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Abstract Retrospective cohort studies in Cameroon found an association between Onchocerca volvulus microfilarial load in childhood (measured in 1991–1993) and risk of developing epilepsy later in life (measured in 2017). We parameterised and integrated this relationship (across children aged 3–15 years) into the previously published, stochastic transmission model, EPIONCHO-IBM, for Simulium damnosum sensu lato-transmitted onchocerciasis. We simulated 19 years (1998–2017) of annual ivermectin mass drug administration (MDA) reflecting coverage in the study area, and modelled epilepsy prevalence and incidence. Scenario-based simulations of 25 years of (annual and biannual) MDA in hyper- and holoendemic settings, with 65% and 80% therapeutic coverage, were also conducted. EPIONCHO-IBM predicted 7.6% epilepsy prevalence (compared to 8.2% in the Cameroon study) and incidence of 317 cases/100,000 person-years (compared to 350). In hyperendemic areas, 25 years of biannual MDA (80% coverage) eliminated onchocerciasis-associated epilepsy (OAE) and protected untreated under-fives from its development. Strengthening onchocerciasis programmes, implementing alternative strategies, and evaluating treatment for under-fives and school-age children are crucial to prevent OAE in highly-endemic settings.

Due to the success of large-scale ivermectin mass drug administration (MDA), the aim of onchocerciasis intervention efforts have shifted from control of the disease to elimination of transmission. This has necessitated a greater understanding and comparison of the performance of diagnostic tools in hypoendemic (low prevalence) settings which had not been incorporated into large-scale MDA programmes before the goal switched from onchocerciasis elimination as a public health problem to elimination (interruption) of transmission (EOT). Data on age, sex and duration of residence were collected, prior to ivermectin treatment, across Gabon in 2015 from 5,829 participants in 67 communities from 14 districts. Skin-snip samples (for detection of Onchocerca volvulus microfilariae) were obtained from 4,350 (75 %) and blood samples (for detection of presence of IgG4 antibodies against the O. volvulus Ov16 antigen) from 4,257 of those skin-snip tested (98 %).Whole blood was tested in the field using the SD Ov16 Rapid Diagnostic Test Prototype (Ov16 RDT). Dried blood spots (DBS) were prepared for all blood-sampled individuals. After assessing DBS quality, 2,990 (70 %) samples underwent valid analysis in the lab using horseradish peroxidase (HRP) Ov16 enzyme-linked immunosorbent assay (Ov16 ELISA). The number of positive individuals varied between diagnostic tools with skin-snip microscopy, Ov16 RDT and Ov16 ELISA detecting 337/4,350 (8 %, 95 % CI =7 %–9 %), 383/4,257 (9 %, 8 %–10 %) and 348/2,990 (12 %, 10 %–13 %), respectively. Data were analysed to understand the age profiles of microfilarial and IgG4 antibody prevalence by diagnostic and mapped across Gabon.These data have reuse potential for policy makers, test manufacturers and country programmes when making determinations at community level of the suitability of using Ov16 RDT for conducting delineation mapping or evaluating the current stage of a community or, more generally, an evaluation unit along the EOT path. Further, these data are of use to transmission dynamics modellers who can fit models to these data to better understand the stage(s) in the O. volvulus lifecycle likely responsible for IgG4 antibody seroconversion in the presence of Ov16 antigen. This is crucial for incorporation of antibody prevalence as an output of onchocerciasis transmission models to permit evaluation of currently proposed serological thresholds to inform decisions about Start- or Stop-MDA in the context of onchocerciasis elimination mapping (OEM) and verification of EOT, respectively.

BackgroundLymphatic filariasis (LF) is a neglected tropical disease (NTD) targeted by the World Health Organization for elimination as a public health problem (EPHP). Since 2000, more than 9 billion treatments of antifilarial medicines have been distributed through mass drug administration (MDA) programmes in 72 endemic countries and 17 countries have reached EPHP. Yet in 2021, nearly 900 million people still required MDA with combinations of albendazole, diethylcarbamazine and/or ivermectin. Despite the reliance on these drugs, there remain gaps in understanding of variation in responses to treatment. As demonstrated for other infectious diseases, some urgent questions could be addressed by conducting individual participant data (IPD) meta-analyses. Here, we present the results of a systematic literature review to estimate the abundance of IPD on pre- and post-intervention indicators of infection and/or morbidity and assess the feasibility of building a global data repository.MethodologyWe searched literature published between 1st January 2000 and 5th May 2023 in 15 databases to identify prospective studies assessing LF treatment and/or morbidity management and disease prevention (MMDP) approaches. We considered only studies where individual participants were diagnosed with LF infection or disease and were followed up on at least one occasion after receiving an intervention/treatment.Principal findingsWe identified 138 eligible studies from 23 countries, having followed up an estimated 29,842 participants after intervention. We estimate 14,800 (49.6%) IPD on pre- and post-intervention infection indicators including microfilaraemia, circulating filarial antigen and/or ultrasound indicators measured before and after intervention using 8 drugs administered in various combinations. We identified 33 studies on MMDP, estimating 6,102 (20.4%) IPD on pre- and post-intervention clinical morbidity indicators only. A further 8,940 IPD cover a mixture of infection and morbidity outcomes measured with other diagnostics, from participants followed for adverse event outcomes only or recruited after initial intervention.ConclusionsThe LF treatment study landscape is heterogeneous, but the abundance of studies and related IPD suggest that establishing a global data repository to facilitate IPD meta-analyses would be feasible and useful to address unresolved questions on variation in treatment outcomes across geographies, demographics and in underrepresented groups. New studies using more standardized approaches should be initiated to address the scarcity and inconsistency of data on morbidity management.

