The Health Impact of Onchocerciasis Control in Africa

__Abstract__ Onchocerciasis is a tropical disease endemic to Sub-Saharan Africa, Yemen, and parts of Latin America, and is caused by the filarial nematode Onchocerca volvulus, which is found exclusively in humans. Adult specimens of this roundworm reside in subcutaneous and deep-tissue nodules, and have an estimated average reproductive life span of about ten years (Duke 1968; Plaisier et al. 1991b). While female worms grow up to 50 cm long and remain sedentary in the nodules, male worms are somewhat smaller (up to 42 cm) and migrate from nodule to nodule, inseminating female worms (Schulz- Key and Albiez 1977; Duke 1993). As long as they are regularly inseminated, female worms produce larvae, so-called microfilariae (mf), which measure up to 360 μm and migrate through the host’s tissues and live up to two years (Duke 1968). Mf may be picked up from the host’s skin by the bite of a blackfly (genus Simulium). In Africa, species of the S. damnosum complex are mainly responsible for transmission of infection, whereas in Latin America, several other Simulium species drive transmission (Basáñez, Churcher, and Grillet 2009; Adler, Cheke, and Post 2010). All Simulium species breed in oxygen-rich water (e.g. river rapids). During their passage through a blackfly, the mf—now called stage L1 larvae—develop and moult into infective stage L3 larvae, which may be transmitted to another human during a fly’s next bloodmeal (Duke, Moore, and De León 1967). A small fraction of the transmitted stage L3 larvae eventually develop into adult worms (male or female). In turn, these may start reproducing after a prepatent period of 12 to 16 months (Duke 1968, 1980), completing the cycle of transmission (Figure 1.1)

In vitro evaluation of defined oligosaccharide fractions in an equine model of inflammation

Background: Dietary supplementation with oligosaccharides has been proven to be beneficial for health in several mammalian species. Next to prebiotic effects resulting in a modulation of gut micro biota, immunomodulatory effects of oligosaccharides have been documented in vivo. Supplementation with defined oligosaccharide fractions has been shown to attenuate allergic responses and enhance defensive immune responses. Despite the accumulating evidence for immunomodulatory effects, very limited information is available regarding the direct mechanism of action of oligosaccharides. This study aims to elucidate the effects of selected oligosaccharide fractions on the lipopolysaccharide (LPS) induced inflammatory response in equine peripheral blood mononuclear cells (PBMCs). We investigated three different products containing either galacto-oligosaccharides (GOS) alone, a combination of GOS with fructo-oligosaccharides (FOS), and a triple combination of GOS and FOS with acidic oligosaccharides (AOS), at different concentrations. These products have been used in an identical composition in various previously published in vivo experiments. As the selected oligosaccharide fractions were derived from natural products, the fractions contained defined amounts of mono- and disaccharides and minor amounts of endotoxin, which was taken into account in the design of the study and the analysis of data. Acquired data were analysed in a Bayesian hierarchical linear regression model, accounting for variation between horses.Results: Exposing cultured PBMCs to either GOS or GOS/FOS fractions resulted in a substantial dose-dependent increase of tumour necrosis factor-α (TNF-α) production in LPS challenged PBMCs. In contrast, incubation with GOS/FOS/AOS resulted in a dose-dependent reduction of both TNF-α and interleukin-10 production following LPS challenge. In addition, incubation with GOS/FOS/AOS significantly increased the apparent PBMC viability, indicating a protective or mitogenic effect. Furthermore, mono- and disaccharide control fractions significantly stimulated the inflammatory response in LPS challenged PBMCs as well, though to a lesser extent than GOS and GOS/FOS fractions.Conclusions: We found distinct immunomodulating effects of the investigated standardised oligosaccharide fractions, which either stimulated or suppressed the LPS induced inflammatory response in PBMCs. Both scenarios require additional investigation, to elucidate underlying modulatory mechanisms, and to translate this knowledge into the clinical application of oligosaccharide supplements in foals and other neonates

