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 Unpublished subgroup and outcome data were obtained to enable detailed analyses.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.
| Discipline Area | Score |
|---|---|
| Geriatrics |  |
| Public Health | |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
In our facility, high-dose influenza vaccine was introduced last year for elderly patients. We were told that it gives increased protection against influenza compared with the standard vaccine. This is the first article I've read that shows evidence of the superior efficacy of the high-dose vaccine.
This study quantified the clinical benefits of high-dose influenza vaccine compared with standard-dose vaccine (e.g., influenza hospitalization rVE 38.5%). The NNV values offer a practical cost-effectiveness reference for vaccination strategies. However, the observed small-study effects call for caution when interpreting rare outcomes. The lack of a significant mortality difference may be due to few deaths or dilution by other factors. Overall, the paper provides strong evidence for updating influenza vaccine recommendations for older adults, but decisions should consider local vaccine coverage, cost-effectiveness, and influenza epidemiology.
