Schistosomiasis is a neglected tropical parasitic disease caused by blood flukes of the genus Schistosoma. Schistosoma japonicum is zoonotic in China, the Philippines, and Indonesia, with bovines acting as major reservoirs of human infection. The primary objective of the trial was to examine the impact of a combination of human mass chemotherapy, snail control through mollusciciding, and SjCTPI bovine vaccination on the rate of human infection.
Methods
A 5-year phase IIIa cluster randomized control trial was conducted among 18 schistosomiasis-endemic villages comprising 18,221 residents in Northern Samar, The Philippines.
Results
Overall, bovine vaccination resulted in a statistically significant decrease in human infection (relative risk [RR] = 0.75; 95% confidence interval [CI] = 0.69 to 0.82) across all trial follow-ups. The best outcome of the trial was when bovine vaccination was combined with snail mollusciciding. This combination resulted in a 31% reduction (RR = 0.69; 95% CI = 0.61 to 0.78) in human infection.
Conclusion
This is the first trial to demonstrate the effectiveness of a bovine vaccine for schistosomiasis in reducing human schistosome infection. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12619001048178).
Allen G. Ross, Donald A. Harn, Delia Chy, Marianette Inobaya, Jerric R. Guevarra, Lisa Shollenberger, Yuesheng Li, Donald P. McManus, Darren J. Gray and Gail M. Williams. 2023. International Journal of Infectious Diseases. S1201-9712(23)00038-3. doi: 10.1016/j.ijid.2023.01.037. Online ahead of print.
Schistosomiasis is a helminthiasis infecting approximately 250 million people worldwide. In 2001, the World Health Assembly (WHA) 54.19 resolution defined a new global strategy for control of schistosomiasis through preventive chemotherapy programmes. This resolution culminated in the 2006 WHO guidelines that recommended empirical treatment by mass drug administration with praziquantel, predominately to school-aged children in endemic settings at regular intervals. Since then, school-based and community-based preventive chemotherapy programmes have been scaled-up, reducing schistosomiasis-associated morbidity. Over the past 15 years, new scientific evidence-combined with a more ambitious goal of eliminating schistosomiasis and an increase in the global donated supply of praziquantel-has highlighted the need to update public health guidance worldwide. In February, 2022, WHO published new guidelines with six recommendations to update the global public health strategy against schistosomiasis, including expansion of preventive chemotherapy eligibility from the predominant group of school-aged children to all age groups (2 years and older), lowering the prevalence threshold for annual preventive chemotherapy, and increasing the frequency of treatment. This Review, written by the 2018-2022 Schistosomiasis Guidelines Development Group and its international partners, presents a summary of the new WHO guideline recommendations for schistosomiasis along with their historical context, supporting evidence, implications for public health implementation, and future research needs.
Nathan C Lo, Fernando Schemelzer Moraes Bezerra, Daniel G Colley, Fiona M Fleming, Mamoun Homeida, Narcis Kabatereine, Fatma M Kabole, Charles H King, Margaret A Mafe, Nicholas Midzi, Francisca Mutapi, Joseph R Mwanga, Reda M R Ramzy, Fadjar Satrija, J Russell Stothard, Mamadou Souncalo Traoré, Joanne P Webster, Jürg Utzinger, Xiao-Nong Zhou, Anthony Danso-Appiah, Paolo Eusebi, Eric S Loker, Charles O Obonyo, Reginald Quansah, Song Liang, Michel Vaillant, M Hassan Murad, Paul Hagan, Amadou Garba. Lancet Infect Dis. 2022 May 17;S1473-3099(22)00221-3. doi: 10.1016/S1473-3099(22)00221-3.
Background: Over the past 20 years, schistosomiasis control has been scaled up. Preventive chemotherapy with praziquantel is the main intervention. We aimed to assess the effect of preventive chemotherapy on schistosomiasis prevalence in sub-Saharan Africa, comparing 2000-10 with 2011-14 and 2015-19.
