Pathological and immunological evaluation of different regimens of praziquantel treatment in a mouse model of Schistosoma mansoni infection

BackgroundOne of the considerable challenges of schistosomiasis chemotherapy is the inefficacy of praziquantel (PZQ) at the initial phase of the infection. Immature schistosomes are not susceptible to PZQ at the curative dose. Here, we investigated the efficacy of different PZQ regimens administered during the initial stage of Schistosoma mansoni infection in mice.Methodology/Principal findingsTwo months-old mice were individually infected with 80 S. mansoni cercariae and divided into one infected-untreated control group (IC) and four PZQ-treated groups: PZQ at 100 mg/kg/day for five consecutive days (group PZQ1), PZQ at 100 mg/kg/day for 28 days (group PZQ2), PZQ at 18 mg/kg/day for 28 days (group PZQ3) and a single dose of PZQ at 500 mg/kg (group PZQ4). The treatment started on day one post-infection (p.i), and each group of mice was divided into two subgroups euthanized on day 36 or 56 p.i, respectively. We determined the mortality rate, the parasitological burden, the hepatic and intestinal granulomas, the serum levels of Th-1, Th-2, and Th-17 cytokines, and gene expression. The treatment led to a significant (p < 0.001) reduction of worm burden and egg counts in the intestine and liver in groups PZQ2 and PZQ3. On 56^th day p.i, there was a significant reduction (p < 0.001) of the number and volume of the hepatic granulomas in groups PZQ2 and PZQ3 compared to group PZQ1 or PZQ4. Moreover, in group PZQ3, the serum levels of IFN-γ, TNF-α, IL-13, and IL-17 and their liver mRNA expressions were significantly reduced while IL-10 and TGF-β gene expression significantly increased. The highest mortality rate (81.25%) was recorded in group PZQ2.Conclusion/SignificanceThis study revealed that the administration of PZQ at 18 mg/kg/day for 28 consecutive days was the optimal effective posology for treating S. mansoni infection at the initial stage in a murine model.     

In Vivo Imaging of Schistosomes to Assess Disease Burden Using Positron Emission Tomography (PET)

Background

Schistosomes are chronic intravascular helminth parasites of humans causing a heavy burden of disease worldwide. Diagnosis of schistosomiasis currently requires the detection of schistosome eggs in the feces and urine of infected individuals. This method unreliably measures disease burden due to poor sensitivity and wide variances in egg shedding. In vivo imaging of schistosome parasites could potentially better assess disease burden, improve management of schistosomiasis, facilitate vaccine development, and enhance study of the parasite''s biology. Schistosoma mansoni (S. mansoni) have a high metabolic demand for glucose. In this work we investigated whether the parasite burden in mice could be assessed by positron emission tomography (PET) imaging with 2-deoxy-2[¹⁸F]fluoro-D-glucose (FDG).

Methodology/Principal Findings

Live adult S. mansoni worms FDG uptake in vitro increased with the number of worms. Athymic nude mice infected with S. mansoni 5–6 weeks earlier were used in the imaging studies. Fluorescence molecular tomography (FMT) imaging with Prosense 680 was first performed. Accumulation of the imaging probe in the lower abdomen correlated with the number of worms in mice with low infection burden. The total FDG uptake in the common portal vein and/or regions of elevated FDG uptake in the liver linearly correlated to the number of worms recovered from infected animals (R² = 0.58, P<0.001, n = 40). FDG uptake showed a stronger correlation with the worm burden in mice with more than 50 worms (R² = 0.85, P<0.001, n = 17). Cryomicrotome imaging confirmed that most of the worms in a mouse with a high infection burden were in the portal vein, but not in a mouse with a low infection burden. FDG uptake in recovered worms measured by well counting closely correlated with worm number (R² = 0.85, P<0.001, n = 21). Infected mice showed a 32% average decrease in total FDG uptake after three days of praziquantel treatment (P = 0.12). The total FDG uptake in untreated mice increased on average by 36% over the same period (P = 0.052).

