Doctors in India studymaternal deaths dataExperts air concernaboutdisease’simpactin poortribalareasPage 5

FT Health Combating MalariaFT SPECIAL REPORT

www.ft.com/reports | @ftreportsMonday April 25 2016

Inside

Development impactbonds raise interestImpact assessment mayrate as good fit for anti-malaria fundraisingPage 2

Mosquito DNA comesunder microscopeGenetic modificationcould prove vital tool forlimiting outbreaksPage 3

Heat is on Big PharmaMedical breakthroughsare needed as resistanceto drugs increasesPage 4

Wrangles continue asbed nets lose effectManufacturers say theWHO should expeditenew product approvalsPage 6

I t should be a time for optimismamong those engaged in the fightagainst malaria. Incidence of thedisease fell 37 per cent globallybetween 2000 and 2015, andmor-

tality by 60 per cent, saving over 6mlives, according to the most recentWorldMalariaReport.

Malaria still kills more than 400,000people a year,most of them children inAfrica. But newweapons are arriving toaid the fight against it, most notably avaccine that could eventually protectmillions frominfection.

So why, with so much good news, isthe mood not more celebratory? Fordecades, a malaria vaccine was seen asthe holy grail of tropical medicine. Yet,now one has arrived, it is causingfraughtdebate.

After 30 years of development byGlaxoSmithKline and its predecessorcompanies, the Mosquirix vaccine —also known as RTS, S — was endorsedlast year by the European drugs regula-torandtheWorldHealthOrganisation.

On the face of it, the rulings were avindication of the hundreds ofmillionsofdollars invested in theproject byGSKand donors led by the Bill & MelindaGatesFoundation.

The recommendations came withstrong caveats andconditions, however,because theclinicaldata in favourof thevaccine were far from overwhelming.

Malaria caseswere reduced bybetweena third and a half in children aged 5-17months — much lower than most vac-cines. Moreover, the WHO concludedthat four separate doses were requiredtoprovideenduringprotection.

Médecins Sans Frontières, the healthcharity, said the benefits did not justifythe investment needed to administermultiple doses in countries with weakhealth systems. MSF said resourceswould be “better placed on scaling up

Dose of reality hits hopes for vaccineTheWorldHealthOrganisation is positivebut wants to seemoreevidence of benefits,writesAndrewWard

No pain, no gain: theWHO has ordered up to five pilot programmes to take place in sub-Saharan Africa — AP Photo/Karel Prinsloo

existingmalaria treatment and preven-tionactivities”.

The WHO was more positive, high-lighting the vaccine’s potential to pre-vent up to 700 deaths per 100,000 vac-cinations, amounting to “a significant

public health impact” and “a high-levelof cost-effectiveness” at an expectedpriceofabout$5perdose.

It said more evidence was needed,however, to prove that the benefitsshown in the controlled environment ofa clinical trial could be replicated inmore haphazard “real world” settings.To test this, theWHOhas orderedup tofive pilot programmes to take place insub-SaharanAfrica. Only if those provesuccessful will a wider go-ahead begiven.

This has left advocates of the vaccineon the defensive. “It’s the first vaccinefor a parasitic infection. That’s a bigdeal,” says JeremyFarrar,directorof theWellcome Trust, the London-basedmedical charity. “So I’m in the glass-half-full camp. You never expect firstgenerationvaccines tobeperfect.”

Thomas Breuer, chief medical officerat GSK’s vaccines unit, says the group istalking to theWHO“on aweekly basis”about the pilot programmes, which areexpected to begin next year. GSK haspromised to price the vaccine at “costplus 5per cent”,with theprofit putbackintofurthermalariaresearch.

GSK’s main collaborator is theMalaria Vaccine Initiative, an offshootof the Seattle-based Path health charitybacked by the Gates Foundation.MVI’sdirector, Ashley Birkett, says research-ers are working on an improved, sec-ond-generation version of RTS, S, whilealso exploring other approaches.Oneofthemost promising is a so-called trans-mission-blocking vaccine that createsantibodies in the blood which, whenimbibed by a mosquito, disables theinsect’s ability to pass on the parasite tootherpeople.

Continuedonpage3

2 ★ † FINANCIAL TIMES Monday 25 April 2016

ContributorsAndrew WardPharmaceuticals correspondent

Andrew JackHead of curated content, FT editorial

Sarah MurrayFreelance journalist

Clive CooksonScience editor

Fergus RyanNews editor on FT world desk

John AglionbyEast Africa correspondent

Amy KazminSouth Asia correspondent

Michael PeelBangkok regional correspondent

Steven BirdDesigner

Alan KnoxPicture editor

Peter ChapmanCommissioning editor

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FTHealth CombatingMalaria

In January, theUK government and theBill & Melinda Gates Foundationannounced funding of £3bn over thenext five years for the battle againstmalaria. Such donor support willremain crucial, yet other andquite innovative forms of fundingprojects could also come to play avital role.

One is the so-called developmentimpactbond, orDIB.The ideaof issuinga DIB to raise money to fund thefight against malaria was born a fewyears ago. At that time, the Roll BackMalaria campaign engaged Dalberg, aglobal development consultancy, tostructure a malaria bond and study itsfeasibility.

“We got the endorsement from RollBack Malaria that this was an interest-ingmodel to test sowe looked at how topilot that inMozambique,” saysBarbaraKong, a senior investment principal atD.CapitalPartners, theDalberg subsidi-arythathasstructuredthebond.

The first malaria bond has yet to beissued but, with a goal of raising $3.5m,so far the bond has secured a commit-ment from Nandos, the restaurantchain, which has pledged funding of$1.5m.

As with social impact bonds,DIBs raise funds fromprivate investors.

Thebonds rely on “outcome funders”—governments, international donors,companies — who commit to payingreturns to investors when a pro-gramme’s goals have been reached.“Outcome funders only pay forthe result once it’s achieved,” says MsKong.

