Single-domain antibodies directed against hemagglutinin and neuraminidase protect against influenza B viruses

Arne Matthys, Jan Felix, Joao Paulo Portela Catani, Kenny Roose, Wim Nerinckx, Benthe Buyten, Daria Fijalkowska, Nico Callewaert, Savvas N. Savvides and Xavier Saelens ()
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Arne Matthys: VIB Center for Medical Biotechnology, VIB
Jan Felix: Ghent University
Joao Paulo Portela Catani: VIB Center for Medical Biotechnology, VIB
Kenny Roose: VIB Center for Medical Biotechnology, VIB
Wim Nerinckx: VIB Center for Medical Biotechnology, VIB
Benthe Buyten: VIB Center for Medical Biotechnology, VIB
Daria Fijalkowska: VIB Center for Medical Biotechnology, VIB
Nico Callewaert: VIB Center for Medical Biotechnology, VIB
Savvas N. Savvides: Ghent University
Xavier Saelens: VIB Center for Medical Biotechnology, VIB

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Influenza B viruses are antigenically diverse and contribute significantly to the annual influenza burden. Here we report influenza B virus neutralizing single-domain antibodies that target highly conserved regions of the hemagglutinin and neuraminidase. Structural studies by single particle electron cryo-microscopy (cryo-EM) revealed that one of these single-domain antibodies prevents the conformational transition of the viral hemagglutinin to the post-fusion state by targeting a quaternary epitope spanning two protomers in the hemagglutinin-stem region. A second single-domain antibody broadly inhibits influenza B neuraminidase activity, including an oseltamivir-resistant neuraminidase, and its complex with neuraminidase elucidated by single particle cryo-EM established that it binds to residues in the neuraminidase catalytic site. Head-to-tail fusions of these single-domain antibodies led to bispecific binders that further improved the neutralization breadth and potency against influenza B viruses. These single-domain antibodies, fused to a human IgG1-Fc domain, fully protected female mice against an otherwise lethal influenza B virus challenge. Our findings underscore the potential of engineered single-domain antibodies to help control influenza B virus infections.

Date: 2025
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DOI: 10.1038/s41467-025-60232-3

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