Conclusion

FDG PET may be useful to non-invasively quantify the worm burden in schistosomiasis-infected animals. Future investigations aiming at minimizing non-specific FDG uptake and to improve the recovery of signal from worms located in the lower abdomen will include the development of more specific radiotracers.     

High prevalence of Schistosoma mansoni infection and stunting among school age children in communities along the Albert-Nile,Northern Uganda: A cross sectional study

BackgroundKnowing the prevalence of schistosomiasis is key to informing programmes to control and eliminate the disease as a public health problem. It is also important to understand the impact of infection on child growth and development in order to allocate appropriate resources and effort to the control of the disease.MethodsWe conducted a survey to estimate the prevalence of schistosomiasis among school aged children in villages along the Albert-Nile shore line in the district of Pakwach, North Western Uganda. A total of 914 children aged between 10–15 years were screened for Schistosoma mansoni using the POC-CCA and Kato Katz (KK) techniques. The infection intensities were assessed by POC-CCA and KK as well as CAA tests. The KK intensities were also correlated with POC-CCA and with CAA intensity. Anthropometric measurements were also taken and multivariate analysis was carried out to investigate their association with infection status.ResultsThe prevalence of schistosomiasis using the POC-CCA diagnostic test was estimated at 85% (95% CI: 83–87), being highest amongst children living closer to the Albert-Nile shoreline. Visual scoring of the POC-CCA results was more sensitive than the Kato Katz test and was positively correlated with the quantified infection intensities by the CAA test. The majority of the children were underweight (BMI<18.5), and most notably, boys had significantly lower height for age (stunting) than girls in the same age range (p < 0.0001), but this was not directly associated with S. mansoni infection.ConclusionHigh prevalence of S. mansoni infection in the region calls for more frequent mass drug administration with praziquantel. We observed high levels of stunting which was not associated with schistosomiasis. There is a need for improved nutrition among the children in the area.     

Mefloquine—An Aminoalcohol with Promising Antischistosomal Properties in Mice

Background

The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the antimalarial drug mefloquine possesses promising antischistosomal properties in mice.

Methodology/Principal Findings

A single dose of mefloquine (200 or 400 mg/kg) administered orally to mice infected with adult Schistosoma mansoni or adult S. japonicum resulted in high or complete total and female worm burden reductions (72.3%–100%). Importantly, high worm burden reductions were also observed for young developing stages of S. mansoni and S. japonicum harbored in the mouse. Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection.

Conclusions/Significance

Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality. Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes. It will be interesting to investigate whether mefloquine, which is widely and effectively used for the treatment of malaria, has an impact on schistosomiasis in areas where both malaria and schistosomiasis co-exist.     

Insights into the mode of action of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89) against adult Schistosoma mansoni worms

Control of morbidity associated with schistosomiasis via chemotherapy largely relies on the drug praziquantel. Repeated therapy with praziquantel has created concerns about the possible selection of resistant worms and necessitated the search for novel drugs to treat schistosomiasis. Here, a murine model was infected with Schistosoma mansoni and treated with oral 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89), which caused a significant reduction in fecundity and egg burden and reduced morbidity when administered at 5-weeks post-infection.The analysis showed that the mode of action occurred through the ingestion of activated N-89 by the worms, and that there was no direct external effect on the S. mansoni worms. Ultrastructural analysis of the treated worms showed disruptions in the gut lumen and the presence of large volumes of material, suggestive of undigested blood meals or red blood cells. In addition, there were reduced vitelline cells in female worms and damage to sub-tegmental musculature in male worms. Eggs recovered from the treated mice showed both damage to the eggs and the production of immature eggs. Expression of mRNA responsible for gut and digestive function and egg production was also significantly affected by N-89 treatment, whereas control genes for musculature showed no significant changes.Thus, N-89 drastically affected the total digestive function and egg production of S. mansoni worms. Physiological processes requiring heme uptake such as egg production and eggshell formation were subsequently affected, suggesting that the compound could be a possible therapeutic drug candidate for schistosomiasis control.     

