Human challenge model of Bordetella pertussis infection

百日咳博德特氏菌感染的人体攻击模型

• 批准号: 10016748
• 负责人: SCOTT A HALPERIN
• 金额: $ 14.57万
• 依托单位: DALHOUSIE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-19 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016748
• 关键词: Acute; Adolescent; Adult; Animal Model; Azithromycin; Biological; Biological Markers; Bordetella pertussis; Budgets; Cells; Child; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Complex; Country; Development; Diagnosis; Disease; Dissection; Documentation; Dose; Epidemiology; Event; Exposure to; Family suidae; Frequencies; Gene Expression; Goals; Grant; Human; Immune; Immune response; Immunity; Immunization; Income; Individual; Infant; Infection; Informed Consent; Measures; Microbiology; Modeling; Mus; Nature; Pamphlets; Papio; Participant; Pathogenesis; Pathogenicity; Pertussis; Pertussis Vaccine; Phase; Polymerase Chain Reaction; Pregnant Women; Prevention; Protocols documentation; Reporting; Reproducibility; Research Ethics; Research Personnel; Respiratory Tract Infections; Serologic tests; Statistical Data Interpretation; Symptoms; System; Testing; Therapeutic; Time; TimeLine; Vaccination; Validation; antimicrobial; associated symptom; cell mediated immune response; data management; data sharing; disorder control; exposed human population; genetic pedigree; human pathogen; improved; infection burden; innovation; insight; low and middle-income countries; material transfer agreement; prevent; recruit; response; tool; transmission process; vaccine efficacy; vaccine trial; vaccinology

PROJECT SUMMARY/ABSTRACT Pertussis (whooping cough) is an acute bacterial respiratory tract infection. Globally, 20–40 million cases of pertussis are reported each year, with approximately 400,000 fatalities.2–4 In low- and middle-income countries, infant immunization with whole-cell pertussis vaccine is used for pertussis control. The primary control strategy in high-income countries has been immunization of all individuals, including routine immunization of infants, children, adolescents, adults, and pregnant women.17–26 This latter approach relies on a reasonable duration of protection so that boosters are needed no more frequently than every ten years. The epidemiologic features of Bordetella pertussis infections in adolescents and adults who are only partially immune from prior infections and immunizations are not well understood, and correlates of protection and duration of protection are not known. Furthermore, diagnosis of infection by culture, polymerase chain reaction (PCR), and serology remains complex, further limiting our understanding of the true burden of infection. A human challenge model will permit studies to better understand pathogenesis and the determinants of infection, disease, immunity, and trans- mission and will serve as a tool for the study of vaccine efficacy and measures to prevent and treat infection. The goal of this proposal is to plan a safe and effective human challenge model of B. pertussis infection in healthy adults. The Clinical Trial Specific Aims are Aim #1, to establish a safe, predictable, and reproducible infectious dose of B. pertussis in healthy adults and the frequency of any challenge-related B. pertussis infection, taking into account prior B. pertussis exposure (infection or vaccination with whole-cell or acellular pertussis vaccine); Aim #2, to characterize the incubation period from the time of challenge to the development of a positive microbiological test or of one or more signs or symptoms, taking into account prior exposure pedigree; Aim #3, to determine the frequency of spontaneous clearance of infection, taking into account prior exposure pedigree; Aim #4, to characterize the clinical course and biologic markers of infection in participants who develop illness and/or are colonized with B. pertussis postchallenge; Aim #5, to explore the time course of a five-day course of azithromycin therapy in clearing experimental infection and/or resolving experimental infection-associated symptoms; and Aim #6, to determine the optimal time frame to evaluate gene expression and the innate, humoral, and cell-mediated immune response following challenge using a systems vaccinology approach, taking into account prior exposure pedigree. The Planning Grant Specific Aims are Aim #1, to develop the protocol for the phase 1 human challenge study; Aim #2, to develop the research ethics package, including informed consent; Aim #3, to develop the regulatory documentation, including investigator’s brochure; Aim #4, to develop all data management documentation, including the statistical analysis plan, data sharing plan, Data and Safety Monitoring Board charter and materials, and material transfer agreements; and Aim #5, to develop the project management plan, clinical trial budget, recruitment plan, and timeline.

项目摘要/摘要 百日咳（百日咳）是一种急性细菌呼吸道感染。全球，有20-40万箱 据报道，百日咳每年有大约40万人死亡。在低收入和中等收入国家中，2-4 用全细胞百日咳疫苗的婴儿免疫用于百日咳。主要控制策略 在高收入国家中 儿童，青少年，成人和孕妇。17-26这种方法依赖于合理的持续时间 保护，因此不需要每十年就需要助推器。流行病学特征 仅在先前感染中部分免疫学的青少年和成年人的百日咳感染 免疫接种尚不清楚，保护和保护持续时间的相关性也不是 已知。此外，通过培养，聚合酶链反应（PCR）和血清学的诊断诊断 复杂，进一步限制了我们对感染真正伯恩的理解。人类挑战模型将允许 更好地理解发病机理的研究以及感染，疾病，免疫学和反式的研究者 任务，将作为研究疫苗效率和预防和治疗感染措施的工具。 该提案的目的是计划在百日咳芽孢杆菌感染的安全有效的人类挑战模型 健康的成年人。临床试验的特定目标是目标1，以建立安全，可预测和可重复的目标 健康成年人中百日咳的传染剂量以及与挑战有关的百日咳频率 感染，考虑到之前的B.百日咳暴露（全细胞或细胞感染或疫苗接种） 百日咳疫苗）；目的＃2，以从挑战到发展时期的孵化期 考虑到阳性微生物测试或一个或多个迹象或症状，请考虑事先暴露 谱系;目标＃3，确定发作的频率感染的频率，同时考虑到 曝光血统；目标＃4，以参与者的临床过程和生物学标记来表征 患病和/或与百日咳B. b. b. thallenge殖民的人；目标＃5，探索时间课程 阿奇霉素疗法为期五天的疗程清除实验感染和/或解决实验 与感染相关的符号；目标＃6，以确定评估基因表达的最佳时间框架 以及使用系统疫苗学挑战之后的先天，体液和细胞介导的免疫响应 考虑到事先曝光的血统。规划赠款具体的目标是目标1， 制定第1阶段人类挑战研究的方案；目标＃2，开发研究伦理计划， 包括知情同意；目标＃3，以制定包括调查员手册在内的监管文件； 目标＃4，开发所有数据管理文档，包括统计分析计划，数据共享 计划，数据和安全监控委员会宪章和材料以及材料转让协议；和目标＃5， 制定项目管理计划，临床试验预算，招聘计划和时间表。