Malaria – Beating the Threat of Insecticide Resistance...figures in the WHO World Malaria Report published in 2015, an estimated 3.2 billion people are at risk of being infected

Malaria – Beating the Threat of Insecticide ResistanceInformation & Facts / March 2016

G reat progress has been made in recent yearsinthefightagainstmalaria,but increasing insecticide resistance poses

aseriousproblem.Therearecurrentlyonlyfourclassesofinsecticidesavailableforadultmosquitocontrolinpublichealthandthenumberofspeciesdevelopingresistancetothemisontherise. BASF isworkingwithinternationalpublichealthpartnerstodevelopanewgenerationofmalariapreventionproductstohelpaddressthischallenge.

Eradicating Malaria – A Bold ProposalMalariaisaproblemin106countries,particularlyintheAfrican,South-EastAsianandEasternMediterraneanregions.Accordingtothelatestfiguresinthe WHO WorldMalariaReportpublishedin2015,anestimated3.2billionpeopleareatriskofbeinginfectedwithmalariaanddevelopingthedisease.TheWHOestimates that 214millionpeoplegloballycontractedmalariain2015and438,000diedofthedisease.Ofthesedeaths,90percentwereinAfricaand70percentwerechildrenundertheageoffive.

PhilanthropistBillGateshasdescribedmalariaasa“masskiller”andhasmadeitatoppriorityofthe

Bill&MelindaGatesFoundation.“Themosquitoisthemostdangerousanimalintheworld,”hesays,“because,whenitcomestokillinghumans,nootheranimalevencomesclose.”

Haltingandreversingtheincidenceofmalariaby2015wasoneofthe UN MillenniumDevelopmentGoals.Theultimateaim,though,istoeradicatethedisease.BillandMelindaGatesmadethisboldproposalataconferenceofexpertsinWashington,D.C.,USAin2007.“Toaspiretoanythinglessisjustfartootimidagoalfortheagewe’rein,”MelindaGatessaid.“It’sawasteoftheworld’stalentandintelligence,andit’swrongandunfairtothepeoplewhoaresufferingfromthisdisease.”

Between2000and2015,hugeprogresshasbeenmade.Thenumberofnewcaseshasdeclinedby37percentgloballyanddeathsfrommalariahavefallenby60percent. WHO estimates that5.9millionchildren’sliveshavebeensavedsince2000.Thenumberofcountriesonthepathtoeliminatingmalariaisincreasing.

Thisprogresshasbeenachievedbyfightingonseveralfronts:byusingRapidDiagnosticTests

In2015:3.2 billionpeople in over 100 countries were at risk of being infected with malaria

214 millionpeople contracted malaria globally

438,000people died of malaria

90%of deaths caused by malaria were in Africa

70%of deaths were children under the age of five

Source: WHO Malaria Fact Sheet:

World Malaria Report 2015

Malaria – beating the threat of insecticide resistanceBy Janet Anderson

“ THE MOSQUITO IS THE MOST DANGEROUS ANIMAL IN THE WORLD, BECAUSE, WHEN

IT COMES TO KILLING HUMANS, NO

OTHER ANIMAL EVEN COMES CLOSE.” Bill Gates Bill & Melinda Gates Foundation

BASF - Malaria Special1 March2016

Shrinking The Malaria Map In2014,ofthe106countrieswithongoingmalariatransmission,16countriesreportedzerocases.Fifty-sevencountriesachievedreductionsinnewmalariacasesbyatleast75%by2015.

(RDT)anddrugsagainsttheplasmodiumparasitethatcausesmalaria,whilesimultaneouslyfightingthemosquitoes,or“vectors”,thattransmitplasmodium.Vectorcontrolisanessentialpartofthefight.Drugsandvaccinescanonlyhaveachanceofeliminatingthediseasewhentransmissionlevelsarereduced.AccordingtotheWHO,vectorcontrolistheonlyinterventionthatcanreducemalariatransmissionfromaveryhighleveltoclosetozero.

