Jo, G.; Yamayoshi, S.; Ma, K. M.; Swanson, O.; Torres, J. L.; Ferguson, J. A.; Fernandez-Quintero, M. L.; Huang, J.; Copps, J.; Rodriguez, A. J.; Steichen, J. M.; Kawaoka, Y.; Han, J.; Ward, A. B.

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 potential antibody precursors containing this DR motif in all donors of a healthy human donor BCR database, highlighting the prevalence of this motif and its potential as vaccine targeting. Our findings reveal shared molecular features in NA active site-targeting antibodies, offering insights for NA-based universal influenza vaccine design.