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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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    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).Highlevelsofimmunization,low

    populationdensity,alowbirthrateandgoodpublichealthcarefacilitiesincreasetheCCS.Low

    vaccineuptake,highpopulationdensity,highbirthrates,highlevelsofimmunodeficiencyandpoor

    publichealthcarefacilitiesdecreasetheCCS(1,4,5).

    AlthoughitmaybedifficulttoaccuratelyestimatetheCCSinlowincome,lowvaccinecoverage

    populations,itiseasytoidentifythesepopulations.Ifdiseasesurveillanceandimmunization

    activitiesaretargetedonthem,andonanynew,atriskpopulationsthatmayemergefollowing

    displacementcausedbyconflictorclimatechange(6),thepotentialtooverlookcirculationofvirus

    intheyearleadinguptoglobalcertificationwillbegreatlyreduced.

    Whatroledoasymptomaticinfectionsplayinvirustransmission?

    Measlescontrolstrategiesassumethatvirustransmissionoccursthroughchainsofclinically

    recognizablemeaslescases,andthesurveillancesystemlargelyreliesontheidentificationofthese

    casesfordetectingandrespondingtooutbreaks.Butasymptomaticinfectionscertainlyoccurand

    mayplayanimportantroleinmeaslestransmission.Serologicalevidenceforacutemeaslesinfection

    amongpeopleexposedtomeaslesvirusbutfailingtodevelopclassicalsymptomshasbeenwell

    documented(7,8,9,10,11,12,13,14,15)andithaslongbeenrecognizedthatmeaslesviruscaninfect

    previouslyimmunepersons,producingclassicsymptomsofmeaslesinsome,butmildorno

    symptomsinmost(16,17,18,19,20).Theestimatedratesofmildorasymptomaticmeaslesinfections

    afterexposuretomeaslescasesarevaried,however,inpartbecauseofdifferentdiagnostic

    techniquesanddifferentcasedefinitionsused,orbecauseofthedifferenttypesofexposure.In

    severalstudiestheratesofmildorasymptomaticinfectionweredeterminedduringoutbreaksin

    whichpersonswerelikelytohavehadmultipleexposurestomeaslescases(16,21,12,8).Astudyof

    mildorasymptomaticmeaslesinfectionsamong44personslikelytohavebeenexposedtoclassic

    measlesduringa3daybustripconcludedthatinpopulationswithhighlevelsofimmunityto

    measles,nonclassicmeaslesinfectionscanoccurinatleast20%ofpreviouslyimmunepersonswith

    closeexposuretoapersonwithclassicmeasles(10).Itispossiblethatmildorasymptomatic

    measlesinfectionsarecommonamongmeaslesimmunepersonsexposedtomeaslescasesandmaybethemostcommonmanifestationofmeaslesduringoutbreaksinhighlyimmunepopulations(10).

    Althoughclinicallyunimportant,asymptomaticmeaslesvirusinfectionscouldbeepidemiologically

    importantifinfectedpersonsarecapableoftransmittingvirus.Althoughatleastonestudyhas

    reportedisolationofmeaslesvirusfromanasymptomaticindividualinclosecontactwithanacute

    case(11),anotherstudyfailedtofindevidenceofvirussheddingfrom11seropositiveacutecase

    contacts(14).Iftransmissionfromasymptomaticcasesdoesoccur,itislikelytobeveryrare,andis

    unlikelytobeefficientenoughtosustaintransmission(11,15),especiallyinthehighlyvaccinated

    populationsexpectedintheyearsimmediatelyfollowingglobalcertificationoferadication.

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    Conclusion

    Ifthecertificationcriteriaarefirmenough,andrequirerigorousvalidation,thentheriskof

    undetectedmeaslestransmissionafterGlobalCertificationisverylow.Ifthecertificationcriteriaare

    lax,orvalidationrequirementsareinadequate,theriskwillhigher.

    Riskassessment:Theriskisintuitivelylow,butuntilthecriteriaforglobalcertificationofmeasleseradicationandtherequirementsforvalidationareestablisheditisnotpossibleto

    estimatetheriskposedbycontinuingwildtypemeaslestransmissioninundetected

    reservoirs.

    Riskoftransmissionofvaccinederivedvirus

    Thedevelopmentofliveattenuatedmeaslesvirusvaccinesbegansoonafterisolationofthevirusby

    EndersandPeeblesin1954(22).ThefirstlicensedattenuatedmeaslesvaccinewasEdmonstonB,

    usedbetween1963and1975butfrequentlyassociatedwithfeverandrash(23).Thefurther

    attenuatedSchwarzandMoratenstrainswerederivedfromtheoriginalEdmonstonstrainthrough

    additionalpassagesinchickembryofibroblasts(Figure1).Despitedifferencesintheirpassage

    history,thesetwovaccinestrainshaveidenticalgenomicsequences(24).TheMoratenvaccineis

    widelyusedintheUnitedStatesofAmerica;theSchwarzvaccineisusedinmanycountries

    throughouttheworld,andtheEdmonstonZagrebvaccine,similarlyderivedfromtheEdmonstonB

    strain,isthemostwidelyusedstrainindevelopingcountries.Otherattenuatedmeaslesvaccines

    havebeenproducedfromlocallyderivedwildtypestrains,particularlyintheRussianFederation

    (Leningrad16),thePeoplesRepublicofChina(Shanghai191)andJapan(CAM70,AIKC)(23).Allof

    thecurrentvaccinevirusesarewelldocumentedandwellcharacterisedwithregardtoprovenance,

    immunogenicity,thermalstabilityandgenomicstructure(25,26,27,28,29,30,31,32,33).Although

    currentvaccinevirusesandtheirwildtypeprogenitorssharemorethan95%sequencehomology,

    theycaneasilybedistinguishedgeneticallyfromcurrentlycirculatingwildtypeviruses.

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    Figure1.Relationshipsofmajorcurrentmeaslesvaccineviruses(fromMoss&Scott,2009(23)).

    Measlesvirusisconsideredtobeoneofthemostcontagiousofhumanpathogens,withaveryhigh

    leveloftransmissibility.Likewildtypevirus,measlesvaccinevirusreplicateseffectivelywithin

    vaccinerecipients,inducingbothhumoralandcellularimmuneresponsessimilartonaturalmeasles

    virusinfection,althoughtheseresponsesareoflowermagnitudeandshorterduration.

    Approximately5%ofchildrendevelopfeverandrashafterreceivingmeaslesvaccine,andviralRNA

    canbedetectedintheurineandrespiratorysecretionsforsomedayspostimmunization(34).

    Vaccineviruscanbeisolatedfromthebloodofrecentvaccinerecipients,andhasbeendetectedin

    samplesoflung,liver,bonemarroworbraintissuesintheveryrarecasesofsevereacutedisease

    followingmeaslesvaccination(35).VirusRNAandantigencanbedetectedintheurineofvaccine

    recipientsforupto1416dayspostimmunization(36,37),butthereisnopublishedevidenceforthe

    transmissionofvaccinevirus.Obviouslythechangescausedbytheattenuationprocesseffectively

    blocktransmissibility.Isitpossibleforvaccinevirustoregainthetransmissibilitycharacteristicsof

    wildtypevirus?

    Thereasonsfornontransmissionofvaccinevirusesarenotfullyunderstood,andarelikelytobe

    complex.Ithasbeenproposedthatlossofabilitytointeractwithepithelialcellreceptorsisakey

    factor(38,39,40).Itisalsopossiblethatmodificationofthevirusmatrix(M)protein,knowntobe

    importantinvirusbuddingfrominfectedcells(41),contributestolossoftransmissibility.Theability

    ofvaccinevirusestointerferewiththeinnateimmuneresponsemayalsobeakeyfactor.Whatever

    thereason,itappearsthattheblockontransmissionofvaccinevirusesishighlyeffective.

    Measlesvirusisserologicallymonotypicandisgeneticallycharacterizedintoeightclades(AH),

    dividedinto23recognizedgenotypes(42,43,44).Allofthecurrentvaccines,whetherderivedfrom

    Edmonstonornot,sharearemarkablenucleotidesequencesimilarityandallaremembersof

    genotypeA(45,24).Duringthe1950sand1960s,onlymeaslesvirusesbelongingtogenotypeAwere

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    isolatedandmayhavehadaworldwidedistributionbeforevaccinationstarted(46,47,48).Thisis

    notthesituationtoday,whentheidentificationofnonvaccinerelatedgenotypeAvirusesisvery

    unusual.Overthepastfifteenyearsamassiveamountofworkhasbeenputintocharacterizing

    measlesvirusesassociatedwithoutbreaks.Althoughtherearestillgaps,virusesfrommostmajor

    outbreaksandfromimportationsinareasthathaveeliminatedindigenousmeasles,arecurrently

    beingsequencedandgeneticallycharacterizedthroughtheWHOLaboratoryNetworksactivities.

    Wenowhaveareasonablycomprehensiveunderstandingofwhichvirusesarecirculatingwhere

    (42,43,44,49,50,51,52,53).

    Againstabackgroundofseveralthousandisolatescharacterized,veryfewgenotypeAviruseshave

    beenidentifiedduringthepast20years.WiththepossibleexceptionofvirusesisolatedintheUKin

    1993(54),nonehasbeenassociatedwithoutbreaks.Whendetectedtheyhavebeensporadiccases

    withuncertainepidemiology,closelyassociatedwithveryrecentreceiptofvaccine,orqueriedas

    laboratorycontaminants(43,55,56,57,58,59,60,61,62).

    Table1summarizesthepublisheddocumentationonthedetectionofgenotypeAmeaslesviruses

    since1990.

    Yearofdetection Country State/Province/Region Numberofisolates Reference

    1990 Japan Handai? 1 (62)

    1991 Argentina BuenosAires 1 (63)

    1993 UK Coventry,England 5 (54)

    1995 SouthAfrica Johannesburg 1 (64)

    1996 RussianFederation Novosibirsk,Siberia 3 (56)

    1996 USA Delaware 1 (60)

    1996 China Hunan 1 (55)

    1996 UK ? 2 (58)

    1996 SouthAfrica Johannesburg 1 (57)

    1998 UK ImportationfromRussia 1 (58)

    1999 Argentina BuenosAires 2 (63)

    1999 China Henan 1 (55)

    2000 UK ? 1 (58)

    2001 Spain Ibiza 1 (59)

    2002 Spain Madrid/Badajos 2 (59)

    2003 Spain Almeria 3 (59)

    2003 China Xinjiang 1 (55)

    2005 Taiwan Taichung/Taipei 2 (61)

    2007 Taiwan Tainan/Taipei 2 (61)

    Table1.PublisheddocumentationonisolationandcharacterizationofgenotypeAmeaslesvirusesfrom1990

    toMay2010.

