6. measles post eradication risk analysis...although there is no direct evidence for...
TRANSCRIPT
Riskanalysisformeaslesreintroductionpostglobalcertificationoferadication
DrRaySanders.July2010
SummaryandconclusionsMeaslesviruswillcontinuetoexistaftercertificationofglobaleradicationasvirusstocksandinfectiousmaterialsheldinlaboratories.Livevirusmayalsoexistinundetectedfocioftransmissionandinpersistentlyandchronicallyinfectedindividuals.Thisanalysisattemptstoidentifyand
evaluatethemainrisksforre‐introductionofmeaslestransmissionpostcertificationoferadicationinaworldinwhichuniversalroutinemeaslesimmunizationisnolongerafeature.
Riskofcontinuing,undetectedwild‐typemeaslestransmissioninhumansThereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreed
requirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirementsfordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedbyundetectedcontinuingtransmission.
Mildorasymptomaticmeaslesinfectionsareprobablyverycommonamongmeasles‐immune
personsexposedtomeaslescases,buttransmissionfromasymptomaticcasesislikelytobeveryrare.Ifitoccursitisunlikelytobeefficientenoughtosustaintransmission,especiallyinthehighlyvaccinatedpopulationsexpectedintheyearsimmediatelyfollowingglobalcertificationof
eradication.However,thepotentialroleofasymptomaticinfectionsinmaintainingtransmissionrequiresfurtherinvestigation.
Ifthecriteriaforglobalcertificationoferadicationarefirmenough,andrequirerigorousvalidation,thentheriskofundetectedmeaslestransmissionaftercertificationisverylow.Ifthecertification
criteriaarelax,orvalidationrequirementsareinadequate,theriskwillbehigher.
Riskoftransmissionofvaccine‐derivedvirusThecurrentlylicensedlive‐attenuatedmeaslesvaccinesaresafeandefficientandhavebeenusedsuccessfullytoprotectmanymillionsofindividualsandpreventmeaslestransmission.Allcurrent
vaccinevirusesarecloselyrelatedandbelongtogenotypeA.Thereisnopublishedconclusiveevidenceforcurrentlylicensedliveattenuatedvaccinevirusesrevertingtowild‐typetransmissibilityorvirulence.Onthecontrary,thevastmajorityofevidencepointstoanimpressivelevelofgenetic
stability.However,sincetheyarelivevirusesthatreplicatewithinvaccinerecipients,theremotepossibilitymustexistthattheycouldreverttowild‐typecharacteristics.Thereisalsonoevidencefortheestablishmentofvaccine‐escapemutants.Evenifvaccinevirusesweretoreverttowild‐type
transmissibility,thereisnoreasontosuspectthattransmissioncouldnotbecontrolledusingcurrentvaccines.
RiskfrompersistentinfectionsThereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe
sheddingofinfectiousvirusorplayanypartinmeaslestransmission.Asthenumberofacutemeaslesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthe
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numberofpotentialSSPEandMIBEcases.AcutemeaslesinfectioninHIV‐infectedindividualstendstobemoresevere,lastlongerandresultinashorterlivedimmunitytore‐infection,butthereisno
publishedevidencetosuggestthatco‐infectionincreasesthepotentialforestablishmentofpersistentmeaslesinfections,eitherwithwild‐typevirusorwithvaccine‐derivedvirus.
Riskfromnon‐humanprimatesAlthoughnon‐humanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and
animal‐animaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootictransmissionorposeathreattohumanpopulations.
Riskoflaboratory‐associatedmeaslesinfectionAlthoughthereisnodirectevidenceforlaboratory‐acquiredmeaslesinfectionsitispossiblethat
theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymildinfections.Thereisnopublishedevidencetosuggestthattheseasymptomaticormildinfectionsresultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinafewhoursatambient
temperatures,andinfectiousmaterialsstoredattemperaturesabove‐30oCcanbeexpectedtoloseallinfectivityoverthecourseofonetotwoyears.Materialsstoredatorbelow‐70oC,orfreezedried,maintaininfectivityformanyyears.
Despitethelackofevidenceforlaboratory‐acquiredmeaslesinfectionsorescapeofvirusintothe
community,thesemustbeconsideredpossibilitiesinapost‐eradicationworld.Anappropriatesystematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythePolioEradicationInitiative,shouldbedeveloped.
