Comparative analysis of immune escape and BCR repertoire remodeling after Omicron BF.7 and JN.1 infections.

SARS-CoV-2 Omicron evolution continues to erode antibody-mediated immunity, but whether infection with antigenically distinct lineages simply amplifies pre-existing memory or redirects humoral recognition toward newly evolved antigenic space remains unclear. Here, we analyzed paired early- and convalescent-phase plasma and whole-blood samples from individuals with sequencing-confirmed BF.7 or JN.1 infection. Integrated neutralization profiling, antigenic cartography, and bulk B cell receptor (BCR) repertoire analysis revealed lineage-associated humoral trajectories. Both breakthrough infections increased cross-variant neutralization, but their updated humoral profiles were not equivalent. BF.7 breakthrough infection broadly boosted neutralization from a BA.5-related background, whereas JN.1 breakthrough infection produced greater gains against BA.2.86, JN.1, and KP.2 and shifted humoral recognition toward late-Omicron antigenic space. Neutralization remained branch-structured, with BQ.1.1 and KP.2 acting as persistent escape nodes within the BA.2/BA.5-related and BA.2.86/JN.1-related branches, respectively. This humoral updating paralleled changes in IGH clonotype counts, repertoire diversity, V/J gene usage, isotype composition, and V-J pairing, whereas major CDR3 length distributions and sequence-logo patterns remained largely conserved. Overall, these findings indicate that antigenically distinct Omicron breakthrough infections generate non-equivalent humoral recall trajectories: BF.7 exposure preferentially reinforced BA.5-related antibody recognition, whereas JN.1 exposure more effectively redirected recognition toward BA.2.86/JN.1-derived variants.