Project Summary The primary goal of current COVID-19 vaccine trials is to measure vaccine efficacy (VE) against clinically significant infection. However, on a population level, vaccine efficacy against all infection, including asymptomatic or very mildly symptomatic infection, is an important endpoint. This proposal outlines an ancillary swab study to the Novavax Phase 3 SARS-CoV-2 vaccine trial (PREVENT-19) to address these knowledge gaps. With the global SARS-CoV-2 pandemic, we recognize a significant need for vaccines that not only modify COVID-19 in SARS-CoV-2 infected individuals but also reduce infection/transmission regardless of symptomatology. In this study, participants will self-swab twice weekly starting at or shortly after their second dose of either SARS-CoV-2 rS/M1 or placebo. These swabs will be tested for SARS-CoV-2 by RT-PCR. Specific Aims of this study are to estimate the efficacy of SARS-CoV-2 rS/M1 vaccine against infection, to estimate the efficacy of SARS-CoV-2 rS/M1 vaccine against asymptomatic/very mildly symptomatic infection, to determine the sequence of breakthrough SARS-CoV-2 infections, to estimate the vaccine efficacy on duration of infection, to estimate the vaccine efficacy against SARS-CoV-2 viral load as a proxy of transmission, and to explore whether observed vaccine efficacy against COVID-19 illness reflects a transition from symptomatic into asymptomatic infections versus an absolute reduction in all SARS-CoV-2 infections. This ancillary swab study will tell us much about the ability of SARS-CoV-2 rS/M1 to reduce infection regardless of symptomatology. In addition, it will provide important information on the ability of the vaccine to reduce duration of infection and transmission.