Biology subjects

Mouline, K.

Publications and source records attributed to Mouline, K..

7 recordsLinked to original sources

bioRxiv2025

Selection of a Lead Long-Acting Formulation of Ivermectin to Target Major Malaria Vectors in Western Africa: Evaluation of Pharmacokinetics and Mosquitocidal Efficacy in Cattle under Laboratory Conditions.

BackgroundIvermectin, a semisynthetic endectocide, is widely used against parasitic nematodes in humans and animals. Its lethality to Anopheles mosquitoes after feeding on treated hosts represents a promising malaria control strategy, particularly against outdoor transmission. However, standard oral formulations for use in humans produce short-lived mosquitocidal blood concentrations, limiting epidemiological impact. To meet WHO Preferred Product Characteristics (PPC) for endectocides against malaria vectors (Hazard Ratios >4 for at least one month), three long-acting injectable ivermectin formulations (LAIFs) based on BEPO(R) depot technology were developed and compared in cattle to identify the most suitable candidate for future human use. MethodsA cattle-Anopheles model was used under laboratory conditions in Bobo-Dioulasso, Burkina Faso. Three LAIF candidates (mdc-STM-001, mdc-STM-002, mdc-STM-003) were injected to calves (n=5 per formulation) at 0.6 mg/kg, with untreated calves as controls (n=5). Plasma ivermectin concentrations were measured over 130 days and analyzed using non-compartmental pharmacokinetics. Direct skin feeding assays were conducted at 15 timepoints (days 2-126 post-injection) using insecticide-susceptible (KIS) and wild-derived resistant (VK5) Anopheles colonies. Efficacy was assessed through 10-day cumulative mortalities, hazard ratios, 50% lethal concentrations (LC50), and duration of exposure above the 10-day LC50, accounting for the extrinsic incubation period of Plasmodium falciparum. ResultsAll formulations were well tolerated. Mdc-STM-001 showed the most favorable pharmacokinetic profile, with a controlled peak concentration (Cmax = 34.5 {+/-} 12.7 ng/mL) and the lowest inter-individual variability (12%). Ten-day hazard ratios exceeded 4 and cumulative mortalities were >50% for at least 60 days in both strains. Median mosquito lifespan remained below 10 days for at least 90 days post-injection. The 10-day LC50 for resistant mosquitoes (3.66 [2.69-4.97] ng/mL) was maintained for [≥]126 days. ConclusionThe Mdc-STM-001 was identified as the optimal candidate. A single injection induced sustained mosquitocidal efficacy for at least two months, achieving HR >4 against both susceptible and resistant Anopheles populations and meeting WHO PPC for malaria endectocides. Although extrapolation from cattle to humans requires caution, the favorable pharmacokinetic profile and robust entomological outcomes support progression to Phase 1 clinical trials. Ivermectins established safety record further strengthens the rationale for clinical development.

pathology↗

bioRxiv2023

Impact of blood meals taken on ivermectin-treated livestock on survival and fecundity of the malaria vector Anopheles coluzzii under laboratory conditions

Treatment of livestock with endectocides such as ivermectin is viewed as a complementary vector control approach to address residual transmission of malaria. However, efficacy of this treatment may vary between animal species. Hence, our purpose was to investigate the effects of ivermectin treatments of common livestock species on life history traits of the opportunistic malaria vector Anopheles coluzzii. Sheep, goats and pigs were treated using injectable veterinary ivermectin formulation at the species-specific doses (recommended dose for all species and high dose in pig). Mosquito batches were exposed to treated and control (not injected) animals at different days after treatment. Daily mosquito mortality was recorded and fecundity assessed through the count of gravid females and the number of eggs they developed. The recommended dose of ivermectin induced a significant decrease in mosquito survival for up to 7 days after injection (DAI), with a decrease of 89.7%, 66.7%, and 48.4% in treated pigs, goats and sheep, respectively, compared to control animals. In treated pigs, the triple therapeutic dose decreased mosquito survival of 68.97% relatively to controls up to 14 DAI. The average number in gravid females Anopheles that survived after feeding on treated animals were reduced when blood-meals were taken on sheep (2.57% and 42.03% at 2 and 7 DAI), or on goats (decrease of the 28.28% and 73.64% respectively at 2 and 7 DAI). This study shows that ivermectin treatments to animals negatively impacts An. coluzzii life history traits and could reduce vector densities in areas where livestock live near humans. However, due to short-term efficacy of single dose treatments, repeated treatments and potentially increased dosages would be required to span the transmission season. The use of long-acting ivermectin formulations is discussed as a mean for extending efficacy while remaining cost effective.