The results might take the form offewer incidences of people going intohospital and lower demand for medi-cine.Also, incomesrisewhenpeopleareno longer falling ill, which means theyalso have more disposable income tospend on consumer goods — outcomesthat could also be tracked, explainsSherwin Charles, co-founder and chiefexecutive ofGoodbyeMalaria, a public-private consortium established to helplaunchthemalariabond.

While DIBs are in their infancy, thosebehind them believe the model lendsitself to combatingmalaria. In order totrigger returns to investors, goals mustbe met that require assessment of theimpactofmeasures.

“Fundersarestarting tobecomemoreawareofusingdata,”saysAunniePattonof the University of Cape Town. Sheleads the innovative finance pro-gramme at the university’s Bertha Cen-tre for Social Innovation and Entrepre-neurship.

While traditional funding is oftendirected towards individual pro-grammes — from drug research to the

provision of mosquito bed nets — theDIB allows for holistic approaches toeradication that might include severalformsof intervention.

Although it was corporate fundingrather thanabond that financed it,Dal-berg’s three-year pilot programme thatconcluded last year in several small dis-tricts in Mozambique demonstratedthat this co-ordinated approachreduced theprevalenceofmalariaby70percent, approximately in linewithglo-bal targets. It is this approach that theGoodbyeMalaria consortium intends toscaleuponce funding is raisedthroughaDIB.

MrCharles argues thatmalariabondscould provide funding for the elimina-tion ofmalaria in places where the dis-ease is loweronthe listofgovernmentordonorpriorities.

Investorsareexpressing interest, saysMs Patton: “Being able to eradicatemalaria and get a financial return isincrediblyattractive.”

However,Mr Charles reports that theGoodbye Malaria consortium facesproblemsgiven thedifficulties that con-front some potential investors. “A lot ofminingcompaniesare inmalariaareas,”says Mr Charles. “[But] because of thedownturn in their business, they don’thave themoney to invest as anoutcomefunder.”

Ms Kong says while it may take timeto secure outcome funders, and DIBswill not remove the need for donorfunding, the underlying rationale forthefinancingmodel is strong.

“It can help mobilise new sources offunding from the private sector,” shesays. “The focus on outcomes brings inmoreefficiency.”

Impact measurement set to playinnovative role in fundraisingFinancing

While charitable giving isstill vital, bonds open way tosome intriguing possibilities,writes Sarah Murray

$3.5mFigure that firstmalaria bond aimsto raise

$1.5mSum pledged byrestaurant chainNandos

F loribe Sefu, the chief ofKimeso, a remote and dustyvillage in the Bandundu prov-inceof theDemocraticRepub-lic of Congo, does not hesitate

ashe reels off frommemory the long listofpricesofdifferentmedical treatmentswhen his people fall ill. One stands outinparticular. “It costsus30,000[Congo-lese francs, some$32] for a blood trans-fusionformalaria,”hesays.

The fact thatheandotherpoorvillag-ershavetopayformedical servicesatallmight be seen as burdensome enough.Such payments consume a significantshare of local farmers’ incomes and actas deterrent to people seeking medicalhelpwhenit is required.

That Mr Sefu highlights the price tagfor amalaria treatment reflects the con-tinuedheavy toll takenby thedisease inthe country. Its effects have persisteddespite a decade of rising global donorassistanceprovidingnewbednets, diag-nostics and drugs that have helpedsharply to reduce malaria’s impactacrossmostofAfrica.

The village head’s account also sug-gests one of two troubling scenarios —either there is significant incidence ofsevere malaria with anaemia, which inextremecases can justify blood transfu-sions, or perverse financial incentivesare encouraging the costly and riskyoveruseofsuchtransfusions.

PeteZacharias fromtheSafeBloodforAfrica Foundation, a South Africancharity supporting improved services,doubts there is overuse of transfusionsbut warns of a lack of funding and datain the DRC. “There is not sufficientattentionbeing paid to blood safety,” hesays.

Such issues are very important notonly for theDRC. It andNigeria accountformore than a third of the annual esti-mated 438,000 deaths in the worldfrom malaria, according to the WorldHealthOrganisation’smalariareport for

2015. Without marked improvements,the absolute numbers will remain highand a deadly threat to the quality of lifeintheDRCandbeyond.

DrHamidouOuattara fromMédecinsSans Frontières, the medical charity,says he is bracing himself for a renewedsurge in malaria cases in the DRC. Hisexpectationis theresultofapatternthatMSFhas observed in the past fewyears,notably in the country’s eastern prov-inces. “The explosion in cases is high,”he says. “Medical structures are over-flowing. It’saproblem.”

In thepast, political instabilityunder-mined medical services and createdsevere difficulties in treating malaria.Whileuncertaintycouldreturn, fornow

the relative peace and resettlement ofpeople in areas previously hit by con-flictbrings a different type of threat.Farmers returning to their fields aregrowing rice and digging ponds to culti-vate fish. Both encourage stagnantwater, a breeding ground for malaria-carryingmosquitoes.

In MSF-supported clinics in the east,DrOuattara seesblood transfusionsasabarometer of the heavy continued bur-den of the disease: “10 per cent of ourpatientswere transfused—because it’saproblem linked to serious malaria.Malaria is themaincauseofhospitalisa-tionforchildren.”

Michael Humes, who overseesthe DRC for the US government’s

President’s Malaria Initiative, says sub-stantial investment in the fight againstmalaria in the past fewyears hasmeanta drop in childmortality in the countryfrom all causes, though much of it islikely through a fall in the burden ofmalaria. He says the most recent sur-veys suggest 70per cent of families nowhave a bed net to protect against mos-quitoes, and over half of children sleepunderthemregularly.

“We are at an interesting time,” saysMr Humes, “with a real emphasis onscalingup”theuseofbednetsacross thecountry. In this, he stresses the roleplayed by strong local leadership fromgovernment officials responsible formalaria. Also of great importance has

been investment in an internet-baseddistrict health information system,which is beginning to increase under-standingofmalariaandhowtorespond.

