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.

概括 Bordetella百日咳导致百日咳（百日咳），这是一种重新体现的全球公共卫生威胁。 在1940年代，引入了一种灭活的全细胞百日咳疫苗，该疫苗大大降低了百日咳导致的死亡率。在1990年代，在美国和世界其他地区开发并引入了一种新的，潜在的毒性细胞疫苗。尽管细胞百日咳（AP）疫苗的副作用较少，但由于AP无法防止鼻咽定殖导致百日咳芽孢杆菌的传播，其保护性疗效可能低于整个细胞疫苗的副作用。 像许多革兰氏阴性病原体一样，Bordetella spp。具有III型分泌设备（T3SA）。它类似于分子注射器和针头，两个蛋白质复合物位于针头上：尖端蛋白和第一个转运蛋白。这些蛋白质是Bordetella spp发病机理所必需的。在Bordetella spp中保守的是95-98％。我们以前已经融合了志贺氏菌。 T3SA尖端和转运蛋白创建DBF，该蛋白用于成功开发针对Shigella spp的新型亚基疫苗抗原。当用室内（in）或肠胃外（IM）施用DBF时，与肠毒素大肠杆菌的粘膜辅助双突变毒素（DMLT）相结合时，可以保护小鼠免受S. flexneri和异型病原体S. s. s. sonnei and S. sonnei and S. sonnei and S. dyysenteriae的致命挑战。 我们类似地生产了Bordetella的融合。在最初的小鼠实验中，融合保护了100％的小鼠免受犬狗窝咳嗽的致病剂的致死性肺挑战。此外，尽管在挑战中施用了高细菌载荷，但在肺中观察到38％的灭菌性。 因此，我们假设我们的融合将引起强大的免疫反应，以防止支气管杆菌和百日咳芽孢杆菌感染。此外，我们假设融合将在呼吸道中引起灭菌免疫力破坏透射链。因此，这项研究的具体目的是：1）评估由输送和IM的融合引起的各自的体液和细胞介导的免疫反应，以及2）确定融合对支气管芽孢杆菌的保护性效果，对支气管杆菌和百国芽孢杆菌的挑战。