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    Riskanalysisformeaslesreintroductionpostglobalcertificationof

    eradication

    DrRaySanders.July2010

    Summaryandconclusions

    Measlesviruswillcontinuetoexistaftercertificationofglobaleradicationasvirusstocksand

    infectiousmaterialsheldinlaboratories.Livevirusmayalsoexistinundetectedfocioftransmission

    andinpersistentlyandchronicallyinfectedindividuals.Thisanalysisattemptstoidentifyand

    evaluatethemainrisksforreintroductionofmeaslestransmissionpostcertificationoferadication

    inaworldinwhichuniversalroutinemeaslesimmunizationisnolongerafeature.

    Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumans

    Thereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreedrequirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements

    fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby

    undetectedcontinuingtransmission.

    Mildorasymptomaticmeaslesinfectionsareprobablyverycommonamongmeaslesimmune

    personsexposedtomeaslescases,buttransmissionfromasymptomaticcasesislikelytobevery

    rare.Ifitoccursitisunlikelytobeefficientenoughtosustaintransmission,especiallyinthehighly

    vaccinatedpopulationsexpectedintheyearsimmediatelyfollowingglobalcertificationof

    eradication.However,thepotentialroleofasymptomaticinfectionsinmaintainingtransmission

    requiresfurtherinvestigation.

    Ifthecriteriaforglobalcertificationoferadicationarefirmenough,andrequirerigorousvalidation,

    thentheriskofundetectedmeaslestransmissionaftercertificationisverylow.Ifthecertification

    criteriaarelax,orvalidationrequirementsareinadequate,theriskwillbehigher.

    Riskoftransmissionofvaccinederivedvirus

    Thecurrentlylicensedliveattenuatedmeaslesvaccinesaresafeandefficientandhavebeenused

    successfullytoprotectmanymillionsofindividualsandpreventmeaslestransmission.Allcurrent

    vaccinevirusesarecloselyrelatedandbelongtogenotypeA.Thereisnopublishedconclusive

    evidenceforcurrentlylicensedliveattenuatedvaccinevirusesrevertingtowildtypetransmissibility

    orvirulence.Onthecontrary,thevastmajorityofevidencepointstoanimpressivelevelofgenetic

    stability.However,sincetheyarelivevirusesthatreplicatewithinvaccinerecipients,theremote

    possibilitymustexistthattheycouldreverttowildtypecharacteristics.Thereisalsonoevidencefor

    theestablishmentofvaccineescapemutants.Evenifvaccinevirusesweretoreverttowildtype

    transmissibility,thereisnoreasontosuspectthattransmissioncouldnotbecontrolledusingcurrent

    vaccines.

    Riskfrompersistentinfections

    Thereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe

    sheddingofinfectiousvirusorplayanypartinmeaslestransmission.Asthenumberofacute

    measlesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthe

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    DrRaySanders.Measlesreintroductionriskanalysis

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    numberofpotentialSSPEandMIBEcases.AcutemeaslesinfectioninHIVinfectedindividualstends

    tobemoresevere,lastlongerandresultinashorterlivedimmunitytoreinfection,butthereisno

    publishedevidencetosuggestthatcoinfectionincreasesthepotentialforestablishmentof

    persistentmeaslesinfections,eitherwithwildtypevirusorwithvaccinederivedvirus.

    Riskfromnonhumanprimates

    Althoughnonhumanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and

    animalanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootictransmission

    orposeathreattohumanpopulations.

    Riskoflaboratoryassociatedmeaslesinfection

    Althoughthereisnodirectevidenceforlaboratoryacquiredmeaslesinfectionsitispossiblethat

    theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymild

    infections.Thereisnopublishedevidencetosuggestthattheseasymptomaticormildinfections

    resultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinafewhoursatambient

    temperatures,andinfectiousmaterialsstoredattemperaturesabove30 oCcanbeexpectedtolose

    allinfectivityoverthecourseofonetotwoyears.Materialsstoredatorbelow70oC,orfreeze

    dried,maintaininfectivityformanyyears.

    Despitethelackofevidenceforlaboratoryacquiredmeaslesinfectionsorescapeofvirusintothe

    community,thesemustbeconsideredpossibilitiesinaposteradicationworld.Anappropriate

    systematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythePolio

    EradicationInitiative,shouldbedeveloped.

    Riskofintentionalreleaseofmeaslesvirus

    Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthepast.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldbe

    repeated,thethreatofmeaslesreleasewouldprobablybeveryeffectiveonceasizablepopulation

    ofsusceptibleindividualshadaccumulated.Thisthreatcouldbecounteredbytheestablishmentofa

    measlesvaccinestockpile,preferablyusinganew,easytomassadminister,nonreplicativemeasles

    vaccine.Thesizeandnatureofanystockpileshouldbedefinedwithinasystematicand

    comprehensiveposteradicationriskmanagementstrategy.

