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

Fabian Sesterhenn, Che Yang, Jaume Bonet, Johannes T. Cramer, Xiaolin Wen, Yimeng Wang, Chi I. Chiang, Luciano A. Abriata, Iga Kucharska, Giacomo Castoro, Sabrina S. Vollers, Marie Galloux, Elie Dheilly, Stéphane Rosset, Patricia Corthésy, Sandrine Georgeon, Mélanie Villard, Charles Adrien Richard, Delphyne Descamps, Teresa DelgadoElisa Oricchio, Marie Anne Rameix-Welti, Vicente Más, Sean Ervin, Jean François Eléouët, Sabine Riffault, John T. Bates, Jean Philippe Julien, Yuxing Li, Theodore Jardetzky, Thomas Krey, Bruno E. Correia*

*Corresponding author for this work
61 Citations (Scopus)


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.

Original languageEnglish
Article numbereaay5051
Issue number6492
Publication statusPublished - 15.05.2020


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