Therearetwomodernmethodsofpreventingmosquitoesfrombitingpeople:insecticide-treatedbednetsandinsecticidesprays.Long-lastinginsecticide treated nets(LLIN)protectpeoplewhiletheysleepandkillmosquitoesthattouchthenets.Indoorresidualspraying(IRS)coats wallsandceilingsofhomeswithaninsecticidethatkillsthemosquitoes.In2014,over200millionLLINsweredeliveredacrossAfrica.Worldwide,in2014,116millionpeoplewereprotectedbyIRS.

“ MAINTAINING EFFECTIVE CONTROL IS BECOMING DIFFICULT AS CONVENTIONAL TOOLS BECOME LESS EFFECTIVE YEAR ON YEAR.” Anton GerickeConsultant for BASF Partner, Avima

The naturally occurring genetic mutations which allow for insecticide resistance in mosquitoes are rare.

When mosquitoes are exposed to insecticides in treated bed nets, sprays and other insect controls...

…the susceptible are killed but the survivors go on toreproduce, transferring the genetic changes that confer resistance to their offspring…

…and so the resistantpopulation grows.

…the resistant mosquitoes eventually become numerous within the population.

WITH THEIR RELATIVELY SHORT LIFE CYCLE AND HIGH RATES OF REPRODUCTION, MOSQUITOES ARE ABLE TO DEVELOP RESISTANCE RAPIDLY.

60 countries reported mosquito resistance to at least one insecticide used for malaria control.

49 countries reported mosquito resistance to two or more insecticides used for malaria control.

Source: WHO World Malaria Report 2015

Total number of countries reporting: 70

Total number of countries reporting: 78

The resistance heat map shows current incidents of resistance in countries across the world:http://irmapperjavascriptwcfservice.cloudapp.net/

86%

63%If this advantage ismaintained by continuallyusing the same insecticide…

HARSH SELECTION: HOW INSECTICIDE RESISTANCE INCREASES IN THE MOSQUITO POPULATION

REPORTED INSECTICIDE RESISTANCE, 2015

Formoreinformationaboutresistancemanagement,includingthelatestversionoftheInsecticideResistanceManagementManualv.3.0fromApril2014,visittheIRACwebsite:http://www.irac-online.org/teams/public-health/

n Malariatransmissionoccursthroughout n Malariatransmissionoccursinsomepartsn Malariatransmissionisnotknowntooccur

BASF - Malaria Special 2March2016

Thesuccessofthesetwomethodshasbeenimpressive;thefightagainstmalariahasbeengoingintherightdirectionforoveradecadeandthemalariamapisshrinking.Butnowthereisaseriousriskthatthesegainscouldbelost.

The Risk Of Increasing Insecticide ResistanceTheproblemofgrowingresistancetotheinsecticidescurrentlyinuseisrecognizedbypublichealthworkers,scientistsandtheWHO.

Partoftheproblemisthattherearecurrentlyonlyfourclassesofinsecticidesavailableforadultmosquitocontrolinpublichealth–pyrethroids,DDT,carbamatesandorganophosphates.Ithasbeenmorethan30yearssinceanewpublichealthinsecticidalactiveingredienthasappearedonthecommercialmarket.AlltheinsecticidesusedforLLINsarebasedonpyrethroids.Theirwidespreadusehasenabledthehighlyadaptablemosquitopopulationtodevelopresistancetothesechemicals.

Thenumberofcountriesreportingresistancegrowseachyear.ReducedsusceptibilitytopyrethroidshasbeenconfirmedinmosquitoesinWest,CentralandEastAfrica.Over60countrieshavereportedresistancetoatleastoneinsecticideand49reportresistancetoallfour.

