Research Article

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

Science  01 Nov 2013:
Vol. 342, Issue 6158, pp. 592-598
DOI: 10.1126/science.1243283

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Designer Vaccine

Respiratory syncytial virus (RSV) is one of the last remaining childhood diseases without an approved vaccine. Using a structure-based approach, McLellan et al. (p. 592) designed over 150 fusion glycoprotein variants, assessed their antibody reactivity, determined crystal structures of stabilized variants, and measured their ability to elicit protective responses. This approach yielded an immunogen that elicits higher protective responses than the postfusion form of the fusion glycoprotein, which is one of the current leading RSV vaccine candidates entering clinical trials. Importantly, highly protective responses were elicited in both mice and macaques.

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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