Managing population immunity to reduce or eliminate the risks of circulation following the importation of polioviruses

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ContentslistsavailableatScienceDirect

Vaccine

jou rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e

Managing

population

immunity

to

reduce

or

eliminate

the

risks

of

circulation

following

the

importation

of

polioviruses

Kimberly

M. Thompson

a,b,∗

_,

_Dominika

_A.

_Kalkowska

a,c

_,

_Radboud

_J.

_Duintjer

_Tebbens

a

a_Kid_Risk,_Inc.,_Orlando,_FL,_USA

b_University_of_Central_Florida,_College_of_Medicine,_Orlando,_FL,_USA

c_Delft_University_of_Technology,_Delft,_The_Netherlands

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received26November2014

Receivedinrevisedform31January2015

Accepted5February2015

Availableonline18February2015

Keywords: Polio Eradication Populationimmunity Vaccine

a

b

s

t

r

a

c

t

Poliovirusimportationsintopolio-freecountriesrepresentamajorconcernduringtheﬁnalphasesof globaleradicationofwildpolioviruses(WPVs).Weextenddynamictransmissionmodelstodemonstrate thedynamicsofpopulationimmunityoutthrough2020forthreecountriesthatonlyusedinactivated poliovirusvaccine(IPV)forroutineimmunization:theUS,Israel,andTheNetherlands.Foreachcountry, weexplorethevulnerabilitytore-establishedtransmissionfollowinganimportationforeachpoliovirus serotype,includingtheimpactofimmunizationchoicesfollowingtheserotype1WPVimportationthat occurredin2013inIsrael.Aspopulationimmunitydeclinesbelowthethresholdrequiredtoprevent transmission,countriesbecomeatriskforre-establishedtransmission.Althoughimportations repre-sentstochasticeventsthatcountriescannotfullycontrolbecausepeoplecrossbordersandpolioviruses mainlycauseasymptomaticinfections,countriescanensurethatanyimportationsdieout.Ourresults suggestthatthegeneralUSpopulationwillremainabovethethresholdfortransmissionthrough2020.In contrast,Israelbecamevulnerabletore-establishedtransmissionofimportationsoflivepoliovirusesby thelate2000s.InIsrael,therecentWPVimportationandoutbreakresponseuseofbivalentoralpoliovirus vaccine(bOPV)eliminatedthevulnerabilitytoanimportationofpoliovirusserotypes1and3forseveral years,butnotserotype2.TheNetherlandsexperiencedaserotype1WPVoutbreakin1992–1993and becamevulnerabletore-establishedtransmissioninreligiouscommunitieswithlowvaccineacceptance aroundtheyear2000,althoughthegeneralpopulationremainswell-protectedfromwidespread trans-mission.Allcountriesshouldinvestinactivemanagementofpopulationimmunitytoavoidthepotential circulationofimportedlivepolioviruses.IPV-usingcountriesmaywishtoconsiderprevention opportu-nitiesand/orensurepreparednessforresponse.CountriescurrentlyusingasequentialIPV/OPVschedule shouldcontinuetousealllicensedOPVserotypesuntilglobalOPVcessationtominimizevulnerability tocirculationofimportedpolioviruses.

1. Introduction

The risk of infectious agents crossing international borders motivatesglobal diseasecoordination and management efforts, includingtheGlobalPolioEradicationInitiative[1].Aslongaswild polioviruses(WPVs)circulateanywhere,theyposesomeriskof importation(i.e.,crossingtheborder)intoallcountries.Not surpris-ingly,oncecountriessucceedinstoppingendemic(i.e.,indigenous) WPVtransmission(i.e.,nationalelimination)andbecome“polio free,” their concerns about WPVs primarily turn to potential

∗ Correspondingauthorat:KidRisk,Inc.,10524MossParkRd.,Ste.204-364,

Orlando,FL32832,USA.Tel.:+16176802836.

E-mailaddress:kimt@kidrisk.org(K.M.Thompson).

importations.Detectionofanimportationtypicallydependsonthe GlobalPolioLaboratoryNetworkﬁndingparalyticcases,and conse-quentlyWPVimportationsthatdonotresultinidentiﬁedparalytic casesgounnoticed.Notableexceptionsoccurredwiththe detec-tionofasymptomaticWPVserotype1(WPV1)transmissionin2013 bytheextensiveIsraelienvironmentalsurveillancesystem,which allowedIsraeltorespondtothecirculationandsuccessfully pre-ventcases[2–4],andsimilardetectionandresponsetothesame WPV1inEgypt[5].

