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


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.

Submission Details

ID: XKNFF3UT3

Submitter: Connie Wang

Submission Date: July 31, 2017, 11:46 a.m.

Version: 1

Publication Details
McLellan JS;Chen M;Joyce MG;Sastry M;Stewart-Jones GB;Yang Y;Zhang B;Chen L;Srivatsan S;Zheng A;Zhou T;Graepel KW;Kumar A;Moin S;Boyington JC;Chuang GY;Soto C;Baxa U;Bakker AQ;Spits H;Beaumont T;Zheng Z;Xia N;Ko SY;Todd JP;Rao S;Graham BS;Kwong PD,Science (2013) Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. PMID:24179220
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1G2C 2000-10-18T00:00:00+0000 2.3 HUMAN RESPIRATORY SYNCYTIAL VIRUS FUSION PROTEIN CORE
1G2C 2000-10-18T00:00:00+0000 2.3 HUMAN RESPIRATORY SYNCYTIAL VIRUS FUSION PROTEIN CORE
3IXT 2009-09-04T00:00:00+0000 2.75 Crystal Structure of Motavizumab Fab Bound to Peptide Epitope
3KPE 2009-11-16T00:00:00+0000 1.47 Solution structure of the respiratory syncytial virus (RSV)six-helix bundle complexed with TMC353121, a small-moleucule inhibitor of RSV
3KPE 2009-11-16T00:00:00+0000 1.47 Solution structure of the respiratory syncytial virus (RSV)six-helix bundle complexed with TMC353121, a small-moleucule inhibitor of RSV
3O41 2010-07-26T00:00:00+0000 1.95 Crystal Structure of 101F Fab Bound to 15-mer Peptide Epitope
3O45 2010-07-26T00:00:00+0000 2.87 Crystal Structure of 101F Fab Bound to 17-mer Peptide Epitope
3RKI 2011-04-18T00:00:00+0000 3.2 Structural basis for immunization with post-fusion RSV F to elicit high neutralizing antibody titers
3RRR 2011-04-30T00:00:00+0000 2.82 Structure of the RSV F protein in the post-fusion conformation
3RRT 2011-04-30T00:00:00+0000 3.2 Structure of the RSV F protein in the post-fusion conformation

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
97.2 RSV fusion (F) glycoprotein P11209 FUS_HRSVR
97.6 RSV fusion (F) glycoprotein P12568 FUS_HRSVL
100.0 RSV fusion (F) glycoprotein P03420 FUS_HRSVA