Abstract
The severity of SARS-CoV-2 illness is influenced by factors including age, sex, pre-existing health conditions, and individual immune responses. However, the mechanisms conferring immunity following antigenic challenge have not been fully elucidated. There are currently no studies evaluating longitudinal proteomic changes in individuals following vaccination and breakthrough, limiting our understanding of the underlying mechanisms driving conferred immunity. In this work, we evaluated the differential protein expression in individuals with (CoV-P) or without (CoV-N) prior SARS-CoV-2 infection following primary vaccination and after breakthrough infection (CoV-BT). Overall, we found that individuals receiving primary vaccination relied on innate immune mechanisms, including complement and coagulation cascades, and natural killer cell-mediated cytotoxicity, while conversely, breakthrough infection immune mechanisms relied on T cell-mediated immunity. These mechanistic differences may help explain heterogeneity associated with vaccine-induced and breakthrough infection-related outcomes.