A Research Agenda for Helminth Diseases of Humans: Modelling for Control and Elimination

Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches

The influenza pandemic preparedness planning tool InfluSim

BACKGROUND: Planning public health responses against pandemic influenza relies on predictive models by which the impact of different intervention strategies can be evaluated. Research has to date rather focused on producing predictions for certain localities or under specific conditions, than on designing a publicly available planning tool which can be applied by public health administrations. Here, we provide such a tool which is reproducible by an explicitly formulated structure and designed to operate with an optimal combination of the competing requirements of precision, realism and generality. RESULTS: InfluSim is a deterministic compartment model based on a system of over 1,000 differential equations which extend the classic SEIR model by clinical and demographic parameters relevant for pandemic preparedness planning. It allows for producing time courses and cumulative numbers of influenza cases, outpatient visits, applied antiviral treatment doses, hospitalizations, deaths and work days lost due to sickness, all of which may be associated with economic aspects. The software is programmed in Java, operates platform independent and can be executed on regular desktop computers. CONCLUSION: InfluSim is an online available software which efficiently assists public health planners in designing optimal interventions against pandemic influenza. It can reproduce the infection dynamics of pandemic influenza like complex computer simulations while offering at the same time reproducibility, higher computational performance and better operability

Modelling the impact of larviciding on the population dynamics and biting rates of Simulium damnosum (s.l.): implications for vector control as a complementary strategy for onchocerciasis elimination in Africa

Background: In 2012, the World Health Organization set goals for the elimination of onchocerciasis transmission by 2020 in selected African countries. Epidemiological data and mathematical modelling have indicated that elimination may not be achieved with annual ivermectin distribution in all endemic foci. Complementary and alternative treatment strategies (ATS), including vector control, will be necessary. Implementation of vector control will require that the ecology and population dynamics of Simulium damnosum sensu lato be carefully considered. Methods: We adapted our previous SIMuliid POPulation dynamics (SIMPOP) model to explore the impact of larvicidal insecticides on S. damnosum (s.l.) biting rates in different ecological contexts and to identify how frequently and for how long vector control should be continued to sustain substantive reductions in vector biting. SIMPOP was fitted to data from large-scale aerial larviciding trials in savannah sites (Ghana) and small-scale ground larviciding trials in forest areas (Cameroon). The model was validated against independent data from Burkina Faso/Côte d’Ivoire (savannah) and Bioko (forest). Scenario analysis explored the effects of ecological and programmatic factors such as pre-control daily biting rate (DBR) and larviciding scheme design on reductions and resurgences in biting rates. Results: The estimated efficacy of large-scale aerial larviciding in the savannah was greater than that of ground-based larviciding in the forest. Small changes in larvicidal efficacy can have large impacts on intervention success. At 93% larvicidal efficacy (a realistic value based on field trials), 10 consecutive weekly larvicidal treatments would reduce DBRs by 96% (e.g. from 400 to 16 bites/person/day). At 70% efficacy, and for 10 weekly applications, the DBR would decrease by 67% (e.g. from 400 to 132 bites/person/day). Larviciding is more likely to succeed in areas with lower water temperatures and where blackfly species have longer gonotrophic cycles. Conclusions: Focal vector control can reduce vector biting rates in settings where a high larvicidal efficacy can be achieved and an appropriate duration and frequency of larviciding can be ensured. Future work linking SIMPOP with onchocerciasis transmission models will permit evaluation of the impact of combined anti-vectorial and anti-parasitic interventions on accelerating elimination of the disease

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

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

Onchocerciasis transmission in Ghana: biting and parous rates of host-seeking sibling species of the Simulium damnosum complex