Riskofintentionalreleaseofmeaslesvirus
Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthepast.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldbe
repeated,thethreatofmeaslesreleasewouldprobablybeveryeffectiveonceasizablepopulationofsusceptibleindividualshadaccumulated.Thisthreatcouldbecounteredbytheestablishmentofameaslesvaccinestockpile,preferablyusinganew,easytomass‐administer,non‐replicativemeasles
vaccine.Thesizeandnatureofanystockpileshouldbedefinedwithinasystematicandcomprehensivepost‐eradicationriskmanagementstrategy.
Risksforreintroductionofmeaslescanbesummarisedasfollows:
Risk Magnitude Tendencyovertime MitigatingactionsContinuingwild‐typemeaslestransmissioninhumans
Lowbutdependsoncertificationcriteriaandvalidationrequirements
Decreasing Basecertificationcriteriaandvalidationrequirementsondynamicandstochasticmodellingdata
Transmissionofvaccine‐derivedvirus
Verylow Dependsonlevelofvaccineuse
Developalternative,non‐replicatingvaccines
Persistentinfections Verylow Decreasing MaintainsurveillanceNon‐humanprimates Verylow Decreasing Maintainsurveillance
Laboratory‐associatedinfection
Verylowbutrisingposteradication
Increasing Developsystematiclaboratorycontainmentstrategy
Intentionalrelease Verylowbutrisingposteradication
Increasing Developvaccinestockpilesaspartofacomprehensiveriskmanagementstrategy
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Areasrequiringfurtherresearchandinvestigationinclude:GreaterunderstandingofthetransmissiondynamicsofmeaslesDevelopingmoremodels,particularlydynamicandstochasticmodelsofmeaslestransmission,
persistenceandeliminationwillberequiredfordevelopingthecertificationcriteriaandvalidationrequirements,particularlyforlow‐income,highdensitypopulations.
Additionaldetailedepidemiologicalandmolecularanalysisisrequiredonimportationsandoutbreaks,particularlythoseoccurringinhighlyimmunizedpopulationsandinpopulationswith
recognizedinadequatelyimmunizedsub‐populations.
Withtherapidincreaseinthenumberofhighlyimmunizedpopulations,opportunitiesforstudyingasymptomaticandatypicalinfectionsandtheirpotentialroleintransmissionshouldbetaken.
Greaterunderstandingofthechangesbroughtaboutbytheattenuationprocess
Moreinformationonthenatureofthechangescausedbyattenuationandthepotentialforvaccinevirusreversiontowild‐typecharacteristicsisrequired.
Moreunderstandingofthenatureofthecomplexinteractionbetweenmeaslesvirusandthehostimmunesystem,includingbothhumoralandcell‐mediatedresponses,wouldprobablybenefit
continueduseofexistingvaccinesanddevelopmentofnewvaccines.
AllgenotypeAvirusesdetectedinassociationwithacutecasesofmeaslesandatypicalvaccineresponsesshouldbethoroughlyscrutinized.Fullepidemiologicalinformationwillberequired,andadditionalsequencedatafrombothclinicalsamplesandcorrespondingviralisolateswillbe
necessarytoruleoutthepossibilityoftransmission.
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TableofContentsError!Bookmarknotdefined.
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Introduction.Wedonotyethaveanagreed,definitivedefinitionformeasleseradication,butareasonabledefinitionmaybe:
“Interruptionofmeaslesvirustransmissiongloballyforaperiodgreaterthanorequalto36
months,inthepresenceofhigh‐qualitysurveillance”(modifiedfromcurrentGlobalandRegionaldefinitionsofRegionalelimination).
Accordingtothisdefinition,measlesviruswillcontinuetoexist,asvirusstocksandinfectiousmaterialsheldinlaboratories.Livevirusmayalsocontinuetoexistinpersistentlyandchronically
infectedindividuals.Whatriskdothesevirusesandmaterialsposeinapost‐eradicationworld?
Forthepurposesofthisanalysispotentialriskshavebeendividedintotwocategories:
• ‘natural’–associatedwithcirculationofwild‐typevirus,viruspersistence,andimmunizationactivities;and
• ‘laboratory’–associatedwithlaboratorywork,storageandintentionalrelease.
Thesetwocategoriesarenotmutuallyexclusive,butdopermitamoresystematic,structured
assessment.
‘Natural’risksconsideredinclude:
a) continuingwild‐typemeaslestransmissioninundetectedhumanreservoirs;b) transmissionofvaccine‐derivedvirus;c) persistentandchronicinfections;
d) non‐humanprimatereservoirs.
