Endectocides for malaria controlBrian D. Foy1, Kevin C. Kobylinski1, Ines Marques da Silva1, Jason L. Rasgon2,3 andMassamba Sylla1

1 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology,

Colorado State University, Fort Collins, CO 80523-1692, USA2 The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health,

Johns Hopkins University, Baltimore, MD 21205, USA3 The Johns Hopkins Malaria Research Institute, Baltimore, MD 21205, USA

Opinion

Systemic endectocidal drugs, used to control nematodesin humans and other vertebrates, can be toxic to Anoph-eles spp. mosquitoes when they take a blood meal from ahost that has recently received one of these drugs. Recentlaboratory and field studies have highlighted the poten-tial of ivermectin to control malaria parasite transmissionif this drug is distributed strategically and more often.There are important theoretical benefits to this strategy,as well as caveats. A better understanding of drug effectsagainst vectors and malaria ecologies are needed. In thenear future, ivermectin and other endectocides couldserve as potent and novel malaria transmission controltools that are directly linked to the control of neglectedtropical diseases in the same communities.

The birth of endectocidesEndectocides are drugs with endoparasitocidal and ecto-parasitocidal activity. Avermectins, the most effective andwell-developed class of endectocides, are 16-memberedring macrocyclic lactones produced from the fermentationbroth of an actinomycete. Ivermectin (IVM) is a semisyn-thetic avermectin derivative that was first licensed in 1981as a veterinary drug. It has since become one of the mostsuccessful drugs discovered owing to its broad spectrumactivity against nematodes and ectoparasites, high poten-cy, long pharmacokinetic persistence in blood and lymph,and excellent safety in vertebrates [1]. IVM is one of theprimary drugs used to control the filarioid nematodesOnchocerca volvulus and Wuchereria bancrofti throughhuman mass drug administrations (MDA) in endemicareas. The drug alleviates disease in individuals as wellas reduces nematode transmission in the community bykilling the transmissible microfilaria stages and impairingthe development and fecundity of adult worms in thehuman [2]. IVM accomplishes this by interfering withthe neuromuscular physiology of invertebrates (Box 1).

Endectocide activity against vectorsInitial ectoparasitocidal studies with the avermectins fo-cused on biting flies, bot flies, fleas, lice, mange mites andticks, and many were found susceptible to the drug. Wilson[3] provided a detailed review of much of this literature 17years ago, focusing on the prospects of using avermectins inarthropod vector management. His analysis concluded thatreducing the ectoparasite abundance on individual animals

Corresponding author: Foy, B.D. (brian.foy@colostate.edu).

1471-4922/$ – see front matter � 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2011.05

is a simplistic way to view the broader promise of endecto-cides for controlling vector-borne diseases. Instead, he ar-gued that the avermectins need to be assessed for theirability to affect all crucial variables of vectorial capacityfrom a vector population, especially reducing the probabilityof vector lifespan below the extrinsic incubation period andreducing the vector feeding frequency through sublethaldoses (Box 2). Vertebrate blood meals, then, could deliverantivector drugs directly into the midguts of vectors toreduce the likelihood of pathogen transmission from theentire vector population. This concept is predicated on highorstrategically targetedcoverage of the host population withthe drug and effective drug pharmacokinetics in the host.

Mosquito studiesInitial mosquito studies with avermectin/IVM demonstrat-ed that Anopheles species were highly sensitive to thesedrugs compared with various Aedes and Culex species [4–6].Studies also demonstrated that sublethal concentrations ofIVM (for the adult mosquito) could reduce female fecundity,the hatch rate of their eggs and survival of progeny larvae[5–8]. In laboratory membrane-feeding experiments match-ing mosquito feeding times to IVM concentrations found inhuman plasma post-MDA (150 mg/kg), we recorded mortal-ity effects, inhibition of re-blood feeding and compoundingmortality effects of sublethal doses in colonized Anophelesgambiae s.s. [9]. Direct human blood feeding experimentsusing colonized mosquitoes and IVM-dosed humans havebeen conducted with Aedes polynesiensis [10], Anophelesfaurauti [11] and recently against An. gambiae s.s. [12].These studies demonstrated reduced survival of mosquitoesthat blood feed on IVM-dosed humans, but reported variabletime periods in which mosquitocidal effects could be main-tained after drug administration. Bockarie et al. [13] per-formed the first field demonstration of the effects of IVM onwild mosquitoes, focusing on the transmission of Wuchereriabancrofti. Wild, engorged, indoor-resting Anopheles punc-tulatus caught from two houses the day after IVM MDA(400 mg/kg) had significantly reduced survivorship com-pared with those captured from two houses of a controluntreated village. In another village, An. punctulatus hadsignificantly reduced survival if caught within three daysafter residents received an IVM (400 mg/kg) plus diethylcar-bamazine (6 mg/kg) MDA compared with those caught pre-MDA, but survivorship was not reduced in mosquitoescollected 28 days post-MDA. The authors also found that

