Associate Professor Texas Biomedical Research Institute San Antonio, Texas, United States
Introduction/Rationale: 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.