Recently,theWorldHealthOrganizationfocusedon importa-tionsasaprimaryconcernforthepolioendgameandestablished temporaryrecommendationsforinternationaltravel immuniza-tionto reducetheinternationalspread of poliovirus[6]. While effortstoincreasetheimmunityofindividualinternational travel-ersmayreducethenumberofimportationevents,thisapproach http://dx.doi.org/10.1016/j.vaccine.2015.02.013

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K.M.Thompsonetal./Vaccine33(2015)1568–1577 1569

doesnot eliminate therisk altogether and focuses onlyonthe nationally less-controllable part of the risk of re-established transmission.Inadditiontotheimportationevent(e.g.,WPV enter-ing the population), the risk of re-established transmission of an imported WPV depends onthe vulnerability of the popula-tionreceivingtheimportedvirustosustaintransmission,which dependsonitspopulationimmunitytopoliovirustransmission[7]. Thus,whilecountriescannoteasilycontrolalloftheborder cross-ingsthatmayleadtoimportationevents[8,9],particularlyfora diseasethatprimarilyspreadsasymptomatically,national immu-nizationdecisionsdeterminepopulationimmunitytotransmission andthustheoverallnationalriskofre-establishedtransmissionof importedpolioviruses[7].

Populationimmunitytotransmissionrepresentsthe aggrega-tionoftheimmunityofallindividuals withina population,and it changes over time with demographic changes (i.e.,births of immunologically-naïveindividuals,deathsofimmuneindividuals, andimmigration)andfactorsthatimpactindividualimmunity(i.e., immunization,infection, and waningof antibodies) [7].Models of populationimmunitymust considerall dynamic inputs, and alsoaccountforthedifferenttypesofimmunologicalprotection provided by oral poliovirus vaccine (OPV) and inactivated poliovirusvaccine(IPV)[7].Asalive,attenuatedvirus,OPVcauses infectionsinvaccinerecipientswhocanspreadtheirinfectionsto effectivelyimmunizecontactsorboosttheirimmunity,providing benefitsbeyondthevaccinerecipient.However,OPVcomeswith asmallriskofvaccine-associatedparalyticpolio(VAPP)[10],and OPV-usingpopulationswithlowimmunitylevelscansupport sus-tainedtransmissionofOPV-relatedvirusesthatevolvetobecome circulatingvaccine-derivedpolioviruses(cVDPVs),whichbehave likeWPVs[10,11].Forserotype2,cVDPVsnowrepresentthe pri-maryimportationriskgiventheabsenceofanyserotype2WPV since2000[8].IncontrasttoOPV,IPVprovidesprotectiononlyto vaccinerecipientsanditdoesnotcomewithVAPPorcVDPVrisks. However,IPVdoesnotprotectaswellasOPVagainstasymptomatic intestinalinfectionsorfecal-oraltransmission[12,13].After suc-cessfulimmunizationwithIPVorrecoveryfromaninfectionwith alivepoliovirus(LPV,i.e.,WPV,cVPDV,OPV,orOPV-relatedvirus) ofaspecificserotype,individualsbenefitfrompermanent homo-typicprotectionfromparalysis,buttheycangetre-infectedand participateasymptomaticallyinhomotypictransmissiontosome degree[12–15].

