PROJECT SUMMARY/ABSTRACT Preventing infections caused by Staphylococcus aureus is a public health imperative, but there is currently no effective vaccine. Clinical trials for S. aureus vaccines and immunotherapeutics have focused on preventing infection in adults with a particularly high burden of S. aureus infections, but no efforts have been made to challenge the existing dogma and develop an immunization strategy that will afford early and broad population- based protection. We hypothesize that seemingly benign exposures to S. aureus in early childhood pattern deleterious immune responses, effectively “trapping” the immune system, a concept introduced by Francis as “original antigenic sin”. Therefore, we predict that a successful S. aureus vaccine will require an alternative, highly mechanistic approach to vaccine design with the goal of overdriving original antigen sin, and implementation in the pediatric population to deliberately drive the host immune response toward a protective phenotype prior to the establishment of natural suboptimal responses. The studies in this proposal will test this hypothesis using tractable animal models of S. aureus infection and clinical studies in healthy and S. aureus–infected children. Taking advantage of the convergence of natural and vaccine-elicited immunity in our mouse model, we will use a novel vaccine and newly synthesized peptide MHC (pMHC) tetramers as tools to precisely define the mechanisms by which synergistic antibody and T cell responses impact local inflammatory responses and bacterial outgrowth at the tissue level. A mechanistic approach to overdrive infection-patterned immunity in the mouse model will be complemented by a targeted investigation in healthy and S. aureus-infected children to determine the onset and impact of patterned immunity. This clinicotranslational approach is anticipated to lay the foundation for future vaccine trials in the pediatric population.