Efforts are being directed toward the elimination of onchocerciasis transmission in endemic areas with community-directed treatment with ivermectin (CDTI) in Africa, which greatly reduces onchocerciasis-associated disease. However, onchocerciasis remains a major public health problem in areas of South Sudan, the Democratic Republic of the Congo, Cameroon, and the Central African Republic. Strengthening onchocerciasis elimination efforts in areas with a high prevalence of disease burden is crucial to decrease transmission, morbidity, and mortality. We argue that clinical trials are needed to investigate the safety and efficacy of ivermectin treatment of Onchocerca volvulus-infected pregnant women and children younger than 5 years. Crucially, 6-monthly administration of ivermectin in school-age children at risk of onchocerciasis-associated epilepsy could be achieved by supplementing annual CDTI with an extra round of ivermectin treatment during Child Health Days in schools and/or other distribution sites every year. These strategies would help achieve the elimination of onchocerciasis and its associated disease burden.

Abstract Background Cysticercosis is a zoonotic neglected tropical disease (NTD) that affects humans and pigs following the ingestion of Taenia solium eggs. Human cysticercosis poses a substantial public health burden in endemic countries. The World Health Organization (WHO) aims to target high-endemicity settings with enhanced interventions in 17 countries by 2030. Between 2008 and 2010, Colombia undertook a national baseline serosurvey of unprecedented scale, which led to an estimated seroprevalence of T. solium cysticercus antibodies among the general population of 8.6%. Here, we use contemporary geostatistical approaches to analyse this unique dataset with the aim of understanding the spatial distribution and risk factors associated with human cysticercosis in Colombia to inform how best to target intervention strategies. Methods We used a geostatistical model to estimate individual and household risk factors associated with seropositivity to T. solium cysticercus antibodies from 29,253 people from 133 municipalities in Colombia. We used both independent and spatially structured random effects at neighbourhood/village and municipality levels to account for potential clustering of exposure to T. solium. We present estimates of the distribution and residual correlation of seropositivity at the municipality level. Results High seroprevalence was identified in municipalities located in the north and south of Colombia, with spatial correlation in seropositivity estimated up to approximately 140 km. Statistically significant risk factors associated with seropositivity to T. solium cysticercus were related to age, sex, educational level, socioeconomic status, use of rainwater, consumption of partially cooked/raw pork meat and possession of dogs. Conclusions In Colombia, the distribution of human cysticercosis is influenced by socioeconomic considerations, education and environmental factors related to the spread of T. solium eggs. This information can be used to tailor national intervention strategies, such as targeting spatial hotspots and more highly exposed groups, including displaced people and women. Large-scale seroprevalence surveys accompanied by geospatial mapping are an essential step towards reaching the WHO’s 2021‒2030 NTD roadmap targets. Graphical Abstract

BackgroundAlbendazole is an orally administered anti-parasitic medication with widespread usage in a variety of both programmatic and clinical contexts. Previous work has shown that the drug's pharmacologically active metabolite, albendazole sulfoxide, is characterised by substantial inter-individual pharmacokinetic variation. This variation might have implications for the efficacy of albendazole treatment, but current understanding of the factors associated with this variation remains incomplete.Methodology/principal findingsWe carried out a systematic review to identify references containing temporally disaggregated data on the plasma concentration of albendazole and/or (its pharmacologically-active metabolite) albendazole sulfoxide following a single oral dose. These data were then integrated into a mathematical modelling framework to infer albendazole sulfoxide pharmacokinetic parameters and relate them to characteristics of the groups being treated. These characteristics included age, weight, sex, dosage, infection status, and whether patients had received a fatty meal prior to treatment or other drugs alongside albendazole. Our results highlight a number of factors systematically associated with albendazole sulfoxide pharmacokinetic variation including age, existing parasitic infection and receipt of a fatty meal. Age was significantly associated with variation in albendazole sulfoxide systemic availability and peak plasma concentration achieved; as well as the clearance rate (related to the half-life) after adjusting for variation in dosage due to differences in body weight between children and adults. Receipt of a fatty meal prior to treatment was associated with increased albendazole sulfoxide systemic availability (and by extension, peak plasma concentration and total albendazole sulfoxide exposure following the dose). Parasitic infection (particularly echinococcosis) was associated with altered pharmacokinetic parameters, with infected populations displaying distinct characteristics to uninfected ones.Conclusions/significanceThese results highlight the extensive inter-individual variation that characterises albendazole sulfoxide pharmacokinetics and provide insight into some of the factors associated with this variation.

