Test-treat-track-test-treat (5T) approach for Schistosoma haematobium elimination on Pemba Island, Tanzania.

BACKGROUND: After decades of praziquantel mass drug administration (MDA), several countries approach schistosomiasis elimination. Continuing MDA in largely uninfected populations no longer seems justified. Alternative interventions to maintain the gains or accelerate interruption of transmission are needed. We report results, strengths, and shortcomings of novel test-treat-track-test-treat (5T) interventions in low Schistosoma haematobium prevalence areas on Pemba, Tanzania. METHODS: School- and household-based surveys were conducted in 2021 and 2022 to monitor the S. haematobium and microhematuria prevalence and assess the impact of interventions. In 2021, 5T interventions were implemented in 15 low-prevalence areas and included: (i) testing schoolchildren in primary and Islamic schools for microhematuria as a proxy for S. haematobium, (ii) treating positive children, (iii) tracking them to their households and to water bodies they frequented, (iv) testing individuals at households and water bodies, and (v) treating positive individuals. Additionally, test-and-treat interventions were implemented in the 22 health facilities of the study area. RESULTS: The S. haematobium prevalence in the school-based survey in 15 low-prevalence implementation units was 0.5% (7/1560) in 2021 and 0.4% (6/1645) in 2022. In the household-based survey, 0.5% (14/2975) and 0.7% (19/2920) of participants were infected with S. haematobium in 2021 and 2022, respectively. The microhematuria prevalence, excluding trace results, in the school-based survey was 1.4% (21/1560) in 2021 and 1.5% (24/1645) in 2022. In the household-based survey, it was 3.3% (98/2975) in 2021 and 5.4% (159/2920) in 2022. During the 5T interventions, the microhaematuria prevalence was 3.8% (140/3700) and 5.8% (34/594) in children in primary and Islamic schools, respectively, 17.1% (44/258) in household members, and 16.7% (10/60) in people at water bodies. In health facilities, 19.8% (70/354) of patients tested microhematuria-positive. CONCLUSIONS: The targeted 5T interventions maintained the very low S. haematobium prevalence and proved straightforward and feasible to identify and treat many of the few S. haematobium-infected individuals. Future research will show whether 5T interventions can maintain gains in the longer-term and expedite elimination. TRIAL REGISTRATION: ISRCTN, ISCRCTN91431493. Registered 11 February 2020, https://www.isrctn.com/ISRCTN91431493 .

Efficacy and safety of single-dose artesunate plus sulfalene/pyrimethamine combined with praziquantel for the treatment of children with Schistosoma mansoni or Schistosoma haematobium in western Kenya: a randomised, open-label controlled trial.

BACKGROUND: Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. METHODS: This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. RESULTS: Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. CONCLUSIONS: A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.

Efficacy of praziquantel drug against Schistosoma haematobium and performance of urine reagent strips among pre-and-school aged children during the high transmission season in North-Western Tanzania.

The World Health Organization calls for schistosomiasis endemic countries to regularly monitor the efficacy of Praziquantel (PZQ) drug, the only antischistosomal drug used for four decades in Tanzania. In response to that call, the current study investigated the efficacy of single dose of PZQ against Schistosoma haematobium during the high transmission season and further assessed, the sensitivity and specificity of urine reagent strips before and after treatment. The study recruited a total of 2,498 -children aged (4 -17 years old) who provided a single urine sample that was visually examined for macro-haematuria, then using urine dipstick and urine filtration technique for microhaematuria and the presence of S. haematobium eggs. The baseline prevalence of S. haematobium eggs positive based on urine filtration test was 29.2 % (95 %CI:27.5-31.0) and that of microhaematuria was 43.1 % (95 %CI:41.1-45.0). Of the infected participants, 40.9 % (95 %CI:37.4-44.6) had a heavy intensity of infection and the geometrical mean intensity (GMI) of infection was 33.7 eggs/10mls of urine. A single dose of PZQ reduced the prevalence of infection to 16.2 %, the GMI of infection to 18.8eggs/10mls of urine and that of microhaematuria to 27.9 %. Cure rate and egg reduction rates (ERR) were 83.8 % and 44.3 % respectively. At baseline, the sensitivity and specificity of the urine reagent strips were 59.7 % and 93.8 %, whereas at post-treatment they were 16.7 % and 93.6 %. When PZQ drug is administered during the high transmission season, its efficacy in term of ERR is poor. The urine reagent strips had low sensitivity but high specificity at pre-and-post PZQ treatment.

