“The emerging pandemic threat of H5N1: Evolutionary adaptations for human transmission, zoonotic spillovers and surveillance gaps”

The increasing zoonotic potential of highly pathogenic avian influenza (HPAI) H5N1 poses a growing threat to global public health. This review examines the molecular and evolutionary mechanisms facilitating H5N1 adaptation in mammalian hosts, focusing on genetic reassortment events, key mutations, and transmission dynamics. Recent mammalian spillover cases, including infections in mink, sea lions, felines, and cattle, suggest a weakening species barrier, with mutations such as PB2-E627K and HA-Q226L enhancing viral replication and host receptor binding affinity. Despite these concerning developments, critical gaps remain in genomic surveillance, particularly in tracking mammalian-adapted variants. Limited sequencing efforts and cross-sectoral data-sharing inefficiencies hinder early detection, increasing the risk of undetected pandemic emergence. Advances in artificial intelligence-driven predictive modeling and the development of broadly neutralizing influenza vaccines offer promising avenues for mitigation. However, a globally coordinated approach integrating real-time genomic tracking, enhanced One Health strategies, and proactive policy interventions is essential. Without immediate action, the risk of a human-adapted H5N1 strain emerging remains a pressing global concern.