Measles, Morbili

Riskanalysisformeaslesreintroductionpostglobalcertificationof eradication
DrRaySanders.July2010
Summaryandconclusions
Measlesviruswillcontinuetoexistaftercertificationofglobaleradicationasvirusstocksand infectiousmaterialsheldinlaboratories.Livevirusmayalsoexistinundetectedfocioftransmission andinpersistentlyandchronicallyinfectedindividuals.Thisanalysisattemptstoidentifyand evaluatethemainrisksforreintroductionofmeaslestransmissionpostcertificationoferadication inaworldinwhichuniversalroutinemeaslesimmunizationisnolongerafeature. Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumans Thereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreed requirementsforvalidationofthesecriteria.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
DrRaySanders.Measlesreintroductionriskanalysis
numberofpotentialSSPEandMIBEcases.AcutemeaslesinfectioninHIVinfectedindividualstends tobemoresevere,lastlongerandresultinashorterlivedimmunitytoreinfection,butthereisno publishedevidencetosuggestthatcoinfectionincreasesthepotentialforestablishmentof persistentmeaslesinfections,eitherwithwildtypevirusorwithvaccinederivedvirus. Riskfromnonhumanprimates Althoughnonhumanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and animalanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootictransmission orposeathreattohumanpopulations. Riskoflaboratoryassociatedmeaslesinfection Althoughthereisnodirectevidenceforlaboratoryacquiredmeaslesinfectionsitispossiblethat theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymild infections.Thereisnopublishedevidencetosuggestthattheseasymptomaticormildinfections resultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinafewhoursatambient temperatures,andinfectiousmaterialsstoredattemperaturesabove30oCcanbeexpectedtolose allinfectivityoverthecourseofonetotwoyears.Materialsstoredatorbelow70oC,orfreeze dried,maintaininfectivityformanyyears. Despitethelackofevidenceforlaboratoryacquiredmeaslesinfectionsorescapeofvirusintothe community,thesemustbeconsideredpossibilitiesinaposteradicationworld.Anappropriate systematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythePolio EradicationInitiative,shouldbedeveloped. Riskofintentionalreleaseofmeaslesvirus Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthe past.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldbe repeated,thethreatofmeaslesreleasewouldprobablybeveryeffectiveonceasizablepopulation ofsusceptibleindividualshadaccumulated.Thisthreatcouldbecounteredbytheestablishmentofa measlesvaccinestockpile,preferablyusinganew,easytomassadminister,nonreplicativemeasles vaccine.Thesizeandnatureofanystockpileshouldbedefinedwithinasystematicand comprehensiveposteradicationriskmanagementstrategy. Risksforreintroductionofmeaslescanbesummarisedasfollows:
Risk
Continuingwildtype measlestransmissionin humans Transmissionofvaccine derivedvirus Persistentinfections Nonhumanprimates Laboratoryassociated infection Intentionalrelease
Magnitude
Lowbutdependson certificationcriteriaand validationrequirements Verylow Verylow Verylow Verylowbutrisingpost eradication Verylowbutrisingpost eradication
Tendencyovertime
Decreasing
Mitigatingactions
Basecertificationcriteria andvalidationrequirements ondynamicandstochastic modellingdata Developalternative,non replicatingvaccines Maintainsurveillance Maintainsurveillance Developsystematic laboratorycontainment strategy Developvaccinestockpiles aspartofacomprehensive riskmanagementstrategy
Dependsonlevelofvaccine use Decreasing Decreasing Increasing
Increasing
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Areasrequiringfurtherresearchandinvestigationinclude: Greaterunderstandingofthetransmissiondynamicsofmeasles Developingmoremodels,particularlydynamicandstochasticmodelsofmeaslestransmission, persistenceandeliminationwillberequiredfordevelopingthecertificationcriteriaandvalidation requirements,particularlyforlowincome,highdensitypopulations. Additionaldetailedepidemiologicalandmolecularanalysisisrequiredonimportationsand outbreaks,particularlythoseoccurringinhighlyimmunizedpopulationsandinpopulationswith recognizedinadequatelyimmunizedsubpopulations. Withtherapidincreaseinthenumberofhighlyimmunizedpopulations,opportunitiesforstudying asymptomaticandatypicalinfectionsandtheirpotentialroleintransmissionshouldbetaken. Greaterunderstandingofthechangesbroughtaboutbytheattenuationprocess Moreinformationonthenatureofthechangescausedbyattenuationandthepotentialforvaccine virusreversiontowildtypecharacteristicsisrequired. Moreunderstandingofthenatureofthecomplexinteractionbetweenmeaslesvirusandthehost immunesystem,includingbothhumoralandcellmediatedresponses,wouldprobablybenefit continueduseofexistingvaccinesanddevelopmentofnewvaccines. AllgenotypeAvirusesdetectedinassociationwithacutecasesofmeaslesandatypicalvaccine responsesshouldbethoroughlyscrutinized.Fullepidemiologicalinformationwillberequired,and additionalsequencedatafrombothclinicalsamplesandcorrespondingviralisolateswillbe necessarytoruleoutthepossibilityoftransmission.
