Background: Staphylococcus aureus is a ubiquitous human and animal pathogen. The superantigenic staphylococcal enterotoxins (SEs) constitute a major group of virulence factors produced by S. aureus. Staphylococcal enterotoxin B (SEB) is a potential biological threat agent produced by many isolates of S. aureus. SEB is considered a category B select agent by the CDC. The SEs are also commonly associated with one of the most prevalent forms of food poisoning and toxic shock syndrome. The most relevant route of exposure from a biodefense standpoint is by inhalation of aerosolized SEB: High doses (LD₅₀ 20 ng/kg) cause fatalities in humans while lower levels (ED₅₀ 0.4 ng/kg) can result in severe incapacitation. The tainting of food and/or water supplies is another route for a terrorist attack. Fighting S. aureus, and its toxins is therefore important regarding both biodefense and public health.
Methods: SEs bind to MHC class II and T cell receptor and thus polyclonally activating T lymphocytes. This results in massive inflammatory cytokine release and toxic shock that can be lethal. By using a structure based approach, a triple mutant of SEB was designed that renders the protein incapable of binding to MHC class II. The mutant protein was produced and successfully tested in mice and non-human primates efficacy models.
Results: Two cGMP lots (over 10000 human doses) were produced. Physiochemical stability testing demonstrated that the vaccine has maintained its integrity and purity during storage. Biological potency assays in mice as well as efficacy studies in rhesus monkeys indicated that the vaccine maintained its full immunogenicity and protective efficacy.
Conclusions: cGMP produced vaccine has been tested in a GLP safety study in non-human primates. The study results indicate that STEBVax is safe and well tolerated at doses 10 fold higher than a projected human dose. No signs of toxicity were observed in monkeys. A dose escalation phase I clinical trial in healthy human volunteers is planned for Summer 2008. Preclinical efficacy and safety data will be presented.