Toxoids of streptococcal pyrogenic exotoxin A are protective in rabbit models of streptococcal toxic shock syndrome

Streptococcal pyrogenic exotoxins (SPEs) are superantigens that have been i mplicated in causing streptococcal toxic shock syndrome (STSS). Most notabl y, SPE serotype A is made by nearly all M-protein serotype 1 and 3 streptoc occi, the M types most associated with the illness (these strains contain o ne or more other SPEs, and those proteins are likely also to contribute to disease). We have prepared double-, triple-, and hexa-amino-acid mutants of SPE A by PCR and other mutagenesis procedures. The sites chosen for mutati on were solvent-exposed residues thought to be important for T-cell recepto r (TCR) or major histocompatibility complex (MHC) class II interaction. The se mutants were nonsuperantigenic for human peripheral blood mononuclear ce lls and rabbit and mouse splenocytes and were nonlethal in two rabbit model s of STSS. In addition, these mutants stimulated protective antibody respon ses. Interestingly, mutants that altered toxin binding to MHC class II were more immunogenic than mutants altering TCR binding. Collectively, these st udies indicate that multiple-site mutants of SPE A are toxoids that may hav e use in protecting against the toxin's effects in STSS.