About the Authors: Matthew R. Behrend * E-mail: behrend04@gmail.com Affiliations Neglected Tropical Diseases, Bill & Melinda Gates Foundation, Seattle, Washington, United States of America, Blue Well ...8, Seattle, Washington, United States of America ORCID logo http://orcid.org/0000-0002-5664-0520 María-Gloria Basáñez Affiliation: MRC Centre for Global Infectious Disease Analysis and London Centre for Neglected Tropical Disease Research, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom Jonathan I. D. Hamley Affiliation: MRC Centre for Global Infectious Disease Analysis and London Centre for Neglected Tropical Disease Research, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom Travis C. Porco Affiliation: Francis I. Proctor Foundation for Research in Ophthalmology, Department of Epidemiology and Biostatistics, and Department of Ophthalmology, University of California, San Francisco, United States of America Wilma A. Stolk Affiliation: Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands Martin Walker Affiliations London Centre for Neglected Tropical Disease Research, Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom, London Centre for Neglected Tropical Disease Research and Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom Sake J. de Vlas Affiliation: Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands ORCID logo http://orcid.org/0000-0002-1830-5668 for the NTD Modelling Consortium Introduction The neglected tropical diseases (NTDs) thrive mainly among the poorest populations of the world.
Onchocerciasis (a filarial disease caused by infection with Onchocerca volvulus and transmitted by blackfly, Simulium, vectors) probably provides the best example of impactful modelling, with its long history of using evidence—mostly from the ONCHOSIM and EPIONCHO transmission models 7—to support decision-making within ongoing multicountry control initiatives (Table 1).
Onchocerciasis modelling and policy impact. https://doi.org/10.1371/journal.pntd.0008033.t001 From the start of the NTD Modelling Consortium in 2015, there have been several other examples of impactful modelling, which could be divided over three major scales of operations: (1) developing WHO guidelines (e.g., for triple-drug therapy, with ivermectin, diethylcarbamazine, and albendazole, against lymphatic filariasis 16, 17); (2) informing funding decisions for new intervention tools (e.g., the development of a schistosomiasis vaccine 18); and (3) guiding within-country targeting of control (e.g., local vector control for human African trypanosomiasis in the Democratic Republic of the Congo 19, 20 and Chad 21).
Relative word frequencies are represented by size of the font. https://doi.org/10.1371/journal.pntd.0008033.g002 Scoring the guidance statements Authors coded the data set individually (MRB, TCP, WAS, SJdV) and jointly (M-GB, JIDH, MW), producing five independently coded sets of data (S1 Table).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 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.
Recently 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.
The 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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding disease transmission in the workplace is essential for protecting workers. To model disease outbreaks, the small populations in many workplaces require that stochastic effects are ...considered, which results in higher uncertainty. The aim of this study was to quantify and interpret the uncertainty inherent in such circumstances. We assessed how uncertainty of an outbreak in workplaces depends on i) the infection dynamics in the community, ii) the workforce size, iii) spatial structure in the workplace, iv) heterogeneity in susceptibility of workers, and v) heterogeneity in infectiousness of workers. To address these questions, we developed a multiscale model: A deterministic model to predict community transmission, and a stochastic model to predict workplace transmission. We extended this basic workplace model to allow for spatial structure, and heterogeneity in susceptibility and infectiousness in workers. We found a non-monotonic relationship between the workplace transmission rate and the coefficient of variation (CV), which we use as a measure of uncertainty. Increasing community transmission, workforce size and heterogeneity in susceptibility decreased the CV. Conversely, increasing the level of spatial structure and heterogeneity in infectiousness increased the CV. However, when the model predicts bimodal distributions, for example when community transmission is low and workplace transmission is high, the CV fails to capture this uncertainty. Overall, our work informs modellers and policy makers on how model complexity impacts outbreak uncertainty. In particular: workforce size, community and workplace transmission, spatial structure and individual heterogeneity contribute in a specific and individual manner to the predicted workplace outbreak size distribution.
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.
Moxidectin is a milbemycin endectocide recently approved for the treatment of human onchocerciasis. Onchocerciasis, earmarked for elimination of transmission, is a filarial infection endemic in ...Africa, Yemen, and the Amazonian focus straddling Venezuela and Brazil. Concerns over whether the predominant treatment strategy (yearly mass drug administration (MDA) of ivermectin) is sufficient to achieve elimination in all endemic foci have refocussed attention upon alternative treatments. Moxidectin's stronger and longer microfilarial suppression compared to ivermectin in both phase II and III clinical trials indicates its potential as a novel powerful drug for onchocerciasis elimination.
This work summarizes the chemistry and pharmacology of moxidectin, reviews the phase II and III clinical trials evidence on tolerability, safety, and efficacy of moxidectin versus ivermectin, and discusses the implications of moxidectin's current regulatory status.