Background: Ghana is renowned for its sibling species diversity of the Simulium damnosum complex, vectors of Onchocerca volvulus. Detailed entomological knowledge becomes a priority as onchocerciasis control policy has shifted from morbidity reduction to elimination of infection. To date, understanding of transmission dynamics of O. volvulus has been mainly based on S. damnosum sensu stricto (s.s.) data. We aim to elucidate bionomic features of vector species of importance for onchocerciasis elimination efforts. Methods: We collected S. damnosum sensu lato from seven villages in four Ghanaian regions between 2009 and 2011, using standard vector collection, and human- and cattle-baited tents. Taxa were identified using morphological and molecular techniques. Monthly biting rates (MBR), parous rates and monthly parous biting rates (MPBR) are reported by locality, season, trapping method and hour of collection for each species. Results: S. damnosum s.s./S. sirbanum were collected at Asubende and Agborlekame, both savannah villages. A range of species was caught in the Volta region (forest-savannah mosaic) and Gyankobaa (forest), with S. squamosum or S. sanctipauli being the predominant species, respectively. In Bosomase (southern forest region) only S. sanctipauli was collected in the 2009 wet season, but in the 2010 dry season S. yahense was also caught. MBRs ranged from 714 bites/person/month at Agborlekame (100% S. damnosum s.s./S. sirbanum) to 8,586 bites/person/month at Pillar 83/Djodji (98.5% S. squamosum). MBRs were higher in the wet season. In contrast, parous rates were higher in the dry season (41.8% vs. 18.4%), resulting in higher MPBRs in the dry season. Daily host-seeking activity of S. damnosum s.s./S. sirbanum was bimodal, whilst S. squamosum and S. sanctipauli had unimodal afternoon peaks. Conclusions: The bionomic differences between sibling species of the S. damnosum complex need to be taken into account when designing entomological monitoring protocols for interventions and parameterising mathematical models for onchocerciasis control and elimination

Impact of long-term treatment of onchocerciasis with ivermectin in Kaduna State, Nigeria: first evidence of the potential for elimination in the operational area of the African Programme for Onchocerciasis Control.

BACKGROUND: Onchocerciasis can be effectively controlled as a public health problem by annual mass drug administration of ivermectin, but it was not known if ivermectin treatment in the long term would be able to achieve elimination of onchocerciasis infection and interruption of transmission in endemic areas in Africa. A recent study in Mali and Senegal has provided the first evidence of elimination after 15-17 years of treatment. Following this finding, the African Programme for Onchocerciasis Control (APOC) has started a systematic evaluation of the long-term impact of ivermectin treatment projects and the feasibility of elimination in APOC supported countries. This paper reports the first results for two onchocerciasis foci in Kaduna, Nigeria. METHODS: In 2008, an epidemiological evaluation using skin snip parasitological diagnostic method was carried out in two onchocerciasis foci, in Birnin Gwari Local Government Area (LGA), and in the Kauru and Lere LGAs of Kaduna State, Nigeria. The survey was undertaken in 26 villages and examined 3,703 people above the age of one year. The result was compared with the baseline survey undertaken in 1987. RESULTS: The communities had received 15 to 17 years of ivermectin treatment with more than 75% reported coverage. For each surveyed community, comparable baseline data were available. Before treatment, the community prevalence of O. volvulus microfilaria in the skin ranged from 23.1% to 84.9%, with a median prevalence of 52.0%. After 15 to 17 years of treatment, the prevalence had fallen to 0% in all communities and all 3,703 examined individuals were skin snip negative. CONCLUSIONS: The results of the surveys confirm the finding in Senegal and Mali that ivermectin treatment alone can eliminate onchocerciasis infection and probably disease transmission in endemic foci in Africa. It is the first of such evidence for the APOC operational area

Onchocerciasis transmission in Ghana: Persistence under different control strategies and the role of the simuliid vectors

