High-dose influenza vaccination in older adults: Insights from FLUNITY-HD

Evaluating high-dose influenza vaccination strategies in older and immunocompromised populations

At ESCMID Global 2026, Dr Anne Marie Reimer Jensen (Center for Translational Cardiology and Pragmatic Randomized Trials (CTCPR), Herlev and Gentofte Hospital, University of Copenhagen, Denmark) discussed findings from the FLUNITY-HD pooled analysis, which evaluated high-dose versus standard-dose influenza vaccination in older adults, including immunocompromised populations.

Drawing on data from the large pragmatic DanFLU-2 and GALFLU studies, she explored the challenges of protecting high-risk patients whose immune responses may be reduced. In this interview, Dr Jensen explains why real-world randomized trial designs are generating valuable evidence, how high-dose vaccination may offer meaningful benefits for vulnerable groups, and what these findings could mean for future influenza prevention strategies and broader public health policy.

Presented at ESCMID 2026: High-dose influenza vaccine effectiveness in immunosuppressed older adults: an individual-level pooled analysis (FLUNITY-HD).

Q. Could you tell us a little about yourself and your background?

My name is Anne Marie Reimer Jensen. I am a medical doctor and PhD student from Copenhagen, Denmark, working in the research group Center for Translational Cardiology and Pragmatic Randomized Trials (CTCPR), Herlev and Gentofte Hospital, University of Copenhagen, led by Prof. Tor Biering-Sørensen.

Q. Why is influenza prevention particularly important in immunosuppressed older adults, and what challenges does this population present for vaccination?

First of all, this is a very high-risk population. Because their immune system is not functioning optimally, they are at greater risk of severe disease, hospitalization, and complications further down the line. So this is exactly the kind of group where prevention matters most.

At the same time, they are also one of the most difficult groups to protect. Because the immune system is impaired, they often do not respond as well, both after previous infections and to the vaccines we currently have available. So they are among the people with the greatest need for prevention, but also among the most challenging to protect effectively.

Q. What makes the FLUNITY-HD pooled analysis a valuable opportunity to better understand vaccine effects in this population?

The study was not originally designed specifically for immunosuppressed patients. It was designed more broadly to generate real-world evidence. FLUNITY-HD combines two separate studies: the DANFLU-2 trial and the GALFLU trial.^1,2,3

DANFLU was the first of these and began in the fall of 2022. We invited almost every Danish citizen aged 65 years or older, with no exclusion criteria. Each season, around one million people were randomly selected for invitation, which represents a very large proportion of the eligible population.

When you compare those who participated with the wider Danish population, they are very similar. Unlike many clinical trials, where participants can be healthier than average, this cohort is much more reflective of real-world populations.

That naturally includes people with immunosuppression. Because the trial was so large, we also captured meaningful numbers of participants with comorbidities. So although the study was not designed specifically for immunocompromised patients, the subgroup itself is as large as many trials conducted solely in that population.

DANFLU-2 was powered on its own for the primary endpoint. Then, in the second season, the protocol was implemented in Galicia, Spain. That increased statistical power, but it also allowed us to assess whether this trial design and the results were generalizable outside Denmark. Galicia has regional registries similar to the Danish national registries, so the same pragmatic setup could be used there.

I think that is one of the most exciting aspects of this work. We are already hearing that more countries may be exploring similar approaches, embedding randomization into routine clinical practice and relying more on passively collected data. That could allow us to generate randomized evidence without always needing traditional double-blind controlled trials.

Q. What key outcomes were assessed when comparing high-dose and standard-dose influenza vaccination?

The primary endpoint was hospitalization for either pneumonia or influenza. That was identified through nationwide registries in Denmark and regional registries in Galicia using ICD-10 coding. The reason pneumonia was included is that influenza is often under-coded in routine practice. A patient may be admitted with respiratory symptoms, tested for influenza, but treated and coded as pneumonia before the test result is available. Including both diagnoses helped capture likely influenza-related admissions.

