Influenza A(H3N2) Subclade K During the 2025-26 Season and Differential Humoral Responses in Vaccinated Individuals Versus Vaccinated Convalescents in Israel.
6 affiliations
- 1The Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan 52621, Israel.
- 2Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
- 3Sheba Pandemic Preparedness Research Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
- 4Infection Prevention and Control Unit, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
- 5School of Health Sciences, Ariel University, Ariel 4070000, Israel.
- 6Pediatric Infectious Disease Unit, Sheba Medical Center, Ramat Gan 52621, Israel.
Abstract
Background/Objectives: During the 2025-26 influenza season, the antigenically distinct A(H3N2) subclade K emerged and spread globally, raising significant concerns regarding seasonal vaccine effectiveness. This study aimed to map antigenic and structural divergence of this novel strain compared to the 2025/26 A(H3N2) vaccine component. Furthermore, we investigated how this vaccine mismatch impacts functional humoral immunity by directly comparing antibody neutralization profiles between individuals with vaccine-induced protection and those with infection-acquired immunity. Methods: Phylogenetic and structural modeling analyses were performed on 2025-26 Israeli influenza samples to identify genetic distances and mutations in the hemagglutinin protein compared to the 2025/26 A(H3N2) vaccine component. Hemagglutination inhibition (HI) and microneutralization assays were conducted using 2025-26 winter serum samples from a cohort of vaccinated healthcare workers and vaccinated convalescents to quantify antibody responses against both vaccine-like and subclade K strains. Results: Phylogenetic analysis revealed a clear dominance of the subclade K strain in Israel during the winter of 2025-26. Significant vaccine mismatch was defined by eight newly identified hemagglutinin mutations in the circulating subclade K strains. Serological testing demonstrated that while vaccination alone produced a modest two-to-three-fold increase in antibody titers, baseline protection against subclade K remained critically low. Conversely, natural infection in vaccinated convalescents elicited a significantly stronger, broader immune response, demonstrating a 6-fold and 13-fold increase in neutralizing antibodies against the vaccine-like and subclade K strains, respectively. Conclusions: Natural infection provides a more pronounced increase in both binding and neutralizing antibodies compared to vaccination alone, which might contribute to broader cross-protection against antigenically drifted variants. These findings highlight the primary limitations of current influenza strain prediction and emphasize the urgent need for faster, more adaptable vaccine manufacturing platforms to better match actual circulating strains.
Related
- Comparative analysis of SARS-CoV-2 immune memory in vaccinated and hybrid individuals two years post-exposure
- Differential physical activity responses to diabetes risk reduction interventions according to prediabetes phenotype in at-risk individuals: pooled analysis from three randomised controlled trials
- Impact of COVID-19 on gastrointestinal disease in vaccinated and unvaccinated individuals: a population-based cohort study in England.
- Early detection of immunoglobulin A against a vaccine backbone protein enables fast, durable, and objective identification of individuals vaccinated against Ebola virus
- A Multidimensional Immune Signature Predicts Susceptibility to Omicron Infection in Vaccinated Individuals
BibTeX
@article{nemet2026influenza,
title = {{Influenza A(H3N2) Subclade K During the 2025-26 Season and Differential Humoral Responses in Vaccinated Individuals Versus Vaccinated Convalescents in Israel.}},
author = {Ital Nemet and Neta S Zuckerman and Nofar Atari and Limor Kliker and Menucha Jurkowicz and Mayan Gilboa and Yael Weiss-Ottolenghi and Nathan Keller and Michal Stein and Gili Regev-Yochay and Yaniv Lustig and Michal Mandelboim},
journal = {Vaccines},
year = {2026},
month = sep,
doi = {10.3390/vaccines14100838},
url = {https://europepmc.org/article/MED/42931366},
note = {CC BY},
}
RIS
TY - JOUR
TI - Influenza A(H3N2) Subclade K During the 2025-26 Season and Differential Humoral Responses in Vaccinated Individuals Versus Vaccinated Convalescents in Israel.
AU - Ital Nemet
AU - Neta S Zuckerman
AU - Nofar Atari
AU - Limor Kliker
AU - Menucha Jurkowicz
AU - Mayan Gilboa
AU - Yael Weiss-Ottolenghi
AU - Nathan Keller
AU - Michal Stein
AU - Gili Regev-Yochay
AU - Yaniv Lustig
AU - Michal Mandelboim
PY - 2026
DA - 2026/09/23
JO - Vaccines
DO - 10.3390/vaccines14100838
UR - https://europepmc.org/article/MED/42931366
AB - Background/Objectives: During the 2025-26 influenza season, the antigenically distinct A(H3N2) subclade K emerged and spread globally, raising significant concerns regarding seasonal vaccine effectiveness. This study aimed to map antigenic and structural divergence of this novel strain compared to the 2025/26 A(H3N2) vaccine component. Furthermore, we investigated how this vaccine mismatch impacts functional humoral immunity by directly comparing antibody neutralization profiles between individuals with vaccine-induced protection and those with infection-acquired immunity. Methods: Phylogenetic and structural modeling analyses were performed on 2025-26 Israeli influenza samples to identify genetic distances and mutations in the hemagglutinin protein compared to the 2025/26 A(H3N2) vaccine component. Hemagglutination inhibition (HI) and microneutralization assays were conducted using 2025-26 winter serum samples from a cohort of vaccinated healthcare workers and vaccinated convalescents to quantify antibody responses against both vaccine-like and subclade K strains. Results: Phylogenetic analysis revealed a clear dominance of the subclade K strain in Israel during the winter of 2025-26. Significant vaccine mismatch was defined by eight newly identified hemagglutinin mutations in the circulating subclade K strains. Serological testing demonstrated that while vaccination alone produced a modest two-to-three-fold increase in antibody titers, baseline protection against subclade K remained critically low. Conversely, natural infection in vaccinated convalescents elicited a significantly stronger, broader immune response, demonstrating a 6-fold and 13-fold increase in neutralizing antibodies against the vaccine-like and subclade K strains, respectively. Conclusions: Natural infection provides a more pronounced increase in both binding and neutralizing antibodies compared to vaccination alone, which might contribute to broader cross-protection against antigenically drifted variants. These findings highlight the primary limitations of current influenza strain prediction and emphasize the urgent need for faster, more adaptable vaccine manufacturing platforms to better match actual circulating strains.
SN - 2076-393X
ER -