Editorial: Increased Respiratory Infections in the 2025–2026 Influenza Season and the (A)H3N2 Virus, a Past Cause of Pandemic Influenza

During the last century, there were four influenza pandemics. In 1968, the A(H3N2) influenza virus caused the third-largest influenza pandemic of the 20th century (Hong Kong ‘flu), which began in China in July 1968 [1,2]. During this pandemic, between 1 million and 4 million people died from influenza worldwide [1,2]. In 1968, the virus was a subtype of influenza that emerged from an antigenic shift from the 1957 H2N2 pandemic virus strain [1,2]. The 1968 influenza pandemic was less severe than the 1918 pandemic, but it still caused significant mortality among the elderly and children [1,2]. Since 1969, the H3N2 influenza virus has circulated as seasonal influenza and has continued to undergo antigenic drift, requiring modifications to seasonal vaccines [1]. Since 1968, the H3N2 influenza virus has had a cumulative, long-term effect on human health, including hospitalizations and mortality, which may have exceeded initial pandemic levels in 1968 and 1969 [1]. Compared with other strains of the influenza virus, H3N2 can be regarded as having the greatest cumulative impact on human health since the mid-20th century [1]. However, in December 2025, Zambon and colleagues reported that in the 2024 to 2025 influenza season in the US, influenza was predominantly associated with infections caused by a mix of H3N2 and H1N1 viruses, with an impact across all age groups, despite vaccination programs [3].

During 2024 and 2025, a highly pathogenic avian influenza virus, A(H5N1), spread rapidly among wild birds, domestic poultry, and mammals, including cattle [4,5]. In the US, human cases of H5N1 influenza have mainly been from contact with infected birds and mammals, but concerns remain about transmission between humans, as mortality rates from human infection with H5N1 influenza are high, exceeding those from infection with SARS-CoV-2 [4,5]. Predictions for the influenza season in the northern hemisphere can be made by observing the southern hemisphere season from June to August [6]. During the 2025 influenza season in Australia and New Zealand, the H3N2 subclade K variant was identified to be genetically and antigenically distinct from the vaccine-targeted variant and previously circulating subclade J influenza viruses [6]. In 2025, in the southern and northern hemispheres and in Asia, the influenza season began early and was more severe [7,8]. On October 3, 2025, the Ministry of Health, Labour and Welfare in Japan declared a nationwide influenza epidemic [9]. In September 2025, more than 6,000 influenza cases were reported in Japan, with 287 patients hospitalized, half of whom were children under 14 years of age, prompting the decision to close schools in Japan [9].

On December 10, 2025, the World Health Organization (WHO) reported a global increase in seasonal influenza, predominantly due to the influenza A(H3N2) virus [7]. Importantly, the genetic drift of H3N2 viruses has led to the emergence of the subclade K variant, which is now detected in most countries, except in South America [7]. Genetic sequence data from the WHO Global Initiative on Sharing All Influenza Data (GISAID) identified A(H3N2) hemagglutinin (HA) clades and subclades, with a rapid recent increase in the subclade of A(H3N2), J.2.4.1 (subclade K) [7]. The H3N2 subclade K viruses are believed to have drifted genetically from related J.2.4 viruses with amino acid changes in hemagglutinin [7]. H3N2 subclade K influenza viruses were prevalent in Australia and New Zealand from August 2025 [7]. Only six months later, in December 2025, the WHO had identified the H3N2 subclade K in more than 34 countries [7]. For these reasons, the WHO has advised continued viral surveillance to monitor patterns of spread and infection rates, to share epidemiological data between countries, and to promote influenza vaccination, particularly for vulnerable populations such as the elderly and children [7].

