Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy

Staphylococcus aureus infections are a major public health issue, and a vaccine is urgently needed. Despite a considerable promise in preclinical models, all vaccines tested thus far have failed to protect humans against S. aureus . Unlike laboratory mice, humans are exposed to S. aureus throughout life. In the current study, we hypothesized that prior exposure to S. aureus “imprints” the immune response to inhibit vaccine-mediated protection. We established a mouse model in which S. aureus skin and soft tissue infection (SSTI) is followed by vaccination and secondary SSTI. Unlike naïve mice, S. aureus -sensitized mice were incompletely protected against secondary SSTI by vaccination with the inactivated α-hemolysin (Hla) mutant Hla H35L . Inhibition of protection was specific for the Hla H35L vaccine and required hla expression during primary SSTI. Surprisingly, inhibition occurred at the level of vaccine-elicited effector T cells; hla expression during primary infection limited the expansion of T cells and dendritic cells and impaired vaccine-specific T cell responses. Importantly, the T cell-stimulating adjuvant CAF01 rescued inhibition and restored vaccine-mediated protection. Together, these findings identify a potential mechanism for the failure of translation of promising S. aureus vaccines from mouse models to clinical practice and suggest a path forward to prevent these devastating infections.