesviridae; Herpesviridae Infections; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Immune response; Immunocompetent; Immunologic Receptors; Incidence; Individual; Infection; Infectious Mononucleosis; Intervention; Knowledge; Libraries; Lymphoproliferative Disorders; Machine Learning; Malignant Neoplasms; Methods; Molecular; Multiple Sclerosis; Nasopharynx Carcinoma; Oncogenic; Patients; Phase; Population; Prevention; Preventive; Primary Infection; Public Health; Recovery; Research Personnel; Risk; Sampling; Serum; Severities; Severity of illness; Stomach Carcinoma; Symptoms; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Technology; Teenagers; Testing; Therapeutic; Therapeutic antibodies; Time; Vaccine Design; Vaccines; Viral Load result; Virus Diseases; Work; adaptive immune response; adaptive immunity; base; career; cohort; cost; design; disorder control; experimental study; high dimensionality; human disease; immune function; insight; lead candidate; long-term sequelae; multiple sclerosis patient; neutralizing monoclonal antibodies; next generation; novel; novel therapeutics; novel vaccines; pathogen; personalized screening; pressure; prevent; prospective; rational design; response; therapeutic development; translational goal; treatment strategy; vaccine development; vaccine trial; virology; young adult

Project Summary/Abstract This project will develop a new technological approach for the comprehensive analysis of adaptive immune responses, which holds the potential to catalyze new strategies to prevent and treat disease. Here we will apply immune profiling techniques recently invented by the PI to investigate the mechanisms of Epstein-Barr virus (EBV) adaptive immune control in clinical cohorts of infected patients. EBV is a highly prevalent pathogen infecting >90% of the world’s population. Primary EBV infection often causes infectious mononucleosis (IM) and long-term sequelae include numerous malignancies, lymphoproliferative disorders, and a strong association with multiple sclerosis. No EBV vaccine is approved to date, and the molecular mechanisms of immune protection from EBV-associated diseases are unclear. Unfortunately, prior technical barriers in high- throughput immune profiling methods have prevented a comprehensive understanding of adaptive immune protection against EBV diseases. A technological approach that identifies the critical features of EBV immune protection will advance new solutions for vaccine and therapeutic development. Therefore, we developed an experimental pipeline to enable rapid and cost-effective analysis of B- and T-cell responses to EBV that is scalable to dozens of human patients per experiment. We hypothesize that a comprehensive B- and T-cell analysis of carefully selected patient cohorts that either can or cannot suppress symptomatic infection will reveal function-based correlates of EBV control. To test this hypothesis, we will apply quantitative immune profiling technologies to analyze cryopreserved longitudinal samples from recently completed prospective clinical studies of IM. Patient samples in our cohort span pre- and post-infection through convalescence and encompass the full range of clinical IM severity scores (from 0, asymptomatic primary infection, to 6, essentially bedridden with IM). Immune profile data will be used to establish adaptive immune correlates of IM disease severity. In addition, we will analyze immune responses in apparently immunocompetent patients with chronic active EBV (CAEBV) disease, or patients who do not adequately suppress EBV infection, to gain insight regarding adaptive immune function and dysfunction in CAEBV. Finally, we will develop a new computational toolkit to rapidly identify immune correlates from high-throughput datasets. Successful completion of this project will constitute the first comprehensive functional B- and T-cell receptor analysis in a human clinical cohort. Our efforts will provide a repertoire-scale, mechanistic understanding of adaptive immunity to EBV and suggest new strategies for treatment and prevention of EBV-associated diseases. Our long-term goal is to develop human immune profiling techniques as a platform approach to accelerate the rational design of vaccines and therapeutics against pathogens of high public health importance, beginning with EBV.

项目总结/摘要 本项目将为适应性免疫的综合分析开发一种新的技术途径 这些反应具有催化预防和治疗疾病的新策略的潜力。这里我们将 应用PI最近发明的免疫分析技术来研究EB病毒的机制 病毒（EBV）的适应性免疫控制在感染患者的临床队列。EB病毒是一种高度流行的病原体 感染了全球90%以上的人口原发性EBV感染常引起传染性单核细胞增多症（IM） 长期的后遗症包括许多恶性肿瘤，淋巴增生性疾病，以及强烈的 与多发性硬化症有关。到目前为止，还没有EB病毒疫苗被批准，并且EB病毒感染的分子机制还不清楚。 对EBV相关疾病的免疫保护尚不清楚。然而，目前的技术壁垒仍然很高， 通量免疫分析方法阻碍了对适应性免疫的全面理解， 预防EBV疾病。一种识别EBV免疫关键特征的技术方法 保护将推动疫苗和治疗开发的新解决方案。因此，我们开发了一个 实验管道，使快速和成本效益的分析B-和T-细胞对EBV的反应， 每个实验可扩展到几十个人类患者。我们假设一个全面的B和T细胞 对精心挑选的能够或不能抑制症状性感染的患者队列进行分析， 揭示EBV控制的基于功能的相关性。为了验证这一假设，我们将应用定量免疫 分析最近完成的前瞻性研究中冷冻保存的纵向样本的分析技术 IM的临床研究我们队列中的患者样本跨越感染前和感染后到恢复期， 包括临床IM严重程度评分的全部范围（从0，无症状原发感染，到6， 基本上因IM而卧床不起）。免疫特征数据将用于建立IM的适应性免疫相关性。 疾病严重程度。此外，我们将分析免疫功能正常的患者的免疫应答， 慢性活动性EBV（CAEBV）疾病或不能充分抑制EBV感染的患者， 关于CAEBV的适应性免疫功能和功能障碍的见解。最后，我们将开发一个新的 计算工具包，以快速识别免疫相关的高通量数据集。成功 该项目的完成将构成第一个全面的功能性B和T细胞受体分析， 人类临床群组。我们的努力将提供一个剧目规模，适应性的机械理解 并提出了治疗和预防EBV相关疾病新策略。我们 长期目标是开发人类免疫谱分析技术，作为一种平台方法， 合理设计针对对公共卫生具有高度重要性的病原体的疫苗和疗法， 关于EBV