Methods: In this spatiotemporal modelling study, we analysed survey data from school-aged children (aged 5-14 years) in 44 countries across sub-Saharan Africa. The data were extracted from the Global Neglected Tropical Diseases database and augmented by 2018 and 2019 survey data obtained from disease control programmes. Bayesian geostatistical models were fitted to Schistosoma haematobium and Schistosoma mansoni survey data. The models included data on climatic predictors obtained from satellites and other open-source environmental databases and socioeconomic predictors obtained from various household surveys. Temporal changes in Schistosoma species prevalence were estimated by a categorical variable with values corresponding to the three time periods (2000-10, 2011-14, and 2015-19) during which preventive chemotherapy interventions were scaled up.
Findings: We identified 781 references with relevant geolocated schistosomiasis survey data for 2000-19. There were 19 166 unique survey locations for S haematobium and 23 861 for S mansoni, of which 77% (14 757 locations for S haematobium and 18 372 locations for S mansoni) corresponded to 2011-19. Schistosomiasis prevalence among school-aged children in sub-Saharan Africa decreased from 23·0% (95% Bayesian credible interval 22·1-24·1) in 2000-10 to 9·6% (9·1-10·2) in 2015-19, an overall reduction of 58·3%. The reduction of S haematobium was 67·9% (64·6-71·1) and that of S mansoni 53·6% (45·2-58·3) when comparing 2000-10 with 2015-19.
Interpretation: Our model-based estimates suggest that schistosomiasis prevalence in sub-Saharan Africa has decreased considerably, most likely explained by the scale-up of preventive chemotherapy. There is a need to consolidate gains in the control of schistosomiasis by means of preventive chemotherapy, coupled with other interventions to interrupt disease transmission.
Funding: European Research Council and WHO.
Christos Kokaliaris, Amadou Garba, Martin Matuska, Rachel N Bronzan, Daniel G Colley, Ameyo M Dorkenoo, Uwem F Ekpo, Fiona M Fleming, Michael D French, Achille Kabore, Jean B Mbonigaba, Nicholas Midzi, Pauline N M Mwinzi, Eliézer K N’Goran, Maria Rebollo Polo, Moussa Sacko, Louis-Albert Tchuem Tchuenté, Edridah M Tukahebwa, Pitchouna A Uvon, Guojing Yang, Lisa Wiesner, Yaobi Zhang, Jürg Utzinger, Penelope Vounatsou. The Lancet Infectious Diseases, 2021, https://doi.org/10.1016/S1473-3099(21)00090-6.
Dan Colley, professor emeritus of microbiology and former director of the Center for Tropical and Emerging Global Diseases, devoted much of his career to studying schistosomiasis, a disease caused by waterborne parasites that is endemic in several African nations. (photo credit: Andrew Tucker)
Schistosomiasis, caused by several species of the parasitic worm Schistosoma, is a disease of poverty. The debilitating illness keeps people in a cycle of poverty due to missed educational and employment opportunities. In children, repeated infections often lead to anemia, malnutrition and learning disabilities. While there are no current preventive drug therapies or vaccines, annual mass drug administration (MDA) is often used to treat all elementary school children in countries where Schistosoma species are endemic.
“Treating with praziquantel through MDA programs is really successful in reducing schistosomiasis,” said Dan Colley, professor emeritus in the Franklin College of Arts and Sciences’ Department of Microbiology and former director of the Center for Tropical and Emerging Global Diseases. “However, in our studies we were seeing a few villages that didn’t really respond to annual MDA with lower numbers of infections. And it wasn’t just a few villages—in any given group of 25 study villages, we saw what we’re calling ‘persistent hotspots.’”
Schistosoma parasites develop in certain species of freshwater snails and are shed into the water where the form of the parasite that infects people can survive up to 24 hours. When an individual comes to the water to bathe, wash clothes, work or play, the parasites invade through the skin.
Several weeks after infection, the worms mature and begin to produce eggs that travel to the person’s bladder or intestines, where they are expelled through urine or stool. When freshwater sources are contaminated with human urine or fecal matter that contain these eggs, the life cycle begins again when the parasite eggs hatch and infect appropriate freshwater snails.
In a recent study published in PLOS ONE, Colley and his colleagues at the University of Georgia, Kenya Medical Research Institute (KEMRI), and Kenya’s Ministry of Health found high use of surface water and low use of latrines were factors associated with being a PHS and likely contributed to persistent levels of Schistosoma infection in these PHS villages—even in the face of annual MDA.
