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Cambodia's goal to eliminate malaria by 2025 is challenged by persistent transmission in forest and forest fringe areas, where people are exposed to Anopheles mosquito bites during the day and night. Volatile pyrethroid spatial repellents (VPSRs) and insecticide-treated clothing (ITC) could address these gaps. This study evaluated the outdoor application of one passive transfluthrin-based VPSR, four etofenprox-ITCs paired with a picaridin topical repellent, and a combination of VPSR and ITC against wild Anopheles landing in Cambodia. A 7 × 7 Latin-square study was conducted over 49 collection nights in temporary open structures in Mondulkiri Province. All interventions substantially reduced Anopheles landing, with protective efficacy ranging from 61 to 95%. Mathematical modeling showed significant reductions in vectoral capacity, especially with the combined ITC and VPSR and VPSR alone, albeit with decreased effectiveness over time. These interventions have the potential to reduce outdoor and daytime Anopheles biting, offering valuable contributions to malaria elimination efforts in Cambodia and the Greater Mekong Subregion, contingent upon achieving effective coverage and adherence., (© 2024. The Author(s).)

Entomological evaluations of vector control tools often use human landing catches (HLCs) as a standard measure of a direct human-vector contact. However, some tools have additional characteristics, such as mortality, and HLCS are not sensitive for measuring other effects beyond landing inhibition. Therefore, additional measures may need to be considered when evaluating these tools for public health use. This study has two main aims (1) the evaluate the accuracy of HLCs as a proxy for feeding and (2) to compare the predicted reduction in vectorial capacity when we do and do not consider these additional characteristics. To achieve this, we analyse previously published semi-field data from an experiment which used HLCs and another where mosquitoes were allowed to feed in the presence of different dosages of the volatile pyrethroid spatial repellent, transfluthrin. We compare results for two mathematical models: one which only considers the reduction in feeding effect and one which also considers mortality before and after feeding (using data gathered by the aspiration of mosquitoes after the semi-field feeding/landing period and 24 h survival monitoring). These Bayesian hierarchical models are parameterised using Bayesian inference. We observe that, for susceptible mosquitoes, reduction in landing is underestimated by HLCs. For knockdown resistant mosquitoes the relationship is less clear; with HLCs sometimes appearing to overestimate this characteristic. We find HLCs tend to under-predict the relative reduction in vectorial capacity in susceptible mosquitoes while over-predicting this impact in knockdown-resistant mosquitoes. Models without secondary effects have lower predicted relative reductions in vectorial capacities. Overall, this study highlights the importance of considering additional characteristics to reduction in biting of volatile pyrethroid spatial repellents. We recommend that these are considered when evaluating novel vector control tools., (© 2024. The Author(s).)

Background: In the Greater Mekong Subregion (GMS), new vector-control tools are needed to target mosquitoes that bite outside during the daytime and night-time to advance malaria elimination., Methods: We conducted systematic literature searches to generate a bionomic dataset of the main malaria vectors in the GMS, including human blood index (HBI), parity proportion, sac proportion (proportion with uncontracted ovary sacs, indicating the amount of time until they returned to host seeking after oviposition) and the resting period duration. We then performed global sensitivity analyses to assess the influence of bionomics and intervention characteristics on vectorial capacity., Results: Our review showed that Anopheles minimus, An. sinensis, An. maculatus and An. sundaicus display opportunistic blood-feeding behaviour, while An. dirus is more anthropophilic. Multivariate regression analysis indicated that environmental, climatic and sampling factors influence the proportion of parous mosquitoes, and resting duration varies seasonally. Sensitivity analysis highlighted HBI and parity proportion as the most influential bionomic parameters, followed by resting duration. Killing before feeding is always a desirable characteristic across all settings in the GMS. Disarming is also a desirable characteristic in settings with a low HBI. Repelling is only an effective strategy in settings with a low HBI and low parity proportion. Killing after feeding is only a desirable characteristic if the HBI and parity proportions in the setting are high., Conclusions: Although in general adopting tools that kill before feeding would have the largest community-level effect on reducing outdoor transmission, other modes of action can be effective. Current tools in development which target outdoor biting mosquitoes should be implemented in different settings dependent on their characteristics., (© 2024. The Author(s).)

Opisthorchis viverrini is a parasitic liver fluke contracted by consumption of raw fish, which affects over 10 million people in Southeast Asia despite sustained control efforts. Chronic infections are a risk factor for the often fatal bile duct cancer, cholangiocarcinoma. Previous modeling predicted rapid elimination of O. viverrini following yearly mass drug administration (MDA) campaigns. However, field data collected in affected populations shows persistence of infection, including heavy worm burden, after many years of repeated interventions. A plausible explanation for this observation is systematic adherence of individuals in health campaigns, such as MDA and education, with some individuals consistently missing treatment. We developed an agent-based model of O. viverrini which allows us to introduce various heterogeneities including systematic adherence to MDA and education campaigns at the individual level. We validate the agent-based model by comparing it to a previously published population-based model. We estimate the degree of systematic adherence to MDA and education campaigns indirectly, using epidemiological data collected in Lao PDR before and after 5 years of repeated MDA, education and sanitation improvement campaigns. We predict the impact of interventions deployed singly and in combination, with and without the estimated systematic adherence. We show how systematic adherence can substantially increase the time required to achieve reductions in worm burden. However, we predict that yearly MDA campaigns alone can result in a strong reduction of moderate and heavy worm burden, even under systematic adherence. We predict latrines and education campaigns to be particularly important for the reduction in overall prevalence, and therefore, ultimately, elimination. Our findings show how systematic adherence can explain the observed persistence of worm burden; while emphasizing the benefit of interventions for the entire population, even under systematic adherence. At the same time, the results highlight the substantial opportunity to further reduce worm burden if patterns of systematic adherence can be overcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kamber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The effectiveness of vector-control tools is often assessed by experiments as a reduction in mosquito landings using human landing catches (HLCs). However, HLCs alone only quantify a single characteristic and therefore do not provide information on the overall impacts of the intervention product. Using data from a recent semi-field study which used time-stratified HLCs, aspiration of non-landing mosquitoes, and blood feeding, we suggest a Bayesian inference approach for fitting such data to a stochastic model. This model considers both personal protection, through a reduction in biting, and community protection, from mosquito mortality and disarming (prolonged inhibition of blood feeding). Parameter estimates are then used to predict the reduction of vectorial capacity induced by etofenpox-treated clothing, picaridin topical repellents, transfluthrin spatial repellents and metofluthrin spatial repellents, as well as combined interventions for Plasmodium falciparum malaria in Anopleles minimus. Overall, all interventions had both personal and community effects, preventing biting and killing or disarming mosquitoes. This led to large estimated reductions in the vectorial capacity, with substantial impact even at low coverage. As the interventions aged, fewer mosquitoes were killed; however the impact of some interventions changed from killing to disarming mosquitoes. Overall, this inference method allows for additional modes of action, rather than just reduction in biting, to be parameterised and highlights the tools assessed as promising malaria interventions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Free-roaming domestic dogs (FRDD), as vectors of zoonotic diseases, are of high relevance for public health. Understanding roaming patterns of dogs can help to design disease control programs and disease transmission simulation models. Studies on GPS tracking of dogs report stark differences in recording periods. So far, there is no accepted number of days required to capture a representative home range (HR) of FRDD. The objective of this study was to evaluate changes in HR size and shape over time of FRDD living in Chad, Guatemala, Indonesia and Uganda and identify the period required to capture stable HR values. Dogs were collared with GPS units, leading to a total of 46 datasets with, at least, 19 recorded days. For each animal and recorded day, HR sizes were estimated using the Biased Random Bridge method and percentages of daily change in size and shape calculated and taken as metrics. The analysis revealed that the required number of days differed substantially between individuals, isopleths, and countries, with the extended HR (95% isopleth value) requiring a longer recording period. To reach a stable HR size and shape values for 75% of the dogs, 26 and 21 days, respectively, were sufficient. However, certain dogs required more extended observational periods., (© 2023. The Author(s).)