Fig.1summarizesthenumberofcalendaryearsthatcountries reportedoneormoreWPVorcVDPVcasesduring2000–2014and demonstratesongoingnationalchallengesassociatedwith main-taining highpopulationimmunity. Social disruptionsappear to represent a significant risk factor (e.g.,Syria, Iraq), which sug-gests that areaswith social unrest(e.g., Somalia, Pakistan, and morerecently,Ukraine,Guinea,Liberia,SierraLeone)maywarrant particularattention.Fullprotectionfromparalyticpoliorequires immunityforallthreepoliovirusserotypes.BothIPVandtrivalent OPV(tOPV)currentlyusedforroutineimmunization(RI)containall threeserotypes,butcountriescanusebivalentOPV(bOPV, contain-ingserotypes1and3)andmonovalentOPV(mOPV)formulations forsupplementalimmunizationactivities(SIAs)[8,16]. Immuniza-tionchoicesimplytrade-offs[16],andcurrentdiscussionsabout thepolioendgameleadtoquestionsaboutthedynamicsof coor-dinatedglobalOPVcessationandtheroleofIPVwithrespectto managing populationimmunity [17–20]. Current plans include globally-coordinatedcessationofserotype-2containingOPV(i.e., OPV2cessation)first,followedbyglobally-coordinatedOPV ces-sationofserotypes1and3(i.e.,OPV1&3cessation)[21].TheGPEI identified6criteriaasprerequisitestoOPV2cessation[21],and wehighlightedtheimportanceofassuringhighenough popula-tionimmunityatthetimeofOPV2usingsufficienttOPVSIAsasan additionalprerequisitetothesafewithdrawalofOPV2[16].

Modelscharacterizingthedynamicsofpoliovirustransmission andpopulationimmunitydemonstratetheimportanceof main-taining high populationimmunity to achieve WPV eradication and successfullystopOPV use[15,17–20,22,23].Priormodeling emphasizesthatOPV-usingcountriesmustkeeptheirpopulation immunity sufﬁciently above the threshold required to prevent transmissioninordertopreventcVDPVemergencespriortoand afterOPVcessation[17–20].Thus,OPV-usingcountriesshoulduse tOPVwithsufﬁcientlyhighcoverage(i.e.,RIwithSIAsasneeded) upuntilthepointofOPV2cessation,atwhichpointtheyshould switchtobOPVandagainmaintainhighcoveragetoensurehigh populationimmunityuntilOPV1&3cessation[16–20].Countries shouldrecognizethattheirvaccinechoiceswillalsoaffecttheir probabilitiesofundetectedLPVcirculationafterapparent interrup-tionoftransmission[24].ThepriormodelsfocusedonOPV-using countries[16–20].However,withallcountriesatriskfor importa-tionsfromanycirculatingWPVsorcVDPVs[8],werecognizethe importanceofconsideringnationalvulnerabilitytore-established transmission following a LPV importation into IPV-only using countries.

2. Methods

We extend our prior modeling [4,15,17–20,22–24] to char-acterizevulnerabilitytore-establishedtransmissionandoptions that IPV-only using countries may considerto reduce or elim-inate their vulnerability (see Appendix A). Briefly, the model tracksthepopulationindifferentimmunitystatesasaresultof births,deaths,immigration,immunization,infection,andwaning. We developed generic model inputs for humanimmunological responses to polioviruses and poliovirus transmission charac-teristics by serotype that remain constant across all modeled situations(i.e.,immunitystateinputsforsusceptibility, infectious-ness,and duration ofthelatentandinfectious periods,kinetics of waning immunity and OPV virus evolution (i.e., to become cVDPVs following sufficient sustained transmission), and rela-tive poliovirus transmissibility and paralysis-to-infection ratios by serotype) based onan extensiveexpert review and elicita-tion process [12,13,15]. We calibrated themodel inputs across tendiverseepidemiologicalsituations(i.e.,geographicareaswith different conditions and experiences with WPVs and cVDPVs), which usedsituation-specificappropriateinputs forpopulation, historicalRIandSIAvaccination,basicreproductivenumber(R0), seasonality, and relative proportion of overall (i.e., fecal-oral andoropharyngeal)transmissionsthatoccurviathe oropharyn-geal route (poro_). _The _calibration _process _focused _on _ensuring that the model inputs yielded behavior and estimates consis-tent withthe actualreportedWPV and/or cVDPV incidenceby age,the actualapparenttiming of WPV die-out(where appro-priate),theabsenceoremergenceofcVDPVs,andavailabledata on secondary OPV transmission and children missed by SIAs [4,15,17–20,22–24].Themodeltracksviraltransmission, includ-ingasymptomaticinfectionsinindividualswithpriorimmunity, and explicitly recognizes that relative susceptibility to infec-tionandrelativeinfectiousnessovertimedeterminetherelative potential contribution to transmission for individuals in each immunitystate[7,15].Aggregatingtheproportionsofindividuals ineachimmunitystate,theirpotentialcontributionto transmis-sion,andconsideringthemixingpropertiesfordifferentagegroups and subpopulations in the model, we characterize population immunity to poliovirus transmission by computing the age-and-subpopulation-mixing-adjustedeffectiveimmuneproportion (EIPM)[20].Wealsocharacterizetheseasonally-varyingimmunity thresholdEIP*=(1−1/R0)abovewhichinfections eventuallydie out[20].

