The episodic resurgence of highly pathogenic avian influenza H5 virus

Highly pathogenic avian influenza (HPAI) H5N1 activity has intensified globally since 2021, replacing the dominant clade 2.3.4.4 H5N8 virus. H5N1 viruses have spread rapidly to four continents, causing increasing reports of mass mortality in wild birds and poultry. The ecological and virological properties required for future mitigation strategies are unclear. Using epidemiological, spatial and genomic approaches, we demonstrate changes in the source of resurgent H5 HPAI and reveal significant shifts in virus ecology and evolution. Outbreak data indicates key resurgent events in 2016/17 and 2020/21 leading up to the panzootic spread of H5N1 in 2021/22, with increases in virus diffusion velocity and greater persistence in wild birds. Genomic analysis shows that the 2016/17 epizootics originated in Asia, where HPAI H5 reservoirs are well documented as persistent. However, in 2020/21, 2.3.4.4b H5N8 viruses emerged in domestic poultry in Africa containing several novel mutations altering the HA structure, receptor binding, and antigenicity. The new H5N1 virus emerged from H5N8 through reassortment in wild birds along the Adriatic flyway around the Mediterranean Sea, and was characterized by extensive reassortment with low pathogenic avian influenza in domestic and wild birds as they spread globally. In contrast, earlier outbreaks of H5N8 were caused by a more stable genetic constellation, revealing dynamic changes in HPAI H5 genomic evolution. These results suggest a shift in the epicenter of HPAI H5 beyond Asia to new regions in Africa, the Middle East, Europe, and North and South America. The persistence of HPAI H5 with resurgence potential in domestic birds indicates that elimination strategies remain a high priority. ### Competing Interest Statement The authors have declared no competing interest.