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

Jason S. McLellan(National Institutes of Health), Man Chen(National Institutes of Health), Michael Joyce(National Institutes of Health), Mallika Sastry(National Institutes of Health), Guillaume B. E. Stewart-Jones(National Institutes of Health), Yongping Yang(National Institutes of Health), Baoshan Zhang(National Institutes of Health), Lei Chen(National Institutes of Health), Sanjay Srivatsan(National Institutes of Health), Anqi Zheng(National Institutes of Health), Tongqing Zhou(National Institutes of Health), Kevin W. Graepel(National Institutes of Health), Azad Kumar(National Institutes of Health), Syed M. Moin(National Institutes of Health), Jeffrey C. Boyington(National Institutes of Health), Gwo‐Yu Chuang(National Institutes of Health), Cinque Soto(National Institutes of Health), Ulrich Baxa(Frederick National Laboratory for Cancer Research), Arjen Q. Bakker(AIMM Therapeutics (Netherlands)), Hergen Spits(AIMM Therapeutics (Netherlands)), Tim Beaumont(AIMM Therapeutics (Netherlands)), Zizheng Zheng(Xiamen University), Ningshao Xia(Xiamen University), Sung‐Youl Ko(National Institutes of Health), John-Paul Todd(National Institutes of Health), Srinivas S. Rao(National Institutes of Health), Barney S. Graham(National Institutes of Health), Peter D. Kwong(National Institutes of Health)
Science
October 31, 2013
10.1126/science.1243283
Cited by 1,112Open Access
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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.

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