systems biology↗

bioRxiv2022

Insecticide resistance and biting behaviour of malaria vectors in rural West-Africa : a data mining study to adress their fine-scale spatiotemporal heterogeneity, drivers, and predictability

AO_SCPLOWBSTRACTC_SCPLOWInsecticide resistance and behavioural adaptation of malaria mosquitoes affect the efficacy of long-lasting insecticide nets - currently the main tool for malaria vector control. To develop and deploy complementary, efficient and cost-effective control interventions, a good understanding of the drivers of these physiological and behavioural traits is needed. In this data-mining exercise, we modelled a set of indicators of physiological resistance to insecticide (prevalence of three target-site mutations) and behavioural resistance phenotypes (early- and late-biting, exophagy) of anopheles mosquitoes in two rural areas of West-Africa, located in Burkina Faso and Cote dIvoire. To this aim, we used mosquito field collections along with heterogeneous, multi-source and multi-scale environmental data. The objectives were i) to assess the small-scale spatial and temporal heterogeneity of physiological resistance to insecticide and behavioural resistance phenotypes, ii) to better understand their drivers, and iii) to assess their spatio-temporal predictability, at scales that are consistent with operational action. The explanatory variables covered a wide range of potential environmental determinants of vector resistance to insecticide or behavioural resistance phenotypes : vector control, human availability and nocturnal behaviour, macro and micro-climatic conditions, landscape, etc. The resulting models revealed many statistically significant associations, although their predictive powers were overall weak. We interpreted and discussed these associations in light of several topics of interest, such as : respective contribution of public health and agriculture in the selection of physiological resistances, biological costs associated with physiological resistances, biological mechanisms underlying biting behaviour, and impact of micro-climatic conditions on the time or place of biting. To our knowledge, our work is the first modeling insecticide resistance and feeding behaviour of malaria vectors at such fine spatial scale with such a large dataset of both mosquito and environmental data.

ecology↗

bioRxiv2022

A six-months, long acting, one-shot injectable formulation of Ivermectin as a complementary malaria vector control tool to target zoophagic Anopheles : laboratory and model-based proofs of concept.

ContextIn the current context of residual plasmodium transmission where zoophagic proclivities of Anopheles intervene, we propose to treat peridomestic animals using the endectocide Ivermectin as a complementary approach to bednets. As Ivermectin remanence with classic veterinary compounds is insufficient to induce a significant decrease in vectors populations, we developed a long-lasting injectable formulation of ivermectin from the BEPO(R) technology designed to release insecticidal concentrations of the molecule for 6 months. The work reported here is a proof of concept that using this new technology could help decrease field Anopheles populations. MethodsEight calves were injected with Ivermectin therapeutic doses of 1.2 mg/kg body weight using 2 long lasting formulations (A and B). Efficacy of the product at killing wild derived An. coluzzii has been evaluated by direct-skin feeding assays from 1 to 210 days after injection (DAI). Efficacy on survival was estimated with Cox proportional hazards mixed models and Kaplan meier estimates. To predict efficacy in field-based scenarii, we used a transmission model fed with an entomological model considering different levels for the Anopheles zoophagic preference, calves vs humans ratios, and bed net use variables. ResultsThe release at mosquitocidal plasmatic concentrations of Ivermectin during 6 months is confirmed for both formulations (Hazard ratios > 1 for both formulations against their vehicle for 210 days). The Ivermectin concentration allowing to kill 90% of the mosquitoes before the extrinsic incubation period of the parasite is achieved (10 days) are 11 and 9 ng/ml for formulations A and B if the blood meal is taken before the infectious one, and 15 and 13 ng/ml if it was taken after. Modeling showed that Ivermectin treatment of calves using BEPO(R) technology would reduce infectious vector populations, from at least 35% for most anthropophagic Anopheles in villages where cattle to human ratio is the lowest, to more than 75% if vectors were zoophagic and calves numbers superior to humans. ConclusionOur study gives the proof of concept that a long-lasting formulation of Ivermectin administered to calves could help decrease field malaria vectors populations, which may, ultimately, have an impact at the epidemiological level.

pharmacology and toxicology↗

bioRxiv2021

Data-driven and interpretable machine-learning modeling to explore the fine-scale environmental determinants of malaria vectors biting rates in rural Burkina Faso

