Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3
Gyunghee Jo, Seiya Yamayoshi, M. Krystal, Olivia Swanson, Jonathan L. Torres, James A. Ferguson, Monica L. Fernández‐Quintero, Jiachen Huang, Jeffrey Copps, Alesandra J. Rodriguez, Jon M. Steichen, Yoshihiro Kawaoka, Julianna Han, Andrew B. Ward
Abstract
Influenza viruses evolve rapidly, driving seasonal epidemics and posing global pandemic threats. While neuraminidase (NA) has emerged as a vaccine target, shared molecular features of NA antibody responses are still not well understood. Here, we describe cryo-electron microscopy structures of the broadly protective human antibody DA03E17, which was previously identified from an H1N1-infected donor, in complex with NA from A/H1N1, A/H3N2, and B/Victoria-lineage viruses. DA03E17 targets the highly conserved NA active site using its long CDR H3, which features a DR (Asp-Arg) motif that engages catalytic residues and mimics sialic acid interactions. We further demonstrate that this motif is conserved among several NA active site-targeting antibodies, indicating a common receptor mimicry strategy. We also identified BCR sequences containing this DR motif across all donors in a healthy human repertoire database, suggesting that such precursors may be relatively common and have vaccine targeting potential. Our findings reveal shared molecular features in NA active site-targeting antibodies that can be harnessed to design broad, immune-focused influenza vaccines.