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In adults 65 to 79 years of age, there appeared to be fewer hospitalizations for influenza or pneumonia with high-dose influenza vaccine than with the standard dose, with a similar incidence of serious adverse events.

Optimizing influenza vaccination in older adults is a public health priority. While high-dose inactivated influenza vaccines (HD-IIV) have shown superior immunogenicity and efficacy over standard-dose vaccines (SD-IIV), there is a shortage of large-scale, individually randomized data evaluating real-world effectiveness against severe outcomes—especially within publicly funded health systems. GALFLU is a pragmatic, individually randomized, open-label clinical trial comparing HD-IIV and SD-IIV in adults aged 65–79 years in Galicia, Spain, during the 2023–2024 and 2024–2025 influenza seasons. The trial embedded individual randomization into the regional vaccination program and exploited digital health registries for comprehensive, low-burden data collection under real-world conditions. The primary outcome is relative vaccine effectiveness (rVE) against a composite of influenza- or pneumonia-related hospitalizations. Secondary and exploratory outcomes include rVE against cardio-respiratory hospitalization, laboratory-confirmed influenza hospitalization, all-cause hospitalization, mortality, and healthcare utilization. The GALFLU protocol was approved by the Comité de ética de la investigación con medicamentos de Galicia (CEIm-G, code 2023/374). Participation was fully voluntary. GALFLU demonstrated the feasibility of large-scale, pragmatic randomized controlled trials within routine clinical practice. Findings from GALFLU will be disseminated in peer-reviewed scientific journals and scientific meetings and shared with relevant authorities. GALFLU provides a reproducible blueprint for future pragmatic evaluations embedded in routine public health settings. The trial was registered in EU Clinical Trials Register (2023–506,977–36-00); ClinicalTrials.gov (NCT06141655). •GALFLU demonstrates the feasibility of large, pragmatic vaccine trials in public systems.•It uses health registries to produce real-world, randomized vaccine evidence.•It helps inform vaccine policy, regulation, and cost-effectiveness assessments.•We provide protocol for robust, low-burden, embedded public health randomized trials.