The accuracy of screening tests for detecting cystic echinococcosis (CE) in livestock depends on characteristics of the host–parasite interaction and the extent of serological cross-reactivity with other taeniid species. The AgB8 kDa protein is considered to be the most specific native or recombinant antigen for immunodiagnosis of ovine CE. A particular DNA fragment coding for rAgB8/2 was identified, that provides evidence of specific reaction in the serodiagnosis of metacestode infection.We developed and validated an IgG Enzyme Linked Immunosorbent Assay (ELISA) test using a recombinant antigen B sub-unit EgAgB8/2 (rAgB8/2) of Echinoccocus granulosus sensu lato (s.l.) to estimate CE prevalence in sheep. A 273 bp DNA fragment coding for rAgB8/2 was expressed as a fusion protein (∼30 kDa) and purified by affinity chromatography.Evaluation of the analytical and diagnostic performance of the ELISA followed the World Organisation for Animal Health (OIE) manual, including implementation of serum panels from: uninfected lambs (n = 79); experimentally infected (with 2,000 E. granulosus s.l. eggs each) sheep with subsequent evidence of E. granulosus cysts by necropsy (n = 36), and animals carrying other metacestode/trematode infections (n = 20). The latter were used to assess the cross-reactivity of rAgB8/2, with these animals being naturally infected with Taenia hydatigena, Thysanosoma actinioides and/or Fasciola hepatica. EgAgB8/2 showed cross-reaction with only one serum sample from a sheep infected with Ta. hydatigena out of the 20 animals tested.Furthermore, the kinetics of the humoral response over time in five 6-month old sheep, each experimentally infected with 2,000 E. granulosus s.l. eggs, was evaluated up to 49 weeks (approximately one year) post infection (n = 5). The earliest detectable IgG response against rAgB8/2 was observed in sera from two and four sheep, 7 and 14 days after experimental infection, respectively. The highest immune response across all five animals was found 16 to 24 weeks post infection.

Echinococcus granulosus sensu lato is a globally prevalent zoonotic parasitic cestode leading to cystic echinococcosis (CE) in both humans and sheep with both medical and financial impacts, whose reduction requires the application of a One Health approach to its control. Regarding the animal health component of this approach, lack of accurate and practical diagnostics in livestock impedes the assessment of disease burden and the implementation and evaluation of control strategies. We use of a Bayesian Latent Class Analysis (LCA) model to estimate ovine CE prevalence in sheep samples from the Río Negro province of Argentina accounting for uncertainty in the diagnostics. We use model outputs to evaluate the performance of a novel recombinant B8/2 antigen B subunit (rEgAgB8/2) indirect enzyme-linked immunosorbent assay (ELISA) for detecting E. granulosus in sheep. Necropsy (as a partial gold standard), western blot (WB) and ELISA diagnostic data were collected from 79 sheep within two Río Negro slaughterhouses, and used to estimate individual infection status (assigned as a latent variable within the model). Using the model outputs, the performance of the novel ELISA at both individual and flock levels was evaluated, respectively, using a receiver operating characteristic (ROC) curve, and simulating a range of sample sizes and prevalence levels within hypothetical flocks. The estimated (mean) prevalence of ovine CE was 27.5% (95%Bayesian credible interval (95%BCI): 13.8%–58.9%) within the sample population. At the individual level, the ELISA had a mean sensitivity and specificity of 55% (95%BCI: 46%–68%) and 68% (95%BCI: 63%–92%), respectively, at an optimal optical density (OD) threshold of 0.378. At the flock level, the ELISA had an 80% probability of correctly classifying infection at an optimal cut-off threshold of 0.496. These results suggest that the novel ELISA could play a useful role as a flock-level diagnostic for CE surveillance in the region, supplementing surveillance activities in the human population and thus strengthening a One Health approach. Importantly, selection of ELISA cut-off threshold values must be tailored according to the epidemiological situation.

Drugs for filariases are under development and clinical trial simulators could help to inform the design of clinical trials. Here, Walker et al. use an individual-based onchocerciasis transmission model to project trial outcomes of a hypothetical macrofilaricidal drug, resolving key design choices.

Abstract Background Many control methods have been implemented to tackle onchocerciasis and great successes have been achieved, leading to a paradigm shift from control of morbidity to interruption of transmission and ultimately elimination. The mandate of the African Programme for Onchocerciasis Control (APOC) ended in 2015, and endemic countries are to plan and conduct elimination activities by themselves, with technical assistance by the Expanded Special Project for Elimination of Neglected Tropical Diseases (ESPEN). To this end, an elimination expert committee was set up in Cameroon in 2018. This committee identified the need to update the data on the current situation of onchocerciasis. The present study aims to systematically review and report all available epidemiological data, including prevalence, intensity and transmission of onchocerciasis to provide pertinent information that will be useful to design optimal strategies to achieve onchocerciasis elimination in Cameroon. Methods PubMed/MEDLINE, EMBASE and Web of Science will be searched from inception onwards. Grey literature will be identified through Google Scholar searches, dissertation databases and other relevant documents such as government reports. Eligible studies will be mostly observational, including cohort and cross-sectional surveys. No limitations will be imposed on publication status and study period. The primary outcomes will be (1) the prevalence and intensity of Onchocerca volvulus infection in humans, (2) transmission intensity and (3) impact of interventions on prevalence, intensity and transmission of onchocerciasis. Secondary outcomes will be environmental and socio-demographic factors supporting the primary outcomes. Two reviewers will independently screen all citations, full-text articles and abstract data. Potential conflicts will be resolved through discussion. Methodological quality including bias will be appraised using appropriate approaches. A narrative synthesis will describe quality and content of the epidemiological evidence. Prevalence and intensity of infection estimates will be stratified according to gender, age, geographical location and year of publication. Discussion This study will provide the health authorities as well as the scientific community with up-to-date information about the epidemiological situation of onchocerciasis in Cameroon. Understanding the spatiotemporal dynamics of the infection will help to define alternative and complementary strategies to accelerate onchocerciasis elimination in the country. Results of this review will also be used to update existing epidemiological models for onchocerciasis in order to fine-tune predictions of elimination timeframes in the country. Systematic review registration This protocol is under registration review in PROSPERO.

