Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

Population genomics of ancient and modern Trichuris trichiura.

The neglected tropical disease trichuriasis is caused by the whipworm Trichuris trichiura, a soil-transmitted helminth that has infected humans for millennia. Today, T. trichiura infects as many as 500 million people, predominantly in communities with poor sanitary infrastructure enabling sustained faecal-oral transmission. Using whole-genome sequencing of geographically distributed worms collected from human and other primate hosts, together with ancient samples preserved in archaeologically-defined latrines and deposits dated up to one thousand years old, we present the first population genomics study of T. trichiura. We describe the continent-scale genetic structure between whipworms infecting humans and baboons relative to those infecting other primates. Admixture and population demographic analyses support a stepwise distribution of genetic variation that is highest in Uganda, consistent with an African origin and subsequent translocation with human migration. Finally, genome-wide analyses between human samples and between human and non-human primate samples reveal local regions of genetic differentiation between geographically distinct populations. These data provide insight into zoonotic reservoirs of human-infective T. trichiura and will support future efforts toward the implementation of genomic epidemiology of this globally important helminth.

Chromosome-level genome of Schistosoma haematobium underpins genome-wide explorations of molecular variation.

Urogenital schistosomiasis is caused by the blood fluke Schistosoma haematobium and is one of the most neglected tropical diseases worldwide, afflicting > 100 million people. It is characterised by granulomata, fibrosis and calcification in urogenital tissues, and can lead to increased susceptibility to HIV/AIDS and squamous cell carcinoma of the bladder. To complement available treatment programs and break the transmission of disease, sound knowledge and understanding of the biology and ecology of S. haematobium is required. Hybridisation/introgression events and molecular variation among members of the S. haematobium-group might effect important biological and/or disease traits as well as the morbidity of disease and the effectiveness of control programs including mass drug administration. Here we report the first chromosome-contiguous genome for a well-defined laboratory line of this blood fluke. An exploration of this genome using transcriptomic data for all key developmental stages allowed us to refine gene models (including non-coding elements) and annotations, discover 'new' genes and transcription profiles for these stages, likely linked to development and/or pathogenesis. Molecular variation within S. haematobium among some geographical locations in Africa revealed unique genomic 'signatures' that matched species other than S. haematobium, indicating the occurrence of introgression events. The present reference genome (designated Shae.V3) and the findings from this study solidly underpin future functional genomic and molecular investigations of S. haematobium and accelerate systematic, large-scale population genomics investigations, with a focus on improved and sustained control of urogenital schistosomiasis.

Achieving equity in UHC interventions: who is left behind by neglected tropical disease programmes in Cameroon?

Background: The UN's Sustainable Development Goals (SDGs) which pledge to leave no one behind for Universal health coverage (UHC) raise the importance of ensuring equitable health outcomes and healthcare delivery. As Neglected Tropical Diseases (NTDs) affect the most disadvantaged and hard to reach populations, they are considered a litmus test for Universal health coverage.Objective: Here, we assess the challenges of implementing Mass Drug Administrations (MDAs) for schistosomiasis prevention and control, in a context of expanded treatment where both community and school-based distribution were carried out, assessing which groups are missed and developing strategies to enhance equity.Methods: This is a qualitative study applying ethnographic observations, in-depth interviews (109) and focus group discussions (6) with key informants and other community members. Participants included community drug distributors, teachers, health workers, and implementing partners across four schistosomiasis endemic regions in Cameroon. Data collected were analysed thematically.Results: Programme implementation gaps have created circumstances where indigenous farmers (originally from the region) and migrating farmers (not originally from the region known as 'strangers' and 'farm hands'), women of reproductive age and school-aged children are continuously missed in MDA efforts in Cameroon. Key implementation challenges that limit access to MDA within this context include inadequate sensitization campaigns that don't sufficiently build trust with different groups; limits in CDD training around pregnancy and reproductive health; lack of alignment between distribution and community availability and the exclusion of existing formal and informal governance structures that have established trusting community relationships.Conclusion: Through identifying key populations missed in MDAs within specific contexts, we highlight how social inclusion and equity could be increased within the Cameroonian context. A main recommendation is to strengthen trust at the community level and work with established partnerships and local governance structures that can support sustainable solutions for more equitable MDA campaigns.

