Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Jessica Marcandalli; Brooke Fiala; Sebastian Ols; Michela Perotti; Willem de van der Schueren; Joost Snijder; Edgar Hodge; Mark Benhaim; Rashmi Ravichandran; Lauren Carter; Will Sheffler; Livia Brunner; Maria Lawrenz; Patrice Dubois; Antonio Lanzavecchia; Federica Sallusto; Kelly K. Lee; David Veesler; Colin E. Correnti; Lance J. Stewart; David Baker; Karin Loré; Laurent Perez; Neil P. King

doi:10.1016/j.cell.2019.01.046

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Jessica Marcandalli, Brooke Fiala, Sebastian Ols, Michela Perotti, Willem de van der Schueren, Joost Snijder, Edgar Hodge, Mark Benhaim, Rashmi Ravichandran, Lauren Carter, Will Sheffler, Livia Brunner, Maria Lawrenz, Patrice Dubois, Antonio Lanzavecchia, Federica Sallusto, Kelly K. Lee, David Veesler, Colin E. Correnti, Lance J. StewartDavid Baker, Karin Loré, Laurent Perez^*, Neil P. King

^*Corresponding author for this work

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

Abstract

Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

Original language	English
Pages (from-to)	1420-1431
Journal	Cell
Volume	176
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2019.01.046
Publication status	Published - 7 Mar 2019
Externally published	Yes

Funding

The authors wish to thank Ratika Krishnamurty for project management support and helpful suggestions, David Jarrossay for scientific advice with flow cytometry data acquisition and cell sorting, the IRB animal house for supporting immunization studies, Drs. Mats Spångberg and Bengt Eriksson and their personnel at the Astrid Fagraeus laboratory at Karolinska Institutet for expert assistance and care of the nonhuman primates, Daniel Ellis for advice in protein production and in vitro assembly, Barney Graham for helpful discussions and advice, and Amy Weiner and Lynda Stuart for support and advice. This work was supported by the Bill and Melinda Gates Foundation ( OPP1120319 to D.B., N.P.K., L.P., and K.L.; OPP1126258 to K.K.L.; OPP1162875 to P.D.), the state of Washington (to D.B.), the Howard Hughes Medical Institute (to D.B.), the Netherlands Organization for Scientific Research (NWO; Rubicon 019.2015.2.310.006 to J.S.), the European Molecular Biology Organisation (EMBO; ALTF 933-2015 to J.S.), the Swedish Research Council (Vetenskapsrådet 2015-02608 to K.L.), an intramural faculty salary grant from Karolinska Institutet (to S.O.), NIAID ( HHSN272201700059C to D.V.), NIGMS ( R01GM120553 to D.V.), a Pew Biomedical Scholars Award (to D.V.), and an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (to D.V.).

Keywords

computational protein design
nanoparticles
neutralizing antibodies
respiratory syncytial virus
self-assembly
vaccines

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2019.01.046

Induction of potentFinal published version, 6.47 MBLicence: CC BY

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Marcandalli, J., Fiala, B., Ols, S., Perotti, M., de van der Schueren, W., Snijder, J., Hodge, E., Benhaim, M., Ravichandran, R., Carter, L., Sheffler, W., Brunner, L., Lawrenz, M., Dubois, P., Lanzavecchia, A., Sallusto, F., Lee, K. K., Veesler, D., Correnti, C. E., ... King, N. P. (2019). Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus. Cell, 176(6), 1420-1431. https://doi.org/10.1016/j.cell.2019.01.046

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title = "Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus",

abstract = "Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.",

keywords = "computational protein design, nanoparticles, neutralizing antibodies, respiratory syncytial virus, self-assembly, vaccines",

author = "Jessica Marcandalli and Brooke Fiala and Sebastian Ols and Michela Perotti and {de van der Schueren}, Willem and Joost Snijder and Edgar Hodge and Mark Benhaim and Rashmi Ravichandran and Lauren Carter and Will Sheffler and Livia Brunner and Maria Lawrenz and Patrice Dubois and Antonio Lanzavecchia and Federica Sallusto and Lee, {Kelly K.} and David Veesler and Correnti, {Colin E.} and Stewart, {Lance J.} and David Baker and Karin Lor{\'e} and Laurent Perez and King, {Neil P.}",

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doi = "10.1016/j.cell.2019.01.046",

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Marcandalli, J, Fiala, B, Ols, S, Perotti, M, de van der Schueren, W, Snijder, J, Hodge, E, Benhaim, M, Ravichandran, R, Carter, L, Sheffler, W, Brunner, L, Lawrenz, M, Dubois, P, Lanzavecchia, A, Sallusto, F, Lee, KK, Veesler, D, Correnti, CE, Stewart, LJ, Baker, D, Loré, K, Perez, L & King, NP 2019, 'Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus', Cell, vol. 176, no. 6, pp. 1420-1431. https://doi.org/10.1016/j.cell.2019.01.046

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AU - Marcandalli, Jessica

AU - Fiala, Brooke

AU - Ols, Sebastian

AU - Perotti, Michela

AU - de van der Schueren, Willem

AU - Snijder, Joost

AU - Hodge, Edgar

AU - Benhaim, Mark

AU - Ravichandran, Rashmi

AU - Carter, Lauren

AU - Sheffler, Will

AU - Brunner, Livia

AU - Lawrenz, Maria

AU - Dubois, Patrice

AU - Lanzavecchia, Antonio

AU - Sallusto, Federica

AU - Lee, Kelly K.

AU - Veesler, David

AU - Correnti, Colin E.

AU - Stewart, Lance J.

AU - Baker, David

AU - Loré, Karin

AU - Perez, Laurent

AU - King, Neil P.

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N2 - Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

AB - Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

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KW - nanoparticles

KW - neutralizing antibodies

KW - respiratory syncytial virus

KW - self-assembly

KW - vaccines

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M3 - Article

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VL - 176

SP - 1420

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JO - Cell

JF - Cell

IS - 6

ER -

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Abstract

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Keywords

UN SDGs

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