Project Summary: There are currently no approved vaccines for Group A Streptococcus (GAS). GAS is a widespread pediatric problem causing an estimated 616 million cases of strep throat each year worldwide. Untreated strep throat can lead to serious autoimmune sequelae such as rheumatic heart disease (RHD) which inadvertently develops out of molecular mimicry from the host immune response to GAS infection. RHD results from damaged heart valves, claiming the lives of 288,000 people each year worldwide, per the World Health Organization. Therefore there is a critical need for a GAS vaccine. We had first studied why some children get recurrent strep throat by studying the tonsillar germinal center response in children who had undergone tonsillectomy for either recurrent strep tonsillitis or non-recurrent tonsillitis. Tonsils are the lymphoid tissue which likely mount the first adaptive immune response to GAS. We observed that children with recurrent strep throat had a deficit in circulating antibodies against a critical GAS virulence factor streptococcus pyrogenic exotoxin A (SpeA). This was an interesting finding as there has been a long clinical association demonstrating the protective nature of SpeA antibodies against the development of GAS toxic shock syndrome. SpeA is a superantigen which is necessary to establish infection in a humanized mouse model. We discovered that SpeA induced CD4+ T cells with the capacity to kill instead of help B cells within germinal centers. We named these cells “killer T follicular helper (Tfh)” cells. We found that children with recurrent strep throat had more SpeA induced “killer Tfh” cells and significantly smaller germinal centers, likely explaining their propensity for recurrent strep infections. We hypothesize that an SpeA toxoid vaccination will protect against GAS pharyngitis or tonsillitis by limiting the development of SpeA-induced “killer Tfh” cells and allowing for the development of GAS-specific germinal center responses to quickly clear a GAS tonsillar infection. This proposal focuses on evaluating whether an SpeA toxoid vaccine will prevent GAS tonsillitis and pharyngitis in a non- human primate model and understanding the impact of SpeA toxoid vaccination in altering the GAS germinal center response. The long term objective is to demonstrate the utility of GAS toxoid vaccinations in preventing disease.