Current decline in schistosome and soil-transmitted helminth infections among school children at Loum, Littoral region, Cameroon.

INTRODUCTION: Soil-transmitted helminth infections (STHs) and schistosomiasis have serious consequences for the health, education and nutrition of children in developing countries. As Loum is known as a highly endemic commune for these infections, several deworming campaigns have been carried out in the past. The purpose of this study was to determine any changes that have occurred since then in the characteristics of these infections among schoolchildren in this site. METHODS: A cross-sectional study was conducted in October 2016 on 289 schoolchildren. Stool and urine samples were collected and examined to determine the prevalence and intensity of helminth infections. RESULTS: The highest prevalence was noted for Schistosoma haematobium (34.2%), followed by Ascaris lumbricoides (8.6%), S. mansoni (4.9%) and Trichuris trichiura (4.9%) in decreasing order. A prevalence of less than 2% was noted for each of the other two helminths. The highest mean intensity was found for S. haematobium (39.6 eggs/10 ml of urine), followed by A. lumbricoides (24.2 eggs per gram of faeces: epg), Strongyloides stercoralis (16.6 epg) and Schistosoma mansoni (12.3 epg). The prevalence of T. trichiura was significantly higher in boys and that of S. haematobium in children aged 10 years or older, while the differences between other values of prevalence or between egg burdens were not significant. CONCLUSION: Compared with values reported in 2003, the prevalence and intensity of schistosomiases and STH infections in Loum has sharply decreased in 2016. Confirmation of this decrease in the years to come allowed to space deworming campaigns among schoolchildren.

Efficacy of Sida pilosa Retz aqueous extract against Schistosoma mansoni - induced granulomatous inflammation in the liver and the intestine of mice: histomorphometry and gastrointestinal motility evaluation.

BACKGROUND: The macerate of Sida pilosa aerial parts is used empirically for the treatment of intestinal helminthiasis. Previous studies have shown that Sida pilosa aqueous extract (SpAE) has schistosomicidal, antioxidant, anti-inflammatory and anti-fibrotic activities in Schistosoma mansoni infection. This study was designed to evaluate the effect of SpAE on the granulomatous inflammation induced by S. mansoni in the liver and the intestine of mice by histomorphometry; as well as on the gastrointestinal motility. METHODS: To study the effect of SpAE on the liver and intestine histomorphometry and on the gastrointestinal motility, SpAE was administered at 200 mg/kg per os to S. mansoni-infected mice for 4 weeks. Praziquantel was used as reference drug. Prior to carrying out sacrifice, a batch of mice was subjected to gastrointestinal transit evaluation with 3% charcoal meal. After sacrifying another batch of mice, we performed histological and morphometric analyses of the liver and the ileum. We measured the following: total proteins, transaminases, malondialdehyde, nitrites, superoxide dismutase, catalase and reduced glutathione. The effect of SpAE (4, 8, 16 and 32 mg/mL) on the ileum contractile activity was evaluated either in the absence or in the presence of pharmacological blockers. RESULTS: SpAE induced a significant reduction of hepatosplenomegaly and intestine enlargement. The number of granulomas was reduced by 52.82% in the liver and 52.79% in the intestine, whereas the volume of hepatic granulomas decreased by 48.76% after SpAE treatment. SpAE also reduced (p < 0.001) the ileal muscular layer thickness. The levels of total proteins, transaminases, malondialdehyde, nitrites, superoxide dismutase, catalase and reduced glutathione were restored after treatment of infected mice with SpAE. A normalization of the gastrointestinal transit was also recorded after SpAE treatment. The effect of SpAE on intestinal motility was mediated via intracellular and extracellular calcium mobilization. CONCLUSION: Our findings provide evidence that SpAE improves granulomatous inflammation induced by S. mansoni both in the liver and in the intestine, as well as it re-establishes normal gastrointestinal transit. SpAE may be used for the development of alternative medicine against S. mansoni infection.

Enhancing collaboration between China and African countries for schistosomiasis control.

