Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2025 Sep 19:2025.08.24.25333689.
doi: 10.1101/2025.08.24.25333689.

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

Anass Abbad  1   2 , Brian Lerman  1   2 , Jordan Ehrenhaus  1   2 , Brian Monahan  1   2 , Gagandeep Singh  1   2 , Adria Wilson  1   2 , Stefan Slamanig  1 , Ashley Aracena  1   2 , Neko Lyttle  1   2 , Jessica Nardulli  1   2 , Keith Farrugia  3 , Zain Khalil  3 , Ana Silvia Gonzalez-Reiche  3 , Emilia Mia Sordillo  4 , Weina Sun  1 , Harm M van Bakel  3 , Viviana Simon  1   2   3   4   5 , Florian Krammer  1   2   4   6   7
Affiliations

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

Anass Abbad et al. medRxiv. .

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, dramatic 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. 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.

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

PubMed Disclaimer

Conflict of interest statement

Declaration of interests FK declares the following conflicts of interest. The Icahn School of Medicine at Mount Sinai has filed patent applications regarding influenza virus vaccines on which FK is listed as inventor. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines and influenza virus therapeutics which list FK as co-inventor. Dr. Simon is also listed on the SARS-CoV-2 serological assays patent. FK has received royalty payments from some of these patents. Mount Sinai has spun out a company, Castlevax, to develop SARS-CoV-2 vaccines. FK is co-founder and scientific advisory board member of Castlevax. FK has consulted for Merck, GSK, Sanofi, Curevac, Gritstone, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. The Simon and van Bakel labs collaborate with Sanofi Pasteur on pathogen surveillance.

Figures

Fig. 1:
Fig. 1:. Neutralizing antibody responses and antigenic relationships following KP.2 vaccination.
(A) Functional classification of 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. Dendrogram illustrate antigenic similarity relationships based on mutation patterns, with variants clustering by phylogenetic relationship. Color intensity reflects the magnitude of predicted functional consequences for each substitution. (B) Neutralizing antibody titers following KP.2 monovalent vaccination across exposure groups against the variant panel for the overall cohort, (C) vaccination-only group, (D) complex hybrid immunity group and (E) recent infection hybrid group. (F) 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 determined by one-way ANOVA with Dunnetťs multiple comparisons test. (G) 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.
See this image and copyright information in PMC

References

    1. Link-Gelles R, Chickery S, Webber A, Ong TC, Rowley EAK, DeSilva MB, Dascomb K, Irving SA, Klein NP, Grannis SJ, Barron MA, Reese SE, McEvoy C, Sheffield T, Naleway AL, Zerbo O, Rogerson C, Self WH, Zhu Y, Lauring AS, Martin ET, Peltan ID, Ginde AA, Mohr NM, Gibbs KW, Hager DN, Prekker ME, Mohamed A, Johnson N, Steingrub JS, Khan A, Felzer JR, Duggal A, Wilson JG, Qadir N, Mallow C, Kwon JH, Columbus C, Vaughn IA, Safdar B, Mosier JM, Harris ES, Chappell JD, Halasa N, Johnson C, Natarajan K, Lewis NM, Ellington S, Reeves EL, DeCuir J, et al. 2025. Interim Estimates of 2024–2025 COVID-19 Vaccine Effectiveness Among Adults Aged >/=18 Years - VISION and IVY Networks, September 2024-January 2025. MMWR Morb Mortal Wkly Rep 74:73–82. - PMC - PubMed
    1. Zhang L, Kempf A, Nehlmeier I, Chen N, Stankov MV, Happle C, Dopfer-Jablonka A, Behrens GMN, Schulz SR, Jack HM, Pohlmann S, Hoffmann M. 2025. Host cell entry and neutralisation sensitivity of SARS-CoV-2 BA.3.2. Lancet Microbe:101165. - PubMed
    1. Guo C, Yu Y, Liu J, Jian F, Yang S, Song W, Yu L, Shao F, Cao Y. 2025. Antigenic and virological characteristics of SARS-CoV-2 variants BA.3.2, XFG, and NB.1.8.1. Lancet Infect Dis 25:e374–e377. - PubMed
    1. Wilks SH, Muhlemann B, Shen X, Tureli S, LeGresley EB, Netzl A, Caniza MA, Chacaltana-Huarcaya JN, Corman VM, Daniell X, Datto MB, Dawood FS, Denny TN, Drosten C, Fouchier RAM, Garcia PJ, Halfmann PJ, Jassem A, Jeworowski LM, Jones TC, Kawaoka Y, Krammer F, McDanal C, Pajon R, Simon V, Stockwell MS, Tang H, van Bakel H, Veguilla V, Webby R, Montefiori DC, Smith DJ. 2023. Mapping SARS-CoV-2 antigenic relationships and serological responses. Science 382:eadj0070. - PMC - PubMed
    1. Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. 2004. Mapping the antigenic and genetic evolution of influenza virus. Science 305:371–6. - PubMed

Publication types

LinkOut - more resources