Yet the DRC, with its sprawling land-mass, fragmented transport and com-municationsnetworkandweak fundingfor government health structures, hasdifficulties with widespread and con-sistent application of techniques totackle malaria. Best estimates suggesttheDRChad16m-26mcases in2014and33,000-72,000deaths. In the absenceofreliable reporting systems, the figuresamounttoguesswork.

In the village of Nsele, in the easternenvirons of the DRC’s capital Kinshasa,it takes villagers over anhour towalk tothenearest clinic. In thepredominantlyrural district’s own rudimentary phar-macy, the only drug available to treatmalaria is sulfadoxine-pyrimethamine(SP).

The medicine is cheap and can helpprevent infections in mothers withyoung children but SP is no longer rec-ommended as the first line of therapyfor people who have already beeninfected.

In larger pharmacies inKinshasa andelsewhere, differentdrugs areavailable,although not only artemisinin-combi-nation therapy (ACT), which is the rec-ommendedtreatment inAfrica.

For now, there are few indicationsthat malaria in the country is provingresistant to ACTs, although a study byMSF in 2013 suggested some patientswere not taking the medicine as pre-scribed, therefore limiting theeffective-nessof thetreatment.

There are also some signs of risingresistancebymosquitoes to insecticide-treatedbednets.

At the same time, efforts to fightmalariaencountermorebasicproblems—a limitedawarenessof thediseaseandits consequences is sometimes amongthem.

InLoma, inthecoastalprovinceofBasCongotothewestofKinshasa, forexam-ple, local residentNanaTekabanza livesin a cramped adobe hut. Inside herhome, she points to a mosquito netrecently given to her by her five chil-dren. The net lies unused and still in itswrapper. “It is too hot to sleep under,”MsTekabanzasays.

Conditions conspire against DRC control effortRaised threat Stabilitymay have returned tothe country but so havemoremosquitoes,Andrew Jack reports

Overwhelmed:three or fourpatients have toshare a bed at anMSF-supportedhospital inBaraka, easternDRCMSF/Eddy VanWessel

‘Theexplosion incases ishigh.Medicalstructuresareoverflowing’

Monday 25 April 2016 ★ FINANCIAL TIMES 3

FTHealth CombatingMalaria

MrBirkett cautions against expectingany vaccine to provide a “silver bullet”against the disease. “Every tool againstmalaria is imperfect. The vaccine is asupplemental tool on top of what wealreadyhave.”

BT Slingsby, chief executive of theGlobal Health Innovative TechnologyFund, the Japanese public-private part-nership which has invested $21m inantimalarial initiatives, says improveddiagnostic technology should beanother priority. His fund is helpingdevelop a test that can be used in thefieldtodiagnosemalaria in10minutes.

“Diagnostics can be a game-changerbyensuring that the rightpeople get theright treatment quickly,” says MrSlingsby. “They can also help tackle

drug resistance by reducing unneces-sarycoursesof treatment.”

Resistance to existing drugs andinsecticides is an ever-present threat toprogressagainstmalaria, as thePlasmo-dium parasites responsible for the dis-ease gradually findways to evade them.Artemisinin-based therapies — thedominant treatment for malaria — isencountering pockets of resistance inSoutheast Asia. Should these strainsspread toAfrica it couldput the gains ofthepast15years intoreverse.

“Progress is still fragile,” says Dr Far-rar. “Back in the 1960swehada surgeofresistance and that couldhappen again.Wehave to comeupwithnewdrugs butin the end we will always be in a racewiththeevolutionof theparasite.

“Somepeople fall into the trapof say-ing it’s all aboutvaccines,or it’s all aboutdrugs or bed nets.We need to get out ofour silos and find the best way of usingthemtogether.”

Continued frompage1

Dose ofreality greetshigh hopesfor vaccine

Thomas Breuer,GSK’s chief medicalofficer, says thegroup speaks tothe WHO ‘on aweekly basis’

R esearchers are waging waragainstmalariaon twobroadfronts. One is developmentofdrugsandvaccinesagainstPlasmodium, the protozoan

parasite thatdirectly causes thedisease.Theotherusesnewtechnology toattackthemosquitoes that transmit the para-sitebetweenpeople.

Long before the 19th century discov-ery of the rolemosquitoes play in trans-mittingmalaria, people recognised thatthe disease was most prevalent inmarshland. They blamed the bad air(mal’aria in old Italian) associated withswamps and, as they drained the land,health improved because mosquitoesno longer had stagnant water in whichtobreed.

This ancient and inadvertentmethodof mosquito control was extendedduring the 20th century with chemicalwarfare, whichwas wagedwith insecti-cidesandinsectrepellents.

The 21st century promises to bringbiology to the forefrontof thebattle.Thisis through releasing geneticallymodified(GM) mosquitoes that either suppressthewild population of disease-transmit-ting insects or replace itwithaGMstrainthatdoesnotcarrytheparasite.

GM insect technology is not yet incommercial use anywhere in the worldand some environmental campaignersoppose its introduction, saying it posesan unacceptable ecological risk. None-theless, researchis increasingrapidly.

There are two main reasons for thecurrent urgency in the battle againstmosquitoes. The most immediate is anew epidemic of Zika, a mosquito-bornedisease, inLatinAmerica.

Although the Aedesmosquitoes thattransmit Zika — and other diseasesincluding dengue, chikungunya andyellow fever — are a different genus totheAnopheles carriers ofmalaria,muchof the research is likely to be applicabletobothtypes.

The second accelerator of GM insectresearch is the emergence over the pastthree years or so of new “gene editing”technology. Inparticular, this involves atechnique called Crispr — pronounced“crisper” — and which is short for“clustered regularly interspaced shortpalindromic repeats”. Themethod ena-bles researchers to manipulate specificgenes—adding, subtractingorchangingDNA — far quicker and more preciselythan previous techniques of geneticengineering.