Endemic status of urogenital schistosomiasis and the efficacy of a single-dose praziquantel treatment in unmapped rural farming communities in Oyo East Local Government Area, Oyo State, Nigeria.

BACKGROUND: Schistosomiasis is endemic in Nigeria, and the treatment is largely concentrated on children enrolled in schools. Consequently, the coverage of non-enrolled school-aged children is often neglected. Ajagba and Awosan are two communities in Nigeria that have never had any control intervention. Hence, this survey was designed to determine the endemicity of urogenital schistosomiasis and to evaluate the efficacy of a single-dose praziquantel in the communities. METHODS: Urine sample (10 mL) of each participant from Ajagba and Awosan communities was filtered through 12µm polycarbonate filter. The filter was placed on a microscope slide, and stained with a drop of 1% Lugol iodine solution. The stained slides were examined under the microscope and the numbers of S. haematobium eggs were counted. Water contact sites were searched for snail hosts and the snails collected were shed for Schistosoma cercariae. Data were analyzed using SPSS version 24.0 and the significance level was set at 95%. RESULTS: The overall prevalence of infection in the Ajagba community was 45.6% with a mean intensity of 61.1 ± 144.5 eggs/10 mL of urine, while the prevalence of infection in the Awosan community was 5.7% with a mean intensity of 1.4 ± 6.8 eggs/10 mL of urine. The school-aged children had a prevalence and mean intensity of infection of 73.1% and 111.6 ± 177.9 eggs/10 mL of urine, respectively. Following treatment, women had a higher egg reduction rate than men (p = 0.0283). Bulinus globosus were found in Ajagba but not in Awosan, with 5.7% shedding Schistosoma spp, cercariae. CONCLUSION: Urogenital schistosomiasis was hyperendemic in the Ajagba community, and hypoendemic in the Awosan community. The presence of Bulinus globosus supported the transmission of the schistosomiasis in the Ajagba community. Communities where schistosomiasis is still actively transmitted in Nigeria should be identified for effective intervention through the MDA programs.

Genome-wide insights into adaptive hybridisation across the Schistosoma haematobium group in West and Central Africa.

Schistosomiasis remains a public health concern across sub-Saharan Africa; current control programmes rely on accurate mapping and high mass drug administration (MDA) coverage to attempt disease elimination. Inter-species hybridisation can occur between certain species, changing epidemiological dynamics within endemic regions, which has the potential to confound control interventions. The impact of hybridisation on disease dynamics is well illustrated in areas of Cameroon where urogenital schistosomiasis, primarily due to Schistosoma haematobium and hybrid infections, now predominate over intestinal schistosomiasis caused by Schistosoma guineensis. Genetic markers have shown the ability to identify hybrids, however the underlying genomic architecture of divergence and introgression between these species has yet to be established. In this study, restriction site associated DNA sequencing (RADseq) was used on archived adult worms initially identified as; Schistosoma bovis (n = 4), S. haematobium (n = 9), S. guineensis (n = 3) and S. guineensis x S. haematobium hybrids (n = 4) from Mali, Senegal, Niger, São Tomé and Cameroon. Genome-wide evidence supports the existence of S. guineensis and S. haematobium hybrid populations across Cameroon. The hybridisation of S. guineensis x S. haematobium has not been demonstrated on the island of São Tomé, where all samples showed no introgression with S. haematobium. Additionally, all S. haematobium isolates from Nigeria, Mali and Cameroon indicated signatures of genomic introgression from S. bovis. Adaptive loci across the S. haematobium group showed that voltage-gated calcium ion channels (Cav) could play a key role in the ability to increase the survivability of species, particularly in host systems. Where admixture has occurred between S. guineensis and S. haematobium, the excess introgressive influx of tegumental (outer helminth body) and antigenic genes from S. haematobium has increased the adaptive response in hybrids, leading to increased hybrid population fitness and viability.

