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Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production. Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST. rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis.

Soil transmitted helminths (STH) infect >1.5 billion people. Mass drug administration (MDA) effectively reduces infection; however, there is evidence for rapid reinfection and risk of potential drug resistance. We conducted a randomized controlled trial in Bangladesh (WASH Benefits, NCT01590095) to assess whether water, sanitation, hygiene and nutrition interventions, alone and combined, reduce STH in a setting with ongoing MDA. In 2012-2013, we randomized 720 clusters of 5551 pregnant women into water treatment, sanitation, handwashing, combined water+sanitation+handwashing (WSH), nutrition, nutrition+WSH (N+WSH) or control arms. In 2015-2016, we enrolled 7795 children, aged 2-12 years, of 4102 available women for STH follow-up and collected stool from 7187. We enumerated STH infections with Kato-Katz. We estimated intention-to-treat intervention effects on infection prevalence and intensity. Participants and field staff were not blinded; laboratory technicians and data analysts were blinded. Prevalence among controls was 36.8% for A. lumbricoides, 9.2% for hookworm and 7.5% for T. trichiura. Most infections were low-intensity. Compared to controls, the water intervention reduced hookworm by 31% (prevalence ratio [PR] = 0.69 (0.50,0.95), prevalence difference [PD] = -2.83 (-5.16,-0.50)) but did not affect other STH. Sanitation improvements reduced T. trichiura by 29% (PR = 0.71 (0.52,0.98), PD = -2.17 (-4.03,-0.38)), had a similar borderline effect on hookworm and no effect on A. lumbricoides. Handwashing and nutrition interventions did not reduce any STH. WSH and N+WSH reduced hookworm prevalence by 29-33% (WSH: PR = 0.71 (0.52,0.99), PD = -2.63 (-4.95,-0.31); N+WSH: PR = 0.67 (0.50,0.91), PD = -3.00 (-5.14,-0.85)) and marginally reduced A. lumbricoides. Effects on infection intensity were similar. In a low-intensity infection setting with MDA, we found modest but sustained hookworm reduction from water treatment and combined WSH interventions. Impacts were more pronounced on STH species with short vs. long-term environmental survival. Our findings suggest possible waterborne transmission for hookworm. Water treatment and sanitation improvements can augment MDA to interrupt STH transmission. NCT01590095.

Helminth parasites control host-immune responses by secreting immunomodulatory glycoproteins. Clinical trials and mouse model studies have demonstrated the potential of helminth-derived glycoproteins for the treatment of immune-related diseases, like allergies and autoimmune diseases. Studies are however hampered by the limited availability of native parasite-derived proteins. Moreover, recombinant protein production systems have thus far been unable to reconstitute helminth-like glycosylation essential for the functionality of some helminth glycoproteins. Here we exploited the flexibility of the N-glycosylation machinery of plants to reconstruct the helminth glycoproteins omega-1 and kappa-5, two major constituents of immunomodulatory Schistosoma mansoni soluble egg antigens. Fine-tuning transient co-expression of specific glycosyltransferases in Nicotiana benthamiana enabled the synthesis of Lewis X (LeX) and LDN/LDN-F glycan motifs as found on natural omega-1 and kappa-5, respectively. In vitro and in vivo evaluation of the introduction of native LeX motifs on plant-produced omega-1 confirmed that LeX on omega-1 contributes to the glycoprotein’s Th2-inducing properties. These data indicate that mimicking the complex carbohydrate structures of helminths in plants is a promising strategy to allow targeted evaluation of therapeutic glycoproteins for the treatment of inflammatory disorders. In addition, our results offer perspectives for the development of effective anti-helminthic vaccines by reconstructing native parasite glycoprotein antigens.

Historically, soil-transmitted helminth (STH) control and prevention strategies have relied on mass drug administration efforts targeting preschool and school-aged children. While these efforts have succeeded in reducing morbidity associated with STH infection, recent modeling efforts have suggested that expanding intervention to treatment of the entire community could achieve transmission interruption in some settings. Testing the feasibility of such an approach requires large-scale clinical trials, such as the DeWorm3 cluster randomized trial. In addition, accurate interpretation of trial outcomes requires diagnostic platforms capable of accurately determining infection prevalence (particularly as infection intensity is reduced) at large population scale and with significant throughput. Here, we describe the development and validation of such a high-throughput molecular testing platform. Through the development, selection, and validation of appropriate controls, we have successfully created and evaluated the performance of a testing platform capable of the semi-automated, high-throughput detection of four species of STH in human stool samples. Comparison of this platform with singleplex reference assays for the detection of these same pathogens has demonstrated comparable performance metrics, with index assay accuracy measuring at or above 99.5% and 98.1% for each target species at the level of the technical replicate and individual extraction respectively. Through the implementation of a rigorous validation program, we have developed a diagnostic platform capable of providing the necessary throughput and performance required to meet the needs of the DeWorm3 cluster randomized trial and other large-scale operational research efforts for STH. Resulting from the rigorous developmental approach taken, the platform we describe here provides the needed confidence in testing outcomes when utilized in conjunction with large-scale efforts such as the DeWorm3 trial. Additionally, the successful development of an evaluation and validation strategy provides a template for the creation of similar diagnostic platforms for other neglected tropical diseases.