Ginger (Zingiber Officinale)-derived nanoparticles in Schistosoma mansoni infected mice: Hepatoprotective and enhancer of etiological treatment

BackgroundNanotechnology has been manufactured from medicinal plants to develop safe, and effective antischistosmal alternatives to replace today’s therapies. The aim of the study is to evaluate the prophylactic effect of ginger-derived nanoparticles (GNPs), and the therapeutic effect of ginger aqueous extract, and GNPs on Schistosoma mansoni (S. mansoni) infected mice compared to praziquantel (PZQ), and mefloquine (MFQ).Methodology/principal findingsEighty four mice, divided into nine different groups, were sacrificed at 6^th, 8^th, and 10^th week post-infection (PI), with assessment of parasitological, histopathological, and oxidative stress parameters, and scanning the worms by electron microscope. As a prophylactic drug, GNPs showed slight reduction in worm burden, egg density, and granuloma size and number. As a therapeutic drug, GNPs significantly reduced worm burden (59.9%), tissue egg load (64.9%), granuloma size, and number at 10^th week PI, and altered adult worm tegumental architecture, added to antioxidant effect. Interestingly, combination of GNPs with PZQ or MFQ gave almost similar or sometimes better curative effects as obtained with each drug separately. The highest therapeutic effect was obtained when ½ dose GNPs combined with ½ dose MFQ which achieved 100% reduction in both the total worm burden, and ova tissue density as early as the 6^th week PI, with absence of detected eggs or tissue granuloma, and preservation of liver architecture.Conclusions/significanceGNPs have a schistosomicidal, antioxidant, and hepatoprotective role. GNPs have a strong synergistic effect when combined with etiological treatments (PZQ or MFQ), and significantly reduced therapeutic doses by 50%, which may mitigate side effects and resistance to etiological drugs, a hypothesis requiring further research. We recommend extending this study to humans.     

Ameliorative effects of Schisandrin B on Schistosoma mansoni-induced hepatic fibrosis in vivo

Schistosomiasis is second only to malaria as the most devastating parasitic disease in the world. It is caused by the helminths Schistosoma mansoni (S. mansoni), S. haematobium, or S. japonicum. Typically, patients with schistosomiasis suffer from symptoms of liver fibrosis and hepatosplenomegaly. Currently, patients were treated with praziquantel. Although praziquantel effectively kills the worm, it cannot prevent re-infection or resolve liver fibrosis. Also, current treatment options are not ample to completely cure liver fibrosis and splenic damages. Moreover, resistance of praziquantel has been reported in vivo and in vitro studies. Therefore, finding new effective treatment agents is urgently needed. Schisandrin B (Sch B) of Schisandra chinensis has been shown to protect against different liver injuries including fatty liver disease, hepatotoxicity, fibrosis, and hepatoma. We herein investigate the potential of using Sch B to treat S. mansoni-induced liver fibrosis. Results from the present study demonstrate that Sch B is beneficial in treating S. mansoni-induced liver fibrosis and splenic damages, through inhibition of inflammasome activation and apoptosis; and aside from that regulates host immune responses. Besides, Sch B treatment damages male adult worm in the mice, consequently helps to reduce egg production and lessen the parasite burden.     

