Clinical Importance of the Newly Emerging Influenza A(H3N2) Subclade K as the Dominant Variant

Annually, seasonal influenza peaks from April to September in the Southern Hemisphere (SH) and from October to May in the Northern Hemisphere (NH), resulting in 3–5 million severe cases and 290,000–650,000 fatalities 1, 2. In 2025, the influenza A(H3N2) subclade K, formerly known as J.2.4.1, emerged unusually early in the NH, detected since week 35 of 2025 in England during the vaccination season, and it represented 33% of all A(H3N2) sequences in the Global Initiative on Sharing All Influenza Data and 90% of all samples in the United Kingdom 3-5. Similarly, the Republic of Korea reported an outbreak initiating two months earlier than the 2024–2025 season, with a 14.4-fold increase in cases during the comparable period, and the Centres for Disease Control and Prevention data demonstrated its detection in 86.8% of samples collected since September 2025, with hospitalisation rates of 4.3 per 100,000 population 6. Subclade K harbours T135K, S144N, N158D, I160K, Q173R, K189R, T328A, and S378N mutations, with deviations from the recommended NH vaccine by the World Health Organisation, and post-vaccination human sera exhibit ≥ 8-folds reduced reactivity, and ferret antisera raised against current vaccine strains poorly recognise viruses from subclades J.2.3, J.2.4, and J.2.5 7, 8. As the K subclade has not dominated the previous seasons, lower population immunity is expected, facilitating its rapid spread and amplifying absence from work and school, hospital overload, and strained healthcare system 7. Clinical presentations remain comparable to typical seasonal H3N2 (myalgia, fever, sore throat, fatigue, and headache; incubation 1–4 days), initiating more rapidly and intensely, and high-risk groups (senior population, individuals with chronic disease, pregnant women, and immunocompromised patients) remain the main concern for severe outcomes and complications, including pneumonia, bronchitis, encephalitis, and myocarditis 2, 4, 7. Notably, it was more frequently observed in younger adults in Australia and New Zealand, with a median age of 20 compared to 25 years in those infected with J.2 and J.2.2 subclades 9. Diagnosis depends on clinical suspicion, and treatment should commence ideally within 36–48 hours of symptom onset. Despite antigenic drift, vaccination remains advisable, as the United Kingdom Health Security Agency estimates efficacy at 70%–75% in children aged 2–17 years and 30%–40% in adults, adequate to reduce severe outcomes and hospitalizations 1, 2, 4. H3N2 variants have historically correlated with elevated hospitalisation and mortality rates, particularly among the elderly and young children, underscoring the necessity for immediate vaccination and infection control measures, especially in light of the 7% reduction in vaccinations administered this year 10. In order to effectively make a clinical diagnosis on this subclade, ongoing reports on clinical reports, timely sharing outcome differences, enhancement of vaccination and infection prevention control strategies, and enhanced diagnostic measures are necessary. The early emergence and dominance of subclade K underscore the continued unpredictability of influenza evolution and the need for evidence-based public health responses to protect vulnerable populations (Figure 1). Summary of the public health impacts, clinical recommendations, and key messages. Erta Rajabi wrote and designed the original draft, Mohammadreza Salehi provided advice for improving the manuscript and conceptualized the study, and Kousha Farhadi was responsible for reviewing the manuscript and visualization. All authors have read and approved the submitted version. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.