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

Jason S. McLellan; Man Chen; M. Gordon Joyce; Mallika Sastry; Guillaume B. E. Stewart-Jones; Yongping Yang; Baoshan Zhang; Lei Chen; Sanjay Srivatsan; Anqi Zheng; Tongqing Zhou; Kevin W. Graepel; Azad Kumar; Syed Moin; Jeffrey C. Boyington; Gwo-Yu Chuang; Cinque Soto; Ulrich Baxa; Arjen Q. Bakker; Hergen Spits; Tim Beaumont; Zizheng Zheng; Ningshao Xia; Sung-Youl Ko; John-Paul Todd; Srinivas Rao; Barney S. Graham; Peter D. Kwong

doi:https://doi.org/10.1126/science.1243283

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

Jason S. McLellan, Man Chen, M. Gordon Joyce, Mallika Sastry, Guillaume B. E. Stewart-Jones, Yongping Yang, Baoshan Zhang, Lei Chen, Sanjay Srivatsan, Anqi Zheng, Tongqing Zhou, Kevin W. Graepel, Azad Kumar, Syed Moin, Jeffrey C. Boyington, Gwo-Yu Chuang, Cinque Soto, Ulrich Baxa, Arjen Q. Bakker, Hergen SpitsTim Beaumont, Zizheng Zheng, Ningshao Xia, Sung-Youl Ko, John-Paul Todd, Srinivas Rao, Barney S. Graham, Peter D. Kwong

Research output: Contribution to journal › Article › Academic › peer-review

688 Citations (Scopus)

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 empty set, 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 empty set 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 empty set-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold

Original language	English
Pages (from-to)	592-598
Journal	Science
Volume	342
Issue number	6158
DOIs	https://doi.org/10.1126/science.1243283
Publication status	Published - 2013

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https://doi.org/10.1126/science.1243283

Cite this

McLellan, J. S., Chen, M., Joyce, M. G., Sastry, M., Stewart-Jones, G. B. E., Yang, Y., Zhang, B., Chen, L., Srivatsan, S., Zheng, A., Zhou, T., Graepel, K. W., Kumar, A., Moin, S., Boyington, J. C., Chuang, G.-Y., Soto, C., Baxa, U., Bakker, A. Q., ... Kwong, P. D. (2013). Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus. Science, 342(6158), 592-598. https://doi.org/10.1126/science.1243283

@article{36683db1634147b6b42c001f5b81b385,

title = "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 empty set, 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 empty set 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 empty set-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold",

author = "McLellan, {Jason S.} and Man Chen and Joyce, {M. Gordon} and Mallika Sastry and Stewart-Jones, {Guillaume B. E.} and Yongping Yang and Baoshan Zhang and Lei Chen and Sanjay Srivatsan and Anqi Zheng and Tongqing Zhou and Graepel, {Kevin W.} and Azad Kumar and Syed Moin and Boyington, {Jeffrey C.} and Gwo-Yu Chuang and Cinque Soto and Ulrich Baxa and Bakker, {Arjen Q.} and Hergen Spits and Tim Beaumont and Zizheng Zheng and Ningshao Xia and Sung-Youl Ko and John-Paul Todd and Srinivas Rao and Graham, {Barney S.} and Kwong, {Peter D.}",

year = "2013",

doi = "https://doi.org/10.1126/science.1243283",

language = "English",

volume = "342",

pages = "592--598",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6158",

}

McLellan, JS, Chen, M, Joyce, MG, Sastry, M, Stewart-Jones, GBE, Yang, Y, Zhang, B, Chen, L, Srivatsan, S, Zheng, A, Zhou, T, Graepel, KW, Kumar, A, Moin, S, Boyington, JC, Chuang, G-Y, Soto, C, Baxa, U, Bakker, AQ, Spits, H , Beaumont, T, Zheng, Z, Xia, N, Ko, S-Y, Todd, J-P, Rao, S, Graham, BS & Kwong, PD 2013, 'Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus', Science, vol. 342, no. 6158, pp. 592-598. https://doi.org/10.1126/science.1243283

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T1 - Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus

AU - McLellan, Jason S.

AU - Chen, Man

AU - Joyce, M. Gordon

AU - Sastry, Mallika

AU - Stewart-Jones, Guillaume B. E.

AU - Yang, Yongping

AU - Zhang, Baoshan

AU - Chen, Lei

AU - Srivatsan, Sanjay

AU - Zheng, Anqi

AU - Zhou, Tongqing

AU - Graepel, Kevin W.

AU - Kumar, Azad

AU - Moin, Syed

AU - Boyington, Jeffrey C.

AU - Chuang, Gwo-Yu

AU - Soto, Cinque

AU - Baxa, Ulrich

AU - Bakker, Arjen Q.

AU - Spits, Hergen

AU - Beaumont, Tim

AU - Zheng, Zizheng

AU - Xia, Ningshao

AU - Ko, Sung-Youl

AU - Todd, John-Paul

AU - Rao, Srinivas

AU - Graham, Barney S.

AU - Kwong, Peter D.

PY - 2013

Y1 - 2013

N2 - 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 empty set, 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 empty set 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 empty set-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold

AB - 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 empty set, 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 empty set 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 empty set-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold

U2 - https://doi.org/10.1126/science.1243283

DO - https://doi.org/10.1126/science.1243283

M3 - Article

C2 - 24179220

SN - 0036-8075

VL - 342

SP - 592

EP - 598

JO - Science

JF - Science

IS - 6158

ER -