‘Laboratory’risksconsideredinclude:
a) laboratory‐acquiredinfections;b) storedinfectiousmaterials;c) virusescapeintothecommunity;
d) intentionalrelease.
Ifuniversalornear‐universalcoveragewithmeaslesvaccineiscontinuedafterglobaleradication,particularlyifamoreeffective,non‐replicatingvaccineisused,theriskofmeaslesreintroductionwillbeminimal.Itislikelythatanumberofnationalauthoritieswill,forpoliticalaswellaspublichealth
reasons,choosetocontinueroutineimmunizationposteradication.Someauthoritiesmayadoptamodifiedimmunizationschedule,suchasasingle‐dosepolicy,orsomeformofcampaignstrategy.Itisalsolikelythatanumberofnationalauthorities,eitherthroughdecisionordefault,willcease
routinemeaslesimmunization.Forthepurposesofthisanalysisithasbeenassumedthatuniversalimmunizationagainstmeasleswillnotbecontinuedposteradication,andthatanincreasingglobal
populationwillbesusceptibletomeaslesinfectionintheyearsfollowingcertification.
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Theanalysisconcludeswithabriefdiscussionofactionsrequiredtoreducetheriskofaccidentalordeliberatereleaseofmeaslesinapost‐eradicationworldandareasthatcouldbenefitfromfurther
research.
Riskofcontinuing,undetectedwild‐typemeaslestransmissioninhumansThereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreedrequirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements
fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedbyundetectedcontinuingtransmission.However,basedoncurrentRegionalandGlobalrecommendationsoncertificationofRegionalmeasleselimination,itislikelythateradicationcriteria
willinclude:
1. Absenceofcirculatingmeaslesvirusforatleastoneyear;2. Adequatesurveillanceincludinggenotypedata.Adequatesurveillancemaybedefinedby:
• Numberofreportedsuspectedmeaslescasesthatarediscardedasnon‐measles
(targets:≥2/100,000populationnationally,≥1/100,000inatleast80%ofdistricts)• Percentageofreportedsuspectedcasesthathaveadequateinvestigationwithin48
hoursofreport(target:≥80%ofreportedsuspectedcases)
• Percentageofreportedsuspectedcasesthathaveadequatespecimenscollected(target:≥80%ofreportedsuspectedcases)
• PercentageofdistrictswithaccesstoaWHO‐accreditedmeaslesdiagnostic
laboratory(target:100%)• PercentageofspecimenswithIgMresultswithin7daysofreceiptinlaboratory
(target:≥90%)
• PercentageofchainsoftransmissionwithRNAsequenceanalysis(target:≥95%)• Someuseofmeaslesavidityassaystodistinguishrecentfromlong‐standing
immunologicalresponses
• Somedemonstrationofalternativesurveillancemechanisms,routineorsupplementary,basedoncasedetection,investigationandreporting;
3. Achievementofhighpopulationimmunity.Populationimmunitymaybedemonstratedby:• ≥95%coveragewithroutineMCV2inalldistricts,or• ≥80%coveragewithroutineMCV1plus≥95%coveragewithSIAfollow‐upinall
districts,or• Someuseofextensiveserosurveydata.
FromexperiencegainedthroughRegionalpolioeliminationandcertification,specificcriteriamaybeusedtofulfilthethreegeneralcriteriaabove,butitisunlikelythatanysinglespecificindicatorwillberequiredtopassorfailvalidation.Thestrictnessandextentofrequirementsforproviding
evidencethatcertificationcriteriahavebeenmetwilllargelydeterminethemagnitudeofriskposedbyundetectedcontinuingmeaslestransmission.Butevenwithrelativelylaxcriteriaandvalidation
requirements,howlikelyisitthatongoingmeaslestransmissionwillbeundetectedforaminimumofoneyearbeforecertification?
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Whatisthesmallestpopulationrequiredtomaintainmeaslestransmission?Measlesepidemicshavegenerallybeencharacterisedbyexplosivecycleswithhighlycomplex
pathogen‐andpopulation‐levelinteractionsthatinfluencetransmissiondynamics(1).Accuratelypredictingthecriticalcommunitysize(CCS)requiredformaintainingmeaslesviruscirculationisdifficultduetothelargenumberofvariablesinvolved.Directobservationandarangeofboth
deterministicandstochasticmodelssuggestthatapopulationof250,000to400,000with5,000to10,000birthsperyearisrequiredtomaintaintransmission(2,3).Highlevelsofimmunization,lowpopulationdensity,alowbirth‐rateandgoodpublichealthcarefacilitiesincreasetheCCS.Low
vaccineuptake,highpopulationdensity,highbirth‐rates,highlevelsofimmunodeficiencyandpoorpublichealthcarefacilitiesdecreasetheCCS(1,4,5).
