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WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children. This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2–6 years were eligible. In cohort 1, participants aged 4–6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2–3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17–21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140. Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1–6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6–93·5] in cohort 1a vs 81·3% [67·4–91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]). Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis. The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

BACKGROUNDPartial protective immunity to schistosomiasis develops over time, following repeated praziquantel (PZQ) treatment. Moreover, animals develop protective immunity after repeated immunization with irradiated cercariae. Here, we evaluated the development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni in healthy, Schistosoma-naive participants using single-sex, controlled human S. mansoni infection.METHODSTwenty-four participants were randomized in a double-blinded (1:1) manner to either the reinfection group, which received 3 exposures (weeks 0, 9, and 18) to 20 male cercariae, or to the infection control group, which received 2 mock exposures with water (weeks 0 and 9) prior to cercariae exposure (week 18). Participants were treated with PZQ (or placebo) at weeks 8, 17, and 30. Attack rates (ARs) after the final exposure (weeks 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events (AEs) were collected for safety.RESULTSTwenty-three participants completed the follow-up. No protective efficacy was observed, given an 82% (9 of 11) AR after the final exposure in the reinfection group and 92% (11 of 12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; P = 0.5). Related AEs were higher after the first infection (45%) compared with the second (27%) and third (28%) infections. Severe acute schistosomiasis was observed after the first infections only (2 of 12 in the reinfection group and 2 of 12 in the infection control group).CONCLUSIONRepeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported following subsequent infections, but did not result in protection against reinfection.TRIAL REGISTRATIONClinicalTrials.gov NCT05085470.FUNDINGEuropean Research Council (ERC) Starting Grant (no. 101075876).

Treatment guidelines for schistosomiasis recommend increasing frequency of preventative chemotherapy (PC) administration of praziquantel to twice per annum in persistent hotspots of transmission, in combination with integrated control strategies. FibroScHot was an individual randomised superiority trial designed to examine twice per annum and four times per annum treatment frequency. It was conducted in two primary schools, Buhirigi and Kaiso, in Hoima District Uganda - a designated Schistosoma mansoni high transmission area in which PC is targeted at children and adults. The baseline parasitology data was assessed against international control programme thresholds of success and the criteria for persistent hotspots. Further, the study also assessed the potential for integrated control strategies within the surrounding communities. The prevalence of infection, heavy infection and the infection intensity were derived for 700 participants from Kato-Katz examination of one stool sample. Neither school met the threshold of morbidity control (<5% with heavy infection). A strong school effect was observed in models of prevalence and prevalence of heavy infection, with these being greater in Kaiso. By prevalence, Kaiso was a high transmission area and Buhirigi a moderate transmission area. Kaiso but not Buhirigi met the definition of a persistent hotspot. Persistent hotspot classification did not change when intensity of infection was used. Intermediate snail hosts were collected at both Kaiso landing site and from the River Hoimo in Buhirigi, though in smaller numbers in the latter. Questionnaire data indicates that reliance on water collection from transmission sites and open defecation occurs more frequently in Kaiso than in Buhirigi. The criteria for persistent hotspots were met in the high transmission but not the moderate transmission community despite neither community meeting the threshold of morbidity control. This disconnect indicates that endemic communities exist in which control has not been achieved but increased frequency of treatment is currently not recommended. FibroScHot will be able to inform on whether widening the current recommendation of increased treatment frequency to these communities will achieve improved control. Evidence provided also indicates scope for the integrated control strategies of vector control and WASH improvements in both the participating communities.

