High-Dose vs Standard-Dose Influenza Vaccines in Older Adults: A Meta-Analysis

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.

To synthesize all evidence from randomized clinical trials comparing HD-IIV with SD-IIV for prevention of hospitalization events and mortality in older adults.

Studies published between December 31, 2009, and September 15, 2025, on PubMed and Embase. Additional data were obtained from trial sponsors.

Randomized clinical trials comparing HD-IIV with SD-IIV in older adults during at least 1 influenza season were eligible.

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 Unpublished subgroup and outcome data were obtained to enable detailed analyses.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.

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.

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.

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.