Crispr has a guidance molecule thatcan be targeted to any stretch of DNA.Then a companion enzyme cuts theDNA in exactly the right place, allowingscientists to snip out unwanted DNA,add newDNAor regulate genetic activ-ity,before joiningupthecutends.

Several labs have reported successfulmosquito-modifyingexperimentsusingCrispr, which include the “gene drive”technique. This process overrides thenormal constraints of evolution andensures that when a GM mosquitomates with an unmodified wild mos-quito almost all of the offspring receivethe edited gene, rather than half, aswould otherwise be the case. As a resultit can spreadvery fast throughan insectpopulation.

Last November, for example, scien-tists at the University of Californiainserted a gene for anti-malaria anti-

bodies with a gene drive system intoAnophelesmosquitoes.Theresearchisatan early stage and further lab tests areneededtoshowhoweffectively theanti-bodiespreventmalaria infection.

“This is a significant first step,” saysAnthony Jamesof theUniversityofCali-fornia, Irvine, the project leader. “Weknow the gene works. The mosquitoeswe created are not the final brand butwe know this technology allows usefficiently tocreate largepopulations.”

Scientists at Imperial College Londonhave created a different type of genedrive, which disrupts egg production infemale Anopheles gambiae, the mostimportant carrier of malaria in Africa.This infertility would quickly reducewildmosquitopopulations—and there-fore the malaria transmission tohumans—tovery lowlevels.

African ecosystems should notbe affected significantly by suppressingjustoneof thecontinent’s 800mosquitospecies, researchers say, while thebenefits to human health could beenormous.

“As with any new technology, therearemanymore stepswewill go throughto test and ensure the safety of theapproach we are pursuing,” says

Professor Austin Burt of ImperialCollege. “Itwill beat least 10moreyearsbefore gene drive malaria mosquitoescouldbeaworking intervention.”

One approach, based on older GMtechnology, however, is much closer tocommercialisation. The “sterile insecttechnology” produced by Oxitec, a UKcompany spun out ofOxford universityin 2002, inserts a “dominant lethalgene” that enables males to mate withfemales but kills their offspring whileyoung.A sufficientnumberof theseGMmales are bred in the laboratory to bereleased and swamp theirwild counter-parts. They mate with all availablefemales, which then fail to reproduce.Theeffect is tosuppressthepestpopula-tiongreatly.

The strategy, tested over the past fiveyears in field trials in several tropicalcountries, means releasing many mil-lions of insects— 10 timesmore at leastthanthewildpopulation.

Oxitec is focusing its research anddevelopment efforts on Aedesmosqui-toes but Hadyn Parry, chief executive,says the company’s scientists haveshown that the same technology can beapplied to the Anopheles mosquitoesthat transmitmalaria.

Scientists zeroin onmosquitoDNA to repeltransmission

BiologyGeneticmodificationmay prove to be vitaltool in reduction of outbreaks, writes Clive Cookson

‘It will be at least 10moreyears before “gene drive”malariamosquitoes couldbe aworking intervention’

Big buzz: Anthony James (above) of the University of California regards developments so far as ‘significant’—Steven Zylius

4 ★ FINANCIAL TIMES Monday 25 April 2016

FTHealth CombatingMalaria

Namibia is one of the driest places onearth,with large tractsof itsoftendesertlandscape having less than 50mm ofrain a year. Nonetheless, it has sufferedthe effects of malaria and, up until2004, as many as 600,000 new caseswerereportedeachyear.

Cases have since fallen about 98 percent to 14,400 a year. While this is aremarkable feat for any health service,theNamibiangovernment is resolved topush on. From 2007, it has been signa-tory to the Elimination 8, or E8, initia-tive,whichaims to stampoutmalaria ineightsouthernAfricancountries.

Namibia’s health and social servicesministry aims to reduce malaria infec-tions to fewer thanone in 1,000 ineverydistrict of the country’s 824,000 sq kmby2017.Understanding thedistributionof the changingmalaria transmission, itsays, “is essential in guiding and defin-ing theeliminationstrategy”.Toachievethis, it is vital to have highly sophisti-cateddata.

Across thecontinent, lyingoffAfrica’seast coast, is Zanzibar, a semi-autono-mous part of Tanzania. Zanzibar’sregional governmentaims to rid its landof malaria and has called in experts,including Andy Tatem, a professor atthe University of Southampton anddirector of the WorldPop projectfocusedonpopulationdistributionsanddynamics. “Malaria is typically notspread over large distances bymosqui-toes.Mosquitoes fly short distances andonly live for a fewdays. It’s humanswhocarry the disease across and betweencountries,”saysProfTatem.

Understanding how humans moveand carry malaria parasites betweenareas is essential to eliminating the dis-ease fromaregion,hesays.

Prof Tatem is also co-director of theFlowminder Foundation, a non-profitorganisation based in Stockholm. Itsmission“is to improvepublichealthandwelfare” indevelopingcountries.

To achieve this, the foundation “col-lects, aggregates, integrates and analy-ses anonymous mobile operator data,satelliteandhouseholdsurveydata”.

When the Zanzibar study began in

2008 there was little information onhow people moved between its islandsandthemainland, soProfTatemandhisteam turned to mobile phone recordsprovidedbytelecomsoperatorZantel totrackpopulationmovement.

The anonymous phone records wereused in conjunction withmalariamapsfrom across the Tanzanian mainland,where travellers from Zanzibar wereexposedtohigher infectionrisks.

Prof Tatem and his colleagues usedthe phone records and risk maps in amathematical model to produce thefirstmalaria importation rate estimatesfor Zanzibar. The model highlightedthat strategies to eliminate the diseasewere costly in the short term comparedwithmaintainingcontrolefforts, suchasindoor spraying and using insecticide-treated bed nets. It also found thatreducing transmission in mainlandTanzaniawouldbeeffective.

