How a Potent Anti-neuraminidase Monoclonal Antibody Navigates Recent Immune-evasive Influenza Strains: A Structural Study by Single-particle CryoEM

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Rapidly evolving influenza A (IAV) and B (IBV) viruses are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly against the highly variable head region of hemagglutinin (HA) and their effectiveness is limited by viral drift and suboptimal immune responses. Here, we describe a neuraminidase (NA)-specific monoclonal antibody (mAb), FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as B/Victoria/2/87-like, B/Yamagata/16/99-like, and ancestral IBV lineages. FNI9 broadly inhibits seasonal IAVs and IBVs, shows synergistic activity when combined with anti-HA stem-directed antibodies, and demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. Structural analyses by single-particle cryo-EM reveal the receptor mimicry mechanism of action of FNI mAbs and demonstrate how FNI9 retains binding to the recent immune-evading H3N2 strains bearing an N-glycan at position 245. The unprecedented preclinical breadth and potency of FNI9 mAb supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

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