ModernToolsetsforDefeatingBothEpidemicandEndemic

InfectiousDiseasesPROF ES S OR AN TON I N O Z I C H I C H I , P R E S I DEN T

P H I L I P . E C K H O F F@ C O M C A S T . N E T

A P R ES ENTAT IO N TO THE 4 9 TH S ES S IO N O F THE INTERNAT IO NAL S EM INAR S O N P LANETAR Y EMERGENC I ES , MAJO RANA C ENTR E , ER I C E , S I C I LY, I TALY

P R O F E S S O R AN TON I N O Z I C H I C H I , P R E S I DEN T

A UGU S T 2 0 - 2 3 , 2 0 1 6

P H I L I P A E C K H O F F AN D L OW EL L L W OOD

P H I L I P . E C K H O F F@ C O M C A S T . N E TOpinions expressedhereinarethoseoftheauthorsonly

ThePathogensResponsibleForInfectiousDiseasesareaGlobalThreat-- TheirActionsConstituteanOngoingPlanetaryEmergencyofFirstMagnitude§MostpathogensareAncient Enemiesofhumanity– often“atleastasoldasWeare”

§ Haveimposed titanic burdens ofmorbidity-&-morta lity§ Mostallofour~100,000,000,000ancestorsdiedofpathogenicdiseasesormalnutrition– not fromthenow-standarddegenerativediseasesoftheDevelopedWorld

§ Havebecome ever-more-threatening ashuman population densities havesoared,speeds-&-scales oftransportation haveclimbed,....§ The1918-20‘influenza’pandemickilled~108 people–wellover5%ofallhumansthenalive§ Beforeitsglobaleradicationin1977– culminatingaWHO-sponsoredcampaignledbyDAHenderson-- smallpoxhadkilled~100,000,000peopleinthe20th centuryalone

§Overallburden§ Over11Mdeaths everyyearfrominfectious diseases, nutritional disorders, andmaternal mortality§ Over7Mofthese annual avoidable deaths occur in children <5yearsold

§Currently-endemic diseases§ Malaria,TBand HIV§ Pneumonia and other respiratoryinfections; enteric infections

§Pathogeneradicationasapathwaytodefinitivelyaddressingendemics– andobviatingepidemics/pandemics§ Resistance isalways anissue fordrugsand vectorcontrol: ”Ourwits against theirgenes!” -- Lederberg§ Intense disease control – anovel ‘feature’ofmodern times -- isvulnerable to reversalsoffunding, political failures andcollapses of social order

§Zoonosesandother pathogenic sourcesofepidemics/pandemics ofemerginginfectiousdiseases,e.g.,§ Ebola, Zika,...§ Antigenically-novel and/or hypervirulent aeroviral strains: influenza, SARS/MERS,...

§ToolsetsforEradicationend-gameareusefulforpandemicsuppression asEradicationandpandemiccontrol aredualproblems

§MostpathogensareAncient Enemiesofhumanity– often“atleastasoldasWeare”§ Haveimposed titanic burdens ofmorbidity-&-morta lity

§ Mostallofour~100,000,000,000ancestorsdiedofpathogenicdiseasesormalnutrition– not fromthenow-standarddegenerativediseasesoftheDevelopedWorld§ Havebecome ever-more-threatening ashuman population densities havesoared,speeds-&-scales oftransportation haveclimbed,....

§ The1918-20‘influenza’pandemickilled~108 people–wellover5%ofallhumansthenalive§ Beforeitsglobaleradicationin1977– culminatingaWHO-sponsoredcampaignledbyDAHenderson-- smallpoxhadkilled~100,000,000peopleinthe20th centuryalone

§Overallburden§ Over11Mdeaths everyyearfrominfectious diseases, nutritional disorders, andmaternal mortality§ Over7Mofthese annual avoidable deaths occur in children <5yearsold

§Currently-endemic diseases§ Malaria,TBand HIV§ Pneumonia and other respiratoryinfections; enteric infections

§Pathogeneradicationasapathwaytodefinitivelyaddressingendemics– andobviatingepidemics/pandemics§ Resistance isalways anissue fordrugsand vectorcontrol: ”Ourwits against theirgenes!” -- Lederberg§ Intense disease control – anovel ‘feature’ofmodern times -- isvulnerable to reversalsoffunding, political failures andcollapses of social order

§Zoonosesandother pathogenic sourcesofepidemics/pandemics ofemerginginfectiousdiseases,e.g.,§ Ebola, Zika,...§ Antigenically-novel and/or hypervirulent aeroviral strains: influenza, SARS/MERS,...