New Insights into the Molecular Epidemiology and Population Genetics of Schistosoma mansoni in Ugandan Pre-school Children and Mothers

Significant numbers of pre-school children are infected with Schistosoma mansoni in sub-Saharan Africa and are likely to play a role in parasite transmission. However, they are currently excluded from control programmes. Molecular phylogenetic studies have provided insights into the evolutionary origins and transmission dynamics of S. mansoni, but there has been no research into schistosome molecular epidemiology in pre-school children. Here, we investigated the genetic diversity and population structure of S. mansoni in pre-school children and mothers living in lakeshore communities in Uganda and monitored for changes over time after praziquantel treatment. Parasites were sampled from children (<6 years) and mothers enrolled in the longitudinal Schistosomiasis Mothers and Infants Study at baseline and at 6-, 12- and 18-month follow-up surveys. 1347 parasites from 35 mothers and 45 children were genotyped by direct sequencing of the cytochrome c oxidase (cox1) gene. The cox1 region was highly diverse with over 230 unique sequences identified. Parasite populations were genetically differentiated between lakes and non-synonymous mutations were more diverse at Lake Victoria than Lake Albert. Surprisingly, parasite populations sampled from children showed a similar genetic diversity to those sampled from mothers, pointing towards a non-linear relationship between duration of exposure and accumulation of parasite diversity. The genetic diversity six months after praziquantel treatment was similar to pre-treatment diversity. Our results confirm the substantial genetic diversity of S. mansoni in East Africa and provide significant insights into transmission dynamics within young children and mothers, important information for schistosomiasis control programmes.     

Schistosoma mansoni: Effect of dietary zinc supplement on egg granuloma in Swiss mice treated with praziqantel

Schistosomiasis is one of the most important parasitic diseases in Egypt and chemotherapy is considered the most effective method of control. This study was conducted to assess the effectiveness of zinc administration against Schistosoma mansoni infection by evaluating the activities of arylesterase and paraoxonase (PON1) enzymes, and the degree of liver damage.One hundred and twenty albino mice were divided into two groups; one was an infected control and the other a treated group which was further subdivided into three according to the praziquantel and zinc supplementation given. Blood and liver samples, collected 10 weeks post-infection, were subjected to parasitological, histopathological, and enzyme assays, and immunological studies. The results showed that dietary zinc supplementation led to marked reduction in worm load, and egg deposition in the liver and intestine.Histopathological examination showed marked reduction in the number and diameter of hepatic granulomas in the treated groups. The activity of arylesterase and PON1 enzymes were partially restored in infected animals receiving zinc. IL-10 mRNA expression was higher in the treated groups than in the infection control group. In conclusion, zinc administration could be a promising adjuvant therapy for S. mansoni infection.     

Effectiveness of school-based preventive chemotherapy strategies for sustaining the control of schistosomiasis in Côte d’Ivoire: Results of a 5-year cluster randomized trial

