The Q226H Mutation in Avian H5N1 Hemagglutinin Mediates a Path towards Structural Adaptation in Humans

Ross A. Edwards; Oluwafemi F. Adu; Egor P. Tchesnokov; Dana Kocíncová; Emma Woolner; Zoe Turner; Duong T. Bui; Lara K. Mahal; Nathan J. Zelyas; John S. Klassen; Andrei P. Drabovich; Kalyan Das; Matthias Götte

doi:10.64898/2026.05.21.726965

ImmunologybioRxivMay 26, 2026

Preprint

The Q226H Mutation in Avian H5N1 Hemagglutinin Mediates a Path towards Structural Adaptation in Humans

Ross A. Edwards iD, Oluwafemi F. Adu iD, Egor P. Tchesnokov iD, Dana Kocíncová iD, Emma Woolner iD, Zoe Turner iD, Duong T. Bui iD, Lara K. Mahal iD, Nathan J. Zelyas iD, John S. Klassen iD, Andrei P. Drabovich iD, Kalyan Das iD, Matthias Götte iD

Abstract

The global outbreak of highly pathogenic avian influenza (HPAI) A(H5N1) among birds and the spillover to mammals increases the risk for humans. A recent case in British Columbia with a clade 2.3.4.4b H5 virus infection revealed a mixture of 226Q/H in the receptor-binding site of hemagglutinin. While significant changes in pre-existing immunity by H1 or H3 polyclonal sera are not evident, we show that the Q226H mutation enables binding to human-type a2-6 sialic acid receptors. High-resolution cryo-EM structures provide a basis for the alteration in receptor preference and show that a possible path towards human adaptation also requires a conformational change of the bound a2-6-sialylated glycan. Continued surveillance for additional mutations that could enhance this phenotype is warranted.

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