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De novo protein design enables the precise induction of RSV-neutralizing antibodies.

  • Sesterhenn F Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Yang C Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Bonet J Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Cramer JT Institute of Virology, Hannover Medical School, Hannover 30625, Germany.
  • Wen X Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Wang Y Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA.
  • Chiang CI Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA.
  • Abriata LA Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Kucharska I Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.
  • Castoro G Institute of Virology, Hannover Medical School, Hannover 30625, Germany.
  • Vollers SS Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Galloux M Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
  • Dheilly E Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Rosset S Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Corthésy P Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Georgeon S Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Villard M Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Richard CA Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
  • Descamps D Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
  • Delgado T Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Madrid, Spain.
  • Oricchio E Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Rameix-Welti MA UMR1173, INSERM, Université de Versailles St. Quentin, 78180 Montigny le Bretonneux, France.
  • Más V Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Madrid, Spain.
  • Ervin S Wake Forest Baptist Medical Center, Winston Salem, NC 27157, USA.
  • Eléouët JF Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
  • Riffault S Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
  • Bates JT University of Mississippi Medical Center, Jackson, MS 39216, USA.
  • Julien JP Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.
  • Li Y Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA.
  • Jardetzky T Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Krey T Institute of Virology, Hannover Medical School, Hannover 30625, Germany.
  • Correia BE Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland. bruno.correia@epfl.ch.
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  • 2020-05-16
Published in:
  • Science (New York, N.Y.). - 2020
Amino Acid Motifs
Antibodies, Neutralizing
Computational Biology
Humans
Immunodominant Epitopes
Protein Conformation
Protein Engineering
Recombinant Fusion Proteins
Respiratory Syncytial Virus Vaccines
Respiratory Syncytial Virus, Human
Single-Domain Antibodies
English De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.
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  • English
Open access status
green
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https://sonar.ch/global/documents/120357
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