Mutating a flexible region of the RSV F protein can stabilize the prefusion conformation

• 成果类型: Article
• 署名作者: Liang, Yu; Shao, Shuai; Li, Xin Yu; Zhao, Zi Xin; Liu, Ning; Liu, Zhao Ming; Shen, Fu Jie; Zhang, Hao; Hou, Jun Wei; Zhang, Xue Feng; Jin, Yu Qin; Du, Li Fang; Li, Xin; Zhang, Jing; Su, Ji Guo; Li, Qi Ming
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14005
• DOI: 10.1126/science.adp2362
• 发表日期: 2024-09-27
• 页码: 1484-1491
• 关键词: fusion-glycoprotein vaccine; cryo-em; DYNAMICS; efficacy; safety

摘要

The respiratory syncytial virus (RSV) fusion (F) glycoprotein is highly immunogenic in its prefusion (pre-F) conformation. However, the protein is unstable, and its conformation must be stabilized for it to function effectively as an immunogen in vaccines. We present a mutagenesis strategy to arrest the RSV F protein in its pre-F state by blocking localized changes in protein structure that accompany large-scale conformational rearrangements. We generated a series of mutants and screened them in vitro to assess their potential for forming a stable pre-F. In animals, the immunogenicity of a representative mutant F protein, with a conformation confirmed by cryo-electron microscopy, elicited levels of neutralizing antibodies and protection against RSV-induced lung damage that were comparable to those of DS-Cav1, a pre-F used in a licensed vaccine.