“Resistanceisareality,”saysAntonGericke,aconsultantforAvima,aSouthAfrica-basedcompanyandBASFpartner.Hehasbeenworkinginmalariavectorcontrolsince1990.AvimasuppliesinsecticidesacrossSouthernAfricaandsupportstheimplementationofIRScampaigns.Gerickeandhiscolleagueshaveextensiveexperiencetrainingpeoplewhoworkinthefield.Theysee,firsthand,thethreatofresistance.“Weknowresistanceisgrowinginsomeplacesbecausethepeopletreatingand monitoring the disease are reporting increasesincasesofmalariawherepreviouslythenumbershadbeendropping,”hesaid.

“Maintainingeffectivecontrolisbecomingdifficultasconventionaltoolsbecomelesseffectiveyearonyear.Thereneedstobedetailedmonitoringofresistance.”

Theproblemhasbeenthefocusofathree-yearresearchprojectcarriedoutinValléedeKou,inBurkinaFasobyProfessorHilaryRanson,headoftheVectorBiologyDepartmentattheLiverpoolSchoolofTropicalMedicineintheUK,andhercolleagues.“BurkinaFasoisknowntobeahot

DrJamesAustin(middle)withProfessorFrankMosha,principleinvestigatorattheKilimanjaroChristianMedicalCentre(right),andAugustMtuy,researchassistantscientistatMaboginiexperimentalhutstation,Tanzania(left).

“ WHAT WE TRIED

TO DO IS TO LOOK

AT HOW QUICKLY

RESISTANCE IS

INCREASING. IT WAS ALREADY CLEAR THAT MOST OF THE MOSQUITO POPULATION HAD SOME LEVEL OF RESISTANCE.”

Tests show chlorfenapyr:n is safe for people when used correctly

n is rapidly metabolized and excreted by mammals

and fish

n is suitable for LLIN and IRS

n shows no cross resistance to the other four classes

of public health pesticides

As an IRS: it has been shown to cause mortality to

mosquitoes for up three months when applied as a

residual spray to surfaces such as wood, thatch, cement,

or mud.

Professor Hilary RansonHead of the Vector Biology Department at the Liverpool School of Tropical Medicine

BASF - Malaria Special3 March2016

spotforinsecticideresistance,”shesaid.“Thereisalotofawarenessthatresistanceisthere.Whatwetriedtodoistolookathowquicklyitisincreasing.Itwasalreadyclearthatmostofthemosquitopopulationhadsomelevelofresistance.Therealsurprisetouswasthatthestrengthofresistancewasincreasingveryrapidly.Within12months,themosquitoesincreasedtheirlevelofresistance10-fold.Thelocalmalariavectorpopulationisnowmorethan1,000-foldmoreresistantthanasusceptiblestrain.”

TheWHOrecognizestheseriousnessofthisthreat.Atthe2014meetingoftheAmericanSocietyofTropicalMedicineandHygiene,DrPedroAlonso,directorofthe WHO GlobalMalariaProgram,said:“Idon’tthinkwecanoveremphasizehowcriticalinsecticideresistanceis,orthethreatthatitimposesonthegainsachievedoverthelastdecade.Weneedtopayverycloseattentiontothisproblem.”

A New Approach Is NeededAttheheartofthecampaigntotacklethethreat

ofinsecticideresistanceistheInnovativeVectorControlConsortium(IVCC),setupin2005withagrantfromtheBill&MelindaGatesFoundationtocombatinsect-bornediseases.IVCCworks with internationalpartnerstosupportthedevelopmentandintroductionofnewinsecticides.

