Background: Older adults are at increased risk of severe influenza outcomes, partly due to reduced immune responses to standard-dose vaccines. High-dose influenza vaccines were thus developed to enhance protection, but evidence of their clinical outcomes and safety remains evolving. Methods: A systematic review and meta-analysis of randomized controlled trials examining the efficacy of high-dose versus standard-dose inactivated influenza vaccines in adults aged ≥65 years was performed. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to January 1, 2026. Clinical outcomes included influenza occurrence, influenza- or pneumonia-related hospitalization, all-cause hospitalization, mortality, and serious adverse events. Random-effects models were used to pool effect estimates. Results: Eight randomized controlled trials including 610,266 participants were analyzed. High-dose influenza vaccination significantly reduced hospitalization due to influenza compared with standard-dose vaccination (odds ratio OR 0.71, 95% confidence interval CI 0.61–0.81; I² = 0%) and modestly reduced hospitalization due to respiratory infection (OR 0.88, 95% CI 0.82–0.95; I² = 53.8%). No statistically significant differences were observed for all-cause hospitalization (OR 0.90, 95% CI 0.80–1.01; I² = 80.5%) or all-cause mortality (OR 0.96, 95% CI 0.90–1.03; I² = 58.6%). Serious adverse events were comparable between groups (OR 1.00, 95% CI 0.97–1.02; I² = 0%). Absolute reductions corresponded to 135 fewer influenza hospitalizations and 266 fewer respiratory infection hospitalizations among high-dose vaccine recipients. Conclusions: High-dose inactivated influenza vaccines improve protection against influenza and influenza-related hospitalization in older adults without increasing serious adverse events. However, their implementation should be considered in the context of local epidemiology, healthcare resources, and policy priorities.
Watanabe et al. (Sun,) studied this question.