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

项目摘要 新冠肺炎大流行在全球范围内继续以指数级速度增长，威胁着健康 系统和世界经济。在新的SARS-CoV-2病毒被确认为 由于新冠肺炎引发的危及生命的疾病，已有2060多万人确诊 全球有75万人死亡。由于几乎没有治疗选择，也没有疫苗，眼下的前景仍然严峻。 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 对再次感染和慢性并发症的免疫力在很大程度上仍不清楚。恢复期的血浆来自 康复的个体越来越多地被用作权宜之计，以降低疾病发病率和 降低死亡率，减缓SARS-CoV-2感染的传播。尽管新冠肺炎疗养血浆似乎 耐受性良好，治疗普遍热情，将需要随机临床试验 确定疗效，更不用说最佳给药了。令人惊讶的是，恢复期的血浆疗法(CPT)有 在历史上被用于治疗和预防多种传染病，但其机制 对行动的认识还不够充分。同样，CPT对宿主对特异性免疫反应的影响 病原体的定义不是很清楚。该应用程序的主要目标是识别细胞和分子免疫 预测新冠肺炎结果和临床治疗反应的信号。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。我们将利用一种独特的先进的流式细胞术管道，单细胞下一代 测序和抗体图谱，以提供CPT对SARS-CoV-2的影响的重点地图- 特异性T细胞和抗体。我们将测定中国人新冠肺炎抗体谱和中和能力 并确定CPT随后如何在表位处塑造新冠肺炎抗体谱 收件人的解决方案。这些探索性研究将为识别与疾病相关的 具有预后和/或预测价值的免疫特征，这是识别靶的关键步骤 干预和保护的关联性。

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.