We consider a Darwinian (evolutionary game theoretic) version of a standard susceptible-infectious SI model in which the resistance of the disease causing pathogen to a treatment that prevents death to infected individuals is subject to evolutionary adaptation. We determine the existence and stability of all equilibria, both disease-free and endemic, and use the results to determine conditions under which the treatment will succeed or fail. Of particular interest are conditions under which a successful treatment in the absence of resistance adaptation (i.e. one that leads to a stable disease-free equilibrium) will succeed or fail when pathogen resistance is adaptive. These conditions are determined by the relative breadths of treatment effectiveness and infection transmission rate distributions as functions of pathogen resistance.

In pursuing novel therapeutic solutions, drug discovery and development rely on efficiently utilising existing knowledge and resources. Repurposing know-how, a strategy that capitalises on previously acquired information and expertise, has emerged as a powerful approach to accelerate drug discovery and development processes, often at a fraction of the costs of de novo developments. For 80 years, collaborating within a network of partnerships, the Swiss Tropical and Public Health Institute (Swiss TPH) has been working along a value chain from innovation to validation and application to combat poverty-related diseases. This article presents an overview of selected know-how repurposing initiatives conducted at Swiss TPH with a particular emphasis on the exploration of drug development pathways in the context of neglected tropical diseases and other infectious diseases of poverty, such as schistosomiasis, malaria and human African trypanosomiasis., (Copyright 2023 Lukas Meier, Marina Antillon, Christian Burri, Nakul Chitnis, Yvette Endriss, Jennifer Keiser, Sarah Moore, Pie Müller, Melissa Penny, Till S. Voss, Pascal Mäser, Jürg Utzinger. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Background: Global interest in malaria elimination has prompted research on active test and treat (TaT) strategies., Methods: A systematic review and meta-analysis were conducted to assess the effectiveness of TaT strategies to reduce malaria transmission., Results: A total of 72 empirical research and 24 modelling studies were identified, mainly focused on proactive mass TaT (MTaT) and reactive case detection (RACD) in higher and lower transmission settings, respectively. Ten intervention studies compared MTaT to no MTaT and the evidence for impact on malaria incidence was weak. No intervention studies compared RACD to no RACD. Compared to passive case detection (PCD) alone, PCD + RACD using standard diagnostics increased infection detection 52.7% and 11.3% in low and very low transmission settings, respectively. Using molecular methods increased this detection of infections by 1.4- and 1.1-fold, respectively., Conclusion: Results suggest MTaT is not effective for reducing transmission. By increasing case detection, surveillance data provided by RACD may indirectly reduce transmission by informing coordinated responses of intervention targeting., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Novel malaria vector control strategies targeting the odour-orientation of mosquitoes during host-seeking, such as 'attract-and-kill' or 'push-and-pull', have been suggested as complementary tools to indoor residual spraying and long-lasting insecticidal nets. These would be particularly beneficial if they can target vectors in the peri-domestic space where people are unprotected by traditional interventions. A randomized double-blind placebo-control study was implemented in western Kenya to evaluate: a 'push' intervention (spatial repellent) using transfluthrin-treated fabric strips positioned at open eave gaps of houses; a 'pull' intervention placing an odour-baited mosquito trap at a 5 m distance from a house; the combined 'push-pull' package; and the control where houses contained all elements but without active ingredients. Treatments were rotated through 12 houses in a randomized-block design. Outdoor biting was estimated using human landing catches, and indoor mosquito densities using light-traps. None of the interventions provided any protection from outdoor biting malaria vectors. The 'push' reduced indoor vector densities dominated by Anopheles funestus by around two thirds. The 'pull' device did not add any benefit. In the light of the high Anopheles arabiensis biting densities outdoors in the study location, the search for efficient outdoor protection and effective pull components needs to continue., (© 2023. The Author(s).)

Background: Survival and gonotrophic cycle duration are important determinants of the vectorial capacity of malaria vectors but there are a limited number of approaches to estimate these quantities from field data. Time-series of observations of mosquitoes at different stages in the life-cycle are under-used., Methods: Anopheles funestus mosquitoes were caught using various methods over a 7.6-year period in Furvela, Mozambique. Survival and oviposition cycle duration were estimated using (i) an existing time-series approach for analysing dissections of mosquitoes caught in light-traps, extended to allow for variability in the duration of the cycle; (ii) an established approach for estimating cycle duration from resting collection data; (iii) a novel time-series approach fitted to numbers and categories of mosquitoes caught in exit-traps., Results: Data were available from 7,396, 6,041 and 1,527 trap-nights for exit-traps, light-traps and resting collections respectively. Estimates of cycle duration varied considerably between the different methods. The estimated proportion of female mosquitoes surviving each day of 0.740 (95% credible interval [0.650-0.815]) derived from light-trap data was much lower than the estimated daily survival of male mosquitoes from the model fitted to exit-trap data (0.881, 95% credible interval [0.747-0.987]). There was no tendency for the oviposition cycle to become shorter at higher temperature while the odds of survival of females through the cycle was estimated to be multiplied by 1.021 for every degree of mean weekly temperature increase (95% credible interval [0.991-1.051]). There was negligible temperature dependence and little inter-annual variation in male survival., Discussion: The time-series approach fitted to the exit-traps suggests that male An. funestus have higher survival than do females, and that male survival was temperature independent and unaffected by the introduction of long-lasting insecticidal nets (LLINs). The patterns of temperature dependence in females are at variance with results of laboratory studies. Time series approaches have the advantage for estimating survival that they do not depend on representative sampling of mosquitoes over the whole year. However, the estimates of oviposition cycle duration were associated with considerable uncertainty, which appears to be due to variability between insects in the duration of the resting period, and the estimates based on exit-trap data are sensitive to assumptions about relative trapping efficiencies., Competing Interests: The authors declare that they have no competing interests., (© 2023 Charlwood et al.)

Malaria cases can be classified as imported, introduced or indigenous cases. The World Health Organization's definition of malaria elimination requires an area to demonstrate that no new indigenous cases have occurred in the last three years. Here, we present a stochastic metapopulation model of malaria transmission that distinguishes between imported, introduced and indigenous cases, and can be used to test the impact of new interventions in a setting with low transmission and ongoing case importation. We use human movement and malaria prevalence data from Zanzibar, Tanzania, to parameterise the model. We test increasing the coverage of interventions such as reactive case detection; implementing new interventions including reactive drug administration and treatment of infected travellers; and consider the potential impact of a reduction in transmission on Zanzibar and mainland Tanzania. We find that the majority of new cases on both major islands of Zanzibar are indigenous cases, despite high case importation rates. Combinations of interventions that increase the number of infections treated through reactive case detection or reactive drug administration can lead to substantial decreases in malaria incidence, but for elimination within the next 40 years, transmission reduction in both Zanzibar and mainland Tanzania is necessary., (© 2023. The Author(s).)