    Table1includesisolatesthatmayrepresentwildtypelineagesthathavesurvivedsincethepre

    vaccinationera.Italsoincludesvirusesisolatedfromveryrecentvaccinerecipientspresentingwith

    classicmeaslessymptoms.Butitmayalsoincludevaccinederivedisolatesthathavebeen

    transmittedfromvaccinerecipientstounvaccinatedcontacts.AlthoughsomeofthesegenotypeA

    viruseshavenucleotidesubstitutionsthatdistinguishthemfromvaccineviruses,thereisno

    publisheddocumentationidentifyingadistinctsetofgeneticmarkersthatconsistentlydifferentiateswildtypevirusesfromattenuatedviruses(46).Measlesvaccinevirusesreisolatedfrom

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    immunosuppressedpatientswithgiantcellpneumoniahavenucleotidesequencesalmostidentical

    tothoseofthevaccinevirus,suggestingthatvaccinevirusesareverystableevenafterprolonged

    replicationinahumanhost(46).

    Numerouspublishedstudiesofseveralthousandsofisolatesfromacutemeaslescasesinvestigated

    overthepast20yearshavefailedtodetectgenotypeAviruses(52,53,65,66,67,68,51,50,69,70)

    (71,72,73,74,75,76,77,78,79,80)(81,82,83).Becauseoftheincreasingintensityofmeasles

    immunizationprogrammes,genotypeAviruses,intheformofvaccineviruses,shouldbethemost

    abundantmeaslesgenotypeonEarth.Giventhattheyaresoinfrequentlyisolatedfrommeasles

    cases,themolecularepidemiologicaldataappearstosupportthecontentionthatvaccinevirusesdo

    notreadilyreverttowildtypetransmissibility.

    Whatistheriskofmeaslesvaccineescapemutants?

    Thereisnoconclusivepublishedevidencefortheemergenceofmeaslesvaccineescapemutants

    (84).MeaslesisatypicalRNAvirusinthatintrinsicerrorsoftheRNApolymeraseandlackof

    proofreadingmechanismsresultsinamutationrateof9x10 5perbaseperreplicationandagenomic

    mutationrateof1.4perreplication(85).Thisiswellwithinthetypicalrangeof103to10

    6mutations

    persiteperreplication(86).Asaconsequenceofthishighmutationrate,RNAviruspopulations,

    eventhoseinitiatedbyasingleinfectiousunit,arenotclonalbutconsistofalargenumberof

    geneticmicrovariantsreferredtoasquasispecies.Despitethehighmutationrate,andunlikeother

    RNAvirusessuchasinfluenzaandHIV,measlesvirusremainsremarkablystable.Howcanlive

    attenuatedvaccinesdevelopedfromwildtypemeaslesvirusesmorethanhalfacenturyagostillbe

    effectiveagainstcirculatingviruses?

    Theanswerisprobablyassociatedwithuseofthesignallinglymphocyticactivationmolecule(SLAM;

    alsoknownasCD150)receptorbythemeasleshaemagglutinin(H)protein,whichisresponsiblefor

    cellattachmentandisamajortargetforneutralizingantibodies(87).Theenvelopeofmeaslesvirus

    hastwotypesofglycoproteinspikes,designatedhaemagglutinin(H)andfusion(F)proteins.TheH

    proteinbindstospecificmolecules(receptors)ontargetcells,whiletheFproteinmediates

    membranefusionbetweenthevirusenvelopeandthehostcellplasmamembranethrough

    cooperationwiththeHprotein.In2000,SLAMwasidentifiedasacellreceptorformeaslesvirus

    (88).SLAMisexpressedoncellsoftheimmunesystem,suchasactivatedlymphocytesanddendritic

    cells(89).StudiesonthecrystallinestructureoftheHproteinhaveshownthatalthoughmostofthis

    glycoproteiniscoveredbysugarchains,thelargesurfaceareathathoststheSLAMbindingsiteis

    freefromsugarchains(90).Mutationsinthisregionarenotpermittedbecausetheyinterferewithreceptorbinding.Thisextremesequencerestrictionallowsforveryefficientproductionof

    neutralizingantibodiesthatblockbindingofthevirustoitsreceptor.Sotheoriginalvaccinestrains,

    developedinthe1960s,arestilleffectiveagainstcurrentwildtypeviruses(91).Analysisofavailable

    sequencedatafromapproximately500isolatessuggeststhatdespitetheerrorproneviral

    polymerase,theaminoacidsequenceofHisstronglyconserved,with60%oftheresiduesbeing

    identicalorverysimilar(92).Itappearsthatanymutationthatchangesthenatureofthese

    conservedresiduesresultsinnonviablevirus.

    Conclusion

    Thereisnocurrentpublisheddatatosupportevidenceforcurrentlylicensedliveattenuatedvaccinevirusesrevertingtowildtypetransmissibility.Onthecontrary,thevastmajorityofevidencepoints

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    toanimpressivelevelofgeneticstability.However,sincetheyarelivevirusesthatreplicatewithin

    vaccinerecipients,thepossibilitymustexistthattheycouldreverttowildtypetransmissibility.

    Thereisstrongexperimentalevidenceforthemonotypicnatureandgeneticstabilityofmeasles

    virusbeingbasedonuseoftheSLAMreceptor.Thereisalsonoevidencefortheestablishmentof

    vaccineescapemutants.Evenifvaccinevirusesweretoreverttowildtypetransmissibility,thereis

    noreasontosuspectthattransmissioncouldnotbecontrolledusingcurrentvaccines.

    Riskassessment:Availableinformationsuggeststhattheriskofcurrentliveattenuated

    vaccinevirusesrevertingtowildtypetransmissibilityisverylow,butitremainsapossibility.

    Riskfrompersistentinfections

    Howlongdoesmeaslesinfectionusuallypersist?

    Inclassicmeaslescasesthereisa1014dayincubationperiodbetweeninfectionandtheonsetof

    clinicalsignsandsymptoms,andinfectedpersonsareusuallycontagiousfrom23daysbeforeand

    uptofourdaysafteronsetoftherash.Hostimmuneresponsestomeaslesvirusareessentialfor

    viralclearance,clinicalrecoveryandtheestablishmentoflongtermimmunity.Earlyinnateimmune

    responsesoccurduringtheprodromalphaseandincludeactivationofnaturalkiller(NK)cellsand

    increasedproductionofinterferons(IFN)and(23,93,94).However,themechanismsandtiming

    ofnormalmeaslesvirusclearancearepoorlyunderstood.Measlesvirushasbeenisolatedfrom

    peripheralbloodmononuclearcells(PBMC)uptoaweek,andfromurineupto10days,after

    appearanceoftherash(95,96).Delayedvirusclearancehasbeendocumentedincasesof

    malnutrition(97,98,99)andpatientswithcellularimmunitydeficiencies(100,101,102).Detectionof

    measlesvirusRNAhasbeenreportedforupto4monthsinacaseofcongenitalmeasles(103),for1

    to4monthsafteruncomplicatedinfectionin90%ofHIV1infectedchildrenandmorethan50%of

    HIVnoninfectedchildren(104,105,106,107).Thesedataareconsistentwithstudiesofrhesus

    macaquesshowingthatvirusclearanceoccursover120150days(108),suggestingthatnormal

    clearanceisaprolongedprocess.DespitethereportedpersistenceofviralRNA,therehavebeenno

    reportsofinfectiousvirussheddingmorethan3to4weeksafterappearanceofsymptoms(98,99).

    Persistentinfectionwithmeaslesvirushasdefinitivelybeenassociatedwithsubacutesclerosing

    panencephalitis(SSPE),aprogressivefatalneurologicaldiseasewithhighlevelsofneuronalinfection

    bymeaslesvirusinthecentralnervoussystem(94).Inimmunocompromisedpatients,persistent

    measlesvirushasbeenlinkedtoanotherneurologicalinfection,measlesinclusionbodyencephalitis

    (MIBE)(109).Multiplesclerosis,chronicallyactiveautoimmunehepatitis,Pagetsdisease,

    otosclerosis,Crohnsdiseaseandautism,amongmanyotherdiseases,havealsobeensuggestedat

    varioustimesaslongtermsequelaeofmeaslesvirusinfection.Noconfirmedevidencehasbeen

    presented,however,tosubstantiatetheseassociations,letaloneproveacausativerelationship.

    WhatistheriskfromSSPEcases?

    SSPEisaslow,progressivediseasethatisinvariablyfatal.Theaverageperiodfrominitialmeasles

    infectiontoSSPEsymptomonset(latency)usuallyrangesbetween4and10years,buthasbeen

    reportedfrom2monthsto23years(110).Childrenarefarmorelikelytodevelopthiscomplication

    thanadults.ReportedSSPEincidencevariesfromapproximately0.2to40casespermillion

    populationperyear.Directcomparisonofdatafromdifferentcountriesisproblematicbecause

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    methodsandqualityofdiagnosishavebeeninconsistent.AnalysesofdatafromtheUKandUSA

    havecalculatedthetrueincidenceofSSPEtobeapproximately411casesofSSPEper100000cases

    ofmeasles.Ahigherriskisassociatedwithearlierinfection:theriskfollowingmeaslesinfection

    under1yearofageis18/100000comparedwith1.1/100000after5yearsofageintheUK(110).

    Obviously,asthenumberofmeaslesinfectionsdeclines,sowillthenumberofpotentialSSPEcases.

    Thediseaseinitiallymanifestsassubtlecognitivelosses,progressingtomoreovertcognitive

    dysfunction,followedbymotorloss,seizuresandeventualorganfailureinvirtuallyallaffected

    individuals.Neuronsinboththegrayandwhitematterareinfected,andthediseaseishistologically

    characterizedbythepresenceofcellularinclusionbodies(111).AserologichallmarkofSSPE,as

    comparedtotheothercentralnervoussystemcomplications,istheelevationofmeaslesspecific

    antibodiesinthebloodandcerebrospinalfluid(94).Mostimportantly,evidencefrombrainbiopsies

    ofSSPEpatientsindicatesthatinfectedneuronsdonotreleasebuddingvirus(112).Basedon

    sequencingstudiesofvirusfromthesespecimensandfromcellspersistentlyinfectedwithmeasles

    virusisolatesfromSSPEpatients,ithasbeenproposedthatthefailureofinfectedneuronstoproducecompleteextracellularvirusmaybeduetodefectsinproteinexpressioncausedby

    extensivepointmutationsintheH,fusion(F)andmatrix(M)genes(113,94,114,115,116).Thereis

    noevidencefortransmissionofmeaslesvirusfromSSPEcases.

    WhatistheriskfromMIBEcases?

    Measlesinclusionbodyencephalitis(MIBE)isararecentralnervoussystemcomplicationfollowing

    acuteMVinfection,hasbeendescribedinchildrenandadultsreceivingimmunosuppressivedrugs

    andthereforeisthoughttochieflyaffectimmunocompromisedhosts.MIBEhasalsobeenreported

    toresultfromreceiptofmeaslesvaccine(117).Theneurologicdiseaseusuallyappears3to6

    monthsaftertheacutemeaslesrash(111),withamediantimeof4months(118).Measlesantigenispresentinthebrain,andvirushasbeenisolateddirectlyfromthebrainsofaffectedindividuals

    (111,119).MIBEdiffersfromSSPEintheabsenceofelevatedserumandcerebrospinalfluid

    neutralizingantibodies(94).Thediseasecourseisrelativelyshort,lastingfromdaystoweeks,

    causingseizures,motordeficits,andstupor,oftenleadingtocomaanddeath.

