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

Abstract

The evolution of severe acute respiratory syndrome coronavirus 2 (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, substantial reductions in neutralizing activity were observed against emerging Omicron variants across all exposure groups. Exposure history showed some influence on neutralization breadth, with self-reported vaccination-only participants exhibiting better 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.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, producing variants that escape vaccine-induced immunity. The current work shows that KP.2 monovalent vaccination provides limited protection against antigenically distant Omicron variants (LP.8.1, LF.7.1, NB.1.8.1, XFG and BA.3.2). These findings highlight the ongoing challenge of maintaining vaccine effectiveness against evolving SARS-CoV-2 variants and argue for continuous updating of vaccines.

Keywords: COVID-19; Omicron; SARS-CoV-2; antigenic cartography; mRNA vaccine.

Fig 1

SARS-CoV-2 spike mutations across major variants. Heatmap displaying amino acid mutations in the SARS-CoV-2 spike protein across eight major variants (WA.1, JN.1, KP.2, LP.8.1, LF.7.1, NB.1.8.1, XFG, and BA.3.2) colored by predicted functional impact on receptor binding, antibody escape, and structural stability. Variants are organized by evolutionary lineage, with spike protein domains (N-terminal domain, receptor-binding domain, S1 and S2) indicated. Mutations shown correspond to the spike sequences of viral isolates used in neutralization assays. Dendrogram illustrate antigenic similarity relationships based on mutation patterns, with variants clustering by phylogenetic relationship. Colors reflect predicted functional consequences for each substitution.

Fig 2

Neutralizing antibody responses and antigenic relationships following KP.2 vaccination. (A) Neutralizing antibody titers following KP.2 monovalent vaccination across exposure groups against the variant panel for the overall cohort, (B) vaccination-only group, (C) complex hybrid immunity group and (D) recent infection hybrid group. (E) Comparative GMT trends across all exposure groups overlaid on a single graph, showing neutralization patterns against each tested variant. Dashed lines connect GMT values for each group. Data are presented as aligned dot plots with individual participant responses connected by lines across the tested virus panel, allowing visualization of individual neutralization patterns. Statistical comparisons between variants within each exposure group are shown above brackets, with significance (ns : P-value >0.05, * : P-value > 0.05, **: P-value ≤ 0.01, ***: P-value ≤ 0.001 and **** : P-value ≤ 0.0001) determined by one-way ANOVA with Dunnett's multiple comparisons test. (F) Antigenic cartography reveals spatial relationships between SARS-CoV-2 variants. Two-dimensional antigenic map constructed from neutralizing antibody titers of the overall KP.2-boosted cohort against the tested variant panel. Each circle represents a virus variant, and each square a unique serum biospecimen, with distances proportional to antigenic differences based on neutralization data. Closely related variants cluster together, while antigenically distinct variants occupy distant positions. Grid lines represent 2-fold changes in neutralizing antibody titers, with each unit corresponding to a 2-fold difference. The map illustrates the antigenic landscape surrounding KP.2, highlighting the substantial antigenic drift of recent Omicron variants (LP.8.1, LF.7.1, NB.1.8.1, XFG) and the intermediate positioning of BA.3.2 relative to the vaccine and ancestral strains.