Inorderforanewinsecticidetobeatresistance,ithastoworkinadifferentwaythanthecurrentlyavailableinsecticides–itneedstohaveanew“modeofaction”.Pyrethroids, DDT,carbamates and organophosphates are neurotoxins,whichmeanstheykillmosquitoesbyimpedingnervetransmission.Since2010, BASF hasbeencollaboratingwiththeIVCCand LSHTMtodevelopandbringtothemarketaninnovativeLLINtocombatresistance,combiningtheinsecticidesalpha-cypermethrinandacompletelynewinsecticideinthepublichealthsector,chlorfenapyr.Chlorfenapyrhasbeenusedinagricultureandurbanpestcontrolworldwidesince1995.Unlikeanyofthecurrentlyavailableinsecticidesformalariause,itbelongstothepyrroleclassofchemistryandhasanentirely

Alpha-cypermethrin Chlorfenapyr Alpha-cypermethrin + chlorfenapyr

At application,resistant and susceptible mosquitoes are present

Minutes later, susceptible mosquitoes die, resistant ones stop feeding

Minutes later, mosquitoes continue to feed and reproduce

At application,no mosquitoes are resistant tochlorfenapyr

Minutes later, susceptible mosquitoes die, resistant ones stop feeding

At application,no mosquitoes are resistant tothe combinationchemistry

Several generations later, resistant population increases

A few dayslater, resistant mosquitoes remain

Several generationslater, mosquitoescontinue to besusceptible

A few days later, mosquitoes die

Several generationslater, mosquitoescontinue to besusceptible

A few dayslater, resistant mosquitoes die

•Susceptiblemosquitoes•Resistantmosquitoes

“ I DON’T THINK WE CAN OVEREMPHASIZE HOW CRITICAL INSECTICIDE RESISTANCE IS, OR

THE THREAT THAT

IT IMPOSES ON THE

GAINS ACHIEVED OVER

THE LAST DECADE. WE

NEED TO PAY VERY

CLOSE ATTENTION TO

THIS PROBLEM.” Dr Pedro AlonsoDirector, WHO Global Malaria Program

BASF - Malaria Special 4March2016

differentmodeofaction,makingitunlikelytoshowcross-resistanceinmosquitoesthatareresistanttoneurotoxicinsecticides.

“Alpha-cypermethrinactsontheinsects’centralnervoussystemandcausesparalysis,”saidDrJamesAustin,globalproductdevelopmentmanager at BASF andatrainedentomologist.“Itsmodeofactionhasprovenextremelyeffectiveinquicklyknockingdownmosquitoes.However,whenlargepartsofaninsectpopulationdieoffquickly,theyfailtoreproduce,leavingasmallnumberthatareresistant.Asthoseremaininginsectsreproduce,thenumberofresistantmembersgrows.”

Unlikethefastknockdownofalpha-cypermethrin,chlorfenapyrdisablesaninsects’abilitytoproduceenergy.Thedelayedmortalityallowsinsectstoreproduceandpassonsusceptiblegenestothenextgeneration.

Thecombinationofchlorfenapyrandalpha-cypermethrinoftenyieldsauniquemetaboliceffectinresistantmosquitoes.Alpha-cypermethrinactivatesthedetoxifyingP450enzymesintheinsectwhichwouldtypicallyrenderitlesseffective.However,thesame

detoxifyingP450enzymesthatdeactivatealpha-cypermethrin,speeduptheactivityofchlorfenapyr,likelyprovidingimprovedperformanceagainstresistantmosquitoes.

TheIVCC,too,seesgreatpromiseforthefuture.“Newapproachesthatsafeguardandexpandactiveagentscurrentlyavailableareessential.That’stheonlywaywearegoingtogetahandleontheever-increasinglevelsofresistance,”said DrRobertSloss,formerportfoliomanagerforpublichealthproductsattheIVCC.

BASF isdevelopinganIRSand anLLINbased onchlorfenapyr.TheLLINis a new generation ofBASF’sInterceptor®mosquitonets,withthetradenameInterceptorG2.TheIRSiscalledSylando®240SC.

Promising Early ResultsAsthisisthefirstuseinpublichealthforchlorfenapyr,ithastobetestedthroughtheWHO PesticideEvaluationScheme(WHOPES) to ensureitmeetsinternationalsafetystandards.Sylando240SCiscurrentlyatanadvancedstageofWHOPEStesting,whileInterceptorG2 isunderevaluation.