High use of surface water and low use of latrine were found to be contributing factors to persistence levels of Schistosoma infection in a new study published in PLOS ONE. Left: Locals washing clothes at Kisian Beach, Lake Victoria. Right: Dan Colley at a site where sand harvesters work.
The study in western Kenya included both villages responding well to MDA (with a declining level of schistosomiasis) and those that are considered persistent hotspots. All the villages have fewer than 2,000 people, and most range between 500 and 1,500 residents. They often contain a crossroads that serves as the town center with a few shops. While the town center and the nearby houses have electricity, homes farther out might not. Villages considered PHS were located closer to open water sources, and more residents were employed in water-based jobs such as car washing and sand harvesting.
It was also found that these PHS villages had fewer latrines than villages that responded well to MDA, which likely led to more human fecal matter washing into the surface waters. The researchers believe that for these PHS villages, increasing latrine availability and use would reduce Schistosoma prevalence. However, it isn’t just a case of “if you build it, they will come.”
There are several barriers that would need to be overcome. Latrines, commonly called outhouses, are often smelly and attract flies and rats, which then attract snakes. In addition to issues of maintenance, there are social and educational components that need to be considered to change practices. But even when the people are willing, increased latrine use doesn’t always work.
Residents of “persistent hot spot” villages in Africa are more likely to be employed in a water-based occupation, such as car washing, than those in villages with lower rates of schistosomiasis. As the parasites that cause the disease must pass through certain species of freshwater snails before infecting humans, better latrine use in these villages may reduce transmission. (Photo courtesy of Dan Colley)
Colley recounts the story of a group of car washers he and other colleagues at KEMRI and the Centers for Disease Control and Prevention worked with for over two decades. These men are well-versed on Schistosoma, and they decided to build a latrine.
“They knew the life cycle as well as we did, maybe better,” recalls Colley.
The car washers even made it an entrepreneurial pursuit by selling toilet paper for a shilling. However, when the rainy season came, the latrine was flooded, and all that waste was washed into the nearby lake where they worked daily.
This story illustrates just one of the challenges public health officials face in trying to incorporate wells and latrines into national programs to eliminate schistosomiasis. Studies like the one by Colley and his colleagues demonstrate the need to look beyond drug treatment when pushing to move from control to elimination of schistosomiasis.
“We can keep doing MDA, which is helpful, but eventually the worms may become drug resistant,” said Colley. “But with persistent hotspots now being found in everyone’s studies, we know we need to do better. That means we need to advocate for access to clean water sources, sanitation and perhaps ultimately vaccines, as well.”
Background: Evidence indicates that whereas repeated rounds of mass drug administration (MDA) programs have reduced schistosomiasis prevalence to appreciable levels in some communities referred to here as responding villages (R). However, prevalence has remained high or less than anticipated in other areas referred to here as persistent hotspot villages (PHS). Using a cross-sectional quantitative approach, this study investigated the factors associated with sustained high Schistosoma mansoni prevalence in some villages despite repeated high annual treatment coverage in western Kenya.
Method: Water contact sites selected based on observation of points where people consistently go to collect water, wash clothes, bathe, swim or play (young children), wash cars and harvest sand were mapped using hand-held smart phones on the Commcare platform. Quantitative cross-sectional surveys on behavioral characteristics were conducted using interviewer-based semi-structured questionnaires administered to assess water usage/contact patterns and open defecation. Questionnaires were administered to 15 households per village, 50 pupils per school and 1 head teacher per school. One stool and urine sample was collected from 50 school children aged 9-12 year old and 50 adults from both responding (R) and persistent hotspot (PHS) villages. Stool was analyzed by the Kato-Katz method for eggs of S. mansoni and soil-transmitted helminths. Urine samples were tested using the point-of-care circulating cathodic antigen (POC-CCA) test for detection of S. mansoni antigen.