BackgroundPreventive chemotherapy using praziquantel is the mainstay for schistosomiasis control. However, there is little evidence on what is supposed to be the most effective school-based treatment strategy to sustain morbidity control. The aim of this study was to compare differences in Schistosoma mansoni prevalence and infection intensity between three different schedules of school-based preventive chemotherapy in an area with moderate prevalence of S. mansoni in Côte d’Ivoire.MethodologySeventy-five schools were randomly assigned to one of three intervention arms: (i) annual school-based preventive chemotherapy with praziquantel (40 mg/kg) over four years; (ii) praziquantel treatment only in the first two years, followed by two years whithout treatment; and (iii) praziquantel treatment in years 1 and 3 without treatment in-between. Cross-sectional parasitologic surveys were carried out prior to each round of preventive chemotherapy. The difference in S. mansoni prevalence and infection intensity was assessed by multiple Kato-Katz thick smears, among children aged 9–12 years at the time of each survey. First-grade children, aged 5–8 years who had never received praziquantel, were also tested at baseline and at the end of the study.Principal findingsOverall, 7,410 children aged 9–12 years were examined at baseline and 7,223 at the final survey. The baseline prevalence of S. mansoni was 17.4%, 20.2%, and 25.2% in arms 1, 2, and 3, respectively. In the final year, we observed the lowest prevalence of 10.4% in arm 1, compared to 18.2% in arm 2 and 17.5% in arm 3. The comparison between arms 1 and 2 estimated an odds ratio (OR) of 0.52 but the difference was not statistically significant (95% confidence interval (CI) = 0.23–1.16). Likewise the difference between arms 1 and 3 lacked statistical significance (OR = 0.55, 95% CI = 0.23–1.29). There was no noteworthy difference observed between arms 2 and 3 (OR = 1.06, 95% CI = 0.64–1.75). The lowest S. mansoni fecal egg counts in the final year survey were observed in arm 1 (7.9 eggs per gram of stool (EPG)). However, compared with 11.5 EPG in arm 2 and 15.4 EPG in arm 3, the difference lacked statistical significance. There were 4,812 first-grade children examined at baseline and 4,513 in the final survey. The overall prevalence of S. mansoni in these children slightly decreased in arms 1 (from 4.5% to 3.6%) and 2 (from 4.7% to 4.3%), but increased in arm 3 (from 6.8% to 7.9%). However, there was no significant difference in prevalence and infection intensity observed between study arms.Conclusions/significanceThe three treatment schedules investigated led to a reduction in the prevalence and intensity of S. mansoni infection among children aged 9–12 years. Comparing intervention arms at the end of the study, no statistically significant differences were observed between annual treatement and the other two treatment schedules, neither in reduction of prevalence nor intensity of infection. It is important to combine our results with those of three sister trials conducted simultaneously in other African countries, before final recommendations can be drawn.     

Protective and Anti-Pathology Effects of Sm Fructose-1,6-Bisphosphate Aldolase-Based DNA Vaccine against Schistosoma mansoni by Changing Route of Injection

This study aimed to evaluate the efficacy of fructose-1,6-bis phosphate aldolase (SMALDO) DNA vaccination against Schistosoma mansoni infection using different routes of injection. The SMALDO has been cloned into the eukaryotic expression vector pcDNA3.1/V5-His TOPO-TA and was used in injecting Swiss albino mice intramuscularly (IM), subcutaneously (SC), or intraperitoneally (IP) (50 µg/mouse). Mice vaccinated with non-recombinant pcDNA3.1 served as controls. Each group was immunized 4 times at weeks 0, 2, 4, and 6. Two weeks after the last booster dose, all mice groups were infected with 80 S. mansoni cercariae via tail immersion. At week 8 post-infection, animals were sacrificed for assessment of parasitological and histopathological parameters. High anti-SMALDO IgG antibody titers were detected in sera of all vaccinated groups (P<0.01) compared to the control group. Both the IP and SC vaccination routes resulted in a significant reduction in worm burden (46.2% and 28.9%, respectively, P<0.01). This was accompanied by a significant reduction in hepatic and intestinal egg counts (41.7% and 40.2%, respectively, P<0.01) in the IP group only. The number of dead eggs was significantly increased in both IP and IM groups (P<0.01). IP vaccination recorded the highest significant reduction in granuloma number and diameter (54.7% and 29.2%, respectively, P<0.01) and significant increase in dead miracidia (P<0.01). In conclusion, changing the injection route of SMALDO DNA vaccination significantly influenced the efficacy of vaccination. SMALDO DNA vaccination via IP route could be a promising protective and anti-pathology vaccine candidate against S. mansoni infection.     

Prevalence and risk factors of schistosomiasis among primary school children in four selected regions of The Gambia

BackgroundThe 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.MethodsWe 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.Principal findingsUrinary 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.ConclusionThe 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.     

Prevalence and Associated Factors of Schistosomiasis among Children in Yemen: Implications for an Effective Control Programme

Background

Schistosomiasis, one of the most prevalent neglected tropical diseases, is a life-threatening public health problem in Yemen especially in rural communities. This cross-sectional study aims to determine the prevalence and associated risk factors of schistosomiasis among children in rural Yemen.

