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What evidence supports the effectiveness of the 2025–2026 flu vaccine against circulating variants?
Executive summary
Available reporting shows mixed evidence about how well recent vaccines protect against currently circulating influenza viruses: Southern Hemisphere 2025 interim data suggest roughly 50% reduction in outpatient visits and hospitalizations [1] while some U.S. and institutional studies from 2024–25 produced variable estimates, from moderate protection in some networks to a Cleveland Clinic employee analysis that found no effectiveness and even a higher risk among vaccinated workers [1] [2] [3]. Regulatory bodies selected 2025–26 vaccine strains based on global surveillance and recommended trivalent formulations that target H1N1, H3N2 and a B/Victoria lineage virus [4] [5].
1. What the surveillance numbers say: interim effectiveness and hospital outcomes
Public health surveillance and multi‑network interim estimates indicate the 2024–25 and early 2025 vaccine seasons produced real reductions in medically attended illness and hospitalizations: U.S. vaccine‑effectiveness networks reported outpatient VE estimates ranging roughly from the mid‑30s to mid‑50s percent and hospitalization VE in the 40–55% range in some networks [2]. Likewise, eight Southern Hemisphere countries’ interim analyses for 2025 reported vaccine protection cutting flu‑related outpatient visits and hospitalizations by about half [1] [6]. These figures support the conventional public‑health position that vaccination reduces severe outcomes even when it does not fully prevent infection [2] [1].
2. Contradictory single‑site findings and methodological caveats
Not all studies align: a large Cleveland Clinic preprint analyzing 53,402 employees reported that vaccinated working‑age adults had a higher adjusted risk of influenza during the 2024–25 season, producing a calculated vaccine effectiveness of −26.9% in that cohort [3]. Professional groups responding to that preprint stressed the need for peer review and caution before changing policy, and an immunization‑managers summary noted the study authors concluded they were “unable to find” effectiveness but that the study has limitations and awaits peer review [7] [3]. Differences in study design, population (healthcare workers vs general population), timing, circulating strains, and statistical adjustment can produce divergent estimates [2] [7].
3. Strain selection and biological plausibility for protection
Vaccine effectiveness depends on how well vaccine strains match circulating viruses. For 2025–26, the FDA, in consultation with federal partners, recommended trivalent vaccine strains for H1N1, H3N2 and B/Victoria based on global surveillance data (A/Victoria/4897/2022 (H1N1)pdm09‑like; A/Croatia/10136RV/2023 (H3N2)‑like; B/Austria/1359417/2021 (B/Victoria)‑like), and WHO and EMA issued parallel composition guidance for the season [4] [8] [9]. These selections create a plausible basis for protection if those strains are the ones that circulate; surveillance from the Southern Hemisphere has been used historically as a predictor for the Northern Hemisphere [1] [9].
4. The mismatch risk: new subclades and surveillance gaps
Commentators warned that late‑emerging subclades — for example an H3N2 “subclade K” that rose after strain selection — can reduce vaccine match and lower effectiveness, and that disruptions to surveillance networks could hinder strain choice [10] [11]. CIDRAP and other outlets reported early estimates suggesting protection could be high for children (70–75% against hospital attendance) but lower in adults (30–40%) if variant mix includes such mismatched subclades [10]. The FDA and WHO process aims to reduce but cannot eliminate this timing and evolution problem [9] [12].
5. Practical implications and remaining uncertainties
Public health agencies (CDC, FDA, EMA) continue to recommend vaccination for most people, citing evidence that vaccines reduce hospitalizations and severe outcomes even when imperfect [5] [2]. However, available sources show uncertainty remains: interim and regional estimates vary, single‑site analyses can diverge from network data, and final effectiveness for 2025–26 will hinge on which strains actually circulate and on ongoing surveillance [2] [3] [1]. Available sources do not mention long‑term randomized controlled trials directly comparing 2025–26 formulations versus circulating viruses in general populations.
6. What to watch this season (and why it matters)
Follow national VE network updates and Southern/Northern Hemisphere surveillance releases: CDC and WHO reporting and the VE networks will publish mid‑season and end‑season estimates that reconcile population‑level protection [2] [9]. Watch for signals of subclade emergence (e.g., H3N2 subclade K) and for consistent reductions in hospitalization across age groups — the clearest real‑world measure of public‑health benefit reported so far [10] [1].
Limitations: This summary uses available interim reports, preprints and regulatory announcements; some papers cited are preliminary or awaiting peer review and estimates differ by study design and population [3] [7] [2].