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Stabilization of #H5 highly pathogenic avian #influenza #hemagglutinin improves #vaccine-elicited neutralizing #antibody responses

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By G.M.

Abstract

Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals, heightening the risk of a human pandemic. Influenza viruses adapted to transmission in birds and some other animals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses, enabling membrane fusion at comparatively high pH levels. Here, we combine five mutations within H5 HA that dramatically increase its melting temperature and promote stable closure of the HA trimer. Structural analysis by cryo-electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions, while maintaining local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than non-stabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative stain electron microscopy and deep mutational scanning showed that site E on the side of the HA receptor binding domain was immunodominant across all groups; however, the stabilized immunogens shifted responses toward the receptor binding site (RBS), eliciting a higher proportion of neutralizing antibodies. These findings highlight that H5 HA-stabilizing mutations enhance the quality of antibody responses across different vaccine formats, underscoring their potential to improve pandemic preparedness vaccines targeting viruses from this widely circulating clade.


Competing Interest Statement

AD, MK, and NPK are inventors on University of Washington licensed patents related to influenza vaccines. NPK consults for AstraZeneca. JDB and BD are inventors on Fred Hutch licensed patents related to deep mutational scanning of viral proteins. JDB consults for Apriori Bio, Invivyd, GSK, Pfizer, and the Vaccine Company.

Funder Information Declared

National Institute of Allergy and Infectious Diseases, P01 AI167966, U19 AI181881, R01 AI141707, 75N93021C00015

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.07.30.667762v1

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