AlthoughitmaybedifficulttoaccuratelyestimatetheCCSinlow‐income,lowvaccinecoverage
populations,itiseasytoidentifythesepopulations.Ifdiseasesurveillanceandimmunizationactivitiesaretargetedonthem,andonanynew,at‐riskpopulationsthatmayemergefollowingdisplacementcausedbyconflictorclimatechange(6),thepotentialtooverlookcirculationofvirus
intheyearleadinguptoglobalcertificationwillbegreatlyreduced.
Whatroledoasymptomaticinfectionsplayinvirustransmission?Measlescontrolstrategiesassumethatvirustransmissionoccursthroughchainsofclinicallyrecognizablemeaslescases,andthesurveillancesystemlargelyreliesontheidentificationofthese
casesfordetectingandrespondingtooutbreaks.Butasymptomaticinfectionscertainlyoccurandmayplayanimportantroleinmeaslestransmission.Serologicalevidenceforacutemeaslesinfectionamongpeopleexposedtomeaslesvirusbutfailingtodevelopclassicalsymptomshasbeenwell
documented(7,8,9,10,11,12,13,14,15)andithaslongbeenrecognizedthatmeaslesviruscaninfectpreviouslyimmunepersons,producingclassicsymptomsofmeaslesinsome,butmildornosymptomsinmost(16,17,18,19,20).Theestimatedratesofmildorasymptomaticmeaslesinfections
afterexposuretomeaslescasesarevaried,however,inpartbecauseofdifferentdiagnostictechniquesanddifferentcasedefinitionsused,orbecauseofthedifferenttypesofexposure.Inseveralstudiestheratesofmildorasymptomaticinfectionweredeterminedduringoutbreaksin
whichpersonswerelikelytohavehadmultipleexposurestomeaslescases(16,21,12,8).Astudyofmildorasymptomaticmeaslesinfectionsamong44personslikelytohavebeenexposedtoclassicmeaslesduringa3‐daybustripconcludedthatinpopulationswithhighlevelsofimmunityto
measles,non‐classicmeaslesinfectionscanoccurinatleast20%ofpreviouslyimmunepersonswithcloseexposuretoapersonwithclassicmeasles(10).Itispossiblethatmildorasymptomaticmeaslesinfectionsarecommonamongmeasles‐immunepersonsexposedtomeaslescasesandmay
bethemostcommonmanifestationofmeaslesduringoutbreaksinhighlyimmunepopulations(10).Althoughclinicallyunimportant,asymptomaticmeaslesvirusinfectionscouldbeepidemiologicallyimportantifinfectedpersonsarecapableoftransmittingvirus.Althoughatleastonestudyhas
reportedisolationofmeaslesvirusfromanasymptomaticindividualinclosecontactwithanacutecase(11),anotherstudyfailedtofindevidenceofvirussheddingfrom11seropositiveacutecasecontacts(14).Iftransmissionfromasymptomaticcasesdoesoccur,itislikelytobeveryrare,andis
unlikelytobeefficientenoughtosustaintransmission(11,15),especiallyinthehighlyvaccinatedpopulationsexpectedintheyearsimmediatelyfollowingglobalcertificationoferadication.
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ConclusionIfthecertificationcriteriaarefirmenough,andrequirerigorousvalidation,thentheriskof
undetectedmeaslestransmissionafterGlobalCertificationisverylow.Ifthecertificationcriteriaarelax,orvalidationrequirementsareinadequate,theriskwillhigher.
Riskassessment:Theriskisintuitivelylow,butuntilthecriteriaforglobalcertificationof
measleseradicationandtherequirementsforvalidationareestablisheditisnotpossibletoestimatetheriskposedbycontinuingwild‐typemeaslestransmissioninundetectedreservoirs.
