Clinical Effectiveness of High-Dose versus Standard-Dose Influenza Vaccines in Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

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.