What causes variability in flu vaccine effectiveness against H3N2?

1. Virus evolution: H3N2’s fast diversifying branches

H3N2 mutates quickly, producing genetically distinct subclades that can differ antigenically from vaccine reference viruses; the newly observed subclade K has drifted from the vaccine’s subclade J/J.2 reference strains and now dominates many samples in places like the UK and Japan, raising concerns about a mismatch that can reduce neutralization by vaccine‑induced antibodies ^{[6] [1] [7]}. WHO and national sequencing efforts document continued diversification of H3N2 (multiple J.2 subclades) and use these data to guide vaccine strain selection, underscoring that antigenic change is a primary driver of VE variability ^{[8] [5]}.

2. Laboratory signals vs. real‑world protection

Laboratory assays — ferret antisera and haemagglutination inhibition tests — show reduced antibody recognition of subclade K compared with vaccine strains, a classic signal of antigenic drift ^{[1] [5]}. However, UK Health Security Agency real‑world VE analyses report the 2025/26 vaccine currently reduces hospital attendance by roughly 70–75% in children and 30–40% in adults, showing that a laboratory “mismatch” does not always translate into complete loss of clinical protection, particularly against severe outcomes ^{[1] [2] [3]}.

3. Vaccine production and egg‑adaptation problems

Historic and scientific reviews identify vaccine manufacturing choices as a modifiable source of VE variability: egg‑grown vaccine strains often acquire adaptive mutations (egg‑passage changes) that alter hemagglutinin glycosylation and antigenicity, which can impair the neutralizing antibody response to circulating H3N2 viruses ^[4]. Regulatory and guidance documents (FDA, WHO) note the selection of candidate vaccine viruses involves balancing surveillance data and manufacturing realities, which can leave vaccines less than perfectly matched in some seasons ^{[9] [8]}.

4. Host immunity: imprinting, age, and repeated vaccination

The literature frames host factors — prior infections, immune “imprinting” from early exposures, repeated annual vaccination, and age — as important but complex contributors to H3N2 VE variation; observational studies find H3N2 VE is often lower than for H1N1 or B even when antigenic match is similar, pointing to host immunity as part of the explanation ^[4]. Surveillance and outcome reports repeatedly show H3N2 seasons hit older adults harder and are associated with lower vaccine performance in those age groups, a pattern reflected in the UK’s reported adult VE numbers ^{[4] [2] [3]}.

5. What surveillance and interim VE numbers tell us — and their limits

Interim VE estimates from southern hemisphere evaluations and multi‑country studies found moderate protection against H3N2 (e.g., adjusted VE ~37% against A(H3N2) hospitalizations in a Southern Hemisphere assessment), indicating partial effectiveness even when H3N2 circulates widely ^[10]. But early season VE is provisional: lab characterisation, real‑world VE, and virus prevalence can change as the season progresses, so current estimates and antigenic assessments must be updated with ongoing surveillance ^{[5] [10]}.

6. Competing perspectives and policy implications

Public health agencies (UKHSA, GOV.UK) stress that vaccination remains the best protection against severe illness and point to encouraging VE in children and meaningful adult protection despite drift ^{[2] [3]}. Journalistic summaries and experts also note that mismatches are common yet vaccines still blunt severe outcomes; others emphasize improving vaccines (non‑egg platforms or broader antigens) as a way to address persistent H3N2 challenges — a debate grounded in evidence but influenced by priorities in manufacturing, cost, and regulatory pathways ^{[1] [4] [9]}.

Limitations and what’s not found in current reporting: sources used here do not provide definitive causal weights (e.g., exact share of VE loss due to egg‑adaptation vs. antigenic drift vs. host immunity) nor long‑term randomized comparisons of vaccine platforms for H3N2 (not found in current reporting).