Breadth of influenza A antibody cross-reactivity varies by virus isolation interval and subtype
- PMID: 40494885
- DOI: 10.1038/s41564-025-02033-4
Breadth of influenza A antibody cross-reactivity varies by virus isolation interval and subtype
Abstract
Influenza virus infections generate antibodies that cross-react with antigenically similar viruses. However, the breadth of cross-reactivity is unclear. Here we analysed 200,000 haemagglutination inhibition (HAI) titrations from ferrets singly infected with A(H3N2) or A(H1N1)pdm09. We identified consistent influenza A virus subtype-specific patterns where breadth of HAI antibody cross-reactivity was associated with isolation time between tested and immunizing viruses. This was independent of virus strains, passage history and genetic mutations. A 6-year interval between virus isolation resulted in minimal HAI titres for A(H3N2), while A(H1N1)pdm09 demonstrated broader cross-reactivity with moderate titre reductions over the same interval. Analysis of HA substitutions revealed more amino acid substitutions between viruses for A(H3N2) and a greater reduction in HAI titres per substitution compared with A(H1N1). Longitudinal analysis of human antisera across age groups suggests that repeat A(H3N2) exposure increased HAI responses within the cross-reactivity range, with greater increases for more recent viruses. These results provide a framework for antigenically evolving pathogens such as influenza viruses.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.
Conflict of interest statement
Competing interests: B.J.C. consults for AstraZeneca, Fosun Pharma, GSK, Haleon, Moderna, Novavax, Roche, Sanofi Pasteur, and Pfizer. S.G.S. reports consulting for AstraZeneca, GSK, Moderna, Novavax, Pfizer, Sanofi, CSL Seqirus and Evo Health. S.S.W. has previously received a speaker’s honorarium from Sanofi. D.A.T.C. reports research funding from Merck and Pfizer to his institution for research unrelated to this work. The other authors declare no competing interests.
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