Background: The World Health Organization (WHO) aims at eliminating onchocerciasis by 2020 in selected African countries. Current control focuses on community-directed treatment with ivermectin (CDTI). In Ghana, persistent transmission has been reported despite long-term control. We present spatial and temporal patterns of onchocerciasis transmission in relation to ivermectin treatment history. Methodology/Principal Findings: Host-seeking and ovipositing blackflies were collected from seven villages in four regions of Ghana with 3–24 years of CDTI at the time of sampling. A total of 16,443 flies was analysed for infection; 5,812 (35.3%) were dissected for parity (26.9% parous). Heads and thoraces of 12,196 flies were dissected for Onchocerca spp. and DNA from 11,122 abdomens was amplified using Onchocerca primers. A total of 463 larvae (0.03 larvae/fly) from 97 (0.6%) infected and 62 (0.4%) infective flies was recorded; 258 abdomens (2.3%) were positive for Onchocerca DNA. Infections (all were O. volvulus) were more likely to be detected in ovipositing flies. Transmission occurred, mostly in the wet season, at Gyankobaa and Bosomase, with transmission potentials of, respectively, 86 and 422 L3/person/month after 3 and 6 years of CDTI. The numbers of L3/1,000 parous flies at these villages were over 100times the WHO threshold of one L3/1,000 for transmission control. Vector species influenced transmission parameters. At Asubende, the number of L3/1,000 ovipositing flies (1.4, 95% CI = 0–4) also just exceeded the threshold despite extensive vector control and 24 years of ivermectin distribution, but there were no infective larvae in host-seeking flies. Conclusions/Significance: Despite repeated ivermectin treatment, evidence of O. volvulus transmission was documented in all seven villages and above the WHO threshold in two. Vector species influences transmission through biting and parous rates and vector competence, and should be included in transmission models. Oviposition traps could augment vector collector methods for monitoring and surveillance

Designing antifilarial drug trials using clinical trial simulators

Lymphatic filariasis and onchocerciasis are neglected tropical diseases (NTDs) targeted for elimination by mass (antifilarial) drug administration. These drugs are predominantly active against the microfilarial progeny of adult worms. New drugs or combinations are needed to improve patient therapy and to enhance the effectiveness of interventions in persistent hotspots of transmission. Several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators (CTSs) project patient outcomes to inform the design of clinical trials but have not been widely applied to NTDs, where their resource-saving payoffs could be highly beneficial. We demonstrate the utility of CTSs using our individual-based onchocerciasis transmission model (EPIONCHO-IBM) that projects trial outcomes of a hypothetical macrofilaricidal drug. We identify key design decisions that influence the power of clinical trials, including participant eligibility criteria and post-treatment follow-up times for measuring infection indicators. We discuss how CTSs help to inform target product profiles

Genome-Wide Interaction-Based Association Analysis Identified Multiple New Susceptibility Loci for Common Diseases

Genome-wide interaction-based association (GWIBA) analysis has the potential to identify novel susceptibility loci. These interaction effects could be missed with the prevailing approaches in genome-wide association studies (GWAS). However, no convincing loci have been discovered exclusively from GWIBA methods, and the intensive computation involved is a major barrier for application. Here, we developed a fast, multi-thread/parallel program named “pair-wise interaction-based association mapping” (PIAM) for exhaustive two-locus searches. With this program, we performed a complete GWIBA analysis on seven diseases with stringent control for false positives, and we validated the results for three of these diseases. We identified one pair-wise interaction between a previously identified locus, C1orf106, and one new locus, TEC, that was specific for Crohn's disease, with a Bonferroni corrected P<0.05 (P = 0.039). This interaction was replicated with a pair of proxy linked loci (P = 0.013) on an independent dataset. Five other interactions had corrected P<0.5. We identified the allelic effect of a locus close to SLC7A13 for coronary artery disease. This was replicated with a linked locus on an independent dataset (P = 1.09×10−7). Through a local validation analysis that evaluated association signals, rather than locus-based associations, we found that several other regions showed association/interaction signals with nominal P<0.05. In conclusion, this study demonstrated that the GWIBA approach was successful for identifying novel loci, and the results provide new insights into the genetic architecture of common diseases. In addition, our PIAM program was capable of handling very large GWAS datasets that are likely to be produced in the future