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Immunomics-Guided Antigen Discovery for Praziquantel-Induced Vaccination in Urogenital Human Schistosomiasis.

ABSTRACT: Despite the enormous morbidity attributed to schistosomiasis, there is still no vaccine to combat the disease for the hundreds of millions of infected people. The anthelmintic drug, praziquantel, is the mainstay treatment option, although its molecular mechanism of action remains poorly defined. Praziquantel treatment damages the outermost surface of the parasite, the tegument, liberating surface antigens from dying worms that invoke a robust immune response which in some subjects results in immunologic resistance to reinfection. Herein we term this phenomenon Drug-Induced Vaccination (DIV). To identify the antigenic targets of DIV antibodies in urogenital schistosomiasis, we constructed a recombinant proteome array consisting of approximately 1,000 proteins informed by various secretome datasets including validated proteomes and bioinformatic predictions. Arrays were screened with sera from human subjects treated with praziquantel and shown 18 months later to be either reinfected (chronically infected subjects, CI) or resistant to reinfection (DIV). IgG responses to numerous antigens were significantly elevated in DIV compared to CI subjects, and indeed IgG responses to some antigens were completely undetectable in CI subjects but robustly recognized by DIV subjects. One antigen in particular, a cystatin cysteine protease inhibitor stood out as a unique target of DIV IgG, so recombinant cystatin was produced, and its vaccine efficacy assessed in a heterologous Schistosoma mansoni mouse challenge model. While there was no significant impact of vaccination with adjuvanted cystatin on adult worm numbers, highly significant reductions in liver egg burdens (45-55%, P<0.0001) and intestinal egg burdens (50-54%, P<0.0003) were achieved in mice vaccinated with cystatin in two independent trials. This study has revealed numerous antigens that are targets of DIV antibodies in urogenital schistosomiasis and offer promise as subunit vaccine targets for a drug-linked vaccination approach to controlling schistosomiasis.

SUBMITTER: Pearson MS

PROVIDER: S-EPMC8186320 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSensitive diagnostics are needed for effective management and surveillance of schistosomiasis so that current transmission interruption goals set by WHO can be achieved. We aimed to screen the Schistosoma haematobium secretome to find antibody biomarkers of schistosome infection, validate their diagnostic performance in samples from endemic populations, and evaluate their utility as point of care immunochromatographic tests (POC-ICTs) to diagnose urogenital schistosomiasis in the field.MethodsWe did a biomarker identification study, in which we constructed a proteome array containing 992 validated and predicted proteins from S haematobium and screened it with serum and urine antibodies from endemic populations in Gabon, Tanzania, and Zimbabwe. Arrayed antigens that were IgG-reactive and a select group of antigens from the worm extracellular vesicle proteome, predicted to be diagnostically informative, were then evaluated by ELISA using the same samples used to probe arrays, and samples from individuals residing in a low-endemicity setting (ie, Pemba and Unguja islands, Zanzibar, Tanzania). The two most sensitive and specific antigens were incorporated into POC-ICTs to assess their ability to diagnose S haematobium infection from serum in a field-deployable format.FindingsFrom array probing, in individuals who were infected, 208 antigens were the targets of significantly elevated IgG responses in serum and 45 antigens were the targets of significantly elevated IgG responses in urine. Of the five proteins that were validated by ELISA, Sh-TSP-2 (area under the curve [AUC]serum=0·98 [95% CI 0·95-1·00]; AUCurine=0·96 [0·93-0·99]), and MS3_01370 (AUCserum=0·93 [0·89-0·97]; AUCurine=0·81 [0·72-0·89]) displayed the highest overall diagnostic performance in each biofluid and exceeded that of S haematobium-soluble egg antigen in urine (AUC=0·79 [0·69-0·90]). When incorporated into separate POC-ICTs, Sh-TSP-2 showed absolute specificity and a sensitivity of 75% and MS3_01370 showed absolute specificity and a sensitivity of 89%.InterpretationWe identified numerous biomarkers of urogenital schistosomiasis that could form the basis of novel antibody diagnostics for this disease. Two of these antigens, Sh-TSP-2 and MS3_01370, could be used as sensitive, specific, and field-deployable diagnostics to support schistosomiasis control and elimination initiatives, with particular focus on post-elimination surveillance.FundingAustralian Trade and Investment Commission and Merck Global Health Institute.

