SARS-CoV-2 humoral and cellular immunity following different combinations of vaccination and breakthrough infection

The elicited anti-SARS-CoV-2 immunity is becoming increasingly complex with individuals receiving a different number of vaccine doses paired with or without recovery from breakthrough infections with different variants. Here we analyze the immunity of individuals that initially received two doses of mRNA vaccine and either received a booster vaccination, recovered from a breakthrough infection, or both. Our data suggest that two vaccine doses and delta breakthrough infection or three vaccine doses and optionally omicron or delta infection provide better B cell immunity than the initial two doses of mRNA vaccine with or without alpha breakthrough infection. A particularly potent B cell response against the currently circulating omicron variant (B. 1.1.529) was observed for thrice vaccinated individuals with omicron breakthrough infection; a 46-fold increase in plasma neutralization compared to two vaccine doses (p < 0.0001). The T cell response after two vaccine doses is not significantly influenced by additional antigen exposures. Of note, individuals with hybrid immunity show better correlated adaptive immune responses compared to those only vaccinated. Taken together, our data provide a detailed insight into SARS-CoV-2 immunity following different antigen exposure scenarios.