Establishing a single-sex controlled human Schistosoma mansoni infection model for Uganda: protocol for safety and dose-finding trial

Abstract

Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A Schistosoma CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for Schistosoma mansoni in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior Schistosoma exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits.

Keywords: human-controlled Schistosoma masoni.

Figure 1.

Step-wise dose escalation diagram. At each dose of cercariae, three volunteers will be infected in group 1. If safety profiles are acceptable at 8 weeks from infection, and all three are infected, a second group of seven volunteers will be infected at the same dose (group 2; green arrows). If safety is acceptable but not all three are infected dose will be escalated (red arrows), If safety profiles remain acceptable, the dose will be escalated until at least eight of ten volunteers are infected at a given dose.

Figure 2.

Trial setting illustrating the location of the clinical research facility that will house the trial work and the two communities, prior minimal schistosome exposure (Nkumba University) or intense schistosome exposure (Kigungu—Lakeshore fishing village) from which the volunteers will be obtained.