§ToolsetsforEradicationend-gameareusefulforpandemicsuppression asEradicationandpandemiccontrol aredualproblems

GlobalDiseaseEradicationEfforts§GlobalEradicationofsmallpox(Variola major)wasadefiningtriumphofOurspecies§ Thepurposeful exterminationofaruinoushumanpathogen

§Keylessonsoftheanti-smallpoxcampaign§ Timely(!)casedetection§ Vaccinationcoverageand(eventual)logisticssufficiency§ Adaptivetactics§ Roleofmid-Campaigntechnical-&-programmaticinnovations

§Rinderpestwasthe2nd GlobalEradicationtriumph§ Recapitulatedlessonsofthesmallpoxeradicationcampaign

§Earlyattemptsagainstotherdiseasesfailed§ Yellowfever§ Malaria

§OtherEradicationCampaignsarenow inlatestages,nearingsuccess§ Polio§ GuineaWorm

§NewefforttoGloballyEradicatemalariaannounced in2007

MalariaEpidemiologyandBurdenhasChangedTremendouslySince2000§Decreaseindeathsfrom839,000in2000to438,000in2015§Source:WMR 2015

§ScaleupofLLINs,IRS,andART§Increaseinfinancing§Changeinproportionofpeoplelivingindifferentlevelsofmalarialendemicity inAfrica

Bhattetal,Nature 2015

TheAfricanMalariaLandscapeHasShifted

Bhattetal,Nature 2015

VectorControlHasPlayedAMajorRole§Just2%ofsub-SaharanAfricanpopulationsleptunderinsecticide-treatednetin2000§≥halfofthispopulationwas‘covered’in2015

§Source:WMR 2015

§ITNsandIRSwereresponsibleformuchofthedeclineinendemicity,accordingtoarecentanalysis

Bhattetal,Nature 2015

EnabledByEver-HigherLevelsofFunding

WorldMalaria Report2015

…ButProgressIsFragile§Riseofpyrethroid resistance(andinsecticide resistancemoregenerally)§Needtoreplacebednetsfrequently,maintaininghighpopulationcoverage§Shiftsinvectorspeciescompositionandfeedingbehaviors§ ObservedchangeinAn.farauti bitingbehaviorinSolomonIslandsfrom1972to2007§ 1972datafromTaylor1975§ 2007datacourtesyTanyaRussell,MTC

§ Couldmakeindoortargeting(netsandspraying)lesseffective

§Fundingcontinuityandsocialorderissues§ RecentexampleofVenezuela

MalariaEradicationIsABig,Long-TermGoal§GlobalMalariaEradicationwasattemptedbefore(~’58- ~’70)§ Itisnoteasytocomplete

§ArenewedeffortwaslaunchedattheMalariaForumin2007§Ideal:theburdenofmalariaisstablyatzeroforever,robusttoanykindofreversal§Pesticideanddrugresistance,economiccrisis,fatigue,etc…

§Givennumbers,time,andpressure,Evolution– “..theirgenes”-- willwinotherwise

§MalariaEradicationisdifficult§Extensiveheterogeneities§Baselinetransmissionintensity§Multiplelocalvectorspecies§Populationdensities§Typesofhousing§Baselinehealthcare§Resistancestatuses§ Immunestatus

§Manylogistic-challenging areas

BasicAnalyticalFrameworkforEradication§Partitionintoregionaleliminationeffortsandprioritize§Reducetransmission§ Vectorcontrol§ Prophylaxis§ Vaccines?

§Clearinfections§ Diagnostics§ Drugs§ Campaigns

§Preventreintroduction§ Casemanagement§ Surveillance§ Aidedby“stickiness”?(DLSmith)

§Availabletools(present+10yrs)§ Drugs§ Single-encounter,radical-cure§ Prophylaxis

§ Diagnostics§ Vaccines?§ Vectorcontrol§ Nets§ IRS§ Larvalcontrol,sourcemanagement§ Newapproaches(e.g.,geneticgambits)

§ Fieldlogisticssupport§ Polioexample

§Modelingandquantitativeanalysis§ Datasystemsandmonitoring

DataAnalysisandMathematicalModelsAidUnderstandingofLocalEpidemiology

2013Round-1 Household PrevalenceGwembe, Southern, Zambia

MalariaSeasonalityinZambia

GWEMBE DISTRICT

RDT-confirmed clinical cases

Lakefron

t

HotDrySeason

UsingMalariaGenomicstoDetectChangesinTransmissioninSenegal

Daniels et al. PNAS 2015

WhatDoesitTaketoCompletetheGlobalEradicationofWildPoliovirus?

