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

Abstract: The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), isan unprecedented global event which has required rapid adaptation to changing clinical and epidemiologicalcircumstances. There are currently limited treatment options available for COVID-19, with an estimated fatalityrate of around 4% globally, and as high as 20-50% among hospitalized populations. Convalescent immuneplasma (CIP) is a promising potential treatment for a wide range of infectious diseases, and one which can bemobilized rapidly even within the confines of resource limitations in the pandemic setting. Prior studies in otherviral pandemics and early evidence from COVID-19 suggests that it may be effective, but formal prospectivestudies of CIP in COVID-19 are lacking. This project is a multidisciplinary collaborative effort frominfectious 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 ourspecial populations for clinical research) where our health system has focused outreach and support. Thecentral hypothesis of this proposal is that early infusion of CIP with high titer anti-SARS-CoV-2 antibodies inhospitalized patients with COVID-19 respiratory disease will prevent progression to critical illness and deaththrough modulation of the anti-SARS-CoV-2 host immune response. This will be tested through three specificaims: Aim 1) Test the effect of high titer CIP on progression to critical illness and death in moderately illhospitalized patients with COVID-19 respiratory disease; Aim 2) Determine the effects of CIP on the hostimmune response. Blood will be collected at 0 (prior to CIP infusion), 7, 14, and 28 days after CIP infusion. Acomprehensive immunologic assessment will be performed, including high-dimensional immunophenotypingby mass cytometry, single-cell RNA sequencing, as well as functional in vitro secretion assays. These will becompared 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-19disease. Subjects will be tested for viral clearance by serial nasal swab to inform duration of viral viability andimplementation 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 deathin COVID-19. Importantly the in-depth follow on immunologic and virologic studies will lead to a betterunderstanding 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.