Schistosomiasis remains an important public health issue, with a large number of cases reported across sub-Saharan Africa, and parts of Asia and Latin America. China was once highly endemic, but has made substantial progress and is moving towards elimination of schistosomiasis. Meanwhile, despite long-term, repeated, school-based chemotherapy in many African countries, more than 90% of all schistosomiasis cases are concentrated in Africa, and hence, this continent constitutes the key challenge for schistosomiasis control. Opportunities and issues for international collaboration in the fight against schistosomiasis are outlined with a focus on China's experiences, including the role of public health authorities and intersectoral collaboration, use of new and effective snail control approaches and diagnostic tools adapted to the specific stage of control, as well as the strengthening of risk mapping and surveillance-response mechanisms. Training courses targeting African governmental officials and professionals, coupled with field visits of African scientists and control programme managers to China, and vice versa, are considered important for improved schistosomiasis control and elimination. The crucial question remains whether the Chinese experience can be translated and applied in African countries to improve the effectiveness of health interventions and scale-up.

Spatial distribution of schistosomiasis and treatment needs in sub-Saharan Africa: a systematic review and geostatistical analysis.

BACKGROUND: Schistosomiasis affects more than 200 million individuals, mostly in sub-Saharan Africa, but empirical estimates of the disease burden in this region are unavailable. We used geostatistical modelling to produce high-resolution risk estimates of infection with Schistosoma spp and of the number of doses of praziquantel treatment needed to prevent morbidity at different administrative levels in 44 countries. METHODS: We did a systematic review to identify surveys including schistosomiasis prevalence data in sub-Saharan Africa via PubMed, ISI Web of Science, and African Journals Online, from inception to May 2, 2014, with no restriction of language, survey date, or study design. We used Bayesian geostatistical meta-analysis and rigorous variable selection to predict infection risk over a grid of 1 155 818 pixels at 5 × 5 km, on the basis of environmental and socioeconomic predictors and to calculate the number of doses of praziquantel needed for prevention of morbidity. FINDINGS: The literature search identified Schistosoma haematobium and Schistosoma mansoni surveys done in, respectively, 9318 and 9140 unique locations. Infection risk decreased from 2000 onwards, yet estimates suggest that 163 million (95% Bayesian credible interval [CrI] 155 million to 172 million; 18·5%, 17·6-19·5) of the sub-Saharan African population was infected in 2012. Mozambique had the highest prevalence of schistosomiasis in school-aged children (52·8%, 95% CrI 48·7-57·8). Low-risk countries (prevalence among school-aged children lower than 10%) included Burundi, Equatorial Guinea, Eritrea, and Rwanda. The numbers of doses of praziquantel needed per year were estimated to be 123 million (95% CrI 121 million to 125 million) for school-aged children and 247 million (239 million to 256 million) for the entire population. INTERPRETATION: Our results will inform policy makers about the number of treatments needed at different levels and will guide the spatial targeting of schistosomiasis control interventions. FUNDING: European Research Council, China Scholarship Council, UBS Optimus Foundation, and Swiss National Science Foundation.

Spatial and temporal distribution of soil-transmitted helminth infection in sub-Saharan Africa: a systematic review and geostatistical meta-analysis.

BACKGROUND: Interest is growing in predictive risk mapping for neglected tropical diseases (NTDs), particularly to scale up preventive chemotherapy, surveillance, and elimination efforts. Soil-transmitted helminths (hookworm, Ascaris lumbricoides, and Trichuris trichiura) are the most widespread NTDs, but broad geographical analyses are scarce. We aimed to predict the spatial and temporal distribution of soil-transmitted helminth infections, including the number of infected people and treatment needs, across sub-Saharan Africa. METHODS: We systematically searched PubMed, Web of Knowledge, and African Journal Online from inception to Dec 31, 2013, without language restrictions, to identify georeferenced surveys. We extracted data from household surveys on sources of drinking water, sanitation, and women's level of education. Bayesian geostatistical models were used to align the data in space and estimate risk of with hookworm, A lumbricoides, and T trichiura over a grid of roughly 1 million pixels at a spatial resolution of 5 × 5 km. We calculated anthelmintic treatment needs on the basis of WHO guidelines (treatment of all school-aged children once per year where prevalence in this population is 20-50% or twice per year if prevalence is greater than 50%). FINDINGS: We identified 459 relevant survey reports that referenced 6040 unique locations. We estimate that the prevalence of hookworm, A lumbricoides, and T trichiura among school-aged children from 2000 onwards was 16·5%, 6·6%, and 4·4%. These estimates are between 52% and 74% lower than those in surveys done before 2000, and have become similar to values for the entire communities. We estimated that 126 million doses of anthelmintic treatments are required per year. INTERPRETATION: Patterns of soil-transmitted helminth infection in sub-Saharan Africa have changed and the prevalence of infection has declined substantially in this millennium, probably due to socioeconomic development and large-scale deworming programmes. The global control strategy should be reassessed, with emphasis given also to adults to progress towards local elimination. FUNDING: Swiss National Science Foundation and European Research Council.

