A Multidonor Plasma Antibody Class with Broad Activity Against H5N1 Neuraminidase 2309455

Abstract Introduction Highly pathogenic H5N1 influenza viruses remain a significant pandemic threat, underscoring the need to define antibody responses that target conserved viral epitopes. Here, we characterize a panel of plasma IgG—derived human neuraminidase (NA)—specific monoclonal antibodies (mAbs) that share a convergent CDR-H3 “DR motif,” previously implicated in substrate mimicry at the NA active site. Methods Using IgG proteomics discovery, ELISA, immunofluorescence assays, enzymatic inhibition, and microneutralization assays, we show that multiple DR-motif mAbs bind H5N1 NA with high potency and directly inhibit NA activity. Results Several antibodies exhibit cross-reactivity with divergent influenza A strains and target overlapping epitopes within the NA catalytic site. Importantly, two DR-motif mAbs (41508 and 125308) confer protection in C57BL/6 mice against lethal challenge with A/Texas/37/2024 (H5N1; clade 2.3.4.4b, genotype B3.13). Conclusion Together, these data define a multidonor class of circulating, functional human NA-directed antibodies with broad antiviral activity and highlight the NA active site as an accessible and vulnerable target for next-generation influenza vaccines and antibody-based countermeasures. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)