“ WE ARE PLEASED TO

BE ABLE TO MAKE

THIS CONTRIBUTION

TO THE FIGHT AGAINST

MALARIA. AS A VIABLE

ALTERNATIVE TO THE

CURRENTLY USED

INSECTICIDES, WE HOPE IT WILL CONTRIBUTE TO SAVING MANY LIVES.” Egon WeinmüllerHead of Business Management, Global Public Health, BASF

Fieldwork:discoveringhowinsecticideresistanceistestedinthefieldatIVCC’strialsiteinMoshi,Tanzania. (ltor)RaphaelN’Guessan,BillGates,SueDesmond-Hellman,DaveMalone.Photo:©Bill&MelindaGatesFoundation/SamanthaReinders

BASF - Malaria Special5 March2016

Biologicaltestsarebeingcarriedout byLSHTM,supportedbyIVCC,toprovechlorfenapyrcanbeeffectiveagainstmosquitoesthathavedevelopedresistance tootherinsecticidesandthat,whenapplied to aLLIN,itcanstillbeeffectiveafter20washes.TestsarebeingcarriedoutinexperimentalhutssetupinBenin,BurkinaFasoandTanzania–allmalariaendemicareas.Thesetestsareanecessaryadditiontolabtests.“Ultimately,youonlygetatruepictureofhowanewproductislikelytoworkagainst realmosquitoesinanAfricansetting,”saidDaveMalone,IVCC’stechnicalmanager.

DrRaphaelN´Guessan,alecturerinmedicalentomologyatLSHTMandaWestAfricaIVCC programmanager,iscarryingoutthetrialsataresearchstationinBenin.Theresultssofararepromising.“Theearlylabtestsofchlorfenapyrshowed that there was no cross resistance withtheotherclassesofinsecticidescurrentlyinuse,”hesays.“Althoughhighlytoxicagainstmosquitoes,chlorfenapyrisslow-actingand,unlikepyrethroids,doesnotpreventbloodfeeding.Interceptor®G2isthereforecoatedwithamixtureofchlorfenapyrandapyrethroid,alpha-cypermethrin.Inexperimentalhuts,thesenetssignificantlyimprovedcontrolofpyrethroid-resistantmalariavectorscomparedtopyrethroid-onlynetsandwithstoodWHOPES standardwashingover20washes.”

ItisclearthatchlorfenapyrisanexcellentpotentialadditionforLLINandIRS,which is why BASF isinvestinginitsdevelopment.“Wearepleasedtobeabletomakethiscontributiontothefightagainstmalaria,”saidEgonWeinmüller,headofbusinessmanagementinglobalpublichealthat BASF.“Asaviablealternativetothecurrentlyusedinsecticides,wehopeitwillcontributeto savingmanylives.”

Progress Only Counts If We Keep GoingProfessorRansonhasbeenwatchingthedevelopmentofchlorfenapyrwithgreatinterest.“Ithinkitisoneofthetoolsthatistheclosesttobeingavailableanddoingsomethingabouttacklingpyrethroidresistance,”shesaid.“We’vegottotakepyrethroidresistanceextremelyseriously.Newproductswithalternativeinsecticidesinthemareurgentlyneededandverywelcome.”

Forthoselivinginmalaria-endemicregions,itisvitalthatthefightcontinues.AsBillGatessaidinaspeechhemadein2007,“Ifyoustophalfway,youdon’tgethalfthebenefit,youcouldendupwithzeropercentofthebenefit.Theprogresscountsonlyifwekeepitgoing.”

“ WE’VE GOT TO TAKE PYRETHROID RESISTANCE EXTREMELY SERIOUSLY. NEW PRODUCTS

WITH ALTERNATIVE

INSECTICIDES IN

THEM ARE URGENTLY

NEEDED AND VERY

WELCOME.” Professor Hilary RansonHead of the Vector Biology Department at the Liverpool School of Tropical Medicine

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