Methods/Findings

Urine and faecal samples were collected from 400 children. Urine samples were examined using filtration technique for the presence of Schistosoma haematobium eggs while faecal samples were examined using formalin-ether concentration and Kato Katz techniques for the presence of S. mansoni. Demographic, socioeconomic and environmental information were collected via a validated questionnaire. Overall, 31.8% of the participants were found to be positive for schistosomiasis; 23.8% were infected with S. haematobium and 9.3% were infected with S. mansoni. Moreover, 39.5% of the participants were anaemic whereas 9.5% had hepatosplenomegaly. The prevalence of schistosomiasis was significantly higher among children aged >10 years compared to those aged ≤10 years (P<0.05). Multivariate analysis confirmed that presence of other infected family member (P<0.001), low household monthly income (P = 0.003), using unsafe sources for drinking water (P = 0.003), living nearby stream/spring (P = 0.006) and living nearby pool/pond (P = 0.002) were the key factors significantly associated with schistosomiasis among these children.

Conclusions/Significance

This study reveals that schistosomiasis is still highly prevalent in Yemen. These findings support an urgent need to start an integrated, targeted and effective schistosomiasis control programme with a mission to move towards the elimination phase. Besides periodic drug distribution, health education and community mobilisation, provision of clean and safe drinking water, introduction of proper sanitation are imperative among these communities in order to curtail the transmission and morbidity caused by schistosomiasis. Screening and treating other infected family members should also be adopted by the public health authorities in combating this infection in these communities.     

Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages

BackgroundThe association of anaemia with intestinal schistosomiasis and hookworm infections are poorly explored in populations that are not limited to children or pregnant women.MethodsWe sampled 1,832 individuals aged 5–90 years from 30 communities in Mayuge District, Uganda. Demographic, village, and parasitological data were collected. Infection risk factors were compared in ordinal logistic regressions. Anaemia and infection intensities were analyzed in multilevel models, and population attributable fractions were estimated.FindingsHousehold and village-level predictors of Schistosoma mansoni and hookworm were opposite in direction or significant for single infections. S. mansoni was found primarily in children, whereas hookworm was prevalent amongst the elderly. Anaemia was more prevalent in individuals with S. mansoni and increased by 2.86 fold (p-value<0.001) with heavy S. mansoni infection intensity. Individuals with heavy hookworm were 1.65 times (p-value = 0.008) more likely to have anaemia than uninfected participants. Amongst individuals with heavy S. mansoni infection intensity, 32.0% (p-value<0.001) of anaemia could be attributed to S. mansoni. For people with heavy hookworm infections, 23.7% (p-value = 0.002) of anaemia could be attributed to hookworm. A greater fraction of anaemia (24.9%, p-value = 0.002) was attributable to heavy hookworm infections in adults (excluding pregnant women) as opposed to heavy hookworm infections in school-aged children and pregnant women (20.2%, p-value = 0.001).ConclusionCommunity-based surveys captured anaemia in children and adults affected by S. mansoni and hookworm infections. For areas endemic with schistosomiasis or hookworm infections, WHO guidelines should include adults for treatment in helminth control programmes.     

Schistosomiasis messaging in endemic communities: Lessons and implications for interventions from rural Uganda,a rapid ethnographic assessment study