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Fig.1.Numberofcalendaryearsduring2000–2014thateachcountryreportedatleastoneparalyticpoliocasescausedbyaWPVorcVDPVindicatinginsufﬁcientpopulation

immunitytostoporpreventtransmission,(a)includingyearswithendemiccirculationand(b)includingonlyyearswithcirculationofcVDPVs*orimportedWPVafter

becomingpolio-free.Basedonthesummarytablefor2000–2012data[8]withupdateddatafor2013and2014[1].

2.1. USmodel

Our prior analysesfor the US suggested that while WPV or cVDPV importations intoa pocket ofunder-vaccinated individ-ualsmightleadtolimitedtransmission[25],theywouldnotlikely leadtore-establishedtransmissioninthegeneralpopulation[22]. Ourcurrentmodelexplicitlyaccountsforbothfecal-oraland orop-haryngealtransmission,whichIPVuseaffectsdifferentially[15]. GiventheevidencethatIPVprotectswellagainstparticipationin oropharyngealtransmission,butnotaswellagainstparticipationin fecal-oraltransmission[12,13],weexplorethereferencecase(RC) ofcontinuedIPV-onlyimmunizationandonedifferentassumption abouttheproportionoftransmissionsviatheoropharyngealroute (poro_),_which_determines_the_relative_importance_of_{oropharyngeal} transmissiononpopulationimmunitywithoutchangingtheoverall R0assumption[15].

2.2. Israelmodel

ForIsrael,ourprioranalysisexploredthehistorical transmis-sionofWPVsandtheimpactsofthe2013WPV1importationand

immunizationresponse onpopulationimmunityfor serotype1 through2015[4].ThemodeldividestheIsraelipopulation geo-graphicallyintotheSouthern districtand therestofIsrael and sociallyintoJewsandnon-Jewsforeachgeographicarea(i.e.,4 preferentially-mixingsubpopulations).Mostofthetransmission of the 2013 WPV1 occurred in the Southern district, particu-larlyamongthenon-Jews[4],butsomelimitedtransmissionalso occurredintherestofIsrael.Basedontheepidemiologyofthe out-breakthatfocusedonBedouincommunitieswithbelow-average hygienestandards,wecharacterizeasomewhathigherR0(i.e.,of 6vs.5elsewhereinIsrael)andlowerporo _(i.e.,_0.6_vs._0.7 else-where)forthenon-JewishsubpopulationintheSoutherndistrict [2,26].TheRCincludestherecentimmunizationresponsetothe actual2013signalofaWPV1detectedbytheIsraelienvironmental surveillancesystem[4].Weextendthemodelthrough2020and forall3serotypes.Weconsiderretrospectivelyseveral hypothet-icalimportationsofWPV1,WPV3,orcVDPV2withhighandlow seasonalityandnotoutbreakresponsetoexplorethetimingof vul-nerabilitytore-establishedtransmission.Withsomecountriesthat currentlyuseIPV/OPVsequentialschedulespossiblyconsidering useofIPV-only,weexplorethecounterfactualofIsraelhistorically

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notswitchingtoIPV-onlyRI(i.e.,continuedsequentialIPV/OPV). Wealsomodeledprospectiveoptionswithhypothetical introduc-tionsofWPV1,WPV3,orcVDPV2,forwhichweassumedtheRC includescontinueduseof2bOPVdosesinRIthroughtheendof thetimehorizon.WeconsideredtherealitythatIsraelcouldstop usingbOPVatanytime(i.e.,2bOPVdosesfrom2014with cessa-tiononindicateddate)[4].WealsoconsideredtheimpactofIsrael usingtOPVinsteadofbOPVinRIstartingonJanuary1,2015(i.e., switchtotOPVin2015withOPVcessationonindicateddate)to demonstratetheimpactofvaccinechoices.

