BuildingonSuccess– MalariaControlandEliminationSwissTPHWinterSymposium2016

Definingsuccessfornextgenerationmalariavaccines

MelissaPenny,Basel8th December2016

Epidemiology and Public HealthHealth Systems Research and Dynamical Modelling

Elimination?

Bhattetal(2015)TheeffectofmalariacontrolonPlasmodiumFalciparuminAfricabetween2000and2015,Nature, 526:207

2000 2015

Vectorcontrol

2000-2015reductioninmalariaincidenceandmortality

• 2015-2030targets:90%casereduction,eliminatein35countries• Successwillnotbesimplecontinuationsofcurrenttoolsand

interventionmixes. Newtoolswillberequired• Drug andinsecticideresistance

Vectorcontrol

MalariaincidenceavertedReductioninmalariaprevalence

treatment

Frameworkfortoolsforelimination

Reducetransmission• Vectorcontrol• Prophylaxis• VaccinesClearinfections• Case-management• Diagnostics• Drugs• Campaignsandreactivecasedetection

andtreatmentPreventreintroduction• Surveillanceandresponse• Casemanagement

Availabletools(present+10years)Combinationswillberequired• Drugs

⎯ Singleencounterradicalcure⎯ Prophylaxis

• Diagnostics• Futurevaccines• Vectorcontrol

⎯ InsecticideTreatedNets⎯ IndoorResidualSpraying⎯ Larvalcontrols,sourcemanagement⎯ Novelpush-pull

• Logisticssupport• Modellingandquantitativeanalysis

Region/geographictailoredinterventionmixes– basedonepidemiologyandcapacity

Designingnewmalariavaccines

Discovery Preclinical Earlyclinical Clinical Implementation

ResearchanddiscoveryAntigendiscovery

PotencyToxicologyScheduleDeliverysystemAdjuvantMechanismofaction

RouteofimmunizationDose/intervalsTargetgroupsAdjuvantEfficacy:challengestudiesTrialDesign

PhaseII/IIIefficacyTrialdesignHealthImpactassessmentEconomics/cost-effectiveness

>10years < 10years

Designingnewmalariavaccines

Discovery Preclinical Earlyclinical Clinical Implementation

ResearchanddiscoveryAntigendiscovery

PotencyToxicologyScheduleDeliverysystemAdjuvantMechanismofaction

RouteofimmunizationDose/intervalsTargetgroupsAdjuvantEfficacy:challengestudiesTrialDesign

PhaseII/IIIefficacyTrialdesignHealthImpactassessmentEconomics/cost-effectiveness

< 10years

Modellingandsimulationtoinformdevelopment

Potentialimpact

• Guide thinkingonmalariadynamics• Exploreminimumpropertiesrequiredofnewtools(e.g.efficacy,duration)

• Testscenarios/strategies:estimateimpactofnewtoolsfordifferenttargetages,coverage,roll-out.Whatcoverageisrequiredtomeethealthgoals?

• Explorecombinationstofindmixesthatoptimise overvariouscriteria

• Effectivenessofinterventionsintherealworldandimpactbeyondtrials

• Economicanalysis

Modellingandsimulation:frameworksfordecisions

Model-basedframeworksDifferentmodeltypes• static• spatial• deterministic• stochastic• compartmental• Individual-based

models

• Naturalhistoryofmalaria

• Mechanismsofactionofnewinterventions

• Earlyestimatesofimpact/protectionandaction

• Efficacyfromlatertrials

Observable/Data /earlyknowledgeof

interventions

Simulationmodelofmalariaepidemiologyandcontrol

Uninfected Infected Infectious

Drug

Death

Sick

• Uncomplicated• Severe

Seektreatment• Treatment• Hospitalised

• Parasitedensities• Infectiousness• Numberofinfections• Immunity• Druglevel

• Healthsystem• Drugs&quality• Adherence• Compliance

• Infectiousness• Mosquitodensity• Feedingcycle• Parasitedevelopment

• Seasonality

Calibratedbyformalfittingtodatafromfieldstudies.