Project description:BackgroundIn many parts of sub-Saharan Africa, urogenital and intestinal schistosomiasis co-occur, and mixed species infections containing both Schistosoma haematobium and S. mansoni can be common. During co-infection, interactions between these two species are possible, yet the extent to which such interactions influence disease dynamics or the outcome of control efforts remains poorly understood.Methodology/principal findingsHere we analyse epidemiological data from three West African countries co-endemic for urogenital and intestinal schistosomiasis (Senegal, Niger and Mali) to test whether the impact of praziquantel (PZQ) treatment, subsequent levels of re-infection or long-term infection dynamics are altered by co-infection. In all countries, positive associations between the two species prevailed at baseline: infection by one species tended to predict infection intensity for the other, with the strength of association varying across sites. Encouragingly, we found little evidence that co-infection influenced PZQ efficacy: species-specific egg reduction rates (ERR) and cure rates (CR) did not differ significantly with co-infection, and variation in treatment success was largely geographical. In Senegal, despite positive associations at baseline, children with S. mansoni co-infection at the time of treatment were less intensely re-infected by S. haematobium than those with single infections, suggesting competition between the species may occur post-treatment. Furthermore, the proportion of schistosome infections attributable to S. mansoni increased over time in all three countries examined.Conclusions/significanceThese findings suggest that while co-infection between urinary and intestinal schistosomes may not directly affect PZQ treatment efficacy, competitive interspecific interactions may influence epidemiological patterns of re-infection post-treatment. While re-infection patterns differed most strongly according to geographic location, interspecific interactions also seem to play a role, and could cause the community composition in mixed species settings to shift as disease control efforts intensify, a situation with implications for future disease management in this multi-species system.

Project description:In Sub-Saharan Africa, urogenital schistosomiasis remains a significant public health problem, causing 150.000 deaths/year with approximately 112 million cases diagnosed. The Niakhar district is a disease hotspot in central Senegal where transmission occurs seasonally with high prevalences. The aim of this study was to determine the effect of annual treatment over 3 years on the seasonal transmission dynamics of S. haematobium in 9 villages in the Niakhar district. Adults and children aged between 5 and 60 years were surveyed from 2011 to 2014. Urine samples were collected door-to-door and examined for S. haematobium eggs at baseline in June 2011, and all participants were treated in August 2011 with PZQ (40 mg/kg). After this initial examination, evaluations were conducted at 3 successive time points from September 2011 to March 2014, to measure the efficacy of the annual treatments and the rates of reinfection. Each year, during the transmission period, from July to November-December, malacological surveys were also carried out in the fresh water bodies of each village to evaluate the infestation of the snail intermediate hosts. At baseline, the overall prevalence of S. haematobium infection was 57.7%, and the proportion of heavy infection was 45.3%, but one month after the first treatment high cure rates (92.9%) were obtained. The overall infection prevalence and proportion of heavy infection intensities were drastically reduced to 4.2% and 2.3%, respectively. The level of the first reinfection in February-March 2012 was 9.5%. At follow-up time points, prevalence levels varied slightly between reinfection and treatment from 9.5% in June 2012 to 0.3% in March 2013, 11.2 in June 2013, and 10.1% April 2014. At the end of the study, overall prevalence was significantly reduced from 57.7% to 10.1%. The overall rate of infested Bulinid snails was reduced after repeated treatment from 0.8% in 2012 to 0.5% in 2013. Repeated annual treatments are suggested to have a considerable impact on the transmission dynamics of S. haematobium in Niakhar, due to the nature of the epidemiological system with seasonal transmission. Thus, to maintain this benefit and continue to reduce the morbidity of urogenital schistosomiasis, other approaches should be integrated into the strategy plans of the National program to achieve the goal of urogenital schistosomiasis elimination in seasonal foci in Senegal.