The studywas to pave theway for theuse ofmobile data for ahost of develop-

ment initiativesacross theworld.The financial and human cost of

malaria is staggering.TheAfricanLead-ers Malaria Alliance estimates that 40per cent of healthcare spending inendemic countries is spent on dealingwith malaria, costing the continentabout $12bn a year. According to the

UK’s Department for InternationalDevelopment (DfID), as many as threeoutof 10hospitalbeds inendemiccoun-triesareoccupiedbymalariapatients.

DfID estimates that up to 39 per centof total health expenditure in Tanzaniais directed to malaria prevention andcare, costing the country 3.4 per cent ofitsgrossdomesticproduct.

Malaria also reduces foreign directinvestment, trade and tourism. ForNamibia, and indeed many Africancountries, tourists are a vital source offoreign currency and employment. Thesignificant reduction inmalaria cases isa boon for international tourism. Thedisease,however,hasstillnotgoneawaycompletely.

In Namibia, Prof Tatem and theNational Vector Borne Disease ControlProgramme worked with Mobile Tele-communications, the country’s largestmobile operator. Satellite images andcasedatawereused tomap theenviron-ment in which mosquitoes thrived.Those images and the anonymousmobile phone records helped create adetailedmapofmalaria transmission.

Before themap, it was estimated that1.2mpeoplewere at high risk, requiringsubstantial costs and effort to reacheveryone with control methods. Thenew map, however, highlighted thatonly 80,000 people were at high risk inthe malaria transmission cycle. Withthat information, the Namibian healthdepartment was better equipped tointervene, by suchas indoor sprayingofinsecticidetodisrupt transmission.

“We’ve made a good start,” saysProf Tatem, “[but] we still have someway togobeforewecanconsignmalariatohistory.”

Mobile phone data help containthe human spread of infectionsSurveillance

Understanding how peoplecarry malaria parasites isessential to eliminating thedisease, reports Fergus Ryan

On the record: phonecalls aided creation of detailed map of transmission

‘We’vemade a good start[but] we still have someway to go beforewe canconsignmalaria to history’

C hina’s first Nobel Prize forphysiology ormedicine was419 years in themaking. TuYouyou, an 85 year-oldchemist, won last year’s

prize for herwork in the 1970sdevelop-ingartemisininasamalaria treatment.

She had been alerted to the potentialof artemisinin — an extract from thesweetwormwoodplant—after scouringChinese literature in search of tradi-tionalherbalremedies for thedisease.

Records of sweet wormwood, orArtemisia annua, being used againstmalaria date back to at least 1596,whenLi Shizhen, a Chinese medical scholar,suggested that itbegiventopatientsasatea.

It is still one of the main weapons intheworld’s armouryagainst thedisease.Treatment courses of artemisinin-based combination therapies increasedfrom 11m in 2005 to 392m in 2013 asglobal health authorities put thedrugatthe centreof their fight against themos-quito-bornescourge.

Concern is growing, however, thatfour centuries after artemisinin’s first

use, the parasites responsible formalariamaybestarting toget thebetterof its ancient powers. Artemisinin-re-sistant strains were first detected eightyears ago in western Cambodia. Caseshave since been detected in Myanmar,Thailand,VietnamandLaos.

For global health leaders, the patternis alarmingly similar to the way resist-ance to chloroquine, another malariatreatment,emerged inSoutheastAsia inthe 1950s and spread toAfrica—wherethe largemajorityofcasesoccur.

“Weseea littlebit ofhistoryrepeatingitself,” says Thierry Diagana, head ofthe Novartis Institute for TropicalDiseases. “Artemisinin resistance hasspread as far as the western border ofThailand and Cambodia. If it crossesinto India it will become amuch biggerchallenge.”

Novartis, the Swiss pharmaceuticalsgroup, commercialised artemisinincombination therapy in the 1990s. Thegroup is among the leaders in the huntfor new drugs to replace artemisinin asitsefficacyfades.

In 2014, the Novartis unit led by

DrDiaganademonstrated the first clini-cal proof-of-concept — a clinical trialshowing that a drug works — for a newmalaria treatment. The compound,codenamedKAE609,worksby interfer-ing with the sodium concentration inboth of the two parasites that cause themajority of cases. Plasmodium vivax iscommon in Asia and South America,while the more virulent Plasmodium

falciparum is most prevalent in Africa.Importantly, KAE 609 also worked inpeople with artemisinin-resistantstrains inSoutheastAsia.

Proof-of-concept data are expectedsoon on a second Novartis compound,known as KAF 156. It has shown prom-iseagainstdrug-resistant strainsofbothparasites as well as a further uniqueadvantage. Unlike artemisinin-based

Hunt is on forways to fightraised insectresistance

PharmaceuticalsDisease-carryingmosquitoes areovercoming ancient remedy, reportsAndrewWard

Prize find: Nobel laureate Tu Youyou scoured Chinese literature in search of traditional herbal medicines— Jin Liwang/Xinhua/AP

‘Artemisinin resistance hasspread [and] if it crossesinto India it will become amuch bigger challenge’

therapies, KAF 156 acts against the par-asites while still in the asymptomatic“liver stage” of the disease, before it hasspreadintothebloodstream.

This would enable it not only totreat sufferers atmalaria’s earliest stage—thediseasecanremaindormant intheliver for months after infection — butalso prevent them passing on theparasite tomosquitoes for furthertrans-mission.

The positive early datamust be repli-cated in larger studies if KAE 609 andKAF 156 are to satisfy regulators. DrDiagana says Novartis aims to have atleastoneof themonthemarketby2021.

The Novartis compounds are amongthe most promising of over 50 antima-larial products being developed in part-nership with theMedicines forMalariaVenture (MMV). Donors including theBill & Melinda Gates Foundation, theUK Department for InternationalDevelopment and the Wellcome Trusthave pledged $865m to the non-profitorganisationsince itwassetupin1999.