Tapeworms (Cestoda) cause neglected diseases that can be fatal and are difficult to treat, owing to inefficient drugs. Here we present an analysis of tapeworm genome sequences using the human-infective species Echinococcus multilocularis , E. granulosus, Taenia solium and the laboratory model Hymenolepis microstoma as examples. The 115- to 141-megabase genomes offer insights into the evolution of parasitism. Synteny is maintained with distantly related blood flukes but we find extreme losses of genes and pathways that are ubiquitous in other animals, including 34 homeobox families and several determinants of stem cell fate. Tapeworms have specialized detoxification pathways, metabolism that is finely tuned to rely on nutrients scavenged from their hosts, and species-specific expansions of non-canonical heat shock proteins and families of known antigens. We identify new potential drug targets, including some on which existing pharmaceuticals may act. The genomes provide a rich resource to underpin the development of urgently needed treatments and control. Genome sequences of human-infective tapeworm species reveal extreme losses of genes and pathways that are ubiquitous in other animals, species-specific expansions of non-canonical heat shock proteins and families of known antigens, specialized detoxification pathways, and metabolism that relies on host nutrients; this information is used to identify new potential drug targets. Four tapeworm genomes sequenced Tapeworms cause echinococcosis and cysticercosis, two of the most severe parasitic diseases found in humans, and both on the World Health Organization's list of neglected tropical diseases. The publication of four tapeworm genome sequences — human-infective tapeworm species Echinococcus multilocularis , E. granulosus , Taenia solium and the laboratory model Hymenolepis microstoma — and identification of potential new drug targets for treating tapeworm infections is therefore a welcome development. Analysis of the sequences provides insights into the evolution of parasitism and reveals extreme losses of genes and pathways ubiquitous in other animals on one hand and species-specific expansions of genes on the other. More than a thousand E. multilocularis proteins emerge as potential targets, and of these, close to 200 with the highest scores may be targeted with existing pharmaceuticals.

Schistosomiasis is one of the most prevalent parasitic diseases, affecting millions of people in developing countries. Amongst the human-infective species, Schistosoma mansoni is also the most commonly used in the laboratory and here we present the systematic improvement of its draft genome. We used Sanger capillary and deep-coverage Illumina sequencing from clonal worms to upgrade the highly fragmented draft 380 Mb genome to one with only 885 scaffolds and more than 81% of the bases organised into chromosomes. We have also used transcriptome sequencing (RNA-seq) from four time points in the parasite's life cycle to refine gene predictions and profile their expression. More than 45% of predicted genes have been extensively modified and the total number has been reduced from 11,807 to 10,852. Using the new version of the genome, we identified trans-splicing events occurring in at least 11% of genes and identified clear cases where it is used to resolve polycistronic transcripts. We have produced a high-resolution map of temporal changes in expression for 9,535 genes, covering an unprecedented dynamic range for this organism. All of these data have been consolidated into a searchable format within the GeneDB (www.genedb.org) and SchistoDB (www.schistodb.net) databases. With further transcriptional profiling and genome sequencing increasingly accessible, the upgraded genome will form a fundamental dataset to underpin further advances in schistosome research.

The genomes of more than 20 helminths have now been sequenced. Here we perform a meta-analysis of all sequenced genomes of nematodes and Platyhelminthes, and attempt to address the question of what are the defining characteristics of helminth genomes. We find that parasitic worms lack systems for surface antigenic variation, instead maintaining infections using their surfaces as the first line of defence against the host immune system, with several expanded gene families of genes associated with the surface and tegument. Parasite excretory/secretory products evolve rapidly, and proteases even more so, with each parasite exhibiting unique modifications of its protease repertoire. Endoparasitic flatworms show striking losses of metabolic capabilities, not matched by nematodes. All helminths do however exhibit an overall reduction in auxiliary metabolism (biogenesis of co-factors and vitamins). Overall, the prevailing pattern is that there are few commonalities between the genomes of independently evolved parasitic worms, with each parasite having undergone specific adaptations for their particular niche.

Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease. Schistosome genomics Two international consortia this week report the whole genome sequences of the blood flukes Schistosoma mansoni and Schistosoma japonicum , two of the three major pathogens that cause schistosomiasis, also called bilharzia. Schistosomiasis is a 'neglected' tropical disease affecting more than 200 million people in 76 countries. Analyses of the new genome sequences provide insights into the molecular architecture and host interactions of these pathogens, as well as avenues for future development of targeted interventions for this disease. These are the first two flatworm genomes to be sequenced, so they offer new angles on the early events in animal evolution, in particular the determination of body pattern and the development of tissues into organs. Schistosoma mansoni and Schistosoma japonicum are the pathogenic agents that cause the tropical disease schistosomiasis. Here, and in an accompanying paper, the genomes of these two flatworms are sequenced and analysed. The results provide insights into the molecular architecture and host interactions of the flatworms, as well as avenues for future development of targeted interventions for schistosomiasis.

The free-living flatworm,Macrostomum lignanohas an impressive regenerative capacity. Following injury, it can regenerate almost an entirely new organism because of the presence of an abundant somatic stem cell population, the neoblasts. This set of unique properties makes many flatworms attractive organisms for studying the evolution of pathways involved in tissue self-renewal, cell-fate specification, and regeneration. The use of these organisms as models, however, is hampered by the lack of a well-assembled and annotated genome sequences, fundamental to modern genetic and molecular studies. Here we report the genomic sequence ofM. lignanoand an accompanying characterization of its transcriptome. The genome structure ofM. lignanois remarkably complex, with ∼75% of its sequence being comprised of simple repeats and transposon sequences. This has made high-quality assembly from Illumina reads alone impossible (N50 = 222 bp). We therefore generated 130× coverage by long sequencing reads from the Pacific Biosciences platform to create a substantially improved assembly with an N50 of 64 Kbp. We complemented the reference genome with an assembled and annotated transcriptome, and used both of these datasets in combination to probe gene-expression patterns during regeneration, examining pathways important to stem cell function.

Improved sanitation has been hypothesized to reduce soil-transmitted helminth (STH) infections by reducing the prevalence and concentration of STH eggs/larvae in soil. We evaluated the effect of a randomized sanitation program (providing households with an improved dual-pit latrine, tools for child/animal feces management, and behavioral messaging) on reducing the prevalence and concentration of STH eggs in soil from household courtyards. We collected soil samples from 1405 households enrolled in the sanitation intervention (n = 419) and control (n = 914) groups of a cluster-randomized controlled trial (WASH Benefits) in rural Bangladesh approximately 2 years after the initiation of the interventions. We analyzed samples for Ascaris lumbricoides , Trichuris trichiura , and hookworm eggs by microscopy. We estimated prevalence ratios (PR) and egg count ratio (ECR) to compare the prevalence of STH eggs and arithmetic and geometric mean egg counts for STH eggs per gram of soil in the sanitation and control arms. Among intervention households, latrines achieved high and sustained user uptake by adults while child open defecation remained common and most households did not dispose of child feces hygienically. In courtyard soil from control households, the prevalence of any STH eggs was 75.7% and the prevalence of any larvated STH eggs was 67.3%. A . lumbricoides was detected in 63.0% of control samples and T . trichiura in 55.7% of control samples; hookworm was not detected in any sample. In the control arm, the arithmetic mean egg count for any STH was 3.96 eggs/dry gram, while the geometric mean was 1.58 eggs/dry gram. There was no difference between the intervention and control groups in the prevalence of any STH eggs (PR = 0.98 (95% CI: 0.91, 1.05)) or mean egg counts (ECR = 0.08 (95% CI: -0.10, 0.26) for geometric mean and 0.07 (95% CI: -0.22, 0.37) for arithmetic mean). Adjusted models gave similar results. A compound-level sanitation intervention that provided improved latrines and tools for disposal of child and animal feces did not have an impact on STH eggs in soil. In order to effectively reduce the prevalence and concentration of STH eggs in the environment, sustained, widespread use of sanitation strategies to isolate and hygienically dispose of child and animal feces may need to complement traditional strategies for containment of adult human feces. Trial Registration: NCT01590095 .