Schistosomiasis is a parasitic infection caused by worms of the genus Schistosoma. It is a neglected tropical disease, affecting mainly populations living in poverty without adequate sanitation.... Show moreSchistosomiasis is a parasitic infection caused by worms of the genus Schistosoma. It is a neglected tropical disease, affecting mainly populations living in poverty without adequate sanitation. Treatment relies on one drug mainly, praziquantel, and its efficacy is dependent on the diagnostic tool used.Due to the parasite’s intravascular localisation, it is difficult to directly quantify them in infected humans. Thus, methods of detection like worm-derived circulating cathodic antigen (CCA) in urine or circulating anodic antigen (CAA) in urine and serum, have gained more attention. This thesis aims to explore and shed light on how to interpret schistosome-related circulating antigens CCA and CAA. We have addressed the interpretation of schistosome related assays in endemic and non-endemic regions, supported by data obtained from an animal study. Different diagnostic value can be attributed to different assays within different contexts. The results highlight the importance of a better understanding of antigen excretion patterns by different species to support optimalisation of antigen-based diagnostics of schistosomiasis. Show less
Koopman, J.P.R.; Houlder, E.L.; Janse, J.J.; Casacuberta-Partal, M.; Lamers, O.A.C.; Sijtsma, J.C.; ... ; Roestenberg, M. 2023
Background A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently,... Show moreBackground A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently, we established CHI-S model using single-sex male-only Schistosoma mansoni (Sm) cercariae in Schistosoma-naive individuals. Given important differences in antigenic profile and human immune responses to schistosomes of different sex, we pioneered a single-sex female-only CHI-S model for future use in vaccine development.Methods We exposed 13 healthy, Schistosoma-naive adult participants to 10 (n = 3) or 20 (n = 10) female cercariae and followed for 20 weeks, receiving treatment with praziquantel (PZQ) 60 mg/kg at week 8 and 12 after exposure.Findings The majority (11/13) participants reported rash and/or itch at the site of exposure, 5/13 had transient symptoms of acute schistosomiasis. Exposure to 20 cercariae led to detectable infection, defined as serum circulating anodic antigen levels >1.0 pg/mL, in 6/10 participants. Despite two rounds of PZQ treatment, 4/13 participants showed signs of persistent infection. Additional one-or three-day PZQ treatment (1 x 60 mg/kg and 3 x 60 mg/kg) or artemether did not result in cure, but over time three participants self-cured. Antibody, cellular, and cytokine responses peaked at week 4 post infection, with a mixed Th1, Th2, and regulatory profile. Cellular responses were (most) discriminative for symptoms.Interpretation Female-only infections exhibit similar clinical and immunological profiles as male-only infections but are more resistant to PZQ treatment. This limits future use of this model and may have important implications for disease control programs. Show less
Availability of accurate tests to diagnose schistosomiasis, a neglected tropical disease caused by parasitic worms, is crucial for successful reduction of the burden of disease and eventually... Show moreAvailability of accurate tests to diagnose schistosomiasis, a neglected tropical disease caused by parasitic worms, is crucial for successful reduction of the burden of disease and eventually moving towards elimination. This thesis provides further evidence on the suitability of CAA detection for diagnosing Schistosoma infections and monitoring treatment efficacy by evaluating the UCP-LF CAA test in the context of various endemic and non-endemic settings. The UCP-LF CAA test is a lateral flow (LF) test for sensitive quantitative detection – using luminescent up-converting reporter particles (UCP) – of circulating anodic antigen (CAA). This antigen is regurgitated by live schistosome worms into the human circulation. The presence of CAA in blood or urine thus reflects an active Schistosoma infection. CAA-levels decrease rapidly after treatment of infected patients with anti-schistosomal drugs. In non-endemic settings (i.e. the absence of reinfection), CAA-levels became undetectable after treatment, indicating clearance of infection. This is in contrast to endemic settings of continuous exposure and ongoing transmission. Here, CAA-levels significantly decreased post-treatment but often remained detectable. Although alternative procedures such as antibody and DNA detection methods remain crucial for certain context-specific purposes, this thesis shows that CAA is the most favorable diagnostic marker currently available for diagnosis of active Schistosoma infections. Show less
Controlled human infection (CHI) models are an important research tool. Healthy volunteers are experimentally infected with a pathogen. In malaria research the model has been used for decades. Here... Show moreControlled human infection (CHI) models are an important research tool. Healthy volunteers are experimentally infected with a pathogen. In malaria research the model has been used for decades. Here, the model was used to test new Plasmodium falciparum strains, NF135.C10 an NF166.C8, and compare these with the commonly used strain NF54. In addition, a genetically modified malaria vaccine, PfSPZ-GA1, was tested. Unfortunately only few volunteers were protected against malaria.For schistosomiasis, a controlled human schistosomiasis infection (CoHSI) model was developed and hereafter a dose finding study with single-sex male only cercariae was performed. This study showed that in 80% of volunteers 20 cercariae were effective to induce an infection. Although the use of 30 cercariae resulted in 100% infection rate two out of three volunteers developed Katayama syndrome. These side effects were less after infection with 20 cercariae.At last suggestions were made to further improve the CHI model by the use of historical controls. Although this study design can only be used in CHI’s with well-know outcomes these study will be safer by reducing the cumulative risks as less volunteers can be used for these trials. Show less
