Real-World Effectiveness of Seasonal Influenza Vaccines During the 2024–2025 Season: Subgroup Analyses by Virus Subtype, Time Since Vaccination, and Diagnostic Method

<b>Background/Objectives</b>: Despite high vaccination coverage, influenza remains a public health concern in South Korea, particularly in older adults. Continuous evaluation of vaccine effectiveness (VE) is essential to optimize immunization strategies. <b>Methods</b>: This study evaluated seasonal influenza VE for preventing laboratory-confirmed influenza using a test-negative design through a hospital-based influenza surveillance system in South Korea from 1 November 2024, to 30 April 2025. Demographic and clinical information was collected through questionnaire surveys and electronic medical records. Influenza was diagnosed using rapid antigen tests (RATs) and reverse transcription polymerase chain reaction (RT-qPCR), and vaccine effectiveness was analyzed using multivariable logistic regression. <b>Results</b>: In total, 3954 participants were included, with 1977 influenza-positive cases and 1977 test-negative controls. Influenza A and B accounted for 93.1% and 7.0% of cases, respectively. The adjusted overall VE was 20.4% (95% confidence interval [CI], 8.2-30.9; <i>p</i> = 0.002). VE was higher in adults aged 50-64 years (46.8%) than in those aged ≥65 years (18.8%). VE was 19.9% against influenza A and 45.7% against A/H3N2. VE was higher among individuals tested using RT-qPCR than among those tested using RATs (21.5% vs. 15.7%), and was also greater during the early period than during the late period (20.5% vs. 11.4%). Vaccination did not reduce influenza-associated hospitalization risk (VE, 17.3%; 95% CI, -9.3 to 37.4). A significant reduction in hospitalization risk was observed in adults aged 50-64 years (VE, 46.8%), with no significant benefit in those aged ≥65 years. <b>Conclusions</b>: The 2024-2025 seasonal influenza vaccine provided moderate protection against laboratory-confirmed influenza in adults, with higher effectiveness in those aged 50-64 years.