OpenMalaria:Individual-basedstochasticsimulatorofmalariaepidemiologyandcontrol

opensource:

https://github.com/SwissTPH/openmalaria/wiki

• Drugs• VectorControl• Vaccine• Masstreatment

Designingnewmalariavaccines

Discovery Preclinical Earlyclinical Clinical Implementation

PhaseII/IIIefficacyTrialdesignHealthImpactassessmentEconomics/cost-effectiveness

< 10years

Example:modellingtoestimateRTS,Simpact

Circumsporozoite proteinGeneticallyengineeredcentralCS-tandemrepeatfusedwithS-antigenofHBs

TheGSKmalariavaccineRTS,S/AS01

RTS,S/AS01PhaseIIIVaccineefficacy(VE)againstclinicaldisease(32monthspostdose3)

VEinchildren[95%CI]3doses

VEininfants[95%CI]3dose

VEinchildren[95%CI]4doses

VEininfants[95%CI]4doses

Clinicalmalaria 35·2%[30·5to39·5] 20·3%[13·6to26·5] 43·9%[39·7to47·8] 20·3%[13·6to26·5]

Severe malaria 4·5%[–20·6to24·5] 7·9%[–23·3to31·2] 34·9%[15·6to50·0] 11·9%[-18·3to34·5]

TheRTS,SClinicalTrialsPartnership(2015)Lancet

Infants6-12weeksofage:7100Children5-17monthsofage:890011centersin7Africancountries

Moderatelyefficaciousvaccine

• EMApositivescientificopinion• WHOrecommendation:pilotimplementationsbeforewidercountry

levelintroduction…toensurethat4dosesofmalariavaccinecanbegiven……in3-5distinctepidemiologicalsettings insub-SaharanAfrica,atsubnationallevel,coveringmoderate-to-hightransmissionsettings

RTS,S clinicaldevelopment

1984 1994 2004 2014 2024 2034

Identificationofcandidate

FirstCHMItrials

PhaseIIIResults

FirstEndemiccountrytrials

StartofPhaseII

Likelymodeofaction

Targetgroupdetermined

WHO:modelbasedpredictionsofimpactbeyondatrial

Vaccinatedandprotected

RationaleProtecttheagegroupswithhighestmalariaburdenFeasibilityindelivery:schedules• 6-12weeks• 5-17months

Rolloutof ACTandITNsGatesMalariaForum: “chartalong-termcoursetoeradicate…...”

FirstEfficacyEstimates

StartofPhaseIII

Estimatesofdurationofeffectonclinicaldisease

EMApositivescientificopinionWHOrecommendation

Age of vaccinee

Cas

es a

vert

ed b

y R

TS,S

• Noone‘perfect’model• Differencesreflectmodelingchoicesanduncertaintyincalibrationdata

• Ensembleapproachallowsexplorationofoutcomeranges

Ensembleapproachtomodelinghealthimpact

WHO requestedpredictionsfor:• Definedtargetagegrouporschedule• Realisticcoverage ofchildren• Harmonised inputsandoutputs• Expectedeffectiveness:%and numbereventsaverted• cost-effectiveness(& comparisonwithinterventions &

vaccines)• Rolein additiontohighcoverageofinsecticidetreated

netsandroutinetreatment

WHY?:• Understandimpactbeyondthetrial

(controlsettings).Trialnotpoweredtoevaluateimpactagainstseverediseaseandmortality,especiallyinlow-moderatetransmissionsettings.

Whatwasnotsimulated:• Indicateimpactoutsideoftestedage

Potentialof alternativevaccinedeliveryorintegrationintootherprograms

Dynamicalmodelingisinformedbytrialdatatoprojectfuturepublichealthimpact

• High treatmentrates• High insecticidetreated

net(ITN)use• Limitedtransmission

settings• <5year follow-up• Data:Vaccineefficacy

Clinical Trial Setting

DATA

Future Use Case

• Range oftreatmentrates• Range ofITNuse• Broadspectrumof

transmissionsettings• >5year impact• Mortalityimpact• Deliverystrategy:

Vaccinationat6-9months,27months

SIMULATIONS

Calibrated Malaria Models• Trial data• Historical

data

Assessed Vaccine

Properties

Predictedpublichealthimpact:generictransmissionsettings

Clinicalcasesavertedper100,000fullyvaccinatedchildrenPfPR2-10 10-65%,4doseschedule:

Avertbetween8%and29%ofclinicalcasesinchildrenlessthan5yearsold

Avertmedian116,482(31,448-160,236)clinicalcases forevery100,000fullyvaccinatedchildren

Model predictions: follow-up 15 years

Penny,Verity,Bever,Sauboin etal. (2016)“Publichealthimpactandcost-effectivenessoftheRTS,S/AS01malariavaccine:asystematiccomparisonofpredictionsfromfourmathematicalmodels”Lancet

Publichealthimpact– ageshiftofclinicaldisease

low endemicity

age (years)

clin

ical

cas

es a

verte

d (t

hous

ands

)

