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: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

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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.

Original language	English (US)
Pages (from-to)	592-598
Number of pages	7
Journal	Science
Volume	342
Issue number	6158
DOIs	https://doi.org/10.1126/science.1243283
State	Published - 2013
Externally published	Yes

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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

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, 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 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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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 {\O}, 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 {\O} 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 {\O}-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 Chuang, {Gwo Yu} and Cinque Soto and Ulrich Baxa and Bakker, {Arjen Q.} and Hergen Spits and Tim Beaumont and Zizheng Zheng and Ningshao Xia and Ko, {Sung Youl} and Todd, {John Paul} and Srinivas Rao and Graham, {Barney S.} and Kwong, {Peter D.}",

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doi = "10.1126/science.1243283",

language = "English (US)",

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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 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.

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 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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Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus

Abstract

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