SARS-CoV-2 infection prior to vaccination amplifies Fc-mediated humoral profiles in an age-dependent manner

Immunity acquired by vaccination following infection, termed hybrid immunity, has been shown to confer enhanced protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by enhancing the breadth and potency of immune responses. Here, we assess Fc-mediated humoral profiles in hybrid immunity and their association with age and vaccine type. Participants are divided into three groups: infection only, vaccination only, and vaccination following infection (i.e., hybrid immunity). Using systems serology, we profile humoral immune responses against spikes and subdomains of SARS-CoV-2 variants. We find that hybrid immunity is characterized by superior Fc receptor binding and natural killer (NK) cell-, neutrophil-, and complement-activating antibodies, which is higher than what can be expected from the sum of the vaccination and infection. These differences between hybrid immunity and vaccine-induced immunity are more pronounced in aged adults, especially for immunoglobulin (Ig)G1, IgG2, and Fcγ receptor-binding antibodies. Our findings suggest that vaccination strategies that aim to mimic hybrid immunity should consider age as an important modifier.