SARS-CoV-2 breakthrough infections imprint signatures of enhanced immunity against COVID-19

SARS-CoV-2-specific immunity has been shaped in recent years by a combination of natural infection, complicated by ongoing viral evolution, and vaccination. However, it has remained unclear to what extent combined antigen challenge, which elicits so-called hybrid immunity, impacts clinical outcomes and subsequent protection against COVID-19. In this study, we evaluated spike-specific humoral and cellular immune responses elicited by hybrid antigen exposure versus vaccination alone, considering the order of challenge and disease severity after infection with SARS-CoV-2. Hybrid antigen exposure was characterized by enhanced humoral and cellular immune responses compared with vaccination alone. CD8+ T cell responses were also more cross-reactive and displayed skewed epitope targeting hierarchies in the context of hybrid immunity. These features were maintained in older adults, who typically exhibit age-related deficits in de novo immunity, especially after breakthrough infections (BTIs). BTIs were further associated with more coordinated adaptive immune responses compared with those elicited by vaccination after infection with SARS-CoV-2. We also found that humoral immune responses, specifically IgG antibody titers targeting the spike protein receptor-binding domain, were better maintained after mRNA vaccination and that cellular immune responses were better maintained after vectored vaccination in the wake of BTIs. Moreover, vaccination was associated with mild disease after subsequent infection, especially among individuals who had received a booster dose. These results suggest that vaccine-induced memory responses, which generally wane over time, can be reactivated and reshaped by BTIs, amplifying features associated with enhanced immunity against SARS-CoV-2.