The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize power calculations for CHMI-based malaria vaccine trials, we developed a novel non-linear statistical model for parasite kinetics as measured by qPCR, using data from mosquito-based CHMI experiments in 57 individuals. We robustly account for important sources of variation between and within individuals using a Bayesian framework. Study power is most dependent on the number of individuals in each treatment arm; inter-individual variation in vaccine efficacy and the number of blood samples taken per day matter relatively little. Due to high inter-individual variation in the number of first-generation parasites, hepatic vaccine trials required significantly more study subjects than erythrocytic vaccine trials. We provide power calculations for hypothetical malaria vaccine trials of various designs and conclude that so far, power calculations have been overly optimistic. We further illustrate how upcoming techniques like needle-injected CHMI may reduce required sample sizes

Feasibility of controlling hookworm infection through preventive chemotherapy: a simulation study using the individual-based WORMSIM modelling framework

Background: Globally, hookworms infect 440 million people in developing countries. Especially children and women of childbearing age are at risk of developing anaemia as a result of infection. To control hookworm infection and disease (i.e. reduce the prevalence of medium and heavy infection to <1 %), the World Health Organization has set the target to provide annual or semi-annual preventive chemotherapy (PC) with albendazole (ALB) or mebendazole (MEB) to at least 75 % of all children and women of childbearing age in endemic areas by 2020. Here, we predict the feasibility of achieving <1 % prevalence of medium and heavy infection, based on simulations with an individual-based model. Methods: We developed WORMSIM, a new generalized individual-based modelling framework for transmission and control of helminths, and quantified it for hookworm transmission based on published data. We simulated the impact of standard and more intense PC strategies on trends in hookworm infection, and explored the potential additional impact of interventions that improve access to water, sanitation, and hygiene (WASH). The individual-based framework allowed us to take account of inter-individual heterogeneities in exposure and contribution to transmission of infection, as well as in participation in successive PC rounds. Results: We predict that in low and medium endemic areas, current PC strategies (including targeting of WCBA) will achieve control of hookworm infection (i.e. the parasitological target) within 2 years. In highly endemic areas, control can be achieved with semi-annual PC with ALB at 90 % coverage, combined with interventions that reduce host contributions to the environmental reservoir of infection by 50 %. More intense PC strategies (high frequency and coverage) can help speed up control of hookworm infection, and may be necessary in some extremely highly endemic settings, but are not a panacea against systematic non-participation to PC. Conclusions: Control of hookworm infection by 2020 is feasible with current PC strategies (including targeting of WCBA). In highly endemic areas, PC should be combined with health education and/or WASH interventions

Required duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative modelling analysis

Background: The World Health Organization (WHO) has set ambitious targets for the elimination of onchocerciasis by 2020-2025 through mass ivermectin treatment. Two different mathematical models have assessed the feasibility of reaching this goal for different settings and treatment scenarios, namely the individual-based microsimulation model ONCHOSIM and the population-based deterministic model EPIONCHO. In this study, we harmonize some crucial assumptions and compare model predictions on common outputs. Methods: Using a range of initial endemicity levels and treatment scenarios, we compared the models with respect to the following outcomes: 1) model-predicted trends in microfilarial (mf) prevalence and mean mf intensity during 25 years of (annual or biannual) mass ivermectin treatment; 2) treatment duration needed to bring mf prevalence below a provisional operational threshold for treatment interruption (pOTTIS, i.e. 1.4 %), and 3) treatment duration needed to drive the parasite population to local elimination, even in the absence of further interventions. Local elimination was judged by stochastic fade-out in ONCHOSIM and by reaching transmission breakpoints in EPIONCHO. Results: ONCHOSIM and EPIONCHO both predicted that in mesoendemic areas the pOTTIS can be reached with annual treatment, but that this strategy may be insufficient in very highly hyperendemic areas or would require prolonged continuation of treatment. For the lower endemicity levels explored, ONCHOSIM predicted that the time needed to reach the pOTTIS is longer than that needed to drive the parasite population to elimination, whereas for the higher endemicity levels the opposite was true. In EPIONCHO, the pOTTIS was reached consistently sooner than the breakpoint. Co

Progress towards onchocerciasis elimination in the participating countries of the African Programme for Onchocerciasis Control: Epidemiological evaluation results

