Authors

Discussion

Despite >25 years of praziquantel (PZQ) mass drug administration targeting Schistosoma haematobium (Sh) in Pemba (Zanzibar), transmission persists, with local prevalences up to 35% reported in 2025, raising concern for PZQ efficacy. Using a genomic surveillance approach, this project aims to identify genetic determinants associated with reduced PZQ responsiveness within Sh populations exposed to long-term treatment pressure. Representing Sh populations subjected to intensive PZQ treatment, whole-genome sequencing was performed on 300 individual miracidia from 172 children attending 17 Pemba schools in 2012 and 2017. Analyses focused on the recently identified PZQ molecular target, TRPM_PZQ, with variants characterised relative to S. mansoni orthologues previously described, and using a cytoplasmic Ca²⁺ reporter assay measuring TRPM_PZQ activity relative to the Sh wild-type in lab generated mutants. In addition, miracidia were collected in 2024–2025 from children attending the same 17 schools as part of a large-scale surveillance programme. Analysis of 2012/2017 samples identified 211 (3.1%) variant sites within TRPM_PZQ. Three mutations detected at low allele frequencies (AF<0.01) were profiled as having reduced PZQ responsiveness, whilst four others caused no difference in PZQ sensitivity. In 2024/2025, 12,598 miracidia were collected from 428 children, including 14 individuals who were positive post-PZQ treatment. This is the first large-scale spatiotemporal genomic surveillance of Sh in relation to PZQ treatment. Allele frequency shifts of TRPM_PZQ variants attributed with decreased PZQ sensitivity in 2012/2017 Sh populations will be monitored in 2025-2025. Analysis of 2024–2025 samples will enable assessment of PZQ-mediated selection and inform control and elimination strategies.