What factors (vaccine match, antigenic drift, egg-adaptation) influenced 2025-2026 H3N2 vaccine effectiveness against hospitalization?
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Executive summary
The 2025–2026 influenza A(H3N2) vaccine’s protection against hospitalization was shaped primarily by how well the vaccine strain matched circulating viruses, by antigenic drift producing the new subclade K, and by differences introduced when viruses are grown in eggs versus cell- or recombinant-based manufacturing; these forces combined to produce a vaccine that offered substantial but imperfect protection against severe disease (partial match, retained protection against hospitalization) [1] [2] [3] [4]. Early network and international estimates place hospitalization protection in the range typically seen in H3N2 years—better against severe outcomes than against outpatient illness—consistent with partial antigenic match and with some manufacturing-related degradation in immune recognition from egg‑adaptation [5] [6] [7].
1. Vaccine match: a partial match that still mattered
Surveillance and vaccine composition decisions left the 2025–2026 vaccine targeting H3N2 strains derived from earlier subclades (egg-based: A/Croatia/10136RV/2023-like; cell/recombinant: A/District of Columbia/27/2023-like), and public reports noted that most characterized circulating viruses were similar to vaccine components though a substantial fraction of H3N2 viruses were antigenically different, leaving a partial match at the population level [1] [6]. That partial match translated into preserved effectiveness against hospitalization—multiple sources report VE against H3N2‑associated hospitalizations in the 30–60% range in early estimates depending on age and setting—illustrating the common pattern that even imperfect matches blunt severe outcomes better than they prevent all infections [5] [6] [7].
2. Antigenic drift and the rise of subclade K
Evolutionary change in hemagglutinin produced subclade K, first detected in mid‑2025 and carrying several mutations in key antigenic sites relative to the vaccine reference strains; public health reviews and European sequencing data documented subclade K’s spread across multiple countries and its early dominance in some regions, implying antigenic drift reduced antibody recognition in some people [2] [3]. Multiple outlets warned that these mutations could enable immune escape sufficient to increase case counts and hospitalizations in vulnerable groups, and early VE estimates reflected that drift: outpatient protection was often lower and statistically uncertain, while protection against hospitalization remained measurable but attenuated compared with ideal seasons [2] [3] [6].
3. Egg‑adaptation: a manufacturing wrinkle that can shrink effectiveness
All US vaccines for 2025–2026 were trivalent, but egg‑based vaccines used a different H3N2 seed (A/Croatia/10136RV/2023-like) than cell/recombinant products (A/District of Columbia/27/2023-like), and egg‑adaptation is known to introduce changes in antigenicity that can reduce immune recognition of circulating H3N2 variants [1]. Reporting highlighted that cell‑based and recombinant vaccines may better preserve the intended antigenic structure, which likely contributed to heterogeneity in effectiveness estimates across vaccine types and age groups, a plausible contributor to the modestly lower VE sometimes seen against H3N2 hospitalizations [1] [4]. Sources note the vaccine was still expected to confer meaningful protection, but they explicitly flag egg‑adaptation as a factor that can erode those gains [1] [7].
4. Other contributors that modulated real‑world VE against hospitalization
Timing and waning immunity can alter observed VE: earlier analyses from recent seasons showed reduced effectiveness the longer the interval from vaccination to illness, which can lower protection in late or early peaks relative to vaccination campaigns [8]. Surveillance gaps (including a temporary federal reporting slowdown) limited precise subclade breakdowns early in the season, complicating real‑time attribution of diminished VE to either mismatch versus drift or to distributional factors such as vaccine type uptake [3]. Finally, consistent with long-standing patterns, multiple networks reported that vaccines tend to retain stronger protection against hospitalization than against outpatient illness even when antigenic mismatch exists [6] [9].
5. Bottom line and competing frames
The dominant explanatory story is multi‑factorial: antigenic drift (subclade K) reduced antibody recognition, egg‑adaptation in many vaccine lots likely further weakened immune match for some recipients, and the vaccine strain selection offered only a partial match—yet vaccines still reduced hospitalizations at levels comparable to prior H3N2 seasons [2] [3] [7] [5] [6]. Public‑health advocates stress that even imperfect vaccines substantially lower severe outcomes and hospitalization risk [5] [4], while some clinical commentaries emphasize the technical limits of egg‑based production and call for broader use of cell/recombinant platforms to reduce that particular source of mismatch [1] [7].