New evidence for high-dose influenza vaccines in older adults: DANFLU-2 trial

Q. Why is vaccine optimization particularly important in older adults?

Older adults, especially those aged 65 years and above, are disproportionately affected by severe outcomes from infections, including influenza. Optimizing vaccination strategies for this more vulnerable population is therefore crucial.

The results we have seen from the FLUNITY-HD pooled analysis, which combines findings from DANFLU and GALFLU, suggest that high-dose influenza vaccine may improve severe outcomes in older adults.^1,2 That is very important because it means we may be able to prevent hospitalization and also cardiovascular complications.

Vaccination as a preventive tool in this high-risk population is key.

Q. What clinical need was DANFLU-2 designed to address, and how does this secondary analysis build upon that?

It is important to distinguish the results I am presenting here at ESCMID from the overall DANFLU-2 trial. My presentation focuses on a secondary analysis, whereas the primary DANFLU-2 results were presented last year at the ESC Congress and published in the New England Journal of Medicine.³

The original DANFLU-2 trial was a pragmatic, registry-based randomized trial designed to investigate whether high-dose versus standard-dose influenza vaccine reduced hospitalization for pneumonia or influenza. What this secondary analysis does is examine laboratory-confirmed influenza in greater detail across different severity levels. We looked at laboratory-confirmed influenza hospitalization, outpatient laboratory-confirmed influenza and non-medically attended laboratory-confirmed influenza.

This gives a fuller picture of vaccine effectiveness across the whole spectrum of disease, from people recovering at home through to those requiring hospitalization. To capture non-medically attended illness, we embedded a substudy using home self-swabbing and digital questionnaires. That allowed us to identify people who stayed at home with influenza and did not access healthcare services.

Q. What were the key findings from DANFLU-2 across hospitalized, outpatient and non-medically attended influenza?

In this secondary analysis, we found a relative vaccine effectiveness signal suggesting benefit with high-dose influenza vaccine compared with standard-dose vaccine across all severity levels studied. That included hospitalized influenza, outpatient influenza and non-medically attended influenza. The findings were consistent across these different levels of severity.

We also performed sensitivity analyses where we changed some of the endpoint definitions, for example by expanding time windows or restricting outcomes to ICD-10 coding. Across those analyses, the findings remained consistent. We also saw consistency across seasons, which strengthens the overall findings.

Q. How valuable was the pragmatic registry-based design, and how important was the consistency of benefit across seasons?

The pragmatic design was absolutely central to the DANFLU trial. It is what made these very large “giga trials” possible. Each season, we identified around one million adults aged 65 years or older using Danish national registries. Invitations were sent through the national digital mailbox system called Digital Post. Participants could review study information, give online consent and book their vaccine visit entirely online, without direct involvement from study staff.

This decentralized approach allowed us to enroll more than 330,000 individually randomized participants. Vaccination took place at around 500 local vaccine clinics across Denmark, meaning participants could attend a nearby clinic rather than travel long distances. That also improved inclusiveness and allowed participation across different regions and social groups.

The consistency of findings across seasons is important because it adds confidence that the observed benefit is not limited to one specific influenza season.

Q. How could these findings influence future influenza vaccination strategies for older adults?

We need to interpret the results carefully, because this is an exploratory secondary analysis and the study was not specifically powered for all of these secondary endpoints. However, we do see encouraging signals suggesting benefit across different severity levels. This adds to the growing evidence base in this area.

Hopefully, as more data become available in the coming years, policymakers and guideline committees may use these findings when shaping future vaccination strategies for older adults. The goal is to provide the best preventive care possible, improve quality of life, reduce winter hospital admissions and ease pressure on healthcare systems.

Q. Are similar studies planned in other populations? What makes Denmark particularly suited to this type of digital trial design?

At the moment, not specifically with influenza vaccine, but my colleagues and I are planning new studies using the same framework with RSV vaccines. We will be looking particularly at immunocompromised patients and whether vaccination can improve outcomes in those who are most vulnerable. There are not currently plans for another influenza study exactly like this one, but hopefully other countries may be inspired by the model. It may be easier in Scandinavian countries because the public registry backbone is so important to making this type of trial possible.

Denmark has a very high level of digital engagement, including among older adults. Surveys have shown that older people in Denmark are among the highest users of digital technology globally. Almost every adult uses the national electronic letter system, so when invitations are sent, they reach people across society.

Digitalization is embedded throughout Danish healthcare. Patients can view notes, test results and appointments on their phones in real time. That level of infrastructure makes these kinds of decentralized studies possible.

Q. How could this platform be used in future vaccine research?

What is especially exciting is not only the individual trial results, but the platform itself. We now have a framework that can be applied to multiple vaccines. We have already used it for influenza and RSV vaccines, and we are also planning studies involving the varicella-zoster vaccine.

Study recruitment was done through the mandatory e-letter system Digital Post, and the consent was done through the trial website, where participants had to sign with the digital identifier ”MitID”. However, identification of potential participants (before recruitment material was sent through Digital Post) was also done through the registries. This creates a low-burden system for participants and a highly efficient system for researchers. It means we can rapidly evaluate how effective new vaccines are, identify which patient groups benefit most and generate evidence that policymakers can use.

In many ways, the platform itself may be just as important as any single result..