Effect of preventive chemotherapy with praziquantel on schistosomiasis among school-aged children in sub-Saharan Africa: a spatiotemporal modelling study.

BACKGROUND: Over the past 20 years, schistosomiasis control has been scaled up. Preventive chemotherapy with praziquantel is the main intervention. We aimed to assess the effect of preventive chemotherapy on schistosomiasis prevalence in sub-Saharan Africa, comparing 2000-10 with 2011-14 and 2015-19. METHODS: In this spatiotemporal modelling study, we analysed survey data from school-aged children (aged 5-14 years) in 44 countries across sub-Saharan Africa. The data were extracted from the Global Neglected Tropical Diseases database and augmented by 2018 and 2019 survey data obtained from disease control programmes. Bayesian geostatistical models were fitted to Schistosoma haematobium and Schistosoma mansoni survey data. The models included data on climatic predictors obtained from satellites and other open-source environmental databases and socioeconomic predictors obtained from various household surveys. Temporal changes in Schistosoma species prevalence were estimated by a categorical variable with values corresponding to the three time periods (2000-10, 2011-14, and 2015-19) during which preventive chemotherapy interventions were scaled up. FINDINGS: We identified 781 references with relevant geolocated schistosomiasis survey data for 2000-19. There were 19 166 unique survey locations for S haematobium and 23 861 for S mansoni, of which 77% (14 757 locations for S haematobium and 18 372 locations for S mansoni) corresponded to 2011-19. Schistosomiasis prevalence among school-aged children in sub-Saharan Africa decreased from 23·0% (95% Bayesian credible interval 22·1-24·1) in 2000-10 to 9·6% (9·1-10·2) in 2015-19, an overall reduction of 58·3%. The reduction of S haematobium was 67·9% (64·6-71·1) and that of S mansoni 53·6% (45·2-58·3) when comparing 2000-10 with 2015-19. INTERPRETATION: Our model-based estimates suggest that schistosomiasis prevalence in sub-Saharan Africa has decreased considerably, most likely explained by the scale-up of preventive chemotherapy. There is a need to consolidate gains in the control of schistosomiasis by means of preventive chemotherapy, coupled with other interventions to interrupt disease transmission. FUNDING: European Research Council and WHO.

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation.

Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold. Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC50 = 4.59 µM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC50 = 0.44 µM, 0.20 µM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum. Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.

Antischistosomal Activity of Origanum majorana, Ziziphus spina-christi, and Salvia fruticosa Plant Extracts on Hamster Infected with Schistosoma haematobium.

World Health Organization (WHO) has approved only one treatment for schistosomiasis, praziquantel (PZQ), but some poor efficacy was noticed in patients during the early stage of infection. Therefore, researchers have intensified their efforts to research new alternative medicines to treat schistosomiasis. In the present study, in vitro as well as in vivo studies have been accomplished to evaluate the effect of Origanum majorana, Ziziphus spina-christi, and Salvia fruticosa extracts in a different concentration 500, 250, 125, 62.5, and 31.25 µg/ml on golden hamster infected by Egyptian strains of schistosome (Schistosoma haematobium). In vitro, the adult worms and schistosomula of S. haematobium were investigated in RPMI-1640 medium for 48 hrs. The results showed that the concentration 500, 250, and 125 µg/ml of Origanum majorana, and Ziziphus spina-christi caused dead of 100% of Egyptian Schistosoma strains of adult worm and schistosomula of S. haematobium within 6 to 12 hrs of incubation. On the other hand, the extract of Salvia fruticosa at concentrations 500, 250, and 125 µg/ml showed death 100% parasites after 12 to 24 hrs of incubation. Inclusion, Origanum majorana, and Ziziphus spina-christi showed effectiveness against Egyptian Schistosoma strains (S. haematobium), a slight decrease in Salvia fruticosa was observed. Therefore, these medical plant extracts may be used as a safe and effective treatment for schistosomiasis.

