Structural characterization of influenza group 1 chimeric hemagglutinins as broad vaccine immunogens

• 成果类型: Article
• 署名作者: Nguyen, Yen Thi Kim; Zhu, Xueyong; Han, Julianna; Rodriguez, Alesandra J.; Sun, Weina; Yu, Wenli; Palese, Peter; Krammer, Florian; Ward, Andrew B.; Wilson, Ian A.
• 署名单位: Scripps Research Institute; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Medical University of Vienna; Scripps Research Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12002
• DOI: 10.1073/pnas.2416628122
• 发表日期: 2025-02-18
• 关键词: virus hemagglutinin; antibody recognition; neutralizing antibodies; globular head; site; stem; epitope; domain

摘要

Chimeric hemagglutinins (cHA) appear to be promising for the design and development of universal influenza vaccines. Influenza A group 1 cHAs, cH5/1, cH8/1, and cH11/1, comprising an H1 stem attached to either an H5, H8, or H11 globular head, have been used sequentially as vaccine immunogens in human clinical trials and induced high levels of broadly protective antibodies. Using X- ray crystallography and negative- stain electron microscopy, we determined structures of cH5/1, cH8/1, and cH11/1 HAs in their apo (unliganded) and antibody Fab- bound states. Stem- reactive antibodies 3E1 and 31.b.09 recognize their cognate epitopes in cH5/1, cH8/1, and cH11/1 HAs. However, with cH5/1, the head domains are rotated by 35 to 45 degrees around the threefold axis of the HA trimer compared to native HA with a more splayed- open conformation at the stem base. cH11/1 with 3E1 is structurally more native- like but resembles cH5/1 with 31.b.09, whereas cH8/1 with 31.b.09 exhibited a range of closed- to- open stem configurations with some separation of head and stem domains. Furthermore, all of these group 1 cHAs effectively bound a broad head trimer interface antibody and other broad stem antibodies. Thus, the cHAs exhibit structural plasticity without compromising the stem and head trimer interface epitopes for elicitation of influenza A group 1 cross- reactive antibodies.