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Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas.sup.1. Novel medicines and vaccines are urgently needed.sup.2,3. An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT02755324?term=NCT02755324&draw=2&rank=1)), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4.sup.+ T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis. A new human challenge model of schistosomiasis, which affects more than 290 million people globally, will aid development of novel therapies and vaccines for this neglected tropical disease., Author(s): Marijke C. C. Langenberg [sup.1] , Marie-Astrid Hoogerwerf [sup.1] , Jan Pieter R. Koopman [sup.1] , Jacqueline J. Janse [sup.1] , Janneke Kos-van Oosterhoud [sup.1] , Carola Feijt [sup.1] [...]

Schistosomiasis is an infection caused by contact with Schistosoma-contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (TH2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human Schistosoma mansoni infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early TH1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of TH2 and regulatory cell subsets. This study demonstrates the shift from TH1 to both TH2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis. Editor's summary: Schistosomiasis infection causes more than 230 million infections worldwide, but immune responses during acute infection are not well understood. To better observe these responses, Houlder et al. used controlled human Schistosoma mansoni infections with either male or female cercaria-stage parasites. T helper 1 (TH1) cell–biased inflammatory responses dominated at early time points (4 weeks after infection), and male and female parasites induced similar responses. At 8 weeks after infection, TH2 and regulatory cell responses were more dominant and were consistent with responses seen during chronic infection. These results highlight the shift in immune responses occurring over the course of infection. —Christiana Fogg [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis is a major global health problem caused by blood-dwelling parasitic worms, which is currently tackled primarily by mass administration of the drug praziquantel. Appropriate drug treatment strategies are informed by diagnostics that establish the prevalence and intensity of infection, which, in regions of low transmission, should be highly sensitive.Methods: To identify sensitive new serological markers of Schistosoma mansoni infections, we have compiled a recombinant protein library of parasite cell-surface and secreted proteins expressed in mammalian cells.Results: Together with a time series of sera samples from volunteers experimentally infected with a defined number of male parasites, we probed this protein library to identify several markers that can detect primary infections with as low as 10 parasites and as early as 5 weeks postinfection.Conclusions: These new markers could be further explored as valuable tools to detect ongoing and previous S mansoni infections, including in endemic regions where transmission is low. [ABSTRACT FROM AUTHOR]

Background: Controlled human hookworm infections could significantly contribute to the development of a hookworm vaccine. However, current models are hampered by low and unstable egg output, reducing generalizability and increasing sample sizes. This study aims to investigate the safety, tolerability, and egg output of repeated exposure to hookworm larvae.Methods: Twenty-four healthy volunteers were randomized, double-blindly, to 1, 2, or 3 doses of 50 Necator americanus L3 larvae at 2-week intervals. Volunteers were monitored weekly and were treated with albendazole at week 20.Results: There was no association between larval dose and number or severity of adverse events. Geometric mean egg loads stabilized at 697, 1668, and 1914 eggs per gram feces for the 1 × 50L3, 2 × 50L3, and 3 × 50L3 group, respectively. Bayesian statistical modeling showed that egg count variability relative to the mean was reduced with a second infectious dose; however, the third dose did not increase egg load or decrease variability. We therefore suggest 2 × 50L3 as an improved challenge dose. Model-based simulations indicates increased frequency of stool sampling optimizes the power of hypothetical vaccine trials.Conclusions: Repeated infection with hookworm larvae increased egg counts to levels comparable to the field and reduced relative variability in egg output without aggravating adverse events.Clinical Trials Registration: NCT03257072. [ABSTRACT FROM AUTHOR]

Summary Background: Within the present era of worldwide travel, it is important for all clinicians to consider the possibility of tropical sprue (TS) in returning patients with persistent diarrhoea after travel. The symptoms and histologic findings of TS can resemble but also be confused with celiac disease (CD). Material and method: Patients at our institute diagnosed with CD or TS in the period January 2000-December 2010 were eligible for inclusion. Of all patients, demographic, clinical, laboratory and endoscopy data on admission and in follow-up were collected retrospectively. Results: 28 CD and 7 TS patients were included. There were no differences in baseline clinical characteristics, duration of stay in a tropical region or in laboratory findings on admission. However, in the majority of CD patients antibodies against endomysium (EMA) or tissue transglutaminase (tTG) were present at presentation but absent in all TS patients at presentation. Conclusions: In returning travellers with persistent diarrhoea, a diagnosis of CD is unlikely in case of absence of anti-EMA or anti-tTG antibodies but conversely increases the likelihood of TS. This distinct immunoserological profile may be of help in selecting the optimal treatment in returning travelers with chronic diarrhoea after staying in a tropical region. [ABSTRACT FROM AUTHOR]

Introduction : The skin stage of malaria is a vital and vulnerable migratory life stage of the parasite. It has been characterised in rodent models, but remains wholly uninvestigated for human malaria parasites. To enable in depth analysis of not genetically modified (non-GMO) Plasmodium falciparum (Pf) sporozoite behaviour in human skin, we devised a labelling technology (Cy5M 2 , targeting the sporozoite mitochondrion) that supports tracking of individual non-GMO sporozoites in human skin. Methods : Sporozoite labelling with Cy5M 2 was performed in vitro as well as via the feed of infected Anopheles mosquitos. Labelling was validated using confocal microscopy and flow cytometry and the fitness of labelled sporozoites was determined by analysis of infectivity to human hepatocytes in vitro , and in vivo in a rodent infection model . Using confocal video microscopy and custom software, single-sporozoite tracking studies in human skin-explants were performed. Results : Both in vitro and in mosquito labelling strategies yielded brightly fluorescent sporozoites of three different Plasmodium species. Cy5M 2 uptake colocalized with MitoTracker ® green and could be blocked using the known Translocator protein (TSPO)-inhibitor PK11195. This method supported the visualization and subsequent quantitative analysis of the migration patterns of individual non-GMO Pf sporozoites in human skin and did not affect the fitness of sporozoites. Conclusions : The ability to label and image non-GMO Plasmodium sporozoites provides the basis for detailed studies on the human skin stage of malaria with potential for in vivo translation. As such, it is an important tool for development of vaccines based on attenuated sporozoites and their route of administration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.