    Althoughonlyaverysmallpercentageofacutemeaslesinfectionswillgoontodeveloppersistent

    complications,afewstudieshavedetectedmeaslesvirusRNAinvariousorgans,onautopsy,of

    elderlyindividualswhodiedofnonviralcauses(120,121).Thesefindingssuggestthatmeaslesvirus

    persistsinthebrains(andotherorgans)ofhealthyindividuals,andmaymanifestitselfincentral

    nervoussystemdiseaseunderconditionsofimmunocompromiseorimmunosuppression.Thishas

    beenunderlinedbythecaseofa13yearoldboythatdevelopedMIBEafterreceivingastemcell

    transplant(119).Neitherthepatientnorthestemcelldonorhadapparentrecentmeaslesexposure

    orvaccination,andneitherhadrecenttraveltomeaslesendemicregions.Thepatientwasbornin

    Chicagoduringthemeaslesepidemicof19891991(birthyear1989).Anundiagnosedcaseof

    measlesintheperiod19891991wouldsuggestalatencyperiodtoMIBEof12years,whichisnot

    typical.CasesofMIBEwithoutclearmeaslesexposureorinfectionhavebeenreported.Inareview

    ofMIBE,18%ofpatientshadnodocumentedmeaslesexposureorinfection(118);however,many

    ofthesecasesoccurredinyearswhenmeasleswasmoreprevalent.Therearenopublishedreports

    ofinfectiousmeaslesvirussheddingfromMIBEcases.

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    DoesHIVcoinfectionpresentariskforpersistentmeaslesinfectionandtransmission?

    Asdiscussedabove,measlesvirusRNAcouldbedetectedinsamplesfrom90%ofHIVinfected

    childrenonemonthafterrecoveryfromacutemeasles(104),butinthisstudynoattemptwasmade

    toculturevirusfromanysamples.InregionsofhighHIV1prevalence,coinfectionwithHIV1more

    thandoublestheoddsofdeathinhospitalizedchildrenwithmeasles(122)andmayslowtherateof

    virusclearanceslightly,butthereisnoevidencethatHIVinfectionleadstoanincreasedriskfor

    persistentmeaslesvirusinfection.NordoesHIVinfectionappeartopresentariskforpersistent

    infectionwiththemeaslesvaccinevirus.Asearchforpersistentmeaslesmumpsandrubellavaccine

    virusesinchildrenwithHIV1infectionfailedtodetectvirusinperipheralbloodmononuclearcells,

    polymorphonuclearleukocytes,orplasma(123).

    Conclusion

    Thereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe

    sheddingofinfectiousvirusorplayanypartinmeaslestransmission. Asthenumberofacute

    measlesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthe

    numberofpotentialSSPEandMIBEcases.

    AcutemeaslesinfectioninHIVinfectedindividualstendstobemoresevere,lastlongerandresultin

    ashorterlivedimmunitytoreinfection,butthereisnopublishedevidencetosuggestthatco

    infectionincreasesthepotentialforestablishmentofpersistentmeaslesinfections,eitherwithwild

    typevirusorwithvaccinederivedvirus.

    Riskassessment:Availableinformationsuggeststhattherelativelysmallnumberof

    persistentmeaslesviruscases,includingthosethatmayresultfromcoinfectionwithHIV,

    poseaverylowriskforreintroductionofmeasles.

    Riskfromnonhumanprimates

    Alargeproportionofourcurrentknowledgeofmeaslesandmeaslesinfectionmechanismshave

    comefromexperimentalinfectionofnonhumanprimates.In1911,GoldbergerandAnderson

    demonstratedthatmacaquesinoculatedwithfilteredsecretionsfrommeaslespatientsdeveloped

    measles,provingthecausativeagentwasavirus(124).Awiderangeofnonhumanprimatespecies

    aresusceptibletoexperimentalinfectionwithmeaslesvirus.Theseinclude Macacamulatta,M.

    fascicularis,M.radiata,M.cyclopis,Papiocristatus,Cercopithecusaethiops,Saimirisciureus,Colobus

    quereza,Pantroglodytes,Callithrixjacchus,Saguinusoedipus,S.fuscicollis,andAotustrivirgatus

    andAtelesspecies(125,126,127).Aswouldbeexpectedfromaneffectiveanimalmodel,many

    speciesrespondtoinfectioninamannerverysimilartohumans(128,129,130).Inadvertent

    transmissionofeithermeasles(fromhumans)orthecloselyrelatedcaninedistempervirus(from

    dogs)tocaptivenonhumanprimateshascausednumerousoutbreakswithsignificantmorbidityand

    mortality(131,127,132,133,134).Nonhumanprimatesinthewildappeartobefreefrommeasles,

    onlycontractinginfectionwhentheycomeintocontactwithinfectedhumans(125).Humanto

    primatediseasetransmissioncanpotentiallycausesignificantmorbidityandmortalityamongwild

    primatepopulations.Serologicalevidenceofmeaslesinfectioninfreerangingpopulationsofnon

    humanprimateshasbeenwelldocumented(135,136,137).Evidenceexistsofmeaslesinfectioninnonhumanprimatepopulationswithfrequentcontactwithhumanpopulations,aswellasinwild

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    populationswithminimalhumancontact(127).Acrosssectionalstudyofwildmacaques( Macaca

    tonkeana)inSulawesi,Indonesia,foundserologicalevidenceofmeaslesevidencein5of15animals

    surveyed(136).

    Becausehumanpopulationsrepresentthelargestreservoirofthemeaslesvirus,itismostlikelythat

    measlesepizooticsinnonhumanprimatepopulationsareinitiatedbyhumantononhumanprimate

    transmissionandsubsequentlyspreadbyanimaltoanimaltransmission.Duetotheirrelativelysmall

    numbers,itisunlikelythatnaturalpopulationsofnonhumanprimatesaresignificantorsustainable

    reservoirsofmeaslesvirus(127).

    Conclusion

    Althoughnonhumanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and

    animaltoanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootic

    transmission.

    Riskassessment:Availableinformationsuggeststhatinfectionsinnonhumanprimatespose

    averylowriskforreintroductionofmeasles.

    Riskoflaboratoryassociatedmeaslesinfection

    Risksposedbylaboratorymaintainedmeaslesviruses,throughaccidentalorintentionalrelease,are

    largelydependentonwhetheruniversalimmunizationagainstmeaslesiscontinuedorifitisstopped

    on,orsoonafter,globalcertification.Ifthedecisionismadetocontinueuniversalimmunization,

    possiblywithnonreplicatingvaccines,theriskposedbylaboratorymaintainedviruswillbevery

    low,sincetherewillbealmostuniversalimmunity.If,however,universalimmunizationstopsafterglobalcertification,therisksposedbylaboratorymaintainedmeaslesinfectiousmaterialswill

    progressivelyincrease,asthenumberofmeaslessusceptiblesinthepopulationincreases.Therisks

    includenotonlyaccidentalreleaseoflivemeaslesvirusfromlaboratoriesandattenuatedvirus

    vaccineproductionfacilities,butthreatofdeliberaterelease.

    Whatistheevidenceforlaboratoryacquiredmeaslesinfection?

    AseriesofsurveysforlaboratoryacquiredinfectionsconductedintheUK

    (138,139,140,141,142,143,144),theUSA(145,146,147,148,149)andJapan(150)failedtoinclude

    measlesamongthelistedinfections.Arecentreviewofprinciplesforpreventionoflaboratory

    associatedinfectionsalsofailedtomakementionofmeasles(151).Anextensiveliteraturesearchfailedtofinddocumentedevidenceoflaboratoryacquiredmeaslesinfection.Thisleavesthree

    possibilities:laboratoryacquiredmeaslesinfectionshavenotoccurred;theinfectionsthathave

    occurredhavebeenbelowthethresholdofsensitivityofthesurveillancesystems;or,measleshas

    beenconsideredatrivialdiseaseandinfectionshavenotbeenreported(152,153).

    Priortothe1970sitistobeexpectedthatalmostallstaffworkinginclinicalmicrobiologyand

    researchlaboratorieswouldhavebeenexposedtomeaslesinfectionduringchildhood.Fromthe

    1970sonwardsitistobeexpectedthatallnewstaffcomingtoworkintheselaboratorieswould

    havereceivedatleastonedoseofmeaslesvaccine.Itisunlikelytherefore,thatexposedlaboratory

    staffwoulddevelopacutemeaslessymptomsfromlaboratoryacquiredinfections.Butgiventhe

    veryhightransmissibilityofmeaslesvirus,itispossiblethatexposuretoinfectiousvirus,and

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    resultingasymptomaticinfections,orverymild,atypicalinfectionshaveoccurred.Iftheyhave

    occurred,itisprobablethattheseinfectionshavegoneundetected,orsimplyoverlookedas

    unimportant.

    Howstableismeaslesvirusintheenvironmentandinlaboratorymaterials?

    Measlesisnotaphysicallyrobustvirus.Itisviableforlessthan2hoursatambienttemperatureson

    surfacesandobjects,whiletheaerosolizedvirustypicallyremainsinfectiveforonly30minutesto2

    hours,dependingonenvironmentalconditions(154,155).Itisverysensitivetoheatandis

    inactivatedafterlessthan40minutesat56C,eveninmediumcontainingaproteinstabilizersuchas

    5%calfserum(156).Virusinmaintenancemediumlosesatleast2logsoftitrewhenstoredat+6oC

    for1420weeksandlosesallinfectivityafter1yearatthistemperature.Additionofaprotein

    stabilizerimprovesviruslongevity,withalossofapproximately2logsoftitreafter1yearat+6oC.

    Interestingly,storageat30oCofferslittleadvantageoverstorageat+6

    oC,witha12loglossoftitre

    over1year.Storageat72oCorbelowresultsinverylittlelossofvirusinfectivity,andinfectious

    materialsmaintainedatthistemperatureshouldretaininfectivityformanyyears(156).Thevirus

    survivesfreezedryingrelativelywelland,whenfreezedriedwithaproteinstabilizer,cansurvive

    storagefordecadesat70oC(156,155).Incommonwithmanyotherenvelopedvirusesitis

    inactivatedbysolvents,suchasetherandchloroform,byacids(pH10),andbyUV

    andvisiblelight.Itisalsosusceptibletomanydisinfectants,including1%sodiumhypochlorite,70%

    alcoholandformalin.

    Whichlaboratorymaterialspresentarisk?

