North American perspective on the highly pathogenic avian influenza H5Nx clade 2.3.4.4b outbreak (November 2021 - March 2025).

Influenza A (H5Nx) highly pathogenic avian influenza viruses of clade 2.3.4.4b were first detected in North America in late 2021, initiating a multi-year outbreak unprecedented in geographic extent, duration, and host range. Surveillance conducted across Canada, the United States, and Mexico has documented widespread detections in wild birds and poultry, and repeated spillover into wild and domestic mammals. Genomic analyses reveal successive lineage replacements and extensive reassortment between Eurasian and North American lineages, with over 100 distinct genotypes identified to date. Recent events, including detection of genotype B3.13 in United States dairy cattle and the emergence of genotype D1.1 across all four North American migratory bird flyways, highlight ongoing viral evolution and cross-species transmission risks. This synthesis provides a continental overview of the outbreak from November 1, 2021, to March 31, 2025, summarizing surveillance results and genomic trends to inform continued One Health preparedness and response efforts.