Shigella Conjugate Vaccine (SCV4) Development, Characterization, and Pre-clinical Evaluation

PROJECT SUMMARY/ABSTRACT Shigella infection is a leading cause of diarrheal illness in young children in resource-limited settings, and results in tens of thousands of deaths each year. Protection against shigellosis is largely associated with antibodies targeting O-specific polysaccharide (OSP) of lipopolysaccharide (LPS) of Shigella spp. A vaccine protective against shigella will need to be effective in young children in resource-limited areas of the world. Young children do not develop high level or durable immune responses against polysaccharides such as OSP unless they are presented in a T cell dependent manner. In comparison, young children mount high level and durable immune responses when polysaccharides are conjugated to carrier protein. Here, we propose an international partnership to advance a quadrivalent shigella conjugate vaccine (SCV4) targeting Shigella flexneri 2a, 3a, 6 and S. sonnei. SCV4 will be comprised of OSPs recovered from identified source strains and will be linked to carrier protein rTTHc using squaric acid chemistry. Our partnership has advanced a cholera conjugate vaccine using this approach that has undergone product development, stability testing, toxicologic assessment and preclinical evaluation, and is initiating Phase 1 evaluation in humans in Q4 '22. We thus propose to adapt our already established scalable and manufacturable protocols, building upon our preliminary data showing that shigella conjugate vaccines using our platform approach are immunogenic and protective in animal models. We will produce SCV4 (monovalent and co-formulated), characterize product, and assess immunogenicity and protective efficacy in mice, guinea pigs and a non-human primate model. Our goal is the development of reproducible, scalable, manufacturing protocols for production of SCVs and SCV4 to support Technology Transfer to a future manufacturing partner. Proposed product development will be through a partnership that includes the Vaccine Process Development Team at the International Vaccine Institute (IVI), South Korea that has expertise in vaccine product development and a history of successful technology transfer to vaccine manufacturers in resource-limited areas. The ultimate goal is development of a SCV that can be incorporated into the Expanded Programme on Immunizations (EPI) for use in 12- 24 month old children in LMIC settings with high shigella burden.