Development of a next generation vaccine to prevent pertussis

开发下一代预防百日咳疫苗

• 批准号: 9473234
• 负责人: Wendy L Picking
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9473234
• 关键词: Acellular Vaccines; Adjuvant; Adverse effects; Antibodies; Bordetella; Bordetella pertussis; Canis familiaris; Cells; Coughing; Cytoplasm; Development; Distal; Dose; Epithelium; Formulation; Foundations; Fruit; Genetic; Immune response; Immunity; Immunization; Immunologist; Infection; Investigation; Lung; Mediating; Modeling; Molecular; Mucous Membrane; Mus; Needles; Pathogenesis; Pertussis; Pertussis Toxin; Pertussis Vaccine; Protein Subunits; Proteins; Public Health; Respiratory System; Shigella; Shigella dysenteriae; Shigella flexneri; Shigella sonnei; Subunit Vaccines; Syndrome; Syringes; Testing; Toxin; Toxoids; Trachea; Type III Secretion System Pathway; United States; Vaccination; Vaccine Antigen; Vaccines; Virulence Factors; Whole Cell Vaccine; cell mediated immune response; cytokine; enterotoxigenic Escherichia coli; experimental study; innovation; mortality; mutant; novel; novel vaccines; pathogen; prevent; protective efficacy; protein complex; respiratory; respiratory colonization; transmission process; trend

SUMMARY Bordetella pertussis causes pertussis (whooping cough), which is a reemerging global public health threat. In the 1940s an inactivated, whole-cell pertussis vaccine was introduced that dramatically reduced the mortality caused by pertussis. A new, potentially less toxic acellular vaccine was developed and introduced in the United States and other parts of the world in the 1990s. Although the acellular pertussis (aP) vaccine has fewer side effects, its protective efficacy is lower than that of the whole cell vaccine potentially due to the inability of aP to prevent nasopharyngeal colonization leading to transmission of B. pertussis. Like many Gram-negative pathogens, Bordetella spp. possess a type III secretion apparatus (T3SA). It resembles a molecular syringe and needle and two protein complexes localize atop the needle: a tip protein and the first translocator protein. These proteins are required for pathogenesis of Bordetella spp. and are 95-98% conserved among Bordetella spp. We have previously fused the Shigella spp. T3SA tip and translocator proteins to create DBF, which was used to successfully develop a novel subunit vaccine antigen against Shigella spp. When administered intranasally (IN) or parenterally (IM), DBF, admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from Enterotoxigenic E. coli, protects mice against a lethal challenge by S. flexneri and the heterologous pathogens S. sonnei and S. dysenteriae. We have similarly produced a fusion for Bordetella. In the initial mouse experiment the fusion protected 100% of the mice from a lethal pulmonary challenge with B. bronchiseptica, the causative agent of canine kennel cough. Furthermore, 38% sterilizing immunity was observed in the lungs despite the high bacterial load administered in the challenge. Thus, we hypothesize that our fusion will elicit a robust immune response that protects against B. bronchiseptica and B. pertussis infection. Additionally, we hypothesize that the fusion will elicit sterilizing immunity in the respiratory tract to break the transmission chain. Thus, the specific aims of this investigation are: 1) Assess the respective humoral and cell-mediated immune responses elicited by the fusion delivered IN and IM and 2) Determine the protective efficacy of the fusion against B. bronchiseptica and B. pertussis challenge.

总结 百日咳杆菌引起百日咳，这是一个重新出现的全球公共卫生威胁。 在20世纪40年代，一种灭活的全细胞百日咳疫苗被引入，大大降低了百日咳引起的死亡率。20世纪90年代，一种新的、潜在毒性较小的无细胞疫苗被开发出来，并在美国和世界其他地区推出。尽管无细胞百日咳（aP）疫苗具有较少的副作用，但其保护效力低于全细胞疫苗，这可能是由于aP不能防止鼻咽定殖导致B传播。百日咳。 与许多革兰氏阴性病原体一样，博德特氏菌属（Bordetella spp.）3.具有III型分泌器官（T3 SA）。它类似于一个分子注射器和针头，两个蛋白质复合物位于针头顶部：尖端蛋白和第一个转运蛋白。这些蛋白质是博德特氏菌属致病所必需的。并且在博德特氏菌属物种中是95-98%保守的。我们之前已经融合了志贺氏菌。T3 SA尖端和转运蛋白，以创建DBF，它被用来成功地开发一种新的亚单位疫苗抗原，针对志贺氏菌属。当鼻内（IN）或胃肠外（IM）给药时，DBF与来自肠杆菌的粘膜佐剂双突变体不稳定毒素（dmLT）混合。coli，保护小鼠免受S.福氏菌和异源病原菌S. sonnei和S.紫菀 我们同样也为博德特氏菌产生了融合体。在最初的小鼠实验中，融合物保护100%的小鼠免受B的致死性肺攻击。支气管败血症，犬舍咳嗽的病原体。此外，尽管在挑战中给予了高细菌负荷，但在肺中观察到38%的灭菌免疫力。 因此，我们假设我们的融合体将引发针对B的强有力的免疫应答。支气管败血症和B.百日咳感染此外，我们假设融合将在呼吸道中引发杀菌免疫，以打破传播链。因此，本研究的具体目的是：1）评估IN和IM递送的融合物引起的各自的体液和细胞介导的免疫应答，和2）确定融合物针对B的保护效力。支气管败血症和B.百日咳攻毒。