Evidence for in vitro and in vivo activity of the antimalarial pyronaridine against Schistosoma.

BACKGROUND: Schistosomiasis is highly prevalent in Africa. Praziquantel is effective against adult schistosomes but leaves prepatent stages unaffected-which is a limit to patient management and elimination. Given the large-scale use of praziquantel, development of drug resistance by Schistosoma is feared. Antimalarials are promising drugs for alternative treatment strategies of Schistosoma infections. Development of drugs with activity against both malaria and schistosomiasis is particularly appealing as schistosome infections often occur concomitantly with malaria parasites in sub-Saharan Africa. Therefore, antiplasmodial compounds were progressively tested against Schistosoma in vitro, in mice, and in a clinical study. RESULTS: Amongst 16 drugs and 1 control tested, pyronaridine, methylene blue and 5 other antimalarials were highly active in vitro against larval stage schistosomula with a 50% inhibitory concentration below 10 µM. Both drugs were lethal to ex vivo adult worms tested at 30 µM with methylene blue also active at 10 µM. Pyronaridine treatment of mice infected with S. mansoni at the prepatent stage reduced worm burden by 82% and cured 7 out of 12 animals, however in mice adult stages remained viable. In contrast, methylene blue inhibited adult worms by 60% but cure was not achieved. In an observational pilot trial in Gabon in children, the antimalarial drug combination pyronaridine-artesunate (Pyramax) reduced S. haematobium egg excretion from 10/10 ml urine to 0/10 ml urine, and 3 out of 4 children were cured. CONCLUSION: Pyronaridine and methylene blue warrant further investigation as candidates for schistosomiasis treatment. Both compounds are approved for human use and evidence for their potential as antischistosomal compounds can be obtained directly from clinical testing. Particularly, pyronaridine-artesunate, already available as an antimalarial drug, calls for further clinical evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03201770.

Mapping Schistosoma haematobium for Novel Interventions against Female Genital Schistosomiasis and Associated HIV Risk in KwaZulu-Natal, South Africa.

Women with female genital schistosomiasis (FGS) have been found to have genital symptoms and a three-fold higher risk of HIV infection. Despite WHO recommendations, regular antischistosomal mass drug administration (MDA) has not yet been implemented in South Africa possibly because of the lack of updated epidemiological data. To provide data for future prevention efforts against FGS and HIV, this study explored Schistosoma haematobium prevalence in girls and young women and the effects of antischistosomal MDA, respectively. Urinary schistosomiasis and genital symptoms were investigated in 70 randomly selected secondary schools in three districts within KwaZulu-Natal and 18 primary schools. All study participants were treated for schistosomiasis, and schools with the highest urinary prevalence were followed up after 1 and 4 years of MDA. At baseline, urine analysis data showed that most schools were within the moderate-risk prevalence category where biennial antischistosomal MDA is recommended, as per WHO guidelines. Young women had high prevalence of genital symptoms (36%) after correcting for sexually transmitted infections. These symptoms may be caused by infection with schistosomes. However, FGS cannot be diagnosed by urine analysis alone. In KwaZulu-Natal rural schools, this study suggests that antischistosomal MDA with praziquantel could prevent genital symptoms in more than 200,000 young women. Furthermore, it is feasible that more than 5,000 HIV infections could be prevented in adolescent girls and young women by treatment and prevention of FGS.