Results: There was higher latrine coverage in R (n = 6) relative to PHS villages (n = 6) with only 33% of schools in the PHS villages meeting the WHO threshold for boy: latrine coverage ratio versus 83.3% in R, while no villages met the girl: latrine ratio requirement. A higher proportion of individuals accessed unprotected water sources for both bathing and drinking (68.5% for children and 89% for adults) in PHS relative to R villages. In addition, frequency of accessing water sources was higher in PHS villages, with swimming being the most frequent activity. As expected based upon selection criteria, both prevalence and intensity of S. mansoni were higher in the PHS relative to R villages (prevalence: 43.7% vs 20.2%; P < 0.001; intensity: 73.8 ± 200.6 vs 22.2 ± 96.0, P < 0.0001), respectively.
Conclusion: Unprotected water sources and low latrine coverage are contributing factors to PHS for schistosomiasis in western Kenya. Efforts to increase provision of potable water and improvement in latrine infrastructure is recommended to augment control efforts in the PHS areas.
Musuva RM, Odiere MR, Mwinzi PNM, Omondi IO, Rawago FO, Matendechero SH, Kittur N, Campbell Jr CH, Colley DG. (2021) Unprotected water sources and low latrine coverage are contributing factors to persistent hotspots for schistosomiasis in western Kenya. PLoS ONE 16(9): e0253115. https://doi.org/10.1371/journal.pone.0253115
Background: The prevalence of Schistosoma mansoni infection is usually assessed by the Kato-Katz diagnostic technique. However, Kato-Katz thick smears have low sensitivity, especially for light infections. Egg count models fitted on individual level data can adjust for the infection intensity-dependent sensitivity and estimate the ‘true’ prevalence in a population. However, application of these models is complex and there is need for adjustments that can be done without modelling expertise. This study provides estimates of the ‘true’ S. mansoni prevalence from population summary measures of observed prevalence and infection intensity using extensive simulations parametrized with data from different settings in sub-Saharan Africa.
Methodology: An individual-level egg count model was applied to Kato-Katz data to determine the S. mansoni infection intensity-dependent sensitivity for various sampling schemes. Observations in populations with varying forces of transmission were simulated, using standard assumptions about the distribution of worms and their mating behavior. Summary measures such as the geometric mean infection, arithmetic mean infection, and the observed prevalence of the simulations were calculated, and parametric statistical models fitted to the summary measures for each sampling scheme. For validation, the simulation-based estimates are compared with an observational dataset not used to inform the simulation.
Principal findings: Overall, the sensitivity of Kato-Katz in a population varies according to the mean infection intensity. Using a parametric model, which takes into account different sampling schemes varying from single Kato-Katy to triplicate slides over three days, both geometric and arithmetic mean infection intensities improve estimation of sensitivity. The relation between observed and ‘true’ prevalence is remarkably linear and triplicate slides per day on three consecutive days ensure close to perfect sensitivity.
Conclusions/significance: Estimation of ‘true’ S. mansoni prevalence is improved when taking into account geometric or arithmetic mean infection intensity in a population. We supply parametric functions and corresponding estimates of their parameters to calculate the ‘true’ prevalence for sampling schemes up to 3 days with triplicate Kato-Katz thick smears per day that allow estimation of the ‘true’ prevalence.
Bärenbold O, Garba A, Colley DG, Fleming FM, Assaré RK, Tukahebwa EM, et al. (2021) Estimating true prevalence of Schistosoma mansoni from population summary measures based on the Kato-Katz diagnostic technique. PLoS Negl Trop Dis 15(4): e0009310. https://doi.org/10.1371/journal.pntd.0009310
Monoclonal antibodies (mAbs) that recognize glycans are useful tools to assess carbohydrates’ structure and function. We sought to produce IgG mAbs to the human milk oligosaccharide (HMO), lacto-N-fucopentaose III (LNFPIII). LNFPIII contains the Lewisx antigen, which is found on the surface of schistosome parasites. mAbs binding the Lewisx antigen are well-reported in the literature, but mAbs recognizing HMO structures are rare. To generate mAbs, mice were immunized with LNFPIII-DEX (P3DEX) plus CpGs in VacSIM®, a novel vaccine/drug delivery platform. Mice were boosted with LNFPIII-HSA (P3HSA) plus CpGs in Incomplete Freund’s Adjuvant (IFA). Splenocytes from immunized mice were used to generate hybridomas and were screened against LNFPIII conjugates via enzyme-linked immunosorbent assay (ELISA). Three positive hybridomas were expanded, and one hybridoma, producing IgG and IgM antibodies, was cloned via flow cytometry. Clone F1P2H4D8D5 was selected because it produced IgG1 mAbs, but rescreening unexpectedly showed binding to both LNFPIII and lacto-N-neotetraose (LNnT) conjugates. To further assess the specificity of the mAb, we screened it on two glycan microarrays and found no significant binding. This finding suggests that the mAb binds to the acetylphenylenediamine (APD) linker-spacer structure of the conjugate. We present the results herein, suggesting that our new mAb could be a useful probe for conjugates using similar linker spacer structures.
