2025/26 subclade-specific influenza A and B vaccine effectiveness estimates and discordant laboratory-based indicators of vaccine match or mismatch

Background: The 2025/26 influenza season included A(H3N2) subclade K predominance with A(H1N1)pdm09 co-circulation and subsequent prolonged influenza B activity. The Canadian Sentinel Practitioner Surveillance Network reports vaccine effectiveness (VE) in the context of genetic and antigenic relatedness to circulating viruses. Methods: We estimated VE by test-negative design among outpatients with medically-attended acute respiratory illness between November and April. We characterized case viruses by whole genome sequencing and hemagglutination inhibition assay. Results: Among 2809/9047 (31%) influenza-positive specimens, 82% (2306/2809) were influenza A with 18% (504/2809) influenza B. Of subtyped influenza A, 85% (1848/2169) were A(H3N2). We sequenced 59% (1099/1848) of A(H3N2) viruses, with 87% (956/1099) subclade K, antigenically-mismatched to subclade J.2 vaccine. VE against A(H3N2) and subclade K was 38% (95% confidence interval: 27%-47%) and 33% (19%-45%). We sequenced 69% (222/323) of A(H1N1)pdm09 viruses, virtually all (n=218) clade 5a.2a.1, including subclades D.3.1 (21%; n=47) and D.3.1.1 (77%; n=171), antigenically-matched to subclade D vaccine. VE against A(H1N1)pdm09, subclades D.3.1 and D.3.1.1 was 28% (4%-47%), -21% (-144%-40%) and 44% (14%-64%). We sequenced 82% (413/504) of influenza B viruses, all B/Victoria, including antigenically-mismatched subclade C.3 (18%; n=74) with D197N gain-of-glycosylation, and antigenically-matched subclade C.5 (82%; n=339) relative to subclade C vaccine. VE against influenza B, subclades C.3 and C.5 was 55% (41%-66%), 10% (-60%-49%) and 68% (51%-79%). Conclusions: The 2025/26 influenza vaccine reduced the risk of A(H3N2), A(H1N1)pdm09 and B/Victoria by over one-third, one-quarter and one-half, respectively. Laboratory-based indicators of vaccine match remain uncertain proxies for actual vaccine protection, reinforcing importance of annual epidemiological monitoring of VE.