Ruopeng Xie1,2, Kimberly M. Edwards1,2, Michelle Wille3,4, Xiaoman Wei1,2, Sook-San Wong1,2, Mark Zanin1,2, Rabeh El-Shesheny6, Mariette Ducatez5, Leo L. M. Poon1,2, Ghazi Kayali7, Richard J. Webby8, Vijaykrishna Dhanasekaran1,2
1 School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
2 HKU-Pasteur Research Pole, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
3 Sydney Institute for Infectious Diseases, School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia
4 Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia
5 Center of Scientific Excellence for Influenza Viruses, National Research Centre, Egypt
6 Institut national de recherche pour l’agriculture, l’alimentation et l’environnement, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
7 Human Link, DMCC, Dubai, United Arab Emirates.
8 Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, USA
*Corresponding author:
Vijaykrishna Dhanasekaran, Associate Professor
School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
email: veej@hku.hk
Highly pathogenic avian influenza (HPAI) H5N1 activity has intensified globally since 2021, increasingly causing mass mortality in wild birds and poultry, and incidental infections in mammals. Still, the ecological and virological properties that underscore future mitigation strategies remain unclear. Using epidemiological, spatial, and genomic approaches, we demonstrate changes in the origins of resurgent HPAI H5 and reveal significant shifts in virus ecology and evolution. Outbreak data shows key resurgent events in 2016/17 and 2020/21, contributing to the emergence and panzootic spread of H5N1 in 2021/22. Genomic analysis reveals that the 2016/17 epizootics originated in Asia, where HPAI H5 reservoirs are documented as persistent. In 2020/21, 2.3.4.4b H5N8 viruses emerged in African poultry, featuring mutations altering HA structure and receptor binding. In 2021/22, a new H5N1 virus evolved through reassortment in wild birds in Europe, undergoing further reassortment with low pathogenic avian influenza in wild and domestic birds during global dissemination. These results highlight a shift in the epicenter of HPAI H5 beyond Asia to new regions and suggest that increasing persistence of HPAI H5 in wild birds is facilitating geographic and host range expansion, accelerating dispersion velocity, and increasing reassortment potential. As earlier outbreaks of H5N1 and H5N8 were caused by more stable genetic constellations, recent genomic changes reflect adaptation across the domestic-wild bird interface. Elimination strategies in domestic birds therefore remain a high priority to limit future epizootic resurgences.