Project-003

HIPC3 Scientific Project 3: Immune response to SARS-CoV-2 natural infection followed by vaccination Abstract This project will characterize the innate and adaptive immune response to SARS-CoV-2 natural infection in the setting of mild disease and follow-on vaccination. We will define signatures correlating with reduced viral shedding, progression to PASC or long COVID, and magnitude of adaptive immune responses in convalescence and after vaccination. Our approach uses cutting-edge multi-omic single-cell technologies to dissect the innate and adaptive immune response and identify correlates of protection, vaccine response, and PASC. We will 1. Define the innate immune response during acute infection and test the hypothesis that interindividual variation in viral shedding duration is partly regulated by differences in innate response. These analyses will also include diverse participants to identify potential contributions by race/ethnicity. 2. Track the evolution and kinetics of T cell responses to natural infection and follow-on vaccination. We hypothesize that specific targeted epitopes and phenotypes will be more protective in short viral shedding, and that vaccines induce unique, protective T cells that are not found in the convalescent repertoire. These studies will also identify key helper T cell phenotypes for mounting robust humoral and cellular responses to natural infection and vaccine. These signatures will also be correlated with innate immune signatures to identify innate-adaptive coordination events 3. Characterize the immune response throughout infection and convalescence in PASC. Innate and adaptive immunity will be analyzed from acute infection through convalescence to understand how inflammation and antiviral response trajectories may differ in PASC compared to successful recovery. These will enable hypotheses on the causal mechanisms of PASC and therapeutic targets from ongoing pathogenic mechanisms. These results will enable improved clinical outcomes, treatment of existing PASC patients, and can guide vaccine developments and boosters. Overall, our longitudinal analysis will associate immune responses throughout disease to concrete functional outcomes including duration of viral shedding, PASC, and vaccine response.