Genetic diversity within Schistosoma haematobium: DNA barcoding reveals two distinct groups.

BACKGROUND: Schistosomiasis in one of the most prevalent parasitic diseases, affecting millions of people and animals in developing countries. Amongst the human-infective species S. haematobium is one of the most widespread causing urogenital schistosomiasis, a major human health problem across Africa, however in terms of research this human pathogen has been severely neglected. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the genetic diversity of Schistosoma haematobium, a DNA 'barcoding' study was performed on parasite material collected from 41 localities representing 18 countries across Africa and the Indian Ocean Islands. Surprisingly low sequence variation was found within the mitochondrial cytochrome oxidase subunit I (cox1) and the NADH-dehydrogenase subunit 1 snad1). The 61 haplotypes found within 1978 individual samples split into two distinct groups; one (Group 1) that is predominately made up of parasites from the African mainland and the other (Group 2) that is made up of samples exclusively from the Indian Ocean Islands and the neighbouring African coastal regions. Within Group 1 there was a dominance of one particular haplotype (H1) representing 1574 (80%) of the samples analyzed. Population genetic diversity increased in samples collected from the East African coastal regions and the data suggest that there has been movement of parasites between these areas and the Indian Ocean Islands. CONCLUSIONS/SIGNIFICANCE: The high occurrence of the haplotype (H1) suggests that at some point in the recent evolutionary history of S. haematobium in Africa the population may have passed through a genetic 'bottleneck' followed by a population expansion. This study provides novel and extremely interesting insights into the population genetics of S. haematobium on a large geographic scale, which may have consequence for control and monitoring of urogenital schistosomiasis.

Assessment of the anthelmintic efficacy of albendazole in school children in seven countries where soil-transmitted helminths are endemic.

BACKGROUND: The three major soil-transmitted helminths (STH) Ascaris lumbricoides, Trichuris trichiura and Necator americanus/Ancylostoma duodenale are among the most widespread parasites worldwide. Despite the global expansion of preventive anthelmintic treatment, standard operating procedures to monitor anthelmintic drug efficacy are lacking. The objective of this study, therefore, was to define the efficacy of a single 400 milligram dose of albendazole (ALB) against these three STH using a standardized protocol. METHODOLOGY/PRINCIPAL FINDINGS: Seven trials were undertaken among school children in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam. Efficacy was assessed by the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) using the McMaster egg counting technique to determine fecal egg counts (FEC). Overall, the highest CRs were observed for A. lumbricoides (98.2%) followed by hookworms (87.8%) and T. trichiura (46.6%). There was considerable variation in the CR for the three parasites across trials (country), by age or the pre-intervention FEC (pre-treatment). The latter is probably the most important as it had a considerable effect on the CR of all three STH. Therapeutic efficacies, as reflected by the FECRs, were very high for A. lumbricoides (99.5%) and hookworms (94.8%) but significantly lower for T. trichiura (50.8%), and were affected to different extents among the 3 species by the pre-intervention FEC counts and trial (country), but not by sex or age. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that a FECR (based on arithmetic means) of >95% for A. lumbricoides and >90% for hookworms should be the expected minimum in all future surveys, and that therapeutic efficacy below this level following a single dose of ALB should be viewed with concern in light of potential drug resistance. A standard threshold for efficacy against T. trichiura has yet to be established, as a single-dose of ALB is unlikely to be satisfactory for this parasite. TRIAL REGISTRATION: ClinicalTrials.gov NCT01087099.