Project description:BackgroundHuman schistosomiasis is a highly prevalent neglected tropical disease (NTD) caused by Schistosoma species. Research on the molecular mechanisms influencing the outcomes of bladder infection by Schistosoma haematobium is urgently needed to develop new diagnostics, therapeutics and infection prevention strategies. The objective of the research study was to determine the microbiome features and changes in urine during urogenital schistosomiasis and induced bladder pathologies.MethodologySeventy participants from Eggua, southwestern Nigeria provided morning urine samples and were screened for urogenital schistosomiasis infection and bladder pathologies in a cross-sectional study. Highthroughput NGS sequencing was carried out, targeting the 16S V3 region. Filtered reads were processed and analyzed in a bioinformatics pipeline.Principal findingsThe study participants (36 males and 34 females, between ages 15 and 65) were categorized into four groups according to status of schistosomiasis infection and bladder pathology. Data analytics of the next-generation sequencing reads revealed that Proteobacteria and Firmicutes dominated and had influence on microbiome structure of both non-infected persons and persons with urogenital schistosomiasis. Furthermore, gender and age influenced taxa abundance independent of infection or bladder pathology. Several taxa distinguished urogenital schistosomiasis induced bladder pathologies from urogenital schistosomiasis infection alone and from healthy persons, including known immune-stimulatory taxa such as Fusobacterium, Sphingobacterium and Enterococcus. Some of these significant taxa, especially Sphingobacterium were projected as markers of infection, while several genera including potentially beneficial taxa such as Trabulsiella and Weissella, were markers of the non-infected. Finally, expected changes in protein functional categories were observed to relate to cellular maintenance and lipid metabolism.ConclusionThe urinary microbiome is a factor to be considered in developing biomarkers, diagnostic tools, and new treatment for urogenital schistosomiasis and induced bladder pathologies.

Project description:BACKGROUND:schistosomiasis is a neglected tropical disease caused by helminths of the genus Schistosoma. The disease has a worldwide distribution, with more cases occurring in Africa. Urogenital schistosomiasis caused by S. haematobium with its associated morbidity is prevalent in many areas of Ghana. Praziquantel is still the recommended drug of choice for schistosomiasis treatment, although a number of studies have reported sub-therapeutic effects and associated treatment failure. The current study, therefore, assessed whether persistent schistosomiasis, with its associated morbidity among children living in endemic areas within the Greater Accra Region of Ghana, is as a result of reinfection or suspected praziquantel resistance. METHODOLOGY:this was a longitudinal study involving a baseline and follow-up sampling after praziquantel treatment. Urine samples were collected from school children (whose parents had also consented) for the detection of S. haematobium ova using a sedimentation technique. The morbidity parameters were examined with urine chemistry strips, as well as microscopy. Viability was assessed using a modified hatchability technique, vital staining (0.4% trypan blue and 1% neutral red) and fluorescent (Hoechst 33258) microscopy. Infected individuals were treated with a single dose of praziquantel (40mg/kg). Resampling to determine reinfection was done sixth months post-treatment, after evidence of total egg clearance. For possible resistance assessment, egg counts and viability testing were conducted on the positive samples at the baseline, as well as weekly post-treatment follow-ups for 12 weeks. RESULTS:out of the 420 school children sampled, 77 were initially positive but, after the sixth month sampling for reinfection assessment, eight out of the initial positives were infected again, giving a reinfection percentage of 10.4%. No suspected praziquantel resistance was recorded in the 21 positives detected out of the 360 sampled for suspected resistance assessment. The egg reduction rate increased weekly in the follow-up samples with a gradual reduction in the egg count. The study also recorded a gradual decrease in the percentage of live eggs after the first week; with all viability testing methods used complimenting each other. The morbidity parameters (proteinuria, haematuria and pyuria) changed between the baseline and post-treatment samples, eventually reducing to zero. CONCLUSIONS:the outcome of this study suggests that the persistent schistosomiasis, with its associated morbidity observed in these endemic communities, is not likely to be as a result of praziquantel resistance, but reinfection. Even though there was no suspected resistance observed in the study, there remains the need to continuously intensify the monitoring of praziquantel in other endemic communities.

