Highlights
– A prespecified pooled individual‑level analysis (FLUNITY‑HD) of 466,320 participants randomized to high‑dose or standard‑dose influenza vaccine showed superior protection for high‑dose vaccine against hospitalisation for influenza or pneumonia (rVE 8.8%, 95% CI 1.7–15.5).
– High‑dose vaccine produced larger relative reductions for laboratory‑confirmed influenza hospitalisation (rVE 31.9%, 19.7–42.2) and ICD‑10–coded influenza hospitalisation (rVE 39.6%, 26.4–50.5).
– Safety profiles were similar between groups; implementation of high‑dose vaccine for older adults could yield meaningful public health benefits.
Background: disease burden and rationale
Older adults carry a disproportionate share of severe influenza‑related outcomes including hospitalisation, complications from cardiorespiratory disease, and death. Immunosenescence reduces vaccine immunogenicity and effectiveness in this population, motivating vaccines formulated to enhance immune response. High‑dose inactivated influenza vaccine (HD‑IIV) contains 60 μg haemagglutinin (HA) antigen per strain versus 15 μg per strain in standard‑dose (SD‑IIV); prior randomized data suggested improved efficacy for HD‑IIV against laboratory‑confirmed influenza and illness in older adults.
Study design and methods (FLUNITY‑HD pooled analysis)
FLUNITY‑HD is a prespecified, individual‑level pooled analysis combining two harmonised pragmatic, individually randomised trials: DANFLU‑2 (Denmark) and GALFLU (Galicia, Spain). DANFLU‑2 enrolled adults aged ≥65 years over three influenza seasons (2022–23, 2023–24, 2024–25); GALFLU enrolled community‑dwelling adults aged 65–79 across two seasons (2023–24, 2024–25). In each trial participants were randomized 1:1 to receive HD‑IIV (60 μg HA per strain) or SD‑IIV (15 μg HA per strain) and followed from 14 days after vaccination to May 31 of the following year each season. Routine healthcare databases provided outcome ascertainment.
The primary endpoint for both the trials and the pooled analysis was hospitalisation for influenza or pneumonia. Secondary endpoints (tested hierarchically) included hospitalisation for any cardiorespiratory disease, laboratory‑confirmed influenza hospitalisation, all‑cause hospitalisation, all‑cause mortality, ICD‑10–coded hospitalisation for influenza, and hospitalisation for pneumonia. The pooled analysis is registered at ClinicalTrials.gov (NCT06506812).
Key findings
Population
The pooled dataset comprised 466,320 individually randomised participants: 233,311 assigned to HD‑IIV and 233,009 to SD‑IIV. Mean age was 73.3 years (SD 5.4); 48.0% were female. Nearly half (48.9%) had at least one chronic condition.
Primary endpoint: hospitalisation for influenza or pneumonia
During follow‑up, hospitalisation for influenza or pneumonia occurred in 1,312 (0.56%) participants in the HD‑IIV group versus 1,437 (0.62%) in the SD‑IIV group. The relative vaccine effectiveness (rVE) for HD‑IIV versus SD‑IIV was 8.8% (95% CI 1.7 to 15.5). The report gives a one‑sided p‑value of 0.0082, indicating statistical superiority for HD‑IIV on the primary endpoint in the pooled analysis.
Secondary endpoints
Cardiorespiratory hospitalisation: 4,720 (2.02%) in the HD‑IIV group vs 5,033 (2.16%) in the SD‑IIV group (rVE 6.3%, 95% CI 2.5–10.0; p=0.0006).
Laboratory‑confirmed influenza hospitalisation: 249 (0.11%) vs 365 (0.16%) (rVE 31.9%, 95% CI 19.7–42.2; p<0.0001). This outcome showed the largest relative benefit for HD‑IIV, consistent with a biological effect on influenza infection leading to severe disease.
All‑cause hospitalisation: 19,921 (8.54%) vs 20,348 (8.73%) (rVE 2.2%, 95% CI 0.3–4.1; p=0.012). Although the absolute difference is modest, large baseline counts make this reduction epidemiologically relevant.
All‑cause mortality was similar between groups: 1,421 (0.61%) in HD‑IIV vs 1,437 (0.62%) in SD‑IIV (rVE 1.2%, 95% CI −6.3 to 8.3; p=0.38).
ICD‑10–coded influenza hospitalisation: 164 (0.07%) in HD‑IIV vs 271 (0.12%) in SD‑IIV (rVE 39.6%, 95% CI 26.4–50.5). Pneumonia hospitalisation: 1,161 (0.50%) vs 1,187 (0.51%) (rVE 2.3%, 95% CI −6.0 to 10.0).
