Increased Zoonotic Risk Posed by Emerging Haemagglutinin Variants of Clade 2.3.4.4b A(H5Nx) High Pathogenicity Avian Influenza Virus

Abstract High pathogenicity avian influenza viruses (HPAIVs) remain a major threat to animal and human health. The clade 2.3.4.4b H5Nx panzootic has been marked by increasing cross-species adaptation, including outbreaks in dairy cattle. The surge in mammalian infections in both wild and captive populations heighten concerns about zoonotic and pandemic potential. Here, we analyse haemagglutinin (HA) evolution in clade 2.3.4.4b H5Nx viruses from 2020 to 2025, focusing on key residues within the receptor-binding domain. We identify HA E185K (mature H5 HA numbering; E189K in H3 numbering) as a novel immune escape mutation that confers increased binding to avian- and human-type sialic acid receptors. Strikingly, this mutation is increasingly prevalent in cattle-derived H5N1 viruses and enhances binding to human-like receptors. However, ferret studies demonstrated that whilst pathogenicity of the E185K virus was comparable to the cattle derived isolate, the E185K mutation did not confer transmission to direct or indirect contact ferrets. Our results reveal a mechanism linking immune escape with expanded receptor specificity, highlighting a potential pathway for mammalian adaptation. These findings underscore the need for continued surveillance of evolving H5Nx viruses to mitigate emerging zoonotic threats.

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Publication Details

Journal
Research Square
Published
2026-11-03
DOI
https://doi.org/10.21203/rs.3.rs-11578744/v1
Primary Topic
Influenza Virus Research Studies
Type
preprint
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preprint

Increased Zoonotic Risk Posed by Emerging Haemagglutinin Variants of Clade 2.3.4.4b A(H5Nx) High Pathogenicity Avian Influenza Virus

Samuel Richardson, William T. Harvey, Thusitha K. Karunarathna, Sofia Riccio et al.
Research Square
Influenza Virus Research Studies
preprint

Increased Zoonotic Risk Posed by Emerging Haemagglutinin Variants of Clade 2.3.4.4b A(H5Nx) High Pathogenicity Avian Influenza Virus

Samuel Richardson, William T. Harvey, Thusitha K. Karunarathna, Sofia Riccio, Maximillian N. J. Woodall, Marek J. Slomka, Jean-Rémy Sadeyen, Mehnaz Qureshi, Ashley C. Banyard, Thomas P. Peacock, Munir Iqbal, William Barclay, Toby Carter, Joe James, Claire Mary Smith, Samantha Lycett, Ksenia Sukhova, Ian Hay Brown, Kelly J. Roper, Simon Johnson, Hannah Klim, Paul Digard, Elizabeth Billington, Tereza Masonou, Jiayun Yang, Yan Liu, Jafar Hassan, Jin Yu, Georgina Ward, Valdez, Dorothy Hawkins, Cecilia Genova
preprint en

Abstract

Abstract High pathogenicity avian influenza viruses (HPAIVs) remain a major threat to animal and human health. The clade 2.3.4.4b H5Nx panzootic has been marked by increasing cross-species adaptation, including outbreaks in dairy cattle. The surge in mammalian infections in both wild and captive populations heighten concerns about zoonotic and pandemic potential. Here, we analyse haemagglutinin (HA) evolution in clade 2.3.4.4b H5Nx viruses from 2020 to 2025, focusing on key residues within the receptor-binding domain. We identify HA E185K (mature H5 HA numbering; E189K in H3 numbering) as a novel immune escape mutation that confers increased binding to avian- and human-type sialic acid receptors. Strikingly, this mutation is increasingly prevalent in cattle-derived H5N1 viruses and enhances binding to human-like receptors. However, ferret studies demonstrated that whilst pathogenicity of the E185K virus was comparable to the cattle derived isolate, the E185K mutation did not confer transmission to direct or indirect contact ferrets. Our results reveal a mechanism linking immune escape with expanded receptor specificity, highlighting a potential pathway for mammalian adaptation. These findings underscore the need for continued surveillance of evolving H5Nx viruses to mitigate emerging zoonotic threats.

Research Square
The Pirbright Institute (GB), Animal and Plant Health Agency (GB), The Francis Crick Institute (GB), University College London (GB), Imperial College London (GB), University of Edinburgh (GB)
Influenza Virus Research Studies
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