ANRV397-EN55-29 ARI 1 November 2009 13:33Malaria Management:Past, Present, and FutureA. Enayati1,2andJ. Hemingway21School of Public Health and Environmental Health Research Centre, MazandaranUniversity of Medical Sciences, Sari, 48175-1553 Iran; email: A.Enayati@liverpool.ac.uk2Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;email: hemingway@liverpool.ac.ukAnnu. Rev. Entomol. 2010. 55:56991First published online as a Review in Advance onSeptember 15, 2009The Annual Review of Entomology is online atento.annualreviews.orgThis articles doi:10.1146/annurev-ento-112408-085423Copyright c2010 by Annual Reviews.All rights reserved0066-4170/10/0107-0569$20.00Key Wordselimination, mosquito, pyrethroid, insecticide, monitoringAbstractThe prospect of malaria eradication has been raised recently by the BillandMelindaGatesFoundationwithsupportfromtheinternationalcommunity. There are signicant lessons to be learned from the ma-jor successes and failures of the eradication campaign of the 1960s, butcessation of transmission in the malaria heartlands of Africa will de-pend on a vaccine and better drugs and insecticides. Insect control is anessential part of reducing transmission. To date, two operational scaleinterventions, indoor residual spraying and deployment of long-lastinginsecticide-treated nets (LLINs), are effective at reducing transmission.Ourabilitytomonitorandevaluatetheseinterventionsneedstobeimproved so that scarce resources can be sensibly deployed, and newinterventions that reduce transmission in a cost-effective and efcientmannerneedtobedeveloped. Newinterventionscouldincludeus-ing transgenic mosquitoes, larviciding in urban areas, or utilizing cost-effectiveconsumerproducts. Alongsidethisinnovativedevelopmentagenda, the potential negative impact of insecticide resistance, partic-ularly on LLINs, for which only pyrethroids are available, needs to bemonitored.569Annu. Rev. Entomol. 2010.55:569-591. Downloaded from arjournals.annualreviews.orgby Calcutta University on 03/26/10. For personal use only.Click here for quick links to Annual Reviews content online, including: Other articles in this volume Top cited articles Top downloaded articles Our comprehensive searchFurtherANNUALREVIEWSANRV397-EN55-29 ARI 1 November 2009 13:33DISTRIBUTION OF MALARIAAND ITS MAJOR VECTORSPlasmodium falciparum originated in Africa andspreadworldwide10,000years ago(74, 87,118). Malaria distributionandtransmission,with latitudinal extremes of 64 degrees northand 32 degrees south, are restricted to altitudesbelow2000 meters and limited by the minimumtemperature required to complete developmentof another malaria parasite, Plasmodium vivax(73, 74).There were anestimated247millionmalariacases among 3.3 billion people at risk in 2006,witharound881,000deaths, most of whomwereunderveyearsof age, 91%of whichoccurinAfrica(211). Endemicityofthedis-ease is dened by the parasite rate, i.e., the pro-portion of a given population carrying asexualparasites in the blood, with hypoendemic de-nedas0.75. Malaria is hy-poendemic in the Mediterranean littoral areasand northern parts of South Africa, epidemic tohyper- and holoendemic in the Horn of Africa,and hyper- or holoendemic in tropical Africa.Only a subset of Anopheles mosquitoestransmits malaria. Two international mappingprojects are currently underway aimed at spa-tial modeling of the geographical distributionof 52 primary malaria vectors. The results fromat least one of these projects should be in thepublic domain by 2010. Malaria was eradicatedfromNorthAmericaandmostofEuropeinthe 1970s, although the vectors are still present(73). The main malaria vectors in North AfricaandtheMediterraneanlittoral areasareAn.atroparvus, An. labranchiae, An. gambiaecom-plex, An. pharoensis, and An. sergentii. In tropi-cal Africa mosquitoes of the An. gambiae andAn.funestus complexes are the main vectors accom-panied by several secondary vectors (4, 23, 43,56, 73, 172). In the Americas the major vectorsare An. albimanus andAn. darlingi. Transmissionoccurs