Risk assessment of 2024 cattle H5N1 using age-stratified serosurveillance data.

The highly pathogenic avian influenza virus A(H5N1) clade 2.3.4.4b has caused a human outbreak in North America since March 2024. Here, we conducted a serosurveillance study to determine the risk of A(H5N1) clade 2.3.4.4b (2024 cattle H5N1) to general population. In the initial screening of 180 serum specimens encompassing all age groups, 2.2% (4/180) had detectable neutralizing antibody (nAb) titres against reverse genetics-derived 2024 cattle H5N1, with all collected from older adults aged ≥60 years old. Further screening showed that 4.2% (19/450) of adults aged ≥60 years old had detectable nAb titres against the 2024 cattle H5N1. 80% (4/5) of serum specimens with nAb titre of ≥40 had detectable Hemagglutination inhibition (HI) titre, and there was a positive correlation between nAb titre and HA binding (r = 0.3325, 95% confidence interval 0.2477-0.4123; P < 0.0001). For individuals aged ≥60 years old, the nAb titre against seasonal H1N1 virus was 4.2-fold higher for those with detectable H5N1 nAb titre than those ≥60 years old ones without (geometric mean titre: 89.3 [95% CI 42.9-185.7] vs 21.3 [95% CI 17.3-26.1], P < 0.0001), but there was no statistically significant difference between H5N1 and H3N2 nAb titre. There was no difference in demographics, comorbidities and clinical frailty scores between individuals with detectable H5N1 nAb and those without. Our findings suggest that most individuals lack nAb response against 2024 cattle H5N1 and there is an urgency to develop and evaluate H5N1 vaccine or prophylactic monoclonal antibodies. Immune imprinting may be responsible for the cross neutralization between H5N1 and H1N1 among older adults.