Malaria persists at low levels on Zanzibar despite the use of vector control and case management. We use a metapopulation model to investigate the role of human mobility in malaria persistence on Zanzibar, and the impact of reactive case detection. The model was parameterized using survey data on malaria prevalence, reactive case detection, and travel history. We find that in the absence of imported cases from mainland Tanzania, malaria would likely cease to persist on Zanzibar. We also investigate potential intervention scenarios that may lead to elimination, especially through changes to reactive case detection. While we find that some additional cases are removed by reactive case detection, a large proportion of cases are missed due to many infections having a low parasite density that go undetected by rapid diagnostic tests, a low rate of those infected with malaria seeking treatment, and a low rate of follow up at the household level of malaria cases detected at health facilities. While improvements in reactive case detection would lead to a reduction in malaria prevalence, none of the intervention scenarios tested here were sufficient to reach elimination. Imported cases need to be treated to have a substantial impact on prevalence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: SARS-CoV-2 variants of concern, such as Omicron (B.1.1.529), continue to emerge. Assessing the impact of their potential viral properties on the probability of future transmission dominance and public health burden is fundamental in guiding ongoing COVID-19 control strategies., Methods: With an individual-based transmission model, OpenCOVID, we simulated three viral properties; infectivity, severity, and immune-evading ability, all relative to the Delta variant, to identify thresholds for Omicron's or any emerging VOC's potential future dominance, impact on public health, and risk to health systems. We further identify for which combinations of viral properties current interventions would be sufficient to control transmission., Results: We show that, with first-generation SARS-CoV-2 vaccines and limited physical distancing in place, a VOC's potential future dominance is primarily driven by its infectivity, which does not always lead to an increased public health burden. However, we also show that highly immune-evading variants that become dominant, even in the case of reduced variant severity, would likely require alternative measures to avoid strain on health systems, such as strengthened physical distancing measures, novel treatments, and second-generation vaccines. Expanded vaccination, that includes a booster dose for adults and child vaccination strategies, is projected to have the biggest public health benefit for a highly infective, highly severe VOC with low immune-evading capacity., Conclusions: These findings provide quantitative guidance to decision-makers at a critical time while Omicron's properties are being assessed and preparedness for emerging VOCs is eminent. We emphasise the importance of both genomic and population epidemiological surveillance., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Background: Substantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence., Methods: A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals., Results: We apply our approach to five malaria interventions under development. Aiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements., Conclusions: Our approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. This study highlights the role of mathematical models to support intervention development. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions., (© 2022. The Author(s).)

Background: As vaccination coverage against SARS-CoV-2 increases amidst the emergence and spread of more infectious and potentially more deadly viral variants, decisions on timing and extent of relaxing effective, but unsustainable, non-pharmaceutical interventions (NPIs) need to be made., Methods: An individual-based transmission model of SARS-CoV-2 dynamics, OpenCOVID, was developed to compare the impact of various vaccination and NPI strategies on the COVID-19 epidemic in Switzerland. OpenCOVID uses the Oxford Containment Health Index (OCHI) to quantify the stringency of NPIs., Results: Even if NPIs in place in March 2021 were to be maintained and the vaccine campaigns rollout rapidly scaled-up, a 'third wave' was predicted. However, we find a cautious phased relaxation can substantially reduce population-level morbidity and mortality. We find that a faster vaccination campaign can offset the size of such a wave, allowing more flexibility for NPIs to be relaxed sooner. Model outcomes were most sensitive to the level of infectiousness of variants of concern observed in Switzerland., Conclusion: A rapid vaccination rollout can allow the sooner relaxation of NPIs, however ongoing surveillance of - and swift responses to - emerging viral variants is of utmost importance for epidemic control., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The study assessed the role of non-commercial cyprinid species in maintaining the opisthorchiasis focus in the middle Ob River basin, Tomsk region, Russia. The source of O. felineus infection for humans and carnivores is fish of the family Cyprinidae. This is the most numerous family, 14 species live in the middle Ob River basin, which includes 6 commercial species and 8 non-commercial species. This study aimed to investigate the current situation on infestation of non-commercial cyprinids with O. felineus metacercariae and their role in maintaining and spreading the natural focus of opisthorchiasis in the middle Ob River basin. We investigated 4 non-commercial species (tench, sunbleak, common bleak, gudgeon), which are highly abundant in water bodies. Tench, common bleak and gudgeon are objects of amateur fishing. These species are traditionally included in the diet of the local population. Opisthorchis felineus metacercariae were recorded in muscles of all the examined fish species. The identification of metacercariae was confirmed by morphological methods and PCR diagnostics. Tench and sunbleak are the main sources of opisthorchiasis infection in the floodplain lakes of the Ob River basin (the prevalence of tench infection is 89.3% and mean intensity of infection is 11.2 metacercariae per fish, the prevalence of sunbleak infection is 50.9% and the intensity of infection is 4.25 metacercariae per fish). The prevalence of infection in the introduced common bleak from the rivers of the middle Ob River basin is rapidly increasing from 2.4 (2016-2018) to 37.5% (2020-2021), and mean intensity of infection increased from 1 to 4.15. The epizootic state of water bodies in the middle Ob River basin remains unfavorable in relation to opisthorchiasis. Tench, common bleak and sunbleak, along with ide and dace, are the main source of infection for humans and animals, which is evidenced by high infection with Opisthorchis felineus metacercariae in these numerous fish species. They pose the greatest danger of infection of people and animals with opisthorchiasis. These species should be included in the campaign to avoid raw and poorly cooked fish in the diet. In addition, such species as roach, bream and sunbleak also pose the danger of infection with opisthorchiasis, but to a lesser extent., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Efforts to improve the impact of long-lasting insecticidal nets (LLINs) should be informed by understanding of the causes of decay in effect. Holes in LLINs have been estimated to account for 7-11% of loss in effect on vectorial capacity for Plasmodium falciparum malaria in an analysis of repeated cross-sectional surveys of LLINs in Kenya. This does not account for the effect of holes as a cause of net attrition or non-use, which cannot be measured using only cross-sectional data. There is a need for estimates of how much these indirect effects of physical damage on use and attrition contribute to decay in effectiveness of LLINs., Methods: Use, physical integrity, and survival were assessed in a cohort of 4514 LLINs followed for up to 4 years in Kenya. Flow diagrams were used to illustrate how the status of nets, in terms of categories of use, physical integrity, and attrition, changed between surveys carried out at 6-month intervals. A compartment model defined in terms of ordinary differential equations (ODEs) was used to estimate the transition rates between the categories. Effects of physical damage to LLINs on use and attrition were quantified by simulating counterfactuals in which there was no damage., Results: Allowing for the direct effect of holes, the effect on use, and the effect on attrition, 18% of the impact on vectorial capacity was estimated to be lost because of damage. The estimated median lifetime of the LLINs was 2.9 years, but this was extended to 5.7 years in the counterfactual without physical damage. Nets that were in use were more likely to be in a damaged state than unused nets but use made little direct difference to LLIN lifetimes. Damage was reported as the reason for attrition for almost half of attrited nets, but the model estimated that almost all attrited nets had suffered some damage before attrition., Conclusions: Full quantification of the effects of damage will require measurement of the supply of new nets and of household stocks of unused nets, and also of their impacts on both net use and retention. The timing of mass distribution campaigns is less important than ensuring sufficient supply. In the Kenyan setting, nets acquired damage rapidly once use began and the damage led to rapid attrition. Increasing the robustness of nets could substantially increase their lifetime and impact but the impact of LLIN programmes on malaria transmission is ultimately limited by levels of use. Longitudinal analyses of net integrity data from different settings are needed to determine the importance of physical damage to nets as a driver of attrition and non-use, and the importance of frequent use as a cause of physical damage in different contexts., (© 2021. The Author(s).)

