Biology subjects

Porciani, A.

Publications and source records attributed to Porciani, A..

5 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

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

Sub-lethal insecticide exposure affects host biting efficiency of Kdr-resistant Anopheles gambiae

AO_SCPLOWBSTRACTC_SCPLOWThe massive use of insecticide-treated nets (ITNs) has drastically changed the environment for malaria vector mosquitoes, challenging their host-seeking behaviour and biting success. Here, we investigated the effect of a brief exposure to an ITN on the biting behaviour of Anopheles mambiae mosquitoes and the interaction between such behaviour and the kdr mutation that confers resistance to pyrethroids. To this aim, we developed a video assay to study the biting behaviour of mosquitoes with similar genetic background, but different kdr locus genotypes (SS i.e. homozygous susceptible, RS i.e. heterozygous and RR i.e. homozygous resistant), after a brief exposure to either control untreated nets or one of two types of pyrethroid-treated nets (deltamethrin or permethrin). In presence of untreated nets, the kdr mutation did not influence mosquito blood feeding success but caused differences in feeding and prediuresis durations and blood meal size. Exposure to deltamethrin ITN decreased the blood feeding success rate of RR and RS mosquitoes, whereas in presence of permethrin ITN, the kdr mutation increased the blood-feeding success of mosquitoes. Exposure to the two types of pyrethroid-treated nets reduced feeding duration, prediuresis duration and blood meal size of all three genotypes. Our study demonstrates a complex interaction between insecticide exposure and the kdr mutation on the biting behavior of mosquitoes, which may substantially impact malaria vector fitness and disease transmission.

animal behavior and cognition↗