Conserved CD4⁺ T cell staphylococcal and streptococcal epitopes enable broad-acting vaccines in mice

Vaccines are effective and much-needed tools against bacterial infection, which mitigate multidrug resistance; however, selection of bacterial antigens that elicit protection and contribute to effective vaccines remains challenging. Here we use immunopeptidomics to identify CD4⁺ T cell vaccine targets in methicillin-resistant Staphylococcus aureus, a clinically significant, antibiotic-resistant bacterium that is susceptible to T cell-mediated control. We identified a highly conserved, immunodominant CD4⁺ T cell epitope in S. aureus that is derived from the core DNA-binding protein Hu (Hup). This epitope was shared across a range of clinically relevant streptococcal and staphylococcal species, and cross-species-reactive Hup-specific CD4⁺ T cells were found in both mice and humans. Immunization of mice with the Hup epitope resulted in the development of broadly protective CD4⁺ T cell immunity capable of limiting disease severity following infection with S. aureus and Streptococcus pneumoniae. These findings suggest that vaccines incorporating antigens derived from core genes conserved across species might confer broad-spectrum protection against multiple clinically relevant, antibiotic-resistant streptococcal and staphylococcal strains.