Feasibility of using a combination of staphylococcal superantigen‐like proteins 3, 7 and 11 in a fusion vaccine for Staphylococcus aureus

Staphylococcus aureus is a significant bacterial pathogen in both community and hospital settings, and the escalation of antimicrobial‐resistant strains is of immense global concern. Vaccination is an inviting long‐term strategy to curb staphylococcal disease, but identification of an effective vaccine has proved to be challenging. Three well‐characterized, ubiquitous, secreted immune evasion factors from the staphylococcal superantigen‐like (SSL) protein family were selected for the development of a vaccine. Wild‐type SSL3, 7 and 11, which inhibit signaling through Toll‐like receptor 2, cleavage of complement component 5 and neutrophil function, respectively, were successfully combined into a stable, active fusion protein (PolySSL7311). Vaccination of mice with an attenuated form of the PolySSL7311 protein stimulated significantly elevated specific immunoglobulin G and splenocyte proliferation responses to each component relative to adjuvant‐only controls. Vaccination with PolySSL7311, but not a mixture of the individual proteins, led to a > 102 reduction in S. aureus tissue burden compared with controls after peritoneal challenge. Comparable antibody responses were elicited after coadministration of the vaccine in either AddaVax (an analog of MF59) or an Alum‐based adjuvant; but only AddaVax conferred a significant reduction in bacterial load, aligning with other studies that suggest both cellular and humoral immune responses are necessary for protective immunity to S. aureus. Anti‐sera from mice immunized with PolySSL7311, but not individual proteins, partially neutralized the functional activities of SSL7. This study confirms the importance of these SSLs for the survival of S. aureus in vivo and suggests that PolySSL7311 is a promising vaccine candidate. This study demonstrates that three secreted immune evasion factors from the staphylococcal superantigen‐like (SSL) protein family—SSL3, 7 and 11—can be successfully fused into a polyprotein. Mice immunized with a functionally inactive version of the polyprotein in the squalene‐based adjuvant (AddaVax), but not the equivalent amount of the individual proteins, developed enhanced neutralizing immunoglobulin G responses and a significant reduction in Staphylococcus aureus tissue burden after a peritoneal challenge. These results suggest that an SSL polyprotein may be a viable vaccine candidate for S. aureus.