Impact of seven years of mass drug administration and recrudescence of Schistosoma haematobium infections after one year of treatment gap in Zanzibar: Repeated cross-sectional studies.

BACKGROUND: Considerable progress towards the elimination of urogenital schistosomiasis was made by the Zanzibar Elimination of Schistosomiasis Transmission project from 2012 till 2016, when biannual praziquantel mass drug administration (MDA) alone or with additional snail control or behaviour change interventions were implemented. Annual MDA was continued in 2017 and 2018, but not in 2019, imposing a 16-month treatment gap. We monitored the Schistosoma haematobium prevalence from 2012 till 2020 and assessed recrudescence patterns with focus on 2020. METHODOLOGY: Repeated cross-sectional surveys were conducted from 2011/12 till 2020 in 90 communities and 90 schools in Zanzibar. Annually, around 4,500 adults and up to 20,000 schoolchildren were surveyed. The S. haematobium prevalence was detected by urine filtration and reagent strips. In 2020, risk factors for infection were investigated using generalized estimated equation models. PRINCIPAL FINDINGS: In adults, the apparent S. haematobium prevalence was 3.9% in 2011 and 0.4% in 2020. In schoolchildren, the prevalence decreased from 6.6% in 2012 to 1.2% in 2019 with vicissitudes over the years. Prominent recrudescence of infection from 2.8% in 2019 to 9.1% (+225%) in 2020 was observed in 29 schools with historically moderate prevalences (≥10%). Compared with 2019, reinfection in 2020 was particularly striking in boys aged 9-16 years. Being male was a risk factor for infection in 2020 (adults: odds ratio (OR): 6.24, 95% confidence interval (95% CI): 1.96-19.60; schoolchildren: OR: 2.06, 95% CI: 1.52-2.78). Living near to a natural freshwater body significantly increased the odds of infection in adults (OR: 2.90, CI: 1.12-7.54). CONCLUSIONS/SIGNIFICANCE: After 11 rounds of MDA over 7 years and a 16-month treatment gap, the urogenital schistosomiasis prevalence considerably rebounded in hotspot areas. Future elimination efforts in Zanzibar should focus on re-intensifying MDA plus additional interventions in hotspot areas. In low-prevalence areas, the strategy might be adapted from MDA to targeted surveillance-response.

Parasitological Observation in Schoolchildren with Urogenital Schistosomiasis Following Treatment with Three Different Brands of Praziquantel.

This study compared the anthelminthic effects of three different brands of praziquantel being used in Sudan against Schistosoma haematobium (S. haematobium) infection. We enrolled 1,286 schoolchildren from six primary schools and examined their urine samples for eggs of S. haematobium at the baseline survey and follow-up two weeks after administering the medication. The schoolchildren were divided into three groups based on the three brands of praziquantel (different material production), with two school children for one brand. The overall baseline prevalence of S. haematobium infection was 15.5%. Two weeks after treatment with brands A, B, and C of praziquantel, cure rates were 87.1%, 82.4% and 83.8% respectively, and the egg-reduction rates were 69.0%, 81.0% and 70.6% respectively. There was no statistically significant difference in cure rates and egg-reduction rates between the three brands. We conclude that the three different commercial brands of praziquantel used in Sudan have similar anthelminthic effects on S. haematobium.

Financial Costs of the Zanzibar Elimination of Schistosomiasis Transmission Project.

