Streptococcus pyogenes (Group A Streptococcus, GAS) is a bacterial pathogen that causes a wide range of toxin-mediated, invasive and autoimmune diseases that collectively cause >500,000 deaths worldwide annually. A commercial vaccine to address the high global burden of GAS disease is an urgent and unmet medical need. We have demonstrated preclinical efficacy of a non-M protein-based vaccine, Combo#5, in murine and nonhuman primate (NHP) models of GAS infection. Combo#5 consists of five highly conserved and protective detoxified GAS antigens: streptococcal C5a peptidase (SCPA), streptolysin O (SLO), streptococcal interleukin-8 (IL-8) protease (SpyCEP), arginine deiminase (ADI) and trigger factor (TF). Our previous preclinical data underline the importance of selecting animal models that closely mimic GAS infection and formulating Combo#5 vaccines to generate a more balanced Th1/Th2-type response. Vaccine technology platforms that achieve this goal are presented.