Super-mAbs for Super-Ags: Developing a novel therapeutic strategy for life-threatening invasive streptococcal disease.

Group A Streptococcus (GAS) is typically associated with relatively mild skin or throat infections but may also progress to extremely dangerous invasive GAS infections (iGAS) with fatality rates of 10-28% even with optimal antibiotics and intensive care. This resulting in >150,000 deaths globally each year. A primary factor in the severity of iGAS are the GAS superantigen exotoxins (SAgs). SAgs function to bind human leukocyte antigens (HLA) and T cell receptors (TCRs) together to drive widespread T cell activation and a massive inflammatory response known as a cytokine storm. iGAS patients get very sick, very quickly, and survivors often face long-term health issues or disability. Concerningly, many countries including Australia have experienced a large increase in iGAS cases after the pandemic including in young children and infants. There is no vaccine against GAS, and the rise in deadly infections has occurred despite GAS being highly susceptible to penicillin. Antibiotic treatment does not remove SAg toxins, and thus there is a critical need for new treatments to compliment antibiotics that target the root cause of inflammation: SAg activation of T cells. Monoclonal antibody (mAb) therapies have transformed the treatment landscape for many infectious diseases including SARS-CoV-2, yet no such therapy exists for iGAS. We hypothesise that monoclonal antibody cocktail to neutralizing superantigens can effectively treat invasive Group A Streptococcal infection. This project will involve characterising human B cell responses to SAgs, developing human mAbs and nanobodies against GAS, and determining antibody efficacy using a combination of in vitro assays and in vivo mouse models. Techniques involved may include flow cytometry, single-cell sequencing, bioinformatics, molecular biology, in silico modelling, and mouse work.