2.3. TheNetherlandsmodel

TheNetherlandsmodelincludestwosubpopulations(i.e.,the orthodoxreformedcommunitiesofabout300,000peopleatthe timeofthe1992–1993outbreak,andthegeneralDutchpopulation) [15].Forthegeneralpopulation,weassumedRIcoveragewith3or moreIPVdosesdecreasedfrom97%1994[15]toabout95%from 2003forward[27].Fortheorthodoxreformedcommunities,weuse abestestimateof40%relativecoveragecomparedtothegeneral population,andgivenuncertaintyweconsiderarangeof20–60% from1994forward.

3. Results

Fig.2showstheUSpopulationimmunity(i.e.,EIPM)andthe threshold(i.e.,EIP*)foreachserotypefrom1995through2020for theRC.Foreachserotype,EIPM>EIP*,whichsuggestsno vulner-abilitytore-establishedpoliovirustransmissionintheUSgeneral population,evenafteralongperiodofIPV-onlyRI,similartoprior studies[22,25].Thus,althoughrealheterogeneityintheUSimplies someriskoflimitedlocalizedtransmissionofimportedLPVswithin somesubpopulationswithmuchlowerthanaverageRIcoverage (e.g.,ruralclustersofreligiousgroupsthatobjecttovaccination ormore urbanupper-income communities thatrefuse vaccina-tionbasedonpersonalbeliefs)[22,25],re-establishedtransmission in the general populationappears unlikely based on projected coverage.Fig.2furtherhighlightsthatsustainedhighpopulation immunityprovided byIPVdepends ontherealisticassumption thatpoliovirustransmissionintheUSprimarilyoccursvia orop-haryngealcontact[12–15].Ifweunrealisticallyincreasetherelative importanceoffecal-oraltransmission(i.e.,decreaseporo_from_0.8 intheRCto0.6),then populationimmunitywould dropbelow thethresholdwithinthenextfewyearsforserotype1andcreep towardsthethresholdforserotypes2and3(forwhichweassume lowervaluesforR0[15].andthuslowerthresholds).Thisdeclinein populationimmunitywouldoccurdespitecontinuedhighRI cov-erageandnochangeintheassumedabsolutetransmissibilityof polioviruses(i.e.,sameR0),anditrelatestothelimitedimpactofIPV onfecal-oraltransmission.Whilewebelievehygieneandsanitation levelsremainhighinmostplacesintheUS,Fig.2suggeststhatany clustersofpeoplelivinginsub-optimalhygieneconditionsinthe UScouldseesomespreaddespitehighRIcoveragewithIPV. Simi-larly,populationsusingIPV-onlywithmorefecal-oraltransmission inothercountriesmaybecomevulnerabletore-established trans-missionofWPVsorcVDPVsmorequicklyover time,even with sustainedhighRIcoverage.

SouthIsraelprovidesanexampleofconditionsconduciveto re-establishedtransmission.Fig.3showshowpopulationimmunity changedfortheRCinIsraelforeachserotypefor2005–2014and suggeststhatextensionoftheIPV/OPVsequentialschedulewould have maintainedpopulationimmunity high enoughto prevent Israelfrombecomingvulnerabletore-establishedtransmission fol-lowinganyWPVorcVDPVimportations.AsshowninFig.3a–c, thepopulationimmunityforthe RCfor eachserotypestartsto

decreaseanddropstoalevelconsistentlybelowtheEIP*,although thisoccursatdifferenttimesforeachserotype,withincreasesin populationimmunityforserotypes1and3startingin2013due totheWPV1 importationandsubsequentbOPVuse. Fig.3 sug-geststhatpopulationimmunitydroppedbelowthethresholdsand exposedIsraeltothepossibilityoflimited,low-leveltransmission inthehighseasonasearlyas2007,2008,and2006,forserotypes 1,2,and3,respectively.