    Measlesvirusinfectiousmaterialsincludeautopsyorclinicalsamples(e.g.pharyngealsecretions,

    urine,blood)frommeaslesinfectedpersonsorrecentliveattenuatedvaccinerecipients,and

    laboratoryderivedmaterials(e.g.virusisolatesandreferencestocks,materialsderivedfrominoculatedcellcultures,laboratoryanimals).Measlesviruspotentialinfectiousmaterials,thosethat

    aresuspectedtocontaininfectiousmeaslesviruses,includepharyngealsecretionsandblood

    samplescollectedforanypurposeatatimeandinaplacewheremeaslesviruseswerecirculating,

    andstoredunderconditionsthatwouldpreservevirusinfectivity.Theyalsoincludeproductsof

    thesematerialsinmeaslesviruspermissivecellsoranimals(157).

    Whattypesofriskdolaboratoriespresent?

    Riskspostmeasleseradicationwillexistattwolevels:

    occupationalriskofexposureamonglaboratorystaff, communityriskoflaboratoryassociatedmeaslesexposure.

    Thethreemostcommonroutesofexposuretoinfectiousagentsinthelaboratoryareingestion,

    inhalation,andinjection(153).Measlesviruscanremaininfectiousonsurfaces,suchaswork

    benchesanddoorhandles,foruptotwohours.Iftransferredfromthehandtothemouth,noseor

    conjunctiva,theycaninitiateinfectionofepithelialcells(158).Althoughtherearenorecorded

    incidentsoflaboratoryacquiredmeaslesvirusinfections,severalsurveysdocumentthefrequent

    occurrenceofingestingmorereadilyrecognizedpathogens,suchasShigellaandSalmonella

    (139,140,141,142,143,147,153).Themostcommonroutefornaturaltransmissionofmeaslesis

    believedtobebyinhalationofaerosolizedvirus;infectiousdropletsbeingproducedbytalking,

    coughingandsneezingbyinfectedindividuals(158).Smallparticles(

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    inhaleddepositprimarilyinthelowerrespiratorytract(159).Laboratoryactivitiesthatexposestaff

    toaerosolsgeneratedfrominfectiousmaterial(e.g.centrifugation,blending,vigorouspipetting,

    etc.),andexposuretoinfectedlaboratoryanimals,presentariskforinfection.Themostcommon

    routefordeliveryofcurrentmeaslesvaccinesisbyinjection.So,injectionandneedlestickinjuries

    involvingmeaslesvirusinfectiousmaterialsobviouslypresentariskforinfection.

    Communitymembersmaybeexposedtoinfectiousmeaslesvirusfrom:

    contaminatedlaboratoryworkers, infectedlaboratoryworkers, contaminatedaireffluents, transportofinfectiousmaterial, escapedinfectiousanimals.

    Again,nopublishedevidenceexistsfortheescapeofinfectiousmeaslesvirusfromthelaboratory

    intothecommunity.Giventherapidinactivationofmeaslesvirusundernormalenvironmentalconditions,thelengthoftimeavailableforinfectiousvirustobecarriedoutofthelaboratoryand

    intothecommunity,eitheronthebodyorclothesofacontaminatedworker,orincontaminatedair

    effluents,isprobablylimitedto2hours.Thisreducestherisktoaverylowlevel.Asdiscussedabove,

    availableevidencesuggeststhatimmunizedindividuals,whodevelopasymptomaticormild

    infections,areunlikelytotransmitthevirus(10),reducingthecommunityrisk.Wecanassumethat

    laboratoriesimplementinggoodlaboratorypractices(GLP)orgoodmanagementpractices(GMP)

    willminimizetherisksofreleasetotheenvironmentbyproperlypackagingandtransporting

    infectiousmaterialsinaccordancewithcurrentinternationallawsandregulations.Giventhesecurity

    concernsthatsurroundlaboratoryanimalhousesandresearchfacilities,thelikelihoodthatmeasles

    infectedanimalswouldescapeintothecommunitymustbeextremelysmall.

    Conclusion

    Althoughthereisnodirectevidenceforlaboratoryacquiredmeaslesinfectionsitispossiblethat

    theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymild

    infections.Thereisnopublishedevidencetosuggestthatthesepossibleasymptomaticormild

    infectionsresultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinacoupleof

    hoursatambienttemperaturesintheenvironment,andinfectiousmaterialsstoredattemperatures

    above30oCcanbeexpectedtoloseallinfectivityoverthecourseofonetotwoyears.

    Despitethelackofevidenceforlaboratoryacquiredmeaslesinfectionsorescapeofvirusintothe

    community,inaposteradicationworldthesemustbeconsideredpossibilitiesduetothehighly

    infectiousnatureofmeasles.

    Riskassessment:Inameaslesposteradicationworldwithoutroutineuniversal

    immunization,measleslaboratories(andmeasleslivevaccineproductionfacilities)willpose

    averylowbutincreasingriskforreintroductionofmeasles.

    Riskofintentionalreleaseofmeaslesvirus

    Bioterroristthreatsdonotworkagainstpopulationsthathavebeenfullyimmunized.However,ina

    posteradicationworldinwhichuniversalroutineimmunizationhasceased,agrowingpopulation

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    willbesusceptibletomeasles,andmeasleswill,eventually,becomeacredibleagentfor

    bioterrorism.Thedevastatingeffectofmeaslesonsusceptiblepopulationsintheprevaccination

    erahasbeenwelldocumented(158).ThisisparticularlytruefortheislandsofthePacific.In1848in

    Hawaii,10,000natives,about10percentofthepopulation,diedduringanepidemic(160,161,162).

    In1861onAneityumintheNewHebrides,thepopulationwasreducedbyabout60percentina

    measlesepidemic(163).In1875inFiji,20,000natives,20to25percentofthepopulation,diedof

    measles(164).In1907,againinFiji,6percentof30,000casesdied,andin1911onRotuma16per

    centofthepopulationdiedofmeasles(165).In1936measlescaused100deathsand14,282casesin

    theGilbertIslands(166),andin1937inHawaii,therewere205deathsfor13,680casesofmeasles

    (167).In1946intheBritishIslandsoftheSouthPacific,therewere1,000deathsfor15,000to

    20,000casesofmeasles(168).Therearemanyotheraccountsofsimilardevastatingmeasles

    epidemicsinisolatedcommunitiesaroundtheworld.

    Withadvancesinmodernmedicaltreatmentitisunlikelythatsimilarmortalityrateswouldbe

    inflictedoneortwogenerationspostmeasleseradication,butdeliberatereleasewouldcause

    extensivedisruptiontomedical,publichealthandsocialservices,andprobablyincurenormous

    containmentcosts.Thethreatofrelease,withtheknowledgeofthepotentialdisruptionand

    financialexpenseitcouldcause,wouldmakemeaslesaneffectiveagentforbioterroristsoncea

    largeenoughpopulationofmeaslessusceptibleshadaccumulated.Measlesisnotcurrentlyincluded

    intheCDCBioterrorismAgentCategories(169,170),butthissituationwillneedtobereviewedin

    theyearsfollowingeradication.

    Conclusion

    Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthe

    past.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldberepeated,thethreatofintentionalreleasewouldprobablybeveryeffectiveonceasizable

    populationofsusceptibleindividualshadaccumulated.

    Riskassessment:Theriskofdeliberatereleaseofmeasleswillbeverylowatthetimeof

    globaleradication,butwillriserapidlywithaccumulationofunvaccinatedmeasles

    susceptibles.

    Actionsrequiredtoreducetheriskofaccidentalordeliberatereleaseof

    measlesOneapproachtoreducingtheriskofmeaslesreintroductionwouldbeadoptionofastrategyto

    minimizeavailabilityofmeaslesvirus,throughremovaloflivevirusesfromlaboratoriesandsecurely

    containingallinfectiousmaterialthatremains,andestablishinganinsurancepolicyintheformofa

    vaccinestockpile.

    Reducingtheriskofaccidentalrelease:alaboratorycontainmentstrategy

    Asystematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythe

    PolioEradicationInitiative(171),startingnowandcontinuingintotheposteradicationera,would

    minimisetheriskofaccidentalreintroductionofmeaslesvirus.Thestrategyestablishedforpolio

    outlinesthreedistinctphases.Phase1wouldlastfromthepresent,whenmeaslescontinuesto

    circulate,tothetimewhenmeaslestransmissionceases.Phase2wouldcoverthecertification

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    period,andPhase3wouldtakeplaceintheposteradication,postglobalcertificationperiod.These

    threePhasesforpoliohavebeenclearlydescribedinaseriesofpublishedGlobalActionPlans

    (172,173,157).

    Thelaboratoryassociatedrisksposedbymeaslesareconsiderablylowerthanthoseposedbypolio,

    andstrategiesforreducingtheriskevenfurthershouldnotsimplyduplicatetheactivitiesdeveloped

    forpolio,butbeproportionateandappropriateformeasles.Thegeneralapproachtakenbythe

    PolioEradicationInitiative,andlessonslearnedfromimplementingthepoliocontainmentstrategy,

    shouldprovideasoundstartingpointformeasles.Strategiesforreducingtheriskinthepre

    eradicationphaseshouldbebasedonthefollowingprinciples:

    minimizingthenumberoflaboratoriesretainingmeaslesvirusinfectiousandpotentialinfectiousmaterials;

    minimizingtherisksofoperationsinlaboratoryandmeasleslivevaccineproductionfacilities;

    minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding; minimizingsusceptibilityofcommunitytomeaslesvirusspread.

    Thehighestrisksarepresentedbythoselaboratoryoperationsinvolvingmeaslesvirusreplication,

    includingthegrowthofvaccinestrainsforlivevaccineproduction.Thelowestrisksarenon

    replicative,biosafetyappropriateoperationsperformedwithpotentiallyinfectiousclinicalmaterials.

    Intheyearsleadinguptoglobaleradicationallworkwithwildmeaslesvirusesshouldrequire

    biosafetylevel2(174),withadditionalrequirementsforrestrictinglaboratoryaccess,and

    maintenanceofaccuraterecordsofmeaslesvirusmaterials.Establishingnationalmeasles

    inventories,andcallstosafelydisposeofallunwantedmeaslesinfectiousandpotentialinfectious

    materials,ashasbeenaccomplishedforpolio,wouldalsoberequired.

    Thesecondphaseofriskreductionwouldconsistessentiallyofvalidatingthecontainmentactivities

    atnational,regionalandgloballevelsasarequirementforGlobalCertification.Stoppinguniversal

    measlesimmunizationpostcertification(thirdphase)willaltertherelativeweightsoftheprinciples

    onwhichminimizingtheriskfromthelaboratoryisbased(157):

    minimizingsusceptibilityofcommunitiestomeaslesvirusspreadwillnolongerapplyinthosecountriesthatelecttostopmeaslesimmunization;

    minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding,intheabsenceofanoninfectiousvaccine,willrelysolelyonpreventionofinfection;

    minimizingthenumberoflaboratoriesretainingmeaslesvirusmaterialsandminimizingtherisksofoperationsinthoselaboratoriesbecomesmuchmoreimportant.