in nine countries of the region that sharethe Amazon rainforest and in eight countries inCentral America and the Caribbean (207). InSouth America, forest and forest fringe malariavectors are An. darlingi, An. aquasalis, An. al-bitarsis, An. bellator, and An. cruzii (73, 172, 207).Although most malaria morbidity and mor-talityoccurinAfrica, thelargest populationat riskof malariais inAsia(74). Malariaislimitedtothewest of Asiaandpartsof theMiddle East. The main vectors in the MiddleEast are An. sacharovi, An. superpictus, An.stephensi, An. arabiensis, and An. culicifacies(1, 5, 38, 92, 95, 141, 167). Incentral AsiamalariaisendemicandthemainvectorsareAn. superpictus, An. pulcherrimus, An. hyrcanus,andAn. sacharovi (173, 188). InSouthAsia(India,Nepal,Bhutan,Bangladesh,Maldives,Sri Lanka, and Indonesia) the main vectors areAn. stephensi, An. culicifacies, An. uviatilis, An.minimus, An. dirus, An. aconitus, and An. macu-latus (93, 174, 179, 193). In East and SoutheastAsia (Myanmar, Laos, Vietnam, Malaysia,Cambodia, Singapore, Brunei, and Philip-pines)themainvectorsareAn.minimus,An.dirus, An. sundaicus, An. maculatus, An. subpictus,andAn. avirostris (18, 47, 52, 94, 132, 178,186, 189, 199). InChinamalariaisendemicin Yunnan Province, which borders Laos andMyanmar. The mainvectors are An. sinensis, An.messeae, and An. minimus (73, 124, 172, 195). InOceania (Papua NewGuinea, Solomon Islands,and Vanuatu) the main vectors are An. farautiand An. punctulatus (45, 107, 108, 127, 216).THE BURDEN OF MALARIAIn 1900, more than 77% of the world popula-tion in 140 countries was at risk of malaria, withmore than 25%in hyper- or holoendemic areas(74). Malaria mortality rates changed dramat-ically in the twentieth century. In 1900, morethan 3.1 million deaths occurred among a totalpopulation of 1.6 billion, a death rate of 19.4per 10,000 people. Approximately 90% of thismortality occurred outside sub-Saharan Africa(14). In Africa the infant malaria-specic mor-tality rate was 9.5 per 1000 people prior to1960 (185).In the rst half of the twentieth century, thesanitation era of malaria control interventions570 EnayatiHemingwayAnnu. Rev. Entomol. 2010.55:569-591. Downloaded from arjournals.annualreviews.orgby Calcutta University on 03/26/10. For personal use only.ANRV397-EN55-29 ARI 1 November 2009 13:33focused on reducing mosquito breeding sites.Mosquito control was successful in the PanamaCanal, Indonesia, Malaysia, theminesoftheZambian copper belt, and in the eradication ofthe recently introduced An. gambiae in Braziland Egypt (74).THE 1960s MALARIAERADICATION CAMPAIGNAND THE ROLE OF DDTThe terms eradication and eliminationhave been used interchangeably in the lit-erature. Here, eradication is dened as apermanent reduction to zero of the worldwideincidence of aninfectious organismas a result ofdeliberate efforts (210). For malaria, this deni-tion means the parasite no longer exists. It doesnot mean the eradication of the mosquitoes thattransmit malaria. Elimination is dened as a re-duction to zero of the local incidence of a speci-ed disease ina dened geographical area (210).Elimination campaigns require sustained vigi-lance to monitor and maintain transmission in-terruption, with a rapid response to small foci oftransmission triggered by imported cases (210).DDTwas introduced in the 1940s andusedbymanynational malariacontrol pro-grams for indoor residual spraying(IRS) inthe global malaria eradication program from1957 to 1969, which excluded tropical Africa.These programs reduced the population at riskof malaria to approximately 50% by 1975 com-paredwith77%in1900(74). Themortalityrate was reduced to 1.61 per 10,000 by 1970,a massive reduction from the 1900 baseline of19.4 (14). Despite the successes, several techni-cal, operational, economic, and political prob-lems halted the malaria eradication campaign.Local malaria control interventions then grad-ually reduced the areas of active transmission tojust under 50% of the world population at riskofmalariaby2000(74).By2004,107coun-tries, with