Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses
Seyhan Boyoglu-Barnum, Geoffrey B Hutchinson, Jeffrey C Boyington, Syed M Moin, Rebecca A Gillespie, Yaroslav Tsybovsky, Tyler Stephens, John R Vaile, Julia Lederhofer, Kizzmekia S Corbett, Brian E Fisher, Hadi M Yassine, Sarah F Andrews, Michelle C Crank, Adrian B McDermott, John R Mascola, Barney S Graham, Masaru Kanekiyo, Seyhan Boyoglu-Barnum, Geoffrey B Hutchinson, Jeffrey C Boyington, Syed M Moin, Rebecca A Gillespie, Yaroslav Tsybovsky, Tyler Stephens, John R Vaile, Julia Lederhofer, Kizzmekia S Corbett, Brian E Fisher, Hadi M Yassine, Sarah F Andrews, Michelle C Crank, Adrian B McDermott, John R Mascola, Barney S Graham, Masaru Kanekiyo
Abstract
The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccine efforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypic protection in animals; however, the protection does not extend to group 2 viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, we show that introducing the group 2 glycan at Asn38HA1 to a group 1 stem-nanoparticle (gN38 variant) based on A/New Caledonia/20/99 (H1N1) broadens antibody responses to cross-react with group 2 HAs. Immunoglobulins elicited by the gN38 variant provide complete protection against group 2 H7N9 virus infection, while the variant loses protection against a group 1 H5N1 virus. The N38HA1 glycan thus is pivotal in directing antibody responses by controlling access to group-determining stem epitopes. Precise targeting of stem-directed antibody responses to the site of vulnerability by glycan repositioning may be a step towards achieving cross-group influenza protection.
Conflict of interest statement
J.C.B., H.M.Y., J.R.M., B.S.G. and M.K. are named inventors of a patent application on stabilized influenza HA stem filed by the National Institutes of Health. All other authors declare no competing interests.
Figures
![Fig. 1. Design and characterization of group…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7005838/bin/41467_2020_14579_Fig1_HTML.jpg)
![Fig. 2. Immunogenicity of H1 stem nanoparticle…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7005838/bin/41467_2020_14579_Fig2_HTML.jpg)
![Fig. 3. Specificity of serum neutralizing activity…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7005838/bin/41467_2020_14579_Fig3_HTML.jpg)
![Fig. 4. Homotypic, heterosubtypic, and cross-group protection…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7005838/bin/41467_2020_14579_Fig4_HTML.jpg)
![Fig. 5. Cross-group neutralization and protective capacity…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7005838/bin/41467_2020_14579_Fig5_HTML.jpg)
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