High-Dose vs Standard-Dose Influenza Vaccines in Older Adults

Importance: High-dose inactivated influenza vaccine (HD-IIV) was developed to enhance immune responses in older adults and has demonstrated superior protection against laboratory-confirmed influenza (LCI) and severe outcomes vs standard-dose inactivated influenza vaccine (SD-IIV). A comprehensive meta-analysis of recent large-scale trials is warranted. Objective: To synthesize all evidence from randomized clinical trials comparing HD-IIV with SD-IIV for prevention of hospitalization events and mortality in older adults. Data Sources: Studies published between December 31, 2009, and September 15, 2025, on PubMed and Embase. Additional data were obtained from trial sponsors. Study Selection: Randomized clinical trials comparing HD-IIV with SD-IIV in older adults during at least 1 influenza season were eligible. Data Extraction and Synthesis: Two reviewers independently screened studies, extracted data, and assessed risk of bias according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Unpublished subgroup and outcome data were obtained to enable detailed analyses. Combined relative vaccine effectiveness (rVE) estimates were calculated with fixed-effects models, with sensitivity analyses using random-effects models. Main Outcomes and Measures: Hospitalizations for influenza, LCI, pneumonia or influenza, cardiorespiratory disease, and all causes and all-cause mortality. Primary analyses included adults 65 years or older, and secondary analyses included prespecified subgroups by age and cardiovascular disease. Results: Eight randomized clinical trials including 605 098 participants were identified, with 5 enrolling older adults from the general population (aged ≥65 years), 2 enrolling nursing home residents (aged ≥65 years), and 1 enrolling patients with cardiovascular disease. Compared with SD-IIV, HD-IIV was associated with significantly reduced hospitalizations for influenza (rVE, 38.5%; 95% CI, 26.5%-48.5%), LCI (rVE, 31.2%; 95% CI, 19.3%-41.4%), pneumonia or influenza (rVE, 11.5%; 95% CI, 5.9%-16.8%), cardiorespiratory disease (rVE, 7.5%; 95% CI, 4.7%-10.3%), and all causes (rVE, 3.3%; 95% CI, 1.8%-4.8%). Mortality did not differ significantly between groups (rVE, 0.9%; 95% CI, -2.1% to 3.8%). Results were overall consistent across subgroup and sensitivity analyses. Conclusions and Relevance: This meta-analysis provides a comprehensive synthesis of evidence from randomized clinical trials comparing HD-IIV with SD-IIV in older adults. HD-IIV was associated with improved protection against hospitalization outcomes, from LCI to all causes, but was not associated with improvement of all-cause mortality. These findings may inform decision-makers in developing vaccine recommendations and policies.