Staphylococcus aureus is one of the most important bacterial pathogens causing human death and disease on a global scale (Klevens, 2007). The rapid generation of antibiotic resistance, coupled with the frequency and severity of staphylococcal disease, underlie the increasing medical need to combat S. aureus infections. As an alternative to inadequate antibiotic therapies, we are dedicating efforts to develop a preventative staphylococcal vaccine.Previously, multiple capsular polysaccharides, or single antigenic proteins have been tested as staphylococcal vaccines, but all have failed in clinical trials, likely for reasons that we have reviewed (Bagnoli, 2012). Expert opinion now advocates a multi-protein vaccine strategy that could raise a broadly protective immune response, neutralizing pathogenic virulence factors like surface lipoproteins and families of secreted pore-forming toxins. To this end, we used Reverse Vaccinology to identify protective staphylococcal antigens that generated immunity in mice against diverse clinical S. aureus isolates (see Mishra, 2012). Additional candidates have been highlighted in the literature, including the leukotoxin LukED which targets the human CCR5 receptor (Alonzo, 2013).To ensure the development of efficacious and safe vaccine antigens, the research project proposes the structure-based optimization of two candidate antigens: (i) an antigen engineered from the Csa protein family that we recently discovered and characterized (Schluepen, 2013) and (ii) an engineered detoxified leukotoxin-E antigen. We recently determined and released the crystal structures of two Csa proteins and of LukE. As pioneers of Structural Vaccinology (Scarselli, 2011; Dormitzer, 2012), we are now ideally poised to exploit this high-resolution information which, coupled with our immunological data, represents an unprecedented knowledgebase to drive the development of a multicomponent vaccine to protect humans against staphylococcal disease.