a total population of 3.2 billion peo-ple, were at risk of malaria transmission. Today,approximately three billion people (40% of theworldspopulation)areatriskofmalariaex-posure. Sixty percent of all malaria cases, 75%of all Plasmodium falciparum malaria cases, andmore than80%of malaria deaths occur inAfrica(184). Malaria is also a major cause of low birthweight, premature birth, infant mortality, andanemia in children and pregnant women (207).Malaria eradicationwas never systemati-cally attempted in Africa, as transmission wasan order of magnitude more intense thanin other continents. However, control in-terventions pre-1960resultedinmore than4.4 million people in South Africa, Swaziland,Zimbabwe, and Mauritius living in areas wherethe malaria eliminationefforts hadreachedconsolidationphase, andtransmissioninfor-est areasof southernCameroonandLiberiaand highland savanna areas in Madagascar andUganda was almost interrupted (97).Elsewhere the question was whether malariatransmissioncouldbeinterruptedonalocalscale. Pilot interventions occurred in ve eco-epidemiological zones in Africa (125). In these,malaria was reduced to low endemicity or eveneliminated in semidesert areas, remote islands,andhighlandsavannawithtropicalandtem-perate climates. In hyperendemic areas, malariawas reduced from hyperendemicity to hypoen-demicity in tropical areas in the forest zone, inthe islands located near the mainland, and inparts of the highland savanna zone. Malaria wasreduced from high endemicity to low mesoen-demicity in the lowland savanna zone. In thePare-Taveta area on the Kenya/Tanzanian bor-der, malaria prevalence was reduced (7, 33) andall-cause mortality rates were halved after veyears of IRS. An. funestus disappeared and thedensity of An. gambiae declined rapidly. How-ever, complete interruption of transmission wasnot achieved.TheNigerianGarki project is themost-citedAfricanattempt at transmissioninter-ruption. High propoxur IRS coverage wassupplemented with mass antimalarial drug ad-ministration(125). Transmissioncontinuedandmodelers argued that this transmission was duelikely to persistent outdoor-resting mosquitoes.It was concluded that, in holoendemic areas ofWest Africa, the elimination of transmission us-ing IRS was not technically feasible (215, 217).www.annualreviews.org Malaria Management 571Annu. Rev. Entomol. 2010.55:569-591. Downloaded from arjournals.annualreviews.orgby Calcutta University on 03/26/10. For personal use only.ANRV397-EN55-29 ARI 1 November 2009 13:33DDT was a major factor in the early suc-cesses. It had a central role in the eliminationof malaria fromVenezuela, Cyprus, Greece, andmuch of Italy and coastal British Guiana (63).When nancial constraints led to a reduction inits use in 1951, it was apparent that transmissiondid not resume (130). The availability of effec-tive antimalarial drugs and detection of insec-ticide resistance in An. sacharovi from Greece,which could have jeopardized sustained malariacontrol, increased the push for a malaria eradi-cation campaign (63, 130, 215).The rate of malaria rebound after local elim-inationwas estimated three years after theTavetaintervention. An. funestuswasstillab-sent, but An. gambiae returned to preinterven-tiondensitiesand2090%ofthepopulationreceived one malaria infective bite per annumduring 1961 compared with all the populationreceiving226infectivebitesperannumbe-fore the intervention. This sustained reductionwas due both to the continued absence of An.funestus and to the increased drug administra-tion (180). Five years after the cessation of IRS,An. funestus had returned (181), and after eightyears, entomological indices returned to prein-tervention levels (182).Despite their impressive health benets, theAfrican trials were universally considered fail-ures because elimination was not achieved.Why was it not possible to sustain these benetsby continuing to spray indenitely? There weretwo major issues: rst, the intensity of effort re-quired to sustain IRS indenitely throughoutentire