Filling gaps on ivermectin knowledge: effects on the survival and reproduction of Anopheles aquasalis, a Latin American malaria vector

Abstract

BackgroundStrategies designed to advance towards malaria elimination rely on the detection and treatment of infections, rather than fever, and the interruption of malaria transmission between mosquitoes and humans. Mass drug administration with anti-malarials directed at eliminating parasites in blood, either to entire populations or targeting only those with malaria infections, are considered useful strategies to progress towards malaria elimination, but may be insufficient if applied on their own. These strategies assume a closer contact with populations, so incorporating a vector control intervention tool to those approaches could significantly enhance their efficacy. Ivermectin, an endectocide drug efficacious against a range of Anopheles species, could be added to other drug-based interventions. Interestingly, ivermectin could also be useful to target outdoor feeding and resting vectors, something not possible with current vector control tools, such as impregnated bed nets or indoor residual spraying (IRS).ResultsAnopheles aquasalis susceptibility to ivermectin was assessed. In vivo assessments were performed in six volunteers, being three men and three women. The effect of ivermectin on reproductive fitness and mosquito survivorship using membrane feeding assay (MFA) and direct feeding assay (DFA) was assessed and compared. The ivermectin lethal concentration (LC) values were LC50 = 47.03 ng/ml [44.68–49.40], LC25 = 31.92 ng/ml [28.60–34.57] and LC5 = 18.28 ng/ml [14.51–21.45]. Ivermectin significantly reduced the survivorship of An. aquasalis blood-fed 4 h post-ingestion (X2 [N = 880] = 328.16, p < 0.001), 2 days post-ingestion (DPI 2) (X2 [N = 983] = 156.75, p < 0.001), DPI 7 (X2 [N = 935] = 31.17, p < 0.001) and DPI 14 (X2 [N = 898] = 38.63, p < 0.001) compared to the blood fed on the untreated control. The average number of oviposited eggs per female was significantly lower in LC5 group (22.44 [SD = 3.38]) than in control (34.70 [SD = 12.09]) (X2 [N = 199] = 10.52, p < 0.001) as well as the egg hatch rate (LC5 = 74.76 [SD = 5.48]) (Control = 81.91 [SD = 5.92]) (X2 [N = 124] = 64.24, p < 0.001). However, no differences were observed on the number of pupae that developed from larvae (Control = 34.19 [SD = 10.42) and group (LC5 = 33.33 [SD = 11.97]) (X2 [N = 124] = 0.96, p > 0.05).ConclusionsIvermectin drug reduces mosquito survivorship when blood fed on volunteer blood from 4 h to 14 days post-ingestion controlling for volunteers’ gender. Ivermectin at mosquito sub-lethal concentrations (LC5) reduces fecundity and egg hatch rate but not the number of pupae that developed from larvae. DFA had significantly higher effects on mosquito survival compared to MFA. The findings are presented and discussed through the prism of malaria elimination in the Amazon region.

Safety, Pharmacokinetics, and Mosquito‐Lethal Effects of Ivermectin in Combination With Dihydroartemisinin‐Piperaquine and Primaquine in Healthy Adult Thai Subjects

“…In a study from Brazil, ivermectin was more lethal to An. aquasalis that directly fed on ivermectin‐treated persons compared with membrane‐fed venous blood from the same volunteers, whereas no difference was observed for An. gambiae in Kenya with similar experimental design .…”

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

“…The result is that any resistance arising in the more susceptible parasites could not be detected until their susceptibility was 10-fold higher 62 . This phenomenon has been called the window of escalation 62 and could be an important concept it if ivermectin is scaled up for vector control given that malaria vectors also differ in their ivermectin susceptibility 16 , 63 , 64 . While Anopheles gambiae 50 and Anopheles minimus seems to be remarkably susceptible based on their low LC 50 , others like Anopheles aquasalis or Anopheles dirus promise to become the dose-defining mosquito species 16 , 63 , 64 for the novel vector control use of the drug.…”

“…This phenomenon has been called the window of escalation 62 and could be an important concept it if ivermectin is scaled up for vector control given that malaria vectors also differ in their ivermectin susceptibility 16 , 63 , 64 . While Anopheles gambiae 50 and Anopheles minimus seems to be remarkably susceptible based on their low LC 50 , others like Anopheles aquasalis or Anopheles dirus promise to become the dose-defining mosquito species 16 , 63 , 64 for the novel vector control use of the drug. Taking advantage of a synergist could potentially delay the emergence of ivermectin resistance in malaria vectors and extend the spectrum of ivermectin towards less susceptible vectors.…”

“…Ivermectin, however, has a relatively short half-life of 18 hours 15 , which would limit the duration of the mosquito-killing effect. Concentrations that kill 50% of Anopheles gambiae in 10 days can only be sustained for around 72 hours after the single dose of 200 mcg/kg commonly used for NTDs; for other less susceptible species like Anopheles aquasalis 16 , this mosquito-killing window can be shorter.…”

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

“…dirus Membrane: blood from treated humans 10-day-LC 50 : 2.9 ng/mL Kobylinski [unpublished] An. minimus 10-day-LC 50 : 0.4 ng/mL Sampaio et al 106 An. aquasalis Membrane: in vitro mixture (blood + ivermectin) Chaccour et al 22 An.…”