.007 Trends in Parasitology, October 2011, Vol. 27, No. 10 423

Box 1. Anthelmintics, insecticides and ligand-gated ion channels

Several classes of both anthelmintic drugs and insecticides selectively

target invertebrate ligand-gated ion channels [41,42]. These members

of the Cys-loop ligand-gated ion channel (LGIC) superfamily are

located at both synaptic and extrasynaptic sites on invertebrate nerve

and muscle cells, and open (or gate) in response to ligands to allow

ions to flow across the cell membrane. Each channel exists as a

pentamer of subunit proteins, which comprise an extensive N

terminal extracellular domain that binds the ligand and four

transmembrane domains (TM1–TM4) [43]. The LGIC genes of insects

encode channel subunit families defined by their corresponding

ligands, including nicotinic acetylcholine receptors (nAChRs) and

glutamate, glycine, histamine and g-amino butyric acid (GABA)-gated

channels [44] (Table I). The nAChRs (not listed in Table I) mediate

excitatory neurotransmission in insects by allowing cations (primarily

Na+ and K+) to pass through their channel, and they have an expanded

and distinct gene family [45]; neonicotinoids are important insecti-

cides that agonize these channels. Insect GABA-gated channels are

antagonized by established insecticide classes such as the cyclo-

dienes (e.g. dieldrin) and phenylpyrazoles (e.g. fipronil) [42]. These

and the other channels in Table I are mostly thought to be permeable

to anions (primarily Cl–) [46], and thus they mediate inhibitory signals

that act by hyperpolarizing the cell membrane potential; however,

Gisselmann et al. [47] reported that Drosophila GRD and LCCH3

subunits can form excitatory heteromultimeric cation channels.

The avermectins specifically hyperpolarize the membrane potential

of invertebrate postsynaptic neurons and muscle fibers through

agonization of the inhibitory glutamate-gated chloride channels

uniquely used by insects to regulate neuromuscular transmission

[36]. This causes flaccid muscle paralysis that can lead to death of the

insect [48]. There is also evidence that IVM agonizes pHCls in flies and

scabies mites [49,50] and HisCls in flies [51], and some evidence that

GABA and GluCl subunits can associate to form heteromultimeric

channels [52]. Whether heteromultimeric channels can form in

mosquitoes and how such channels would be regulated between

two different ligands is not clear. These issues might affect the

susceptibility of mosquitoes to IVM and potential cross-resistance

between IVM and other insecticides such as dieldrin. Furthermore,

GluCl and GABA-receptor subunits have splice isoforms stemming

from exon 3, which generates the crucial ligand binding domain in the

N terminus [53]. Interestingly, GluCl and pHCl exist as single genes in

Dipterans, whereas the GABA-, glycine- and histidine-gated subunit

encoding genes have mostly expanded into two or more paralogs

within species of Diptera (Table I).

One primary reason for the excellent safety profile of IVM is that

GluCls do not exist in mammals [48]. The orthologous mammalian

channel subunits of GluCls are the distantly related glycine-gated

cation channel subunits, and although these can be activated by IVM

at high concentrations [54], they exist only in the central nervous

system and are sequestered behind the blood–brain barrier. The

blood–brain barrier is not easily crossed by large macrolide molecules

such as IVM owing to their affinity for P-glycoprotein xenobiotic

transporters abundant in the vascular endothelium of the brain [55].