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TableofContents
Error!Bookmarknotdefined.
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Introduction.
Wedonotyethaveanagreed,definitivedefinitionformeasleseradication,butareasonable definitionmaybe: Interruptionofmeaslesvirustransmissiongloballyforaperiodgreaterthanorequalto36 months,inthepresenceofhighqualitysurveillance(modifiedfromcurrentGlobalandRegional definitionsofRegionalelimination). Accordingtothisdefinition,measlesviruswillcontinuetoexist,asvirusstocksandinfectious materialsheldinlaboratories.Livevirusmayalsocontinuetoexistinpersistentlyandchronically infectedindividuals.Whatriskdothesevirusesandmaterialsposeinaposteradicationworld? Forthepurposesofthisanalysispotentialriskshavebeendividedintotwocategories: naturalassociatedwithcirculationofwildtypevirus,viruspersistence,andimmunization activities;and laboratoryassociatedwithlaboratorywork,storageandintentionalrelease.
Thesetwocategoriesarenotmutuallyexclusive,butdopermitamoresystematic,structured assessment. Naturalrisksconsideredinclude: a) b) c) d) continuingwildtypemeaslestransmissioninundetectedhumanreservoirs; transmissionofvaccinederivedvirus; persistentandchronicinfections; nonhumanprimatereservoirs.
Laboratoryrisksconsideredinclude: a) b) c) d) laboratoryacquiredinfections; storedinfectiousmaterials; virusescapeintothecommunity; intentionalrelease.
Ifuniversalornearuniversalcoveragewithmeaslesvaccineiscontinuedafterglobaleradication, particularlyifamoreeffective,nonreplicatingvaccineisused,theriskofmeaslesreintroductionwill beminimal.Itislikelythatanumberofnationalauthoritieswill,forpoliticalaswellaspublichealth reasons,choosetocontinueroutineimmunizationposteradication.Someauthoritiesmayadopta modifiedimmunizationschedule,suchasasingledosepolicy,orsomeformofcampaignstrategy.It isalsolikelythatanumberofnationalauthorities,eitherthroughdecisionordefault,willcease routinemeaslesimmunization.Forthepurposesofthisanalysisithasbeenassumedthatuniversal immunizationagainstmeasleswillnotbecontinuedposteradication,andthatanincreasingglobal populationwillbesusceptibletomeaslesinfectionintheyearsfollowingcertification.
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Theanalysisconcludeswithabriefdiscussionofactionsrequiredtoreducetheriskofaccidentalor deliberatereleaseofmeaslesinaposteradicationworldandareasthatcouldbenefitfromfurther research.
Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumans
Thereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreed requirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby undetectedcontinuingtransmission.However,basedoncurrentRegionalandGlobal recommendationsoncertificationofRegionalmeasleselimination,itislikelythateradicationcriteria willinclude: 1. 2. Absenceofcirculatingmeaslesvirusforatleastoneyear; Adequatesurveillanceincludinggenotypedata.Adequatesurveillancemaybedefinedby: Numberofreportedsuspectedmeaslescasesthatarediscardedasnonmeasles (targets:2/100,000populationnationally,1/100,000inatleast80%ofdistricts) Percentageofreportedsuspectedcasesthathaveadequateinvestigationwithin48 hoursofreport(target:80%ofreportedsuspectedcases) Percentageofreportedsuspectedcasesthathaveadequatespecimenscollected (target:80%ofreportedsuspectedcases) PercentageofdistrictswithaccesstoaWHOaccreditedmeaslesdiagnostic laboratory(target:100%) PercentageofspecimenswithIgMresultswithin7daysofreceiptinlaboratory (target:90%) PercentageofchainsoftransmissionwithRNAsequenceanalysis(target:95%) Someuseofmeaslesavidityassaystodistinguishrecentfromlongstanding immunologicalresponses Somedemonstrationofalternativesurveillancemechanisms,routineor supplementary,basedoncasedetection,investigationandreporting; Achievementofhighpopulationimmunity.Populationimmunitymaybedemonstratedby: 95%coveragewithroutineMCV2inalldistricts,or 80%coveragewithroutineMCV1plus95%coveragewithSIAfollowupinall districts,or Someuseofextensiveserosurveydata.
