Evolution of protective SARS-CoV-2-specific B- and T-cell responses upon vaccination and Omicron breakthrough infection

Abstract Vaccine breakthrough infections with SARS-CoV-2 Omicron induced a higher level of protection compared to triple vaccination and contributed to herd immunity on a population level. To address the underlying immunological mechanisms, we studied the evolution of SARS-CoV-2-specific antibody and Tcell responses during vaccination and upon breakthrough infection in Bavarian residents between February 2021 and December 2022. Further, we investigated the temporal distance between completed vaccination and break-through infection, as well as any occurring re-infection. Each vaccination significantly increased peak neutralization titers against Wuhan, Delta, and Omicron BA.5 with simultaneous increases in circulating spike-specific Tcell frequencies. After vaccination, Omicron BA.5 neutralization titers were most significantly associated with a reduced hazard rate for SARS-CoV-2 infection, also when accounting for spikespecific Tcell responses. Yet, 97% of triple vaccinees became SARS-CoV-2 infected, often within a few months after their third vaccination. Breakthrough infections further boosted neutralization magnitude and breadth, broadened virusspecific Tcell responses to non-vaccine-encoded antigens and protected with an efficiency of 88% from further infections by December 2022. This effect was then assessed by utilizing mathematical modelling, which accounted for time-dependent infection risk in Bavaria, as well as the antibody and Tcell concentration at any time point after breakthrough infection. Our findings suggest that cross-variant protective hybrid immunity induced by vaccination and breakthrough infection was an important contributor to the reduced virus transmission observed in Bavaria in late 2022 and thereafter.