Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron breakthrough infection (BTI) induced better protection than triple vaccination. To address the underlying immunological mechanisms, we studied antibody and T cell response dynamics during vaccination and after BTI. Each vaccination significantly increased peak neutralization titers with simultaneous increases in circulating spike-specific T cell frequencies. Neutralization titers significantly associated with a reduced hazard rate for SARS-CoV-2 infection. Yet, 97% of triple vaccinees became SARS-CoV-2 infected. BTI further boosted neutralization magnitude and breadth, broadened virus-specific T cell 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 modeling, which accounted for time-dependent infection risk, the antibody, and T cell concentration at any time point after BTI. Our findings suggest that cross-variant protective hybrid immunity induced by vaccination and BTI was an important contributor to the reduced virus transmission observed in Bavaria in late 2022 and thereafter.