Resistance evaluation and surveillance initiative for schistosomiasis treatment: study protocol for the RESIST project

BACKGROUND: The Zanzibar islands have implemented mass drug administration (MDA) with praziquantel against Schistosoma haematobium infections since the 2000s, achieving elimination of schistosomiasis as a public health problem in most areas. However, a few hotspots with high prevalence of infection remain, where MDA-driven selection of drug-resistance within the S. haematobium populations might contribute to persistent transmission. Recent advances in understanding the molecular basis of praziquantel action on the Schistosoma transient receptor potential ion channel (TRPMPZQ) now facilitate screening Schistosoma populations for genetic signatures that may point to reduced praziquantel efficacy, or even resistance. METHODS: This observational study is implemented from 2024 to 2027 and contains four components: (1) Cross-sectional surveys in Pemba: Single urine samples are collected from ~ 14,400 students across 15 schools to assess the geographic distribution of S. haematobium infection prevalence and intensity, and for miracidia collection. (2) Longitudinal studies in Pemba: Quintuple urine samples are collected from ~ 945 students across two schools before and two weeks after MDA to assess S. haematobium egg reduction rates (ERR), and for miracidia collection. (3) Genome-wide analyses of the S. haematobium miracidia collected in 1 and 2, (a) across Pemba over multiple time points (including archived specimens collected in 2012 and 2017) to quantify spatiotemporal patterns of parasite genetic variation; and (b) before and two weeks after MDA to identify any genetic variants under selection and potentially associated with praziquantel sensitivity. 4) Modelling to: (a) analyse correlation of observed S. haematobium ERR and miracidia genetic profiles; (b) predict the impact of MDA and mitigation strategies on emergence of drug resistance; and (c) design cost-efficient survey strategies for pharmacovigilance. DISCUSSION: The combination of parasitological fieldwork, genomic analyses, and mathematical modelling will deliver new insights into how MDA has shaped genetic diversity of S. haematobium populations, how this might affect drug efficacy and contribute to persistent hotspots, and how this can best be monitored and mitigated. This project will lay the foundations for population-based research into drug resistance in Schistosoma with important implications for novel drugs in the pipeline. TRIAL REGISTRATION: ISRCTN, ISRCTN59331501. Registered 24 October 2024, https://www.isrctn.com/ISRCTN59331501 .