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

项目总结/摘要 志贺氏菌感染是资源有限环境中幼儿腹泻病的主要原因， 每年导致成千上万人死亡预防志贺氏菌病主要是 与靶向脂多糖（LPS）的O-特异性多糖（OSP）的抗体相关， 志贺菌预防志贺氏菌的疫苗需要在儿童中有效， 资源有限的地区。幼儿不能形成高水平或持久的免疫力 针对OSP等多糖的反应，除非它们存在于T细胞依赖性细胞中 方式相比之下，幼儿在以下情况下会产生高水平和持久的免疫反应： 多糖与载体蛋白结合。在此，我们提议建立国际伙伴关系， 以福氏志贺菌2a、3a、6和志贺菌S. sonnei。SCV 4将由从已鉴定的来源菌株中回收的OSP组成，并将与 与载体蛋白rTTHC结合。我们的合作关系引发了霍乱 使用这种方法的结合疫苗已经过产品开发，稳定性测试， 毒理学评估和临床前评价，并正在启动人体I期评价， 22年第四季度。因此，我们建议调整我们已经建立的可扩展和可制造的协议， 基于我们的初步数据，显示使用我们的平台的志贺菌结合疫苗 方法在动物模型中具有免疫原性和保护性。我们将生产SCV 4（单价和 共配制），表征产品，并评估小鼠中的免疫原性和保护功效， 豚鼠和非人灵长类动物模型。我们的目标是开发可复制的，可扩展的， 生产SCV和SCV 4的制造协议，以支持技术转移到 未来的制造业合作伙伴。拟议的产品开发将通过合作伙伴关系， 包括国际疫苗研究所（IVI）的疫苗工艺开发小组， 韩国拥有疫苗产品开发的专业知识和成功的技术历史 向资源有限地区的疫苗生产商转让。最终目标是发展一个 SCV可纳入扩大免疫方案，用于12- LMIC环境中志贺氏菌高负荷的24个月大儿童。

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.