Background: An accurate test for the diagnosis and post-treatment follow-up of patients with schistosomiasis is needed. We assessed the performance of different laboratory parameters, including the... Show moreBackground: An accurate test for the diagnosis and post-treatment follow-up of patients with schistosomiasis is needed. We assessed the performance of different laboratory parameters, including the up-converting reporter particle technology lateral flow assay to detect circulating anodic antigen (UCP-LF CAA), for the post-treatment follow-up of schistosomiasis in migrants attending a dedicated outpatient clinic in a non-endemic country.Methods: Routine anti-Schistosoma serology results and eosinophil counts were obtained of patients with positive urine/stool microscopy and/or PCR (confirmed cases) or only positive serology (possible cases), and at least one follow-up visit at 6 (T6) or 12 (T12) months after praziquantel treatment. All sera samples were tested with the UCP-LF CAA assay.Results: Forty-eight patients were included, 23 confirmed and 25 possible cases. The percentage seropositivity and median antibody titers did not change significantly during follow-up. UCP-LF CAA was positive in 86.9% of confirmed and 20% of possible cases. The percentage positivity and median CAA levels decreased significantly post-treatment, with only two patients having positive CAA levels at T12.Conclusions: The UCP-LF CAA assay proved useful for the diagnosis of active infection with Schistosoma spp. and highly valuable for post-treatment monitoring in migrants, encouraging the development of a commercial test. Show less
Schistosome infection is recognized as a potentially modifiable risk factor for HIV in women by the World Health Organization. Alterations in cervicovaginal bacteria have been associated with HIV... Show moreSchistosome infection is recognized as a potentially modifiable risk factor for HIV in women by the World Health Organization. Alterations in cervicovaginal bacteria have been associated with HIV acquisition and have not been studied in schistosome infection. We collected cervical swabs from Tanzanian women with and without S. mansoni and S. haematobium to determine effects on cervicovaginal microbiota. Infected women were treated, and follow-up swabs were collected after 3 months. 16S rRNA sequencing was performed on DNA extracted from swabs. We compared 39 women with S. mansoni with 52 uninfected controls, and 16 with S. haematobium with 27 controls. S. mansoni-infected women had increased abundance of Peptostreptococcus (p = 0.026) and presence of Prevotella timonesis (p = 0.048) compared to controls. High-intensity S. haematobium infection was associated with more diverse cervicovaginal bacterial communities than uninfected controls (p = 0.0159). High-intensity S. mansoni infection showed a similar trend (p = 0.154). At follow-up, we observed increased alpha diversity in S. mansoni (2.53 vs. 1.72, p = 0.022) and S. haematobium (2.05 vs. 1.12, p = 0.066) infection groups compared to controls. Modifications in cervicovaginal microbiota, particularly increased diversity and abundance of taxa associated with bacterial vaginosis and HIV (Peptostreptococcus, Prevotella), were associated with schistosome infection. Show less
Schistosomiasis is an acute and chronic disease caused by blood dwelling parasitic trematodes of the genus Schistosoma, and it is classified as the second most socioeconomically devastating... Show moreSchistosomiasis is an acute and chronic disease caused by blood dwelling parasitic trematodes of the genus Schistosoma, and it is classified as the second most socioeconomically devastating parasitic disease, second only to malaria. Currently the wormload is determined by the Kato-Katz method, which is not always reliable. In order to prepare diagnostic tools able to capture specific anti-carbohydrate antibodies or develop conjugate vaccines targeting these carbohydrate structures, sufficient amounts of well-defined fragments are needed. This thesis describes the synthesis of several glycans of these glycans present on the S. mansoni parasite, focusing mainly on the Circulating Anodic Antigen (CAA) and glycans bearing the unique α-(1-2)-L-Fucose-α-(1-2)-L-Fucose motifs. These glycans have been attached to gold nanoparticles and these particles were screened against several monoclonal antibodies and sera of individuals suffering from schistosomiasis. Show less
During a schistosome infection, the host generates a plethora of antibodies against schistosome glycans. This thesis looks into the anti-schistosome-glycan antibody dynamics in different hosts with... Show moreDuring a schistosome infection, the host generates a plethora of antibodies against schistosome glycans. This thesis looks into the anti-schistosome-glycan antibody dynamics in different hosts with the aim of identifying targets that are relevant in the context of infection and protection. Show less