Table1 shows how many ofthe foursubpopulations in the Israelmodelparticipatedintransmissionandtheoverall transmis-sionbehaviorinthemodelfollowinghypotheticalintroductions of imported WPV1, WPV3, and cVDPV2. In the context of the resultsshowninFig.3,theresultsinthetopofTable1suggest thatthedevelopmentofoutbreaksandre-established transmis-sionrequiresanextendedperiodofpopulationimmunitybelow thethreshold,withre-establishedtransmissioninthegeneral pop-ulationshowninTable1(top)possibleinIsraelforimportationsas earlyas2009,2012,and2010forserotypes1,2,and3,respectively. Fig.4ashowsthepopulationimmunityforserotype1fortheRC andforseveralalternativeprospectivedatesforstoppingserotype 1OPVuse,whichdemonstratesthatpopulationimmunitybegins decliningassoonasuseofOPVstops,evenwithhighIPV cover-age.Fig.4b–dshowsthepopulationimmunityoftheRCmodeled prospectivelyforserotypes1,2,and3,respectively,alongwith sev-eraloptionsforhomotypicOPVcessationdatesandconsideringthe switchfrombOPVtotOPVinJanuary2015untilthehomotypicOPV cessationdateindicated.Table1(bottom)indicatesthedegreeof spreadofimportedWPV1,WPV3,orcVDPV2fordifferent prospec-tivehypotheticalintroductiontimesduring2015–2020.Themodel suggeststhatcontinuedOPVusewouldpreventanyimportationof theincludedOPVserotypes(i.e.,allserotypesfortOPV,serotypes 1and3forbOPV)fromspreading.FortheRC,asshowninthe ret-rospectiveanalysis(Table1,top)acVDPV2importedafter2012 leadstowidespreadtransmission,sotheprospectiveintroduction inNovember2015takesoff.IfIsraeldecidedtousetOPVinstead ofbOPVfromJanuary2015untilglobalOPV2cessation,thenthe modelsuggeststhiswouldpreventre-establishedserotype2 trans-missionassociatedwithaNovember2015importation.Themodel resultsalsosuggestthatIsraelmightagainbecomevulnerabletoa WPV1importation3yearsafterdiscontinuedbOPVuse(i.e.,the February2017importationdies-outthesameyearwhereas the February2019importationspreadsandleadstosustained trans-missioninthefollowingyear).Similarly,discontinuedbOPVuse would allowtransmissionof a WPV3 importation4 years after discontinuedbOPVuse.

Fig. 5 shows the expected population immunity in The Netherlands through 2020. Unlike the US model, we explicitly characterizedasubpopulationoforthodoxreformedcommunities withknownlowvaccineacceptance,becausethesecommunities represent a signiﬁcant proportion of the population and they historically experienced poliovirus outbreaks in 1978 [28] and 1992–1993[29]andameaslesoutbreakasrecentlyas2013[30]. Unlike theunder-vaccinatedAmishcommunities intheUS, the Dutchorthodoxreformedcommunitiesremaininrelativelyclose geographicproximityinadditiontotheirsocialclustering[31].Also unliketheUS,whichusedOPV-onlyforRIforseveraldecadesbefore switchingtoanIPV/OPVsequentialscheduleforafewyearsand thentoIPV-onlyRIin2000[32],TheNetherlandsusedanIPV-only RIschedulesinceitintroducedpoliovirusvaccinationinthe1950s [33],which implieslowerpopulationimmunitytotransmission intheDutchgeneralpopulation.Thepresenceofa preferentially-mixingsubpopulationwithverylow RIcoverageimplies thata WPVorcVDPV ofanyserotypecancirculateinthis subpopula-tionandthereforeinTheNetherlands.Fig.5aandbshowsthat forserotypes1and2,whichhavenotcirculatedwidelysinceat least1978,populationimmunityappearswellbelowthethreshold

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Fig.2. PopulationimmunityintheUSgeneralpopulationbyserotypefortheRCcomparedtothethreshold(EIP*)from1995forward,andforhypotheticallylowerproportion

oftransmissionsviatheoropharyngealroute(poro₌_0.6).

asa resultofthelow coveragein theorthodoxreformed com-munitiesandabsenceofnaturalimmunityfromanoutbreak.This impliesthata WPVorcVDPV oftheseserotypescouldestablish widespreadtransmissionifintroducedintotheorthodoxreformed communities.Forserotype3,populationimmunityremains some-whathigherduetotheWPV3outbreakinthesecommunitiesin 1992–1993,butit also decreasesbelowthethreshold ata rate thatdependsonthesubpopulationcoverageassumptions(Fig.5c). Fig.5d providesthebreakdownofpopulationimmunityforthe generalpopulation,which remainsabovethethreshold,and for

thesubpopulation,whichdoesnot (similarbreakdowns forthe othertwoserotypesnotshown).Fig.5dsuggeststhatalthougha WPVorcVDPVintroducedinTheNetherlandscouldcirculateinthe orthodoxreformedcommunities,thegeneralpopulationremains well-protectedand would mostlikely notsustainextensive re-establishedtransmission(similartotheUS,Fig.2).Althoughthe orthodoxcommunitiesmaybeneﬁttosomeextentfromhigh pop-ulationimmunityinthegeneralpopulation,virusesmayormaynot takeoffdependingonchanceandthetimingandplaceof introduc-tion[25].OurresultsoverallsuggesthighvulnerabilitytoaWPV

