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#Evolution of #antibody cross-reactivity to #influenza #H5N1 #neuraminidase from an N2-specific germline

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By G.M.

Abstract

The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and 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, there is a lack of molecular understanding of how this cross-reactivity develops. Using a phage display antibody library derived from 245 healthy donors, this study isolates an antibody, known as HB420, that cross-reacts with the neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo. Cryo-EM analysis shows that HB420 targets the neuraminidase active site by mimicking sialic acid binding through a single Asp residue. Additionally, the inferred germline of HB420 is N2-specific but acquires cross-reactivity to H5N1 neuraminidase through somatic hypermutations. Overall, our findings provide insights into how neuraminidase antibody evolves breadth, which has important implications for the development of broadly protective influenza vaccines.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.06.20.660733v1

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