We estimated the financial costs of different interventions against urogenital schistosomiasis, implemented by the Zanzibar Elimination of Schistosomiasis Transmission (ZEST) project, on Pemba and Unguja islands, Tanzania. We used available data on project activities, resources used, and costs reported in the accounting information systems of ZEST partners. The costs were estimated for all the activities related to snail control, behavior change interventions, the impact assessment surveys, and management of the whole program. Costs are presented in US$ for the full duration of the ZEST project from 2011/2012 to 2017. The total financial costs of implementing snail control activities over 5 years, excluding the costs for donated Bayluscide, were US$55,796 on Pemba and US$73,581 on Unguja, mainly driven by personnel costs. The total financial costs of implementing behavior change activities were US$109,165 on Pemba and US$155,828 on Unguja, with costs for personnel accounting for 47% on Pemba and 69% on Unguja. Costs of implementing biannual mass drug administration refer to the estimated 2.4 million treatments provided on Pemba over 4 years (2013-2016), and do not include the costs of donated praziquantel. The total cost per provided treatment was, on average, US$0.21. This study showed the value of exploiting administrative data to estimate costs of major global health interventions. It also provides an evidence base for financial costs and main cost drivers of implementing multiple combinations of intervention sets that inform decisions regarding the feasibility and affordability of implementing schistosomiasis control and elimination strategies.

Characteristics of persistent hotspots of Schistosoma mansoni in western Côte d'Ivoire.

BACKGROUND: Preventive chemotherapy with praziquantel is the cornerstone of schistosomiasis control. However, in some social-ecological settings, the prevalence and/or intensity of Schistosoma infection does not lower meaningfully despite multiple rounds of preventive chemotherapy, a phenomenon termed persistent hotspot (PHS). We assessed the characteristics of PHS in a Schistosoma mansoni-endemic area of Côte d'Ivoire. METHODS: In October 2016, a cross-sectional survey was conducted in 14 schools in the western part of Côte d'Ivoire, one year after multiple rounds of preventive chemotherapy. In each school, 50 children aged 9-12 years provided two stool samples and one urine sample. Stool samples were subjected to triplicate Kato-Katz thick smears for S. mansoni diagnosis. Urine samples were examined by a filtration method for S. haematobium eggs. PHS was defined as failure to achieve a reduction in the prevalence of S. mansoni infection of at least 35% and/or a reduction of infection intensity of at least 50%. Six schools underwent more detailed investigations, including a questionnaire survey for demographic characteristics and a malacological survey. RESULTS: In the six schools subjected to detailed investigations, the overall prevalence of S. mansoni and S. haematobium was 9.5% and 2.6%, respectively. Four schools were classified as PHS. The S. mansoni prevalence in the four PHS was 10.9% compared to 6.6% in the remaining two schools. The S. mansoni infection intensity, expressed as arithmetic mean eggs per gram of stool (EPG) among infected children, was 123.8 EPG in PHS and 18.7 EPG in the other two schools. Children bathing in open freshwater bodies were at higher odds of S. mansoni infection (odds ratio: 4.5, 95% confidence interval: 1.6-12.6). A total of 76 human-water contact sites (53 in PHS and 23 in the other schools) were examined and 688 snails were collected, including potential intermediate host snails of Schistosoma (Biomphalaria pfeifferi, Bulinus forskalii, Bu. globosus and Bu. truncatus). CONCLUSION: Children in PHS schools bathed more frequently in open freshwater bodies, and hence, they are more exposed to Schistosoma transmission. Our findings call for an integrated control approach, complementing preventive chemotherapy with other interventions, particularly in PHS settings.

Challenges in Protocol Development and Interpretation of the Schistosomiasis Consortium for Operational Research and Evaluation Intervention Studies.

In 2010, the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) began the design of randomized controlled trials to compare different strategies for praziquantel mass drug administration, whether for gaining or sustaining control of schistosomiasis or for approaching local elimination of Schistosoma transmission. The goal of this operational research was to expand the evidence base for policy-making for regional and national control of schistosomiasis in sub-Saharan Africa. Over the 10-year period of its research programs, as SCORE operational research projects were implemented, their scope and scale posed important challenges in terms of research performance and the final interpretation of their results. The SCORE projects yielded valuable data on program-level effectiveness and strengths and weaknesses in performance, but in most of the trials, a greater-than-expected variation in community-level responses to assigned schedules of mass drug administration meant that identification of a dominant control strategy was not possible. This article critically reviews the impact of SCORE's cluster randomized study design on performance and interpretation of large-scale operational research such as ours.