§Progressoverpasttwoyears— comparedtoa12-monthwindowfromJune2014

§Needtoclearlastpockets-of-contagion inNigeria,Pakistan,andAfghanistan

PolioRiskMapsforTargetingVaccination

Upfill-Brownetal.,BMCMedicine2014

MoreWasNeededforPolioinNigeria§BetterPopulation Maps§ Remotesensingandfeatureextractiontomapwherepeoplelive

§ Developmentofnewmicroplans

§VaccinatorTracking§ Super-resolutionphotogrammetry- andGPS-enabled§ Real-timecoverageestimation§ Targetingofun-reachedneighborhoods,evenhouses

§Investment inColdChaintechnologies§ Storage§ Outreach§ Situationalawareness

§Accessandsecurityforvaccinators

VaccinatorTrackingwithImprovedPopulationMapsAllowsReal-timeCoverageEstimates

PolioInvestmentsHelpedInterruptEbolainNigeria!

ButWeareNotReadyforNextEpidemic

InnovationisNeededforEndemicDiseaseEradicationandSuppressionofPandemics§AreasforInnovation§ Innovation inVaccine ColdChainsupport§ Innovation inVaccines§ Innovation inDrugsandDrugDelivery§ Innovation inNovelVector Control§ Innovation inImmunological Tools

§DeliveryandLogisticsarekey!§ Innovation thatfacilitates thisareverydesirable§ Informationsystems

§Internationalenablingenvironment§ Rapid,extensively-rehearsed set-of-responses§ Pre-authorization andfunding-in-the-bank

InnovationinVaccineColdChainSupport§Newcost-efficientvaccinerefrigeratorsforchallenging(e.g., low-qualitypower)conditions§ E.g.,MetaFridge

§New-technologyvaccineoutreachsupport§ Evaporatescoldwater/ice atlowpressure toprovideshelf-stable, weight-efficient thermal battery

§ Aimedtosupplantpresent ice-filled carriers

UnprecedentedLogisticsSupportEnabledVia‘BoilingIce’

Device initially turnedon(Charged inSeattle)

Ambient temperature measured onoutsideofcarrier. Variations causedbymovement of

device, exposure tosunetc.

Lidopeningsofdevice, vaccinator retrievingvaccines fromunit.

Day1 Day2 Day3 Day4 Day5

InnovationinDrugs§Gastricretentiondevicesthatreleasedrugsoverdaystoweeksaftersingle-occasionoralingestion

§Extendpharmacokineticsfar beyondtraditionaltimeconstants

§Improveseaseofdelivery,achievablecoverageandadherence, anddurationofbiomedicalaction

§BobLangerandGioTraversoatMIThavedemonstratedworkingprototypesforivermectin

InnovationinVaccines

comprehensiveandenduringimmunizationatbirth§ Reliable protection againstall vaccination-preventable pathogenic diseases

§Timed-release packagingforimmunogens

§Receive entirecourseofatimedpulsatile-release vaccinationseriesinasingleinjection§ Technology demonstrated forIPVbyBobLangerandAnaJaklenec atMIT

§ Alsosupports single injection administration ofpreviously-incompatible vaccines

§Nowfirmlyonthepathtocomprehensiveandenduringimmunizationatbirth§ Reliable protection againstall vaccination-preventable pathogenic diseases

InnovationinModifiedMosquitoes—GeneDriveforIndividualAnophelesSpecies

8Years AfterReleasePopulation EliminatedConstruct AtFixationMixofWildtype andGene DriveLossofConstruct

Burt,PhilTransRoySoc B2014 Eckhoffetal,under review

Available drive techniques Effectofgermline homing

InnovationinImmunologicalTools

ThePathwayForwardThePathwayForwardMajorPlanetaryEmergency§Infectious DiseasesareaMajorPlanetaryEmergency

§ Theongoing annualdeathtollisnotablysevere§ We’verecentlyseen ≤10%ofthehumanracepathogen-slaughtered in2years

§ Pandemicrisksfromemergingpathogensthreateneveryone,everywhere,continually§ EbolainHouston&Lagos; ZikainMiami&New York;SARSinBeijing&Toronto

§ Especially‘ifanythingreally goeswrong’inamajorpopulation-pool

§Innovation — guided byscientificstudy, computation, andstrategy— isurgentlyneeded to informenhanceactions§ Extantmeansaredubiouslysufficient– andarebeingcontinually‘outgrown,’aswellasover-matched

§International partnerships— withestablished, pre-staffed/equipped/exercised, pre-funded responsecapacities— arecorecomponents ofwhatarerequired

§ThesamecapabilitiescanbeexercisedtocompletediseaseregionaleliminationandEradicationefforts— whilekeeping thesefullypreparedtoaddresshyper-epidemics