Staphylococcus aureus (S. aureus) is a leading cause of both healthcare-and community-associated infections globally, which result in severe disease and readily developing antibiotic resistance. Developing an efficacious vaccine against S. aureus is urgently required. In the present study, we selected five conserved antigens, including the secreted factors α-hemolysin (Hla), staphylococcal enterotoxin B (SEB) and the three surface proteins staphylococcal protein A (SpA), iron surface determinant B N2 domain (IsdB-N2) and manganese transport protein C (MntC). They were all well-characterized virulence factor of S. aureus and developed a recombinant five-antigen S. aureus vaccine (rFSAV), rFSAV provided consistent protection in S. aureus lethal sepsis and pneumonia mouse models, and it showed broad immune protection when challenged with a panel of epidemiologically relevant S. aureus strains. Meanwhile, rFSAV immunized mice were able to induce comprehensive cellular and humoral immune responses to reduce bacterial loads, inflammatory cytokine expression, inflammatory cell infiltration and decrease pathology after challenge with a sub-lethal dose of S. aureus. Moreover, the importance of specific antibodies in protection was demonstrated by antibody function tests in vitro and in vivo. Altogether, our data demonstrate that rFSAV is a potentially promising vaccine candidate for defensing against S. aureus infection.

Humans, as natural carriers of Staphylococcus aureus (SA), have developed nonprotective immune imprints that can be reactivated by SA antigen vaccination and that contribute to the failure of SA vaccine trials. To test whether an epitope-focused vaccine strategy can overcome this issue, we explored the protective epitope of the notable SA antigen MntC. A surface loop of MntC (Loop101) was found to be essential for SA to absorb manganese(II) ion and survive oxidative stress. Our Loop101-deficient versus -competent MntC-based differential screening identified a Loop101-specific human monoclonal antibody (Hm0686). Hm0686 blocked SA from absorbing manganese(II) ion and exhibited a strong opsonophagocytic activity, suggesting that Hm0686-targeted Loop101 may be a protective epitope. A Loop101 epitope vaccine but not the whole MntC antigen protected against SA infection in mice with prior exposure–induced nonprotective imprints. Thus, this effective protective epitope–based vaccine strategy may be explored to overcome nonprotective immune imprints in humans.