Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases

Abstract

Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC₅₀ values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177-407 mg) for afoxolaner, or 410 mg (IQR, 278-648 mg) for fluralaner, could provide an insecticidal effect lasting 50-90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.

Keywords: insecticide; isoxazoline; malaria; vector control; zika fever.

Fig. 1.

Insecticidal activity of fluralaner and afoxolaner on vectors. (A) Cartoon of the binding pockets of insecticides on the GABA or the glutamate-gated chloride channel (16, 17). The putative binding sites of ivermectin, isoxazolines, and dieldrin are depicted on a subunit of the pentameric structure of the channel, in purple, orange, and red, respectively. (B) Chemical structures of fluralaner and afoxolaner. (C) Survival (expressed as percentage of engorged individuals) of Anopheles, A. aegypti, and C. pipiens mosquitoes and P. argentipes and L. longipalpis sand flies at 24 h after feeding on fluralaner- (Left) and afoxolaner- (Right) supplemented blood meals. The species or strain is indicated in the legend of each graph with the known resistance mutation(s) in superscript. Error bars for the Anopheles and Aedes data indicate SEs based on duplicate experiments with approximately 30 mosquitoes each; on the Culex data, they indicate SEs based on four replicate experiments with approximately 15 mosquitoes each; on the Phlebotomus data, they indicate SEs based on duplicate experiments with 100 flies each. Data points of the Lutzomyia data indicate results of a single experiment with 100 flies per concentration and per compound.

Fig. 2.

Modeled impact of mass drug administration of an isoxazoline drug. Reduction in the incidence of both symptomatic (clinical) and asymptomatic infections in Zika (Top) and clinical incidence and cumulative clinical incidence in malaria (Bottom) after 2 y of fluralaner/afoxolaner mass drug administration (MDA) during the transmission season (indicated by the pink shaded areas), with either 30% or 80% of the population age >5 y receiving the drug each year. The model assumes a mosquitocidal drug dose resulting in blood levels >IC₉₉ for 90 d. The two initial years of treatment are followed by three transmission seasons without further intervention.

Fig. 3.

Predicted impact of mass administration of an isoxazoline drug on malaria incidence in Africa. The figure shows cumulative reduction in incidence during 2 y of fluralaner/afoxolaner mass drug administration covering 30% of the population age >5 y, dosed once per year optimally timed in relation to the start of the transmission season. The model uses available data on regional disease prevalence in 2015 and a seasonality profile as illustrated in SI Appendix, Fig. S2.