Riskoftransmissionofvaccine‐derivedvirusThedevelopmentofliveattenuatedmeaslesvirusvaccinesbegansoonafterisolationofthevirusbyEndersandPeeblesin1954(22).ThefirstlicensedattenuatedmeaslesvaccinewasEdmonstonB,usedbetween1963and1975butfrequentlyassociatedwithfeverandrash(23).Thefurther
attenuatedSchwarzandMoratenstrainswerederivedfromtheoriginalEdmonstonstrainthroughadditionalpassagesinchickembryofibroblasts(Figure1).Despitedifferencesintheirpassagehistory,thesetwovaccinestrainshaveidenticalgenomicsequences(24).TheMoratenvaccineis
widelyusedintheUnitedStatesofAmerica;theSchwarzvaccineisusedinmanycountriesthroughouttheworld,andtheEdmonston‐Zagrebvaccine,similarlyderivedfromtheEdmonstonBstrain,isthemostwidelyusedstrainindevelopingcountries.Otherattenuatedmeaslesvaccines
havebeenproducedfromlocallyderivedwild‐typestrains,particularlyintheRussianFederation(Leningrad‐16),thePeople’sRepublicofChina(Shanghai‐191)andJapan(CAM‐70,AIK‐C)(23).Allofthecurrentvaccinevirusesarewelldocumentedandwellcharacterisedwithregardtoprovenance,
immunogenicity,thermalstabilityandgenomicstructure(25,26,27,28,29,30,31,32,33).Althoughcurrentvaccinevirusesandtheirwild‐typeprogenitorssharemorethan95%sequencehomology,theycaneasilybedistinguishedgeneticallyfromcurrentlycirculatingwild‐typeviruses.
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Figure1.Relationshipsofmajorcurrentmeaslesvaccineviruses(fromMoss&Scott,2009(23)).
Measlesvirusisconsideredtobeoneofthemostcontagiousofhumanpathogens,withaveryhighleveloftransmissibility.Likewild‐typevirus,measlesvaccinevirusreplicateseffectivelywithinvaccinerecipients,inducingbothhumoralandcellularimmuneresponsessimilartonaturalmeasles
virusinfection,althoughtheseresponsesareoflowermagnitudeandshorterduration.Approximately5%ofchildrendevelopfeverandrashafterreceivingmeaslesvaccine,andviralRNAcanbedetectedintheurineandrespiratorysecretionsforsomedayspost‐immunization(34).
Vaccineviruscanbeisolatedfromthebloodofrecentvaccinerecipients,andhasbeendetectedinsamplesoflung,liver,bonemarroworbraintissuesintheveryrarecasesofsevereacutediseasefollowingmeaslesvaccination(35).VirusRNAandantigencanbedetectedintheurineofvaccine
recipientsforupto14‐16dayspost‐immunization(36,37),butthereisnopublishedevidenceforthetransmissionofvaccinevirus.Obviouslythechangescausedbytheattenuationprocesseffectivelyblocktransmissibility.Isitpossibleforvaccinevirustoregainthetransmissibilitycharacteristicsof
wild‐typevirus?
Thereasonsfornon‐transmissionofvaccinevirusesarenotfullyunderstood,andarelikelytobecomplex.Ithasbeenproposedthatlossofabilitytointeractwithepithelialcellreceptorsisakeyfactor(38,39,40).Itisalsopossiblethatmodificationofthevirusmatrix(M)protein,knowntobe
importantinvirusbuddingfrominfectedcells(41),contributestolossoftransmissibility.Theabilityofvaccinevirusestointerferewiththeinnateimmuneresponsemayalsobeakeyfactor.Whateverthereason,itappearsthattheblockontransmissionofvaccinevirusesishighlyeffective.
Measlesvirusisserologicallymonotypicandisgeneticallycharacterizedintoeightclades(A–H),
dividedinto23recognizedgenotypes(42,43,44).Allofthecurrentvaccines,whetherderivedfromEdmonstonornot,sharearemarkablenucleotidesequencesimilarityandallaremembersofgenotypeA(45,24).Duringthe1950sand1960s,onlymeaslesvirusesbelongingtogenotypeAwere
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isolatedandmayhavehadaworld‐widedistributionbeforevaccinationstarted(46,47,48).Thisisnotthesituationtoday,whentheidentificationofnon‐vaccinerelatedgenotypeAvirusesisvery
unusual.Overthepastfifteenyearsamassiveamountofworkhasbeenputintocharacterizingmeaslesvirusesassociatedwithoutbreaks.Althoughtherearestillgaps,virusesfrommostmajoroutbreaksandfromimportationsinareasthathaveeliminatedindigenousmeasles,arecurrently
beingsequencedandgeneticallycharacterizedthroughtheWHOLaboratoryNetwork’sactivities.Wenowhaveareasonablycomprehensiveunderstandingofwhichvirusesarecirculatingwhere(42,43,44,49,50,51,52,53).
