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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antibodies, Neutralizing / immunology
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Antigens, Viral / chemistry*
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Antigens, Viral / genetics
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Antigens, Viral / immunology
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Crystallography, X-Ray
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Cysteine / chemistry
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Cysteine / genetics
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Glycoproteins / chemistry*
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Glycoproteins / genetics
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Glycoproteins / immunology
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Humans
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Macaca
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Mice
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Protein Engineering
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Protein Multimerization
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Protein Stability
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Protein Structure, Tertiary
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Respiratory Syncytial Virus Infections / prevention & control*
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Respiratory Syncytial Virus Vaccines / chemistry*
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Vaccination
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Viral Fusion Proteins / chemistry*
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Viral Fusion Proteins / genetics
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Viral Fusion Proteins / immunology
Substances
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Antibodies, Neutralizing
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Antigens, Viral
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Glycoproteins
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Respiratory Syncytial Virus Vaccines
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Viral Fusion Proteins
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Cysteine
Associated data
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PDB/4MMQ
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PDB/4MMR
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PDB/4MMS
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PDB/4MMT
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PDB/4MMU
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PDB/4MMV