Advances in structure-based vaccine design

• Structures of protective epitopes allow novel vaccine design approaches.
• Structure-based methods enable the design of germline-targeting immunogens.
• A minimized, hexameric immunogen protects mice from six strains of Group B Streptococcus.
• Discontinuous epitopes can be structurally reproduced on scaffold proteins.
• Design of multiple epitopes on one antigen created a vaccine candidate for MenB.

Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. Crystal structures of antigens containing one or more protection epitopes, especially when in complex with a protective antibody, are the launching point for immunogen design. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline-targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The contacts between antigen and neutralizing antibody define a structural epitope, and methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single immunogen. We review these recent structural vaccinology efforts to engineer germline-targeting, epitope-specific, and/or broad coverage immunogens.