Vaccination is a key measure to prevent severe influenza in adults aged ≥80 years, who experience the highest burden of respiratory and cardiovascular complications. Because immunosenescence reduces the effectiveness of standard-dose vaccines (SD-IIV), enhanced formulations such as high-dose vaccines (HD-IIV) are recommended in the elderly. Real-world data on their effectiveness in adults aged ≥80 years remain limited. The aim of this study was to quantify the relative vaccine effectiveness (rVE) of HD-IIV versus SD-IIV in preventing severe influenza disease in adults aged ≥80 years, assessed through respiratory and cardiovascular outcomes.

Retrospective, population-based cohort study conducted in Andalusia, Spain, during the 2024–2025 influenza season, including 279 649 vaccinated adults aged ≥80 years. Data on sociodemographic characteristics, influenza vaccines, chronic diseases, and clinical outcomes were taken from the Andalusian health population database. We used a directed acyclic graph to illustrate the assumed relationships between variables. The rVE of HD-IIV versus SD-IIV was estimated using augmented inverse probability weighting models.

Compared with SD-IIV, HD-IIV was associated with a lower risk of hospitalization for influenza (rVE = 34.0%; 95% CI = 15.8–52.2%). HD-IIV also showed improved effectiveness against laboratory-confirmed influenza (rVE = 42.1%; 95% CI = 22.9–61.3%), hospitalization for acute myocardial infarction (rVE = 26.4%; 95% CI = 5.6–47.2%), for stroke (rVE = 32.9%; 95% CI = 17.4–48.4%), for pulmonary embolism (rVE = 26.7%; 95% CI = 0.7–52.6%) and for overall cardiovascular outcomes (rVE = 6.6%; 95% CI = 0.9–12.2%). No association was observed for hospitalization because of pneumonia, influenza/pneumonia, heart failure, respiratory outcomes, or in-hospital mortality.

Among adults aged ≥80 years, HD-IIV seemed more effective than SD-IIV in preventing hospitalization for influenza and secondary cardiovascular outcomes, supporting its use in this at-risk population.