SCORE Studies on the Impact of Drug Treatment on Morbidity due to Schistosoma mansoni and Schistosoma haematobium Infection.

The Schistosomiasis Consortium for Operational Research (SCORE) was funded in 2008 to improve the evidence base for control and elimination of schistosomiasis-better understanding of the systemic morbidities experienced by children in schistosomiasis-endemic areas and the response of these morbidities to treatment, being essential for updating WHO guidelines for mass drug administration (MDA) in endemic areas. This article summarizes the SCORE studies that aimed to gauge the impact of MDA-based treatment on schistosomiasis-related morbidities. Morbidity cohort studies were embedded in the SCORE's larger field studies of gaining control of schistosomiasis in Kenya and Tanzania. Following MDA, cohort children had less undernutrition, less portal vein dilation, and increased quality of life in Year 5 compared with baseline. We also conducted a pilot study of the Behavioral Assessment System for Children (BASC-2) in conjunction with the Kenya gaining control study, which demonstrated beneficial effects of treatment on classroom behavior. In addition, the SCORE's Rapid Answers Project performed systematic reviews of previously available data, providing two meta-analyses related to morbidity. The first documented children's infection-related deficits in school attendance and achievement and in formal tests of learning and memory. The second showed that greater reductions in egg output following drug treatment correlates significantly with reduced odds of most morbidities. Overall, these SCORE morbidity studies provided convincing evidence to support the use of MDA to improve the health of school-aged children in endemic areas. However, study findings also support the need to use enhanced metrics to fully assess and better control schistosomiasis-associated morbidity.

SCORE Operational Research on Moving toward Interruption of Schistosomiasis Transmission.

As part of its diverse portfolio, the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) included two cluster-randomized trials evaluating interventions that could potentially lead to interruption of schistosomiasis transmission (elimination) in areas of Africa with low prevalence and intensity of infection. These studies, conducted in Zanzibar and Côte d'Ivoire, demonstrated that multiyear mass drug administration (MDA) with praziquantel failed to interrupt the transmission of urogenital schistosomiasis, even when provided biannually and/or supplemented by small-scale implementation of additional interventions. Other SCORE activities related to elimination included a feasibility and acceptability assessment of test-treat-track-test-treat (T5) strategies and mathematical modeling. Future evaluations of interventions to eliminate schistosomiasis should recognize the difficulties inherent in conducting randomized controlled trials on elimination and in measuring small changes where baseline prevalence is low. Highly sensitive and specific diagnostic tests for use in very low-prevalence areas for schistosomiasis are not routinely available, which complicates accurate measurement of infection rates and assessment of changes resulting from interventions in these settings. Although not encountered in these two studies, as prevalence and intensity decrease, political and community commitment to population-wide MDA may decrease. Because of this potential problem, SCORE developed and funded the T5 strategy implemented in Egypt, Kenya, and Tanzania. It is likely that focal MDA campaigns, along with more targeted approaches, including a T5 strategy and snail control, will need to be supplemented with the provision of clean water and sanitation and behavior change communications to achieve interruption of schistosome transmission.

Impact of Different Mass Drug Administration Strategies for Gaining and Sustaining Control of Schistosoma mansoni and Schistosoma haematobium Infection in Africa.