0 5 10 15

010

2030

40

(PfPR2−10=10%)

high endemicity

age (years)

clin

ical

cas

es a

verte

d (t

hous

ands

)

0 5 10 15

010

2030

40

(PfPR2−10=50%)

Clinicalcasesavertedper100,000fullyvaccinatedchildrenbyage

Vaccinatedchildrennotbecominginfected

Vaccineprotectionwornoff,leftwithlowerimmunitycomparedtonon-vaccinated

Age(years) Age(years)

Penny,Verity,Bever,Sauboin etal. (2016)“Publichealthimpactandcost-effectivenessoftheRTS,S/AS01malariavaccine:asystematiccomparisonofpredictionsfromfourmathematicalmodels”Lancet

• RTS,Sislikelytohavepositiveimpactwithpotentialforsubstantialpublichealthbenefits,butthatcarefulconsiderationofthecost-effectivenesscomparedtootherinterventionsshouldbemadeinthecontextoflocalprioritiesandhealthsystems.

Cost-effectivenessrangeandcomparisonwithothermalariapreventativeinterventions

1.Whiteetal.2011(MalariaJournal)ITN:Insecticide-Treated Nets;IRS:IndoorResidual Spraying;IPT:IntermittentPreventive Treatment

RangesshowvariationsacrosscountriesandmodelsforRTS,Sandacrossstudiesforotherinterventions

WHOandGAVIperspective:comparisontootherinterventions• Vaccinepricerangetestedfrom$2to$10

perdose• Cost-effectivenessestimatesforother

malariainterventionsfromliterature1

• Cost-effectivenessestimatesfromtheliteraturehavebeenmadeinadifferentcontextthancurrentmodelingwork

Penny,Verity,Bever,Sauboin etal. (2016)“Publichealthimpactandcost-effectivenessoftheRTS,S/AS01malariavaccine:asystematiccomparisonofpredictionsfromfourmathematicalmodels”Lancet

Country-levelorsub-nationalperspective:estimatesofRTS,Simpactandcost-effectiveness

Mixofprevalencelevels

Seasonality

Accesstocare&costofillness

DTPcoverage

country-levelestimates

Costofvaccination

Country-specificinputsDemographics

models

Cumulativenumberofclinicalcasesavertedper100,000vaccinated(atyear10followingvaccineintroduction)

Galactionova etal.(2016)“Countryspecificpredictionsofthecost-effectivenessofmalariavaccineRTS,S/AS01inendemicAfrica” Vaccine

1984 1994 2004 2014 2024 2034

Identificationofcandidate

FirstCHMItrials

PhaseIIIResults

FirstEndemiccountrytrials

StartofPhaseII

Rolloutof ACTandITNsGatesMalariaForum: “chartalong-termcoursetoeradicate…...”

Likelymodeofaction

Referenceperiodformodellingofnextgenerationmalariavaccines

FirstEfficacyEstimates

Targetgroupdetermined

Estimatesofdurationofeffectonclinicaldisease

StartofPhaseIII

Nextgenerationmalariavaccines

Target/schedules/eliminationgoals

NextgenerationmalariavaccinesCHMI/trials

WHO:modelbasedpredictionsofimpactbeyondatrial

SuccessforRTS,Sandfuturevaccines

Modellingtoguidethinkingforfuturemalariavaccines

Discovery Preclinical Earlyclinical Clinical Implementation

< 10years

Modellingandsimulationtoinformdevelopment

Vaccinesmusthaveimpactontransmission,ratherthanjustonmortalityandmorbidityreduction• Immunogenicityandimmunecorrelates(Whiteetal(2015)LancetInf.Dis.)• Prioritizationoftargetproductprofiles (combinations,doses,tradeoffbetweenefficacy,

durationofprotection,coverage)• immunizationschedulesanddeliveryroutes (andfeasibility)• targetdemographicgroups• Dosing(andfeasibility)• Settings(prevalence,seasonality,healthsystems)• TPPforMassvaccination:high-riskpopulations(pregnantwomen)• UseofControlledhumanmalariainfectionandmodelsforcandidateprioritization

Minimalandoptimalproperties,alternative deliveries

rain

Durationofprotection

rain rain

Malaria

Idealeliminationvaccine

Foreseeable:vaccinewithshorterdurationofprotectionvaccine

Booster Booster

rain

Malaria

rain

Malaria

Adapted from BMGF and PATH-MVI

Roleforelimination:exampletransmissioneffects0.