Gambiense human African trypanosomiasis is a deadly disease that has been declining in incidence since the start of the Century, primarily due to increased screening, diagnosis and treatment of infected people. The main treatment regimen currently in use requires a lumbar puncture as part of the diagnostic process to determine disease stage and hospital admission for drug administration. Fexinidazole is a new oral treatment for stage 1 and non-severe stage 2 human African trypanosomiasis. The World Health Organization has recently incorporated fexinidazole into its treatment guidelines for human African trypanosomiasis. The treatment does not require hospital admission or a lumbar puncture for all patients, which is likely to ease access for patients; however, it does require concomitant food intake, which is likely to reduce adherence. Here, we use a mathematical model calibrated to case and screening data from Mushie territory, in the Democratic Republic of the Congo, to explore the potential negative impact of poor compliance to an oral treatment, and potential gains to be made from increases in the rate at which patients seek treatment. We find that reductions in compliance in treatment of stage 1 cases are projected to result in the largest increase in further transmission of the disease, with failing to cure stage 2 cases also posing a smaller concern. Reductions in compliance may be offset by increases in the rate at which cases are passively detected. Efforts should therefore be made to ensure good adherence for stage 1 patients to treatment with fexinidazole and to improve access to care., Competing Interests: The authors have declared that no competing interests exist.

Background: Larviciding against malaria vectors in Africa has been limited to indoor residual spraying and insecticide-treated nets, but is increasingly being considered by some countries as a complementary strategy. However, despite progress towards improved larvicides and new tools for mapping or treating mosquito-breeding sites, little is known about the optimal deployment strategies for larviciding in different transmission and seasonality settings., Methods: A malaria transmission model, OpenMalaria, was used to simulate varying larviciding strategies and their impact on host-seeking mosquito densities, entomological inoculation rate (EIR) and malaria prevalence. Variations in coverage, duration, frequency, and timing of larviciding were simulated for three transmission intensities and four transmission seasonality profiles. Malaria transmission was assumed to follow rainfall with a lag of one month. Theoretical sub-Saharan African settings with Anopheles gambiae as the dominant vector were chosen to explore impact. Relative reduction compared to no larviciding was predicted for each indicator during the simulated larviciding period., Results: Larviciding immediately reduced the predicted host-seeking mosquito densities and EIRs to a maximum that approached or exceeded the simulated coverage. Reduction in prevalence was delayed by approximately one month. The relative reduction in prevalence was up to four times higher at low than high transmission. Reducing larviciding frequency (i.e., from every 5 to 10 days) resulted in substantial loss in effectiveness (54, 45 and 53% loss of impact for host-seeking mosquito densities, EIR and prevalence, respectively). In seasonal settings the most effective timing of larviciding was during or at the beginning of the rainy season and least impactful during the dry season, assuming larviciding deployment for four months., Conclusion: The results highlight the critical role of deployment strategies on the impact of larviciding. Overall, larviciding would be more effective in settings with low and seasonal transmission, and at the beginning and during the peak densities of the target species populations. For maximum impact, implementers should consider the practical ranges of coverage, duration, frequency, and timing of larviciding in their respective contexts. More operational data and improved calibration would enable models to become a practical tool to support malaria control programmes in developing larviciding strategies that account for the diversity of contexts., (© 2021. The Author(s).)

