The de novo design of functional proteins can expand the natural protein repertoire and their application, but the computational design of de novo proteins with complex structural, functional motifs is challenging. One application for computationally designed proteins is in vaccinology — the design of immunogens that elicit targeted neutralizing antibody responses. Sesterhenn et al. developed a computational design strategy, TopoBuilder, and engineered an epitope-focused immunogen cocktail comprising three antigenic sites of the respiratory syncytial virus fusion protein, which induced robust neutralizing responses in mice and nonhuman primates. Thus, the authors provide a proof-of principle to functionalize de novo proteins with complex functional motifs.