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TitleEvolution of antibody cross-reactivity to influenza H5N1 neuraminidase from an N2-specific germline.
Journal, issue, pagesCell Host Microbe, Vol. 33, Issue 11, Page 1916-11928.e6, Year 2025
Publish dateNov 12, 2025
AuthorsHuibin Lv / Yang Wei Huan / Qi Wen Teo / Chunke Chen / Tossapol Pholcharee / Akshita B Gopal / Madison R Ardagh / Jessica J Huang / Ruipeng Lei / Xin Chen / Yuanxin Sun / Yun Sang Tang / Arjun Mehta / Mateusz Szlembarski / Kevin J Mao / Emily X Ma / Lucas E Wittenborn / Meixuan Tong / Lucia A Rodriguez / Letianchu Wang / Chris K P Mok / Nicholas C Wu /
PubMed AbstractThe ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and its occasional spillover to humans have raised concerns about a potential H5N1 pandemic. Although ...The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and its occasional spillover to humans have raised concerns about a potential H5N1 pandemic. Although recent studies have shown that pre-existing human antibodies can recognize H5N1 neuraminidase, the molecular basis of how this cross-reactivity develops remains poorly understood. In this study, we used a phage display antibody library derived from 245 healthy donors to isolate an antibody, HB420, that cross-reacts with neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo. Cryogenic electron microscopy analysis reveals that HB420 targets the neuraminidase active site by mimicking sialic acid binding through a single Asp residue. Furthermore, the inferred germline of HB420 is N2 specific but acquires cross-reactivity to H5N1 neuraminidase through somatic hypermutation. Overall, our findings provide insights into how neuraminidase antibody evolves breadth, which has important implications for the development of broadly protective influenza vaccines.
External linksCell Host Microbe / PubMed:41109220
MethodsEM (single particle)
Resolution2.16 Å
Structure data

70808

9osr

EMDB-70808, PDB-9osr:
Structure of Fab HB420 in complex with influenza H3N2 A/Moscow/10/1999 neuraminidase
Method: EM (single particle) / Resolution: 2.16 Å

Source
  • homo sapiens (human)
  • influenza a virus
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Influenza / Neuraminidase / Antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex

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