Immune imprinting toward SARS-CoV-2 XBB: implications for vaccine strategy and variant risk assessment

The immune imprinting against SARS-CoV-2 subvariants that dynamically evolves through sequential vaccination and infection has been rarely studied. Using antigenic cartography and neutralizing antibody (NAb) profiling, we demonstrate that prototype-targeting vaccination followed by Delta/early Omicron breakthrough infections maintained dominant wild-type (WT)-focused immunity. However, XBB.1.5-adapted vaccination after BA.5 outbreaks shifted immune imprinting toward XBB.1.9.1, altering the antigenic landscape. NAb analysis revealed progressive WT-specific immunity enhancement through three-dose vaccination followed by BA.5 breakthrough infection (GMT: I-I = 35, I-I-I = 72, I-I-I-B5 = 807), followed by sharp decline after XBB reinfection (GMT: I-I-I-B5-XBB = 231), confirming XBB's antigenic divergence. To investigate the relationship between population immune dynamics and XBB infection risk following the BA.5/BF.7 wave, we analyzed the immune status of XBB breakthrough-infected and uninfected individuals from May to June 2023 (5-7 months post-wave). Utilizing an infection model calibrated to NAb titers against XBB.1.9.1, we estimated the 50% protective NAb titer against XBB infection to be 1:12.6. Retrospective analysis revealed that 80.3% of the population fell below this threshold in mid-2023, aligning with subsequent XBB resurgence. However, only 33.8% exhibited sub-protective JN.1 titers (<12.6) by August 2024, explaining the absence of JN.1-driven endemicity. This longitudinal study maps the immune imprint transitions from WT dominance to XBB adaptation, providing critical insights into vaccine strategy optimization and emerging variant risk assessment. The work highlights how iterative immune exposures reshape population protection landscapes against evolving coronaviruses.