Early Drivers of Humoral Immunity to SARS-CoV-2 Infections

Abstract The duration and nature of humoral immunity to SARS-CoV-2 (CoV2) infection need to be better understood. While most studies have focused on the immune response in patients with clinical illness, little is known about the antibody response to CoV2 immediately after exposure and before the onset of illness, especially in asymptomatic individuals. It is important to understand how this impacts long- term immunological memory. This supplement aims to extend the objectives of the original grant to address these gaps in our knowledge by prospectively following household contacts compared to clinical cases of CoV2 to determine innate and adaptive immune events associated with early viral exposure. We have conducted a comprehensive evaluation of samples from these patients, including RNA sequencing of peripheral blood cells, proteomic analysis of oral secretions (the site of initial CoV2 replication), measurement of viral load using N protein levels, and CoV2-specific IgA and IgG in blood and saliva. We have identified innate and adaptive signatures associated with viral clearance and among household contacts that may be associated with their failure to be infected or, if infected, fail to develop clinical illness. We have identified CoV2 antigens, notably the N protein that is expressed on CoV-2 infected cells, which are targets of ADCC. Antibodies generated by the N protein can similarly kill infected cells with various variants of concern, suggesting a potential variant- transcending target. We have also tracked the humoral immune response in a long-term cohort of nursing home residents to the CoV-2 mRNA vaccine and subsequent booster responses. This supplement will continue these ongoing studies and allow their completion.