This report summarizes the design and outcomes of randomized controlled operational research trials performed by the Bill & Melinda Gates Foundation-funded Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) from 2009 to 2019. Their goal was to define the effectiveness and test the limitations of current WHO-recommended schistosomiasis control protocols by performing large-scale pragmatic trials to compare the impact of different schedules and coverage regimens of praziquantel mass drug administration (MDA). Although there were limitations to study designs and performance, analysis of their primary outcomes confirmed that all tested regimens of praziquantel MDA significantly reduced local Schistosoma infection prevalence and intensity among school-age children. Secondary analysis suggested that outcomes in locations receiving four annual rounds of MDA were better than those in communities that had treatment holiday years, in which no praziquantel MDA was given. Statistical significance of differences was obscured by a wider-than-expected variation in community-level responses to MDA, defining a persistent hot spot obstacle to MDA success. No MDA schedule led to elimination of infection, even in those communities that started at low prevalence of infection, and it is likely that programs aiming for elimination of transmission will need to add supplemental interventions (e.g., snail control, improvement in water, sanitation and hygiene, and behavior change interventions) to achieve that next stage of control. Recommendations for future implementation research, including exploration of the value of earlier program impact assessment combined with intensification of intervention in hot spot locations, are discussed.

Application of Schistosomiasis Consortium for Operational Research and Evaluation Study Findings to Refine Predictive Modeling of Schistosoma mansoni and Schistosoma haematobium Control in Sub-Saharan Africa.

An essential mission of the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was to help inform global health practices related to the control and elimination of schistosomiasis. To provide more accurate, evidence-based projections of the most likely impact of different control interventions, whether implemented alone or in combination, SCORE supported mathematical modeling teams to provide simulations of community-level Schistosoma infection outcomes in the setting of real or hypothetical programs implementing multiyear mass drug administration (MDA) for parasite control. These models were calibrated using SCORE experience with Schistosoma mansoni and Schistosoma haematobium gaining and sustaining control studies, and with data from comparable programs that used community-based or school-based praziquantel MDA in other parts of sub-Saharan Africa. From 2010 to 2019, models were developed and refined, first to project the likely SCORE control outcomes, and later to more accurately reflect impact of MDA across different transmission settings, including the role of snail ecology and the impact of seasonal rainfall on snail abundance. Starting in 2014, SCORE modeling projections were also compared with the models of colleagues in the Neglected Tropical Diseases Modelling Consortium. To explore further possible improvement to program-based control, later simulations examined the cost-effectiveness of combining MDA with environmental snail control, and the utility of early impact assessment to more quickly identify persistent hot spots of transmission. This article provides a nontechnical summary of the 11 SCORE-related modeling projects and provides links to the original open-access articles describing model development and projections relevant to schistosomiasis control policy.

Parasite Population Genetic Contributions to the Schistosomiasis Consortium for Operational Research and Evaluation within Sub-Saharan Africa.

Analyses of the population genetic structure of schistosomes under the "Schistosomiasis Consortium for Operational Research and Evaluation" (SCORE) contrasting treatment pressure scenarios in Tanzania, Niger, and Zanzibar were performed to provide supplementary critical information with which to evaluate the impact of these large-scale control activities and guide how activities could be adjusted. We predicted that population genetic analyses would reveal information on a range of important parameters including, but not exclusive to, recruitment and transmission of genotypes, occurrence of hybridization events, differences in reproductive mode, and degrees of inbreeding, and hence, the evolutionary potential, and responses of parasite populations under contrasting treatment pressures. Key findings revealed that naturally high levels of gene flow and mixing of the parasite populations between neighboring sites were likely to dilute any effects imposed by the SCORE treatment arms. Furthermore, significant inherent differences in parasite fecundity were observed, independent of current treatment arm, but potentially of major impact in terms of maintaining high levels of ongoing transmission in persistent "biological hotspot" sites. Within Niger, naturally occurring Schistosoma haematobium/Schistosoma bovis viable hybrids were found to be abundant, often occurring in significantly higher proportions than that of single-species S. haematobium infections. By examining parasite population genetic structures across hosts, treatment regimens, and the spatial landscape, our results to date illustrate key transmission processes over and above that which could be achieved through standard parasitological monitoring of prevalence and intensity alone, as well as adding to our understanding of Schistosoma spp. life history strategies in general.