Abstract
SARS-CoV-2 ancestral strain-induced immune imprinting poses great challenges to updating vaccines for new variants. Studies showed that repeated Omicron exposures could override immune imprinting induced by inactivated vaccines but not mRNA vaccines, a disparity yet to be understood. Here, we analyzed the immune imprinting alleviation in inactivated vaccine (CoronaVac) cohorts after a long-term period following breakthrough infections (BTI). We observed in CoronaVac-vaccinated individuals who experienced BA.5/BF.7 BTI, the proportion of Omicron-specific memory B cells (MBCs) substantially increased after an extended period post-Omicron BTI, with their antibodies displaying enhanced somatic hypermutation and neutralizing potency. Consequently, the neutralizing antibody epitope distribution encoded by MBCs post-BA.5/BF.7 BTI after prolonged maturation closely mirrors that in BA.5/BF.7-infected unvaccinated individuals. Together, these results indicate the activation and expansion of Omicron-specific naïve B cells generated by first-time Omicron exposure helped to alleviate CoronaVac-induced immune imprinting, and the absence of this process should have caused the persistent immune imprinting seen in mRNA vaccine recipients.