However, that is small comparedwiththe billions of dollars invested by thepharmaceuticals industry inmore com-mercially attractive disease areas suchas cancer, and progress is slow. It typi-cally takes about 10 years to get a newdrug from early stage development tomarket and less than 10per cent of can-didatesmakeitall theway.

TheMMV is not relying solely on bigpharmaceuticals groups. It has alsoawarded research grants for academicsto pursue assets from its so-calledMalaria Box of compounds that haveshown potential against the disease buthave lackedfundingfordevelopment.

Back in China, last year’s Nobel PrizeforMs Tu— she is neither a doctor norprofessor — has stirred pride but alsosurprise that shereceived littlepreviousrecognition in her own country. Theofficial Xinhua news agency said thatthe four-decade gap between her dis-covery and the award showed that “sci-ence isneverabout instantsuccess.”

The spread of artemisinin-resistantmalaria is adding urgency to the searchfor a fresh generation of drugs. In herNobel lecture in Stockholm in Decem-ber, Ms Tu issued a “severe warning”over the looming threat to the drug shehelpeddiscover.

Dr Diagana says that Novartis and itspartners aremoving as fast as possible.“It’sagoodtimeformalariadrugdiscov-ery,” he says. “But we need to makeprogress quickly so we can avoidanother global failure like we had withchloroquine.”

Monday 25 April 2016 ★ † FINANCIAL TIMES 5

mentgoals and the sustainabledevelop-ment goals,” he says. “They talk about[lack of] development being a big partofwhyglobalhealthepidemicssurvive.”

While most manufacturers do nothave factories in Africa, they do haveresearch facilities on the continent.Swiss-based Vestergaard, one of theworld’s biggest producers, says it is noteconomically viable to manufacturenets inAfricabuthasa laboratoryat theUniversityofGhana.

Helen Pates Jamet, head of entomol-ogy at the company, says it is “crucial tomaintain a strong presence on theground, bothbybeing able to access therightmosquitoes and building capacityinAfricatoaddresscapacitygaps”.

She says products developed at thelaboratory are tested and used by staffandtheirextendedfamilies.

The good news for manufacturerssuch as A to Z is that, although morecountries are moving towards elimina-tionanderadicationofmalaria,demandfornets isnot likelytoabatesoon.

“In order to cement the progress thathas been made nets are going to con-tinue to be necessary for many years,”Ms Pates Jamet says. “And even if therewasn’tmalaria, people still like to sleepunderanet tokeepmosquitoesaway.”

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Logic would suggest that A to Z TextileMills is a company in the right place attheright time.This family-ownedenter-priseon thewesternoutskirts ofArushain northern Tanzania is one of the larg-est makers of long-lasting insecticidalbed nets inAfrica, where 90 per cent ofsuchnetsare found.

Yet, despite being nearer to themainmarket thanmostof its competitorsanda buoyant demand, Kalpesh Shah, oneof thedirectors, says thecompany in thepastyearhadto layoffalmost600of the4,500 staff who make the nets. This isthanks to fierce competition with com-panies manufacturing elsewhere in theworld,particularlyeastAsia.

Themajority of theworld’smosquitonetbusiness is fundedbydonors suchaswestern aid agencies. But most offertendersbasedonthepriceat thepointofdispatch from the factory without tak-ing into account delivery costs, whichare borne by manufacturers. Mr Shah

says A to Z would “have some sort ofparity” if donors considered overallcosts. “Wehave to import all of our rawmaterials and so we’re always going tobeexpensive[at thepointofdispatch].”

TheGlobal Fund to fightAids, Tuber-culosis andMalaria does have a tenderprocess that “uses delivery to marketprices”, it says. “This is more effectiveand cost-efficient for the Global Fundandthepeoplewhowill receive thenets.Procuring nets close to where they willbe usedmeans we savemoney on ship-pingcostsanddelivery ismuchfaster."

Since the Global Fund introducedmarket delivery tenders in 2012, A to Zhas won “the largest portion of the ten-ders for the Global Fund for bed netsworldwide”, it says.But,despite this, thecompanysays it is still losingout.

Mr Shah says A to Z, which claims tohave started with a single sewingmachine five decades ago,made almost25mnets in the past year, about a sixthof the demand in sub-Saharan Africa.Most were delivered to east and south-ernAfrica, placeswhere, because of thefactory’s location, it is competitiveonanoverall costbasis.Thecostofdoingbusi-ness in Africa, however, means manu-facturers suchasA toZcannot competeentirely equally. “Distribution costs to

west Africa are higher from TanzaniathanVietnam,”hesaysof thesouth-eastAsian nation, which is also one of theworld’s leading producers. “This dem-onstrates the challenges of doing busi-ness in Africa and whymoremanufac-turersarenotbasedhere.”

Asteadilymorecrowdedmarketplaceis making life tougher. Since 2010 thenumber of manufacturers of WorldHealth Organisation-approved nets hasrisen significantly, to the extent thatannual global output capacity is morethan300m.Aidagencytenders—which

comprise the majority of demand —totalabout60percentof that.

Indeed,A toZ,whichalsomakesagri-cultural bags, garments and plasticproducts, only started manufacturingbed nets thanks to a corporate socialresponsibility partnership with Sumi-tomoChemical. It beganwith a transferof technologypilot project in 2003. Fiveyears later this progressed into amanu-facturing joint venture, even thoughboth companies conduct marketingoperations individually and sometimescompete for tenders.

Adam Flynn, a Sumitomo strategiccommunications and marketing man-ager, admits: “African manufacturingwouldn’tbeanaccountant’s firstchoice.

“But, with our corporate and socialresponsibilityethos,we’re takinga long-termview,”hesays. “Wethinkwehaveamoral duty toAfrica and it has the skillsandarichtextileheritage.”

Inaddition to thenetsmadebyAtoZ,MrFlynnhails the social, economic andindirect health benefits that accruefrom manufacturing in Africa. Forexample, he cites the jobs that havebeen created at A to Z —most filled bywomen — as another way of helping tofightdiseasessuchasmalaria.