Schistosomiasis is among the most common parasitic diseases in the world, with over 142 million people infected in low- and middle-income countries. Measuring population-level transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected using stool microscopy, which is logistically difficult at program scale and has low sensitivity when people have low infection burdens. We compared serological measures of transmission based on antibody response to S. mansoni soluble egg antigen (SEA) with stool-based measures of infection among 3,663 preschool-age children in an area endemic for S. mansoni in western Kenya. We estimated force of infection among children using the seroconversion rate and examined how it varied geographically and by age. At the community level, serological measures of transmission aligned with stool-based measures of infection (ρ = 0.94), and serological measures provided more resolution for between-community differences at lower levels of infection. Force of infection showed a clear gradient of transmission with distance from Lake Victoria, with 94% of infections and 93% of seropositive children in communities <1.5 km from the lake. Force of infection increased through age 3 y, by which time 65% (95% CI: 53%, 75%) of children were SEA positive in high-transmission communities—2 y before they would be reached by school-based deworming programs. Our results show that serologic surveillance platforms represent an important opportunity to guide and monitor schistosomiasis control programs, and that in high-transmission settings preschool-age children represent a key population missed by school-based deworming programs.
Benjamin F. Arnold, Henry Kanyi, Sammy M. Njenga, Fredrick O. Rawago, Jeffrey W. Priest, W. Evan Secor, Patrick J. Lammie, Kimberly Y. Won, and Maurice R. Odiere. Proc Natl Acad Sci U S A. 2020 Aug 31;202008951. doi: 10.1073/pnas.2008951117.
We assessed the feasibility of using a test, treat, track, test, and treat (5T) active surveillance strategy to identify and treat individuals with schistosomiasis in three very low-prevalence villages in Kafr El Sheikh Governorate, Egypt. Primary index cases (PICs) were identified using the point-of-care circulating cathodic antigen (POC-CCA) assay in schools, in rural health units (retesting individuals with positive Kato-Katz examinations over the previous 6 months), and at potential water transmission sites identified by PICs and field observations. Primary cases identified potential second-generation cases-people with whom they shared water activities-who were then tracked, tested, and treated if infected. Those sharing water activities with second-generation cases were also tested. The yield of PICs from the three venues were 128 of 3,576 schoolchildren (3.6%), 42 of 696 in rural health units (6.0%), and 83 of 1,156 at water contact sites (7.2%). There were 118 second- and 19 third-generation cases identified. Persons testing positive were treated with praziquantel. Of 388 persons treated, 368 (94.8%) had posttreatment POC-CCA tests 3-4 weeks after treatment, and 81.8% (301) became negative. The 67 persons remaining positive had negative results after a second treatment. Therefore, all those found positive, treated, and followed up were negative following one or two treatments. Analysis of efforts as expressed in person-hours indicates that 4,459 person-hours were required for these 5T activities, with nearly 65% of that time spent carrying out interviews, treatments, and evaluations following treatment. The 5T strategy appears feasible and acceptable as programs move toward elimination.
Reda M R Ramzy, Amal Rabiee, Khaled M Abd Elaziz, Carl H Campbell, Nupur Kittur, Daniel G Colley, Ayat A Haggag. Am J Trop Med Hyg. 2020 Jul 13. doi: 10.4269/ajtmh.20-0156.