    Wearecurrentlyconsideringtheprospectofglobalcessationofmeaslestransmissionapproximately

    adecadefromnow,allowingreasonabletimetodevelopanappropriatemeasleslaboratory

    containmentstrategyandforlaboratoryresearchonmeaslesvirusestocontinueundercurrent,

    biosafetylevel2,conditions.Italsoallowstimeforcontinueddevelopmentofalternativemeasles

    vaccinesandspecificantivirals.

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    Developingavaccinestockpile

    Liveattenuatedmeaslesvaccineshavebeenhighlysuccessfulinprotectingpopulationsagainst

    measlesandstoppingmeaslestransmission.Asdiscussedabove,thesevaccinesareverysafe,and

    poseonlyasmallpotentialriskforestablishingtransmissionofvaccinederivedvirusesinapost

    eradicationworld.Toremovethisriskanewvaccinethathasnocapacityforreplicationor

    transmissionisrequired(175).Theidealmeaslesvaccinewouldbeinexpensive,safe,heatstable,

    immunogenicinneonatesorveryyounginfants,andadministeredasasingledosewithouttheneed

    touseaneedleorsyringe(93),be100%effectiveand100%incapableoftransmission.Whilesucha

    vaccinewouldhaveclearbenefitsfortheeradicationofmeasles,itwouldbeasavaccinefor

    stockpilingposteradicationthatitwouldcomeintoitsown.Severalvaccinecandidateswithsomeof

    thesecharacteristicsareundergoingdevelopmentandtesting.Featuresofthesenew,potential

    measlesvaccineshavebeenextensivelyreviewed(175,176).

    Howlargeameaslesvaccinestockpilewouldberequiredisverydifficulttopredictwithout

    modelling.Requirementswouldobviouslybedynamic,dependingonsomefairlycomplexvariables,

    includingthenumberofsusceptiblesaccumulatinginthecommunity,theeffectivenessofthe

    vaccine,transmissiondynamicsofthevirusandtheeffectivenesswithwhichanyeventrequiringan

    immunizationresponsewasdetected,reportedandrespondedto.Decisionsonsuchbig,expensive

    itemsasestablishingameaslesvaccinestockpileshouldnotbetakeninisolation,butconsidered

    systematicallyandincludedinaconsensusriskmanagementstrategy,ashasbeenachievedforpolio

    (177,178,179,180,181,182).Developmentofapostmeasleseradicationriskmanagementstrategy

    shouldbeginassoonaspossible.

    AreasrequiringfurtherresearchTherisksofreintroductionofmeaslespostglobaleradicationmaybereducedbyapplying

    knowledgeacquiredthroughkeyareasofresearchconductedintheyearsleadinguptoeradication.

    Thesekeyareasincludethefollowing:

    Greaterunderstandingofthetransmissiondynamicsofmeasles

    Indrawingupthecertificationcriteriaandvalidationrequirementsitwillbenecessarytoengage

    expertsfamiliarwiththedevelopmentofdynamicandstochasticmodelsofmeaslestransmission,

    persistenceandelimination.Thiswillbeparticularlyimportantfordeterminingthecertificationand

    validationrequirementsforlowincome,highdensitypopulations.Basedontheexperiencegained

    inpolioeradication,thiswillbemostrelevantforselectedpopulationsinAfrica,theIndiansubcontinentandlargerefugee/migrantpopulationcamps.

    Importantinformationcanalsoprobablybegainedfromdetailedepidemiologicalandmolecular

    analysisofoutbreaks,particularlythoseoccurringinhighlyimmunizedpopulations,highdensity

    populations,andingenerallyhighlyimmunizedpopulationswithinadequatelyimmunizedsub

    populations.

    Withtherapidincreaseinthenumberofhighlyimmunizedpopulations,opportunitiesforstudying

    asymptomaticandatypicalinfectionsandtheirpotentialroleintransmissionshouldbetaken.

    Greaterunderstandingofthechangesbroughtaboutbytheattenuationprocess

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    Ifcurrentlylicensedattenuatedmeaslesvaccinesaretobeusedinaposteradicationworld,more

    informationonthenatureofthechangescausedbyattenuationandthepotentialforreversionto

    wildtypecharacteristicswillberequired.Analternativewouldbetospeedupdevelopment,testing

    andintroductionofnewmeaslesvaccinesthatarenotdependentonliveattenuatedvirus.

    Moreunderstandingofthenatureofthecomplexinteractionbetweenmeaslesvirusandthehost

    immunesystem,includingbothhumoralandcellmediatedresponses,wouldprobablybenefit

    continueduseofexistingvaccinesanddevelopmentofnewvaccines.

    Intheyearsleadinguptoglobaleradication,allgenotypeAvirusesdetectedinassociationwith

    acutecasesofmeaslesshouldbethoroughlyscrutinized.Fullepidemiologicalinformationwillbe

    required,andadditionalsequencedatafrombothclinicalsamplesandcorrespondingviralisolates

    willbenecessarytoruleoutthepossibilityoftransmissionofvaccinederivedvirus.Thorough

    geneticanalyses,includingfullgenomicsequencing,shouldbeperformedonselectedvaccine

    virusesthatareassociatedwithcommonvaccinereactionsaswellasthosedetectedintheveryrare

    severreactionstovaccination.

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    Bibliography

    1. AndersonRM.Biologicalchallengestoposteradication.Herdimmunityandthedesignofvaccinationprograms.InKnoblerS,

    LederbergJ,PrayLA.ConsiderationsforviralDiseaseeradication.Lessonslearnedandfuturestrategies.Workshopsummary.

    Washington:NationalAcademicPress;2002.p.6577.

    2. BlackFL.Measlesendemicityininsularpopulations:criticalcommunitysizeanditsevolutionaryimplication.JournalofTheoretical

    Biology.1966;11(2):p.207211.

    3. KeelingMJ,GrenfellBT.Diseaseextinctionandcommunitysize:modellingthepersistenceofmeasles.Science.1997;275:p.6567.

    4. KouadioIK,KamigakiT,OshitaniH.Measlesoutbreaksindisplacedpopulations:areviewoftransmission,morbidityandmortality

    associatedfactors.BMCInternationalHealthandHumanRights.2010;10:5.

    5. SzuszEK,GarrisonLP,BauchCT.Areviewofdataneededtoparameterizeadynamicmodelofmeaslesindevelopingcountries.BMC

    ResearchNotes.2010;3:75.

    6. TooleMJ,SteketeeRW,WaldmanRJ,NieburgP.Measlespreventionandcontrolinemergencysettings.BulletinoftheWorldHealth

    Organization.1989;67:p.381388.

    7. EdmostonMB,AddissDG,McPhersonJT,BergJL,CircoSR,DavisJP.Mildmeaslesandsecondaryvaccinefailureduringasustained

    outbreakinahighlyvaccinatedpopulation.JAMA.1990;263:p.24672471.

    8. HuissS,DamienB,SchneiderF,MullerCP.Characteristicsofasymptomaticsecondaryimmuneresponsestomeaslesvirusinlate

    convalescentdonors.ClinicalandExperimentalImmunology.1997;109(3):p.416420.

    9. OzanneG,DHalewynMA.Secondaryimmuneresponseinavaccinatedpopulationduringalargemeaslesepidemic.Journalof

    ClinicalMicrobiology.1992;30:p.17781782.

    10. HelfandRF,KimDK,GaryHEJ,EdwardsGL,BissonGP,PapaniaMJ,etal.Nonclassicmeaslesinfectionsinanimmunepopulation

    exposedtomeaslesduringacollegebustrip.JournalofMedicalVirology.1998;56(4):p.337341.

    11. VardasE,KreisS.Isolationofmeaslesvirusfromanaturallyimmune,asymptomaticallyre infectedindividual.JournalofClinical

    Virology.1999;13(3):p.173179.

    12. ChenRT,MarkowitzLE,AlbrechtP,StewartJA,MofensonLM,PrebludSR,etal.Measlesantibody:reevaluationofprotect ivetiters.

    JournalofInfectiousDiseases.1990;162(5):p.10361042.

    13. WhittleHC,AabyP,SambB,JensenH,BennettJ,SimondonF.Effectofsubclinicalinfectiononmaintainingimmunityagainst

    measlesinvaccinatedchildreninWestAfrica.Lancet.1999;353(9147):p.98102.

    14. LievanoFA,PapaniaMJ,HelfandRF,HarpazR,WallsL,KatzRS,etal.Lackofevidenceofmeaslesvirussheddinginpeoplewith

    inapparentmeaslesvirusinfections.Journalofinfectiousdiseases.2004;189Suppl1:p.165170.

    15. SonodaS,TN.Detectionofmeaslesvirusgenomeinlymphocytesfromasymptomatic healthychildren.JournalofMedicalVirology.

    2001;65(2):p.381387.

    16. CherryJD,FeiginRD,LobesLAJ,HinthornDR,ShackelfordPG,ShirleyRH,etal.Urbanmeaslesinthevaccineera:aclinical,

    epidemiologic,andserologicstudy.JournalofPediatrics.1972;81(2):p.217230.

    17. CherryJD,FeiginRD,LobesLAJ,ShackelfordPG.Atypicalmeaslesinchildrenpreviouslyimmunizedwithattenuatedmeaslesvirus

    vaccines.Pediatrics.1972;50(5):p.712717.

  • 7/27/2019 measles, morbili

    23/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page23

    18. SmithFR,CurranAS,RacitiKA,BlackFL.Reportedmeaslesinpersonsimmunologicallyprimedbypriorvaccination.Journalof

    Pediatrics.1982;101(3):p.391393.

    19. ReyesMA,deBorreroMF,RoaJ,BergonzoliG,SaraviaNG.Measlesvaccinefailureafterdocumentedseroconversion.Pediatric

    InfectiousDiseaseJournal.1987;6(9):p.848851.

    20. AabyP,BukhJ,LeerhyJ,LisseIM,MordhorstCH,PedersenIR.Vaccinatedchildrengetmildermeaslesinfect ion:acommunitystudy

    fromGuineaBissau.JournalofInfectiousDiseases.1986;154(5):p.858863.

    21. LinnemannCCJ,RotteTC,SchiffGM,YoutseyJL.Aseroepidemiologicstudyofameaslesepidemicinahighlyimmunizedpopulation.

    AmericanJournalofEpidemiology.1972;95(3):p.238246.

    22. EndersJF,PeeblesTC.Propagationintissueculturesofcytopathicagentsfrompatientswithmeasles.ProceedingsoftheSocietyfor

    ExperimentalBioliologyandMedicine.1954;86:p.277286.

    23. MossWJ,ScottS.WHOImmunologicalBasisforImmunizationSeries.Module7:Measles.Geneva:WorldHealthOrganization;2009.

    24. ParksCL,LerchRA,WalpitaP,WangHP,SidhuMS,UdemSA.Comparisonofpredictedaminoacidsequencesofmeaslesvirusstrains

    intheEdmonstonvaccinelineage.JournalofVirology.2001;75:p.910920.