Project description:BackgroundUrogenital schistosomiasis is a neglected tropical disease most prevalent in sub-Saharan Africa. In the Senegal river basin, the construction of the Diama dam led to an increase and endemicity of schistosomiasis. Since 2009, praziquantel has frequently been used as preventive chemotherapy in the form of mass administration to Senegalese school-aged children without monitoring of the treatment efficacy and the prevalence after re-infection. This study aims to determine the current prevalence of urogenital schistosomiasis (caused by Schistosoma haematobium), the efficacy of praziquantel, and the re-infection rates in children from five villages with different water access.MethodsThe baseline prevalence of S. haematobium was determined in August 2020 in 777 children between 5 and 11 years old and a single dose of praziquantel (40 mg/kg) was administered to those positive. The efficacy of praziquantel and the re-infection rates were monitored 4 weeks and 7 months after treatment, respectively, in 226 children with a high intensity of infection at baseline.ResultsAt the baseline, prevalence was low among children from the village of Mbane who live close to the Lac de Guiers (38%), moderate among those from the villages of Dioundou and Khodit, which neighbor the Doue river (46%), and very high at Khodit (90.6%) and Guia (91.2%) which mainly use an irrigation canal. After treatment, the observed cure rates confirmed the efficacy of praziquantel. The lowest cure rate (88.5%) was obtained in the village using the irrigation canal, while high cure rates were obtained in those using the lake (96.5%) and the river (98%). However, high egg reduction rates (between 96.7 and 99.7%) were obtained in all the villages. The re-infection was significantly higher in the village using the canal (42.5%) than in the villages accessing the Lac de Guiers (18.3%) and the Doue river (14.8%).ConclusionPraziquantel has an impact on reducing the prevalence and intensity of urogenital schistosomiasis. However, in the Senegal river basin, S. haematobium remains a real health problem for children living in the villages near the irrigation canals, despite regular treatment, while prevalence is declining from those frequenting the river and the Lac de Guiers. Trial registration ClinicalTrials.gov, NCT04635553. Registered 19 November 2020 retrospectively registered, https://www.Clinicaltrialsgov/ct2/show/NCT04635553?cntry=SN&draw=2&rank=4.

Project description:BackgroundUrogenital schistosomiasis due to Schistosoma haematobium is a serious underestimated public health problem affecting 112 million people - particularly in sub-Saharan Africa. Microscopic examination of urine samples to detect parasite eggs still remains as definitive diagnosis. This work was focussed on developing a novel loop-mediated isothermal amplification (LAMP) assay for detection of S. haematobium DNA in human urine samples as a high-throughput, simple, accurate and affordable diagnostic tool to use in diagnosis of urogenital schistosomiasis.Methodology/principal findingsA LAMP assay targeting a species specific sequence of S. haematobium ribosomal intergenic spacer was designed. The effectiveness of our LAMP was assessed in a number of patients´ urine samples with microscopy confirmed S. haematobium infection. For potentially large-scale application in field conditions, different DNA extraction methods, including a commercial kit, a modified NaOH extraction method and a rapid heating method were tested using small volumes of urine fractions (whole urine, supernatants and pellets). The heating of pellets from clinical samples was the most efficient method to obtain good-quality DNA detectable by LAMP. The detection limit of our LAMP was 1 fg/µL of S. haematobium DNA in urine samples. When testing all patients´ urine samples included in our study, diagnostic parameters for sensitivity and specificity were calculated for LAMP assay, 100% sensitivity (95% CI: 81.32%-100%) and 86.67% specificity (95% CI: 75.40%-94.05%), and also for microscopy detection of eggs in urine samples, 69.23% sensitivity (95% CI: 48.21%-85.63%) and 100% specificity (95% CI: 93.08%-100%).Conclusions/significanceWe have developed and evaluated, for the first time, a LAMP assay for detection of S. haematobium DNA in heated pellets from patients´ urine samples using no complicated requirement procedure for DNA extraction. The procedure has been named the Rapid-Heat LAMPellet method and has the potential to be developed further as a field diagnostic tool for use in urogenital schistosomiasis-endemic areas.

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Immunomics-Guided Antigen Discovery for Praziquantel-Induced Vaccination in Urogenital Human Schistosomiasis.

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