Influenza A (H3N2) viruses appear to have entered a new phase of evolution. Analysis of more than 24,000 viral sequences revealed increasing diversification within clade J.2 and the emergence of a new subclade, K, which carries mutations associated with immune escape.

Laboratory data indicated reduced neutralization of several emerging variants by antibodies induced by current influenza vaccines, with the greatest reduction observed for subclade K. These findings highlight the need for enhanced surveillance to inform risk assessments and public health planning ahead of the 2025-2026 northern hemisphere influenza season.

After several seasons of relative genetic stability, influenza A (H3N2) viruses showed renewed evolutionary activity during the 2024-2025 influenza season, with mutations emerging in key regions of the hemagglutinin protein involved in immune response recognition.

Some of these regions, known as cluster transition sites, are associated with shifts into new antigenic clusters that reduce recognition by antibodies generated during previous infections or vaccinations.

To characterize these changes, researchers have analyzed more than 24,000 H3N2 sequences from viruses circulating in the northern and southern hemispheres between September 2024 and August 2025. Nearly all sequences belonged to the J.2 subclade.

Mutation patterns in emerging variants were evaluated by comparing them with those of the reference vaccine strains.

The analysis confirmed ongoing diversification within J.2 and identified a new variant, designated as subclade K, which was previously classified as J.2.4.1.

Subclade K carries three key mutations at hemagglutinin sites implicated in immune escape, along with additional changes that may further increase antigenic divergence. This variant was first detected during the 2025 influenza season in the southern hemisphere.

Based on the number and location of these mutations, the authors suggested that subclade K could become the dominant H3N2 lineage during the 2025-2026 influenza season in the northern hemisphere.

Each year, the World Health Organization (WHO) updates the influenza vaccine composition to match the circulating strains. For the 2025 southern hemisphere influenza season and the 2025-2026 northern hemisphere influenza season, the WHO replaced the J subclade vaccine strain used in 2024-2025 with a strain from subclade J.2. Despite this update, J.2 viruses continued to diversify.

To assess the impact on vaccine-induced immunity, researchers analyzed hemagglutination inhibition test data from influenza surveillance centers and compared antibody responses to the vaccine strain with those to circulating variants.

Antibody recognition remained strong for viruses closely related to the original J.2 lineage, declined for more antigenically divergent variants, and was markedly reduced for subclade K viruses based on limited but consistent data.

These findings do not suggest that the vaccines would be completely ineffective, but rather that protection may be less optimal against some emerging lineages, as occurs periodically with seasonal influenza.

The simultaneous emergence of multiple variants with changes in regions recognized as antigenically critical confirms the accelerated evolution of influenza A (H3N2).

This trend justifies the importance of strengthening surveillance systems that integrate genomic sequencing, antigenic characterization, human serology, and epidemiologic indicators such as vaccine effectiveness and disease burden to support timely risk assessment.

A WHO recommendation issued in September 2025 to adopt a J.2.4 strain for the 2026 southern hemisphere influenza vaccine reflects this evolutionary trajectory but came too late to influence the 2025-2026 northern hemisphere vaccination campaign. The recommendation did not include subclade K, which emerged only recently and lacked sufficient antigenic data at the time of strain selection.

This story was translated from Univadis France, part of the Medscape Professional Network.