BackgroundIn onchocerciasis endemic areas in Africa, heterogenous biting rates by blackfly vectors on humans are assumed to partially explain age- and sex-dependent infection patterns with Onchocerca volvulus. To underpin these assumptions and further improve predictions made by onchocerciasis transmission models, demographic patterns in antibody responses to salivary antigens of Simulium damnosum s.l. are evaluated as a measure of blackfly exposure.Methodology/principal findingsRecently developed IgG and IgM anti-saliva immunoassays for S. damnosum s.l. were applied to blood samples collected from residents in four onchocerciasis endemic villages in Ghana. Demographic patterns in antibody levels according to village, sex and age were explored by fitting generalized linear models. Antibody levels varied between villages but showed consistent patterns with age and sex. Both IgG and IgM responses declined with increasing age. IgG responses were generally lower in males than in females and exhibited a steeper decline in adult males than in adult females. No sex-specific difference was observed in IgM responses.Conclusions/significanceThe decline in age-specific antibody patterns suggested development of immunotolerance or desensitization to blackfly saliva antigen in response to persistent exposure. The variation between sexes, and between adults and youngsters may reflect differences in behaviour influencing cumulative exposure. These measures of antibody acquisition and decay could be incorporated into onchocerciasis transmission models towards informing onchocerciasis control, elimination, and surveillance.

The Infectious Diseases Data Observatory (IDDO, https://www.iddo.org) has launched a clinical data platform for the collation, curation, standardisation and reuse of individual participant data (IPD) on treatments for two of the most globally important neglected tropical diseases (NTDs), schistosomiasis (SCH) and soil-transmitted helminthiases (STHs). This initiative aims to harness the power of data-sharing by facilitating collaborative joint analyses of pooled datasets to generate robust evidence on the efficacy and safety of anthelminthic treatment regimens. A crucial component of this endeavour has been the development of a Research Agenda to promote engagement with the SCH and STH research and disease control communities by highlighting key questions that could be tackled using data shared through the IDDO platform. Here, we give a contextual overview of the priority research themes articulated in the Research Agenda—a ‘living’ document hosted on the IDDO website—and describe the three-stage consultation process behind its development. We also discuss the sustainability and future directions of the platform, emphasising throughout the power and promise of ethical and equitable sharing and reuse of clinical data to support the elimination of NTDs.

Background: Childhood anaemia affects 1.8 billion people globally. Little is known about the long-term impact of mass drug administration (MDA) for the control of soil-transmitted helminthiases (STH) on the spatiotemporal variation of anaemia prevalence and severity. We describe the long-term spatiotemporal impact of a 5-year STH MDA programme (2007–2011) on the prevalence of anaemia and anaemia severity in school-aged children (SAC) in Burundi. Methodology/Principal Findings: We used annual haemoglobin concentration and STH data collected during 2007–2011 in 31 schools in Burundi. Spatial dependence in prevalence and severity of anaemia was assessed using semivariograms. Bayesian geostatistical models were developed to (a) quantify the role of STH (adjusted for other anaemia determinants) in the spatiotemporal distribution of anaemia prevalence/severity, and (b) predict the geographical variation of both outcomes across Burundi. Adjusted population data were used to estimate the geographical distribution of the number of SAC at risk of anaemia and with low and moderate/severe anaemia. Infections with Ascaris lumbricoides and Trichuris trichiura were positively and significantly associated with childhood anaemia; hookworm infections were not. A significant decrease in anaemia prevalence, from 40–50% (2008) to 10–20% (2011) was predicted in western areas. The predicted prevalence of low-severity anaemia decreased from 40–50% (2008) to

Recent evidence suggests that, in some foci, elimination of onchocerciasis from Africa may be feasible with mass drug administration (MDA) of ivermectin. To achieve continental elimination of transmission, mapping surveys will need to be conducted across all implementation units (IUs) for which endemicity status is currently unknown. Using boosted regression tree models with optimised hyperparameter selection, we estimated environmental suitability for onchocerciasis at the 5 × 5-km resolution across Africa. In order to classify IUs that include locations that are environmentally suitable, we used receiver operating characteristic (ROC) analysis to identify an optimal threshold for suitability concordant with locations where onchocerciasis has been previously detected. This threshold value was then used to classify IUs (more suitable or less suitable) based on the location within the IU with the largest mean prediction. Mean estimates of environmental suitability suggest large areas across West and Central Africa, as well as focal areas of East Africa, are suitable for onchocerciasis transmission, consistent with the presence of current control and elimination of transmission efforts. The ROC analysis identified a mean environmental suitability index of 0·71 as a threshold to classify based on the location with the largest mean prediction within the IU. Of the IUs considered for mapping surveys, 50·2% exceed this threshold for suitability in at least one 5 × 5-km location. The formidable scale of data collection required to map onchocerciasis endemicity across the African continent presents an opportunity to use spatial data to identify areas likely to be suitable for onchocerciasis transmission. National onchocerciasis elimination programmes may wish to consider prioritising these IUs for mapping surveys as human resources, laboratory capacity, and programmatic schedules may constrain survey implementation, and possibly delaying MDA initiation in areas that would ultimately qualify.

