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: Nov. 30, 2016, 11:16 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
3KPE 2009-12-22 1.47 Solution structure of the respiratory syncytial virus (RSV)six-helix bundle complexed with TMC353121, a small-moleucule inhibitor of RSV
3O41 2010-10-13 1.95 Crystal Structure of 101F Fab Bound to 15-mer Peptide Epitope
1G2C 2001-01-03 2.3 HUMAN RESPIRATORY SYNCYTIAL VIRUS FUSION PROTEIN CORE
5C69 2015-09-23 2.3 Crystal Structure of Prefusion-stabilized RSV F variant PR-DM
5EA4 2015-12-09 2.3 Crystal Structure of Inhibitor JNJ-49153390 in Complex with Prefusion RSV F Glycoprotein
5C6B 2015-09-23 2.4 Crystal Structure of Prefusion-stabilized RSV F variant SC-TM
4MMS 2013-11-20 2.4 Crystal Structure of Prefusion-stabilized RSV F Variant Cav1 at pH 5.5
5KWW 2017-08-02 2.5 Crystal Structure of Inhibitor JNJ-53718678 In Complex with Prefusion RSV F Glycoprotein
5K6F 2016-08-10 2.59 Crystal structure of prefusion-stabilized RSV F single-chain 9-19 DS-Cav1 variant.
5EA8 2015-12-09 2.6 Crystal Structure of Prefusion RSV F Glycoprotein Fusion Inhibitor Resistance Mutant D489Y
4CCF 2013-11-13 2.65 Structure of Respiratory Syncytial Virus F protein head domain
5K6H 2016-09-21 2.65 Crystal structure of prefusion-stabilized RSV F single-chain 9-10 DS-Cav1 A149C-Y458C variant.
5EA3 2015-12-09 2.75 Crystal Structure of Inhibitor JNJ-2408068 in Complex with Prefusion RSV F Glycoprotein
5EA6 2015-12-09 2.75 Crystal Structure of Inhibitor BTA-9881 in Complex with Prefusion RSV F Glycoprotein
3IXT 2010-01-19 2.75 Crystal Structure of Motavizumab Fab Bound to Peptide Epitope
4MMV 2013-11-20 2.81 Crystal Structure of Prefusion-stabilized RSV F Variant DS-Cav1-TriC at pH 9.5
3RRR 2011-06-08 2.82 Structure of the RSV F protein in the post-fusion conformation
5EA7 2015-12-09 2.85 Crystal Structure of Inhibitor BMS-433771 in Complex with Prefusion RSV F Glycoprotein
3O45 2010-10-13 2.87 Crystal Structure of 101F Fab Bound to 17-mer Peptide Epitope
5K6G 2016-09-28 2.9 Crystal structure of prefusion-stabilized RSV F single-chain 9-24 DS-Cav1 variant.
5K6I 2016-08-17 2.92 Crystal structure of prefusion-stabilized RSV F single-chain 9-10 DS-Cav1 A149C-Y458C, S46G-E92D-S215P-K465Q variant.
5K6B 2016-08-31 2.98 Crystal structure of prefusion-stabilized RSV F single-chain 9 DS-Cav1 variant.
4MMU 2013-11-20 3.0 Crystal Structure of Prefusion-stabilized RSV F Variant DS-Cav1 at pH 5.5
6APB 2018-03-21 3.0 Crystal Structure of Non-Neutralizing Infant Antibody ADI-14359 in Complex with Postfusion RSV F Glycoprotein
4MMT 2013-11-20 3.05 Crystal Structure of Prefusion-stabilized RSV F Variant DS-Cav1 at pH 9.5
5EA5 2015-12-09 3.05 Crystal Structure of Inhibitor TMC-353121 in Complex with Prefusion RSV F Glycoprotein
5U68 2017-02-15 3.08 Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus
4MMR 2013-11-20 3.1 Crystal Structure of Prefusion-stabilized RSV F Variant Cav1 at pH 9.5
5TPN 2017-02-01 3.14 Crystal structure of RSV F in complex with human antibody hRSV90
3RKI 2011-05-18 3.2 Structural basis for immunization with post-fusion RSV F to elicit high neutralizing antibody titers
3RRT 2011-06-08 3.2 Structure of the RSV F protein in the post-fusion conformation
4MMQ 2013-11-20 3.25 Crystal Structure of Prefusion-stabilized RSV F Variant DS
6OE4 2019-04-17 3.3 Prefusion RSV F monomer bound by neutralizing antibody CR9501
5TOJ 2017-02-22 3.3 Crystal structure of the RSV F glycoprotein in complex with the neutralizing single-domain antibody F-VHH-4
5W23 2017-12-06 3.4 Crystal Structure of RSV F in complex with 5C4 Fab
5UDC 2017-05-17 3.45 Crystal Structure of RSV F A2 Bound to MEDI8897
6DC3 2019-07-10 3.5 RSV prefusion F bound to RSD5 Fab
6DC5 2019-07-10 3.5 RSV prefusion F in complex with AM22 Fab
5K6C 2016-10-12 3.58 Crystal structure of prefusion-stabilized RSV F single-chain 9-10 DS-Cav1 variant.
4JHW 2013-05-01 3.6 Crystal Structure of Respiratory Syncytial Virus Fusion Glycoprotein Stabilized in the Prefusion Conformation by Human Antibody D25
5TOK 2017-02-22 3.8 Crystal structure of the RSV F glycoprotein in complex with the neutralizing single-domain antibody F-VHH-L66
5J3D 2016-10-26 4.08 Crystal structure of human Fab 14N4 in complex with post-fusion RSV F
6APD 2018-03-21 4.1 Crystal structure of RSV F bound by AM22 and the infant antibody ADI-19425
6OE5 2019-04-17 4.1 Splayed open prefusion RSV F captured by CR9501 and motavizumab Fabs
4ZYP 2015-07-29 5.5 Crystal Structure of Motavizumab and Quaternary-Specific RSV-Neutralizing Human Antibody AM14 in Complex with Prefusion RSV F Glycoprotein

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