Againstabackgroundofseveralthousandisolatescharacterized,veryfewgenotypeAviruseshave
beenidentifiedduringthepast20years.WiththepossibleexceptionofvirusesisolatedintheUKin1993(54),nonehasbeenassociatedwithoutbreaks.Whendetectedtheyhavebeensporadiccaseswithuncertainepidemiology,closelyassociatedwithveryrecentreceiptofvaccine,orqueriedas
laboratorycontaminants(43,55,56,57,58,59,60,61,62).
Table1summarizesthepublisheddocumentationonthedetectionofgenotypeAmeaslesvirusessince1990.
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.
Table1includesisolatesthatmayrepresentwild‐typelineagesthathavesurvivedsincethepre‐vaccinationera.Italsoincludesvirusesisolatedfromveryrecentvaccinerecipientspresentingwith
classicmeaslessymptoms.Butitmayalsoincludevaccine‐derivedisolatesthathavebeentransmittedfromvaccinerecipientstounvaccinatedcontacts.AlthoughsomeofthesegenotypeAviruseshavenucleotidesubstitutionsthatdistinguishthemfromvaccineviruses,thereisno
publisheddocumentationidentifyingadistinctsetofgeneticmarkersthatconsistentlydifferentiateswild‐typevirusesfromattenuatedviruses(46).Measlesvaccinevirusesre‐isolatedfrom
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immunosuppressedpatientswithgiantcellpneumoniahavenucleotidesequencesalmostidenticaltothoseofthevaccinevirus,suggestingthatvaccinevirusesareverystableevenafterprolonged
replicationinahumanhost(46).
Numerouspublishedstudiesofseveralthousandsofisolatesfromacutemeaslescasesinvestigatedoverthepast20yearshavefailedtodetectgenotypeAviruses(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,shouldbethemostabundantmeaslesgenotypeonEarth.Giventhattheyaresoinfrequentlyisolatedfrommeaslescases,themolecularepidemiologicaldataappearstosupportthecontentionthatvaccinevirusesdo
notreadilyreverttowild‐typetransmissibility.
Whatistheriskofmeaslesvaccine‐escapemutants?Thereisnoconclusivepublishedevidencefortheemergenceofmeaslesvaccineescapemutants(84).MeaslesisatypicalRNAvirusinthatintrinsicerrorsoftheRNApolymeraseandlackof
proofreadingmechanismsresultsinamutationrateof9x10‐5perbaseperreplicationandagenomicmutationrateof1.4perreplication(85).Thisiswellwithinthetypicalrangeof10‐3to10‐6mutationspersiteperreplication(86).Asaconsequenceofthishighmutationrate,RNAviruspopulations,
eventhoseinitiatedbyasingleinfectiousunit,arenotclonalbutconsistofalargenumberofgeneticmicrovariantsreferredtoasquasispecies.Despitethehighmutationrate,andunlikeotherRNAvirusessuchasinfluenzaandHIV,measlesvirusremainsremarkablystable.Howcanlive
attenuatedvaccinesdevelopedfromwildtypemeaslesvirusesmorethanhalfacenturyagostillbeeffectiveagainstcirculatingviruses?
Theanswerisprobablyassociatedwithuseofthesignallinglymphocyticactivationmolecule(SLAM;alsoknownasCD150)receptorbythemeasleshaemagglutinin(H)protein,whichisresponsiblefor
cellattachmentandisamajortargetforneutralizingantibodies(87).Theenvelopeofmeaslesvirushastwotypesofglycoproteinspikes,designatedhaemagglutinin(H)andfusion(F)proteins.TheHproteinbindstospecificmolecules(receptors)ontargetcells,whiletheFproteinmediates
membranefusionbetweenthevirusenvelopeandthehostcellplasmamembranethroughcooperationwiththeHprotein.In2000,SLAMwasidentifiedasacellreceptorformeaslesvirus(88).SLAMisexpressedoncellsoftheimmunesystem,suchasactivatedlymphocytesanddendritic
cells(89).StudiesonthecrystallinestructureoftheHproteinhaveshownthatalthoughmostofthisglycoproteiniscoveredbysugarchains,thelargesurfaceareathathoststheSLAMbindingsiteisfreefromsugarchains(90).Mutationsinthisregionarenotpermittedbecausetheyinterferewith
receptorbinding.Thisextremesequencerestrictionallowsforveryefficientproductionofneutralizingantibodiesthatblockbindingofthevirustoitsreceptor.Sotheoriginalvaccinestrains,developedinthe1960s,arestilleffectiveagainstcurrentwild‐typeviruses(91).Analysisofavailable
sequencedatafromapproximately500isolatessuggeststhatdespitetheerror‐proneviralpolymerase,theaminoacidsequenceofHisstronglyconserved,with60%oftheresiduesbeingidenticalorverysimilar(92).Itappearsthatanymutationthatchangesthenatureofthese
conservedresiduesresultsinnon‐viablevirus.