Table I. The ligand-gated ion channel genes (excluding the nAChRa family) of Diptera

Ligand Paralog name Anopheles gambiae Aedes aegypti Culex quinquefasciatus Drosophila

melanogaster

Glutamate GluCl AGAP001434b AAEL003003 CPIJ010616 FBgn0024963

pH (hydroxyl ions) pHCl AGAP005599 CPIJ002294 FBgn0036542

GABA RDL AGAP006028 AAEL008354 CPIJ008419 FBgn0004244

LCCH3 AGAP000038 AAEL010710 CPIJ014518 FBgn0010240

GRD AGAP011349 CPIJ006773 FBgn0001134

FBgn0030707

Glycine AGAP007707 AAEL001568 CPIJ017366 FBgn0029733

AAEL004513 CPIJ009348 FBgn0036727

FBgn0039840

Histidine HisCl1 AGAP012975 AAEL003028 CPIJ017412 FBgn0037950

ort AGAP001913 AAEL012248 CPIJ013943 CPIJ013955 FBgn0003011

HisCl2 AGAP001990 AAEL006047 CPIJ006949

AAEL015452 CPIJ002292

AAEL001272 CPIJ002295

Unknown AGAP010694 AAEL003958 CPIJ011023

Unknown AGAP000039 AAEL015091 FBgn0033558

aAbbreviations: nAChR, nicotinic acetylcholine receptor; GABA, g-aminobutyric acid.

bAccession numbers for orthologous and paralogous genes were identified in the Vectorbase, Flybase, Ensemble and NCBI databases.

Opinion Trends in Parasitology October 2011, Vol. 27, No. 10

the number of bites per person per month significantlyincreased one month after the MDA (see Box 2 for possibleexplanation). We recently conducted similar experimentsfollowing IVM MDAs for onchocerciasis control (150 mg/kg)in southeastern Senegalese villages [14]. IVM MDA signifi-cantly reduced the direct survivorship of An. gambiae s.l.mosquitoes for six days following MDA in villages from threereplicate experiments when only �80% of the villagers werecovered in the MDA. The field data also demonstrated thatthe true IVM MDA effects lasted three times longer thanpredicted from our laboratory experiments [9]. These dataare likely to still be an underestimate because they did notaccount for IVM sublethal effects such as knockdown andinhibited recovery and re-blood feeding that we know occursin the lab. Modeling the field data demonstrated that thebasic reproductive rate of malaria (R0) could be significantly

424

reduced if MDA was given at monthly intervals or shorter.Lastly, sporozoite rates were analyzed from these samecaptured mosquitoes. Mean sporozoite rates in mosquitoescaptured from treated villages decreased 79% from before totwo weeks after MDA, whereas sporozoite rates from nearbypair-matched untreated villages increased over the sametime periods. Logistic regression analysis of treatment bytime confirmed the difference between control and treatedvillages to be significantly different [15].

The promise and pitfalls of using ivermectin for malariatransmission controlMalaria remains a significant threat to human health inthe developing world, and the rapid development of newcontrol strategies is essential. Since the failed global ma-laria eradication campaign of the early 1960s, it has been

Box 2. Effects of mass endectocide administration on mosquito populations

Ivermectin MDA directly results in the death of a significant proportion

of existing biting Anopheles mosquitoes [13,14] and should increase

mortality rates of a proportion of mosquitoes that imbibe a sublethal

amount of drug [9]. This should have the dual effect of skewing the age

structure of the vector population towards the younger age classes that

do not participate in transmission and reduce the population density of

adult vectors. This was investigated using a previously developed

simulation model [14] that incorporated a minor modification of larval

density dependence, as described in [56].

pd ¼p0

1 þ ða � Lt Þg(1)

p0 = survival of larvae in the absence of density dependent regulation,

pd = survival of larvae under density dependent regulation, Lt = number

of larvae at time t, a = carrying capacity constant (0.0002) and g =

intraspecific competition constant (1.0) derived from [56].

An ivermectin MDA was simulated to a village in southeastern

Senegal covering 80% of the villagers (see text and [14]). The MDA

results in the hastened death of a significant proportion of the adult

Anopheles gambiae females. Coupled with the emergence of new

adult females from the standing larval population, the population age

structure shifts towards younger age classes for more than three

weeks post-MDA (Figure Ia). Focusing only on abundance, there is a

precipitous but temporary drop in the standing adult female mosquito

population size (Figure Ib) that is most severe one week post-MDA

(26% population reduction). The population remains below pre-MDA

levels for up to three weeks post-MDA, but by one month post-MDA

the population has rebounded to slightly higher (approximately 4%)

than pre-MDA levels (Figure Ic). The adult replenishment rate will be

influenced by local environmental conditions, including the amount

of standing water during the MDA, temperature and weather, thus

this example is meant to be illustrative rather than predictive. The

rebound effect and local environmental conditions are likely to

explain the increased bites/person/month observed 28 days after a

single MDA [13]. However, given that the majority of the adult female

mosquito population is young in the month following MDA,

regardless of the population size and local environmental conditions,

there will be fewer infectious (sporozoite-transmitting) mosquitoes

following treatment [15].

