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 novel protein design algorithm, termed TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. Both in mice and non-human primates, cocktails of three de novo designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused pre-existing antibody responses towards defined neutralization epitopes. Overall, our de novo design approach opens the possibility of targeting specific epitopes for vaccine and therapeutic antibody development, and more generally will be applicable to design de novo proteins displaying complex functional motifs.

De novo protein design enables precise induction of functional antibodies in vivo