Human challenge model of Bordetella pertussis infection

项目概要/摘要 百日咳（百日咳）是一种急性细菌性呼吸道感染。全球范围内，有 20-4000 万例 每年都有百日咳报告，导致大约 40 万人死亡。2-4 在低收入和中等收入国家， 婴儿全细胞百日咳疫苗免疫用于控制百日咳。主要控制策略 高收入国家已对所有人进行免疫接种，包括对婴儿进行常规免疫接种， 儿童、青少年、成人和孕妇。17-26 后一种方法依赖于合理的持续时间 保护，使得助推器的使用频率不超过每十年一次。流行病学特征 对先前感染仅部分免疫的青少年和成人的百日咳博德特氏菌感染 和免疫接种尚未得到很好的理解，保护和保护持续时间的相关性也不清楚 已知。此外，仍然需要通过培养、聚合酶链反应 (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 更好地了解感染、疾病、免疫和反转录的发病机制和决定因素的研究 使命并将作为研究疫苗功效和预防和治疗感染措施的工具。 该提案的目标是规划一种安全有效的百日咳博德特氏菌感染人类挑战模型 健康的成年人。临床试验的具体目标是目标#1，建立安全、可预测和可重复的 健康成人中百日咳博德特氏菌的感染剂量以及任何与攻击相关的百日咳博德特氏菌的频率 感染，考虑到先前的百日咳博德特氏菌暴露（感染或接种全细胞或非细胞疫苗） 百日咳疫苗）；目标#2，描述从挑战到发展的潜伏期 微生物学检测呈阳性或一种或多种体征或症状，考虑到之前的接触情况 血统书；目标#3，确定感染自发清除的频率，同时考虑之前的情况 暴露血统；目标#4，描述参与者感染的临床病程和生物标志物 攻击后患病和/或感染百日咳博德特氏菌的人；目标#5，探索时间进程 为期五天的阿奇霉素治疗清除实验性感染和/或解决实验性感染 感染相关症状；目标#6，确定评估基因表达的最佳时间范围 以及使用系统疫苗学进行攻击后的先天、体液和细胞介导的免疫反应 方法，考虑到先前暴露的谱系。规划补助金的具体目标是目标#1， 制定第一阶段人类挑战研究的方案；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，包括研究者手册； 目标#4，制定所有数据管理文档，包括统计分析计划、数据共享 计划、数据和安全监测委员会章程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.