MDAs of ivermectin have been occurring for >15 years in many

areas of Africa, and Latin America for onchocerciasis control, and thus

one might question why those areas have not seen obvious signs of

reduced malaria parasite prevalence, incidence or associated disease.

These programs only administer MDAs once or twice per year, which

will not result in a sustained interruption of the malaria transmission

cycle. Furthermore, these MDAs often do not coincide with malaria

transmission seasons in the same area. Most importantly, asexual

parasitemias in humans can be remarkably stable even in the absence

of sporozoite transmission, as is seen in parasitological surveys of

humans over transmission seasons [57]. Only sustained reductions in

malaria parasite transmission will eventually result in reductions of

malaria prevalence or disease.

600

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TRENDS in Parasitology

Figure I. A model of female adult Anopheles gambiae age structure and abundance following an ivermectin mass drug administration. (a) Models of combined age

structure and abundance prior to mass drug administration (pre-MDA, red line) and 1–4 weeks post-MDA (black, green, blue and orange lines, respectively). (b) The

modeled effect of a single MDA on female adult abundance over time. (c) Discrete number output of the abundance model on a weekly timescale. Derived from [14].

Opinion Trends in Parasitology October 2011, Vol. 27, No. 10

acknowledged that malaria can only be controlled andpotentially eliminated from specific geographical areaswith combinations of tools in integrated malaria manage-ment programs [16]. The diverse epidemiology of malariaaround the world highlights the need for many differentintegrated management control tools. Those that synergizewith existing tools, as well as existing health infrastruc-tures, will make these integrated programs a reality. IVMMDAs could be a powerful and synergistic new tool forintegrated malaria and neglected tropical disease (NTD)control in defined areas.

The most effective malaria vector control tools are long-lasting insecticide treated nets (LLITNs) and indoor resid-ual spraying (IRS), both of which are designed to killendophagic vectors that enter houses or repel them fromhouses, although there is some evidence that LLITNs havean effect on malaria transmission by exophagic vectors [17].Targeting endophilic vectors has been the ‘low-hangingfruit’ for malaria vector control because in-home measures

focus on a more controllable environment, but it is increas-ingly recognized that we must control parasite transmis-sion by both exophagic and exophilic vectors if we are everto have success in the new malaria elimination and eradi-cation campaigns being championed [18]. IVM offers anovel mode of delivery to a mosquito, an oral mosquitocidaldrug that will be in a person’s blood, and thus it will reachboth endophagic and exophagic vectors. Furthermore,adaptive changes (e.g. shifting to crepuscular biting orexophagy) will not protect these mosquitoes from drugexposure, as they have for control via LLITNs or IRS.

A second benefit of IVM is the low potential for mosquitocross-resistance from current malaria control and agricul-tural operations. Mass dichlorodiphenyltrichloroethane(DDT) and pyrethroid agricultural applications have con-tributed to the spread of insecticide resistance into mosquitopopulations, threatening malaria control applications usingthe same insecticides [19]. Avermectin-family agriculturalpesticides, by contrast, are relatively expensive and rarely

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Opinion Trends in Parasitology October 2011, Vol. 27, No. 10

used in outdoor applications in the developing world. Fur-thermore, macrocyclic lactone drugs have a different molec-ular target and mode of action than insecticides currentlyused for LLITN and IRS (Box 1). Lastly, there is no evidence,to date, that pyrethroid resistance mechanisms in vectorscross-targets IVM [20].

Thirdly, IVM MDAs have potential value to inhibit thedevelopment of malaria parasite resistance to drugs tar-geting asexual and sexual stages in the human host. Anyescapee parasites harboring drug-resistant alleles muststill develop in the mosquito to be spread to new hosts. IfIVM MDAs were concomitantly deployed with MDAs ofantimalarials, a potentially resistant parasite strain islikely to die in the mosquito host and never be propagated.Importantly, under the new malaria elimination and erad-ication agendas, development of antimalarials that can besafely used in MDAs has been identified as an enhancedresearch priority [21].

