In a Danish RSV vaccine trial, the immunosuppressed had the most to gain, the least proof

People whose immune systems are suppressed — by disease or by the drugs that treat it — are among those most likely to end up in hospital with respiratory syncytial virus. They are also the group in which RSV vaccines have been least tested, because efficacy trials usually enrol healthier volunteers. A prespecified analysis of a large Danish trial, published in The Lancet Healthy Longevity on October 6, tries to close part of that gap, and lands on an honest, awkward answer [s1].

The trial behind the analysis

DAN-RSV was a pragmatic, open-label, nationwide randomised trial run in Denmark in November and December 2024 [s1]. Adults aged 60 and older were randomised 1:1 to a single dose of the bivalent RSV prefusion F vaccine, RSVpreF, or to no vaccine [s1]. Because it ran on national registries, outcomes could be tracked for everyone: the primary outcome was hospitalisation for RSV-related respiratory tract disease, with follow-up from 14 days after the study visit through to the end of May 2025 [s1].

This paper is the prespecified subgroup analysis by immunosuppression status [s1]. Immunosuppression was defined from registry records of at least one hospital encounter with an immunosuppressive condition or treatment [s1]. Because the definition and the outcomes all came from nationwide registries rather than self-report or clinic visits, the comparison captured the whole randomised population without the dropout that erodes many pragmatic trials [s1].

What the numbers showed

Of 131,276 participants, 5,199 — just 4.0% — were immunosuppressed [s1]. Across the whole trial only 21 people were hospitalised with RSV-related respiratory tract disease: seven of them immunosuppressed, 14 not [s1].

The clearest finding is about risk, not the vaccine. Among people who got no vaccine, the immunosuppressed were hospitalised for RSV more than nine times as often: 4.68 versus 0.50 events per 1,000 person-years [s1]. That is the case for paying this group special attention.

On the vaccine itself, the overall result held: RSVpreF reduced RSV-related hospitalisations by 83.3% (95% confidence interval 42.9 to 96.9) [s1]. But split by subgroup, the estimates were 60.5% effectiveness among the immunosuppressed — with a confidence interval running from -141.4% to 96.2% — against 92.3% (48.7 to 99.8) among everyone else [s1]. The test for whether immunosuppression changed the effect was not significant (p for interaction = 0.22) [s1].

Why that wide interval is the whole story

A confidence interval stretching from minus 141% to plus 96% is, in plain terms, a result that cannot rule anything out. It is compatible with the vaccine working very well in immunosuppressed people and with it doing nothing. That is not because the vaccine failed; it is because seven events cannot support a precise estimate. The authors are careful about this: the point estimate was "numerically lower" in the immunosuppressed group, but there was "no statistical evidence of heterogeneity between subgroups" [s1].

This is a textbook case of a trial that was not powered for the question being asked of it. Subgroup analyses inherit only a fraction of a trial's events, and here the subgroup was 4% of participants and a third of an already tiny outcome count. The honest reading is that DAN-RSV cannot tell us whether RSVpreF protects immunosuppressed older adults as well as it protects everyone else. The absence of a significant interaction is not evidence the vaccine works equally well; it is evidence the study was too small to detect a difference if one exists.

What it does and does not support

What the analysis supports firmly is the targeting logic: immunosuppressed older adults carry a far higher baseline risk of severe RSV, so even an uncertain vaccine effect translates into a larger potential absolute benefit. The estimated absolute rate reduction was 2.83 events per 1,000 person-years in the immunosuppressed against 0.46 in everyone else — though the former, too, had an interval crossing zero [s1]. The interpretation the authors reach — that prioritising RSV vaccination in this high-risk group "could have clinical benefits" — is a statement about risk and plausibility, not proof of efficacy in the subgroup.

It is also worth noting the trial was funded by Pfizer, which makes RSVpreF, and that several authors are company employees [s1]. That does not undermine a registry-based hospitalisation outcome, which is hard to manipulate, but it is part of the record.

What to watch

Whether larger trials or pooled registry analyses can generate a precise effectiveness estimate for immunosuppressed adults; and whether guideline bodies lean on baseline-risk arguments like this one to prioritise the group for vaccination while the direct evidence remains thin.

This article describes a single prespecified subgroup analysis and is informational only. It is not medical advice.

Sources

• [s1] RSV prefusion F vaccine effectiveness in older adults with immunosuppression: a prespecified analysis of the DAN-RSV trial, The Lancet Healthy Longevity, 2026, online ahead of print, published 2026-10-06. PMID 42838078.