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Pi-Shan Hsu,1,2 Ie-Bin Lian,3,4 Day-Yu Chao2 1Department of Family Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 2Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan; 3Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, Taiwan; 4Department of Applied Math, National Chung-Hsing University, Taichung, TaiwanCorrespondence: Day-Yu ChaoGraduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung 401, TaiwanTel +886-4-22840694Fax +886-4-22852186Email dychao@nchu.edu.twIe-Bin Lian Tel +886-4-7232105 ext. 3222Fax +886-4-7211192Email maiblian@cc.ncue.edu.twBackground: Influenza is a major cause of morbidity and mortality in the elderly worldwide. Influenza vaccination can prevent morbidity/mortality from influenza infection. A gap of 1– 2 years, before an epidemic strain is recommended by the World Health Organization (WHO) to be the vaccine strain in Southeast Asia, has been reported; this results in a high rate of vaccine mismatch and excess influenza-associated morbidity. The aim of the current study was to evaluate the effect of repeated vaccination on vaccine effectiveness (VE) among the elderly in Taiwan, during years with and without early appearance of antigenically drifted strains.Methods: A historical cohort study was conducted to evaluate the impact of repeated vaccination on the reduction of influenza-associated hospitalization among persons older than 64 years over two influenza seasons: 2007– 08, with all circulating virus strains mismatched, and 2008– 09, with all virus strains matched with the vaccine strains, considering four exposure effects, namely current vaccine effect, sequential vaccination effect, residual protection effect and no vaccination effect. Propensity score matching on vaccination status was performed to ensure similar baseline characteristics between the groups that received and did not receive vaccination.Results: Only current-year vaccination in combination with prior history of annual revaccination significantly reduced the risk of hospitalization, with adjusted hazard ratios of 0.68 (95% CI: 0.54, 0.85) and 0.74 (95% CI: 0.57, 0.95) during the 2007– 08 and 2008– 09 influenza seasons, respectively. Further stratification showed that even during the 2007– 08 influenza season, when all vaccinations were mismatched with the circulating strains, sequential vaccinations still significantly reduced influenza-associated hospitalization in the female population aged 68– 74 and 75– 84 years, with adjusted VE of 25.2% (95% CI: − 9.6, 49.0%) and 36.9% (95% CI: 17.1, 52.0%), respectively.Conclusion: Our study supports the recommendation of annual revaccination against influenza in the elderly, even though the circulating strain of influenza virus was antigenically mismatched with the vaccine strains.Keywords: vaccine effectiveness, trivalent influenza vaccine, elderly, prior vaccination history, repeated vaccination, propensity score matching