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A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

ABSTRACT: In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of Anopheles mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Following the publication by WHO of the preferred product characteristics for endectocides as vector control tools, this roadmap provides a comprehensive view of processes needed to make ivermectin available as a vector control tool by 2024 with a completely novel mechanism of action. The roadmap covers various aspects, which include 1) the definition of optimal dosage/regimens for ivermectin MDA in both humans and livestock, 2) the risk of resistance to the drug and environmental impact, 3) ethical issues, 4) political and community engagement, 5) translation of evidence into policy, and 6) operational aspects of large-scale deployment of the drug, all in the context of a drug given as a prevention tool acting at the community level. The roadmap reflects the insights of a multidisciplinary group of global health experts who worked together to elucidate the path to inclusion of ivermectin in the toolbox against malaria, to address residual transmission, counteract insecticide resistance, and contribute to the end of this deadly disease.

SUBMITTER: The Ivermectin Roadmappers

PROVIDER: S-EPMC7008306 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

Billingsley Peter P Binka Fred F Chaccour Carlos C Foy Brian B Gold Silvia S Gonzalez-Silva Matiana M Jacobson Julie J Jagoe George G Jones Caroline C Kachur Patrick P Kobylinski Kevin K Last Anna A Lavery James V JV Mabey David D Mboera David D Mbogo Charles C Mendez-Lopez Ana A Rabinovich N. Regina NR Rees Sarah S Richards Frank F Rist Cassidy C Rockwood Jessica J Ruiz-Castillo Paula P Sattabongkot Jetsumon J Saute Francisco F Slater Hannah H Steer Andrew A Xia Kang K Zullinger Rose R

The American journal of tropical medicine and hygiene 20200201 2s

In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of <i>Anopheles</i> mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Fol ...[more]

PMID: 31971144

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Project description:BackgroundDomesticated animals play a role in maintaining residual transmission of Plasmodium parasites of humans, by offering alternative blood meal sources for malaria vectors to survive on. However, the blood of animals treated with veterinary formulations of the anti-helminthic drug ivermectin can have an insecticidal effect on adult malaria vector mosquitoes. This study therefore assessed the effects of treating cattle with long-acting injectable formulations of ivermectin on the survival of an important malaria vector species, to determine whether it has potential as a complementary vector control measure.MethodsEight head of a local breed of cattle were randomly assigned to either one of two treatment arms (2 × 2 cattle injected with one of two long-acting formulations of ivermectin with the BEPO® technology at the therapeutic dose of 1.2 mg/kg), or one of two control arms (2 × 2 cattle injected with the vehicles of the formulations). The lethality of the formulations was evaluated on 3-5-day-old Anopheles coluzzii mosquitoes through direct skin-feeding assays, from 1 to 210 days after treatment. The efficacy of each formulation was evaluated and compared using Cox proportional hazards survival models, Kaplan-Meier survival estimates, and log-logistic regression on cumulative mortality.ResultsBoth formulations released mosquitocidal concentrations of ivermectin until 210 days post-treatment (hazard ratio > 1). The treatments significantly reduced mosquito survival, with average median survival time of 4-5 days post-feeding. The lethal concentrations to kill 50% of the Anopheles (LC50) before they became infectious (10 days after an infectious blood meal) were maintained for 210 days post-injection for both formulations.ConclusionsThis long-lasting formulation of ivermectin injected in cattle could complement insecticide-treated nets by suppressing field populations of zoophagic mosquitoes that are responsible, at least in part, for residual malaria transmission. The impact of this approach will of course depend on the field epidemiological context. Complementary studies will be necessary to characterize ivermectin withdrawal times and potential environmental toxicity.

Project description:BackgroundMalaria vector control activities in Sudan rely largely on Long-Lasting Insecticidal Nets (LLINs), Indoor Residual Spray (IRS) and Larval Source Management (LSM). The present study attempted to determine cost effectiveness of inputs and operations of vector control interventions applied in different environmental settings in central and eastern Sudan, as well as their impact.MethodsThe inputs utilized and cost of each vector control activity, operational achievements and impact of the applied malaria vector control activities; IRS, LLINs and LSM were determined for eight sites in Al Gazira state (central Sudan) and Al Gadarif state (eastern Sudan). Operational costs were obtained from data of the National Malaria Control Program in 2017. Impact was measured using entomological indicators for Anopheles mosquitoes.ResultsThe total cost per person per year was $1.6, $0.85, and $0.32 for IRS, LLINs and LSM, respectively. Coverage of vector control operations was 97%, 95.2% and 25-50% in IRS, LLINs and LSM, respectively. Vectorial capacity of malaria vectors showed statistically significant variations (P < 0.034) and ranged 0.294-0.65 in areas implemented LSM in comparison to 0.097-0.248 in areas applied IRS and LLINs, respectively. Both indoor and outdoor biting Anopheles mosquitoes showed noticeable increase that reached 3-12 folds in areas implemented LSM in comparison to areas implemented IRS and LLINs. Annual malaria prevalence was 13.1-21.1% in areas implemented LSM in comparison to 3.20%, 4.77% in areas implemented IRS and LLINs, respectively.ConclusionIRS and LLINs are cost effective control measures due to adequate inputs and organized process. However, the unit cost of LSM intervention per outcome and subsequently the impact is hugely affected by the low coverage. The very weak support for implementation of LSM which includes inputs resulted in weakness of its process and consequently its impact. Implementation of LSM by local government in urban settings is challenged by many factors the most important are maintenance of adequate stable level of funding, un-adequate number of well trained health workers, unstable political and administrative conditions and weak infrastructure. These challenges are critical for proper implementation of LSM and control of malaria in urban settings in Sudan.