BackgroundSimulium damnosum sensu lato (s.l.) blackflies transmit Onchocerca volvulus, a filarial nematode that causes human onchocerciasis. Human landing catches (HLCs) is currently the sole method used to estimate blackfly biting rates but is labour-intensive and questionable on ethical grounds. A potential alternative is to measure host antibodies to vector saliva deposited during bloodfeeding. In this study, immunoassays to quantify human antibody responses to S. damnosum s.l. saliva were developed, and the salivary proteome of S. damnosum s.l. was investigated.Methodology/principal findingsBlood samples from people living in onchocerciasis-endemic areas in Ghana were collected during the wet season; samples from people living in Accra, a blackfly-free area, were considered negative controls and compared to samples from blackfly-free locations in Sudan. Blackflies were collected by HLCs and dissected to extract their salivary glands. An ELISA measuring anti-S. damnosum s.l. salivary IgG and IgM was optimized and used to quantify the humoral immune response of 958 individuals. Both immunoassays differentiated negative controls from endemic participants. Salivary proteins were separated by gel-electrophoresis, and antigenic proteins visualized by immunoblot. Liquid chromatography mass spectrometry (LC-MS/MS) was performed to characterize the proteome of S. damnosum s.l. salivary glands. Several antigenic proteins were recognized, with the major ones located around 15 and 40 kDa. LC-MS/MS identified the presence of antigen 5-related protein, apyrase/nucleotidase, and hyaluronidase.Conclusions/significanceThis study validated for the first time human immunoassays that quantify humoral immune responses as potential markers of exposure to blackfly bites. These assays have the potential to facilitate understanding patterns of exposure as well as evaluating the impact of vector control on biting rates. Future studies need to investigate seasonal fluctuations of these antibody responses, potential cross-reactions with other bloodsucking arthropods, and thoroughly identify the most immunogenic proteins.

BackgroundDensity dependence in helminth establishment and heterogeneity in exposure to infection are known to drive resilience to interventions based on mass drug administration (MDA). However, the interaction between these processes is poorly understood. We developed a novel individual-based model for onchocerciasis transmission, EPIONCHO-IBM, which accounts for both processes. We fit the model to pre-intervention epidemiological data and explore parasite dynamics during MDA with ivermectin.Methodology/principal findingsDensity dependence and heterogeneity in exposure to blackfly (vector) bites were estimated by fitting the model to matched pre-intervention microfilarial prevalence, microfilarial intensity and vector biting rate data from savannah areas of Cameroon and Côte d'Ivoire/Burkina Faso using Latin hypercube sampling. Transmission dynamics during 25 years of annual and biannual ivermectin MDA were investigated. Density dependence in parasite establishment within humans was estimated for different levels of (fixed) exposure heterogeneity to understand how parametric uncertainty may influence treatment dynamics. Stronger overdispersion in exposure to blackfly bites results in the estimation of stronger density-dependent parasite establishment within humans, consequently increasing resilience to MDA. For all levels of exposure heterogeneity tested, the model predicts a departure from the functional forms for density dependence assumed in the deterministic version of the model.Conclusions/significanceThis is the first, stochastic model of onchocerciasis, that accounts for and estimates density-dependent parasite establishment in humans alongside exposure heterogeneity. Capturing the interaction between these processes is fundamental to our understanding of resilience to MDA interventions. Given that uncertainty in these processes results in very different treatment dynamics, collecting data on exposure heterogeneity would be essential for improving model predictions during MDA. We discuss possible ways in which such data may be collected as well as the importance of better understanding the effects of immunological responses on establishing parasites prior to and during ivermectin treatment.

Abstract Background An estimated 25 million people are currently infected with onchocerciasis (a parasitic infection caused by the filarial nematode Onchocerca volvulus and transmitted by Simulium vectors), and 99% of these are in sub-Saharan Africa. The African Programme for Onchocerciasis Control closed in December 2015 and the World Health Organization has established a new structure, the Expanded Special Project for the Elimination of Neglected Tropical Diseases for the coordination of technical support for activities focused on five neglected tropical diseases in Africa, including onchocerciasis elimination. Aims In this paper we argue that despite the delineation of a reasonably well-defined elimination strategy, its implementation will present particular difficulties in practice. We aim to highlight these in an attempt to ensure that they are well understood and that effective plans can be laid to solve them by the countries concerned and their international partners. Conclusions A specific concern is the burden of disease caused by onchocerciasis-associated epilepsy in hyperendemic zones situated in countries experiencing difficulties in strengthening their onchocerciasis control programmes. These difficulties should be identified and programmes supported during the transition from morbidity control to interruption of transmission and elimination.

