Refinement of a novel staphylococcal superantigen-like poly protein vaccine

Staphylococcus aureus is a community- and hospital-associated pathogen of global significance. Despite several decades of investment there is no licenced vaccine and antimicrobial resistance is increasing, complicating effective treatment of infection. We have developed a novel fusion vaccine (PolySSL) containing mutated forms of three immune evasion factors, Staphylococcal Superantigen-Like (SSL) proteins 3, 7 and 11, that are common to all S. aureus isolates. Mice given the PolySSL vaccine have a robust specific serum IgG response, attenuated signs of infection, and a significantly reduced S. aureus tissue burden after an intra-peritoneal challenge with S. aureus. A comparison of six different versions of the vaccine (PolySSL 3711, 7113, 7311 and DualSSL 73, 311, 711) suggests inclusion of all three SSLs is required, the 7113 order produces the most significant reduction in bacterial liver and kidney burden, and that SSL7 is the most important component. The likely requirement for a multi-valent vaccine was examined by immunising groups of mice with six PolySSL7113 variants (adjuvanted with AdjuPhos) encompassing most S. aureus strains of clinical significance. SSL7 was confirmed to be the dominant antigen eliciting endpoint titres ≥10⁵ irrespective of the variant used, whereas IgG responses to SSL3 and SSL11 were lower (∼10³) and more variable. The highest inhibition of the interaction between the six wildtype variants of SSL7 and either IgA or complement C5 was typically obtained with variant-matched anti-sera. Conversely, anti-sera from these mice showed failed to stop SSL3 from blocking TLR2 signalling. An improved version of the PolySSL vaccine has been generated by altering the protein order, but these data suggest a multi-valent vaccine will be required to elicit robust inhibitory cross-variant antibody responses. A path to further improvement may be through use of a different adjuvant to broaden and enhance immunity to SSLs 3, 7 and 11.