Despite vaccination, SARS-CoV-2 evolution leads to breakthrough infections and reinfections worldwide. Knowledge of hybrid immunization is crucial for future broad-spectrum SARS-CoV-2 vaccines.

In this study, we investigated neutralizing antibodies (nAbs) against the SARS-CoV-2 ancestral virus (wild-type [WT]), pre-Omicron VOCs, Omicron subvariants, and SARS-CoV-1 using plasma collected from four distinct cohorts: individuals who received three doses of BBIBP-CorV/CoronaVac vaccines, those who experienced BA.5 breakthrough infections, those with XBB breakthrough infections, and those with BA.5-XBB consecutive infections following three-dose vaccination.

Following Omicron breakthrough infections, the levels of nAbs against WT and pre-Omicron VOCs were higher due to immune imprinting established by WT-based vaccination, in comparison to nAbs against Omicron variants. Interestingly, the XBB breakthrough infections elicited a broader neutralization spectrum against SARS-CoV-2 variants compared to the BA.5 breakthrough infections. This observation suggests that the XBB variant demonstrates superior immunogenicity relative to BA.5. Notably, hybrid immunization of BA.5 breakthrough infections after WT vaccination led to additional immune imprinting, resulting in a broadened neutralization profile against both WT and BA.5 variants in BA.5-XBB consecutive infections. However, the duration of nAbs was shorter in these reinfections compared to the breakthrough infections. Additionally, the expanded immune imprinting from previous WT vaccination and BA.5 breakthrough infections account for the enhanced plasma neutralization immunodominance observed in the antigenic cartography for BA.5-XBB consecutive infections.

Overall, we demonstrated a persistent and expanded effect of immune imprinting from prior SARS-CoV-2 exposures. Thus, future vaccines should specifically address the latest variants, and booster shots should be given at a longer interval after the previous infection or vaccination.