Antibody responses to SARS-CoV-2 variants LP.8.1, LF.7.1, NB.1.8.1, XFG and BA.3.2 following KP.2 monovalent mRNA vaccination.

The evolution of SARS-CoV-2 has resulted in antigenically distinct variants that challenge vaccine-induced immunity. The KP.2 monovalent mRNA vaccine was deployed in 2024 to address immune escape by emerging SARS-CoV-2 subvariants. We assessed neutralizing antibody responses in 56 adults with varied exposure histories following KP.2 vaccination against emerging variants including LP.8.1, LF.7.1, NB.1.8.1, XFG, and BA.3.2. While KP.2 vaccination enhanced neutralization against homologous variants, dramatic reductions in neutralizing activity were observed against FLiRT variants across all exposure groups. Critically, exposure history profoundly influenced neutralization breadth, with vaccination-only participants exhibiting superior cross-neutralization compared to individuals with hybrid immunity. Antigenic cartography revealed substantial antigenic distances between KP.2 and emerging variants, highlighting significant immune escape potential that threatens vaccine protection. Overall, our data suggest that KP.2 boosting predominantly enhances cross-reactive responses imprinted by previously encountered spike antigens, with limited adaptation to antigenically drifted variants. IN BRIEF: SARS-CoV-2 continues to evolve, producing variants that escape vaccine-induced immunity. Abbad et al. show that KP.2 monovalent vaccination provides limited protection against antigenically distant FLiRT variants (LP.8.1, LF.7.1, NB.1.8.1, XFG) and BA.3.2. Surprisingly, vaccination-only individuals exhibited broader cross-neutralizing responses than those with hybrid immunity, suggesting that infection history may narrow antibody responses through immune imprinting. These findings highlight the ongoing challenge of maintaining vaccine effectiveness against evolving SARS-CoV-2 variants. HIGHLIGHTS: KP.2 vaccination shows reduced neutralization against emerging variant strainsVaccination-only individuals exhibit broader responsesRecent infections before vaccination create bias toward ancestral strainBinding antibodies remain strong despite poor neutralization of new variantsAntigenic mapping show major antigenic distances between KP.2 and emerging variants.