Scientific Core: BSL3 Virology and Animal Models

Project Summary - BSL3 Virology and Animal Models Core The COVID-19 pandemic has disrupted all aspects of society across the globe. The overarching theme of this P01 proposal is to study immune responses to infection with SARS-CoV-2 and their reactivity against other coronaviruses (CoVs) such that immunization strategies resulting in broad neutralizing activity can be tested with the ultimate goal of developing a vaccine that will provide protection against likely future emerging CoVs. The goals of the BSL3 Virology and Animal Models Core (Charles Rice/Margaret MacDonald) are to generate reagents and develop and perform assays in support of the objectives of three Research Projects, headed by Drs. Michel Nussenzweig and Marina Caskey (Project 1), Drs. Paul Bieniasz and Theodora Hatziioannou (Project 2) and Dr. Pamela Bjorkman (Project 3). Together the three Projects, the Virology and Animal Models Core and the Administrative Core aim to accomplish the Program's goal of defining the breadth of serological immunity in SARS-CoV-2 infected or vaccinated individuals, to define any conserved epitopes targeted by neutralizing antibodies, to investigate mechanisms of neutralization using structural and functional approaches, and to test in small animal models immunogens designed to elicit antibodies with maximum neutralization breadth. To meet the program goals, molecular virology, cell culture and animal model approaches will be taken by the BSL3 Virology and Animal Models Core in four Aims to 1) develop CoV working stocks for in vitro and in vivo use (Projects 1, 2 and 3), 2) develop facile systems for testing the neutralization activity of sera and cloned antibodies using trans-packaged replicons (TPRs) bearing the spike proteins of a broad range of CoVs, including those of potential pandemic concern (Projects 2 and 3), 3) conduct in vitro neutralization assays against SARS- CoV-2 and other CoVs or TPRs using the best candidate sera and cloned antibodies from humans and animal models from all three Projects and 4) perform immunization and protection experiments in small animal models to test the efficacy of candidate monoclonal antibodies and vaccination strategies. Overall, the work will contribute significantly to the development of pan-CoV vaccine candidates that can be used to mitigate the threat of future CoV pandemics.