ConclusionThereisnocurrentpublisheddatatosupportevidenceforcurrentlylicensedliveattenuatedvaccine
virusesrevertingtowild‐typetransmissibility.Onthecontrary,thevastmajorityofevidencepoints
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toanimpressivelevelofgeneticstability.However,sincetheyarelivevirusesthatreplicatewithinvaccinerecipients,thepossibilitymustexistthattheycouldreverttowild‐typetransmissibility.
ThereisstrongexperimentalevidenceforthemonotypicnatureandgeneticstabilityofmeaslesvirusbeingbasedonuseoftheSLAMreceptor.Thereisalsonoevidencefortheestablishmentofvaccine‐escapemutants.Evenifvaccinevirusesweretoreverttowild‐typetransmissibility,thereis
noreasontosuspectthattransmissioncouldnotbecontrolledusingcurrentvaccines.
Riskassessment:Availableinformationsuggeststhattheriskofcurrentlive‐attenuatedvaccinevirusesrevertingtowild‐typetransmissibilityisverylow,butitremainsapossibility.
Riskfrompersistentinfections
Howlongdoesmeaslesinfectionusuallypersist?Inclassicmeaslescasesthereisa10–14dayincubationperiodbetweeninfectionandtheonsetofclinicalsignsandsymptoms,andinfectedpersonsareusuallycontagiousfrom2–3daysbeforeand
uptofourdaysafteronsetoftherash.Hostimmuneresponsestomeaslesvirusareessentialforviralclearance,clinicalrecoveryandtheestablishmentoflong‐termimmunity.Earlyinnateimmune
responsesoccurduringtheprodromalphaseandincludeactivationofnaturalkiller(NK)cellsandincreasedproductionofinterferons(IFN)‐αandβ(23,93,94).However,themechanismsandtimingofnormalmeaslesvirusclearancearepoorlyunderstood.Measlesvirushasbeenisolatedfrom
peripheralbloodmononuclearcells(PBMC)uptoaweek,andfromurineupto10days,afterappearanceoftherash(95,96).Delayedvirusclearancehasbeendocumentedincasesofmalnutrition(97,98,99)andpatientswithcellularimmunitydeficiencies(100,101,102).Detectionof
measlesvirusRNAhasbeenreportedforupto4monthsinacaseofcongenitalmeasles(103),for1to4monthsafteruncomplicatedinfectionin90%ofHIV‐1‐infectedchildrenandmorethan50%ofHIVnon‐infectedchildren(104,105,106,107).Thesedataareconsistentwithstudiesofrhesus
macaquesshowingthatvirusclearanceoccursover120–150days(108),suggestingthatnormalclearanceisaprolongedprocess.DespitethereportedpersistenceofviralRNA,therehavebeennoreportsofinfectiousvirussheddingmorethan3to4weeksafterappearanceofsymptoms(98,99).
Persistentinfectionwithmeaslesvirushasdefinitivelybeenassociatedwithsubacutesclerosing
panencephalitis(SSPE),aprogressivefatalneurologicaldiseasewithhighlevelsofneuronalinfectionbymeaslesvirusinthecentralnervoussystem(94).Inimmunocompromisedpatients,persistentmeaslesvirushasbeenlinkedtoanotherneurologicalinfection,measlesinclusionbodyencephalitis
(MIBE)(109).Multiplesclerosis,chronicallyactiveautoimmunehepatitis,Paget’sdisease,otosclerosis,Crohn’sdiseaseandautism,amongmanyotherdiseases,havealsobeensuggestedatvarioustimesaslong‐termsequelaeofmeaslesvirusinfection.Noconfirmedevidencehasbeen
presented,however,tosubstantiatetheseassociations,letaloneproveacausativerelationship.