3.
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 measlesinfectionsarecommonamongmeaslesimmunepersonsexposedtomeaslescasesandmay bethemostcommonmanifestationofmeaslesduringoutbreaksinhighlyimmunepopulations(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,butuntilthecriteriaforglobalcertificationof measleseradicationandtherequirementsforvalidationareestablisheditisnotpossibleto 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 publisheddocumentationidentifyingadistinctsetofgeneticmarkersthatconsistentlydifferentiates wildtypevirusesfromattenuatedviruses(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 proofreadingmechanismsresultsinamutationrateof9x105perbaseperreplicationandagenomic mutationrateof1.4perreplication(85).Thisiswellwithinthetypicalrangeof103to106mutations 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).Mutationsinthisregionarenotpermittedbecausetheyinterferewith receptorbinding.Thisextremesequencerestrictionallowsforveryefficientproductionof neutralizingantibodiesthatblockbindingofthevirustoitsreceptor.Sotheoriginalvaccinestrains, developedinthe1960s,arestilleffectiveagainstcurrentwildtypeviruses(91).Analysisofavailable sequencedatafromapproximately500isolatessuggeststhatdespitetheerrorproneviral polymerase,theaminoacidsequenceofHisstronglyconserved,with60%oftheresiduesbeing identicalorverysimilar(92).Itappearsthatanymutationthatchangesthenatureofthese conservedresiduesresultsinnonviablevirus. Conclusion Thereisnocurrentpublisheddatatosupportevidenceforcurrentlylicensedliveattenuatedvaccine virusesrevertingtowildtypetransmissibility.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,ithasbeenproposedthatthefailureofinfectedneuronsto producecompleteextracellularvirusmaybeduetodefectsinproteinexpressioncausedby 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).Measlesantigenis presentinthebrain,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.TheseincludeMacacamulatta,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).Evidenceexistsofmeaslesinfectionin nonhumanprimatepopulationswithfrequentcontactwithhumanpopulations,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,universalimmunizationstopsafter globalcertification,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).Anextensiveliteraturesearch failedtofinddocumentedevidenceoflaboratoryacquiredmeaslesinfection.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+6oC,witha12loglossoftitre over1year.Storageat72oCorbelowresultsinverylittlelossofvirusinfectivity,andinfectious materialsmaintainedatthistemperatureshouldretaininfectivityformanyyears(156).Thevirus survivesfreezedryingrelativelywelland,whenfreezedriedwithaproteinstabilizer,cansurvive storagefordecadesat70oC(156,155).Incommonwithmanyotherenvelopedvirusesitis inactivatedbysolvents,suchasetherandchloroform,byacids(pH<5),alkalis(pH>10),andbyUV andvisiblelight.Itisalsosusceptibletomanydisinfectants,including1%sodiumhypochlorite,70% alcoholandformalin.
Whichlaboratorymaterialspresentarisk?
Measlesvirusinfectiousmaterialsincludeautopsyorclinicalsamples(e.g.pharyngealsecretions, urine,blood)frommeaslesinfectedpersonsorrecentliveattenuatedvaccinerecipients,and laboratoryderivedmaterials(e.g.virusisolatesandreferencestocks,materialsderivedfrom inoculatedcellcultures,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(<5dropletnuclei)of suspendedevaporatedresiduescanmoveaboutroomsandbuildingsonaircurrentsandwhen
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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.Giventherapidinactivationofmeaslesvirusundernormalenvironmental conditions,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.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldbe repeated,thethreatofintentionalreleasewouldprobablybeveryeffectiveonceasizable populationofsusceptibleindividualshadaccumulated. Riskassessment:Theriskofdeliberatereleaseofmeasleswillbeverylowatthetimeof globaleradication,butwillriserapidlywithaccumulationofunvaccinatedmeasles susceptibles.
