A new approach to de novo protein design dubbed "TopoBuilder" allows researchers to develop complex antigens that, when used in vaccines, elicit antibody responses that target the weaknesses in some of the most intractable viral pathogens, including respiratory syncytial virus (RSV). According to a study that tested this approach in mouse and non-human primate models, the platform holds promise to overcome long-standing obstacles in vaccine development. While de novo protein design has allowed the creation of many novel proteins, most of the proteins generated through this approach lack biological function. Current computational methods are not capable of producing the protein scaffolds required to mimic the structurally complex epitopes of many viral pathogens. To address this, Fabian Sesterhenn and colleagues created Topobuilder, a novel computational protein design approach to engineering de novo immunogens that match the structural complexity observed in many known neutralization epitopes. In this approach, key immunogenic epitopes are grafted onto de novo scaffold proteins. To demonstrate Topobuilder's abilities, Sesterhenn et al. generated three epitope-focused immunogens designed to induce a targeted neutralizing antibody response to RSV. In vaccination trials in mouse and non-human primate models, this cocktail of immunogens successfully generated a robust immune response against the virus's targeted neutralizing epitopes. What's more, the results indicate that the novel immunogen trio refocused pre-existing antibody responses to RSV toward the defined epitope targets as well, boosting the effectiveness of previous vaccines.
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