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

志贺氏菌结合疫苗 (SCV4) 的开发、表征和临床前评估

• 批准号: 10704325
• 负责人: Edward T. Ryan
• 金额: $ 101.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704325
• 关键词: Acids; Address; Amines; Animal Model; Animals; Antibodies; Bacteria; Bangladesh; Biological Assay; Biomedical Engineering; Biotechnology; Carbohydrate Chemistry; Carrier Proteins; Cavia; Cessation of life; Chemicals; Chemistry; Child; Cholera; Conjugate Vaccines; Cyclic GMP; Data; Development; Enteral; Evaluation; Formulation; Future; General Hospitals; Generations; Goals; Human; Immune response; Immunity; Immunization; Immunologics; Individual; Industry; International; Investments; Knowledge; Korea; Koreans; Link; Lipopolysaccharides; Macaca; Manufacturer; Massachusetts; Modeling; Monoclonal Antibodies; Mus; O Antigens; Oligosaccharides; Pharmacologic Substance; Polysaccharides; Preclinical Testing; Preparation; Primates; Procedures; Process; Production; Protocols documentation; Public Health; Recording of previous events; Reproducibility; Research; Resource-limited setting; Serotyping; Shigella; Shigella Infections; Shigella Vaccines; Shigella flexneri; Shigella sonnei; Source; South Korea; Species Specificity; T-Lymphocyte; Technology Transfer; Tetanus Toxin; Typhoid Fever; United States National Institutes of Health; Universities; Vaccines; Vibrio cholerae; Virulent; Work; clinically relevant; cost; diarrheal disease; experience; guinea pig model; immunogenic; immunogenicity; industry involvement; international center; international partnership; intraperitoneal; low and middle-income countries; manufacture; manufacturing run; meetings; nonhuman primate; pathogen; phase 1 testing; pre-clinical; preclinical evaluation; product development; programs; protective efficacy; response; stability testing; technology platform; timeline; vaccine development

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.

项目概要/摘要 志贺氏菌感染是资源有限环境中幼儿腹泻疾病的主要原因， 每年导致数万人死亡。 与针对脂多糖 (LPS) 的 O 特异性多糖 (OSP) 的抗体相关 志贺氏菌疫苗需要对幼儿有效。 世界上资源有限的地区的幼儿无法形成高水平或持久的免疫力。 对 OSP 等多糖的反应，除非它们以 T 细胞依赖性形式存在 相比之下，幼儿在以下情况下会产生高水平且持久的免疫反应。 在这里，我们建议建立国际合作伙伴关系以将多糖与载体蛋白缀合。 开发针对福氏志贺氏菌 2a、3a、6 和 S 的四价志贺氏菌结合疫苗 (SCV4)。 sonnei.SCV4 将由从已识别的来源菌株中回收的 OSP 组成，并将被链接起来。 我们的合作伙伴关系已推动霍乱的发展。 使用这种方法的结合疫苗已引入产品开发、稳定性测试、 毒理学评估和临床前评估，并正在启动人体第一阶段评估 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， 我们的初步数据显示，志贺氏菌结合疫苗使用我们的平台 方法在动物模型中具有免疫原性和保护性，我们将生产 SCV4（单价和 共同配制），表征产品并评估小鼠的免疫原性和保护功效， 我们的目标是开发可重复、可扩展、 用于生产 SCV 和 SCV4 的制造协议，以支持向 未来的制造合作伙伴将通过合作伙伴关系进行产品开发。 包括位于南方的国际疫苗研究所 (IVI) 的疫苗工艺开发团队 韩国在疫苗产品开发方面拥有专业知识和成功技术的历史 向资源有限地区的疫苗生产商转移的最终目标是开发疫苗。 SCV 可纳入扩大免疫计划 (EPI)，用于 12- 志贺氏菌负担高的中低收入国家地区 24 个月大的儿童。