A pragmatic individually randomized trial to evaluate the effectiveness of high-dose vs standard-dose influenza vaccine in older adults: Rationale and design of the DANFLU-2 trial - 07/10/25

Doi : 10.1016/j.ahj.2025.07.069

Niklas Dyrby Johansen, MD, PhD ^a,^b, Daniel Modin, MD ^a,^b, Matthew M. Loiacono, PhD ^c, Rebecca C. Harris, MBioch, MSc, PhD ^d, Marine Dufournet, PhD ^e, Carsten Schade Larsen, MD, DMSc ^f,^g, Lykke Larsen, MD, PhD ^h, Lothar Wiese, MD, PhD ⁱ, Michael Dalager-Pedersen, MD, PhD ^j,^k, Brian L. Claggett, PhD ^l, Kristoffer Grundtvig Skaarup, MD ^a,^b, Filip Søskov Davidovski, MD ^a,^b, Scott D. Solomon, MD ^l, Martin J. Landray, PhD ^m, Gunnar H. Gislason, MD, PhD ^a,^n,^o,^p, Lars Køber, MD, DMSc ^n,^q, Pradeesh Sivapalan, MD, PhD ^n,^r, Cyril Jean-Marie Martel, PhD ^s, Jens Ulrik Stæhr Jensen, MD, PhD ^n,^r, Tor Biering-Sørensen, MD, MSc, MPH, PhD ^a,^b,^q,^t,^⁎
^a Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark
^b Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
^c Sanofi, Swiftwater, PA, USA
^d Sanofi, Singapore
^e Sanofi, Lyon, France
^f Department of Clinical Medicine, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
^g Danske Lægers Vaccinations Service/European LifeCare Group, Søborg, Denmark
^h Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
ⁱ Department of Infectious Diseases, Zealand University Hospital, Roskilde, Denmark
^j Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark
^k Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
^l Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
^m Nuffield Department of Population Health, University of Oxford, Oxford, UK
ⁿ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
^o The Danish Heart Foundation, Copenhagen, Denmark
^p The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
^q Department of Cardiology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
^r Respiratory Medicine Section, Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark
^s Statens Serum Institut, Epidemiological Infectious Disease Preparedness, Copenhagen, Denmark
^t Steno Diabetes Center Copenhagen, Herlev, Denmark

^⁎Reprint requests: Tor Biering-Sørensen, MD, MSc, MPH, PhD, Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte Hospitalsvej 8, 3.th., Hellerup 2900, Denmark.Center for Translational Cardiology and Pragmatic Randomized TrialsDepartment of CardiologyCopenhagen University Hospital – Herlev and GentofteGentofte Hospitalsvej 8, 3.th.Hellerup2900Denmark

Highlights

•	High-dose influenza vaccine reduces laboratory-confirmed influenza, but its effectiveness against severe cardio-respiratory outcomes in the older general population has not been assessed in a fully powered, individually randomized trial.
•	DANFLU-2 is a pragmatic, individually randomized trial to assess the relative effectiveness of high-dose vs standard-dose influenza vaccine against cardio-respiratory hospitalizations in older adults ≥65 years.
•	Utilizing innovative recruitment and online informed consent methods, the trial has randomized 332,438 participants over 3 influenza seasons.
•	DANFLU-2 is the largest individually randomized influenza vaccine trial ever conducted.
•	The trial will provide high-quality data on the effectiveness of high-dose influenza vaccine in preventing hospitalizations to inform vaccination policies on a global level.

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Résumé

Background

The high-dose inactivated influenza vaccine (HD-IIV) has been shown to reduce the incidence of influenza infection compared with standard-dose inactivated influenza vaccine (SD-IIV); however, its effectiveness in preventing severe respiratory and cardiovascular outcomes in the older general population has not yet been assessed in a fully powered individually randomized trial.

Methods

DANFLU-2 is an ongoing pragmatic, registry-based, open-label, active-controlled, individually randomized trial conducted in Denmark during the 2022/2023, 2023/2024, and 2024/2025 influenza seasons. Utilizing innovative electronic recruitment strategies and an online informed consent process, the trial has enrolled 332,438 older adults ≥65 years; enrollment was completed in October 2024. Participants were randomly allocated in a 1:1 ratio to either HD-IIV or SD-IIV. Baseline, endpoint, and safety data are primarily obtained from the nationwide Danish administrative health registries. The primary endpoint is hospitalization for influenza or pneumonia with the trial also powered to assess the first secondary endpoint of hospitalization for any cardio-respiratory disease. The additional secondary endpoints of all-cause hospitalization and mortality will be tested hierarchically. Key ancillary analyses include cost-effectiveness and health care resource consumption assessments as well as a home self-swab sub-cohort.

Discussion

DANFLU-2 is the largest individually randomized influenza vaccine trial ever conducted and will provide critical, high-quality evidence on the effectiveness of HD-IIV against cardio-respiratory hospitalizations and mortality in the older general population.

Trial registration

Clinicaltrials.gov: NCT05517174, registered August 24, 2022, NCT05517174.

Le texte complet de cet article est disponible en PDF.

Plan

Background

Purpose

Methods

Study design and organization

Trial Population and Recruitment

Randomization and blinding

Intervention and comparator

Data collection and data sources

Endpoints

Safety monitoring

Power and sample size

Statistical analysis

Additional prespecified analyses

Ethical statement

Discussion

Conclusions

CRediT authorship contribution statement

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P. 186-198 - janvier 2026 Retour au numéro

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A pragmatic individually randomized trial to evaluate the effectiveness of high-dose vs standard-dose influenza vaccine in older adults: Rationale and design of the DANFLU-2 trial - 07/10/25

Highlights

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Background

Methods

Discussion

Trial registration

Plan

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