Controlled human infection models can be helpful to study pathogenesis and immune responses as a basis for the development of vaccines. In controlled human infection models, human challenge agents are used to infect healthy volunteers, therefore, ethical considerations include that the exposure studies need to be safe and results should be meaningful, e.g. contribute to a better cure. Both in the US and in Europe, the level of Good Manufacturing Practice required is related to the phase of the study (‘sliding scale Good Manufacturing Practice’), and, hence, is much more open to speedy drug development than anticipated. Recommendations included: the development of guidelines for human challenge agents; a focus on strain selection, in particular with regard to strain infectivity, stability and purity; the use of whole genome sequencing; a reference repository of challenge agents, the need for early exchange with regulators to ensure acceptability of strain selection and manufacturing for later drug development; sharing of models and challenge agents.
Bibliographical noteFunding Information:
Development of the pertussis CHIM is supported through a European Union Innovative Medicines Initiative project, PERISCOPE. The first step was the selection of a strain that was representative of current European disease isolated and was well characterized in laboratory studies. Strain B1917 was selected and used for the production of a GMP challenge stock [ 24 ]. Phase A of the CHIM development was determination of the standard inoculum dose, resulting in B. pertussis colonization in at least 70% of the exposed subjects without causing disease. Colonization in 70% of subjects was chosen to avoid a saturating dose and so that the immune status of subjects who are or are not colonised could be compared to understand the immune correlates of protection against colonization. Secondary objectives were to characterize: the microbiological dynamics after challenge; the effectiveness of azithromycin therapy; pre- and post-challenge B. pertussis-specific immunity in volunteers; and environmental shedding of B. pertussis following nasal inoculation. Of note, nasal wash was more sensitive that per-nasal swabs used in pertussis diagnosis, probably due to the larger area sampled. Furthermore, it is a less invasive technique and preferred by participants. This study showed that a dose of 10 5 colony forming units would consistently result in 80% colonization [ 25 ], with only minor symptoms reported. Furthermore, seroconversion occurred in some but not all colonised individuals. Azithromycin treatment resulted in complete eradication within 48h in 88% of the colonised individuals and no environmental shedding was detected [ 25 ]. Hence, the next phase will be an outpatient study.