As the 2025 to 2026 influenza season unfolds, clinicians face a rapidly evolving landscape shaped by the emergence of the influenza A(H3N2) subclade K virus. This novel variant, first detected in June of last year in New York, has swiftly become the dominant A(H3N2) strain in multiple countries, raising concerns about vaccine effectiveness, clinical outcomes, and the need for proactive countermeasures.
Influenza A(H3N2) is known for its high evolutionary rate and propensity to cause severe epidemics, particularly among older adults. According to a JAMA report published last month, the 2024 to 2025 season was marked by significant morbidity and mortality across all age groups, despite moderate vaccine effectiveness.1 The emergence of the K subclade—also known as J.2.4.1—now signals a new front in the ongoing battle against influenza. By July 2025 this variant had been detected in patients in the United Kingdom, Australia, parts of Africa and Asia, and the United States, with rapid increases during the following months.
The report’s coauthor, Frederick G. Hayden, MD, said this variant has multiple hemagglutinin [HA] substitutions compared with the World Health Organization-recommended prototype A(H3N2) vaccine strain for the 2025 to 2026 northern hemisphere influenza season. “Several of these substitutions occur in the receptor-binding domain and are predicted to cause significant antigenic variation,” said Dr. Hayden, Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine.
So far, the trajectory of this flu season has been characterized by a rapid, early surge in cases, particularly in December, with activity reaching historic highs for that time of year. The US Centers for Disease Control and Prevention (CDC) has classified the season as moderately severe, with estimates of at least 22 million illnesses, 280,000 hospitalizations, and 12,000 deaths as of January 31, 2026.2
Children under 18 years of age have been hit particularly hard, with the highest peak weekly hospitalization rate observed since the 2010 to 2011 season. According to the National Center for Health Statistics, a total of 60 pediatric deaths have occurred. Of children eligible for vaccination and with known status, about 90% of pediatric deaths occurred in those not fully vaccinated.2
By early February, the CDC reported that seasonal influenza activity remained elevated across the United States. National data showed stable or decreasing trends in activity; however, the Pacific Northwest was continuing to experience increasing activity. While influenza A activity is decreasing, influenza B activity is increasing nationally.
Public health laboratories confirmed that 91.5% of positive specimens were influenza A, predominantly H3N2 subclade K, per the CDC’s week 4 report.2 This genetic characterization indicates a relatively homogenous circulating strain.2
Early vaccine effectiveness data from the United Kingdom suggest that current vaccines still offer meaningful protection against severe outcomes, especially in children.
“Vaccines demonstrated 72% to 75% effectiveness against ED visits and hospitalizations in children, most of whom received the live-attenuated intranasal vaccine, whereas injected vaccines were less effective [32% to 39%] in adults,” Dr. Hayden said. “These data indicate that the vaccine will provide some protection against severe outcomes caused by K subclade variant infections, although ongoing assessments are needed.”
A pair of more recent analyses, one from France and one from China, back up the UK findings and suggest that seasonal influenza vaccination provided moderate protection during the early months of the 2025 to 2026 flu season, despite the mismatch.3,4
The clinical burden of the 2024 to 2025 influenza season was substantial, with the CDC estimating 2.9 million illnesses, 30,000 hospitalizations, and 1,200 deaths (including one child) by early December 2025.1 During the 2024 to 2025 season, adults aged 65 years and older accounted for 57% of hospitalizations, and 44% of pediatric deaths occurred in previously healthy children.1
Dr. Hayden said that increasing overall vaccine uptake, particularly in those in close contact with people at increased risk of influenza complications, is especially important this year.
“Increasing vaccination of school-aged children can limit the spread of influenza within a community—an important strategy to maximize the overall benefit of influenza vaccination,” he said.
While vaccination remains the cornerstone of influenza prevention, Dr. Hayden also highlighted the critical role of antiviral therapy and nonpharmaceutical interventions in treatment. Almost all currently circulating influenza viruses, including the K subclade, are fully susceptible to neuraminidase inhibitors and the endonuclease inhibitor baloxavir. Prompt initiation of antiviral therapy is associated with reduced illness duration, fewer complications, and reduced mortality, particularly in hospitalized patients on administration of therapy early during the illness.1
Ongoing surveillance, research, and innovation in influenza prevention and treatment are needed, Dr. Hayden said. Vaccines with shorter production timelines, including mRNA-based platforms, are under investigation and may offer an opportunity for responding more rapidly to emerging variants. Novel antivirals and combination therapies are also in development, with the potential to improve outcomes in severe and high-risk cases, he said.
“In influenza seasons with a significant mismatch between vaccines and the circulating strain of A(H3N2), the population impact often includes excess mortality, including in children and older adults; outbreaks in vulnerable care settings; and increases in hospitalization across all ages,” Dr. Hayden said.
“Increasing age-appropriate vaccine uptake now, avoiding exposure to people who are ill, and the timely use of currently available antivirals for prophylaxis and treatment will reduce the burden of this season’s anticipated epidemic.”
References
1. Zambon M, Hayden FG. Influenza A(H3N2) subclade K virus: threat and response. JAMA. 2026;335(4):307-310. doi:10.1001/jama.2025.259032
2. Weekly US Influenza Surveillance Report: Key updates for week 4, ending January 31, 2026. US Centers for Disease Control and Prevention. January 23, 2026. https://www.cdc.gov/fluview/surveillance/2026-week-04.html
3. De Clercq A, Blanquart F, Vieillefond V, et al; RELAB study group. Interim vaccine effectiveness against influenza virus among outpatients, France, October 2025 to January 2026. Euro Surveill. 2026;31(2):2500992. doi:10.2807/1560-7917.ES.2026.31.2.2500992
4. Shen Y, Zhang D, Feng Z, et al. Moderate protection from vaccination against influenza A(H3N2) subclade K in Beijing, China, September to December 2025. Euro Surveill. 2026;31(2):2500993. doi:10.2807/1560-7917.ES.2026.31.2.2500993
