An RNA vaccines systems approach to Group A streptococcus vaccine discovery

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Abstract/summary There is currently no vaccine in clinical use to combat group A streptococcal infection, despite the considerable global burden of acute and chronic disease attributable to this pathogen. The long-term goal of this work is the development of a combination vaccine that can combat group A streptococcal pharyngitis worldwide, without risk of vaccine escape, in order to eradicate future cases of rheumatic heart disease and reduce the risk of invasive infections. The objective of this proposal is to use self-amplifying RNA (saRNA) technology to identify the optimum combination of antigens to include in a new, broad-acting group A streptococcal saRNA vaccine that protects against experimental nasopharyngeal and soft tissue infection. Adults are broadly immune to group A streptococcal pharyngitis, whereas younger children are highly susceptible. The rationale for our approach, is that understanding adult immunity to group A streptococcus will directly inform the requirements for immunity in children. Pooled immunoglobulin donated by adults contains antibodies that promote clearance of group A streptococcus, both in human blood and in experimental models. Having identified and ranked the antigenic targets of these antibodies, this project will use saRNA to evaluate each antigen alone, and in combination. The specific aims are: (1) Develop saRNA constructs that express the new panel of streptococcal antigens. (2) Rank individual saRNA antigens based on protective efficacy in experimental murine soft tissue infection challenge and in nasopharyngeal infection challenge. (3) Evaluate second order interactions between top-ranking saRNA antigens via paired combinations in soft tissue and nasopharyngeal models of infection. (4) Predict the optimum combination of up to 5 saRNA antigens to combat nasopharyngeal infection, using computer- assisted modelling and test the optimized combination in vivo, using standard and humanized murine models of infection, as well as following nasal immunization. Deliverables from the work will be an optimized combination saRNA vaccine that provides protection from experimental group A streptococcal infection, and a methodology to advance combination vaccine discovery in the future. The longer-term impact on human health would be considerable: Elimination of group A streptococcal pharyngitis would reduce antimicrobial consumption, reduce the health and socio-economic burden of streptococcal disease, reduce future cases of invasive streptococcal infection and rheumatic heart disease and therefore reduce global mortality from this infection.