BackgroundImproving the knowledge and understanding of the environmental determinants of malaria vectors abundances at fine spatiotemporal scales is essential to design locally tailored vector control intervention. This work aimed at exploring the environmental tenets of human-biting activity in the main malaria vectors (Anopheles gambiae s.s., Anopheles coluzzii and Anopheles funestus) in the health district of Diebougou, rural Burkina Faso. MethodsAnopheles human-biting activity was monitored in 27 villages during 15 months (in 2017-2018), and environmental variables (meteorological and landscape) were extracted from high resolution satellite imagery. A two-step data-driven modeling study was then carried-out. Correlation coefficients between the biting rates of each vector species and the environmental variables taken at various temporal lags and spatial distances from the biting events were first calculated. Then, multivariate machine-learning models were generated and interpreted to i) pinpoint primary and secondary environmental drivers of variation in the biting rates of each species and ii) identify complex associations between the environmental conditions and the biting rates. ResultsMeteorological and landscape variables were often significantly correlated with the vectors biting rates. Many nonlinear associations and thresholds were unveiled by the multivariate models, both for meteorological and landscape variables. From these results, several aspects of the bio-ecology of the main malaria vectors were precised or hypothesized for the Diebougou area, including breeding sites typologies, development and survival rates in relation to weather, flight ranges from breeding sites, dispersal related to landscape openness. ConclusionsUsing high resolution data in an interpretable machine-learning modeling framework proved to be an efficient way to enhance the knowledge of the complex links between the environment and the malaria vectors at a local scale. More broadly, the emerging field of interpretable machine-learning has significant potential to help improving our understanding of the complex processes leading to malaria transmission.

ecology↗

bioRxiv2019

Anopheles bionomic, insecticide resistance and malaria transmission in southwest Burkina Faso: a pre-intervention study

BackgroundThe present study presents results of entomological surveys conducted to address the malaria vectors bionomic, insecticide resistance and transmission prior to the implementation of new strategies complement long-lasting insecticidal nets (LLINs) in the framework of a randomized control trial in southwest Burkina Faso. MethodsWe conducted entomological surveys in 27 villages during the dry cold season (January 2017), dry hot season (March 2017) and rainy season (June 2017). We carried out hourly catches (from 17:00 to 09:00) inside and outside 4 houses in each village using the Human Landing Catch technique. Mosquitoes were identified using morphological taxonomic keys. Specimens belonging to the Anopheles gambiae complex and Funestus Group were identified using molecular techniques as well as detection of Plasmodium falciparum infection and insecticide resistance target-site mutations. ResultsEight Anopheles species were detected in the area. Anopheles funestus s.s was the main vector during the dry cold season. It was replaced by Anopheles coluzzii during the dry hot season whereas An. coluzzii and An. gambiae s.s. were the dominant species during the rainy season. Species composition of the Anopheles population varied significantly among surveys. All researched target site mutation of insecticide resistance (kdr-w, kdr-e and ace-1) were detected in all members of the An. gambiae complex of the area but at different frequencies. We observed early and late biting phenotypes in the main malaria vector species. Entomological inoculation rates were 0.087, 0.089 and 0.375 infected bites per human per night during dry cold season, dry hot season and rainy season, respectively. ConclusionThe intensity of malaria transmission was high despite the universal coverage with LLINs. We detected early and late biting phenotypes in the main malaria vector species as well as physiological insecticide resistance mechanisms. These vectors might mediate residual transmission. These data highlight the need to develop complementary tools in addition to LLINs in order to better control resistant malaria vectors and to monitor insecticide resistance.

epidemiology↗

bioRxiv2017

Field evidence for manipulation of mosquito host selection by the human malaria parasite, Plasmodium falciparum

Whether the malaria parasite Plasmodium falciparum can manipulate mosquito host choice in ways that enhance parasite transmission toward humans is unknown. We assessed the influence of P. falciparum on the blood-feeding behaviour of three of its major vectors (Anopheles coluzzii, An. gambiae and An. arabiensis) in Burkina Faso. Host preference assays using odour-baited traps revealed no effect of infection on mosquito long-range anthropophily. However, the identification of the blood meal origin of mosquitoes showed that females carrying sporozoites, the mature transmissible stage of the parasite, displayed a 24% increase in anthropophagy compared to both females harbouring oocysts, the parasite immature stage, and uninfected individuals. Using a mathematical model, we further showed that this increased anthropophagy in infectious females resulted in a > 250% increase in parasite transmission potential, everything else being equal. This important epidemiological consequence highlights the importance of vector control tools targeting infectious females.

evolutionary biology↗