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Urinary schistosomiasis, the result of infection by Schistosoma haematobium (Sh), remains a major global health concern. A schistosome vaccine could represent a breakthrough in schistosomiasis control strategies, which are presently based on treatment with praziquantel (PZQ). We report the safety and efficacy of the vaccine candidate recombinant 28-kDa glutathione S-transferase of Sh (rSh28GST) designated as Bilhvax, in a phase 3 trial conducted in Senegal. After clearance of their ongoing schistosomiasis infection with two doses of PZQ, 250 children aged 6-9 years were randomized to receive three subcutaneous injections of either rSh28GST/Alhydrogel (Bilhvax group) or Alhydrogel alone (control group) at week 0 (W0), W4, and W8 and then a booster at W52 (one year after the first injection). PZQ treatment was given at W44, according to previous phase 2 results. The primary endpoint of the analysis was efficacy, evaluated as a delay of recurrence of urinary schistosomiasis, defined by a microhematuria associated with at least one living Sh egg in urine from baseline to W152. During the 152-week follow-up period, there was no difference between study arms in the incidence of serious adverse events. The median follow-up time for subjects without recurrence was 22.9 months for the Bilhvax group and 18.8 months for the control group (log-rank p = 0.27). At W152, 108 children had experienced at least one recurrence in the Bilhvax group versus 112 in the control group. Specific immunoglobulin (Ig)G1, IgG2, and IgG4, but not IgG3 or IgA titers, were increased in the vaccine group. While Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached. The lack of effect may be the result of several factors, including interference by individual PZQ treatments administered each time a child was found infected, or the chosen vaccine-injection regimen favoring blocking IgG4 rather than protective IgG3 antibodies. These observations contrasting with results obtained in experimental models will help in the design of future trials. ClinicalTrials.gov NCT 00870649.

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.

Schistosomiasis affects 218 million people worldwide, with most infections in Africa. Prevalence studies suggest that people with chronic schistosomiasis may have higher risk of HIV-1 acquisition and impaired ability to control HIV-1 replication once infected. We hypothesized that: (1) pre-existing schistosome infection may increase the odds of HIV-1 acquisition and that the effects may differ between men and women, and (2) individuals with active schistosome infection at the time of HIV-1 acquisition may have impaired immune control of HIV-1, resulting in higher HIV-1 viral loads at HIV-1 seroconversion. We conducted a nested case-control study within a large population-based survey of HIV-1 transmission in Tanzania. A population of adults from seven villages was tested for HIV in 2007, 2010, and 2013 and dried blood spots were archived for future studies with participants' consent. Approximately 40% of this population has Schistosoma mansoni infection, and 2% has S. haematobium. We tested for schistosome antigens in the pre- and post-HIV-1-seroconversion blood spots of people who acquired HIV-1. We also tested blood spots of matched controls who did not acquire HIV-1 and calculated the odds that a person with schistosomiasis would become HIV-1-infected compared to these matched controls. Analysis was stratified by gender. We compared 73 HIV-1 seroconverters with 265 controls. Women with schistosome infections had a higher odds of HIV-1 acquisition than those without (adjusted OR = 2.8 [1.2-6.6], p = 0.019). Schistosome-infected men did not have an increased odds of HIV-1 acquisition (adjusted OR = 0.7 [0.3-1.8], p = 0.42). We additionally compared HIV-1 RNA levels in the post-seroconversion blood spots in HIV-1 seroconverters with schistosomiasis versus those without who became HIV-infected in 2010, before antiretroviral therapy was widely available in the region. The median whole blood HIV-1 RNA level in the 15 HIV-1 seroconverters with schistosome infection was significantly higher than in the 22 without schistosomiasis: 4.4 [3.9-4.6] log10 copies/mL versus 3.7 [3.2-4.3], p = 0.017. We confirm, in an area with endemic S. mansoni, that pre-existing schistosome infection increases odds of HIV-1 acquisition in women and raises HIV-1 viral load at the time of HIV-1 seroconversion. This is the first study to demonstrate the effect of schistosome infection on HIV-1 susceptibility and viral control, and to differentiate effects by gender. Validation studies will be needed at additional sites.

