ABSTRACT
Viral infections can have profound and durable functional impacts on the immune system. There is an urgent need to characterize the long-term immune effects of SARS-CoV-2 infection given the persistence of symptoms in some individuals and the continued threat of novel variants including the recent rapid acceleration in infections. As the majority of COVID-19 patients experienced mild disease, here we use systems immunology approaches to comparatively assess the post-infection immune status (mean: 151 [5th - 95th percentile: 58 - 235] days after diagnosis) and subsequent innate and adaptive responses to seasonal influenza vaccination (as an "immune challenge") in 33 previously healthy individuals after recovery from mild, non-hospitalized COVID-19, as compared to 40 age- and sex-matched healthy controls with no history of COVID-19. Sex-specific, temporally stable shifts in signatures of metabolism, T-cell activation, and innate immune/inflammatory processes suggest that mild COVID-19 can establish new post-infection immunological set-points. COVID-19-recovered males had an increase in CD71hi B-cells (including influenza-specific subsets) before vaccination and more robust innate, influenza-specific plasmablast, and antibody responses after vaccination compared to healthy males. Intriguingly, by day 1 post-vaccination in COVID-19-recovered subjects, the expression of numerous innate defense/immune receptor genes (e.g., Toll-like receptors) in monocytes increased and moved away from their post-COVID-19 repressed state toward the pre-vaccination baseline of healthy controls, and these changes tended to persist to day 28 in females, hinting that the acute inflammatory responses induced by vaccination could partly reset the immune states established by prior mild COVID-19. Our study reveals sex-dimorphic immune imprints and in vivo functional impacts of mild COVID-19 in humans, suggesting that prior COVID-19 could change future responses to vaccination and in turn, vaccines could help reset the immune system after COVID-19, both in an antigen-agnostic manner.