Development and validation of S protein as a group A streptococcus vaccine

About This Grant

PROJECT SUMMARY Group A Streptococcus (GAS) is among the most common infectious agents worldwide, with an estimated 700 million infections and half-million deaths per year, numbers that increase annually. These factors, in addition to the growing prevalence of antimicrobial-resistant strains, it is vital to investigate new and innovative approaches for GAS infection treatment or prevention. Developing a universal vaccine is a promising long-term solution for improving the global burden of GAS. Unfortunately, attempts to develop a vaccine have been largely unsuccessful. For instance, the risk of molecular-mimicry based autoimmunity precludes the native forms of the gold standard GAS antigen, M protein, from being further developed in its native form. Additionally, sequencing efforts have identified many M protein serotypes, making universal coverage highly unlikely. Our published data indicates a promising new candidate for a GAS vaccine, S protein. We revealed S protein is a required GAS virulence factor in vitro and in vivo. New unpublished data shows recombinant S protein-immunized animals display a robust reduction in GAS colony-forming units compared to naïve animals in a skin infection model. Strikingly, we also demonstrate the ability of S protein to immunize mice surpasses that of M protein. Importantly, unlike M protein, S protein sequences are nearly identical among various GAS serotypes and contain no cross- reactive human sequences. We further determined that anti-S protein antibodies bind the surface of multiple GAS serotypes and verified them to be cross-reactive. These preclinical data underscore S protein is a viable GAS vaccine candidate but also highlight a novel area of further investigation. The overall goal of this R21 application is to further validate S protein as a novel protective vaccine against GAS, a human pathogen responsible for nearly 1 billion infections worldwide per year. This work is significant as our proposed study can potentially reduce the health burden of over 1 billion humans infected with GAS. Our studies are innovative, as they will provide pharmacokinetic insight into a novel vaccine antigen for GAS treatment. Our team, composed of clinicians and researchers, has expertise in GAS pathogenesis and immunity, vaccination studies, animal models, and the most powerful proteomics instrument currently on market. Therefore, our team is well-positioned to study GAS vaccine development in innovative fashions.