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Fig.3. PopulationimmunityinIsraelbyserotypefortheRCcomparedtothethreshold(EIP*)andifIsraelhypotheticallyhadmaintainedanIPV/OPVsequentialschedule.

orcVDPVintroductioninclustersofunder-vaccinatedpeoplein IPV-usinghigh-incomecountries.

4. Discussion

Maintaining high population immunity to poliovirus trans-missionshouldrepresenta priorityfor allcountriesduetothe importationriskofWPVsorcVDPVs.MostOPV-using countries probablyfaceamoresigniﬁcantriskofcreatingadomesticcVDPV priortoorafterOPVcessationthanfromimportationofacVDPV, andforthesecountriesweemphasizethatnationalrisksofcVDPV creationaloneshouldmotivateeffortstomaintainhighpopulation immunitythroughoutthepolioendgame[4,15,17–20,22,23]. How-ever,IPV-onlyusingcountriesshouldrecognizethattheystillface importationrisksandconsideropportunitiestodecreasetheirrisks,

including establishingsensitive environmentalsurveillance and ensuringaccesstoOPVforanyneededoutbreakresponse[34,35]. WithsuccessfulcessationofWPV1circulationinIsraelconﬁrmed, IsraelwouldlikelybeneﬁtfromswitchingfromtheuseofbOPVto tOPVforitstwoRIOPVdosesstartinginearly2015untilthetime ofcoordinatedglobalOPV2cessationtomaximizeitsserotype2 populationimmunity.However,suchastrategycouldprove chal-lengingfromapolicyperspective,becausethiswouldintroduce serotype2LPVintoIsraelintheabsenceofanalreadycirculating cVDPV2.UsingtOPVnowwouldprovideIsraelwithsome insur-ancesuchthatanyimportationsofcVDPV2sfromothercountries, whichIsraelcannotfullycontrol,willnotre-establishtransmission andnecessitateanotheroutbreakresponse.However,Israelcould alsodecidetoacceptthelowriskofacVDPV2importationandfocus onpreparednessinsteadofprevention.PriortointroducingtOPV

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Fig.5. OverallpopulationimmunityinTheNetherlandsbyserotypefortheRCcomparedtothethreshold(EIP*)from1990forwardforall3serotypesfordifferentassumptions

(i.e.,20%,40%,and60%)ofrelativecoverageintheorthodoxreformedcommunities(comparedtothegeneralpopulation)andfortype1thebreakdownofpopulationimmunity

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Table1

Vulnerabilitytore-establishedtransmissioninIsraelfollowingahypotheticalimportationofWPV1,WPV3,orcVDPV2between2008and2012(retrospective)andbetween

2015and2020(prospective)fordifferentimmunizationscenariosandresultingtransmissionbehavioroftheimportedviruswithinthe4modeledsubpopulationsinthe

absenceoffurtheroutbreakresponsemeasures.

Timingof introduction

Immunization assumptions scenario

Numberofsubpopulationsaffected (outof4)aftervirusintroduction indicated

Transmissionbehaviorofintroduced virus

WPV1 cVDPV2 WPV3 WPV1 cVDPV2 WPV3

Retrospectivescenarios

Feb9,2008 Referencecase(RC) 4 1 1 Lowlevelin2008,

re-establishedin2009

Die-outin2008 Die-outin2008

Feb9,2009 Referencecase 4 1 2 Re-establishedin2009 Lowlevelin2009,

Lowlevelin2009, re-establishedin2010

Feb9,2010 Referencecase 4 1 3 Re-establishedin2010 Re-establishedin2010 Lowlevelin2010,