countries, and second, insecticide resis-tance. Resistance was seen as a threat to sustain-ability, and the more frequent and complete thespraying operation, the more likely resistancewould evolve (61).MODELS OF MALARIA CONTROLMathematical models were developed to deter-minewhethereradicationwaspossibleunderagivenset of constraints. Macdonaldsearlymodel of malaria control (110) suggested thatthe most vulnerable element in the malaria cy-cle was survivorship of adult female Anopheles.He suggested that the worst malaria transmis-sion conditions known in Africa could be over-come by an increase in the daily mortality of themosquitoes from 5% to about 45% (110).Quantitativeaspects of transmissionwerestressed, in which the basic reproduction rateof malaria (R0) is an essential concept, as a mea-sure of the intensity of transmission. R0 is theexpected number of secondary cases producedby a single infection in a completely suscepti-blepopulationfortheentireinfectiveperiod(110). If R0is less than 1, the disease will beeliminated(110, 142). Successful vectorcon-trol should reduce vectorial capacity to less than0.01, producing an R0 of less than 1. To be ofpractical use, the malaria models must be ro-bust. Early models didnot consider humanpop-ulationdynamics, seasonal Anopheles populationdynamics, vector characteristics, human immu-nity, parasite diversity, insecticide and drug re-sistance dynamics, spatial heterogeneity, or en-vironmental changes (120). Smith et al. (183)recently revised R0calculations and their im-plicationsformalariacontrol. Originally, R0was based on a quantitative description of theP. falciparumlifecyclethatassumesthathu-man populations are effectively innite and thatall humans are bitten at the same rate. How-ever, human populations are nite and bitingis heterogeneous (i.e., mosquitoes do not bitedifferent age groups, sexes, and races equally),which increases R0, because those who are bit-tenmostaremorelikelytobecomeinfectedand will subsequently infect a large number ofmosquitoes, amplifying transmission. The spa-tial scale of malaria transmission is also affectedby vector ecology, especially the distribution oflarval habitatandhost-seekingbehavior, andby human population density, movement, anddistribution (183).THE COMPONENTS OFVECTORIAL CAPACITYVectorial capacityis theaveragenumber ofinfectious bites, with a given parasite, thatoriginates fromonecaseof malaria inunittime, assuming that all the female mosquitoes572 EnayatiHemingwayAnnu. Rev. Entomol. 2010.55:569-591. Downloaded from arjournals.annualreviews.orgby Calcutta University on 03/26/10. For personal use only.ANRV397-EN55-29 ARI 1 November 2009 13:33biting the case individual become infected(58). Vectorial capacity can be used to evaluatedifferent interventions, and in nonendemicareas it is the best measure of receptivity (theprobability that an infectious case, havingarrivedintheeliminatedarea, will causeanoutbreak of local transmission, and the rapiditywith which such an outbreak will expand).Vectorial capacity varies with time, vector,and parasite species. A number of simplifyingassumptions are involved, for example, thatthe mosquito transmits the infection but is notaffected by it, that its death rate is independentof age, and that a single value for humanfeedingandmosquitosurvival applies toallAnopheles females(126). IntheGarki project(125) vectorial capacity preintervention was re-duced 100-fold post-intervention but was still45 times higher than the critical level of 0.01.THE STABILITY INDEXAlthough the intensity of malaria transmissionis sensitive to adult mosquito mortality, controlinterventions suchas long-lastinginsecticideimpregnated nets (LLINs) and IRS that targetthis parameter are inefcient. Maximizing thebenets depends on the fraction of mosquitoesthat are killed or repelled and on the stabilityindex, the average number of bites by an av-eragemosquitoduringanormallifetime. Anindex of >2.5 indicates stable malaria; between2.5 and 0.5 indicates intermediate stability; and