Background: The African Programme for Onchocerciasis Control (APOC) was created in 1995 to establish community-directed treatment with ivermectin (CDTi) in order to control onchocerciasis as a public health problem in 20 African countries that had 80 % of the global disease burden. When research showed that CDTi may ultimately eliminate onchocerciasis infection, APOC was given in 2008 the additional objective to determine when and where treatment can be safely stopped. We report the results of epidemiological evaluations undertaken from 2008 to 2014 to assess progress towards elimination in CDTi areas with ≥6 years treatment. Methods: Skin snip surveys were undertaken in samples of first-line villages to determine the prevalence of O. volvulus microfilariae. There were two evaluation phases. The decline in prevalence was evaluated in phase 1A. Observed and model-predicted prevalences were compared after correcting for endemicity level and treatment coverage. Bayesian statistics and Monte Carlo simulation were used to classify the decline in prevalence as faster than predicted, on track or delayed. Where the prevalence approached elimination levels, phase 1B was launched to determine if treatment could be safely stopped. Village sampling was extended to the whole CDTi area. Survey data were analysed within a Bayesian framework to determine if stopping criteria (overall prevalence <1.4 % and maximum stratum prevalence <5 %) were met. Results: In phase 1A 127 665 people from 639 villages in 54 areas were examined. The prevalence had fallen dramatically. The decline in prevalence was faster than predicted in 23 areas, on track in another 23 and delayed in eight areas. In phase 1B 108 636 people in 392 villages were examined in 22 areas of which 13 met the epidemiological criteria for stopping treatment. Overall, 32 areas (25.4 million people) had reached or were close to elimination, 18 areas (17.4 million) were on track but required more years treatment, and in eight areas (10.4 million) progress was unsatisfactory. Conclusions: Onchocerciasis has been largely controlled as a public health problem. Great progress has been made towards elimination which already appears to have been achieved for millions of people. For most APOC countries, nationwide onchocerciasis elimination is within reach

The effect of assortative mixing on stability of low helminth transmission levels and on the impact of mass drug administration: Model explorations for onchocerciasis

BACKGROUND: Stable low pre-control prevalences of helminth infection are not uncommon in field settings, yet it is poorly understood how such low levels can be sustained, thereby challenging efforts to model them. Disentangling possible facilitating mechanisms is important, since these may differently affect intervention impact. Here we explore the role of assortative (i.e. non-homogenous) mixing and exposure heterogeneity in helminth transmission, using onchocerciasis as an example.METHODOLOGY/PRINCIPAL FINDINGS: We extended the established individual-based model ONCHOSIM to allow for assortative mixing, assuming that individuals who are relatively more exposed to fly bites are more connected to each other than other individuals in the population as a result of differential exposure to a sub-population of blackflies. We used the model to investigate how transmission stability, equilibrium microfilarial (mf) prevalence and intensity, and impact of mass drug administration depend on the assumed degree of assortative mixing and exposure heterogeneity, for a typical rural population of about 400 individuals. The model clearly demonstrated that with homogeneous mixing and moderate levels of exposure heterogeneity, onchocerciasis could not be sustained below 35% mf prevalence. In contrast, assortative mixing stabilised onchocerciasis prevalence at levels as low as 8% mf prevalence. Increasing levels of assortative mixing significantly reduced the probability of interrupting transmission, given the same duration and coverage of mass drug administration.CONCLUSIONS/SIGNIFICANCE: Assortative mixing patterns are an important factor to explain stable low prevalence situations and are highly relevant for prospects of elimination. Their effect on the pre-control distribution of mf intensities in human populations is only detectable in settings with mf prevalences <30%, where high skin mf density in mf-positive people may be an indication of assortative mixing. Local spatial variation in larval infection intensity in the blackfly intermediate host may also be an indicator of assortative mixing

African Program for Onchocerciasis Control 1995–2010: Impact of Annual Ivermectin Mass Treatment on Off-Target Infectious Diseases

Since its initiation in 1995, the African Program for Onchocerciasis Control (APOC) has had a substantial impact on the prevalence and burden of onchocerciasis through annual ivermectin mass treatment. Ivermectin is a broad-spectrum anti-parasitic agent that also has an impact on other co-endemic parasitic infections. In this study, we roughly assessed the additional impact of APOC activities on the burden of the most important off-target infections: soil-transmitted helminthiases (STH; ascariasis, trichuriasis, hookworm, and strongyloidiasis), lymphatic filariasis (LF), and scabies. Based on a literature review, we formulated assumptions about the impact of ivermectin treatment on the disease burden of these off-target infections. Using data on the number of ivermectin treatments in APOC regions and the latest estimates of the burden of disease, we then calculated the impact of APOC activities on off-target infections in terms of disability-adjusted life years (DALYs) averted. We conservatively estimated that between 1995 and 2010, annual ivermectin mass treatment has cumulatively averted about 500 thousand DALYs from co-endemic STH infections, LF, and scabies. This impact comprised approximately an additional 5.5% relative to the total burden averted from onchocerciasis (8.9 million DALYs) and indicates that the overall cost-effectiveness of APOC is even higher than previously reported