Abstract Background Recently, several epidemiological studies performed in Onchocerca volvulus-endemic regions have suggested that onchocerciasis-associated epilepsy (OAE) may constitute an important but neglected public health problem in many countries where onchocerciasis is still endemic. Main text On October 12–14th 2017, the first international workshop on onchocerciasis-associated epilepsy (OAE) was held in Antwerp, Belgium. The workshop was attended by 79 participants from 20 different countries. Recent research findings strongly suggest that O. volvulus is an important contributor to epilepsy, particularly in meso- and hyperendemic areas for onchocerciasis. Infection with O. volvulus is associated with a spectrum of epileptic seizures, mainly generalised tonic-clonic seizures but also atonic neck seizures (nodding), and stunted growth. OAE is characterised by an onset of seizures between the ages of 3–18 years. Multidisciplinary working groups discussed topics such as how to 1) strengthen the evidence for an association between onchocerciasis and epilepsy, 2) determine the burden of disease caused by OAE, 3) prevent OAE, 4) improve the treatment/care for persons with OAE and affected families, 5) identify the pathophysiological mechanism of OAE, and 6) deal with misconceptions, stigma, discrimination and gender violence associated with OAE. An OAE Alliance was created to increase awareness about OAE and its public health importance, stimulate research and disseminate research findings, and create partnerships between OAE researchers, communities, advocacy groups, ministries of health, non-governmental organisations, the pharmaceutical industry and funding organizations. Conclusions Although the exact pathophysiological mechanism underlying OAE remains unknown, there is increasing evidence that by controlling and eliminating onchocerciasis, OAE will also disappear. Therefore, OAE constitutes an additional argument for strengthening onchocerciasis elimination efforts. Given the high numbers of people with epilepsy in O. volvulus-endemic regions, more advocacy is urgently needed to provide anti-epileptic treatment to improve the quality of life of these individuals and their families.

Abstract Background Onchocerciasis and lymphatic filariasis (LF) are major filarial infections targeted for elimination in most endemic sub-Saharan Africa (SSA) countries by 2020/2025. The current control strategies are built upon community-directed mass administration of ivermectin (CDTI) for onchocerciasis, and ivermectin plus albendazole for LF, with evidence pointing towards the potential for novel drug regimens. When distributing microfilaricides however, considerable care is needed to minimise the risk of severe adverse events (SAEs) in areas that are co-endemic for onchocerciasis or LF and loiasis. This work aims to combine previously published predictive risk maps for onchocerciasis, LF and loiasis to (i) explore the scale of spatial heterogeneity in co-distributions, (ii) delineate target populations for different treatment strategies, and (iii) quantify populations at risk of SAEs across the continent. Methods Geographical co-endemicity of filarial infections prior to the implementation of large-scale mass treatment interventions was analysed by combining a contemporary LF endemicity map with predictive prevalence maps of onchocerciasis and loiasis. Potential treatment strategies were geographically delineated according to the level of co-endemicity and estimated transmission intensity. Results In total, an estimated 251 million people live in areas of LF and/or onchocerciasis transmission in SSA, based on 2015 population estimates. Of these, 96 million live in areas co-endemic for both LF and onchocerciasis, providing opportunities for integrated control programmes, and 83 million live in LF-monoendemic areas potentially targetable for the novel ivermectin-diethylcarbamazine-albendazole (IDA) triple therapy. Only 4% of the at-risk population live in areas co-endemic with high loiasis transmission, representing up to 1.2 million individuals at high risk of experiencing SAEs if treated with ivermectin. In these areas, alternative treatment strategies should be explored, including biannual albendazole monotherapy for LF (1.4 million individuals) and ‘test-and-treat’ strategies (8.7 million individuals) for onchocerciasis. Conclusions These maps are intended to initiate discussion around the potential for tailored treatment strategies, and highlight populations at risk of SAEs. Further work is required to test and refine strategies in programmatic settings, providing the empirical evidence needed to guide efforts towards the 2020/2025 goals and beyond.

Abstract Background Investigating the effect of successive annual deworming rounds on the spatiotemporal distribution of infection prevalence and numbers at risk for soil-transmitted helminths (STHs) can help identify communities nearing elimination and those needing further interventions. In this study, we aim to quantify the impact of an 8-year mass drug administration (MDA) programme (from 2007 to 2014) on the spatiotemporal distribution of prevalence of STH infections and to estimate the number of school-aged children infected with STHs in Burundi. Methods During annual longitudinal school-based surveys in Burundi between 2007 and 2011, STH infection and anthropometric data for a total of 40,656 children were collected; these data were supplemented with data from a national survey conducted in 2014. Bayesian model based geostatistics (MBG) were used to generate predictive prevalence maps for each STH species and year. The numbers of children at-risk of infection per district between 2008 and 2014 were estimated as the product of the predictive prevalence maps and population density maps. Results Overall, the degree of spatial clustering of STH infections decreased between 2008 and 2011; in 2014 the geographical clusters of all STH infections reappeared. The reduction in prevalence was small for Ascaris lumbricoides and Trichuris trichiura in the centre and central north of the country. Our predictive prevalence maps for hookworm indicate a reduction in prevalence along the periphery of the country. The predicted number of children infected with any STH species decreased substantially between 2007 and 2011, but in 2014 there was an increase in the predicted number of children infected with A. lumbricoides and T. trichiura. In 2014, the districts with the highest predicted number of children infected with A. lumbricoides, T. trichiura and hookworms were Kibuye district (n = 128,903), Mabayi district (n = 35,302) and Kiremba (n = 87,511), respectively. Conclusions While the MDA programme in Burundi resulted in a reduction in STH prevalence, this reduction was spatiotemporally heterogeneous, with some pockets of high prevalence remaining, suggesting that treatment coverage and complementary interventions should be evaluated to improve impact.

