Development of streptococcal pyrogenic exotoxin C vaccine toxoids that areprotective in the rabbit model of toxic shock syndrome

Streptococcal pyrogenic exotoxin C (SPE C) is a superantigen produced by ma ny strains of Streptococcus pyogenes that (along with streptococcal pyrogen ic exotoxin A) is highly associated with streptococcal toxic shock syndrome (STSS) and other invasive streptococcal diseases. Based on the three-dimen sional structure of SPE C, solvent-exposed residues predicted to be importa nt for binding to the TCR or the MHC class II molecule, or important for di merization, were generated. Based on decreased mitogenic activity of variou s single-site mutants, the double-site mutant Y15A/N38D and the triple-site mutant Y15A/H35A/N38D were constructed and analyzed for superantigenicity, toxicity (lethality), immunogenicity, and the ability to protect against w ild-type SPE C-induced STSS. The Y15A/N38D and Y15A/H35A/N38D mutants were nonmitogenic for rabbit splenocytes and human PBMCs and nonlethal in two ra bbit models of STSS, yet both mutants were highly immunogenic. Animals vacc inated with the Y15A/N38D or Y15A/H35A/N38D toroids were protected from cha llenge with wild-type SPE C, Collectively, these data indicate that the Y15 A/N38D and Y15A/H35A/N38D mutants may be useful as toroid vaccine candidate s.