In our models, IVM MDAs might be able to significantlyreduce malaria parasite transmission in a community ifgiven once a month or more frequently [14] (Box 2). Currentonchocerciasis control regimens only require MDA once ortwice per year to be effective, and community directedtreatment programs are now effectively employed to achievethe highest sustained coverage of endemic communities [2].The threat of drug resistance by nematodes associated withmore frequent IVM MDAs deserves consideration (dis-cussed below). Additionally, the logistic demands and costsassociated with more frequent IVM MDA must beaddressed. The community directed treatment models haveproven highly efficacious and cost-effective [22,23]; theirenhancement by integration with antimalaria measures(more IVM MDAs, bednet distribution) and control of soil-transmitted helminthes (STHs) via more MDAs (see below)is likely to only enhance their cost:benefit ratio. Merck,through its Mectizan Donation Program, currently coversthe majority of the cost of IVM MDAs for onchocerciasiscontrol [23]. It is probable that international health and aidagencies would need to step in to bear the added costs if amassive scale-up of IVM MDAs for malaria parasite trans-mission control were to occur. Most obvious to all of theseconcerns, IVM MDA could be most manageable in areas withseasonal malaria transmission, such as the Sahel andSudano-Guinean habits, or during epidemics, but could beless tractable in areas with year-round transmission. How-ever, sustained malaria control or elimination from anycontinental area is expected to require the application ofcontrol tools, expanded health infrastructure and constantmalaria surveillance over decades [16], all of which will beexpensive and logistically demanding in their own right.When this fact is taken into consideration, the argumentthat frequent IVM MDAs might be unsustainable undersuch needed programs seems weak.

The safety of frequent IVM administrations would needto be monitored, but reports of frequently dosed individualsand communities have not been associated with increasesin IVM-related toxicity or severe adverse reactions [24,25].The primary health concern of widespread IVM MDA inAfrica is associated with the presence of high Loa loamicrofilaremias in some individuals who might have se-vere adverse events following drug administration [26].

426

Current prevention efforts against this rely on a rapidassessment of loasis in endemic areas planned for IVMMDA.

The added benefit of frequent IVM dosing scheduleswould be the reduction in prevalence and intensities ofSTHs in the same malaria-afflicted communities. IVM ishighly efficacious against Strongyloides sterocoralis, vari-ably active against roundworms (Ascaris lumbricoides) andwhipworms (Trichuris trichiura), and weakly activeagainst hookworms (Necator americanus and Ancyclos-toma duodenale) [27]. The most recent evidence fromNigeria points to significant reduction in the prevalenceof roundworms and whipworms among children from vil-lages that have participated in yearly IVM MDA for on-chocerciasis control for 13 years [28]. Malaria and STHsare co-endemic across large areas of sub-Saharan Africa[29], and both malaria infections and high STH intensities(particularly hookworms) can result in anemia [30]. Coin-fections with malaria and intestinal helminths can in-crease the likelihood of anemia in children and inpregnant women, and coinfections of women can resultin significantly greater risks for adverse birth outcomes[31]. The disease synergies between malaria and STHs,and the possibility of combined control of nematodes andmalaria with simple MDA regimens, should be a powerfulincentive to bundle such regimens into integrated healthprograms of co-endemic areas.

More frequent endectocide exposure would undoubtedlyincrease selection on nematode populations to developdrug resistance. There are reports of suboptimal responsesof Onchocerca volvulus to IVM, which seem to be associatedwith genetic selection [32]. Anthelmintic resistance hasbeen a problem in veterinary helminths, where 100%coverage rates and frequent drug administration of sheepflocks and cattle herds can be common. Differential GluCland P-glycoprotein alleles are associated with IVM resis-tance in Haemonchus contortus and Cooperia onchophora[33,34]. The most viable option for limiting the potential fordrug resistance under a frequent IVM MDA regimen wouldprobably be combination and/or rotational chemotherapyusing other anthelmintic drug classes, such as the benzi-midazoles. Similarly, frequent IVM MDAs should not beconsidered as monotherapy treatment programs thatwould continue indefinitely, but instead as part of a con-certed integrated disease management program with de-fined endpoints. Both MDA timing and coverage rates willalso influence the selection of resistance alleles in hel-minths [35]. Human MDAs rarely achieve >80% coveragebecause of limitations on who can take the drugs, logisticsand noncompliance. This probably creates refugia in un-treated people where nonresistant helminths can prolifer-ate and might outcompete helminths harboring resistancealleles if such alleles confer lower fitness. More frequentIVM MDAs for malaria control might also be limited to therainy season when mosquitoes are transmitting the mostmalaria. This season is also when preparasitic stages ofhelminths can best survive outside the host in moist soils,thus better preserving any non-drug selected alleles amongthe population.

