Current Status of Clade 2.3.4.4b H5N1 Highly Pathogenic Avian Influenza Virus Transmission in Mammals

Since late 2020, clade 2.3.4.4b H5N1 highly pathogenic avian influenza viruses (HPAIVs) have expanded globally, infecting wild birds, poultry, and an increasing range of mammals. Sustained transmission has occurred in minks and dairy cattle, accompanied by key polymerase basic 2 (PB2) mutations (e.g., E627K, D701N), signaling mammalian adaptation and heightened zoonotic risk. From 2021 to early 2025, 82 human cases, including fatalities in China and the US, underscored rising public health concerns, although no sustained human-to-human transmission has been detected. This review summarizes the epidemiology, transmission dynamics, and molecular evolution of clade 2.3.4.4b H5N1 in mammals. Large-scale outbreaks in US dairy cattle and associated human cases highlight significant cross-species risks, while China’s high poultry vaccination coverage, rapid culling, and nationwide surveillance demonstrate the value of proactive prevention. These contrasting experiences emphasize the need for targeted surveillance, reinforced biosecurity, accelerated countermeasure development, and global coordination under the One Health framework.