Biology subjects

Belem, A. M. G.

Publications and source records attributed to Belem, A. M. G..

3 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

Whole-genome sequencing of major malaria vectors reveals the evolution of new insecticide resistance variants in a longitudinal study in Burkina Faso

Intensive deployment of insecticide based malaria vector control tools results in the rapid evolution of phenotypes resistant to these chemicals. Understanding this process on the genomic level is essential for the deployment of successful interventions. Using whole genome sequencing data of 1409 individual An. Gambiae s.l. collected from 2012 to 2017, we investigated the change in genetic structure and the evolution of the insecticide resistance variants in natural populations over time and space. The results showed similar and constant nucleotide diversity and negative Tajimas D between An. gambiae s.s. and An. coluzzii. PCA and FST showed a clear genetic structure in the An. gambiae s.l. species. Genome-wide FST and H12 scans identified genomic regions under divergent selection and also having an implication in the adaptations to ecological changes. Novel voltage-gated sodium channel pyrethroid resistance target-site alleles (V402L, I1527T) were identified at increasing frequencies alongside the established kdr alleles (Vgsc-L995F, Vgsc-L995S and N1570Y) within the An. gambiae s.l. populations. Organophosphate metabolic resistance markers were also identified, at increasing frequencies, within the An. gambiae s.s. populations from 2012 to 2017, including the SNP Ace1-G280S and its associated duplication. Variants simultaneously identified in the same vector populations raise concerns about the long-term efficacy of new-generation bednets and the recently introduced organophosphate pirimiphos-methyl indoor residual spraying. These findings highlighted the benefit of genomic malaria vector surveillance for the detection of new insecticide resistance variants, the monitoring of the existing resistance variants, and also to get insights into the evolutionary processes driving insecticide resistance. Author SummaryGenomic surveillance of malaria vectors is crucial for understanding the genetic variation in natural vector populations and also guiding the implementation of novel and innovative vector control tools. Application of sequencing technologies in vector studies provide insights on the genetic and evolutionary phenomena of vectors that could have impact on vector control strategies. By analyzing the whole genome data of 1409 wild An. gambiae s.l. mosquito collected between 2012 and 2017, we showed an emergence of novel insecticide resistance markers alongside increasing frequencies of existing insecticide resistance variants over time in Burkina Faso. We showed the benefit of genomic surveillance of malaria vectors for the monitoring of the insecticide resistance variants and also providing insights into the evolutionary processes driving insecticide resistance.

evolutionary 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↗