BackgroundOver 240 million people are infected with schistosomiasis, the majority in sub-Saharan Africa. In Uganda, high infection rates exist in communities on the shores of Lake Victoria. Praziquantel mass drug administration (MDA) delivered by village health teams is the mainstay of schistosomiasis control. However, treatment uptake remains suboptimal, with many people unaware of treatment or thinking it is only for children. Furthermore, people are often rapidly reinfected post-treatment due to continued exposure. In three Schistosoma mansoni high endemicity lake-shore communities in Mayuge district, Eastern Uganda, we investigated the sources of schistosomiasis information, remembered content of information, and the perception of information and related practices towards the control of schistosomiasis.Methods and principal findingsData were collected from September 2017 to March 2018 using a rapid ethnographic assessment that included transect walks, observations, individual in-depth interviews and focus group discussions. Data were analysed thematically using iterative categorisation. We found that the main sources of schistosomiasis information included health workers at government facilities, village health teams, teachers, and radio programmes produced by the Ministry of Health. These messages described the symptoms of schistosomiasis, but did not mention the side effects of praziquantel treatment. Despite this messaging, the main cause of the disease and transmission was unclear to most participants. The translation of schistosomiasis on the radio into the local language ‘ekidada’—meaning swollen stomach—increased, rather than reduced, confusion about the cause(s) of schistosomiasis, due to believed links between ekidada and witchcraft, and prompted a reluctance to engage with treatment or preventative efforts.Conclusion and significanceThis study highlights gaps in schistosomiasis messaging. We recommend MDA is complemented by effective, evidence-based messaging on schistosomiasis transmission, prevention, and treatment, that is sensitive to local language and context issues, resulting in clear, concise, and consistent messages, to increase effectiveness.     

Impact of Schistosoma mansoni on Malaria Transmission in Sub-Saharan Africa

Background

Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children.

Methodology

We developed a co-epidemic model of malaria and S. mansoni transmission dynamics which takes into account key epidemiological interaction between the two diseases in terms of elevated malaria incidence among individuals with S. mansoni high egg output. The model was parameterized for S. mansoni high-risk endemic communities, using epidemiological and clinical data of the interaction between S. mansoni and malaria among children in sub-Saharan Africa. We evaluated the potential impact of the S. mansoni–malaria interaction and mass treatment of schistosomiasis on malaria prevalence in co-endemic communities.

Principal Findings

Our results suggest that in the absence of mass drug administration of praziquantel, the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission, in S. mansoni high-risk endemic communities. However, when malaria treatment is used in combination with praziquantel, mass praziquantel administration may increase the effectiveness of malaria control intervention strategy for reducing malaria prevalence in malaria- S. mansoni co-endemic communities.

Conclusions/Significance

Schistosomiasis treatment and control programmes in regions where S. mansoni and malaria are highly prevalent may have indirect benefits on reducing malaria transmission as a result of disease interactions. In particular, mass praziquantel administration may not only have the direct benefit of reducing schistosomiasis infection, it may also reduce malaria transmission and disease burden.     

The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species

Treatment and control of schistosomiasis depends on a single drug, praziquantel, but this is not ideal for several reasons including lack of potency against the juvenile stage of the parasite, dose size, and risk of resistance. We have optimised the properties of a series of compounds we discovered through high throughput screening and have designed candidates for clinical development. The best compounds demonstrate clearance of both juvenile and adult S. mansoni worms in a mouse model of infection from a single oral dose of < 10 mg/kg. Several compounds in the series are predicted to treat schistosomiasis in humans across a range of species with a single oral dose of less than 5 mg/kg.     

Sustaining Control of Schistosomiasis Mansoni in Western C?te d’Ivoire: Results from a SCORE Study,One Year after Initial Praziquantel Administration

Background

The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) has launched several large-scale trials to determine the best strategies for gaining and sustaining control of schistosomiasis and transitioning toward elimination. In Côte d’Ivoire, a 5-year cluster-randomized trial is being implemented in 75 schools to sustain the control of schistosomiasis mansoni. We report Schistosoma mansoni infection levels in children one year after the initial school-based treatment (SBT) with praziquantel and compare with baseline results to determine the effect of the intervention.

Methodology

The baseline cross-sectional survey was conducted in late 2011/early 2012 and the first follow-up in May 2013. Three consecutive stool samples were collected from 9- to 12-year-old children in 75 schools at baseline and 50 schools at follow-up. Stool samples were subjected to duplicate Kato-Katz thick smears. Directly observed treatment (DOT) coverage of the SBT was assessed and the prevalence and intensity of S. mansoni infection compared between baseline and follow-up.