Background: The gambiense human African trypanosomiasis (gHAT) elimination programme in the Democratic Republic of Congo (DRC) routinely collects case data through passive surveillance and active screening, with several regions reporting no cases for several years, despite being endemic in the early 2000s., Methods: We use mathematical models fitted to longitudinal data to estimate the probability that selected administrative regions have already achieved elimination of transmission (EOT) of gHAT. We examine the impact of active screening coverage on the certainty of model estimates for transmission and therefore the role of screening in the measurement of EOT., Results: In 3 example health zones of Sud-Ubangi province, we find there is a moderate (>40%) probability that EOT has been achieved by 2018, based on 2000-2016 data. Budjala and Mbaya reported zero cases during 2017-18, and this further increases our respective estimates to 99.9% and 99.6% (model S) and to 87.3% and 92.1% (model W). Bominenge had recent case reporting, however, that if zero cases were found in 2021, it would substantially raise our certainty that EOT has been met there (99.0% for model S and 88.5% for model W); this could be higher with 50% coverage screening that year (99.1% for model S and 94.0% for model W)., Conclusions: We demonstrate how routine surveillance data coupled with mechanistic modeling can estimate the likelihood that EOT has already been achieved. Such quantitative assessment will become increasingly important for measuring local achievement of EOT as 2030 approaches., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Many control programmes against neglected tropical diseases have been interrupted due to the coronavirus disease 2019 (COVID-19) pandemic, including those that rely on active case finding. In this study we focus on gambiense human African trypanosomiasis (gHAT), where active screening was suspended in the Democratic Republic of Congo (DRC) due to the pandemic. We use two independent mathematical models to predict the impact of COVID-19 interruptions on transmission and reporting and achievement of the 2030 elimination of transmission (EOT) goal for gHAT in two moderate-risk regions of the DRC. We consider different interruption scenarios, including reduced passive surveillance in fixed health facilities, and whether this suspension lasts until the end of 2020 or 2021. Our models predict an increase in the number of new infections in the interruption period only if both active screening and passive surveillance were suspended, and with a slowed reduction-but no increase-if passive surveillance remains fully functional. In all scenarios, the EOT may be slightly pushed back if no mitigation, such as increased screening coverage, is put in place. However, we emphasise that the biggest challenge will remain in the higher-prevalence regions where EOT is already predicted to be behind schedule without interruptions unless interventions are bolstered., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Infection with the liver fluke, Opisthorchis felineus , caused by the consumption of infected raw or undercooked cyprinid fish is common in humans and carnivores in the middle Ob River basin (Tomsk region, Russia) and can lead to diseases in humans. The goal of this study was the status of fish infection with O. felineus metacercariae in order to assess the role of fish in the infection of the human population in the middle Ob River basin. Of the 14 Cyprinidae species recorded in the middle Ob River basin, we examined 6 cyprinid species for prevalence and intensity of infection with O. felineus metacercariae. Five of these species ( Leuciscus idus , Leuciscus leuciscus , Rutilus rutilus , Abramis brama , and Carassius gibelio ) are of commercial value, while the common bleak is an object of amateur fishing. In addition, we conducted a survey of the fish consumption habits as part of a community-based cross-sectional study in the rural Shegarsky district, Tomsk region, Russian Federation. O. felineus metacercariae were observed in muscles of all examined species except for the Prussian carp. The ide is the main infection source in the Ob River (prevalence of infection, 100%, and intensity, 50.5 metacercariae per fish) and the common dace in the Tom River (91.1% and 12.7 metacercariae). Although the two alien species (bream and common bleak) are susceptible to infection with O. felineus metacercariae, the prevalence of infection in these fish and in the roach did not exceed 3%. The prevalence and intensity of infection in fish increased with age and size. The infection characteristics of fish in different water flows were different. The cyprinid species account on average for 69.8% of the commercial fish harvested in the Tomsk region. According to epidemiological survey, among 600 participants, 87.5% ( n  = 525) of respondents consumed river fish, with the most popular fish being cyprinids including Prussian carp, dace, ide and bream, followed by pike and perch. Thus, the epizootological state of the water flows in the middle Ob River basin is adverse with respect to opisthorchiasis, as indicated by high infection rates of liver fluke metacercariae in ide and common dace, which are abundant species of high commercial value. An extremely high prevalence of infection suggests a strong transmission cycle with a high rate of infection from infected humans and/or animal reservoir hosts to snails and fish. In addition to treating humans, there should be a strong focus on identifying these potential reservoir hosts to reduce subsequent infection in humans. Furthermore, since the intensity of infection in humans is determined by the presence of fish species such as ide and dace in the diet, they should be included in a dietary change campaign by eliminating the consumption of raw fish., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: Semi-field experiments with human landing catch (HLC) measure as the outcome are an important step in the development of novel vector control interventions against outdoor transmission of malaria since they provide good estimates of personal protection. However, it is often infeasible to determine whether the reduction in HLC counts is due to mosquito mortality or repellency, especially considering that spatial repellents based on volatile pyrethroids might induce both. Due to the vastly different impact of repellency and mortality on transmission, the community-level impact of spatial repellents can not be estimated from such semi-field experiments., Methods: We present a new stochastic model that is able to estimate for any product inhibiting outdoor biting, its repelling effect versus its killing and disarming (preventing host-seeking until the next night) effects, based only on time-stratified HLC data from controlled semi-field experiments. For parameter inference, a Bayesian hierarchical model is used to account for nightly variation of semi-field experimental conditions. We estimate the impact of the products on the vectorial capacity of the given Anopheles species using an existing mathematical model. With this methodology, we analysed data from recent semi-field studies in Kenya and Tanzania on the impact of transfluthrin-treated eave ribbons, the odour-baited Suna trap and their combination (push-pull system) on HLC of Anopheles arabiensis in the peridomestic area., Results: Complementing previous analyses of personal protection, we found that the transfluthrin-treated eave ribbons act mainly by killing or disarming mosquitoes. Depending on the actual ratio of disarming versus killing, the vectorial capacity of An. arabiensis is reduced by 41 to 96% at 70% coverage with the transfluthrin-treated eave ribbons and by 38 to 82% at the same coverage with the push-pull system, under the assumption of a similar impact on biting indoors compared to outdoors., Conclusions: The results of this analysis of semi-field data suggest that transfluthrin-treated eave ribbons are a promising tool against malaria transmission by An. arabiensis in the peridomestic area, since they provide both personal and community protection. Our modelling framework can estimate the community-level impact of any tool intervening during the mosquito host-seeking state using data from only semi-field experiments with time-stratified HLC.

Background: Gambiense human African trypanosomiasis ([gHAT] sleeping sickness) is a vector-borne disease that is typically fatal without treatment. Intensified, mainly medical-based, interventions in endemic areas have reduced the occurrence of gHAT to historically low levels. However, persistent regions, primarily in the Democratic Republic of Congo (DRC), remain a challenge to achieving the World Health Organization's goal of global elimination of transmission (EOT)., Methods: We used stochastic models of gHAT transmission fitted to DRC case data and explored patterns of regional reporting and extinction. The time to EOT at a health zone scale (~100 000 people) and how an absence of reported cases informs about EOT was quantified., Results: Regional epidemiology and level of active screening (AS) both influenced the predicted time to EOT. Different AS cessation criteria had similar expected infection dynamics, and recrudescence of infection was unlikely. However, whether EOT has been achieved when AS ends is critically dependent on the stopping criteria. Two or three consecutive years of no detected cases provided greater confidence of EOT compared with a single year (~66%-75% and ~82%-84% probability of EOT, respectively, compared with 31%-51%)., Conclusions: Multiple years of AS without case detections is a valuable measure to assess the likelihood that the EOT target has been met locally., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Malaria burden has significantly changed or decreased over the last 20 years, however, it remains an important health problem requiring the rigorous application of existing tools and approaches, as well as the development and use of new interventions. A malaria vaccine has long been considered a possible new intervention to aid malaria burden reduction. However, after decades of development, only one vaccine to protect children has completed phase 3 studies. Before being widely recommended for use, it must further demonstrate safety, impact and feasibility in ongoing pilot implementation studies. Now is an appropriate time to consider the use-cases and health targets of future malaria vaccines. These must be considered in the context of likely innovations in other malaria tools such as vector control, as well as the significant knowledge gaps on the appropriate target antigens, and the immunology of vaccine-induced protection. Here we discuss the history of malaria vaccines and suggest some future use-cases for future malaria vaccines that will support achieving malaria health goals in different settings., Competing Interests: MAP was funded by her Swiss National Science Foundation Professorship PP00P3 170702. MAP declares funding from PATH's Malaria Vaccine Initiative to support modelling for the Malaria Vaccine Implementation Program and past funding from the Bill and Melinda Gates Foundation. TAS declares funding from Bill and Melinda Gates OPP 1032350. MT declares past funding from the Bill and Melinda Gates Foundation and from PATH-MVI; the latter in the frame of the RTS,S clinical development. All other authors declare that they have no competing interests., (© 2020 The Authors.)

Since the turn of the century, the global community has made great progress towards the elimination of gambiense human African trypanosomiasis (HAT). Elimination programs, primarily relying on screening and treatment campaigns, have also created a rich database of HAT epidemiology. Mathematical models calibrated with these data can help to fill remaining gaps in our understanding of HAT transmission dynamics, including key operational research questions such as whether integrating vector control with current intervention strategies is needed to achieve HAT elimination. Here we explore, via an ensemble of models and simulation studies, how including or not disease stage data, or using more updated data sets affect model predictions of future control strategies., Competing Interests: The authors have declared that no competing interests exist.