Different agencies have emphasized the need to evaluate current serological methods for screening patients with suspected urogenital schistosomiasis. However, there is still a lack of evidence regarding the most appropriate methods for this purpose. Here we assessed the diagnostic efficacy of a newly developed serological technique that utilizes the recombinant protein Sh -TSP-2, applied to the urine and serum of migrants suspected of having urogenital schistosomiasis. The sensitivity, specificity, positive and negative predictive values of an in-house enzyme-linked immunosorbent assay (ELISA) using the recombinant protein Sh -TSP-2 were analysed and compared with other commercial serological methods. Due to the limitations of microscopy as a perfect reference method, a latent class analysis (LCA) and composite reference standard (CRS) approach was used to determine the sensitivity and specificity of each test. According to the LCA model, the commercial tests NovaLisa ® and immunochromatography test (ICT) immunoglobulin G–immunoglobulin M (IgG–IgM) presented the highest sensitivity (100%), whereas the Sh -TSP-2 serum ELISA test had 79.2%. The Sh -TSP-2 urine and serum ELISA tests had the highest specificities among the serological methods (87.5 and 75%, respectively). CRS modelling showed that the ICT IgG–IgM, NovaLisa ® and Sh -TSP-2 serum tests led in sensitivity at 97.1, 88.6 and 71.4%, respectively, with all tests except that the ICT IgG–IgM test having a specificity >90%. Sh -TSP-2 has been validated as a screening tool for patients suspected of having urogenital schistosomiasis. Although commercial serological tests have shown higher sensitivities, Sh -TSP-2 could be valuable for confirming results from tests with lower specificity. Nevertheless, further studies with larger patient cohorts are necessary to fully verify its potential.

Urogenital schistosomiasis caused by Schistosoma haematobium affects approximately 110 million people globally, with the majority of cases in low- and middle-income countries. Schistosome infections have been shown to impact the host immune system, gene expression, and microbiome composition. Studies have demonstrated variations in pathology between schistosome subspecies. In the case of S. haematobium, infection has been associated with HIV acquisition and bladder cancer. However, the underlying pathophysiology has been understudied compared to other schistosome species. This systematic review comprehensively investigates and assimilates the effects of S. haematobium infection on systemic and local host mucosal immunity, cellular gene expression and microbiome. We conducted a systematic review assessing the reported effects of S. haematobium infections and anthelmintic treatment on the immune system, gene expression and microbiome in humans and animal models. This review followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42022372607). Randomized clinical trials, cohort, cross-sectional, case-control, experimental ex vivo, and animal studies were included. Two reviewers performed screening independently. We screened 3,177 studies and included 94. S. haematobium was reported to lead to: (i) a mixed immune response with a predominant type 2 immune phenotype, increased T and B regulatory cells, and select pro-inflammatory cytokines; (ii) distinct molecular alterations that would compromise epithelial integrity, such as increased metalloproteinase expression, and promote immunological changes and cellular transformation, specifically upregulation of genes p53 and Bcl-2; and (iii) microbiome dysbiosis in the urinary, intestinal, and genital tracts. S. haematobium induces distinct alterations in the host's immune system, molecular profile, and microbiome. This leads to a diverse range of inflammatory and anti-inflammatory responses and impaired integrity of the local mucosal epithelial barrier, elevating the risks of secondary infections. Further, S. haematobium promotes cellular transformation with oncogenic potential and disrupts the microbiome, further influencing the immune system and genetic makeup. Understanding the pathophysiology of these interactions can improve outcomes for the sequelae of this devastating parasitic infection.

