BackgroundLarge scale administration of the anthelminthic drug praziquantel (PZQ) to at-risk populations is the cornerstone of schistosomiasis control, although persisting high prevalence of... Show moreBackgroundLarge scale administration of the anthelminthic drug praziquantel (PZQ) to at-risk populations is the cornerstone of schistosomiasis control, although persisting high prevalence of infections in some areas and growing concerns of PZQ resistance have revealed the limitations of this strategy. Most studies assessing PZQ efficacy have used relatively insensitive parasitological diagnostics, such as the Kato-Katz (KK) and urine-filtration methods, thereby overestimating cure rates (CRs). This study aims to determine the efficacy of repeated PZQ treatments against Schistosoma mansoni infection in school-aged children in Cote d'Ivoire using the traditional KK technique, as well as more sensitive antigen- and DNA-detection methods.MethodsAn open-label, randomised controlled trial will be conducted in school-aged children (5 to 18years) from the region of Taabo, Cote d'Ivoire, an area endemic for S. mansoni. This 8-week trial includes four two-weekly standard doses of PZQ in the intense treatment intervention group and one standard dose of PZQ in the standard treatment control group. The efficacy of PZQ will be evaluated in stool samples using the KK technique and real-time PCR as well as in urine using the point-of-care circulating cathodic antigen test and the up-converting phosphor, lateral flow, circulating anodic antigen assay. The primary outcome of the study will be the difference in CR of intense versus standard treatment with PZQ on individuals with a confirmed S. mansoni infection measured by KK. Secondary outcomes include the difference in CR and intensity reduction rate between the intense and standard treatment groups as measured by the other diagnostic tests, as well as the accuracy of the different diagnostic tests, and the safety of PZQ.DiscussionThis study will provide data on the efficacy of repeated PZQ treatment on the clearance of S. mansoni as measured by several diagnostic techniques. These findings will inform future mass drug administration policy and shed light on position of novel diagnostic tools to evaluate schistosomiasis control strategies.Trial registrationThe study is registered at EudraCT (2016-003017-10, date of registration: 22 July 2016) and (NCT02868385, date of registration: 16 August 2016). Show less
Hoekstra, P.T.; Partal, M.C.; Amoah, A.S.; Lieshout, L. van; Corstjens, P.L.A.M.; Tsonaka, S.; ... ; Dam, G.J. van 2018
Sm-p80-based vaccine efficacy for Schistosoma mansoni was evaluated in a baboon model of infection and disease. The study was designed to replicate a human vaccine implementation scenario for... Show moreSm-p80-based vaccine efficacy for Schistosoma mansoni was evaluated in a baboon model of infection and disease. The study was designed to replicate a human vaccine implementation scenario for endemic regions in which vaccine would be administered following drug treatment of infected individuals. In our study, the Sm-p80-based vaccine reduced principal pathology producing hepatic egg burdens by 38.0% and egg load in small and large intestines by 72.2% and 49.4%, respectively, in baboons. Notably, hatching rates of eggs recovered from liver and small and large intestine of vaccinated animals were significantly reduced, by 60.4%, 48.6%, and 82.3%, respectively. Observed reduction in egg maturation/hatching rates was supported by immunofluorescence and confocal microscopy showing unique differences in Sm-p80 expression in worms of both sexes and matured eggs. Vaccinated baboons had a 64.5% reduction in urine schistosome circulating anodic antigen, a parameter that reflects worm numbers/health status in infected hosts. Preliminary analyses of RNA sequencing revealed unique genes and canonical pathways associated with establishment of chronic disease, praziquantel-mediated parasite killing, and Sm-p80-mediated protection in vaccinated baboons. Overall, our study demonstrated efficacy of the Sm-p80 vaccine and provides insight into some of the epistatic interactions associated with protection. Show less
Schistosomiasis is a helminthic worm infection that affects 260 million people worldwide, 90% of whom live in sub-Saharan Africa. In Tanzania, where the research in this thesis was conducted, two... Show moreSchistosomiasis is a helminthic worm infection that affects 260 million people worldwide, 90% of whom live in sub-Saharan Africa. In Tanzania, where the research in this thesis was conducted, two species of schistosomes are highly endemic (Schistosoma haematobium and S. mansoni), with more than 50% of adults infected with one or both schistosome species in many regions. In and of itself, schistosomiasis causes significant morbidity and mortality, with an estimated 200,000 deaths annually and 3.31 million disability-adjusted life-years. The possibility that it additionally impacts HIV transmission and disease progression render treatment and control of this neglected tropical disease even more urgent. This thesis focuses on HIV prevention and disease management in sub-Saharan Africa. It will first describe population-based epidemiological work in Tanzania associating HIV with S. haematobium and with S. mansoni. Subsequent chapters focus on treatment of S. haematobium infection in women, where it causes genital tract disease, and on the effects of schistosome infection on immunological response to treatment in people living with HIV infection. The final chapter focuses on implementation science work with high potential to improve HIV prevention and early diagnosis in Tanzania. Show less
In Africa, polyparasitism is the rule rather than the exception. The aim of this thesis was to get a detailed insight into the micro-geographical distribution and patterns of S. mansoni and S.... Show moreIn Africa, polyparasitism is the rule rather than the exception. The aim of this thesis was to get a detailed insight into the micro-geographical distribution and patterns of S. mansoni and S. haematobium co-infections, and how this affects host morbidity. A community-wide study was carried out in a co-endemic focus in the north of Senegal, combining epidemiological, ecological, immunological, and geographical analyses. This multidisciplinary approach led to several new insights. Spatial analyses showed significant clustering of Schistosoma infection and morbidity even on a micro scale; S. mansoni and S. haematobium hotspots were found in different sections of one community. Another major finding was that the presence of S. mansoni in co-infections might protect against S. haematobium-specific urinary tract morbidity. Furthermore, it was observed that S. haematobium antigens induced stronger cytokine responses than those of S. mansoni, indicating that the first species may be more immunogenic. The results of this thesis provide new leads for further research on disease etiology and underlying mechanisms in Schistosoma co-infections. Such knowledge is key to rationalizing and optimizing current schistosomiasis control strategies in co-endemic areas and to developing successful elimination strategies in the future. Show less
Schistosomes are parasitic helminths that cause chronic infections in over 200 million people in tropical and sub-tropical areas around the world. Glycoproteins from the eggs of the parasite... Show moreSchistosomes are parasitic helminths that cause chronic infections in over 200 million people in tropical and sub-tropical areas around the world. Glycoproteins from the eggs of the parasite Schistosoma mansoni induce various immune responses in the human host, including T-cell modulation and granuloma formation. Three major, immunogenic egg glycoproteins have been identified; omega-1, IPSE/_1 and kappa-5. The studies in this thesis have unraveled structural and molecular details of the interaction between these three glycoproteins and innate immune cells of the host. Firstly, we have studied the structural details of the N-glycans expressed on these three glycoproteins. Most notably, omega-1 and IPSE/_1 carry diantennary N-glycans which mainly display Lewis X motifs, while kappa-5 expresses triantennary N-glycans with LDN motifs. Then, we have investigated the interaction of the egg glycoproteins with C-type lectin receptors on antigen-presenting immune cells. We show that specific glycan motifs on the egg glycoproteins determine differential binding to these lectin receptors. Finally, we have investigated functional effects of omega-1 and kappa-5. We show that the Th2-modulating capacity of omega-1 is dependent on both glycan-lectin interactions as well as its RNase activity. We found that kappa-5 contains granuloma-inducing properties, which are partly mediated by its LDN motifs. Show less
