Sialic acid-anchored haemagglutinin stalk neutralizing antibody M-SiaB enhances protection against highly pathogenic influenza H5N1/Texas/2024.

The recently emerged cattle H5N1/Texas/2024 strain highlights the need for effective prophylactic and therapeutic drug interventions, yet most existing neutralizing antibodies (NAbs) have limited efficacy against genetically divergent pathogenic influenza viruses. Here we engineer a sialic acid-anchored tandem M-SiaB by fusing a hemagglutinin (HA) stalk-specific monoclonal NAb with a sialic acid-receptor-binding domain (SiaB). M-SiaB shows 4- to 20-fold greater neutralizing potency against diverse authentic influenza viruses compared to the parental NAb and suppresses multiple stages of the viral life cycle, including viral attachment, entry and release. Importantly, intranasal M-SiaB confers markedly enhanced protection against nasal challenges with the pathogenic H1N1/PR8 and H5N1/Texas/2024 strains. Notably, a single dose of M‑SiaB maintains survival after a highly lethal H5N1/Texas/2024 challenge for up to 21 days. These findings demonstrate that simultaneously targeting HA stalk and sialic acid-receptor is a promising strategy to enhance the potency and breadth of NAbs against genetically divergent pathogenic influenza viruses.