Potential Non-Specific Benefits of Seasonal Influenza Vaccination: Evidence, Knowledge Gaps, and Future Directions

Seasonal influenza vaccination is a cornerstone of public health, providing well-established protection against infection, hospitalization, and mortality. In recent years, increasing attention has been directed toward the possibility that influenza vaccination may be associated with health effects extending beyond prevention of influenza itself. This narrative review synthesizes current evidence on these potential effects, integrating epidemiological findings with emerging mechanistic insights. The most consistent evidence relates to cardiovascular outcomes, with a number of studies, i.e., clinical trials, observational studies, and meta-analyses, reporting associations between influenza vaccination and a reduced risk of major adverse cardiovascular events. Influenza vaccination has also been associated with reduced antibiotic use at the population level, largely through prevention of influenza and its complications, thereby potentially contributing to efforts to mitigate antimicrobial resistance. Emerging epidemiological evidence further suggests an association between influenza vaccination and a lower risk of neurodegenerative disorders, including Alzheimer's disease. Associations have also been reported between influenza vaccination and lower risk of selected malignancies; however, the generalizability of these findings remains uncertain. At the mechanistic level, experimental and immunological studies indicate that influenza vaccination can modulate innate and adaptive immune responses, including features consistent with trained immunity and heterologous protection, thereby providing biological plausibility for some epidemiological observations. Importantly, though, for most non-influenza outcomes, causal relationships have not been established, and residual confounding and healthy-vaccinee effects cannot be excluded. Future research integrating epidemiology, immunology, and systems biology, particularly based on well-designed randomized clinical trials and mechanistic human studies, is needed to clarify the contexts, populations, and vaccine characteristics in which such effects may occur. Overall, while seasonal influenza vaccination remains a highly effective intervention for influenza prevention, its potential broader health implications warrant continued rigorous investigation.