The Gambia initiated a control programme for schistosomiasis in 2015. In light of this, recent and comprehensive data on schistosomiasis is required to effectively guide the control programme. This study aimed to evaluate the prevalence and associated risk factors of schistosomiasis among primary school children in The Gambia. We utilised data from a previous study conducted in 2015 in 4 regions of The Gambia: North Bank Region (NBR), Lower River Region (LRR), Central River Region (CRR) and Upper River Region (URR). In the parent study, ten schools were selected randomly from each region. Urine and stool samples collected from 25 boys and 25 girls (7-14 years) in each school were examined for urinary schistosomiasis (Schistosoma haematobium infection) and intestinal schistosomiasis (Schistosoma mansoni infection) using urine filtration, dipstick and Kato-Katz methods. Urinary schistosomiasis had an overall prevalence of 10.2% while intestinal schistosomiasis had a prevalence of 0.3% among the sampled school children. Prevalence of urinary schistosomiasis was significantly different among regions (χ 2 = 279.958, df = 3, p < 0.001), with CRR (27.6%) being the most endemic region, followed by URR (12.0%), then LRR (0.6%), and NBR (0.0%). Prevalence of intestinal schistosomiasis was also significantly variable among regions, with 4 of the 5 positive cases detected in CRR and 1 case in URR. Every school sampled in CRR had at least one student infected with S. haematobium, 50% of schools in URR had S. haematobium infection, and just one school in LRR had S. haematobium infection. While S. haematobium infection was significantly higher in boys (χ 2 = 4.440, df = 1, p = 0.035), no significant difference in infection rate was observed among age groups (χ 2 = 0.882, df = 2, p = 0.643). Two of the 5 students infected with S. mansoni were boys and 3 were girls. Four of these 5 students were in the 10-12 years age group and 1 was in the 7-9 years age group. Macrohaematuria and microhaematuria were found to be statistically associated with presence of S. haematobium eggs in urine. Being a male was a risk factor of S. haematobium infection. Bathing, playing and swimming in water bodies were found to pose less risk for S. haematobium infection, indicating that the true water contact behaviour of children was possibly underrepresented. The findings of this study provide invaluable information on the prevalence of schistosomiasis in The Gambia. This was useful for the schistosomiasis control efforts of the country, as it guided mass drug administration campaigns in eligible districts in the study area. More studies on S. mansoni and its intermediate snail hosts are required to establish its true status in The Gambia. As children sometimes tend to provide responses that potentially please the research or their teacher, data collection frameworks and approaches that ensure true responses in studies involving children should be devised and used.

Variations in vaccine responses have been observed between populations. A role for helminth infections has been proposed due to their immunomodulatory properties. In a secondary analysis of data from a randomised trial assessing effects of anthelminthic treatment on vaccine responses, we examined associations between helminth infections at baseline prior to vaccine administration, and vaccine responses among adolescents (9-17 years) in Koome Islands, Lake Victoria, Uganda. Participants received BCG [week 0], yellow fever (YF-17D), oral typhoid (Ty21a), HPV-prime [week 4], and HPV-boost, tetanus/diphtheria [week 28]. Outcomes were BCG-specific interferon-γ ELISpot responses and antibody responses to yellow-fever-, typhoid-, HPV-, tetanus- and diphtheria-specific antigens measured at two time points post vaccination. infection was determined as positive if either the plasma Circulating Anodic Antigen (CAA) assay or stool PCR were positive. Hookworm and were determined by stool PCR. Linear mixed effects regression was used to assess associations. Among 478 adolescents, 70% were (Sm) infected and 23% hookworm infected at baseline. was associated with lower Typhi O:LPS-specific IgG responses (adjusted geometric mean ratio (aGMR) 0.69 (0.57-0.83)), and hookworm with higher diphtheria-specific IgG (aGMR 1.16 (1.02, 1.31)) and lower HPV-16-specific IgG (aGMR 0.70 (0.55, 0.90)) post-vaccination. High intensity was associated with lower BCG-specific interferon-γ and Typhi O:LPS-specific IgG. We found inverse associations between and responses to two live vaccines, whereas hookworm was positively associated with diphtheria-specific IgG. These findings support the hypothesis that helminth infections can modulate vaccine responses, while also highlighting potential heterogeneity in the direction of these effects.

