The Winners Take It All? Evolutionary Success of H5Nx Reassortants in the 2020–2024 Panzootic

Avian influenza viruses undergo frequent genetic reassortment, which can coincide with phenotypic changes in transmission, pathogenicity, and host species niche. Since 2020, clade 2.3.4.4b H5 high pathogenicity avian influenza viruses (HPAIVs) have driven a global panzootic, causing mass mortality in wild birds, poultry, and, for the first time, repeated spillover infections in a variety of mam-malian species. This resurgence of H5 HPAIV has coincided with a dramatic increase in the number of circulating reassortant strains; however, the scale, impact and drivers of these reassortants remain unknown. Here, we combined statistical and phylodynamic modelling to reconstruct the global evolutionary dynamics of H5Nx viruses across four epizootic seasons (2020-2024). We identified 209 genetically distinct reassortants, stratified into three transmission categories based on their phylogenetic and epidemiological profiles. Accounting for sampling depth and HPAIV incidence, we estimated that reassortants emerged most frequently in Asia, but ‘major’ reassortants associated with increased host range, inter-seasonal persistence, and long-range dissemination, more frequently emerged from Europe. Altogether, reassortant emergence followed an episodic pattern in which most reassortants were transient, but 3% seeded large clusters of secondary reassortants soon after their own emergence. Statistical modelling revealed that reassortant success was strongly shaped by ecological factors, including circulation in specific wild bird orders and the ability to infect a wider range of host niches. Reassortant dispersal was linked to poultry trade intensity, particularly in North America. Collectively, our findings reveal reassortment dynamics in H5 HPAIVs and identify key virological and ecological drivers underpinning the emergence and global spread of successful reassortants. These insights support the importance of enhanced surveillance to track evolution of H5 HPAIV and identify traits relevant for consideration in pandemic risk assessment.