DANFLU was also powered for a key secondary endpoint of cardiorespiratory hospitalizations. Previous studies had suggested that preventing influenza might also reduce cardiac events such as myocardial infarction or heart failure admissions, so that was an important outcome to assess.

For the FLUNITY analysis, I also looked at laboratory-confirmed influenza hospitalizations, where admissions were linked to a positive influenza test. That served as a useful validation of the combined pneumonia/influenza endpoint.

We also assessed all-cause hospitalization and all-cause mortality in the immunosuppressed subgroup analysis.

Q. How do you think these findings could influence future recommendations for immunocompromised populations?

That is a very good question. DANFLU-2 was a fully powered trial on its own, but the primary endpoint in that trial alone did not reach statistical significance. There was an estimated relative vaccine effectiveness of around 6%, so there was a signal, but it narrowly crossed the significance threshold.

When DANFLU was combined with GALFLU in the FLUNITY-HD pooled analysis, the primary endpoint did become statistically significant. So clinically, that creates a slightly more nuanced picture, particularly because DANFLU was by far the larger trial.

What I focus on most is that both studies showed fairly consistent estimates for influenza-specific outcomes, where relative vaccine effectiveness was around 30%.

It is also important to remember that this was not a comparison with no vaccine, it was a comparison between two active vaccines. Both groups were already receiving protection, which means the relative difference may appear modest even when the clinical value is meaningful. For immunosuppressed patients, background risk is much higher. That means the absolute benefit of improved protection may be more substantial.

I would not necessarily conclude that every patient with immunosuppression should automatically receive a high-dose vaccine. This is a very broad category that includes people with hematologic malignancies, transplant recipients, people living with HIV, primary immunodeficiencies, and those receiving immunosuppressive therapies. These groups are very different.

We need to look deeper into the data to understand whether certain subgroups benefit particularly strongly, and whether some are so immunocompromised that even a high-dose vaccine may not generate a sufficient response. I suspect there will be important differences.

So overall, the data suggest that the benefit seen in the broader population likely extends to immunosuppressed patients as a whole, but clinicians will still need to interpret that in the context of the individual patient sitting in front of them.

Q. What does the study tell us about tailoring vaccine strategies?

I think it is difficult to say this trial directly supports highly personalized medicine. In many ways, it represents the opposite, it is broad, pragmatic, and population-based.

What it does show is that these trial designs are feasible, and that vulnerable populations can be included at scale. That is valuable because many individual hospitals only see relatively small numbers of these patients, so generating evidence in the traditional way would be extremely difficult.

The trade-off, of course, is that we lose granularity. We do not have immunogenicity data, blood samples, or detailed antibody responses. That makes it harder to apply findings to one highly specific subgroup or one individual patient.

So these trials are probably most useful for informing public health strategy and broader vaccine policy. For individual clinicians, we will still need smaller, more detailed studies with richer biological data.

Q. What do you think are the most important updates or most exciting things at ESCMID 2026 this year?

We have been presenting a lot around this pragmatic trial design, which I think is very exciting, not only for DANFLU, but also for DANRSV, which uses a similar setup for RSV vaccination.

I have also seen several AI-focused sessions which look very exciting, particularly the idea of using very large datasets in smarter ways and perhaps eventually combining big data with more personalized approaches.

References

1. Johansen ND, Modin D, Pardo-Seco J, et al. Effectiveness of high-dose influenza vaccine against hospitalisations in older adults (FLUNITY-HD): an individual-level pooled analysis. Lancet. 2025;406(10518):2425–2434. DOI:10.1016/S0140-6736(25)01742-8
2. Johansen ND, Modin D, Loiacono MM, et al. High-dose influenza vaccine effectiveness against hospitalization in older adults. N Engl J Med. 2025;393:2291–2302. DOI:10.1056/NEJMoa2509907
3. Pardo-Seco J, Rodríguez-Tenreiro-Sánchez C, Giné-Vázquez I, et al. High-dose influenza vaccine to reduce hospitalizations. N Engl J Med. DOI: 10.1056/NEJMoa2509834