Preventive chemotherapy with praziquantel (PZQ) is the cornerstone of schistosomiasis control. However, a single dose of PZQ (40 mg/kg) does not cure all infections. Repeated doses of PZQ at short intervals might increase efficacy in terms of cure rate (CR) and intensity reduction rate (IRR). Here, we determined the efficacy of a single versus four repeated treatments with PZQ on Schistosoma mansoni infection in school-aged children from Côte d'Ivoire, using two different diagnostic tests. An open-label, randomized controlled trial was conducted from October 2018 to January 2019. School-aged children with a confirmed S. mansoni infection based on Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) urine cassette test were randomly assigned to receive either a single or four repeated doses of PZQ, administered at two-week intervals. The primary outcome was the difference in CR between the two treatment arms, measured by triplicate KK thick smears 10 weeks after the first treatment. Secondary outcomes included CR estimated by POC-CCA, IRR by KK and POC-CCA, and safety of repeated PZQ administration. During baseline screening, 1,022 children were assessed for eligibility of whom 153 (15%) had a detectable S. mansoni infection, and hence, were randomized to the standard treatment group (N = 70) and the intense treatment group (N = 83). Based on KK, the CR was 42% (95% confidence interval (CI) 31-52%) in the standard treatment group and 86% (95% CI 75-92%) in the intense treatment group. Observed IRR was 72% (95% CI 55-83%) in the standard treatment group and 95% (95% CI 85-98%) in the intense treatment group. The CR estimated by POC-CCA was 18% (95% CI 11-27%) and 36% (95% CI 26-46%) in the standard and intense treatment group, respectively. Repeated PZQ treatment did not result in a higher number of adverse events. The observed CR using KK was significantly higher after four repeated treatments compared to a single treatment, without an increase in adverse events. Using POC-CCA, the observed CR was significantly lower than measured by KK, indicating that PZQ may be considerably less efficacious as concluded by KK. Our findings highlight the need for reliable and more accurate diagnostic tools, which are essential for monitoring treatment efficacy, identifying changes in transmission, and accurately quantifying the intensity of infection in distinct populations. In addition, the higher CR in the intense treatment group suggests that more focused and intense PZQ treatment can help to advance schistosomiasis control. www.clinicaltrials.gov NCT02868385.

Mass drug administration (MDA) using praziquantel is the WHO-recommended approach for control of schistosomiasis. However, few studies have compared the impact of different schedules of MDA on the resultant infection levels. We wished to evaluate whether annual MDA was more effective than less frequent treatments for reducing community-level prevalence and intensity of Schistosoma mansoni infections. We performed a cluster randomized trial (ISRCTN 14849830) of 3 different MDA frequencies over a 5 year period in 75 villages with moderate (10%-24%) initial prevalence of S. mansoni in school children in western Kenya. Praziquantel was distributed by school teachers to students either annually, the first 2 years, or every other year over a 4 year period. Prevalence and intensity of infection were measured by stool examination in 9-12 year old students using the Kato-Katz method at baseline, each treatment year, and for the final evaluation at year 5. S. mansoni prevalence and intensity were also measured in first year students at baseline and year 5. Twenty-five schools were randomly assigned to each arm. S. mansoni prevalence and infection intensity in 9-12 year old students significantly decreased within each arm from baseline to year 5 but there were no differences between arms. There were no differences in infection levels in first year students either within or between arms. Strategies employing 2 or 4 rounds of MDA had a similar impact in schools with moderate initial prevalence, suggesting that schistosomiasis control can be sustained by school-based MDA, even if provided only every other year.

Background Schistosoma mansoni ( S. mansoni ) infection is a significant public health problem in Ethiopia, and has wide distribution in the country. The impact of the disease is particularly high on school-age children. Nationwide 385 endemic districts were identified, whereby control and elimination interventions are underway using school-based annual mass drug administration (MDA) with praziquantel. The national elimination program targets endemic districts as a whole. The aim of this study was to identify the transmission foci of Schistosoma mansoni and determine prevalence of soil-transmitted helminths (STHs) in Abeshge district. Methods The study was conducted from April to May, 2019 among school-age children randomly selected from public elementary schools in Abeshge district, South-central Ethiopia. Demographic information and data on risk factors of S. mansoni infection were gathered using pre-tested questionnaire. Moreover, a stool sample was collected from each child and examined using Kato-Katz thick smear technique. The data were analyzed using STATA_MP version 12. Results A total of 389 school-age children from five public elementary schools were included in the study. The overall prevalence of S. mansoni and STHs was 19.3% (75/389) and 35% (136/389), respectively. The prevalence of S. mansoni was 60.6% in Kulit Elementary school, while it was zero in Geraba. The prevalence of S. mansoni was significantly higher among males (AOR = 2.6, 95% CI 1.3–5.1), those with habit of swimming and/or bathing in rivers (AOR = 2.9, 95%CI 1.3–5.1) and involved in irrigation activities (AOR = 2.9, 95% CI 1.0–8.3). Overall, the prevalence of S. mansoni was significantly higher among school children attending Kulit Elementary School compared to those attending the remaining schools (AOR = 12.5, 95%CI 6.2–25.1). Conclusion A wide variation of S. mansoni prevalence was observed among the school children in the different schools. Control interventions better identify and target foci of S. mansoni transmission, instead of targeting the district homogenously.