The potential impact of human visceral leishmaniasis vaccines on population incidence

Human visceral leishmaniasis (VL) vaccines are currently under development and there is a need to understand their potential impact on population wide VL incidence. We implement four characteristics from different human VL vaccine candidates into two published VL transmission model variants to estimate the potential impact of these vaccine characteristics on population-wide anthroponotic VL incidence on the Indian subcontinent (ISC). The vaccines that are simulated in this study 1) reduce the infectiousness of infected individuals towards sand flies, 2) reduce risk of developing symptoms after infection, 3) reduce the risk of developing post-kala-azar dermal leishmaniasis (PKDL), or 4) lead to the development of transient immunity. We also compare and combine a vaccine strategy with current interventions to identify their potential role in elimination of VL as a public health problem. We show that the first two simulated vaccine characteristics can greatly reduce VL incidence. For these vaccines, an approximate 60% vaccine efficacy would lead to achieving the ISC elimination target (<1 VL case per 10,000 population per year) within 10 years' time in a moderately endemic setting when vaccinating 100% of the population. Vaccinating VL cases to prevent the development of PKDL is a promising tool to sustain the low incidence elimination target after regular interventions are halted. Vaccines triggering the development of transient immunity protecting against infection lead to the biggest reduction in VL incidence, but booster doses are required to achieve perduring impact. Even though vaccines are not yet available for implementation, their development should be pursued as their potential impact on transmission can be substantial, both in decreasing incidence at the population level as well as in sustaining the ISC elimination target when other interventions are halted.Human visceral leishmaniasis (VL) vaccines are currently under development and there is a need to understand their potential impact on population wide VL incidence. We implement four characteristics from different human VL vaccine candidates into two published VL transmission model variants to estimate the potential impact of these vaccine characteristics on population-wide anthroponotic VL incidence on the Indian subcontinent (ISC). The vaccines that are simulated in this study 1) reduce the infectiousness of infected individuals towards sand flies, 2) reduce risk of developing symptoms after infection, 3) reduce the risk of developing post-kala-azar dermal leishmaniasis (PKDL), or 4) lead to the development of transient immunity. We also compare and combine a vaccine strategy with current interventions to identify their potential role in elimination of VL as a publi

Uncertainty quantification and sensitivity analysis of COVID-19 exit strategies in an individual-based transmission model

Many countries are currently dealing with the COVID-19 epidemic and are searching for an exit strategy such that life in society can return to normal. To support this search, computational models are used to predict the spread of the virus and to assess the efficacy of policy measures before actual implementation. The model output has to be interpreted carefully though, as computational models are subject to uncertainties. These can stem from, e.g., limited knowledge about input parameters values or from the intrinsic stochastic nature of some computational models. They lead to uncertainties in the model predictions, raising the question what distribution of values the model produces for key indicators of the severity of the epidemic. Here we show how to tackle this question using techniques for uncertainty quantification and sensitivity analysis. We assess the uncertainties and sensitivities of four exit strategies implemented in an agent-based transmission model with geographical stratification. The exit strategies are termed Flattening the Curve, Contact Tracing, Intermittent Lockdown and Phased Opening. We consider two key indicators of the ability of exit strategies to avoid catastrophic health care overload: the maximum number of prevalent cases in intensive care (IC), and the total number of IC patient-days in excess of IC bed capacity. Our results show that uncertainties not directly related to the exit strategies are secondary, although they should still be considered in comprehensive analysis intended to inform policy makers. The sensitivity analysis discloses the crucial role of the intervention uptake by the population and of the capability to trace infected individuals. Finally, we explore the existence of a safe operating space. For Intermittent Lockdown we find only a small region in the model parameter space where the key indicators of the model stay within safe bounds, whereas this region is larger for the other exit strategies