Actionsrequiredtoreducetheriskofaccidentalordeliberatereleaseof measles
Oneapproachtoreducingtheriskofmeaslesreintroductionwouldbeadoptionofastrategyto 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: 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): minimizingsusceptibilityofcommunitiestomeaslesvirusspreadwillnolongerapplyin thosecountriesthatelecttostopmeaslesimmunization; minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding,inthe absenceofanoninfectiousvaccine,willrelysolelyonpreventionofinfection; minimizingthenumberoflaboratoriesretainingmeaslesvirusmaterialsandminimizingthe risksofoperationsinthoselaboratoriesbecomesmuchmoreimportant. minimizingthenumberoflaboratoriesretainingmeaslesvirusinfectiousandpotential infectiousmaterials; minimizingtherisksofoperationsinlaboratoryandmeasleslivevaccineproduction facilities; minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding; minimizingsusceptibilityofcommunitytomeaslesvirusspread.
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.
Areasrequiringfurtherresearch
Therisksofreintroductionofmeaslespostglobaleradicationmaybereducedbyapplying knowledgeacquiredthroughkeyareasofresearchconductedintheyearsleadinguptoeradication. Thesekeyareasincludethefollowing:
Greaterunderstandingofthetransmissiondynamicsofmeasles
Indrawingupthecertificationcriteriaandvalidationrequirementsitwillbenecessarytoengage expertsfamiliarwiththedevelopmentofdynamicandstochasticmodelsofmeaslestransmission, persistenceandelimination.Thiswillbeparticularlyimportantfordeterminingthecertificationand validationrequirementsforlowincome,highdensitypopulations.Basedontheexperiencegained inpolioeradication,thiswillbemostrelevantforselectedpopulationsinAfrica,theIndiansub continentandlargerefugee/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,asymptomaticallyreinfectedindividual.JournalofClinical Virology.1999;13(3):p.173179. 12. ChenRT,MarkowitzLE,AlbrechtP,StewartJA,MofensonLM,PrebludSR,etal.Measlesantibody:reevaluationofprotectivetiters. 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.Detectionofmeaslesvirusgenomeinlymphocytesfromasymptomatichealthychildren.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.
Page22
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.Vaccinatedchildrengetmildermeaslesinfection: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.
Page23
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.Geneticvariabilityofwildtypemeaslesviruses, 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).
Page24
56. SantibanezS,HeiderA,GerikeE,AgafonovA,SchreierE.GenotypingofmeaslesvirusisolatesfromcentralEuropeandRussia. JournalofMedicalVirology.1999;58(3):p.313320. 57. TruongAT,KreisS,AmmerlaanW,HartterHK,AduF,OmilabuSA,etal.Genotypicandantigeniccharacterizationofhemagglutinin proteinsofAfricanmeaslesvirusisolates.VirusResearch.1999;62(1):p.8995. 58. RamsayME,JinL,WhiteJ,LittonP,CohenB,BrownD.TheeliminationofindigenousmeaslestransmissioninEnglandandWales. JournalofInfectiousDiseases.2003;187(Suppl1):p.S198207. 59. MosqueraMM,OryF,EchevarraJE.MeaslesvirusgenotypecirculationinSpainafterimplementationofthenationalmeasles eliminationplan20012003.JournalofMedicalVirology.2005;75(1):p.137146. 60. RotaJS,RotaPA,ReddSB,ReddSC,PattamadilokS,BelliniWJ.GeneticanalysisofmeaslesvirusesisolatedintheUnitedStates, 19951996.JournalofInfectiousDiseases.1998;177:p.204208. 61. ChengWY,LeeL,RotaPA,YangDC.MolecularevolutionofmeaslesvirusescirculatedinTaiwan19922008.Virologyjournal.2009; 6:p.219. 62. KobuneF,FunatuM,TakahashiH,FukushimaM,KawamotoA,IizukaS,etal.Characterizationofmeaslesvirusesisolatedafter measlesvaccination.Vaccine.1995;13(4):p.370372. 63. BarreroPR,ZandomeniRO,MistchenkoAS.MeaslesviruscirculationinArgentina:19911999.BriefReport.ArchivesofVirology. 