Protective human monoclonal antibodies target conserved sites of vulnerability on the underside of influenza virus neuraminidase

Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Vol. 57; no. 3; p. 574
Main Authors:	Lederhofer, Julia, Tsybovsky, Yaroslav, Nguyen, Lam, Raab, Julie E, Creanga, Adrian, Stephens, Tyler, Gillespie, Rebecca A, Syeda, Hubza Z, Fisher, Brian E, Skertic, Michelle, Yap, Christina, Schaub, Andrew J, Rawi, Reda, Kwong, Peter D, Graham, Barney S, McDermott, Adrian B, Andrews, Sarah F, King, Neil P, Kanekiyo, Masaru
Format:	Journal Article
Language:	English
Published:	United States 12-03-2024
Subjects:	Animals Antibodies, Monoclonal Antibodies, Viral Humans Influenza A Virus, H3N2 Subtype Influenza Vaccines Influenza, Human Mice Neuraminidase Orthomyxoviridae Infections Swine Viral Proteins - genetics influenza B cell dark side NA bnab underside neuraminidase antigenic site epitope cryo-EM human monoclonal antibody mAb
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Summary:	Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that target the underside of the NA globular head domain, inhibit viral propagation of a wide range of human H3N2, swine-origin variant H3N2, and H2N2 viruses, and confer both pre- and post-exposure protection against lethal H3N2 infection in mice. Cryo-EM structures of two such antibodies in complex with NA reveal non-overlapping epitopes covering the underside of the NA head. These sites are highly conserved among N2 NAs yet inaccessible unless the NA head tilts or dissociates. Our findings help guide the development of effective countermeasures against ever-changing influenza viruses by identifying hidden conserved sites of vulnerability on the NA underside.
ISSN:	1097-4180
DOI:	10.1016/j.immuni.2024.02.003