期刊
SCIENCE
卷 342, 期 6158, 页码 592-598出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1243283
关键词
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资金
- National Institute of Allergy and Infectious Diseases
- National Natural Science Foundation of China [81161120419, 812111615]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
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 empty set, 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 empty set 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 empty set-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
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