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Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.

Science (New York, N.Y.) (2013-11-02)
Jason S McLellan, Man Chen, M Gordon Joyce, Mallika Sastry, Guillaume B E Stewart-Jones, Yongping Yang, Baoshan Zhang, Lei Chen, Sanjay Srivatsan, Anqi Zheng, Tongqing Zhou, Kevin W Graepel, Azad Kumar, Syed Moin, Jeffrey C Boyington, Gwo-Yu Chuang, Cinque Soto, Ulrich Baxa, Arjen Q Bakker, Hergen Spits, Tim Beaumont, Zizheng Zheng, Ningshao Xia, Sung-Youl Ko, John-Paul Todd, Srinivas Rao, Barney S Graham, Peter D Kwong
ABSTRACT

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.

MATERIALS
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Brand
Product Description

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