    Risksforreintroductionofmeaslescanbesummarisedasfollows:

    Risk Magnitude Tendencyovertime MitigatingactionsContinuingwildtype

    measlestransmissionin

    humans

    Lowbutdependson

    certificationcriteriaand

    validationrequirements

    Decreasing Basecertificationcriteria

    andvalidationrequirements

    ondynamicandstochastic

    modellingdata

    Transmissionofvaccine

    derivedvirus

    Verylow Dependsonlevelofvaccine

    use

    Developalternative,non

    replicatingvaccines

    Persistentinfections Verylow Decreasing Maintainsurveillance

    Nonhumanprimates Verylow Decreasing Maintainsurveillance

    Laboratoryassociated

    infection

    Verylowbutrisingpost

    eradication

    Increasing Developsystematic

    laboratorycontainment

    strategy

    Intentionalrelease Verylowbutrisingpost

    eradication

    Increasing Developvaccinestockpiles

    aspartofacomprehensive

    riskmanagementstrategy

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    TableofContentsError!Bookmarknotdefined.

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    Theanalysisconcludeswithabriefdiscussionofactionsrequiredtoreducetheriskofaccidentalor

    deliberatereleaseofmeaslesinaposteradicationworldandareasthatcouldbenefitfromfurther

    research.

    Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumansThereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreed

    requirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements

    fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby

    undetectedcontinuingtransmission.However,basedoncurrentRegionalandGlobal

    recommendationsoncertificationofRegionalmeasleselimination,itislikelythateradicationcriteria

    willinclude:

    1. Absenceofcirculatingmeaslesvirusforatleastoneyear;2. Adequatesurveillanceincludinggenotypedata.Adequatesurveillancemaybedefinedby:

    Numberofreportedsuspectedmeaslescasesthatarediscardedasnonmeasles(targets:2/100,000populationnationally,1/100,000inatleast80%ofdistricts)

    Percentageofreportedsuspectedcasesthathaveadequateinvestigationwithin48hoursofreport(target:80%ofreportedsuspectedcases)

    Percentageofreportedsuspectedcasesthathaveadequatespecimenscollected(target:80%ofreportedsuspectedcases)

    PercentageofdistrictswithaccesstoaWHOaccreditedmeaslesdiagnosticlaboratory(target:100%)

    PercentageofspecimenswithIgMresultswithin7daysofreceiptinlaboratory(target:90%)

    PercentageofchainsoftransmissionwithRNAsequenceanalysis(target:95%) Someuseofmeaslesavidityassaystodistinguishrecentfromlongstanding

    immunologicalresponses

    Somedemonstrationofalternativesurveillancemechanisms,routineorsupplementary,basedoncasedetection,investigationandreporting;

    3. Achievementofhighpopulationimmunity.Populationimmunitymaybedemonstratedby: 95%coveragewithroutineMCV2inalldistricts,or 80%coveragewithroutineMCV1plus95%coveragewithSIAfollowupinall

    districts,or

    Someuseofextensiveserosurveydata.

    FromexperiencegainedthroughRegionalpolioeliminationandcertification,specificcriteriamaybe

    usedtofulfilthethreegeneralcriteriaabove,butitisunlikelythatanysinglespecificindicatorwill

    berequiredtopassorfailvalidation.Thestrictnessandextentofrequirementsforproviding

    evidencethatcertificationcriteriahavebeenmetwilllargelydeterminethemagnitudeofriskposed

    byundetectedcontinuingmeaslestransmission.Butevenwithrelativelylaxcriteriaandvalidation

    requirements,howlikelyisitthatongoingmeaslestransmissionwillbeundetectedforaminimum

    ofoneyearbeforecertification?

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    Whatisthesmallestpopulationrequiredtomaintainmeaslestransmission?

    Measlesepidemicshavegenerallybeencharacterisedbyexplosivecycleswithhighlycomplex

    pathogenandpopulationlevelinteractionsthatinfluencetransmissiondynamics(1).Accurately

    predictingthecriticalcommunitysize(CCS)requiredformaintainingmeaslesviruscirculationis

    difficultduetothelargenumberofvariablesinvolved.Directobservationandarangeofboth

    deterministicandstochasticmodelssuggestthatapopulationof250,000to400,000with5,000to

    10,000birthsperyearisrequiredtomaintaintransmission(2,3).Highlevelsofimmuniz