Current World Health Organization (WHO) guidelines recommend annual mass drug administration using praziquantel in areas with high schistosome endemicity. Yet little is known about incidence and reinfection rates after treatment in women with frequent exposure to schistosomes. We sought to quantify response to anti-schistosome treatment and incident S. mansoni infections in a cohort of rural women living in a schistosome-endemic area of northwest Tanzania. We enrolled women with and without S. mansoni infection into a 12-month longitudinal cohort. Every 3 months, women were tested for schistosome infection using microscopic examinations for ova on filtered urine, Kato Katz slides, and serum Circulating Anodic Antigen (CAA). Those with schistosome infection received treatment with praziquantel 40 mg/kg according to the standard of care. We studied 35 women who were S. mansoni positive by stool microscopy and 46 women without schistosome infection who returned for at least one follow-up. Of the women who were initially infected, 14 (40%) were schistosome-positive at a follow-up visit. Four women developed incident infections, for a cumulative incidence of 8.7% and incidence rate of 0.99 per 100 person-months throughout the year among initially uninfected women. Only 3 women were egg-positive at any follow-up. Women with persistent, recurrent, or incident infection during the study period were significantly younger (p = 0.032) and had fewer children than women who remained uninfected or those who cleared the infection and did not experience recurrence (p = 0.003). Having fewer children remained significant after controlling for age (p = 0.023). There was no difference in initial intensity of infection by CAA or stool egg count, HIV status, or socioeconomic status. Although most water contact behaviors were comparable between the two groups, women with recurrent or incident schistosome infections were significantly more likely to have recently swum in the lake (p = 0.023). Our data suggests that annual praziquantel treatment reduces intensity of schistosome infections but is insufficient in providing stable parasite eradication in over a third of women in endemic communities. Furthermore, microscopy lacks adequate sensitivity to evaluate efficacy of treatment in this population. Our work demonstrates that further investigation into treatment efficacy and reinfection rates is warranted and suggests that increased frequency of praziquantel treatment is needed to improve cure rates in high-risk populations.

Schistosomiasis has been reported in 78 endemic countries and affects 240 million people worldwide. The digenetic parasite Schistosoma mansoni needs fresh water to compete its life cycle. There, it is susceptible to soluble compounds that can affect directly and/or indirectly the parasite's biology. The cercariae stage is one of the key points in which the parasite is vulnerable to different soluble compounds that can significantly alter the parasite's life cycle. Molluscicides are recommended by the World Health Organization for the control of schistosomiasis transmission and Euphorbia milii latex is effective against snails intermediate hosts. We used parasitological tools and electron microscopy to verify the effects of cercariae exposure to natural molluscicide (Euphorbia milii latex) on morphology, physiology and fitness of adult parasite worms. In order to generate insights into key metabolic pathways that lead to the observed phenotypes we used comparative transcriptomics and proteomics. We describe here that the effect of latex on the adult is not due to direct toxicity but it triggers an early change in developmental trajectory and perturbs cell memory, mobility, energy metabolism and other key pathways. We conclude that latex has not only an effect on the vector but applies also long lasting schistosomastatic action. We believe that these results are of interest not only to parasitologists since it shows that natural compounds, presumably without side effects, can have an impact that occurred unexpectedly on developmental processes. Such collateral damage is in this case positive, since it impacts the true target of the treatment campaign. This type of treatment could also provide a rational for the control of other pests. Our results will contribute to enforce the use of E. milii latex in Brazil and other endemic countries as cheap alternative or complement to mass drug treatment with Praziquantel, the only available drug to cure the patients (without preventing re-infection).