This systematic review (August 2025–June 2026) evaluated influenza vaccine effectiveness (VE) and safety across multiple US seasons, covering older adults, adults, pregnant individuals, infants, children, adolescents, young adults, and immunocompromised persons. It included 69 eligible studies: 21 RCTs, 23 comparative observational studies, 7 non-comparative safety studies, and 18 disease burden studies.
Influenza vaccines reduced hospitalization risk in older adults (VE 19–43%) and mortality (VE 29–66%). In children and adolescents (6 months–17 years), VE against influenza-associated death was 80% (95% CI, 75–84%) over 8 seasons. Maternal vaccination reduced symptomatic influenza in infants by 44.4% (95% CI, 31–55%). High-dose vs. standard-dose vaccine showed relative VE of 43.6% (95% CI, 27.5–56.3%) against hospitalization in older adults. A self-controlled case series of ~9.97 million vaccinees found no increased risk of Guillain-Barré syndrome or other serious adverse events, alone or co-administered with RSV or COVID-19 vaccines.
- VE estimates span multiple seasons and formulations, making direct comparison difficult due to heterogeneity in study design, circulating strains, and populations. - Observational studies are subject to residual confounding (e.g., healthy vaccinee bias), even when adjusted. - Coverage of immunocompromised populations and some age subgroups remained limited.
Influenza vaccination should be strongly recommended across all high-risk groups—especially older adults (consider high-dose formulation), children, and pregnant patients—given consistent reductions in severe disease and death with no new safety signals. Co-administration with RSV or COVID-19 vaccines appears safe.
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