    25. KrugmanS.FurtherattenuatedMeaslesVaccine:CharacteristicsandUse.ReviewsofInfectiousDiseases.1983;5:p.477481.

    26. HirayamaM.MeaslesVaccinesUsedinJapan.ReviewsofInfectiousDiseases.1983;5:p.495503.

    27. PeradzeTV,SmorodintsevAA.EpidemiologyandSpecificProphylaxisofMeasles.ReviewsofInfectiousDiseases.1983;5:p.487490.

    28. XiangJ,ChenZ.MeaslesVaccineinthePeople'sRepublicofChina.ReviewsofInfectiousDiseases.1983;5:p.506510.

    29. MakinoS.DevelopmentandCharacteristicsofLiveAIKCMeaslesVirusVaccine:ABriefReport.ReviewsofInfectiousDiseases.1983;

    5:p.504505.

    30. BorgesMB,CarideE,JaborAV,MalachiasJMN,FreireMS,HommaA,etal.StudyofthegeneticstabilityofmeaslesvirusCAM70

    vaccinestrainafterserialpassagesinchickenembryofibroblastsprimarycultures.VirusGenes.2008;36:p.3544.

    31. BorgesMBJ,MannGF,FreireMdS.BiologicalCharacterizationofClonesDerivedfromtheEdmonstonStrainofMeaslesVirusin

    ComparisonwithSchwarzandCAM70VaccineStrains.MemInstOswaldoCruz,RiodeJaneiro.1996;91:p.507514.

    32. TaminA,RotaPA,WangZD,HeathJL,AndersonLJ,BelliniWJ.Antigenicanalysisofcurrentwildtypeandvaccinestrainsofmeasles

    virus.JournalofInfectiousDiseases.1994;170:p.795801.

    33. ZhangY,ZhouJ,BelliniWJ,XuW,RotaPA.GeneticcharacterizationofChinesemeaslesvaccinesbyanalysisofcompletegenomic

    sequencesJ.Journalofmedicalvirology.2009;81:p.14771483.

    34. WardB,BoulianneN,RatnamS,GuiotMC,CouilardM,DeSerresG.Cellularimmunityinmeaslesvaccinefailure:demonstrationof

    measlesantigenspecificlymphoproliferativeresponsesdespitelimitedserumantibodyproductionafterrevaccination.Journalof

    InfectiousDiseases.1995;172:p.15911955.

    35. CohenJI.Vaccineassociatedcasesduetoimmunizationwithlivevirusvaccines.InKnoblerS,LederbergJ,PrayLA.Considerations

    forViralDiseaseEradication.LessonslearnedandFuturestrategies.Washington,DC:NationalAcademyPress;2002.p.9097.

    36. RotaPA,KhanAS,DurigonE,YuranT,VillamarzoYS,BelliniWJ.DetectionofMeaslesVirusRNAinUrineSpecimensfromVaccine

    Recipients.JournalofClinicalMicrobiology.1995;33:p.24852488.

    37. LlanesRodasR,LiuC.Rapiddiagnosisofmeaslesfromurinarysedimentsstainedwithfluorescentantibody.NewEnglandJournalof

    Medicine.1966;275:p.516523.

  • 7/27/2019 measles, morbili

    24/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page24

    38. TakedaM.Measlesvirusbreaksthroughepithelialcellbarrierstoachievetransmission.JournalofClinicalInvestigation.2008;118:

    p.23862389.

    39. LeonardVHJ,SinnPL,HodgeG,MiestT,DevauxP,OezguenN,etal.Measlesvirusblindtoitsepithelialcellreceptorremainsvirulent

    inrhesusmonkeysbutcannotcrosstheairwayepitheliumandisnotshed.JournalofClinicalInvestigation.2008;118:p.24482458.

    40. LudlowM,AllenI,SchneiderSchauliesJ.Systemicspreadofmeaslesvirus:overcomingtheepithelialandendothelialbarriers.

    ThrombosisandHaemostasis.2009;102(6):p.10501056.

    41. HarrisonMS,SakaguchiT,SchmittAP.Paramyxovirusassemblyandbudding:Buildingparticlesthattransmitinfections.International

    JournalofBiochemistryandCellBiology.2010;InPress(doi:10.1016/j.biocel.2010.04.005).

    42. WorldHealthOrganization.Globaldistributionofmeaslesandrubellagenotypesupdate.WeeklyEpidemiologicalRecord.2006;81:

    p.474479.

    43. RiddellMA,RotaJS,RotaPA.Reviewofthetemporalandgeographicaldistributionofmeaslesvirusgenotypesintheprevaccineand

    postvaccineeras.VirologyJournal.2005;2:p.87.

    44. RotaPA,FeatherstoneDA,BelliniWJ.Molecularepidemiologyofmeaslesvirus.Currenttopicsinmicrobiologyandimmunology.

    2009;330:p.129150.

    45. RotaJS,WangZD,RotaPA,BelliniWJ.ComparisonofsequencesoftheH,F,andNcodinggenesofmeaslesvirusvaccinestrains.

    Virusresearch.1994;31:p.317330.

    46. BelliniWJ,RotaPA.Geneticdiversityofwildtypemeaslesviruses:implicationsforglobalmeasleseliminationprograms.Emerging

    InfectiousDieases.1998;4(1):p.2935.

    47. ChristensenLS,SchollerS,SchierupMH,VestergaardBF,MordhorstCH.Sequenceanalysisofmeaslesvirusstrainscollectedduring

    thepreandearlyvaccinationerainDenmarkrevealsaconsiderablediversityofancientstrains.Actapathologica,microbiologica,et

    immunologicaScandinavica.2002;110:p.113122.

    48. RotaPA,BloomAE,VanchiereJA,BelliniWJ.Evolutionofthenucleoproteinandmatrixgenesofwildtypestrainsofmeaslesvirus

    isolatedfromrecentepidemics.Virology.1994;198(2):p.724730.

    49. RotaPA,RotaJS,ReddSB,PapaniaMJ,BelliniWJ.Geneticanalysisofmeaslesvirusesisolatedintheunitedstatesbetween1989and

    2001:absenceofanendemicgenotypesince1994.Journalofinfectiousdiseases.2004;189Suppl1:p.S160164.

    50. KremerJR,BrownKE,JinL,ale.Highgeneticdiversityofmeaslesvirus,WorldHealthOrganizationEuropeanRegion,20052006.

    Emerginginfectiousdiseases.2008;14(1):p.107114.

    51. ShulgaSV,RotaPA,KremerJR,NaumovaMA,MullerCP,TikhonovaNT,etal.Geneticvariability ofwildtypemeaslesviruses,

    circulatingintheRussianFederationduringtheimplementationoftheNationalMeaslesEliminationProgram,20032007.Clinical

    microbiologyandinfection.2009;15:p.528537.

    52. ChiboD,BirchCJ,RotaPA,CattonMG.MolecularcharacterizationofmeaslesvirusesisolatedinVictoria,Australia,between1973

    and1998.JournalofGeneralVirology.2000;81:p.25112518.

    53. TipplesGA,GrayM,GarbuttM,RotaPA,ProgramCMS.GenotypingofmeaslesvirusinCanada:19792002.Journalofinfectious

    diseases.2004;189Suppl1:p.S171176.

    54. OutlawMC,PringleCR.SequencevariationwithinanoutbreakofmeaslesvirusintheCoventryareaduringspring/summer1993.

    VirusResearch.1995;39(1):p.311.

    55. ZhangY,ZhuZ,RotaPA,JiangX,HuJ,ale.MolecularepidemiologyofmeaslesvirusesinChina,19952003.VirologyJournal.2007

    February;4(14).

  • 7/27/2019 measles, morbili

    25/31

  • 7/27/2019 measles, morbili

    26/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page26

    hokkaidodistrict,Japan,2007.JapaneseJournalofInfectiousDiseases.2009;62(3):p.209211.

    75. GrothC,BottigerB,PlesnerA,ChristiansenA,GlismannS,HoghB.NosocomialmeaslesclusterinDenmarkfollowinganimported

    case,December2008January2009.EuroSurveillance.2009;14(8):p.19126.

    76. CarrMJ,ConwayA,WatersA,MoranJ,HassanJ,HallWW,etal.MolecularepidemiologyofcirculatingmeaslesvirusinIreland2002

    2007.JournalofMedicalVirology.2009;81(1):p.125129.

    77. NigatuW,JinL,CohenBJ,NokesDJ,EtanaM,CuttsFT,etal.MeaslesvirusstrainscirculatinginEthiopiain19981999:molecular

    characterisationusingoralfluidsamplesandidentificationofanewgenotype.JournalofMedicalVirology.2001;65(2):p.373380.

    78. LemmaE,SmitSB,BeyeneB,NigatuW,BabaniyiOA.GeneticcharacterizationandprogressionofB3measlesgenotypeinEthiopia:a

    studyoffivemeaslesoutbreakcases.EthiopianMedicalJournal.2008;46(1):p.7985.

    79. KokotasSN,BolanakiE,SgourasD,PogkaV,LogothetiM,KossivakisA,etal.CocirculationofgenotypesD4andD6inGreeceduring

    the2005to2006measlesepidemic.DiagnosticMicrobiologyandInfectiousDisease.2008;62(1):p.5866.

    80. ChironnaM,PratoR,SallustioA,MartinelliD,GerminarioC,LopalcoP,etal.Geneticcharacterizationofmeaslesvirusstrains

    isolatedduringanepidemicclusterinPuglia,Italy20062007.VirologyJournal.2007Sept21;4:p.90.

    81. WichmannO,HellenbrandW,SagebielD,SantibanezS,AhlemeyerG,VogtG,etal.LargemeaslesoutbreakataGermanpublic

    school,2006.PediatricInfectiousDiseaseJournal.2007;26(9):p.782786.

    82. JiY,XuS,ZhangY,ZhuZ,MaoN,JiangX,etal.GeneticcharacterizationofwildtypemeaslesvirusesisolatedinChina,20062007.

    VirologyJournal.2010;7(1):p.105.

    83. TruongAT,MuldersMN,GautamDC,AmmerlaanW,deSwartRL,KingCC,etal.GeneticanalysisofAsianmeaslesvirusstrainsnew

    endemicgenotypeinNepal.VirusResearch.2001;76(1):p.7178.

    84. GriffinDE.Measles.InKnipeDM,HowleyPM,GriffinDE,LambRA,MartinMA,RoizmanB,etal.,editors.FieldsVirology.5thed.

    Philadelphia:LippincottWilliams&Wilkins;2007.p.15511585.

    85. SchragSJ,RotaPA,BelliniWJ.SpontaneousMutationRateofMeaslesVirus:DirectEstimationBasedonMutationsConferring

    MonoclonalAntibodyResistance.JournalofVirology.1999;73(1):p.5154.

    86. HollandJJ,delaTorreJC,SteinhauerDA.RNAviruspopulationsasquasispecies.CurrentTopicsinMicrobiologyandImmunology.

    1992;176:p.120.

