ABSTRACT
Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy and address ongoing vaccine supply challenges. Here, we longitudinally profiled SARS-CoV-2 spike (S)-specific serological and memory B cell (MBC) responses in individuals receiving either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous mRNA booster immunization induced significantly higher serum neutralizing antibody and MBC responses compared to homologous ChAdOx1 boosting. Specificity mapping of circulating S-specific B cells revealed that mRNA-1273 booster immunization dramatically immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273-boosted participants displayed higher binding affinities and increased breadth of reactivity against variants of concern (VOCs) relative to those isolated from ChAdOx1-boosted participants. Overall, the results provide fundamental insights into the B cell response induced by ChAdOx1 and a molecular basis for the enhanced immunogenicity observed following heterologous mRNA booster vaccination.
