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: 10609455
• 负责人: Jay H. Bream
• 金额: $ 24.56万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609455
• 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 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; burden of illness; comparison control; convalescent plasma; cytokine; density; effective therapy; efficacy evaluation; immune activation; improved; infectious disease treatment; insight; mortality; neutralizing antibody; new technology; next generation sequencing; novel; pathogen; predictive signature; prevent; prognostic value; randomized, clinical trials; 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.

项目摘要 COVID-19大流行继续在地球仪各地呈指数级增长，威胁着健康 系统和世界经济。在新的SARS-CoV-2病毒被确定为 由于威胁生命的疾病COVID-19，已有超过2060万例确诊病例， 全球75万人死亡。由于治疗选择很少，也没有疫苗，近期前景仍然严峻。 即使在不太严重的情况下，疾病也可能延长，恢复缓慢，并产生长期后果，例如 对再感染和慢性并发症的免疫力仍然很不清楚。恢复期血浆来自 康复者越来越多地被用作缓解疾病发病率的权宜之计， 降低死亡率并减缓SARS-CoV-2感染的传播。尽管COVID-19恢复期血浆似乎 耐受性良好，并且对治疗有普遍的热情，需要进行随机临床试验， 确定疗效，更不用说最佳输送。令人惊讶的是，恢复期血浆疗法（CPT） 在历史上被用于治疗和预防许多传染病，但其机制 的行动没有完全理解。同样地，CPT对宿主对特异性抗体的免疫应答的影响也被证实。 病原体没有很好的定义。本申请的主要目标是鉴定细胞和分子免疫 预测COVID-19结果和治疗临床反应的特征。我们建议利用样本 从约翰霍普金斯正在进行的恢复期血浆临床试验中， 临床结果。我们将利用先进的流式细胞术，单细胞下一代， 测序和抗体分析，以提供一个重点地图绘制的影响CPT对SARS-CoV-2- 特异性T细胞和抗体。我们将确定COVID-19抗体谱和中和能力， 恢复期供体，并定义CPT随后如何在表位处塑造COVID-19抗体谱 在收件人的决议。这些探索性研究将为识别疾病相关性 具有预后和/或预测价值的免疫特征，其是鉴定用于治疗的靶的关键步骤。 干预和保护的相关因素。