    87. deSwartRL,YkselS,OsterhausAD.Relativecontributionsofmeaslesvirushemagglutininandfusionproteinspecificserum

    antibodiestovirusneutralization.JournalofVirology.2005;79(17):p.1154711551.

    88. TatsuoH,OnoN,TanakaK,YanagiY.SLAM(CDw150)isacellularreceptorformeaslesvirus.Nature.2000;406:p.893897.

    89. VeilletteA.ImmuneregulationbySLAMfamilyreceptorsandSAPrelatedadaptors.NatureReviewsImmunology.2006;6:p.5666.

    90. HashiguchiT,KajikawaM,MaitaN,TakedaM,KurokiK,SasakiK,etal.Crystalstructureofmeaslesvirushemagglutininprovides

    insightintoeffectivevaccines.ProceedingsoftheNationalAcademyofSciences.2007;104(49):p.1953519540.

    91. SantibanezS,NiewieskS,HeiderA,SchneiderSchauliesJ,BerbersGA,ZimmermannA,etal.Probingneutralizingantibodyresponses

    againstemergingmeaslesviruses(MVs):immuneselectionofMVbyHproteinspecificantibodies?JournalofGeneralVirology.

    2005;86(Pt2):p.365374.

    92. RuigrokRW,GerlierD.StructureofthemeaslesvirusHglycoproteinshedslightonanefficientvaccine.ProceedingsoftheNational

    AcademyofSciences.2007;104(52):p.2063920640.

  • 7/27/2019 measles, morbili

    27/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page27

    93. MossWJ,GriffinDE.Globalmeasleselimination.NatureReviews.Microbiology.2006;4(12):p.900908.

    94. RimaBK,DuprexWP.Molecularmechanismsofmeaslesviruspersistence.VirusResearch.2005;111(1):p.132147.

    95. ForthalDN,AarnaesS,BlandingJ,delaMazaL,TillesJG.Degreeandlengthofviremiainadultswithmeasles.JournalofInfectious

    Diseases.1992;166(2):p.421424.

    96. GresserI,KatzSl.Isolationofmeaslesvirusfromurine.NewEnglandJournalofMedicine.1960;263:p.452454.

    97. DossetorJ,WhittleHC,GeenwoodBM.Persistentmeaslesinfectioninmalnourishedchildren.BritishMedicalJournal.1977;1:p.

    16331635.

    98. ScheifeleDW,ForbesCE.ProlongedgiantcellexcretioninsevereAfricanmeasles.Pediatrics.1972;50(6):p.867873.

    99. MitusAEJF,MCJ,HollowayA.Persistenceofmeaslesvirusanddepressionofantibodyformationinpatientswithgiantcell

    pneumoniaaftermeasles.NewEnglandJournalofMedicine.1959;261:p.882889.

    100. BudkaH,UrbanitsS,LiberskiPP,EichingerS,PopowKrauppT.Subacutemeaslesvirusencephalitis:anewandfatalopportunistic

    infectioninapatientwithAIDS.Neurology.1996;46(2):p.586587.

    101. EndersJF,McCarthyK,MitusA,JCW.Isolationofmeaslesvirusatautopsyincasesofgiantcellpneumoniawithoutrash.New

    EnglandJournalofMedicine.1959;261:p.875881.

    102. MarkowitzLE,ChandlerFW,RoldanEO,SaldanaMJ,RoachKC,HutchinsSS,etal.Fatalmeaslespneumoniawithoutrashinachild

    withAIDS.JournalofInfectiousDiseases.1988;158(2):p.480483.

    103. NakataY,NakayamaT,IdeY,KizuR,KoinumaG,BambaM.Measlesvirusgenomedetecteduptofourmonthsinacaseofcongenital

    measles.ActaPaediatrica.2002;91(11):p.12631265.

    104. PermarS,MossWJ,RyonJJ,MonzeM,CuttsF,QuinnTC,etal.Prolongedmeaslesvirussheddinginhumanimmunodeficiencyvirus

    infectedchildren,detectedbyreversetranscriptasepolymerasechainreaction.JournalofInfectiousDiseases.2001;183(4):p.532

    538.

    105. RiddellMA,ChiboD,KellyHA,CattonMG,BirchCJ.Investigationofoptimalspecimentypeandsamplingtimefordetectionof

    measlesvirusRNAduringameaslesepidemic.JournalofClinicalMicrobiology.2001;39(1):p.375376.

    106. vanBinnendijkRS,vandenHofS,vandenKerkhofH,KohlRH,WooninkF,BerbersGA,etal.Evaluationofserologicalandvirological

    testsinthediagnosisofclinicalandsubclinicalmeaslesvirusinfectionsduringanoutbreakofmeaslesinTheNetherlands.Journalof

    InfectiousDiseases.2003;188(6):p.898903.

    107. RiddellMA,MossWJ,HauerD,MonzeM,GriffinDE.SlowclearanceofmeaslesvirusRNAafteracuteinfection.JournalofClinical

    Virology.2007;39(4):p.312317.

    108. PanCH,ValsamakisA,ColellaT,NairN,AdamsRJ,PolackFP,etal.Modulationofdisease,Tcellresponses,andmeaslesvirus

    clearanceinmonkeysvaccinatedwithHencodingalphavirusrepliconparticles.ProceedingsoftheNationalAcademyofSciences.

    2005;102(33):p.1158111588.

    109. terMeulenV,StephensonJR,KrethHW.Subacutesclerosingpanencephalitis.InFraenkelConratH,WagnerRR,editors.

    ComprehensiveVirology,vol.18.NewYork:PlenumPress;1983.p.105159.

    110. CampbellH,AndrewsN,BrownKE,MillerE.ReviewoftheeffectofmeaslesvaccinationontheepidemiologyofSSPE.International

    JournalofEpidemiology.2007;36:p.13341348.

    111. YoungVA,RallGF.Makingittothesynapse:Measlesvirusspreadinandamongneurons.CurrentTopicsinMicrobiologyand

    Immunology.2009;330:p.330.

  • 7/27/2019 measles, morbili

    28/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page28

    112. PaulaBarbosaMM,CruzC.Nervecellfusioninacaseofsubacutesclerosingpanencephalitis.AnnalsofNeurobiology.1981;9:p.

    400403.

    113. CattaneoR,SchmidA,BilleterMA,SheppardRD,UdemSA.Multipleviralmutationsratherthanhostfactorscausedefectivemeasles

    virusgeneexpressioninasubacutesclerosingpanencephalitiscellline.JournalofVirology.1988;62(4):p.13881397.

    114. AyataM,KomaseK,ShingaiM,MatsunagaI,KatayamaY,OguraH.Mutationsaffectingtranscriptionalterminationinthepgeneend

    ofsubacutesclerosingpanencephalitisviruses.JournalofVirology.2002;76(2):p.1306213068.

    115. HottaH,NiheiK,AbeY,KatoS,JiangDP,NaganoFujiiM,etal.Fulllengthsequenceanalysisofsubacutesclerosingpanencephalitis

    (SSPE)virus,amutantofmeaslesvirus,isolatedfrombraintissuesofapatientshortlyafteronsetofSSPE.Microbiologyand

    Immunology.2006;50(7):p.525534.

    116. JiangDP,IdeYH,NaganoFujiiM,ShojiI,HottaH.SinglepointmutationsoftheMproteinofameaslesvirusvariantobtainedfroma

    patientwithsubacutesclerosingpanencephalitiscriticallyaffectsolubilityandsubcellularlocalizationoftheMproteinandcellfree

    virusproduction.MicrobesandInfection.2009;11(4):p.467475.

    117. BitnunA,ShannonP,DurwardA,RotaPA,BelliniWJ,GrahamC,etal.Measlesinclusionbodyencephalitiscausedbythevaccine

    strainofmeaslesvirus.Clinicalinfectiousdiseases.1999;29:p.855861.

    118. MustafaMMWSWNBWTCSJ.Subacutemeaslesencephalitisintheyoungimmunocompromisedhost:reportoftwocasesdiagnosed

    bypolymerasechainreactionandtreatedwithribavirinandreviewoftheliterature.ClinicalInfectiousDiseases.1993;16(5):p.654

    660.

    119. FreemanAF,JacobsohnDA,ShulmanST,BelliniWJ,JaggiP,deLeonG,etal.Anewcomplicationofstemcelltransplantation:

    measlesinclusionbodyencephalitis.Pediatrics.2004;114(5):p.e657660.

    120. KatayamaYKKNATYHMHH.Detect ionofmeaslesvirusmRNAfromautopsiedhumantissues.JournalofClinicalMicrobiology.1998;

    36(1):p.299301.

    121. KatayamaY,HottaH,NishimuraA,TatsunoY,HommaM.DetectionofmeaslesvirusnucleoproteinmRNAinautopsiedbraintissues.JournalofGeneralVirology.1995;76(12):p.32013204.

    122. MossWJ,FisherC,ScottS,MonzeM,RyonJJ,QuinnTC,etal.HIVtype1infectionisariskfactorformortalityinhospitalized

    Zambianchildrenwithmeasles.ClinicalInfectiousDiseases.2008;46(4):p.523527.

    123. FrenkelLMNKGACJ.Asearchforpersistentmeasles,mumps,andrubellavaccinevirusinchildrenwithhumanimmunodeficiency

    virustype1infection.ArchivesofPediatricsandAdolescentMedicine.1994;148(1):p.5760.

    124. GardnerMB,LuciwPA.Macaquemodelsofhumaninfectiousdisease.ILARJournal.2008;49(2):p.220255.

    125. MacArthurJA,MannPG,OreffoV,ScottGB.Measlesinmonkeys:anepidemiologicalstudy.JournalofHygiene.1979;83(2):p.207

    212.

    126. ElMubarakH,YkselS,vanAmerongenG,MulderPG,MukhtarMM,OsterhausAD,etal.Infectionofcynomolgusmacaques

    (Macacafascicularis)andrhesusmacaques(Macacamulatta)withdifferentwildtypemeaslesviruses.JournalofGeneralVirology.

    2007;88:p.20282034.

    127. JonesEngelL,EngelGA,SchillaciMA,LeeB,HeidrichJ,ChaliseM,etal.Consideringhumanprimatetransmissionofmeaslesvirus

    throughtheprismofriskanalysis.AmericalJournalofPrimatology.2006;68(9):p.868879.

    128. ZhuYD,HeathJ,CollinsJ,GreeneT,AntipaL,RotaP,etal.Experimentalmeasles.II.Infect ionandimmunityintherhesusmacaque.

    Virology.1997;233(1):p.8592.

    129. vanBinnendijkRS,vanderHeijdenRW,vanAmerongenG,UytdeHaagFG,OsterhausAD.Viralreplicationanddevelopmentofspecificimmunityinmacaquesafterinfectionwithdifferentmeaslesvirusstrains.JournalofInfectiousDiseases.1994;170(2):p.

  • 7/27/2019 measles, morbili

    29/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page29

    443448.