“Look at the millennium develop-

Net makers afforded scant protective coverAfricaGlobalmarketcanmake life tough forlocalmanufacturers,reports John Aglionby

India’svast tribalbelt,whichrangesacross itscentralheartlandandupitseasternflank, ishometo indigenousandanimistcommunities,whosedisparatemothertonguestraditionallyhadnowrittenform.Isolatedandundeveloped, theseregionshavesomeof India’shighest incidenceofmalaria,asmosquitoes thrive in itsdenseforests.Thetribalbeltalsohassomeof India’shighestratesofwomendyingduringorafterpregnancyandchildbirth.

India’spublichealthestablishmenthasnot identifiedmalariaasacontributoryfactor inthecountry’sestimated44,000maternaldeathseachyear.Nordoes Indiahavespecificpolicies forroutinetestingandtreatmentofmalaria inpregnantwomen,unless theyreport todoctorsexhibitingclassicmalariasymptoms.

Publichealthprofessionalsworkinginthetribal regionsareconvinced,however, that thedisease isanunderlyingfactor inasignificantnumberof thematernaldeathstheysee.TheybelieveIndianeedsnewapproachesto identifyingandtreatingpregnantwomeninfectedwiththeparasites inordertoprotect themandtheirunbornchildren.

“Weusually findthereare20to30percentmorematernaldeaths indistrictsthathavemalariacomparedwiththosethatdon’t,”saysPrabirChatterjee,adoctorat thestatehealthresourcecentre inChattisgarh,a tribalbelt state.“Myinterpretation is that the20to30percentmaybeduetomalaria.”

InmanyAfricancountrieswithahighincidenceofmalaria,pregnantwomenareroutinelyscreenedformalariaorgivenpreventivetreatment. InIndia,malariahasneverbeentreatedasabigproblemforpregnantwomen,as thenational incidence isrelatively low.

Doctorsworking inthetribalareassayIndianeedsdifferentprotocols formalariahotspots.Specifically, theyadvocatethatpregnantwomenbetestedroutinely formalariaduringtheirprenatalcheck-upsusing low-costrapid

diagnostickits.Womenfoundtobeinfectedcouldreceivetreatmenttoensuretheydonotdevelopafull-blowncaseof thedisease.Manyprivatehospitals followsuchpractices.

“Ismalaria inpregnancyanissue?Yes,”says JohnOommen,adoctoratChristianHospital intheremoteBissamcuttakdistrictofOrissa,anotherstate inthetribalbelt. “Howbig?Nobodyknows.Aresomethingsbeingdone?Yes.Canwedomore?Yes.”

Researchers fromtheLondonSchoolofHygieneandTropicalMedicineareconductinga long-termstudyin

Jharkhandstate,also inthetribalbelt,toassesswhetherroutinemalariascreeningwould improvematernalhealth.Theresultsareexpectedtotiltthedebateonwhetherthecostofsuchaninterventionwouldbeworth it forIndia’scash-strappedpublichealthsystem.“Weareatacrossroads,”saysSuranjeenPallipamula,amaternalmortalityexpert in Jharkhand.“Wecan’t reallysay it shouldbedone.Wearestillwaiting forevidencetosee if it’seffectiveorefficient.”

Chattisgarhofficialsdecidedlastyeartorequiresuchtestingaspartofantenatalcare inhigh-malariadistricts.Theschemehasyet tobe implementedfully. In Jharkhand,someurgesuchscreeningonapilotbasis inareaswiththehighestburdenofmalaria.“Webelievethemalariaprogrammeisdefinitely improvingeveryday,”saysDrPallipamula.“Butunlessyoufocusonpregnantwomen,youarenotgoingtoimpactmalaria inpregnancy.”

India’smalariaburdenisdebatedhotlybetweenthegovernmentandindependentresearchers.NewDelhiestimates ithassome1mcasesandafewhundredfatalitiesayear.Researcherswhohavestudiedmortalitypatternssay125,000to277,000malaria fatalitiesayear isamore“plausiblerange”.

India’spolicy isonlytocountamalariacaseordeath if thedisease isconfirmedbyblood-testatagovernmenthospital.Criticsbelievethisseverelyunderestimates thetrueburden,asmanyailing Indiansseekprivate treatment,orneverseeadoctor.

What isclear is thatmalaria isdisproportionatelyconcentrated inthetribalbeltanditspoorly-educatedindigenouscommunitieswhichhavelimitedpublichealthcareprovision.

Ananalysis intheIndianJournalofMedicalResearchlastyearobservedthatdistrictswithatribalpopulationof30percentormoreaccount for just8percentof India’s totalpopulation.Yetthesedistrictsaccount for46percentofIndia’s totalmalariacasesandmalariadeaths.

Forpregnantwomenandtheirunbornbabies,malariacanhavesevereconsequencesrangingfromlowbirthweight tomiscarriage. Itcanleavewomenseverelyanaemic, raisingriskofcomplicationsduring labouranddelivery,particularly theriskofsevere,possibly lethal,post-partumbleeding.

Doctors focus onrole of disease inmaternal deathsIndia

Experts in deprived tribalareas say pregnant womenneed better treatment andtesting, writes Amy Kazmin

Doubts: critics contest official data

‘Is malaria in pregnancy anissue? Yes. Howbig?Nobody knows’

Up in the air: Africa would not be ‘an accountant’s first choice’ —Charles Ommanney/Getty

6 ★ FINANCIAL TIMES Monday 25 April 2016

H ilary Ranson is concernedabout data that defy thelongstanding trend inAfrica that theuseof insec-ticide-treated bed nets to

kill mosquitoes substantially reducesmalariadeaths.

In Burkina Faso, Uganda and someregions in a growing number of othercountries, mosquito resistance to pyre-throids, the only insecticide approvedforbednetssincethe1980s, is rising.