Currently, the increase in influenza cases is significantly impacting healthcare systems in the US, Europe, and parts of Asia [7]. Because H3N2 subclade K (J.2.4.1) harbors mutations in the hemagglutinin protein (including K2N, S144N, and T135K), the virus may evade some prior immunity from vaccination or from immune responses generated by earlier infections or earlier vaccine strains [7]. Studies are ongoing to evaluate the effectiveness of current influenza vaccines. Recent data from the UK Health Security Agency (UKHSA) showed that current vaccines are effective in preventing severe influenza symptoms, with 72–75% effectiveness in reducing hospital admissions in children and adolescents (<18 years), and 32–39% effectiveness in reducing hospital admissions for influenza in adults [10]. This study showed that current vaccines were effective in reducing the clinical effects of infection from the H3N2 influenza virus [10].

On 20 November 2025, the European Centre for Disease Prevention and Control (ECDC). published an assessment of the threat of circulating H3N2 subclade K in the European Union and European Economic Area (EU/EEA) [11]. The ECDC found that, compared with previous years, influenza cases increased unusually early in the EU/EEA, driven by H3N2 subclade K in up to 50% of cases [11]. The ECDC identified several concerns indicating the risk of continued spread and a burden on healthcare services in Europe due to a mismatch between H3N2 antigenic and serological findings, suggesting reduced immunity in populations without recent viral exposure [11].

On January 5, 2026, the US Centers for Disease Control and Prevention (CDC) released data showing that the 2025–2026 influenza season, which ended on December 27, 2025, had reached a 30-year high in the incidence of respiratory illnesses presenting with fever, sore throat, and cough [12]. Respiratory infections resulted in more than 120,000 hospitalizations and up to 5,000 deaths, including nine children [12]. Rates of respiratory infections have risen earlier in the season and are higher than these rates from the same period in previous years [12]. In the US, this trend has been driven by the spread of the new subclade K variant of the H3N2 influenza virus [12]. Further concerns have been raised about the effectiveness of this season’s influenza vaccines against the new H3N2 variant [10,11].

During the COVID-19 pandemic, there was a 99% global reduction in influenza diagnoses, and in 2020, global mortality rates from influenza fell to record-low levels during influenza seasons in the southern and northern hemispheres [13]. However, as social restrictions were lifted, zoonotic avian and swine influenza variants were identified in humans [13]. In December 2023, the US CDC published an update to the 2024 Advisory Committee on Immunization Practices (ACIP) Adult Immunization Schedule, at a time when vaccine hesitancy or non-compliance was associated with increasing reports of vaccine-preventable infections, including influenza [14]. In 2025, the 78th World Health Assembly of the WHO adopted the Pandemic Agreement to identify gaps and inequities in the global response to the COVID-19 pandemic to enhance international coordination for pandemic prevention, preparedness, and response, including equitable access to vaccines, diagnostics, and therapeutics [15]. These preparations are relevant to the 2025–2026 influenza season.

Disease X was the term first used by the WHO in 2018 for a candidate disease caused by a priority pathogen, Pathogen X, potentially capable of causing a global pandemic [16,17]. In 2018, before the COVID-19 pandemic due to SARS-CoV-2, the WHO prioritized 10 diseases under the Research and Development Blueprint and acknowledged that influenza was a significant public health problem that required surveillance and management, as reflected in the initiatives in place at the time [16,17]. Although the quotation from psychologists, including Albert Ellis and BF Skinner, that “the best predictor of future behavior is past behavior,” refers to human behavior [18], influenza and SARS-CoV-2 are the two types of Pathogen X on the list of causes of Disease X that have previously caused human pandemics [16,17]. For this reason, when influenza, including H3N2, spreads rapidly, there is justified concern regarding its ongoing and future behavior and its potential to cause another influenza pandemic [1].

Conclusions

In the 20th century, there were four influenza pandemics, one of which was caused by the H3N2 virus. The 21st century has yet to experience pandemic-level influenza, but since 2025, the world has experienced a resurgence of influenza cases driven by the H3N2 virus K subclade variant. The ability of this new H3N2 influenza virus variant to evade innate and acquired immunity to influenza remains uncertain. These findings, combined with recent concerns regarding the interspecies spread of H5N1 influenza, indicate that this is not the time to underestimate the persistent pandemic potential of influenza and highlight the increasing importance of infection surveillance and monitoring, as well as the continued development of effective influenza vaccines.