Safety
Serious adverse event incidence was similar between groups (16,032 events in HD‑IIV vs 15,857 in SD‑IIV). The pooled analysis did not identify new safety signals; event counts indicate comparable serious adverse event profiles.
Interpretation and clinical significance
FLUNITY‑HD provides robust randomized evidence that HD‑IIV confers superior protection compared with SD‑IIV against a clinically important composite endpoint—hospitalisation for influenza or pneumonia—in older adults. The magnitude of relative benefit is modest on the composite primary outcome (rVE 8.8%) but larger and clinically meaningful for laboratory‑confirmed influenza hospitalisation (rVE ~32%) and ICD‑10‑coded influenza hospitalisation (rVE ~40%). These findings align with prior randomized evidence that HD‑IIV improves protection in older adults (e.g., DiazGranados et al., NEJM 2014) and bolster the biological plausibility that enhanced antigen content improves protection against influenza infection, which in turn reduces downstream severe cardiorespiratory complications and hospitalisations.
Because the trials were pragmatic, deployed across multiple seasons and countries, and used routine healthcare databases for outcome capture, the results have strong relevance for real‑world policy decisions. The all‑cause hospitalisation signal—although small in relative terms—may translate into substantial absolute numbers of prevented admissions when applied across national vaccination programmes covering millions of older adults.
Strengths and limitations
Strengths include the large sample size (over 460,000 randomized participants), the prespecified individual‑level pooled analysis of harmonised trial protocols, randomized allocation, inclusion of multiple seasons and settings, and use of pragmatic, routinely collected outcomes reflecting health system burden.
Limitations to consider: the trials were conducted in Denmark and Galicia (Spain), populations with high baseline vaccine uptake and particular health system patterns, which may limit generalisability to settings with different demographics, circulation patterns, or healthcare access. Outcome ascertainment relied primarily on routine administrative data and ICD coding; while laboratory‑confirmed influenza hospitalisations provide a high‑specificity outcome with large rVE, administrative codes may misclassify etiology for some admissions. The absolute event rates were low for some endpoints (e.g., laboratory‑confirmed influenza hospitalisation), which affects absolute risk reductions despite favorable relative effects. The trials were funded by Sanofi, the manufacturer of HD‑IIV, and although randomisation mitigates bias, sponsorship should be noted when interpreting trial conduct and reporting. Finally, details on blinding and healthcare‑seeking behaviour effects in pragmatic trial conduct can influence outcomes and warrant appraisal in the full paper.
Implications for practice and policy
This pooled randomized evidence supports preferential use of HD‑IIV for older adults where supply and cost permit. Many guideline bodies have moved toward preferential recommendations for enhanced‑formulation influenza vaccines (higher antigen dose, adjuvanted, or recombinant) in older adults on the basis of prior RCTs and observational studies; FLUNITY‑HD strengthens the randomized evidence base by demonstrating consistent benefit for a pragmatic composite of severe outcomes. Policy makers should weigh the incremental vaccine cost and availability constraints against the potential to avert hospital admissions, reduce strain on healthcare systems during influenza seasons, and prevent influenza‑related cardiorespiratory decompensation in frail older adults.
Research gaps and future directions
Remaining questions include comparative effectiveness between different enhanced formulations (high‑dose vs adjuvanted vs recombinant), duration of improved protection across varying influenza strains and seasons, subgroup effects in the very old (≥80 years) and those with multimorbidity, cost‑effectiveness analyses across diverse health systems, and the impact on outpatient illness and functional outcomes important to older adults. External replication in low‑ and middle‑income settings and head‑to‑head trials comparing enhanced formulations would further refine policy choices.
Conclusion
FLUNITY‑HD, a prespecified pooled individual‑level analysis of two pragmatic randomized trials, demonstrates that high‑dose influenza vaccine reduces hospitalisation for influenza or pneumonia and other severe influenza‑associated outcomes compared with standard‑dose vaccine in older adults. The results provide strong randomized support for wider adoption of high‑dose vaccine in this vulnerable population and inform policy decisions aimed at reducing influenza‑related healthcare burden among older adults.
Funding and clinicaltrials.gov
Funding: Sanofi.
ClinicalTrials.gov registration: NCT06506812 (FLUNITY‑HD pooled analysis).
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 Oct 17:S0140‑6736(25)01742‑8. doi: 10.1016/S0140‑6736(25)01742‑8. Epub ahead of print. PMID: 41115437.
2. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high‑dose versus standard‑dose influenza vaccine in older adults. N Engl J Med. 2014 Aug 14;371(7):635‑645.
