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
Abstract
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 Asn38 HA1 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 N38 HA1 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.