This study is part of work package 2 of the Periscope consortium. The Periscope consortium brings together internationally renowned scientists with many years of experience in B. pertussis research, clinical trials, bioinformatics, immunology and public health to promote scientific and technological innovation in pertussis vaccine development and to foster the creation of a laboratory and scientific network that facilitates the testing and helps expedite the development of novel pertussis vaccines in Europe. This study, the development of a human challenge model for B. pertussis, is one of the models that will accelerate the development and registration of novel pertussis vaccines and will provide samples for studies performed within the network.~This is a prospective controlled human challenge study consisting of two phases; Phase A: Development of a B. pertussis human challenge model; pilot to establish the standard inoculum The first aim of phase A is to determine a 'standard inoculum' (SI), which results in safe colonisation of 70% of volunteers. This level of colonisation of 70% has been selected so that baseline immune profiles of individuals who are, or are not colonised following challenge can be assessed and biomarkers of protection from colonisation identified. It is acknowledged that for the future use of the human challenge model for efficacy evaluation of experimental vaccine candidates, it would be optimal if the percentage of subjects successfully colonised were at least 70%. The SI will be identified in a dose escalating or de-escalating experiment commencing at 103 colony forming units B. pertussis administered intranasally. Each group of 5 volunteers will be sequentially inoculated at half log-fold increasing/decreasing doses until the endpoint is reached. The experiment will be continued until the SI yields 10 subjects who are colonised at day 14. Volunteers will be screened to exclude those with evidence of recent B. pertussis infection using anti-pertussis toxin (PT) immunoglobulin G (IgG) ELISA as evidence to allow evaluation of seroconversion. Following the challenge chemical, haematological and clinical parameters will be monitored and nasal swab samples will be cultured at regular intervals to assure safety of the volunteers and to identify the presence of B. pertussis. At day 14 after the challenge, or at the onset of symptoms, whichever occurs soonest, eradication therapy in the form of azithromycin 500 mg once a day for 3 days will be given. Further mucosal and blood samples will be taken over the follow up period of one year.~The second aim of phase A is to identify the 'colonisation period'; the earliest day after inoculation at which colonisation of the nasopharynx (as detected by culture) is observed in 100% of those volunteers who show seroconversion at day 28. This time period will be used to establish the length of participation required from volunteers in future studies. The colonisation period will be deemed biologically relevant if B. pertussis specific mucosal and systemic antibodies are elicited in people who are colonised for the colonisation period. A quantitative PCR assay to detect B. pertussis in nasopharyngeal samples will be evaluated to determine if this can provide more rapid information in addition to culture.~The third aim of phase A is to access environmental shedding of B. pertussis following nasal inoculation of healthy volunteers with B. pertussis. These shedding results will used to determine the length of admission and isolation in phase B. The shedding of B. pertussis by challenged volunteers will be assessed using personal aerosol samplers and environmental sampling. Efficacy of eradication therapy will be assessed.~Phase B: Development of a modified B. pertussis human challenge model In phase B the pilot study data from phase A will be used to design a more practical model, if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. The final protocol for phase B will be presented as a protocol amendment, because it will be based on the standard inoculum and colonisation period identified in Phase A.~Volunteers in phase B will not be preselected to exclude those with evidence of recent B. pertussis infection. The standard inoculum determined in phase A will be used for all volunteers and eradication therapy will be given after the colonisation period based on the data of phase A. Approximately 30 individuals will receive the intranasal SI and as control group approximately 15 individuals will receive intranasal sham. Both groups will be treated with azithromycin for three days at the end of the colonisation period.~Aims:~To confirm that the following parameters of the model in phase B are similar to that seen in phase A:~Volunteer safety~Colonisation rate~Colonisation period~Genetic/expression changes in B. pertussis during challenge~Environmental shedding~Efficacy of eradication therapy~To compare the pattern of detection of B. pertussis in nasopharyngeal samples by qPCR to that seen in phase A.~To assess B. pertussis-specific immunity before and after inoculating healthy volunteers with B. pertussis, comparing the data from successfully colonised participants with the data from those not colonised and the control group.
This is a prospective controlled human challenge study consisting of two phases; Phase A: Development of a B. pertussis human challenge model; pilot to establish the standard inoculum Phase B: Development of a modified B. pertussis human challenge model