Elimination of schistosomiasis as a public health problem and interruption of transmission in selected areas are key goals of the World Health Organization for 2025. Conventional parasitological methods are insensitive for the detection of light-intensity infections. Techniques with high sensitivity and specificity are required for an accurate diagnosis in low-transmission settings and verification of elimination. We determined the accuracy of a urine-based up-converting phosphor-lateral flow circulating anodic antigen (UCP-LF CAA) assay for Schistosoma haematobium diagnosis in low-prevalence settings in Zanzibar, Tanzania. A total of 1,740 urine samples were collected in 2013 from children on Pemba Island, from schools where the S. haematobium prevalence was <2%, 2-5%, and 5-10%, based on a single urine filtration. On the day of collection, all samples were tested for microhematuria with reagent strips and for the presence of S. haematobium eggs with microscopy. Eight months later, 1.5 ml of urine from each of 1,200 samples stored at -20°C were analyzed by UCP-LF CAA assay, while urine filtration slides were subjected to quality control (QCUF). In the absence of a true 'gold' standard, the diagnostic performance was calculated using latent class analyses (LCA). The 'empirical' S. haematobium prevalence revealed by UCP-LF CAA, QCUF, and reagent strips was 14%, 5%, and 4%, respectively. LCA revealed a sensitivity of the UCP-LF CAA, QCUF, and reagent strips of 97% (95% confidence interval (CI): 91-100%), 86% (95% CI: 72-99%), and 67% (95% CI: 52-81%), respectively. Test specificities were consistently above 90%. The UCP-LF CAA assay shows high sensitivity for the diagnosis of S. haematobium in low-endemicity settings. Empirically, it detects a considerably higher number of infections than microscopy. Hence, the UCP-LF CAA employed in combination with QCUF, is a promising tool for monitoring and surveillance of urogenital schistosomiasis in low-transmission settings targeted for elimination.

Some snails act as intermediate hosts (vectors) for parasitic flatworms (flukes) that cause neglected tropical diseases, such as schistosomiases. Schistosoma haematobium is a blood fluke that causes urogenital schistosomiasis and induces bladder cancer and increased risk of HIV infection. Understanding the molecular biology of the snail and its relationship with the parasite could guide development of an intervention approach that interrupts transmission. Here, we define the genome for a key intermediate host of S. haematobium —called Bulinus truncatus —and explore protein groups inferred to play an integral role in the snail’s biology and its relationship with the schistosome parasite. Bu. truncatus shared many orthologous protein groups with Biomphalaria glabrata —the key snail vector for S. mansoni which causes hepatointestinal schistosomiasis in people. Conspicuous were expansions in signalling and membrane trafficking proteins, peptidases and their inhibitors as well as gene families linked to immune response regulation, such as a large repertoire of lectin-like molecules. This work provides a sound basis for further studies of snail-parasite interactions in the search for targets to block schistosomiasis transmission. The snail Bulinus truncatus is an intermediate host of the carcinogenic human blood fluke Schistosoma haematobium . Here the authors report the genome of Bu. truncatus , explore protein groups inferred to play a role in its interaction with the schistosome parasite, and identify expansions in gene families linked to immune response regulation.