Moxidectin's superior clinical performance has the potential to substantially reduce times to elimination compared to ivermectin. If donated, moxidectin could mitigate the additional programmatic costs of biannual ivermectin distribution because, unlike other alternatives, it can use the existing community-directed treatment infrastructure. A pediatric indication (for children <12 years) and determination of its usefulness in onchocerciasis-loiasis co-endemic areas will greatly help fulfill the potential of moxidectin for the treatment and elimination of onchocerciasis.
Density 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.
Density 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.
This 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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Current models of parasite evolution do not account for host senescence.•An age-structured model of parasite evolution is developed.•The average age at infection determines virulence ...evolution.•Virulence evolves differently under frequency- and density-dependent transmission.
Although mortality increases with age in most organisms, senescence is missing from models of parasite evolution. Since virulence evolves according to the host’s mortality, and since virulence influences the intensity of transmission, which determines the average age at infection and thus the mortality rate of a senescing host, we expected that epi-evolutionary feedbacks would underlie the evolution of virulence in a population of senescing hosts. We tested this idea by extending an age-structured model of epidemiological dynamics with the parasite’s evolution. A straightforward prediction of our model is that stronger senescence forces the evolution of higher virulence. However, the model also reveals that the evolved virulence depends on the average age at infection, giving an evolutionary feedback with the epidemiological situation, a prediction not found when assuming a constant mortality rate with age. Additionally, and in contrast to most models of parasite evolution, we found that the virulence at the evolutionary equilibrium is influenced by whether the force of infection depends on the density or on the frequency of infected hosts, due to changes in the average age at infection. Our findings suggest that ignoring age-specific effects, and in particular senescence, can give misleading predictions about parasite evolution.
Protecting healthcare professionals is crucial in maintaining a functioning healthcare system. The risk of infection and optimal preventive strategies for healthcare workers during the COVID-19 ...pandemic remain poorly understood. Here we report the results of a cohort study that included pre- and asymptomatic healthcare workers. A weekly testing regime has been performed in this cohort since the beginning of the COVID-19 pandemic to identify infected healthcare workers. Based on these observations we have developed a mathematical model of SARS-CoV-2 transmission that integrates the sources of infection from inside and outside the hospital. The data were used to study how regular testing and a desynchronisation protocol are effective in preventing transmission of COVID-19 infection at work, and compared both strategies in terms of workforce availability and cost-effectiveness. We showed that case incidence among healthcare workers is higher than would be explained solely by community infection. Furthermore, while testing and desynchronisation protocols are both effective in preventing nosocomial transmission, regular testing maintains work productivity with implementation costs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug-based interventions are at the heart of global efforts to reach elimination as a public health problem (trachoma, soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis) or ...elimination of transmission (onchocerciasis) for five of the most prevalent neglected tropical diseases tackled via the World Health Organization preventive chemotherapy strategy. While for some of these diseases there is optimism that currently available drugs will be sufficient to achieve the proposed elimination goals, for others-particularly onchocerciasis-there is a growing consensus that novel therapeutic options will be needed. Since in this area no high return of investment is possible, minimizing wasted money and resources is essential. Here, we use illustrative results to show how mathematical modelling can guide the drug development pathway, yielding resource-saving and efficiency payoffs, from the refinement of target product profiles and intended context of use, to the design of clinical trials.
Abstract
Background
Mass drug administration (MDA) of ivermectin for onchocerciasis has been disrupted by the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modelling can help predict how ...missed/delayed MDA will affect short-term epidemiological trends and elimination prospects by 2030.
Methods
Two onchocerciasis transmission models (EPIONCHO-IBM and ONCHOSIM) are used to simulate microfilarial prevalence trends, elimination probabilities and age profiles of Onchocerca volvulus microfilarial prevalence and intensity for different treatment histories and transmission settings, assuming no interruption, a 1-y (2020) interruption or a 2-y (2020–2021) interruption. Biannual MDA or increased coverage upon MDA resumption are investigated as remedial strategies.
Results
Programmes with shorter MDA histories and settings with high pre-intervention endemicity will be the most affected. Biannual MDA is more effective than increasing coverage for mitigating COVID-19’s impact on MDA. Programmes that had already switched to biannual MDA should be minimally affected. In high-transmission settings with short treatment history, a 2-y interruption could lead to increased microfilarial load in children (EPIONCHO-IBM) and adults (ONCHOSIM).
Conclusions
Programmes with shorter (annual MDA) treatment histories should be prioritised for remedial biannual MDA. Increases in microfilarial load could have short- and long-term morbidity and mortality repercussions. These results can guide decision-making to mitigate the impact of COVID-19 on onchocerciasis elimination.
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