Casacuberta Partal, M.; Janse, J.J.; Schuijlenburg, R. van; Vries, J.J.C. de; Erkens, M.A.A.; Suijk, K.; ... ; Roestenberg, M. 2020
Background: Travellers infected with Schistosoma spp. might be pauci- or even asymptomatic on first presentation. Therefore, schistosomiasis may remain undiagnosed in this population. Active... Show moreBackground: Travellers infected with Schistosoma spp. might be pauci- or even asymptomatic on first presentation. Therefore, schistosomiasis may remain undiagnosed in this population. Active infection, as evidenced by the presence of the tissue-dwelling worm, can be demonstrated via the detection of adult worm-derived circulating anodic antigen (CAA) utilising a robust well-described lateral flow-(LF) based test applying background-free up-converting reporter particles (UCP). In this prospective study, we assessed the diagnostic value of serum and urine UCP-LF CAA test in comparison with two Schistosoma-specific serological assays detecting antibodies against adult worm antigen-immuno fluorescence assay (AWA-IFA) and against soluble egg antigen-enzyme-linked immunosorbent assay (SEA-ELISA) antigens in travellers.Methods: Samples were collected from 106 Dutch travellers who reported freshwater contact in sub-Saharan Africa and who were recruited up to 2 years after return. Subjects were asked to complete a detailed questionnaire on travel history, water contact, signs and symptoms compatible with schistosomiasis.Results: Two travellers were positive by serum CAA and an additional one by urine CAA. A total of 22/106 (21%) samples were antibody positive by AWA-IFA and 9/106 (9%) by SEA-ELISA. At follow-up 6 weeks and 6 months after praziquantel treatment, all seropositives remained antibody positive whereas CAA was cleared. Seropositivity could not be predicted by the type of fresh water-related activity, country visited or symptoms reported.Conclusion: The low number of UCP-LF CAA positives suggests that in travellers, active infections often do not establish or have very low worm burden. Based on our high seroconversion rates, we conclude that the AWA-IFA assay is the most sensitive test to detect schistosome exposure. Given the lack of predictive symptoms or risk factors, we recommend schistosomiasis screening at least by serology in all travellers with reported freshwater contact in high-endemic areas. 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
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
Schistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most... Show moreSchistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most antibodies raised during schistosome infection are directed against glycans, some of which are thought to be protective. Developing schistosomula are considered most vulnerable to immune attack, and better understanding of local antibody responses raised against glycans expressed by this life stage might reveal possible glycan vaccine candidates for future vaccine research. In this tehsis we adressed the spatial and temporal expression of glycans expressed during the critical larval stages of schistosome development and we studied the (protective) antibody responses against these glycans in animals and infected human populations. Together these studies thereby contribute to an important basis for the understanding of the anti-glycan antibody responses towards Schistosoma in general and towards the vulnerable schistosomulum in particular. Show less
The work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It... Show moreThe work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It presents data from studies conducted in rural and semi urban areas of Lambaréné (Gabon) where the burden of malaria and helminths is particularly important. Although scarce previous studies have indicated an effect of helminths on malaria outcomes and immune response to Plasmodium spp. parasite in co-infected subjects. However it is still debated how consistent is this effect across study sites and teams and what its immunological basis is. Show less
Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of... Show more Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of low birth weight in sub-Saharan Africa are very young maternal age, first pregnancy, poor gestational nutrition and small stature of the mother. In Gabon, besides malaria, the other two major parasitic infections namely urogenital schistosomiasis and the filarial infection Loa loa, are common in pregnant women. Maternal schistosomiasis like malaria showed to be associated with higher proportions of low birth weight babies. Mefloquine as an alternative preventive treatment, despite showing no difference with sulphadoxine – pyrimethamine in preventing low birth weight, was however more effective in preventing malaria infection and anaemia. Mefloquine administered for the prevention of malaria was effective against concomitant urogenital schistosomiasis, suggesting that mefloquine could seriously be considered as a combined intervention for both malaria and schistosomiasis during pregnancy, and an alternative to praziquantel. Maternal infection with L. loa was associated with expansion in the neonatal cord blood of functionally activate Tregs that kept Th1 and Th17 immune responses in check, providing some insights on the impact of in utero exposure on the offspring’s development and health. Show less
Downs, J.A.; Corstjens, P.L.A.M.; Mngara, J.; Lutonja, P.; Isingo, R.; Urassa, M.; ... ; Dam, G.J. van 2015
