Enhanced Influenza Vaccines in Older Adults: A Systematic Review of High-Dose, MF59-Adjuvanted, and mRNA-Based Vaccines

Importance: Enhanced influenza vaccination for older adults now includes high-dose inactivated, MF59-adjuvanted, and newer mRNA-based approaches. Direct comparison across these platforms is difficult because the available studies vary in design, comparator, population, influenza season, and endpoint. Objective: To synthesize comparative evidence for high-dose, mRNA-based, and MF59-adjuvanted influenza vaccines in older adults using three parallel evidence syntheses. Study selection: Eligible studies included adults aged ≥ 65 years or a prespecified subgroup aged ≥ 65 years and compared high-dose, MF59-adjuvanted, or mRNA-based influenza vaccines with standard-dose influenza vaccine or another enhanced influenza vaccine. Eligible outcomes included laboratory-confirmed influenza illness, influenza-related or broader hospitalization outcomes, mortality, immunogenicity, and safety. Outcome ascertainment varied across studies: mRNA clinical efficacy and one observational MF59 study used laboratory-confirmed influenza endpoints, whereas several hospitalization and claims-based studies relied on prespecified diagnostic codes without laboratory confirmation. Randomized controlled trials and comparative observational studies were included. Data extraction and synthesis: For each report, we recorded the design, study population, influenza season, vaccine and comparator, endpoint definitions, analytic population, effect estimates, key limitations, and evidence of cohort overlap. Randomized studies were appraised with RoB 2 and nonrandomized studies with ROBINS-I, and certainty was evaluated using GRADE. Evidence was synthesized in three parallel streams: randomized clinical efficacy/effectiveness, randomized immunogenicity/safety, and observational comparative effectiveness. Clinically comparable direct comparisons were synthesized descriptively and presented using study-specific relative and absolute effect estimates. Results: Fifteen reports were included. For high-dose versus standard-dose vaccine, GALFLU and DANFLU-2 showed consistent reductions in influenza-specific hospitalization, corresponding to approximately 0.4–0.5 fewer influenza hospitalizations per 1000 vaccinated with high-dose vaccine. Effects on the influenza/pneumonia composite were heterogeneous and attenuated by the pneumonia component. FinFluHD found a nonsignificant 5.5% relative reduction in respiratory or cardiovascular hospitalization and was markedly underpowered following early termination. INVESTED found no reduction in all-cause death or cardiopulmonary hospitalization in a high-risk cardiovascular population (hazard ratio, 1.06; 95% CI, 0.97–1.17). Compared with licensed standard-dose vaccine, mRNA-1010 reduced RT-PCR-confirmed influenza episodes satisfying protocol-defined ILI criteria, including in the prespecified subgroup aged ≥ 65 years. In a separate randomized comparison with high-dose vaccine, mRNA-1010 produced stronger day-29 immune responses; that trial did not assess clinical efficacy. MF59-adjuvanted vaccine showed consistent observational benefit versus standard-dose quadrivalent vaccine, including in a small test-negative study of laboratory-confirmed severe influenza (adjusted relative vaccine effectiveness, 59.2%; 95% CI, 14.6–80.5%). Comparisons between MF59-adjuvanted and high-dose vaccines were mixed: earlier studies suggested comparable effectiveness, whereas overlapping 2019–2020 claims analyses favored the adjuvanted vaccine primarily for code-defined and outpatient encounters. All observational comparisons remained susceptible to residual confounding, outcome misclassification, and population overlap. Conclusions: Evidence differed substantially by outcome and study design. High-dose vaccine has the strongest randomized evidence for reducing influenza-specific hospitalization versus standard-dose vaccine. mRNA-1010 has randomized efficacy evidence versus standard-dose vaccine and superior immunogenicity versus high-dose vaccine but lacks direct severe-clinical-outcome comparisons with enhanced vaccines. MF59-adjuvanted vaccine shows observational benefit versus standard-dose vaccine, whereas comparative effectiveness versus high-dose vaccine remains uncertain. No universal ranking of enhanced vaccine platforms is supported.