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

摘要 新冠肺炎大流行是由严重急性呼吸系统综合症冠状病毒2型引起的， 史无前例的全球性事件，需要迅速适应不断变化的临床和流行病学 情况。目前可用于新冠肺炎的治疗选择有限，估计死亡人数 全球发病率约为4%，住院人群中高达20%-50%。恢复期免疫 血浆(CIP)是一种很有前途的治疗多种传染病的潜在方法，而且可以 在大流行背景下，即使在资源有限的范围内也能迅速动员起来。之前在其他领域的研究 病毒大流行和新冠肺炎的早期证据表明，它可能是有效的，但正式的预期 目前，对新冠肺炎企业间合作伙伴关系的研究还很匮乏。该项目是多学科合作的成果，来自 传染病(Tania Thomas博士，医学博士，公共卫生硕士)，肺部和危重护理(Jeffrey Sturek博士，医学博士，博士)， 和细胞疗法(Lawrence Lum博士，医学博士，DSC博士)：评估CIP在COVID- 19感染。在这个主要是农村集水区的流行病学项目中，入学人数一直持续到2020年- 2021年由发病率迅速上升的亚群推动，特别是在拉丁裔社区(我们的一个 临床研究的特殊人群)，我们的卫生系统将重点放在外联和支持上。这个 这一建议的中心假设是早期给予CIP和高滴度的抗SARS-CoV-2抗体。 新冠肺炎呼吸道疾病住院患者将防止病情恶化和死亡 通过调节抗SARS-CoV-2宿主免疫反应。这将通过三个具体的 目的：目的：1)测试高滴度CIP对中危重病进展和死亡的影响 新冠肺炎呼吸系统疾病住院患者；目的2)确定环丙沙星对宿主的影响 免疫反应。分别于0天(CIP前)、7天、14天和28天采血。一个 将进行全面的免疫学评估，包括高维免疫表型分析 通过质量细胞术、单细胞RNA测序以及体外分泌功能分析。这些将是 与未经治疗的对照组相比。统计建模将用于检验与临床结果的相关性； 目的3)利用亚基因组信使核糖核酸分析定位新冠肺炎病毒的清除过程 疾病。受试者将通过连续鼻拭子进行病毒清除测试，以告知病毒存活时间和 实施社会隔离做法对于返回距离/隔离有限的环境至关重要。 这项研究的完成将有助于回答有关CIP对危重疾病和死亡的影响的关键问题 在新冠肺炎。重要的是，对免疫学和病毒学的深入后续研究将导致更好的 了解进展为危重疾病的机制，具有靶向免疫的可能性- 中介疗法和病毒活性的诊断分析，可以立即为临床护理提供信息。

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.