Project Abstract This proposal outlines the scientific agenda for the COVID-19 Prevention Network (CoVPN) Vaccines Leadership Operations Center (LOC) for implementation of a natural history trial for acute SARS-CoV-2 infection in hospitalized and non-hospitalized individuals: “A Prospective Study of Acute Immune Responses to SARS-CoV-2 Infection.” With the onset of the COVID-19 pandemic, we recognize there is a significant gap in knowledge in the field on the contribution of innate and adaptive immune functions in modifying COVID-19 disease and in clearing viral infection and in the ability of vaccines to prevent or modify COVID-19 disease in SARS-CoV-2 infected individuals. Addressing this gap, the National Institute of Health (NIH) led rapid constitution of the CoVPN, partnering 5 NIH supported clinical trial networks, to create an enhanced network of physician scientists at 64 United States (US) and 55 international clinical trial sites in 15 countries dedicated to developing globally effective vaccines for SARS-CoV-2. Due to its extensive experience implementing global HIV vaccine trials over the last 20 years, the HIV Vaccine Trials Network (HVTN) LOC was selected as the LOC for CoVPN vaccine trials. We believe the CoVPN is well placed to study the natural history gaps and rapidly deploy this information in the development of SARS-CoV-2 neutralizing vaccines and mAb therapies. In this study we propose initiating an observational cohort study of approximately 950 acutely infected persons recruited at 17 United States (US) and 43 international clinical trial sites over an 8 month period. Adults 18 years and older with RT-PCR positive SARS-CoV-2 test results will be enrolled competitively across trial sites until the full cohort is reached. Participants will follow up for 6 clinic visits over a 28 day period and receive a final remote contact one month after the last visit. Participants who experience clinical decompensation will be referred for hospital evaluation. Specific aims of the study are to generate standardized datasets characterizing the SARS-CoV-2 viral kinetics and the quality, magnitude, and kinetics of humoral, innate and cellular immune responses to SARS-CoV-2 infection in asymptomatic and acutely symptomatic participants (in both hospitalized and non-hospitalized individuals) from a diversity of geographic and genetic backgrounds. This natural history study will tell us much about the adaptive immune responses in persons who are acutely infected from SARS-CoV-2 and will shed light on the role the immune system plays in successfully clearance of infection. It will improve our understanding of the dynamics and duration of responses against variants of concern, including Omicron, as well as the epitope specificity and other defining signatures, and will inform rational design and testing of preventive and therapeutic vaccines and monoclonal antibodies. Lastly, this study will inform the network on critical issues associated with implementation of current and future COVID-19 vaccine trials.

Project Narrative The outbreak of SARS-CoV-2 across the globe presents an unprecedented health risk to the world’s population and requires intensive study of key gaps in our understanding of the immune response and what adaptations lead to protective immunity. In this study, the CoVPN will apply its laboratory, biostatistical and vaccine trial leadership expertise to assess this response in approximately 950 persons at 17 US & 43 international sites over an 8 month period. The goal of this protocol is to rapidly assess the viral kinetics of acute SARS-CoV-2 infection from ancestral strain and variants of concern (VOC) and the spectrum of humoral, innate and adaptive cellular responses induced by COVID-19.