Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses

摘要

The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccineefforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypicprotection in animals; however, the protection does not extend to group 2viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, weshow that introducing the group 2 glycan at Asn38HA1 to a group 1 stem-nanoparticle (gN38variant) based on A/New Caledonia/20/99 (H1N1) broadens antibody responses to crossreactwith group 2 HAs. Immunoglobulins elicited by the gN38 variant provide completeprotection against group 2 H7N9 virus infection, while the variant loses protection against agroup 1 H5N1 virus. The N38HA1 glycan thus is pivotal in directing antibody responses bycontrolling access to group-determining stem epitopes. Precise targeting of stem-directedantibody responses to the site of vulnerability by glycan repositioning may be a step towardsachieving cross-group influenza protection.