2001;146:p.815823. 64. KreisS,VardasE,WhistlerT.SequenceanalysisofthenucleocapsidgeneofmeaslesvirusisolatesfromSouthAfricaidentifiesanew genotype.JournalofGeneralVirology.1997;78(7):p.15811587. 65. ZhangY,JiY,JiangX,XuS,ZhuZ,ZhengL,etal.GeneticcharacterizationofmeaslesvirusesinChina,2004.VirologyJournal.2008;5: p.120. 66. ZhangY,DingZ,WangH,LiL,PangY,BrownKE,etal.NewMeaslesVirusGenotypeAssociatedwithOutbreak,China.Emerging InfectiousDiseases.2010;16(6):p.943947. 67. VaidyaSR,WairagkarNS,RajaD,KhedekarDD,GunasekaranP,ShankarS,etal.FirstdetectionofmeaslesgenotypeD7fromIndia. VirusGenes.2008;36(1):p.3134. 68. JiY,ZhangY,XuS,ZhuZ,ZuoS,JiangX,etal.MeaslesresurgenceassociatedwithcontinuedcirculationofgenotypeH1virusesin China,2005.VirologyJournal.2009;8(6):p.135. 69. MuwongeA,NanyunjaM,RotaPA,BwogiJ,LoweL,LiffickSL,etal.Newmeaslesgenotype,Uganda.EmergingInfectiousDiseases. 2005;11(10):p.15221526. 70. MbuguaFM,OkothFA,GrayM,KamauT,KaluA,EggersR,etal.MolecularepidemiologyofmeaslesvirusinKenya.Journalof MedicalVirology.2003;71(4):p.599604. 71. RotaPA,LiffickSL,RotaJS,KatzRS,ReddS,PapaniaM,etal.MolecularepidemiologyofmeaslesvirusesintheUnitedStates,1997 2001.Emerginginfectiousdiseases.2002;8:p.902908. 72. ChenTH,KuttyP,LoweLE,HuntEA,BlosteinJ,EspinozaR,etal.MeaslesOutbreakAssociatedWithanInternationalYouthSporting EventintheUnitedStates,2007.PediatricInfectiousDiseaseJournal.2010April;[Epubaheadofprint]. 73. SchmidD,HolzmannH,SchwarzK,KasperS,KuoHW,AberleSW,etal.MeaslesoutbreaklinkedtoaminoritygroupinAustria,2008. EpidemiologyandInfection.2010;138(3):p.415425. 74. NaganoH,JinushiM,TanabeH,YamaguchiR,OkanoM.Epidemiologicalandmolecularstudiesofmeaslesatdifferentclustersin
Page25
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.
Page26
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.
Page27
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.DetectionofmeaslesvirusmRNAfromautopsiedhumantissues.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.Infectionandimmunityintherhesusmacaque. Virology.1997;233(1):p.8592. 129. vanBinnendijkRS,vanderHeijdenRW,vanAmerongenG,UytdeHaagFG,OsterhausAD.Viralreplicationanddevelopmentof specificimmunityinmacaquesafterinfectionwithdifferentmeaslesvirusstrains.JournalofInfectiousDiseases.1994;170(2):p.
Page28
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.
Page29
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:JBLippincott Co.;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.
Page30
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.Policydecisionoptionsduringthefirst5yearsfollowingcertification 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.
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Riskanalysisformeaslesreintroductionpostglobalcertificationof eradication

Dependsonlevelofvaccine use Decreasing Decreasing Increasing

Thesetwocategoriesarenotmutuallyexclusive,butdopermitamoresystematic,structured assessment. Naturalrisksconsideredinclude: a) b) c) d) continuingwildtypemeaslestransmissioninundetectedhumanreservoirs; transmissionofvaccinederivedvirus; persistentandchronicinfections; nonhumanprimatereservoirs.

Laboratoryrisksconsideredinclude: a) b) c) d) laboratoryacquiredinfections; storedinfectiousmaterials; virusescapeintothecommunity; intentionalrelease.

Theanalysisconcludeswithabriefdiscussionofactionsrequiredtoreducetheriskofaccidentalor deliberatereleaseofmeaslesinaposteradicationworldandareasthatcouldbenefitfromfurther research.

resultingasymptomaticinfections,orverymild,atypicalinfectionshaveoccurred.Iftheyhave occurred,itisprobablethattheseinfectionshavegoneundetected,orsimplyoverlookedas unimportant.

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