Background: A clear understanding of mosquito biology is fundamental to the control efforts of mosquito-borne diseases such as malaria. Mosquito mark-release-recapture (MMRR) experiments are a popular method of measuring the survival and dispersal of disease vectors; however, examples with African malaria vectors are limited. Ethical and technical difficulties involved in carrying out MMRR studies may have held back research in this area and, therefore, a device that marks mosquitoes as they emerge from breeding sites was developed and evaluated to overcome the problems of MMRR., Methods: A modified self-marking unit that marks mosquitoes with fluorescent pigment as they emerge from their breeding site was developed based on a previous design for Culex mosquitoes. The self-marking unit was first evaluated under semi-field conditions with laboratory-reared Anopheles arabiensis to determine the marking success and impact on mosquito survival. Subsequently, a field evaluation of MMRR was conducted in Yombo village, Tanzania, to examine the feasibility of the system., Results: During the semi-field evaluation the self-marking units successfully marked 86% of emerging mosquitoes and there was no effect of fluorescent marker on mosquito survival. The unit successfully marked wild male and female Anopheles gambiae sensu lato (s.l.) in sufficiently large numbers to justify its use in MMRR studies. The estimated daily survival probability of An. gambiae s.l. was 0.87 (95% CI 0.69-1.10) and mean dispersal distance was 579 m (95% CI 521-636 m)., Conclusions: This study demonstrates the successful use of a self-marking device in an MMRR study with African malaria vectors. This method may be useful in investigating population structure and dispersal of mosquitoes for deployment and evaluation of future vector control tools, such as gene drive, and to better parameterize mathematical models.

Background: Field studies are evaluating if mass drug administration (MDA) might shorten the time to elimination of Plasmodium falciparum malaria, when vector control measures and reactive surveillance strategies are scaled-up. A concern with this strategy is that there may be resurgence of transmission following MDA., Methods: A conceptual model was developed to classify possible outcomes of an initial period of MDA, followed by continuously implementing other interventions. The classification considered whether elimination or a new endemic stable state is achieved, and whether changes are rapid, transient, or gradual. These categories were informed by stability analyses of simple models of vector control, case management, and test-and-treat interventions. Individual-based stochastic models of malaria transmission (OpenMalaria) were then used to estimate the probability and likely rates of resurgence in realistic settings. Effects of concurrent interventions, including routine case management and test-and-treat strategies were investigated., Results: Analysis of the conceptual models suggest resurgence will occur after MDA unless transmission potential is very low, or the post-MDA prevalence falls below a threshold, which depends on both transmission potential and on the induction of bistability. Importation rates are important only when this threshold is very low. In most OpenMalaria simulations the approximately stable state achieved at the end of the simulations was independent of inclusion of MDA and the final state was unaffected by importation of infections at plausible rates. Elimination occurred only with high effective coverage of case management, low initial prevalence, and high intensity test-and-treat. High coverage of case management but not by test-and-treat induced bistability. Where resurgence occurred, its rate depended mainly on transmission potential (not treatment rates)., Conclusions: A short burst of high impact MDA is likely to be followed by resurgence. To avert resurgence, concomitant interventions need either to substantially reduce average transmission potential or to be differentially effective in averting or clearing infections at low prevalence. Case management at high effective coverage has this differential effect, and should suffice to avert resurgence caused by imported cases at plausible rates of importation. Once resurgence occurs, its rate depends mainly on transmission potential, not on treatment strategies.

Background: Reactive case detection (RCD) is an integral part of many malaria control and elimination programmes and can be conceived of as a way of gradually decreasing transmission. However, it is unclear under what circumstances RCD may have a substantial impact on prevalence, how likely it is to lead to local elimination, or how effective it needs to be to prevent reintroduction after transmission has been interrupted., Methods: Analyses and simulations of a discrete time compartmental susceptible-infectious-susceptible (SIS) model were used to understand the mechanisms of how RCD changes transmission dynamics and estimate the impact of RCD programmes in a range of settings with varying patterns of transmission potential and programme characteristics. Prevalence survey data from recent studies in Zambia were used to capture the effects of spatial clustering of patent infections., Results: RCD proved most effective at low prevalence. Increasing the number of index cases followed was more important than increasing the number of neighbours tested per index case. Elimination was achieved only in simulations of situations with very low transmission intensity and following many index cases. However, RCD appears to be helpful in maintaining the disease-free state after achieving malaria elimination (through other interventions)., Conclusion: RCD alone can eliminate malaria in only a very limited range of settings, where transmission potential is very low, and improving the coverage of RCD has little effect on this range. In other settings, it is likely to reduce disease burden. RCD may also help maintain the disease-free state in the face of imported infections. Prevalence survey data can be used to estimate a targeting ratio (the ratio of prevalence found through RCD to that in the general population) which is an important determinant of the effect of RCD.

Background: Most impact prediction of malaria vector control interventions has been based on African vectors. Anopheles albimanus, the main vector in Central America and the Caribbean, has higher intrinsic mortality, is more zoophilic and less likely to rest indoors. Therefore, relative impact among interventions may be different. Prioritizing interventions, in particular for eliminating Plasmodium falciparum from Haiti, should consider local vector characteristics., Methods: Field bionomics data of An. albimanus from Hispaniola and intervention effect data from southern Mexico were used to parameterize mathematical malaria models. Indoor residual spraying (IRS), insecticide-treated nets (ITNs), and house-screening were analysed by inferring their impact on the vectorial capacity in a difference-equation model. Impact of larval source management (LSM) was assumed linear with coverage. Case management, mass drug administration and vaccination were evaluated by estimating their effects on transmission in a susceptible-infected-susceptible model. Analogous analyses were done for Anopheles gambiae parameterized with data from Tanzania, Benin and Nigeria., Results: While LSM was equally effective against both vectors, impact of ITNs on transmission by An. albimanus was much lower than for An. gambiae. Assuming that people are outside until bedtime, this was similar for the impact of IRS with dichlorodiphenyltrichloroethane (DDT) or bendiocarb, and impact of IRS was less than that of ITNs. However, assuming people go inside when biting starts, IRS had more impact on An. albimanus than ITNs. While house-screening had less impact than ITNs or IRS on An. gambiae, it had more impact on An. albimanus than ITNs or IRS. The impacts of chemoprevention and chemotherapy were comparable in magnitude to those of strategies against An. albimanus. Chemo-prevention impact increased steeply as coverage approached 100%, whilst clinical-case management impact saturated because of remaining asymptomatic infections., Conclusions: House-screening and repellent IRS are potentially highly effective against An. albimanus if people are indoors during the evening. This is consistent with historical impacts of IRS with DDT, which can be largely attributed to excito-repellency. It also supports the idea that housing improvements have played a critical role in malaria control in North America. For elimination planning, impact estimates need to be combined with feasibility and cost-analysis.

Background: As areas move closer to malaria elimination, a combination of limited resources and increasing heterogeneity in case distribution and transmission favour a shift to targeted reactive interventions. Reactive case detection (RCD), the following up of additional individuals surrounding an index case, has the potential to target transmission pockets and identify asymptomatic cases in them. Current RCD implementation strategies vary, and it is unclear which are most effective in achieving elimination., Methods: OpenMalaria, an established individual-based stochastic model, was used to simulate RCD in a Zambia-like setting. The capacity to follow up index cases, the search radius, the initial transmission and the case management coverage were varied. Suitable settings were identified and probabilities of elimination and time to elimination estimated. The value of routinely collected prevalence and incidence data for predicting the success of RCD was assessed., Results: The results indicate that RCD with the aim of transmission interruption is only appropriate in settings where initial transmission is very low (annual entomological inoculation rate (EIR) 1-2 or prevalence approx. < 7-19% depending on case management levels). Every index case needs to be followed up, up to a maximum case-incidence threshold which defines the suitability threshold of settings for elimination using RCD. Increasing the search radius around index cases is always beneficial., Conclusions: RCD is highly resource intensive, requiring testing and treating of 400-500 people every week for 5-10 years for a reasonable chance of elimination in a Zambia-like setting.

