Exposure-, infection, and vaccine-induced immune responses to SARS-COV-2

Abstract

There is tremendous diversity in the way individuals experience severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. We analyzed immune responses to SARS-CoV-2 in the context of susceptibility to infection before and after vaccination. Within a cohort of subjects who were highly exposed to SARS-CoV-2 prior to vaccination and seronegative against the immunodominant spike (S) protein, there was evidence of cross-reactive immunoglobulin (Ig) G to nucleocapsid (N) from common -coronavirus exposure and specific cellular immune responses against SARS-CoV-2 envelope (E), membrane (Mem), N, and S proteins. There was no evidence of underlying innate protection or natural immunity against SARS-CoV-2. Considering that the strength of the cellular immune responses correlated with time since exposure, we speculated that either rapid cellular immune responses or abortive infection resulted in infection being contained below the threshold for direct viral detection or generation of a humoral immune response. We analyzed the characteristics and significance of circulating vaccine-induced IgA in a post-vaccination cohort with a relatively high incidence of breakthrough infection. Higher levels of vaccine-induced IgA were negatively associated with breakthrough infection. Breakthrough Omicron infection increased anti-ancestral S IgA responses more than booster vaccines. Longitudinal analysis of post-infection anti-S IgA decay showcased the durability of infection-induced responses. As reported for IgG responses, vaccination with ancestral SARS-CoV-2 S antigen-imposed imprinting on circulating IgA responses. This research addressees the variability in humoral and cellular immune responses to SARS-CoV-2 and illustrates how the timing and nature of exposure to viral antigens impact the responses generated.