Abstract
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 language | English |
|---|---|
| Article number | eaay5051 |
| Journal | Science |
| Volume | 368 |
| Issue number | 6492 |
| ISSN | 0036-8075 |
| DOIs | |
| Publication status | Published - 15.05.2020 |
Funding
We thank W. R. Schief, P. Gainza, S. T. Reddy, and B. Lemaitre for helpful discussions and comments on the manuscript; J. E. Crowe, Jr., for providing site IV antibodies; A. McCarthy at ESRF for beam line support; the Behavioral Science Foundation (H. Hotchin, A. Beierschmitt, and R. Palmour) for the NHP immunization and PBMC isolation; and ExcellGene (Monthey, Switzerland) for help with mammalian protein expression. We also thank several EPFL facilities: PTPSP (K. Lau, A. Reynaud, F. Pojer, D. Hacker, L. Durrer, and S. Quinche) for protein expression and crystallography support; the phenogenomics center (C. Waldvogel, R. Doenlen) for support with mouse experiments; CIME and PTBIOEM (D. Demurtas and S. Nazarov) for electron microscopy support; the flow cytometry core facility; the gene expression core facility for support with next-generation sequencing; and SCITAS for support in high performance computing. The computational simulations were also partially facilitated by the CSCS Swiss National Supercomputing Centre. Funding: This work was supported by the Swiss Initiative for Systems Biology (SystemsX.ch), the European Research Council (Starting Grant 716058), the Swiss National Science Foundation (310030_163139), and the EPFL?s Catalyze4Life initiative. F.S. was supported by an SNF/Innosuisse BRIDGE Proof-of-Concept Grant. J.B. was supported by an EPFL Fellows Postdoctoral Fellowship. T.K. received funding from the German Center of Infection Research (DZIF) and the Cluster of Excellence RESIST (EXC 2155) of the German Research Foundation. J.T.C. was funded by ERA-Net PrionImmunity project 01GM1503 (Federal Ministry of Education and Research, Germany). V.M. received funding from AESI-18 (Instituto de Salud Carlos III grant MPY 375/18). J.-P.J. received funding from the Canada Research Chairs program. T.J. and X.W. received funding from NIH NIAID R01 AI137523. The funders had no role in study design, data collection and analysis, decision to publish, or preparation
