Streptococcus pyogenes (Group A Streptococcus, GAS) is a human pathogen, responsible for millions of infections annually worldwide, and it remains among the top ten infectious diseases causing mortality. Currently, no licensed vaccine exists against GAS. In our previous studies, we examined the recognition of all GAS proteins in humans, and compared anti-GAS immunity between adults and children. Based on these results, we developed a novel vaccine strategy that led to the identification of key components in a new GAS vaccine utilizing a new innovative cationic based adjuvant system. Here we will present our vaccine strategy, the methods we used to identify the vaccine components, and how the vaccine was able to combat GAS through multiple mechanisms, activate macrophages and neutrophils to phagocytose the bacteria, and generate robust long-lived systemic and local Th1/Th17 T cell-mediated anti-GAS responses. The future clinical path for this vaccine will be discussed.