Aug7,2011 Referencecase 4 3 1 Lowlevelin2011,

Die-outin2011

Aug7,2012 Referencecase 4 4 1 Lowlevelin2012,

Die-outin2012

Anytime Continuedsequential

IPV/OPV

0 0 0 Nospread Nospread Nospread

Prospectivescenarios

Nov1,2015 Referencecase 0 4 0 Nospread Lowlevelin2016,

Nospread

Feb9,2017‘ 2bOPVdosesfrom

2014withbOPV cessationinOct2015

1 4 1 Die-outin2017 Lowlevelin2017,

Die-outin2017

Feb9,2019 2bOPVdosesfrom

2014withbOPV cessationinOct2015 3 4 1 Lowlevelin2019, re-establishedin2020 Lowlevelin2019, re-establishedin2020 Die-outin2019

Nov1,2015 SwitchtotOPVinJan

2015

0 0 0 Nospread Nospread Nospread

Feb9,2017 SwitchtotOPVinJan

2015withtOPV cessationinApr2016

1 1 1 Die-outin2017 Die-outin2017 Die-outin2017

2015withtOPV cessationinApr2016 1 1 1 Lowlevelin2019, re-establishedin2021* Lowlevelin2019, re-establishedin2021* Die-outin2019

2015,switchbackto

bOPVinApr2016with

OPVcessationinApr

2019

1 1 1 Die-outin2019 Lowlevelin2019,

re-establishedin2021*

Die-outin2019

Abbreviations:bOPV,bivalenttypes1and3oralpoliovirusvaccine;IPV,inactivatedpoliovirusvaccine;PV1,2,3,poliovirustype1,2,or3,respectively;tOPV,trivalentoral

poliovirusvaccine.

* _Possible_{re-establishment}_in₂₀₂₁_(outside_the_analytical_time_frame)_based_on_observed_trend.

inRI,Israelipolicymakersmaywanttoconsiderfurthermodeling oftheactualoptions,whichmayincludeSIAsorexpandedtarget agesinRInotaddressedhere.

Our results suggest that countries using or considering an IPV/OPVsequential schedule shouldcontinue touse theglobal formulation of OPV with all serotypes allowable up until the timeofcoordinatedOPVcessationbyserotypeoccurs(e.g.,tOPV now, bOPV after OPV2 cessation). Countries should recognize that the adoption of an IPV-only immunization schedule may makesomepopulationsvulnerabletore-establishedtransmission followingLPV importations, evenwithrelativelyhighcoverage, particularlyin thecontextof hygiene andsanitation conditions that favor fecal-oral transmission.Similarly, substitution of IPV forOPVdosesinRImayleadtoreductionsinoverallpopulation immunity and countries should consider this as they manage theirrisks in the polio endgame [36]. Countries considering a switchfromIPV/OPVusetoIPV-only toeliminateVAPP should weightheexpected smallreduction in VAPP cases[37] against theriskofoutbreaksofimportedWPVorcVDPVinthecontextof anyunder-vaccinatedsubpopulationsorsubpopulationthatmay

support fecal-oral poliovirustransmission. All countriesshould recognizetheimportanceofnot“demonizing”OPVwhenmaking changes in national immunization policyin case OPV becomes neededforoutbreakresponseduringtheendgame.

Theintroductionofimportedvirusesintoclustersof suscepti-bleindividualsrepresentsahighrisk,andcountriesshouldexplore opportunitiestopotentiallyincreasepopulationimmunityinthese groupstotheextentpossibleandmonitorthesegroupsfor indi-cations of transmission throughout the endgame. Focusing on preventionandriskmanagementwillrepresentanimportant strat-egytosuccessfullyachieveWPVeradicationandsuccessfulOPV cessation, but it may imply greater than currently anticipated demandsfortOPVintheshortterm.Failingtounderstandand man-agepopulationimmunityinallcountrieswillmostlikelycontinue todelaypolioeradicationgoals,increasetheneedsforvaccineand otherresourcesforoutbreakresponse,andincreaseoverallcosts. Conﬂictofintereststatement

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Acknowledgments

WethanktheBillandMelindaGatesFoundationforprovidinga contracttoKidRisk,Inc.tosupportcompletionofthisworkunder WorkOrder4533-25298.Thecontentsofthismanuscriptaresolely theresponsibilityoftheauthorsanddonotnecessarilyrepresent theofﬁcialviewsoftheBillandMelindaGatesFoundation. AppendixA. Supplementarydata

Supplementary data associated with this article can be found,intheonlineversion,athttp://dx.doi.org/10.1016/j.vaccine. 2015.02.013.

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