Abstract Background The number of migrants working in Malaysia has increased sharply since the 1970’s and there is concern that infectious diseases endemic in other (e.g. neighbouring) countries may be inadvertently imported. Compulsory medical screening prior to entering the workforce does not include parasitic infections such as toxoplasmosis. Therefore, this study aimed to evaluate the seroprevalence of T. gondii infection among migrant workers in Peninsular Malaysia by means of serosurveys conducted on a voluntary basis among low-skilled and semi-skilled workers from five working sectors, namely, manufacturing, food service, agriculture and plantation, construction and domestic work. Methods A total of 484 migrant workers originating from rural locations in neighbouring countries, namely, Indonesia (n = 247, 51.0%), Nepal (n = 99, 20.5%), Bangladesh (n = 72, 14.9%), India (n = 52, 10.7%) and Myanmar (n = 14, 2.9%) were included in this study. Results The overall seroprevalence of T. gondii was 57.4% (n = 278; 95% CI: 52.7–61.8%) with 52.9% (n = 256; 95% CI: 48.4–57.2%) seropositive for anti-Toxoplasma IgG only, 0.8% (n = 4; 95% CI: 0.2–1.7%) seropositive for anti-Toxoplasma IgM only and 3.7% (n = 18; 95% CI: 2.1–5.4%) seropositive with both IgG and IgM antibodies. All positive samples with both IgG and IgM antibodies showed high avidity (> 40%), suggesting latent infection. Age (being older than 45 years), Nepalese nationality, manufacturing occupation, and being a newcomer in Malaysia (excepting domestic work) were positively and statistically significantly associated with seroprevalence (P

BackgroundThe cestode Taenia solium causes the neglected (zoonotic) tropical disease cysticercosis, a leading cause of preventable epilepsy in endemic low and middle-income countries. Transmission models can inform current scaling-up of control efforts by helping to identify, validate and optimise control and elimination strategies as proposed by the World Health Organization (WHO).Methodology/principal findingsA systematic literature search was conducted using the PRISMA approach to identify and compare existing T. solium transmission models, and related Taeniidae infection transmission models. In total, 28 modelling papers were identified, of which four modelled T. solium exclusively. Different modelling approaches for T. solium included deterministic, Reed-Frost, individual-based, decision-tree, and conceptual frameworks. Simulated interventions across models agreed on the importance of coverage for impactful effectiveness to be achieved. Other Taeniidae infection transmission models comprised force-of-infection (FoI), population-based (mainly Echinococcus granulosus) and individual-based (mainly E. multilocularis) modelling approaches. Spatial structure has also been incorporated (E. multilocularis and Taenia ovis) in recognition of spatial aggregation of parasite eggs in the environment and movement of wild animal host populations.Conclusions/significanceGaps identified from examining the wider Taeniidae family models highlighted the potential role of FoI modelling to inform model parameterisation, as well as the need for spatial modelling and suitable structuring of interventions as key areas for future T. solium model development. We conclude that working with field partners to address data gaps and conducting cross-model validation with baseline and longitudinal data will be critical to building consensus-led and epidemiological setting-appropriate intervention strategies to help fulfil the WHO targets.

Abstract Background The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI). Methods A previous model for the transmission dynamics of Schistosoma mansoni was adapted here to S. haematobium. These models were fitted to longitudinal cohort (infection intensity) monitoring and evaluation data. Changes in the FOI following up to three annual rounds of praziquantel were estimated for Burkina Faso, Mali, Niger, Tanzania, Uganda, and Zambia in sub-Saharan Africa (SSA) according to country, baseline endemicity and schistosome species. Since schistosomiasis transmission is known to be highly focal, changes in the FOI at a finer geographical scale (that of sentinel site) were also estimated for S. mansoni in Uganda. Results Substantial and statistically significant reductions in the FOI relative to baseline were recorded in the majority of, but not all, combinations of country, parasite species, and endemicity areas. At the finer geographical scale assessed within Uganda, marked heterogeneity in the magnitude and direction of the relative changes in FOI was observed that would not have been appreciated by a coarser-scale analysis. Conclusions Reductions in the rate at which humans acquire schistosomes have been achieved in many areas of SSA countries assisted by the SCI, while challenges in effectively reducing transmission persist in others. Understanding the underlying heterogeneity in the impact and performance of the control intervention at the level of the transmission site will become increasingly important for programmes transitioning from morbidity reduction to elimination of infection. Such analyses will require a fine-scale approach. The lack of association found between programmatic variables, such as therapeutic treatment coverage (recorded at district level) and changes in FOI (at sentinel site level) is discussed and recommendations are made.

