H3N2 Influenza: Clinical Insights, Antiviral Resistance, and Next-Generation Strategies for Global Control
H3N2 influenza remains a persistent health concern worldwide, as it undergoes rapid antigenic drift, leading to vaccine mismatch and the development of antiviral resistance. It has a clinical manifestation with mild respiratory illness to severe complications, with a disproportionate impact on children, the elderly, and immunocompromised populations, with epidemiological evidence confirming its high socioeconomic burden. The presence of other respiratory pathogens further complicates the diagnosis and treatment of the problem and increases the need for multiplex diagnostics and integrated surveillance platforms. Although seasonal vaccines have improved, they have been reported to be less effective against H3N2 due to antigenic variation and egg-adapted mutations, leading to the consideration of next-generation approaches, including universal and mRNA-based vaccines as well as nanotechnology-based vaccines, with the capacity to induce broad and long-lasting protection. Simultaneously, the emergence of antiviral resistance in selected H3N2 strains indicates the necessity of new antivirals, combination therapy, and host-directed therapy to improve clinical outcomes. Enhancing real-time genomic monitoring, fast diagnostic capacity, and worldwide data exchange is crucial to monitor virus evolution, inform vaccine strain selection, and support emerging artificial intelligence-assisted and precision public health approaches. H3N2 influenza needs a multi-pronged strategy to be effectively controlled through the integration of innovative vaccine technologies, innovative therapeutic strategies, and robust international collaboration to guarantee fair access and scalable interventions. Finally, it will be important to translate these scientific developments into clinical and population health practice to decrease the global burden of H3N2 influenza and enhance preparedness for future seasonal epidemics and pandemic threats.