Origin and diversification of the human parasite Schistosoma mansoni.

Schistosoma mansoni is the most widespread of the human-infecting schistosomes, present in 54 countries, predominantly in Africa, but also in Madagascar, the Arabian Peninsula, and the Neotropics. Adult-stage parasites that infect humans are also occasionally recovered from baboons, rodents, and other mammals. Larval stages of the parasite are dependent upon certain species of freshwater snails in the genus Biomphalaria, which largely determine the parasite's geographical range. How S. mansoni genetic diversity is distributed geographically and among isolates using different hosts has never been examined with DNA sequence data. Here we describe the global phylogeography of S. mansoni using more than 2500 bp of mitochondrial DNA (mtDNA) from 143 parasites collected in 53 geographically widespread localities. Considerable within-species mtDNA diversity was found, with 85 unique haplotypes grouping into five distinct lineages. Geographical separation, and not host use, appears to be the most important factor in the diversification of the parasite. East African specimens showed a remarkable amount of variation, comprising three clades and basal members of a fourth, strongly suggesting an East African origin for the parasite 0.30-0.43 million years ago, a time frame that follows the arrival of its snail host. Less but still substantial variation was found in the rest of Africa. A recent colonization of the New World is supported by finding only seven closely related New World haplotypes which have West African affinities. All Brazilian isolates have nearly identical mtDNA haplotypes, suggesting a founder effect from the establishment and spread of the parasite in this large country.

Determination of ED50 values for praziquantel in praziquantel-resistant and -susceptible Schistosoma mansoni isolates.

The dose of praziquantel required to kill 50% of adult worms in vivo (i.e. the ED50) was estimated for nine different isolates of Schistosoma mansoni in infected mice. Four of the isolates were selected because they had not knowingly been in contact with the drug (i.e. they were putatively praziquantel-susceptible). Five putatively praziquantel-resistant isolates were chosen because they had been selectively bred for drug-resistance in the laboratory and/or had previously been shown to be relatively resistant to praziquantel in the field. The work was performed in three laboratories in different countries using pre-agreed and comparable experimental protocols. All four praziquantel-susceptible isolates had ED50s estimated to be <100 mg/kg (mean=70+/-7 SD; median=68), while all five putatively praziquantel-resistant isolates had estimated ED50s >100 mg/kg (mean=209+/-48 SD; median=192). Thus, the five praziquantel-resistant isolates, including two that had been subjected to drug pressure during more than 20 passages in mice, had drug ED50s that were approximately three times as great as those of the praziquantel-susceptible isolates. Two of the five isolates in the putatively resistant group had previously been passaged 15 or more times in mice without administration of drug-pressure, but had ED50s consistent with the other three isolates in the group, indicating that the trait of praziquantel-resistance did not necessarily impair biological fitness during laboratory passage. The protocols used here to estimate the praziquantel ED50s of S. mansoni isolates should be useful for establishing and monitoring the drug susceptibility/resistance profiles of parasite isolates freshly obtained from endemic areas, particularly those in which increased usage of the drug is likely to occur.

Efficacy of praziquantel against Schistosoma haematobium infection in children.

A study was performed to determine the efficacy of praziquantel (PZQ) against Schistosoma haematobium. Children (n = 592) infected with S. haematobium received either a single treatment with PZQ (40 mg/kg) or two or three treatments with PZQ at three-week intervals after the initial treatment and efficacy was monitored for nine weeks. Cure rates at three-weeks post-treatment were low (< 50%), suggesting either that worms are killed very slowly or, more likely, that eggs continue to be released from tissues after worm death. Interestingly, a single dose of PZQ showed high efficacy (cure rate > 83% and egg reduction rate > 98%) when assessed from six weeks post-treatment onward. There were no significant differences in cure rates or intensity of infection between the three cohorts at any point in the study, despite the different treatment regimens. Since children were in contact with transmission sites during the study period, the results suggest good efficacy of PZQ against all stages of S. haematobium, including the immature worms.