Principal Findings

The S. mansoni prevalence in the 75 schools surveyed at baseline was 22.1% (95% confidence interval (CI): 19.5–24.4%). The DOT coverage was 84.2%. In the 50 schools surveyed at baseline and one year after treatment, the overall prevalence of S. mansoni infection decreased significantly from 19.7% (95% CI: 18.5–20.8%) to 12.8% (95% CI: 11.9–13.8%), while the arithmetic mean S. mansoni eggs per gram of stool (EPG) among infected children slightly increased from 92.2 EPG (95% CI: 79.2–105.3 EPG) to 109.3 EPG (95% CI: 82.7–135.9 EPG). In two of the 50 schools, the prevalence increased significantly, despite a DOT coverage of >75%.

Conclusions/Significance

One year after the initial SBT, the S. mansoni prevalence had decreased. Despite this positive trend, an increase was observed in some schools. Moreover, the infection intensity among S. mansoni-infected children was slightly higher at the 1-year follow-up compared to the baseline situation. Our results emphasize the heterogeneity of transmission dynamics and provide a benchmark for the future yearly follow-up surveys of this multi-year SCORE intervention study.     

Cysteine Peptidases as Schistosomiasis Vaccines with Inbuilt Adjuvanticity

Schistosomiasis is caused by several worm species of the genus Schistosoma and afflicts up to 600 million people in 74 tropical and sub-tropical countries in the developing world. Present disease control depends on treatment with the only available drug praziquantel. No vaccine exists despite the intense search for molecular candidates and adjuvant formulations over the last three decades. Cysteine peptidases such as papain and Der p 1 are well known environmental allergens that sensitize the immune system driving potent Th2-responses. Recently, we showed that the administration of active papain to mice induced significant protection (P<0.02, 50%) against an experimental challenge infection with Schistosoma mansoni. Since schistosomes express and secrete papain-like cysteine peptidases we reasoned that these could be employed as vaccines with inbuilt adjuvanticity to protect against these parasites. Here we demonstrate that sub-cutaneous injection of functionally active S. mansoni cathepsin B1 (SmCB1), or a cathepsin L from a related parasite Fasciola hepatica (FhCL1), elicits highly significant (P<0.0001) protection (up to 73%) against an experimental challenge worm infection. Protection and reduction in worm egg burden were further increased (up to 83%) when the cysteine peptidases were combined with other S. mansoni vaccine candidates, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH) and peroxiredoxin (PRX-MAP), without the need to add chemical adjuvants. These studies demonstrate the capacity of helminth cysteine peptidases to behave simultaneously as immunogens and adjuvants, and offer an innovative approach towards developing schistosomiasis vaccines     

Schistosoma mansoni infection induces plasmablast and plasma cell death in the bone marrow and accelerates the decline of host vaccine responses

Schistosomiasis is a potentially lethal parasitic disease that profoundly impacts systemic immune function in chronically infected hosts through mechanisms that remain unknown. Given the immunoregulatory dysregulation experienced in infected individuals, this study examined the impact of chronic schistosomiasis on the sustainability of vaccine-induced immunity in both children living in endemic areas and experimental infections in mice. Data show that chronic Schistosoma mansoni infection impaired the persistence of vaccine specific antibody responses in poliovirus-vaccinated humans and mice. Mechanistically, schistosomiasis primarily fostered plasmablast and plasma cell death in the bone marrow and removal of parasites following praziquantel treatment reversed the observed cell death and partially restored vaccine-induced memory responses associated with increased serum anti-polio antibody responses. Our findings strongly suggest a previously unrecognized mechanism to explain how chronic schistosomiasis interferes with an otherwise effective vaccine regimen and further advocates for therapeutic intervention strategies that reduce schistosomiasis burden in endemic areas prior to vaccination.