Convalescent Immune Plasma for the Treatment of COVID-19: Mechanisms Underlying the Host Immunologic and Virologic Response

用于治疗 COVID-19 的恢复期免疫血浆：宿主免疫学和病毒学反应的机制

• 批准号: 10213475
• 负责人: Donald E Brown
• 金额: $ 48.36万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213475
• 关键词: 2019-nCoV; Antibodies; Area; Biological Assay; Blood; COVID-19; COVID-19 pandemic; Catchment Area; Cell Therapy; Cessation of life; Clinical; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Communities; Critical Care; Critical Illness; Cytometry; Data; Disease; Disease Outbreaks; Doctor of Philosophy; Ebola; Enrollment; Epidemiology; Event; Fatality rate; Health system; Immune Plasma; Immune Targeting; Immune response; Immunity; Immunologics; Immunophenotyping; In Vitro; Incidence; Infection; Infusion procedures; Lung; Lung diseases; Maps; Mediating; Messenger RNA; Nose; Odds Ratio; Outcome; Outpatients; Patients; Pharmacology; Phase II Clinical Trials; Plasma; Population; Population Density; Probability; Procedures; Prospective Studies; RNA analysis; Resources; Retrospective Studies; Rural; Safety; Social isolation; Statistical Models; Swab; Testing; Therapeutic; Universities; Viral; Virginia; Virus Diseases; Vulnerable Populations; clinical care; design; diagnostic assay; high dimensionality; improved; multidisciplinary; named group; neutralizing antibody; outreach; pandemic disease; pathogen; prevent; response; single-cell RNA sequencing; therapy design; transfusion medicine; virology

Abstract The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an unprecedented global event which has required rapid adaptation to changing clinical and epidemiological circumstances. There are currently limited treatment options available for COVID-19, with an estimated fatality rate of around 4% globally, and as high as 20-50% among hospitalized populations. Convalescent immune plasma (CIP) is a promising potential treatment for a wide range of infectious diseases, and one which can be mobilized rapidly even within the confines of resource limitations in the pandemic setting. Prior studies in other viral pandemics and early evidence from COVID-19 suggests that it may be effective, but formal prospective studies of CIP in COVID-19 are lacking. This project is a multidisciplinary collaborative effort from infectious disease (Dr. Tania Thomas, MD, MPH), pulmonary and critical care (Dr. Jeffrey Sturek, MD, PhD), and cell therapy (Dr. Lawrence Lum, MD, DSc): a phase 2 clinical trial evaluating the efficacy of CIP in COVID- 19 infection. The epidemiology in this largely rural catchment area projects continued enrollment through 2020- 2021 fueled by subpopulations with rapid upswing in incidence, particularly in the latinx community (one of our special populations for clinical research) where our health system has focused outreach and support. The central hypothesis of this proposal is that early infusion of CIP with high titer anti-SARS-CoV-2 antibodies in hospitalized patients with COVID-19 respiratory disease will prevent progression to critical illness and death through modulation of the anti-SARS-CoV-2 host immune response. This will be tested through three specific aims: Aim 1) Test the effect of high titer CIP on progression to critical illness and death in moderately ill hospitalized patients with COVID-19 respiratory disease; Aim 2) Determine the effects of CIP on the host immune response. Blood will be collected at 0 (prior to CIP infusion), 7, 14, and 28 days after CIP infusion. A comprehensive immunologic assessment will be performed, including high-dimensional immunophenotyping by mass cytometry, single-cell RNA sequencing, as well as functional in vitro secretion assays. These will be compared to un-treated controls. Statistical modeling will be used to test associations with clinical outcome; Aim 3) Utilize subgenomic messenger RNA analysis to map the course of virologic clearance in COVID-19 disease. Subjects will be tested for viral clearance by serial nasal swab to inform duration of viral viability and implementation of social isolation practices critical for return to settings where distancing/isolation are limited. Completion of this study will help answer a critical question about the effect of CIP on critical illness and death in COVID-19. Importantly the in-depth follow on immunologic and virologic studies will lead to a better understanding of the mechanisms of progression to critical illness with the potential for targeted immune- mediated therapeutics and a diagnostic assay for viral viability that could immediately inform clinical care.

摘要 由严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）引起的COVID-19大流行， 这是一个前所未有的全球性事件，需要迅速适应不断变化的临床和流行病学 情节目前COVID-19的治疗方案有限，估计死亡率 全球约为4%，在住院人群中高达20-50%。恢复期免疫 等离子体（CIP）是一种有前途的潜在治疗广泛的感染性疾病， 即使在大流行病背景下资源有限的情况下也能迅速动员起来。其他领域的既往研究 病毒大流行和COVID-19的早期证据表明，它可能是有效的，但正式的前景 缺乏针对COVID-19的CIP研究。该项目是一个多学科的合作努力， 传染病（Tania托马斯博士，医学博士，公共卫生硕士），肺部和重症监护（Jeffrey Sturek博士，医学博士，博士）， 和细胞疗法（Dr. Lawrence Lum，MD，DSc）：一项评估CIP在COVID-1中疗效的2期临床试验， 19感染在这个主要是农村集水区项目的流行病学继续招生到2020年- 2021年，发病率迅速上升的亚群，特别是拉丁裔社区（我们的一个 临床研究的特殊人群），我们的卫生系统重点推广和支持。的 该建议的中心假设是，早期输注CIP与高滴度抗SARS-CoV-2抗体， 患有COVID-19呼吸道疾病的住院患者将防止病情恶化和死亡 通过调节抗SARS-CoV-2宿主免疫应答。这将通过三个具体的测试 目的：1）检测高滴度CIP对中度疾病患者进展为危重病和死亡的影响。 COVID-19呼吸道疾病住院患者;目的2）确定CIP对宿主的影响 免疫反应将在CIP输注后0（CIP输注前）、7、14和28天采集血液。一 将进行全面的免疫学评估，包括高维免疫表型分析 通过质谱细胞术、单细胞RNA测序以及功能性体外分泌测定。这些将是 与未处理的对照相比。将使用统计建模来检验与临床结局的相关性; 目的3）利用亚基因组信使RNA分析绘制COVID-19病毒清除过程 疾病将通过连续鼻拭子检测受试者的病毒清除率，以告知病毒活力的持续时间， 实施社会隔离做法，这对于返回距离/隔离有限的环境至关重要。 这项研究的完成将有助于回答一个关键问题，即CIP对危重病和死亡的影响 在COVID-19。重要的是，对免疫学和病毒学研究的深入研究将导致更好的 了解进展为危重疾病的机制，具有靶向免疫的潜力， 介导的治疗方法和病毒活力的诊断测定，可以立即通知临床护理。