Traditional microscopic examination of urine or stool for schistosome eggs lacks sensitivity compared to measurement of schistosome worm-derived circulating antigens in serum or urine. The ease and non-invasiveness of urine collection makes urine an ideal sample for schistosome antigen detection. In this study several user-friendly, lateral-flow (LF) based urine assays were evaluated against a composite reference that defined infection as detection of either eggs in urine or anodic antigen in serum. In a Tanzanian population with a prevalence of 40-50% ( prevalence <2%), clinical samples from 44 women aged 18 to 35 years were analyzed for infection. Urine and stool samples were examined microscopically for eggs, and serum samples were analyzed for the presence of the anodic antigen. Urines were further subjected to a set of LF assays detecting (circulating) anodic (CAA) and cathodic antigen (CCA) as well as antibodies against soluble egg antigens (SEA) and crude cercarial antigen preparation (SCAP). The urine LF anodic antigen assay utilizing luminescent upconverting reporter particles (UCP) confirmed its increased sensitivity when performed with larger sample volume. Qualitatively, the anodic antigen assay performed on 250 μL urine matched the performance of the standard anodic antigen assay performed on 20 μL serum. However, the ratio of anodic antigen levels in urine vs. serum of individual patients varied with absolute levels always higher in serum. The 10 μL urine UCP-LF cathodic antigen assay correlated with the commercially available urine POC-CCA (40 μL) test, while conferring better sensitivity with a quantitative result. Urinary antibodies against SEA and SCAP overlap and correlate with the presence of urinary egg and serum anodic antigen levels. The UCP-LF anodic antigen assay using 250 μL of urine is an expedient user-friendly assay and a suitable non-invasive alternative to serum-based antigen testing and urinary egg detection. Individual biological differences in the clearance process of the circulating antigens are thought to explain the observed high variation in the type and level of antigen (anodic or cathodic) measured in urine or serum. Simultaneous detection of anodic and cathodic antigen may be considered to further increase accuracy.

The hypothesis that repeated treatments enhance acquired immunity against schistosomes by stimulating strong T helper 2 responses was tested. Schistosoma haematobium–infected schoolchildren were monitored for 3 years. During the first 2 years, children who did not receive chemotherapy were compared with those treated once or repeatedly. After specific immune responses were measured at 24 months, praziquantel was given to all children to clear any schistosome infections. Twelve months later, the infection status of the children was determined and compared with cytokine profiles at month 24, to gain insight into which immunologic profiles can predict resistance or susceptibility to schistosome infections. Repeated treatment led to high specific levels of interleukin (IL)–5 and low interferon-γ production but did not protect against reinfection. After adjusting for variables, such as sex, age, and infection status at study onset, high levels of parasite-specific IL-10 were a risk factor for reinfection, and high levels of IL-5 were associated with hematuria development

Schistosoma haematobium is the causative pathogen for urogenital schistosomiasis. To achieve progress towards schistosomiasis elimination, there is a critical need for developing highly sensitive and specific tools to monitor transmission in near-elimination settings. Although antibody detection is a promising approach, it is usually unable to discriminate active infections from past ones. Moreover, crude antigens such as soluble egg antigen (SEA) show cross-reactivity with other parasitic infections, and it is difficult to formulate the standard preparations. To resolve these issues, the performances of recombinant antigens have been evaluated. The antibody responses against recombinant S. haematobium serine-protease inhibitor (ShSerpin) and RP26 were previously shown to reflect active schistosome infection in humans. Furthermore, antibody detection using multiple recombinant antigens has been reported to improve the accuracy of antibody-based assays compared to single-target assays. Therefore, we examined the performances of ShSerpin, RP26 and the mixture of these antigens for detecting S. haematobium low-intensity infection and assessed the potential for transmission monitoring. We collected urine and plasma samples from school-aged children in Kwale, Kenya and evaluated S. haematobium prevalence by number of eggs in urine and worm-derived circulating anodic antigen (CAA) in plasma. Among 269 pupils, 50.2% were CAA-positive by the lateral flow test utilizing up-converting phosphor particles (UCP-LF CAA), while only 14.1% were egg-positive. IgG levels to S. haematobium SEA (ShSEA), ShSerpin, RP26, and the mixture of ShSerpin and RP26 were measured by ELISA. The mixture of ShSerpin and RP26 showed the highest sensitivity, 88.7%(125/141)among the four antigens in considering indecisive UCP-LF CAA results as negative. IgG detection against the ShSerpin-RP26 mixture demonstrated better sensitivity for detection of active S. haematobium infection. This recombinant antigen mixture is simpler to produce with higher reproducibility and can potentially replace ShSEA in monitoring transmission under near-elimination settings.