Project Abstract This proposal outlines the scientific agenda for the COVID-19 Prevention Network (CoVPN) Vaccines Leadership Operations Center (LOC) for implementation of the COVID-19 vaccine efficacy trial entitled “A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Assess the Efficacy and Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults Aged 18 Years and Older.” With the global COVID-19 pandemic, we recognize a significant need for vaccines that modify COVID-19 in SARS-CoV-2 infected individuals. Addressing this gap, the National Institutes 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. This phase 3, placebo-controlled, double-blinded study will test the efficacy of Ad26.COV2.S, a recombinant, replication-incompetent adenovirus type 26 (Ad26) vector constructed to encode the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein to modify COVID-19 disease in adults 18 year of age and older. Participants will be recruited from clinical trial sites across the US, Latin America and South Africa using data analytics to target high risk individuals with a diverse racial and ethnic profile. Participants will receive symptomatic screening for SARS-CoV-2 infection, and if they become infected will be monitored with frequent clinical check-ins and remote monitoring of vital signs. Infected individuals who progress to moderate-severe COVID-19 will be referred for hospitalization. All trial endpoint assays will be done using qualified and validated assays for diagnosis and immune monitoring. Specific aims of this study are to demonstrate efficacy of Ad26.COV2.S to prevent COVID-19, to evaluate the safety, tolerability and reactogenicity of one intramuscular (IM) injection of 1x1011 viral particles (vp) or placebo, to assess the ability to prevent infection with SARS-CoV-2, to assess the ability to modify COVID-19 disease, to assess the ability to prevent emergency room visits, and to evaluate the binding and neutralizing antibody responses. This efficacy trial will tell us much about the adaptive immune response in persons who receive a SARS-CoV-2 S protein-based vaccine and about their ability to modify the disease course of COVID-19. In addition, it will improve our understanding of the dynamics and duration of these immune responses and will inform rational design and testing of preventive and therapeutic monoclonal antibody interventions. Lastly, the results of this trial will be used to assess registration of this vaccine product as well as to modify future COVID- 19 vaccine trials planned over the next 12 months.

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 world class laboratory, biostatistical and vaccine trial leadership expertise to assess this response in 30,000 persons at clinical trial sites across the US, Latin America and South Africa. The goal of this protocol is to rapidly assess the efficacy of Ad26.COV2.S, a recombinant, replication-incompetent adenovirus type 26 (Ad26) vector vaccine, to prevent SARS-CoV-2 infection and/or modify the severity of COVID-19 disease in SARS-CoV-2 infected individuals.