We use partial differential equations to describe the dynamics of an Aedes aegypti mosquito population on an island, and the effects of a sterile male release. The model includes mosquito movement and an Allee effect to capture extinction events. We apply optimal control theory to identify the release strategy that eliminates the mosquitoes most rapidly, conditional on a limited availability of sterile males. The optimal solution for a single location is to initially release a substantial number of mosquitoes and to subsequently release fewer sterile males proportionally to the decreasing female population. The optimal solution for the whole island is intractable given a constraint on the total daily release of sterile males. The best approximation to the spatial optimal control strategy is to focus on the high mosquito density areas first and then move outwards (in both directions along the periphery of the island), until all areas have been covered, retaining throughout sufficient release intensity to prevent reintroduction in the already cleared areas., (Copyright © 2019. Published by Elsevier Inc.)

Rabies transmission was interrupted for several months in N'Djamena, the capital city of Chad, after two mass vaccination campaigns of dogs. However, there was a resurgence in cases, which was not predicted by previous models of rabies transmission. We developed a deterministic metapopulation model with importation of latent dogs, calibrated to four years of weekly incidence data from passive surveillance, to investigate possible causes for the early resurgence. Our results indicate that importation of latently infective dogs better explains the data than heterogeneity or underreporting. Stochastic implementations of the model suggest that the two vaccination campaigns averted approximately 67 cases of dog rabies (out of an estimated 74 cases without vaccination) and 124 human exposures (out of an estimated 148 human exposures without vaccination) over two years. Dog rabies vaccination is therefore an effective way of preventing rabies in the dog population and to subsequently reduce human exposure. However, vaccination campaigns have to be repeated to maintain the effect or reintroduction through importation has to be prevented., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malaria and some other tropical diseases are currently targeted for elimination and eventually eradication. Since resources are limited, prioritisation of countries or areas for elimination is often necessary. However, this prioritisation is frequently conducted in an ad hoc manner. Lower transmission areas are usually targeted for elimination first, but for some areas this necessitates long and potentially expensive surveillance programs while transmission is eliminated from neighbouring higher transmission areas. We use a mathematical model to compare the implications of prioritisation choices in reducing overall burden and costs. We show that when the duration of the elimination program is independent of the transmission potential, burden is always reduced most by targeting high transmission areas first, but to reduce costs the optimal ordering depends on the actual transmission levels. In general, when overall transmission potential is low and the surveillance cost per secondary case compared to the cost per imported case is low, targeting the higher transmission area for elimination first is favoured., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We adapt a population-based model of Opisthorchis viverrini transmission dynamics to determine the effectiveness of three different interventions. The model includes the definitive hosts, humans; the reservoir hosts, dogs and cats; and the intermediate hosts, snails and fish. We consider the interventions: education campaigns to reduce the consumption of raw or undercooked fish, improved sanitation and treatment through mass drug administration. We fit model parameters to a data set from two islands in southern Lao PDR. We calculate the control reproduction number, simulate different scenarios and optimise the interventions with optimal control. We look at the potential of the interventions to eliminate transmission within 20 years. The model shows that education and improved sanitation need a very high coverage to fulfil the goal of elimination, whereas annual drug distribution at medium coverage is sufficient. The best solution is a combination of drug distribution at a medium level of coverage and as high as possible coverage of education and improved sanitation., (Copyright © 2018. Published by Elsevier Inc.)

Background: Current strategies to control mosquito-transmitted infections use insecticides targeted at various stages of the mosquito life-cycle. Control is increasingly compromised by the evolution of insecticide resistance but there is little quantitative understanding of its impact on control effectiveness. We developed a computational approach that incorporates the stage-structured mosquito life-cycle and allows tracking of insecticide resistant genotypes. This approach makes it possible to simultaneously investigate: (i) the population dynamics of mosquitoes throughout their whole life-cycle; (ii) the impact of common vector control interventions on disease transmission; (iii) how these interventions drive the spread of insecticide resistance; and (iv) the impact of resistance once it has arisen and, in particular, whether it is sufficient for malaria transmission to resume. The model consists of a system of difference equations that tracks the immature (eggs, larvae and pupae) and adult stages, for males and females separately, and incorporates density-dependent regulation of mosquito larvae in breeding sites., Results: We determined a threshold level of mosquitoes below which transmission of malaria is interrupted. It is based on a classic Ross-Macdonald derivation of the malaria basic reproductive number (R 0 ) and may be used to assess the effectiveness of different control strategies in terms of whether they are likely to interrupt disease transmission. We simulated different scenarios of insecticide deployment by changing key parameters in the model to explore the comparative impact of insecticide treated nets, indoor residual spraying and larvicides., Conclusions: Our simulated results suggest that relatively low degrees of resistance (in terms of reduced mortality following insecticide contact) can induce failure of interventions, and the rate of spread of resistance is faster when insecticides target the larval stages. The optimal disease control strategy depends on vector species demography and local environmental conditions but, in our illustrative parametrisation, targeting larval stages achieved the greatest reduction of the adult population, followed by targeting of non-host-seeking females, as provided by indoor residual spraying. Our approach is designed to be flexible and easily generalizable to many scenarios using different calibrations and to diseases other than malaria.

Canine rabies transmission was interrupted in N'Djaména, Chad, following two mass vaccination campaigns. However, after nine months cases resurged with re-establishment of endemic rabies transmission to pre-intervention levels. Previous analyses investigated district level spatial heterogeneity of vaccination coverage, and dog density; and importation, identifying the latter as the primary factor for rabies resurgence. Here we assess the impact of individual level heterogeneity on outbreak probability, effectiveness of vaccination campaigns and likely time to resurgence after a campaign. Geo-located contact sensors recorded the location and contacts of 237 domestic dogs in N'Djaména over a period of 3.5 days. The contact network data showed that urban dogs are socially related to larger communities and constrained by the urban architecture. We developed a network generation algorithm that extrapolates this empirical contact network to networks of large dog populations and applied it to simulate rabies transmission in N'Djaména. The model predictions aligned well with the rabies incidence data. Using the model we demonstrated, that major outbreaks are prevented when at least 70% of dogs are vaccinated. The probability of a minor outbreak also decreased with increasing vaccination coverage, but reached zero only when coverage was near total. Our results suggest that endemic rabies in N'Djaména may be explained by a series of importations with subsequent minor outbreaks. We show that highly connected dogs hold a critical role in transmission and that targeted vaccination of such dogs would lead to more efficient vaccination campaigns., Competing Interests: The authors have declared that no competing interests exist.

Background: Control of gambiense sleeping sickness relies predominantly on passive and active screening of people, followed by treatment., Methods: Mathematical modeling explores the potential of 3 complementary interventions in high- and low-transmission settings., Results: Intervention strategies that included vector control are predicted to halt transmission most quickly. Targeted active screening, with better and more focused coverage, and enhanced passive surveillance, with improved access to diagnosis and treatment, are both estimated to avert many new infections but, when used alone, are unlikely to halt transmission before 2030 in high-risk settings., Conclusions: There was general model consensus in the ranking of the 3 complementary interventions studied, although with discrepancies between the quantitative predictions due to differing epidemiological assumptions within the models. While these predictions provide generic insights into improving control, the most effective strategy in any situation depends on the specific epidemiology in the region and the associated costs.

