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 cr...