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations.

Abstract In a Letter to the Editor, Eberhard et al. question the validity of our model of skin snip sensitivity and argue against the use of skin snips to evaluate onchocerciasis elimination by mass drug administration. Here we discuss their arguments and compare model predictions with observed data to assess the validity of our model.

Albendazole (ABZ), a benzimidazole (BZ) anthelmintic (AH), is commonly used for treatment of soil-transmitted helminths (STHs). Its regular use increases the possibility that BZ resistance may develop, which, in veterinary nematodes is caused by single nucleotide polymorphisms (SNPs) in the β-tubulin gene at positions 200, 167 or 198. The relative importance of these SNPs varies among the different parasitic nematodes of animals studied to date, and it is currently unknown whether any of these are influencing BZ efficacy against STHs in humans. We assessed ABZ efficacy and SNP frequencies before and after treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm infections.Studies were performed in Haiti, Kenya, and Panama. Stool samples were examined prior to ABZ treatment and two weeks (Haiti), one week (Kenya) and three weeks (Panama) after treatment to determine egg reduction rate (ERR). Eggs were genotyped and frequencies of each SNP assessed.In T. trichiura, polymorphism was detected at codon 200. Following treatment, there was a significant increase, from 3.1% to 55.3%, of homozygous resistance-type in Haiti, and from 51.3% to 67.8% in Kenya (ERRs were 49.7% and 10.1%, respectively). In A. lumbricoides, a SNP at position 167 was identified at high frequency, both before and after treatment, but ABZ efficacy remained high. In hookworms from Kenya we identified the resistance-associated SNP at position 200 at low frequency before and after treatment while ERR values indicated good drug efficacy.Albendazole was effective for A. lumbricoides and hookworms. However, ABZ exerts a selection pressure on the β-tubulin gene at position 200 in T. trichiura, possibly explaining only moderate ABZ efficacy against this parasite. In A. lumbricoides, the codon 167 polymorphism seemed not to affect drug efficacy whilst the polymorphism at codon 200 in hookworms was at such low frequency that conclusions cannot be drawn.

BACKGROUND:To date schistosomiasis control programmes based on chemotherapy have largely aimed at controlling morbidity in treated individuals rather than at suppressing transmission. In this study, a mathematical modelling approach was used to estimate reductions in the rate of Schistosoma mansoni reinfection following annual mass drug administration (MDA) with praziquantel in Uganda over four years (2003-2006). In doing this we aim to elucidate the benefits of MDA in reducing community transmission. METHODS:Age-structured models were fitted to a longitudinal cohort followed up across successive rounds of annual treatment for four years (Baseline: 2003, TREATMENT: 2004-2006; n = 1,764). Instead of modelling contamination, infection and immunity processes separately, these functions were combined in order to estimate a composite force of infection (FOI), i.e., the rate of parasite acquisition by hosts. RESULTS:MDA achieved substantial and statistically significant reductions in the FOI following one round of treatment in areas of low baseline infection intensity, and following two rounds in areas with high and medium intensities. In all areas, the FOI remained suppressed following a third round of treatment. CONCLUSIONS/SIGNIFICANCE:This study represents one of the first attempts to monitor reductions in the FOI within a large-scale MDA schistosomiasis morbidity control programme in sub-Saharan Africa. The results indicate that the Schistosomiasis Control Initiative, as a model for other MDA programmes, is likely exerting a significant ancillary impact on reducing transmission within the community, and may provide health benefits to those who do not receive treatment. The results obtained will have implications for evaluating the cost-effectiveness of schistosomiasis control programmes and the design of monitoring and evaluation approaches in general.

Trachoma, the worldwide leading infectious cause of blindness, is due to repeated conjunctival infection with Chlamydia trachomatis. The effects of control interventions on population levels of infection and active disease can be promptly measured, but the effects on severe ocular sequelae require long-term monitoring. We present an age-structured mathematical model of trachoma transmission and disease to predict the impact of interventions on the prevalence of blinding trachoma.The model is based on the concept of multiple reinfections leading to progressive conjunctival scarring, trichiasis, corneal opacity and blindness. It also includes aspects of trachoma natural history, such as an increasing rate of recovery from infection and a decreasing chlamydial load with subsequent infections that depend upon a (presumed) acquired immunity that clears infection with age more rapidly. Parameters were estimated using maximum likelihood by fitting the model to pre-control infection prevalence data from hypo-, meso- and hyperendemic communities from The Gambia and Tanzania. The model reproduces key features of trachoma epidemiology: 1) the age-profile of infection prevalence, which increases to a peak at very young ages and declines at older ages; 2) a shift in this prevalence peak, toward younger ages in higher force of infection environments; 3) a raised overall profile of infection prevalence with higher force of infection; and 4) a rising profile, with age, of the prevalence of the ensuing severe sequelae (trachomatous scarring, trichiasis), as well as estimates of the number of infections that need to occur before these sequelae appear.We present a framework that is sufficiently comprehensive to examine the outcomes of the A (antibiotic) component of the SAFE strategy on disease. The suitability of the model for representing population-level patterns of infection and disease sequelae is discussed in view of the individual processes leading to these patterns.