Trypanosoma brucei gambiense causes human African trypanosomiasis (HAT). Between 1990 and 2015, almost 440000 cases were reported. Large-scale screening of populations at risk, drug donations, and efforts by national and international stakeholders have brought the epidemic under control with <2200 cases in 2016. The World Health Organization (WHO) has set the goals of gambiense-HAT elimination as a public health problem for 2020, and of interruption of transmission to humans for 2030. Latent human infections and possible animal reservoirs may challenge these goals. It remains largely unknown whether, and to what extend, they have an impact on gambiense-HAT transmission. We argue that a better understanding of the contribution of human and putative animal reservoirs to gambiense-HAT epidemiology is mandatory to inform elimination strategies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We develop and analyse two population-based models of the transmission dynamics of the worm parasite Opisthorchis viverrini. The life cycle of O. viverrini includes humans, cats and dogs as definitive hosts; and snails and fish as intermediate hosts. The first model has only one definitive host (humans) while the second model has two additional hosts: the reservoir hosts, cats and dogs. We define reproduction numbers and endemic equilibrium points for the two models. We use prevalence data for the five hosts from two islands in Lao People's Democratic Republic to estimate distributions of parameter values. We use these distributions to compute the sensitivity index and the partial rank correlation coefficient of the basic reproduction number and the endemic equilibrium point to the parameters. We calculate distributions of the host-specific type-reproduction number to show that humans are necessary to maintain transmission and can sustain transmission without additional reservoir hosts. Therefore interventions targeting humans could be sufficient to interrupt transmission of O. viverrini., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite the existence of effective rabies vaccines for dogs, dog-transmitted human rabies persists and has reemerged in Africa. Two consecutive dog vaccination campaigns took place in Chad in 2012 and 2013 (coverage of 71% in both years) in the capital city of N'Djaména, as previously published. We developed a deterministic model of dog-human rabies transmission fitted to weekly incidence data of rabid dogs and exposed human cases in N'Djaména. Our analysis showed that the effective reproductive number, that is, the number of new dogs infected by a rabid dog, fell to below one through November 2014. The modeled incidence of human rabies exposure fell to less than one person per million people per year. A phylodynamic estimation of the effective reproductive number from 29 canine rabies virus genetic sequences of the viral N-protein confirmed the results of the deterministic transmission model, implying that rabies transmission between dogs was interrupted for 9 months. However, new dog rabies cases appeared earlier than the transmission and phylodynamic models predicted. This may have been due to the continuous movement of rabies-exposed dogs into N'Djaména from outside the city. Our results show that canine rabies transmission to humans can be interrupted in an African city with currently available dog rabies vaccines, provided that the vaccination area includes larger adjacent regions, and local communities are informed and engaged., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Despite great achievements by insecticide-treated nets (ITNs) and indoor residual spraying (IRS) in reducing malaria transmission, it is unlikely these tools will be sufficient to eliminate malaria transmission on their own in many settings today. Fortunately, field experiments indicate that there are many promising vector control interventions that can be used to complement ITNs and/or IRS by targeting a wide range of biological and environmental mosquito resources. The majority of these experiments were performed to test a single vector control intervention in isolation; however, there is growing evidence and consensus that effective vector control with the goal of malaria elimination will require a combination of interventions., Method and Findings: We have developed a model of mosquito population dynamic to describe the mosquito life and feeding cycles and to optimize the impact of vector control intervention combinations at suppressing mosquito populations. The model simulations were performed for the main three malaria vectors in sub-Saharan Africa, Anopheles gambiae s.s, An. arabiensis and An. funestus. We considered areas having low, moderate and high malaria transmission, corresponding to entomological inoculation rates of 10, 50 and 100 infective bites per person per year, respectively. In all settings, we considered baseline ITN coverage of 50% or 80% in addition to a range of other vector control tools to interrupt malaria transmission. The model was used to sweep through parameters space to select the best optimal intervention packages. Sample model simulations indicate that, starting with ITNs at a coverage of 50% (An. gambiae s.s. and An. funestus) or 80% (An. arabiensis) and adding interventions that do not require human participation (e.g. larviciding at 80% coverage, endectocide treated cattle at 50% coverage and attractive toxic sugar baits at 50% coverage) may be sufficient to suppress all the three species to an extent required to achieve local malaria elimination., Conclusion: The Vector Control Optimization Model (VCOM) is a computational tool to predict the impact of combined vector control interventions at the mosquito population level in a range of eco-epidemiological settings. The model predicts specific combinations of vector control tools to achieve local malaria elimination in a range of eco-epidemiological settings and can assist researchers and program decision-makers on the design of experimental or operational research to test vector control interventions. A corresponding graphical user interface is available for national malaria control programs and other end users.

Background: Increasing coverage of malaria vector control interventions globally has led to significant reductions in disease burden. However due to its high recurrent cost, there is a need to determine if and when vector control can be safely scaled back after transmission has been reduced., Methods and Findings: A mathematical model of Plasmodium falciparum malaria epidemiology was simulated to determine the impact of scaling back vector control on transmission and disease. A regression analysis of simulation results was conducted to derive predicted probabilities of resurgence, severity of resurgence and time to resurgence under various settings. Results indicate that, in the absence of secular changes in transmission, there are few scenarios where vector control can be removed without high expectation of resurgence. These, potentially safe, scenarios are characterized by low historic entomological inoculation rates, successful vector control programmes that achieve elimination or near elimination, and effective surveillance systems with high coverage and effective treatment of malaria cases., Conclusions: Programmes and funding agencies considering scaling back or withdrawing vector control from previously malaria endemic areas need to first carefully consider current receptivity and other available interventions in a risk assessment. Surveillance for resurgence needs to be continuously conducted over a long period of time in order to ensure a rapid response should vector control be withdrawn.

Background: Mass drug administration (MDA) has been proposed as an intervention to achieve local extinction of malaria. Although its effect on the reproduction number is short lived, extinction may subsequently occur in a small population due to stochastic fluctuations. This paper examines how the probability of stochastic extinction depends on population size, MDA coverage and the reproduction number under control, R c . A simple compartmental model is developed which is used to compute the probability of extinction using probability generating functions. The expected time to extinction in small populations after MDA for various scenarios in this model is calculated analytically., Results: The results indicate that mass drug administration (Firstly, R c must be sustained at R c  < 1.2 to avoid the rapid re-establishment of infections in the population. Secondly, the MDA must produce effective cure rates of >95% to have a non-negligible probability of successful elimination. Stochastic fluctuations only significantly affect the probability of extinction in populations of about 1000 individuals or less. The expected time to extinction via stochastic fluctuation is less than 10 years only in populations less than about 150 individuals. Clustering of secondary infections and of MDA distribution both contribute positively to the potential probability of success, indicating that MDA would most effectively be administered at the household level., Conclusions: There are very limited circumstances in which MDA will lead to local malaria elimination with a substantial probability.