How did real-world effectiveness studies for 2025-2026 influenza compare to randomized trial efficacy?
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Executive summary
Real-world effectiveness studies for the 2024–25 and early 2025 seasons generally showed moderate protection against medically attended illness and hospitalization — typically roughly 37%–63% in U.S. networks and about 50% in pooled Southern Hemisphere data — while randomized trials of newer or older formulations have shown higher, strain- or product-specific efficacy in selected populations (for example, a 24% greater efficacy for high‑dose vs standard vaccine in older adults reported in randomized trials) [1] [2] [3].
1. Real-world networks mostly found moderate, variable protection
Multiple U.S. vaccine‑effectiveness networks produced interim estimates for 2024–25 showing outpatient VE estimates that varied by age and setting — for example, outpatient VE ranged from roughly 37% to 56% and inpatient VE from about 39% to 62% depending on age group — indicating the vaccine reduced medically attended influenza and hospitalizations but not perfectly [1] [4].
2. Southern Hemisphere pooled surveillance gave a clearer headline: about half
A pooled analysis of eight Southern Hemisphere countries for the 2025 season estimated that the 2025 seasonal vaccine reduced influenza‑associated outpatient visits by 50.4% and hospitalizations by 49.7%, a result that public health agencies cited as a helpful signal for the 2025–26 Northern Hemisphere composition [2] [5].
3. Observational designs drive heterogeneity and interpretation limits
The real‑world estimates come from observational, test‑negative and sentinel‑surveillance studies pooled across networks; these designs adjust for factors such as age, region and calendar time but remain subject to selection, testing, and confounding biases that can shift VE estimates up or down across populations and seasons [6] [1]. Available sources do not present a single definitive real‑world VE number because estimates vary by age group, virus subtype, vaccine type, and study network [1] [7].
4. Randomized trials show higher, product- and population‑specific efficacy
Randomized controlled trials cited in reviews and product evaluations demonstrate stronger efficacy for specific vaccines in defined groups: for adults ≥65, a randomized double‑blind trial found the high‑dose Fluzone vaccine was about 24% more effective than a standard‑dose vaccine at preventing laboratory‑confirmed influenza over two seasons [3]. A phase‑3 trial of an mRNA influenza vaccine showed immunogenicity and noninferiority/superiority endpoints versus an inactivated comparator in adults 18–64, signaling promising trial efficacy for newer platforms [8].
5. One high-profile observational outlier complicates headlines
A Cleveland Clinic preprint of employees reported a statistically higher hazard of recorded influenza in vaccinated versus unvaccinated working‑age staff for 2024–25 (calculated VE −26.9%), but that result comes from a single, non–peer‑reviewed preprint and contrasts with multi‑network CDC and international surveillance showing benefit; the Association of Immunization Managers emphasized the preprint was not peer‑reviewed and explicitly said it "should not be used to guide clinical practice" [9] [10]. This disagreement illustrates how single observational studies — especially preprints — can generate outsized media attention despite conflicting broader evidence [10].
6. Why randomized efficacy and real‑world effectiveness diverge
Randomized trials measure efficacy under controlled conditions in selected participants with predefined endpoints (often lab‑confirmed influenza), producing cleaner estimates for a product in that population; real‑world VE reflects broader populations, variable prior immunity, different vaccine uptake rates, circulating strains and implementation realities, so effectiveness is typically lower and more variable than trial efficacy [8] [1]. Sources show both approaches are complementary: trials establish product potential; observational surveillance measures population impact [8] [1].
7. What this means for 2025–26 guidance and public health messaging
Public health agencies continued to recommend annual vaccination for everyone ≥6 months because pooled surveillance and network analyses found meaningful reductions in medically attended illness and hospitalizations; regulators and advisory committees also updated strain composition and product options for 2025–26 based on global surveillance and trial data [1] [11] [12]. At the same time, reporting on single preprints and variability across networks created room for misinterpretation, so agencies urged reliance on aggregated, peer‑reviewed and network data [10] [1].
Limitations: this analysis uses the supplied reports and excerpts; available sources do not include every trial or all peer‑reviewed VE papers for 2025–26, and some items cited (for example, the Cleveland Clinic preprint) were not peer‑reviewed at the time of reporting [9] [10].