Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus

作者：Jason S. McLellan, Man Chen, Michael Gordon Joyce, Mallika Sastry, Guillaume B. E. Stewart-Jones, Yongping Yang, Baoshan Zhang, Lei Chen, Sanjay R Srivatsan, Anqi Zheng, Tongqing Zhou, Kevin W. Graepel, Azad Kumar, Syed Mohammad Moin, Jeffrey C. Boyington, Gwo‐Yu Chuang, Cinque S. Soto, Ulrich Baxa, Arjen Q. Bakker, Hergen Spits, Tim Beaumont, Zizheng Zheng, Ningshao Xia, Sung‐Youl Ko, John-Paul M. Todd, Srinivas S. Rao, Barney S. Graham, Peter D. Kwong · 发表于：Science · 年份：2013 · DOI：10.1126/science.1243283 · 被引用次数：1171 · 研究领域：Respiratory viral infections research、Pneumonia and Respiratory Infections、Immunodeficiency and Autoimmune Disorders

Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.