Project 1: Serological Correlates of SARS CoV2 Immunity and Disease

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Abstract Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and the Middle East Respiratory coronavirus (MERS-CoV) in 2012. In Dec 2019, a third novel CoV designated SARS-CoV-2 emerged in Wuhan China and has caused over 13 million cases, >570,000 deaths in >220 countries. In the expanding US epidemic, SARS- CoV2 has caused >137,000 deaths and significantly more severe infections characterized by pneumonia, severe acute respiratory distress syndrome (ARDS), coagulopathies, and inflammatory disorders. Incredibly, careful analyses of zoonotic bat CoV has revealed the presence of numerous group 2b SARS-like, group 2c MERS-like and remarkably, group 1 strains that replicate efficiently in primary human airway or gut enteroid cultures. To prepare for future CoV calamities, defined diagnostic assays and serologic investigations are essential for tracking current and future outbreaks and evaluate type specific and broad serologic immunity associated with population immunity. The goal of this U54 Center Program is to develop novel type- and group-specific serologic and neutralization assays (Project 1-Baric, Project 2-, Core B and C) designed to characterize the serological repertoire and to identify key domain-specific mucosal and systemic neutralizing and non-neutralizing antibodies after SARS-CoV-2 infection. One key underlying hypothesis is that IgA and IgG repertoires are different across mucosal and systemic compartments and target unique and overlapping epitope domains in the SARS-CoV2 S glycoprotein. Another underlying hypothesis is that intervention strategies can altered the memory B cell and antibody repertoires in mucosal and serologic compartments. Finally the program develops novel mouse models of human disease designed to mechanistically address fundamental immune innate and adaptive interactions associated with protective immunity. The Project uses novel technologies, basic and applied strategies to build a portfolio of reagents that map, track and treat SARS-CoV2 and other SARS-like group 2b CoV of the future. In Aim 1, we evaluate the kinetics, magnitude, durability of type specific neutralizing antibody responses after infection. Aim 2 characterizes the breadth of the mucosal and systemic serologic repertoires across Sarbecoviruses. In Aim 3, we characterize the antibodies in the mucosal and serum serologic repertoires using a variety of in vitro and in vivo platforms, designed to reveal correlates associated with protective immunity. To achieve our goals, the project interfaces closely with other projects and cores within the Center.