Research Project
10016748
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.
