Human challenge model of Bordetella pertussis infection

项目摘要/摘要 百日咳是一种急性细菌性呼吸道感染。在全球范围内，2000-4000万例 据报告，每年有百日咳病例，低收入和中等收入国家约有400,000人死亡。 婴儿接种全细胞百日咳疫苗用于控制百日咳。主要控制策略 在高收入国家，所有人都接种了疫苗，包括对婴儿进行常规免疫， 儿童、青少年、成人和孕妇。17-26后一种方法依赖于 保护，使助推器的使用不超过每十年一次。流行性出血热流行病学特征 对先前感染仅部分免疫的青少年和成人中的百日咳杆菌感染 免疫接种没有被很好地理解，保护和保护持续时间的相关性也不是很清楚 为人所知。此外，通过培养、聚合酶链式反应(PCR)和血清学来诊断感染 复杂，进一步限制了我们对感染真正负担的理解。人类挑战模型将允许 研究更好地了解发病机制和感染、疾病、免疫和反式病毒的决定因素。 它将成为研究疫苗效力以及预防和治疗感染措施的工具。 这项建议的目标是计划一个安全和有效的人类百日咳杆菌感染的挑战模型。 健康的成年人。临床试验的具体目标是目标1，建立一种安全、可预测和可重复的 健康成人百日咳杆菌感染剂量和任何挑战相关百日咳杆菌感染频率 感染，考虑到先前的百日咳杆菌暴露(感染或接种全细胞或无细胞疫苗 百日咳疫苗)；目的2，描述从发病到发病的潜伏期 微生物检测呈阳性，或有一个或多个体征或症状，并考虑到先前的接触 系谱；目标3，确定感染自发清除的频率，考虑到先前 暴露家谱；目的#4，描述参与者的临床病程和感染的生物标志物 发生疾病和/或感染百日咳杆菌感染后的人；目标5，探索 阿奇霉素治疗清除实验性感染和/或解决实验性感染的五天疗程 感染相关症状；以及目标6，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后的先天、体液和细胞介导的免疫反应 方法，考虑到先前的暴露血统。规划拨款的具体目标是目标1，以 制定人类挑战研究第一阶段的方案；目标2，制定研究伦理包， 包括知情同意；目标3，制定监管文件，包括调查员手册； 目标#4，开发所有数据管理文件，包括统计分析计划、数据共享 计划、数据和安全监测委员会章程和材料以及材料转让协议；以及目标5 制定项目管理计划、临床试验预算、招募计划和时间表。

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.