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What clinical trial or real-world effectiveness data exist for the 2025–2026 influenza vaccine so far?
Executive summary
Interim, peer-reviewed and real‑world data through late 2025 show mixed evidence about recent seasonal influenza vaccine performance. U.S. interim VE estimates for 2024–25 indicate measurable protection against medically attended influenza and hospitalization in many age groups (examples: pediatric outpatient VE up to 60% and hospitalization VE up to 78%) [1], while a large Cleveland Clinic preprint of employees reported a calculated negative VE (−26.9%) for 2024–25 in working‑age adults [2].
1. What major government networks report so far — broad protection in surveillance data
Four U.S. VE networks (IVY, VISION, US Flu VE, NVSN) produced interim 2024–25 estimates showing that seasonal vaccination reduced medically attended influenza and influenza‑associated hospitalization in many groups; reported outpatient VE values in children/adolescents ranged from ~32% to 60%, and hospitalization VE reached as high as 78% in some pediatric network estimates [1]. CDC’s consolidated data pages and MMWR summarize these network results and caution that estimates are preliminary and adjusted for confounders like age, geography and calendar time [3] [1].
2. Large institutional preprint that contradicted surveillance findings
A Cleveland Clinic analysis of ~53,400 employees published as a medRxiv preprint found a higher risk of laboratory‑confirmed influenza among vaccinated working‑age employees versus unvaccinated, yielding a calculated VE of −26.9% (HR 1.27, 95% CI 1.07–1.51) over 25 weeks; authors concluded they “were unable to find that the influenza vaccine has been effective in preventing infection” in that cohort [2]. This study is a preprint (not peer‑reviewed) and drew rapid commentary and contextual critique in outlets noting its limitations and that it does not prove causation [4].
3. Southern Hemisphere 2025 real‑world signals relevant to 2025–26 composition
Interim analyses from eight Southern Hemisphere countries covering the 2025 season — whose vaccine composition matches the 2025–26 Northern Hemisphere formulation — estimated about 50% reduction in influenza‑associated outpatient visits and ~49–50% reduction in hospitalizations (pooled estimate) during March–September 2025, suggesting moderate effectiveness if similar viruses circulate in the north [5] [6]. Public health authors explicitly note these Southern Hemisphere findings as a useful but not definitive precursor for Northern Hemisphere impact [5].
4. Strain matching and early variant warnings — why estimates can diverge
Experts flagged emerging H3N2 subclade K variants and possible mismatches with vaccine reference strains, which can lower observed VE, especially in older adults; some early preprint and surveillance sequencing reports indicate concern about a mismatch that could reduce adult protection even as children may remain well protected [7]. Regulatory decisions for the 2025–26 trivalent vaccine were made after reviewing global surveillance, and the FDA and manufacturers published the selected strains and noted prior midseason VE data for 2024–25 when advising composition [8] [9].
5. Clinical trials and randomized evidence relevant to 2025–26 (ongoing and recent trials)
Randomized, large trials continue to shape choices: recent trials and big randomized studies published in 2025 established benefits of high‑dose and adjuvanted vaccines in older adults (DANFLU‑2, GALFLU and others) and phase‑3 trials of mRNA seasonal influenza candidates have been completed or reported, adding to the evidence base for vaccine options though many of those trial results address product comparisons rather than that season’s trivalent formulation specifically [10] [11] [12]. Systematic reviews note ongoing peer‑reviewed support for the safety and effectiveness of respiratory virus immunizations heading into 2025–26 [13].
6. How to reconcile conflicting studies and what limitations reporters emphasize
Differences arise because study designs diverge: test‑negative VE networks use outpatient/hospital surveillance and adjust for multiple confounders [3] [1], Cleveland Clinic used a time‑dependent Cox model within an employment cohort and is a preprint with potential selection and behavioral confounding [2]. Public commentary and immunization managers highlighted the small absolute infection rate in the Cleveland Clinic cohort (2.02%) and warned against overinterpreting a single institutional preprint relative to multi‑site surveillance [14] [4].
7. Bottom line for clinicians and the public ahead of 2025–26
Available interim surveillance and Southern Hemisphere real‑world estimates point to moderate effectiveness (roughly ~50% against medically attended illness and meaningful protection against hospitalization) if viruses match circulation patterns [5] [6], but institution‑specific anomalies and emerging variant signals underscore uncertainty and the need to continue monitoring [2] [7]. Public health agencies (CDC, FDA) continue to recommend annual vaccination and have published composition and guidance for the 2025–26 trivalent season [15] [8].
Limitations: reporting is a mix of preprints, interim MMWR surveillance, and regional Southern Hemisphere estimates; available sources do not mention long‑term peer‑reviewed VE meta‑analyses for 2025–26 at this time.