The possibility of IVM resistance developing in mosqui-toes is currently theoretical. Drug exposure (both in

Opinion Trends in Parasitology October 2011, Vol. 27, No. 10

quantity and in duration) of a mosquito population wouldbe far less compared with helminths that live primarilyinside the host, and only female adult mosquitoes would beexposed. Furthermore, the drug exposure of females wouldbe lessened if the malaria vector species had some zoopha-gic tendencies. A laboratory study of selected IVM resis-tance in Drosophila was the result of target site mutations,but the flies also had compromised fitness [36]. There arefield reports of abamectin resistance in plant pests arisingfrom intensive abamectin spraying operations [37]. Poten-tially confounding variables are IVM effects on femalefecundity, egg hatch rate and larval survival, and thepossibility of resistant alleles already being present incurrent mosquito populations. However, these potentialconfounders are negatively countered by the variables ofincomplete human coverage during MDA, heterogeneity inmosquito blood meal choice and some mosquito immigra-tion from untreated MDA border areas. On the whole, wethink IVM resistance would be less likely to develop inmalaria vectors if a frequent but sufficiently spaced IVMMDA strategy was deployed, and only on a seasonal basis.For example, if IVM MDAs were administered every threeweeks over the course of a five month malaria transmissionseason, it would only require six to seven MDAs that couldbe conducted through community directed treatment pro-grams. Smaller numbers of dry season and early and latewet season mosquitoes would reproduce without drugpressure, and young, non-infectious adult mosquitoes inthe middle of the wet season would still be able to lay eggsover interval periods when the drug is not in human blood.This strategy has some of the properties of the ‘evolution-proof’ malaria control strategies proposed by Read et al.[38].

Finally, malaria transmission driven by zoophagic ma-laria vectors might be particularly amenable to endecto-cide MDAs. An enhanced zooprophylaxis strategy [39]might be achieved by administration of avermectin endec-tocides to livestock kept near domiciles. Indeed, Fritz et al.[8] recently demonstrated that IVM administered to cattlesignificantly affected the survival and fecundity of An.gambiae s.s. blood feeding on these cattle. The pharmaco-kinetics of IVM in livestock has been optimized by deliverystrategies that allow for a longer half-life of the drug inanimals and sustained release into the blood stream, thusallowing for fewer treatments of the cattle. Both directinjection with non-aqueous preparations and sustained-release implants [40] can achieve these results. Addition-ally, many other avermectin derivatives have been devel-oped by veterinary pharmaceutical companies for usein livestock and pets (e.g. selemectin, doramectin, eprino-mectin, moxidectin) which have enhanced pharmacokinet-ic profiles or reduced toxicity to certain breeds, andwhich have differential activity against malaria vectors(N. Walker, unpublished). The added benefit of enhancedzooprophylaxis would be that the owners would havehealthier animals by deworming.

Concluding remarksWe have presented various arguments in favor of develop-ing endectocides, particularly IVM, as novel tools for thecontrol of malaria. These arguments include a novel mode

of drug action compared with currently used insecticides,potential to target many vector species regardless of theirbiting habits, high sensitivity of the vectors to extremelylow concentrations of drug, possible reduced potential fordeveloping drug resistance by the mosquito and cross-activity against intestinal helminths. The argumentsagainst developing these tools include logistic difficultiesand higher costs associated with more frequent MDAs, andthe potential to foster endectocide resistance in helminthpopulations. Ultimately, field data must be collected tovalidate or invalidate the specific arguments, as well as toaddress unforeseen issues. In our opinion, the promise ofendectocides as novel and synergistic malaria controltools is great for many malaria-endemic regions acrossthe globe.

AcknowledgmentsB.D.F., K.C.K., I.M.D.S. and M.S. acknowledge support from NationalInstitutes of Health grant R21 AI079528, Grand Challenges Explorationsgrant 51995 from the Bill and Melinda Gates Foundation, and CRC grant1686174 from Colorado State University.

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