Project description:BackgroundOutdoor malaria transmission hinders malaria elimination efforts in the Amazon region and novel vector control tools are needed. Ivermectin mass drug administration (MDA) to humans kills wild Anopheles, targets outdoor-feeding vectors, and can suppress malaria parasite transmission. Laboratory investigations were performed to determine ivermectin susceptibility, sporontocidal effect and inhibition of time to re-feed for the primary Amazonian malaria vector, Anopheles darlingi.MethodsTo assess ivermectin susceptibility, various concentrations of ivermectin were mixed in human blood and fed to An. darlingi. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with Probit analysis was used to calculate lethal concentrations of ivermectin that killed 50% (LC50), 25% (LC25) and 5% (LC5) of mosquitoes. To examine ivermectin sporonticidal effect, Plasmodium vivax blood samples were collected from malaria patients and offered to mosquitoes without or with ivermectin at the LC50, LC25 or LC5. To assess ivermectin inhibition of mosquito time to re-feed, concentrations of ivermectin predicted to occur after a single oral dose of 200 μg/kg ivermectin were fed to An. darlingi. Every day for 12 days thereafter, individual mosquitoes were given the opportunity to re-feed on a volunteer. Any mosquitoes that re-blood fed or died were removed from the study.ResultsIvermectin significantly reduced An. darlingi survivorship: 7-day-LC50 = 43.2 ng/ml [37.5, 48.6], -LC25 = 27.8 ng/ml [20.4, 32.9] and -LC5 = 14.8 ng/ml [7.9, 20.2]. Ivermectin compound was sporontocidal to P. vivax in An. darlingi at the LC50 and LC25 concentrations reducing prevalence by 22.6 and 17.1%, respectively, but not at the LC5. Oocyst intensity was not altered at any concentration. Ivermectin significantly delayed time to re-feed at the 4-h (48.7 ng/ml) and 12-h (26.9 ng/ml) concentrations but not 36-h (10.6 ng/ml) or 60-h (6.3 ng/ml).ConclusionsIvermectin is lethal to An. darlingi, modestly inhibits sporogony of P. vivax, and delays time to re-feed at concentrations found in humans up to 12 h post drug ingestion. The LC50 value suggests that a higher than standard dose (400-μg/kg) is necessary to target An. darlingi. These results suggest that ivermectin MDA has potential in the Amazon region to aid malaria elimination efforts.

Project description:BACKGROUND:Identification of malaria vector breeding sites can enhance control activities. Although associations between malaria vector breeding sites and topography are well recognized, practical models that predict breeding sites from topographic information are lacking. We used topographic variables derived from remotely sensed Digital Elevation Models (DEMs) to model the breeding sites of malaria vectors. We further compared the predictive strength of two different DEMs and evaluated the predictability of various habitat types inhabited by Anopheles larvae. METHODS:Using GIS techniques, topographic variables were extracted from two DEMs: 1) Shuttle Radar Topography Mission 3 (SRTM3, 90-m resolution) and 2) the Advanced Spaceborne Thermal Emission Reflection Radiometer Global DEM (ASTER, 30-m resolution). We used data on breeding sites from an extensive field survey conducted on an island in western Kenya in 2006. Topographic variables were extracted for 826 breeding sites and for 4520 negative points that were randomly assigned. Logistic regression modelling was applied to characterize topographic features of the malaria vector breeding sites and predict their locations. Model accuracy was evaluated using the area under the receiver operating characteristics curve (AUC). RESULTS:All topographic variables derived from both DEMs were significantly correlated with breeding habitats except for the aspect of SRTM. The magnitude and direction of correlation for each variable were similar in the two DEMs. Multivariate models for SRTM and ASTER showed similar levels of fit indicated by Akaike information criterion (3959.3 and 3972.7, respectively), though the former was slightly better than the latter. The accuracy of prediction indicated by AUC was also similar in SRTM (0.758) and ASTER (0.755) in the training site. In the testing site, both SRTM and ASTER models showed higher AUC in the testing sites than in the training site (0.829 and 0.799, respectively). The predictability of habitat types varied. Drains, foot-prints, puddles and swamp habitat types were most predictable. CONCLUSIONS:Both SRTM and ASTER models had similar predictive potentials, which were sufficiently accurate to predict vector habitats. The free availability of these DEMs suggests that topographic predictive models could be widely used by vector control managers in Africa to complement malaria control strategies.

Dataset Information

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

Publications

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

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