    130. deSwartRL.Measlesstudiesinthemacaquemodel.Currenttopicsinmiocrobiologyandimmunology.2009;330:p.5572.

    131. ChoiYK,SimonMA,KimDY,YoonBI,KwonSW,WLK,etal.FatalmeaslesvirusinfectioninJapanesemacaques(Macacafuscata).

    VeterinaryPathology.1999;36(6):p.594600.

    132. WillyME,WoodwardRA,ThorntonVB,WolffAV,FlynnBM,HeathJL,etal.ManagementofameaslesoutbreakamongOldWorld

    nonhumanprimates.LaboratoryAnimalScience.1999;49:p.4248.

    133. YoshikawaY,OchikuboF,MatsubaraY,TsuruokaH,IshiiM,ShirotaK,etal.Naturalinfectionwithcaninedistempervirusina

    Japanesemonkey(Macacafuscata).VeterinaryMicrobiology.1989;20(3):p.193205.

    134. SunZ,LiA,YeH,ShiY,HuZ,ZengL.NaturalinfectionwithcaninedistempervirusinhandfeedingRhesusmonkeysinChina.

    VeterinaryMicrobiology.2010;141(34):p.374378.

    135. BhattPN,BrandtCD,WeissR,FoxJP,ShafferMF.ViralinfectionsofmonkeysintheirnaturalhabitatinsouthernIndia.II.Serological

    evidenceofviralinfection.AmericanJournalofTropicalMedicineandHygiene.1966;15(4):p.561566.

    136. JonesEngelL,EngelGA,SchillaciMA,BaboR,FroehlichJ.Detectionofantibodiestoselectedhumanpathogensamongwildandpet

    macaques(Macacatonkeana)inSulawesi,Indonesia.AmericalJournalofPrimatology.2001;54(3):p.171178.

    137. ShahKV,SouthwickCH.Prevalenceofantibodiestocertainvirusesinseraoffreelivingrhesusandofcaptivemonkeys.Indian

    JournalofMedicalResearch.1965;53:p.488500.

    138. GristNR.Hepatitisandotherinfectionsinclinicallaboratorystaff,1979.JournalofClinicalPathology.1981;34(6):p.655658.

    139. GristNR.InfectionsinBritishclinicallaboratories198081.JournalofClinicalPathology.1983;36(2):p.121126.

    140. GristNR,EmslieJ.InfectionsinBritishclinicallaboratories,19823.JournalofClinicalPathology.1985;38(7):p.721725.

    141. GristNR,EmslieJA.InfectionsinBritishclinicallaboratories,19845.JournalofClinicalPathology.1987;40(8):p.826829.

    142. GristNR,EmslieJA.InfectionsinBritishclinicallaboratories,198687.JournalofClinicalPathology.1989;42(7):p.677681.

    143. GristNR,EmslieJA.InfectionsinBritishclinicallaboratories,19881989.JournalofClinicalPathology.1991;44(8):p.667669.

    144. WalkerD,CampbellD.AsurveyofinfectionsinUnitedKingdomlaboratories,19941995.JournalofClinicalPathology.1999;52(6):

    p.415418.

    145. SulkinSE,PikeRM.Surveyoflaboratoryacquiredinfections.AmericanJournalofPublicHealthandtheNation'sHealth.1951;41(7):

    p.769781.

    146. PikeRM,SulkinSE,SchulzeML.Continuingimportanceoflaboratoryacquiredinfections.AmericanJournalofPublicHealthandthe

    Nation'sHealth.1965;55:p.190199.

    147. PikeRM.Laboratoryassociatedinfections:summaryandanalysisof3921cases.HealthLaboratoryScience.1976;13(2):p.105114.

    148. PikeRM.Laboratoryassociatedinfections:incidence,fatalities,causes,andprevention.AnnualReviewofMicrobiology.1979;33:p.

    4166.

    149. VesleyD,HartmannHM.Laboratoryacquiredinfectionsandinjuriesinclinicallaboratories:a1986survey.AmericanJournalof

    PublicHealth.1988;78(9):p.12131215.

  • 7/27/2019 measles, morbili

    30/31

    DrRaySanders.Measlesreintroductionriskanalysis

    Page30

    150. ShimojoH.VirusinfectionsinlaboratoriesinJapan.BibliothecaHaematologica.1975;(40):p.771773.

    151. KimmanTG,SmitE,KleinMR.Evidencebasedbiosafety:areviewoftheprinciplesandeffectivenessofmicrobiologicalcontainment

    measures.ClinicalMicrobiologyReviews.2008;21(3):p.403425.

    152. CollinsCH.Laboratoryacquiredinfections:history,incidence,causes,andprevention.3rded.Oxford:ButterworthHeinemannLtd;

    1993.

    153. SewellDL.LaboratoryAssociatedInfectionsandBiosafety.ClinicalMicrobiologyReviews.1995;8(3):p.398405.

    154. GershonAA.MeaslesVirus(Rubeola).InMandellG,DouglasR,BennettJ,editors.PrinciplesandPracticeofInfectiousDiseases.3rd

    ed.NewYork:ChurchillLivingstone;1990.p.1279.

    155. ReddS,MarkowitzE,KatzS.Measlesvaccine.InPlotkinSA,OrensteinWA,editors.Vaccines.3rded.Philadelphia:Saunders;1999.p.

    222266.

    156. MusserSJ,UnderwoodGE,WeedSD,OssewaardeJL.StudiesonMeaslesVirus.II.PhysicalPropertiesandInactivationStudiesof

    MeaslesVirus.JournalofImmunology.1960;85:p.292297.

    157. DowdleW,vanderAvoortH,deGourvilleE,DelpeyrouxF,DesphandeJ,HoviT,etal.Containmentofpoliovirusesaftereradication

    andOPVcessation:characterizingriskstoimprovemanagement.RiskAnalysis.2006;26(6):p.14491469.

    158. NorrbyE,OxmanMN.MeaslesVirus.InFieldsBN,KnipeDM,ChanockR,HirschMS,LMJ,PMT,etal.,editors.Virology.2nded.New

    York:RavenPressLtd;1990.p.10131044.

    159. HatchTF.Distributionanddepositionofinhaledparticlesintherespiratorytract.BacteriologicalReviews.1961;25:p.237240.

    160. DamonSC.DecreaseofPolynesianRaces.TheFriend.1849;7(3):p.20.

    161. LeeWS.TheIslandNewYork:Holt,RinehartandWinston;1966.

    162. ThrumTG.HawaiianEpidemics.InThrumTG,editor.HawaiianAlmanacandAnnual.Honolulu:PressPublishingCompany;1897.p.

    97.

    163. MumfordEP,MohrJL.ManualontheDistributionofCommunicableDiseasesandTheirVectorsintheTropics,PacificIslandsSection,

    PartI.SupplementtoAmericanJournalofTropicalMedicine.1944;24:p.126.

    164. HirschA.Handbookofgeographicalandhistoricalpathology.In.London:NewSydenhamSociety;1983.p.154170.

    165. CorneyBG.ANoteonanEpidemicofMeaslesatRotuma,1911.ProceedingsoftheRoyalSocietyforMedicine.1913;6:p.138142.

    166. SimmonsJS,WhayneTF,AndersonGW,HorackHM.PartTwo,ThePacificArea.InGlobalEpidemiology. Philadelphia:JBLippincottCo.;1944.p.264and437.

    167. EnrightJR.SeasonalIncidenceofCommunicableDiseasesinHawaii.TheHawaiiHealthMessenger.1949.

    168. BabbotFL,GordonJE.ModemMeasles.AmericanJournalofMedicalSciences.1954;228:p.334361.

    169. CentersforDiseaseControlandPrevention.EmergencyPreparednessandResponse.[Online].;2007[cited2010June10.Available

    from:HYPERLINK"http://www.bt.cdc.gov/bioterrorism/overview.asp" http://www.bt.cdc.gov/bioterrorism/overview.asp .

    170. RotzLD,KhanAS,LillibridgeSR,OstroffSM,HughesJM.Publichealthassessmentofpotentialbiologicalterrorismagents.Emerging

    InfectiousDiseases.2002;8(2):p.225230.

  • 7/27/2019 measles, morbili

    31/31

    DrRaySanders.Measlesreintroductionriskanalysis

    171. DowdleWR,WolffC,SandersR,LambertS,BestM.Willcontainmentofwildpoliovirusinlaboratoriesandinactivatedpoliovirus

    vaccineproductionsitesbeeffectiveforglobalcertification?BulletinoftheWorldHealthOrganization.2004;82(1):p.5962.

    172. WorldHealthOrganization.WHOglobalactionplanforlaboratorycontainmentofwildpolioviruses.Geneva:WorldHealth

    Organization,VaccinesandBiologicals;1999.ReportNo.:WHO/V&B/99.32.

    173. WorldHealthOrganization.WHOglobalactionplanforlaboratorycontainmentofwildpolioviruses.Secondedition.Geneva:World

    HealthOrganization,VaccinesandBiologicals;2004.ReportNo.:WHO/V&B/03.11.

    174. WorldHealthOrganization.Laboratorybiosafetymanual.3rded.Geneva:WorldHealthOrganization;2004.

    175. PtzMM,BoucheFB,deSwartRL,MullerCP.Experimentalvaccinesagainstmeaslesinaworldofchangingepidemiology.

    InternationalJournalforParasitology.2003;33(56):p.525545.

    176. GriffinDE,PanCH.Measles:oldvaccines,newvaccines.CurrentTopicsinMicrobiologyandImmunology.2009;330:p.191212.

    177. AylwardRB,SutterRW,CochiSL,ThompsonKM,JafariH,HeymannD.Riskmanagementinapoliofreeworld.RiskAnalysis.2006;

    26(6):p.14411448.

    178. FinePE,RitchieS.Perspective:determinantsoftheseverityofpoliovirusoutbreaksintheposteradicationera.RiskAnalysis.2006;

    26(6):p.15331540.

    179. SangrujeeN,DuintjerTebbensRJ,CceresVM,ThompsonKM.Policydecisionoptionsduringthefirst5yearsfollowingcertif ication

    ofpolioeradication.MedscapeGeneralMedicine.2003;5(4):p.35.

    180. ThompsonKM,TebbensRJ,PallanschMA,KewOM,SutterRW,AylwardRB,etal.Therisks,costs,andbenefitsofpossiblefuture

    globalpoliciesformanagingpolioviruses.AmericanJournalofPublicHealth.2008;98(7):p.13221330.

    181. TebbensRJD,PallanschMA,AlexanderJP,ThompsonKM.Optimalvaccinestockpiledesignforaneradicateddisease:Applicationto

    polio.Vaccine.2010;28:p.43124327.

    182. TebbensRJD,PallanschMA,KewOM,CaceresVM,JafariH,CochiSL,etal.RisksofParalyticDiseaseDuetoWildorVaccineDerived

    PoliovirusAfterEradication.RiskAnalysis.2006;26(6):p.14711505.