Profiling the immune response to convalescent plasma therapy during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

分析严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染期间恢复期血浆治疗的免疫反应

• 批准号: 10373738
• 负责人: Jay H. Bream
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-13 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373738
• 关键词: 2019-nCoV; Acute Disease; Acute Respiratory Distress Syndrome; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Antibodies; Antibody Repertoire; Antibody Response; Antigen-Antibody Complex; Antiviral Agents; Automobile Driving; Biological Assay; Blood; COVID-19; COVID-19 pandemic; COVID-19 pathogenesis; COVID-19 patient; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Communicable Diseases; Data; Development; Dexamethasone; Diffuse; Disease; Disease Progression; Effectiveness; Epitopes; Flow Cytometry; Funding; Goals; Health system; Healthcare Systems; Hospitalization; Human; Immune; Immune Plasma; Immune response; Immunity; Immunoglobulin G; Immunoglobulins; Immunologics; Individual; Infection; Inflammatory Response; Integration Host Factors; Intervention; Life; Link; Maps; Measures; Mediating; Molecular; Monitor; Morbidity - disease rate; N-terminal; Newly Diagnosed; Nucleocapsid Proteins; Outcome; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Plasma Proteins; Predictive Value; Predisposition; Prevention; Preventive vaccine; Property; Proteins; Public Health; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Recovery; Resolution; SARS-CoV-2 antibody; SARS-CoV-2 infection; Sampling; Serology test; Shapes; Standardization; Subgroup; Supportive care; System; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Technology; Therapeutic; Therapeutic Effect; Time; Tissues; Vaccines; Virus; Work; adaptive immune response; adaptive immunity; airway inflammation; antigen-specific T cells; base; burden of illness; convalescent plasma; cytokine; density; effective therapy; immune activation; improved; infectious disease treatment; insight; mortality; neutralizing antibody; new technology; next generation sequencing; novel; pathogen; predictive signature; prevent; prognostic value; remdesivir; response; severe COVID-19; single-cell RNA sequencing; therapy outcome; tool; treatment response; viral RNA

Project Summary The COVID-19 pandemic continues to grow at an exponential pace around the globe threatening health systems and the world economy. In the 9 months since the novel SARS-CoV-2 virus was identified as the cause of the life-threatening disease COVID-19, there have been over 20.6 million confirmed cases and over 750,000 deaths globally. With few options for treatment and no vaccine, the immediate outlook remains grim. Even in less severe cases, illness can be prolonged, recovery slow with long term consequences, such as immunity to re-infection and chronic complications remain largely unknown. Convalescent plasma from recovered individuals is being increasingly used as a stopgap treatment to mitigate disease morbidity and mortality and slow the spread of SARS-CoV-2 infection. Although COVID-19 convalescent plasma appears to be well-tolerated and there is general enthusiasm for the treatment, randomized clinical trials will be required to determine efficacy not to mention optimum delivery. Surprisingly, convalescent plasma therapy (CPT) has been used historically for the treatment and prevention of numerous infectious diseases, but the mechanisms of action are not fully understood. Likewise, the effects of CPT on the host immune response to the specific pathogen are not well defined. The primary goal of this application is to identify cellular and molecular immune signatures that predict COVID-19 outcomes and clinical response to therapy. We propose to leverage samples from ongoing convalescent plasma clinical trials at Johns Hopkins to link CPT-induced immune signatures with clinical outcomes. We will utilize a unique pipeline of advanced flow cytometry, single cell next generation sequencing and antibody profiling to provide a focused map charting the effects of CPT on SARS-CoV-2- specific T cells and antibody. We will determine the COVID-19 antibody profile and neutralization capacity in convalescent donors and define how CPT subsequently shapes the COVID-19 antibody profile at epitope resolution in recipients. These exploratory studies will provide a basis for identifying disease-associated immune signatures with prognostic and/or predictive value which is a critical step in identifying targets for intervention and correlates of protection.

项目概要 COVID-19 大流行在全球范围内继续呈指数级增长，威胁着健康 体系和世界经济。自新型 SARS-CoV-2 病毒被确定为新冠病毒以来的 9 个月内 导致危及生命的疾病 COVID-19 的病因，已确诊病例超过 2060 万例 全球有 75 万人死亡。由于治疗选择很少，也没有疫苗，当前的前景仍然严峻。 即使在不太严重的情况下，疾病也可能会持续很长时间，恢复缓慢，并产生长期后果，例如 对再次感染和慢性并发症的免疫力仍然很大程度上未知。恢复期血浆来自 康复者越来越多地被用作减轻疾病发病率和 死亡率并减缓 SARS-CoV-2 感染的传播。尽管 COVID-19 恢复期血浆似乎 如果耐受性良好并且对治疗有普遍热情，则需要进行随机临床试验 确定疗效，更不用说最佳交付。令人惊讶的是，恢复期血浆疗法（CPT）已 历史上曾用于治疗和预防多种传染病，但其机制 的行动没有被完全理解。同样，喜树碱（CPT）对宿主对特定物质的免疫反应的影响 病原体尚不明确。该应用的主要目标是识别细胞和分子免疫 预测 COVID-19 结果和临床治疗反应的特征。我们建议利用样本 来自约翰·霍普金斯大学正在进行的恢复期血浆临床试验，将 CPT 诱导的免疫特征与 临床结果。我们将利用先进的流式细胞术、下一代单细胞的独特管道 测序和抗体分析可提供重点图谱，描绘 CPT 对 SARS-CoV-2 的影响 特异性T细胞和抗体。我们将确定 COVID-19 抗体谱和中和能力 恢复期捐赠者并定义 CPT 随后如何在表位形成 COVID-19 抗体谱 收件人的决议。这些探索性研究将为识别疾病相关疾病提供基础 具有预后和/或预测价值的免疫特征，这是识别目标的关键步骤 干预和保护的相关性。