000.

020.

040.

060.

08

Low transmission Medium transmission High transmission

prop

ortio

n of

vec

tors

infe

cted

at e

ach

feed

EPI

EPI booster

EPI mass vaccination

0 5 10 15 20 0 5 10 15 20time (years)

0 5 10 15 20

Pre-erythrocytic vaccines• Observesomereductionoftransmissionwithhighinitial

efficacy(herdimmunitywhendeliveredviamassvaccination)• Interruptionoftransmissionforlowtransmissionsettings

Penny et al. (2008) Plos One

Modellingcanguide thinkingon:• Coverageofmassvaccination

toachievesuccess• Longevityofprotection

required? =minimalandTargetProductProfiles

• Determinantsofsuccess:minimumcoveragelevel?minimumnumberofrounds?

• Costsavings?

Predictionsoftransmissionblockingvaccineeffectsovertime

TransmissionblockingvaccinesPossibletoinduceherdimmunityandinterrupttransmissionwhendeliveredviamassvaccination

Massvaccination

prop

ortio

nofvectors

infected

ate

achfeed

Lowtransmission Mediantransmission

0 5 10 15 20 0 5 10 15 20

time(years)

0.00

0.02

0.04

0.06

0.08

EPIMassvaccination

time(years)

Immunizinginfants

Modellingcanguide thinkingon:• Howmanyrounds,coverageand

timingofmassvaccinationtoachievesuccess?

• Longevityofprotectionrequired?• Otherinterventioncombinationsto

accelerateinterruption oftransmission

Penny et al. (2008) Plos One

Episodes per person year

0

1

2

3

4

Years since start of intervention

-1 1 3 5 7 9 11 13 15 17 19 21

Clinical incidence envelopearm2=no int

Episodes per person year

0

1

2

3

4

Years since start of intervention

-1 1 3 5 7 9 11 13 15 17 19 21

Clinical incidence envelopearm2=IRS

Episodes per person year

0

1

2

3

4

Years since start of intervention

-1 1 3 5 7 9 11 13 15 17 19 21

Clinical incidence envelopearm2=rescue

Clin

ical

epi

sode

s pe

r per

son

per a

nnum

No intervention

IRS

IRS & SSM-TBV

Years since start of program

Combinationwithotherinterventions

No IRS or SSM-TBVIRS IRS and SSM-TBV

Exampleeffectonclinicalincidenceandprobabilitytointerrupttransmission

• Profileofnewinterventionsneededontopofexistinginterventionstoachieveelimination

• Whichsettings?

Smith et al. (2008) Trends in Parasitology

Challengesformodellingclose-to-elimination

Vivax andothermalariaspecies

Lowtransmissionandeliminationsettings• Parasitediversityandparasiterelatednessastransmissiondeclines• Incidencebyagewithchangingpopulationandindividualimmunity• Data:mostmodelsdesignedandparameterised forhyper- andmesoendemic settings

Effectsofpopulationsizeandconnectivityonthechancesofelimination• Connectionbetweenpopulations(movementsofpeople/mosquitoes)makeeliminationmoredifficult• Bothpopulationsizeandconnectivityarehardtoquantify

Fromdefiningsuccesstoachievingsuccess

Otherimportanttoolsforinnovatingnewinterventions:• Community• Ideas• Integrationofalldisciplinesinthe

developmentpathwaythroughtoimplementation

Availabletools(present+10years)Combinationswillberequired• Drugs

⎯ Singleencounterradicalcure⎯ Prophylaxis

• Diagnostics• Newvaccines• Vectorcontrol

⎯ InsecticideTreatedNets⎯ IndoorResidualSpraying⎯ Larvalcontrols,sourcemanagement⎯ Novelpush-pull

• Fieldlogisticssupport• Modellingandquantitativeanalysis

With many thanks to WHO Advisory Committeethe RTS,S Clinical Trials Partnership and Clinical trial units, and vaccinated children and their families.

Acknowledgements

ChristopheSauboinNicholasVandeVelde

RobertVerityMichaelWhiteJamieGriffinAzra Ghani

MelissaPennyKatyaGalactionovaPeterPemberton-RossNicolasMaireOlivierBrietTomSmithMarcelTannerMalariamodellingteamatSwissTPH

StefanFlascheMarkJit

CaitlinBeverEdwardWengerPhilipEckhoff

Farzana MuhibDebAtherlyCarlaBotting

FundingPATH-MalariaVaccineInitiativeBillandMelindaGatesfoundation