Effectiveness of the quadrivalent high-dose influenza vaccine for prevention of cardiovascular and respiratory events in people aged 65 years and above: Rationale and design of a real-world pragmatic randomized clinical trial

Background Influenza has been an acknowledged cause of respiratory disease for decades. However, considerable related, and often unappreciated, disease burden stems from cardiovascular complications, exacerbations of underlying medical conditions and secondary respiratory complications, with the highest burden in the elderly. This novel study combines the gold standard method of a randomized controlled trial with real-world data collection through national registries, to assess the relative effectiveness of high-dose (QIV-HD) vs standard-dose quadrivalent influenza vaccine (QIV-SD) in preventing cardio-respiratory hospitalizations in a large cohort of adults aged >= 65 years. Methods and results This trial (NCT04137887) is a Phase III/IV, modified double-blinded, randomized, registry-based trial, conducted by the Finnish Institute for Health and Welfare (THL). Participants (n >120 000) are being enrolled over multiple influenza seasons and randomized (1:1) to receive QIV-HD or QIV-SD. Participant follow-up is based on data collection up to 11 months post-vaccination using Finnish national health registries. The primary objective is to demonstrate the relative superior effectiveness of QIV-HD over QIV-SD in preventing cardio-respiratory hospitalizations up to 6 months post-vaccination. Safety will be assessed using automated online tools throughout the study, with causality assessed using statistical and probabilistic methods; serious adverse reactions and adverse events of special interest will be investigated individually. Conclusion This large, real-world, randomized study will provide valuable insight into the contribution of influenza in causing severe cardio-respiratory events, and the role of vaccination with QIV-HD in reducing these outcomes compared to the current standard of care.