Yet, despite efforts to launch newproducts that will keep killingmosqui-toes, their introduction has been tardy.“I have been shocked,” says Prof Ran-son, head of the department of vectorbiologyat theLiverpoolSchoolofTropi-cal Medicine. “There is pretty effectivebed net coverage but malaria cases aregoingup. I really feel this is the tipof theiceberg forAfrica.”

Work is underwayby companies andacademics, including those at Prof Ran-son’s university, to replace pyrethroidswith new chemical compounds, but shepredicts none will be available until atleast2020.

Several companies have developedalternatives that couldbea stopgap, butthey have yet to be deployed. Studiesshowthatadding thecompoundpipero-nylbutoxide (PBO)neutralisesmosqui-toes’ ability to resist pyrethroids. Theseinclude Sumitomo’s Olyset Plus andVestergaard’sPermaNet3.0.

Mikkel Vestergaard, chief executive

ofVestergaard, is frustratedby the slowprogress of his new nets, which includeboth apyrethroid andPBO.Approval ofthembyavariedandevolvingconstella-tion of expert groups convened by theWorldHealth Organisation (WHO) hasbeen pending since 2007. Without agreen light, donors and malaria-endemic countries are reluctant to buyanddistributethenets.

“WHOhas lost sight of its own guide-lines and processes,” Mr Vestergaardsays. “We’re seeing resistance in 78countries and we ought to have a newmodel. If you see clear evidence for anewtool, it shouldbeused.But if it takes10 years to fail to approve a net— threeyears more than to approve a cancerdrug—clearlysomething iswrong.”

An editorial in The Lancet medicaljournal this yearwarned: “With nonewinsecticide class to replace the pyre-throidsexpectedforadecade, thethreatof resistance derailing malaria controlhasbecomean issueofurgency that canno longer be ignored without risking aglobalpublichealthcatastrophe.”

Pedro Alonso, director of the globalmalaria programme at the WHO, saysthe evidence for PBO nets is unclear.They have been shown in some tests tobemore effective in killing pyrethroid-resistant mosquitoes but questionsremain about their efficacy in reducingthe incidenceofmalaria.

“The subject is complex and some ofour colleagues from industry may not

have been as reasonable as one wouldexpect,”DrAlonsosays.

“There is insufficient information onthepotential publichealth impact theseproductswouldhave.TheWHOfranklyhas followed its processes and has beenveryreasonable.”

He adds: “The innovators wanted anoutright recommendationofworldwideapplication of these tools. I’m sorry tosay the evidence does not sustain that.Wehave toberesponsible.This ispublichealthandwehave todowhat isbest forthepublic.”

EgonWeinmueller, businessmanage-ment head in the global publichealth division of German chemicals

multinationalBASF,which isalsodevel-opingnew insecticides, is not convincedby this argument. “Academia wants tocontinue their testing forever. Theirbusiness is testing and having enoughmoney to keep on testing. We havealreadybeentesting for10years.”

Hewants amorepragmatic approachthat ensures any new insecticide is safebut permits small-scale comparativetrials in different African districts todemonstrate efficacy. “That way wecould see what actually happens,” hesays. “We’re not putting anyone in dan-ger. We would have small-scale feed-back, which would be very practical,providedataandspeeduptheprocess.”

Industry wantsWHO toacceleratetesting regimePublic healthNewproducts delayed as argumentsabout efficacy continue, reportsAndrew Jack

Prof Ranson agrees. “There is enoughevidence out there. Now is the time toget it out. I share industry’s frustration.The goalposts keep changing. The bigproblem for the WHO is they have gotthemselves into a corner. They haveargued strongly for universal coverageof nets but the newer ones are more

Malaria deaths have declined worldwide but a big fightis on in Southeast Asia to stop the disease making acomeback. The UN-backed Global Fund is sinking$100m into an multi-agency regional programme toquell the rising resistance in mosquitoes to artemisinin,the main drug used to fight the disease.The eradication campaign is in what Professor

François Nosten, a malaria researcher and regionalexpert, calls a “tight race against time” to haltresistance before it spreads west to India and onwardto Africa. “It is hard work but seems to be working,”

Prof Nosten says of the effort, which is concentratedon countries clustered around the Mekong river.Artemisinin resistance has been recorded in the past

eight years in the “Mekong Five” of Vietnam, Thailand,Myanmar, Cambodia and Laos, even as the region hasreported a sharp fall in malaria deaths. Mark Dybul, theGlobal Fund’s executive director, says the increase ofresistance in mosquitoes “threatens to undo hard-fought gains” in the region and worldwide.The Global Fund’s programme focuses on

eradication among the people seen as most likely to

spread the disease, among them itinerant farmers andother seasonal workers. Those involved in the effortrange from scientific researchers to nurses andvolunteers equipped with test kits and drugs deployedin resistant mosquito hotspots such as the Thai-Myanmar border.The Fund says a pilot mass drug administration

programme appears to have been a success. Now thescaled-up campaign needs to achieve similar results —and quickly.Michael Peel

Eradication campaign Teams ‘race against time’ in the ‘Mekong Five’ countries

Hard fought gains: a Thai medic carries out a blood test on a child at a clinic in Kanchanaburi near the border with Myanmar —Pornchai Kittiwongsakul/AFP/Getty Images

‘Academiawants tocontinue their testingforever.We have alreadybeen testing for 10 years’

expensive. They don’t want to say netsare failing — they are worried aboutdonorswalkingaway.”

MrVestergaardsays thepriceofexist-ing bed nets has fallen sharply, in partbecause of thedrop in the oil price fromwhich the netmaterial is derived, from$5 tonearer $2.At scale, he sayshisnewPBOnetswouldcostabout$3.

He warns that without more stream-lining of WHO processes, the ability tokeep upwithmalaria’s rising resistancerisks being jeopardised. “Whether ornot companies are speaking openlyabout this, it’s clear that all of them arequestioning the value of investing inmalariaprevention.”

FTHealth CombatingMalaria