Name
Structures of hemagglutinin (HA) for understanding the human infectivity of H5N1 Influenza A
Presenter
Ross A. Edwards, University of Alberta
Co-Author(s)
Ross A. Edwards1,2, Dana Kocincova1, Egor P. Tchesnokov, Oluwafemi F. Adu, Anakhpriya Dhillon, Matthias Götte1, Kalyan Das1,2 1Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, AB, Canada 2Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
Abstract Category
Discovering & Evolving
Abstract
Subtype H5N1 of the influenza A virus is commonly associated with infection in hosts but currently crossover to humans is a rare but alarming event. In Canada, the first and only case to date being reported in late 2024 in a pediatric patient in British Columbia (BC). Hemagglutinin (HA) is an historically well studied surface protein of influenza virus that plays important roles in viral infectivity and is also the target of vaccines. Viral genome sequencing of a tracheal-aspirate specimen from the patient revealed two key mutations in the receptor binding pocket – Q226H and E190D. Reactivity of this HA to monoclonal antibodies elicited against various HA domains was determined by ELISA. An anti-stem antibody (MEDI8852) recognizing an epitope conserved across influenza subtypes bound H5N1 BC HA. Similarly, subtype-broad antibodies specific for the monomer interface interact with this HA. While most antibodies targeting the receptor-binding site of earlier H5N1 clades were not effective, 100F4 and 65C6, directed against the more conserved lateral head region, retained the ability to recognize HA of BC H5N1 virus. Here we present single-particle cryo-EM structures of the surface hemagglutinin protein from the single Canadian patient in complex with (i) broadly neutralizing antibodies, MEDI8852, 100F4 and 65C6, and (ii) avian and human-like receptor analogs. The structures of antibody-bound BC H5N1 hemagglutinin help reveal how conserved stem elements and recent acquired mutations influence antibody and glycan recognition. These structural insights outline the vulnerability of emerging strains and will aid the design of more durable vaccines and therapeutics.