WhatistheriskfromSSPEcases?SSPEisaslow,progressivediseasethatisinvariablyfatal.TheaverageperiodfrominitialmeaslesinfectiontoSSPEsymptomonset(latency)usuallyrangesbetween4and10years,buthasbeen
reportedfrom2monthsto23years(110).Childrenarefarmorelikelytodevelopthiscomplicationthanadults.ReportedSSPEincidencevariesfromapproximately0.2to40casespermillionpopulationperyear.Directcomparisonofdatafromdifferentcountriesisproblematicbecause
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methodsandqualityofdiagnosishavebeeninconsistent.AnalysesofdatafromtheUKandUSAhavecalculatedthetrueincidenceofSSPEtobeapproximately4–11casesofSSPEper100000cases
ofmeasles.Ahigherriskisassociatedwithearlierinfection:theriskfollowingmeaslesinfectionunder1yearofageis18/100000comparedwith1.1/100000after5yearsofageintheUK(110).Obviously,asthenumberofmeaslesinfectionsdeclines,sowillthenumberofpotentialSSPEcases.
Thediseaseinitiallymanifestsassubtlecognitivelosses,progressingtomoreovertcognitivedysfunction,followedbymotorloss,seizuresandeventualorganfailureinvirtuallyallaffected
individuals.Neuronsinboththegrayandwhitematterareinfected,andthediseaseishistologicallycharacterizedbythepresenceofcellularinclusionbodies(111).AserologichallmarkofSSPE,ascomparedtotheothercentralnervoussystemcomplications,istheelevationofmeaslesspecific
antibodiesinthebloodandcerebrospinalfluid(94).Mostimportantly,evidencefrombrainbiopsiesofSSPEpatientsindicatesthatinfectedneuronsdonotreleasebuddingvirus(112).Basedonsequencingstudiesofvirusfromthesespecimensandfromcellspersistentlyinfectedwithmeasles
virusisolatesfromSSPEpatients,ithasbeenproposedthatthefailureofinfectedneuronstoproducecompleteextracellularvirusmaybeduetodefectsinproteinexpressioncausedbyextensivepointmutationsintheH,fusion(F)andmatrix(M)genes(113,94,114,115,116).Thereis
noevidencefortransmissionofmeaslesvirusfromSSPEcases.
WhatistheriskfromMIBEcases?Measlesinclusionbodyencephalitis(MIBE)isararecentralnervoussystemcomplicationfollowingacuteMVinfection,hasbeendescribedinchildrenandadultsreceivingimmunosuppressivedrugs
andthereforeisthoughttochieflyaffectimmunocompromisedhosts.MIBEhasalsobeenreportedtoresultfromreceiptofmeaslesvaccine(117).Theneurologicdiseaseusuallyappears3to6monthsaftertheacutemeaslesrash(111),withamediantimeof4months(118).Measlesantigenis
presentinthebrain,andvirushasbeenisolateddirectlyfromthebrainsofaffectedindividuals(111,119).MIBEdiffersfromSSPEintheabsenceofelevatedserumandcerebrospinalfluidneutralizingantibodies(94).Thediseasecourseisrelativelyshort,lastingfromdaystoweeks,
causingseizures,motordeficits,andstupor,oftenleadingtocomaanddeath.Althoughonlyaverysmallpercentageofacutemeaslesinfectionswillgoontodeveloppersistent
complications,afewstudieshavedetectedmeaslesvirusRNAinvariousorgans,onautopsy,ofelderlyindividualswhodiedofnon‐viralcauses(120,121).Thesefindingssuggestthatmeaslesviruspersistsinthebrains(andotherorgans)ofhealthyindividuals,andmaymanifestitselfincentral
nervoussystemdiseaseunderconditionsofimmunocompromiseorimmunosuppression.Thishasbeenunderlinedbythecaseofa13year‐oldboythatdevelopedMIBEafterreceivingastemcelltransplant(119).Neitherthepatientnorthestemcelldonorhadapparentrecentmeaslesexposure
orvaccination,andneitherhadrecenttraveltomeasles‐endemicregions.ThepatientwasborninChicagoduringthemeaslesepidemicof1989‐1991(birthyear1989).Anundiagnosedcaseofmeaslesintheperiod1989‐1991wouldsuggestalatencyperiodtoMIBEof12years,whichisnot
typical.CasesofMIBEwithoutclearmeaslesexposureorinfectionhavebeenreported.InareviewofMIBE,18%ofpatientshadnodocumentedmeaslesexposureorinfection(118);however,many
ofthesecasesoccurredinyearswhenmeasleswasmoreprevalent.TherearenopublishedreportsofinfectiousmeaslesvirussheddingfromMIBEcases.
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DoesHIVco‐infectionpresentariskforpersistentmeaslesinfectionandtransmission?Asdiscussedabove,measlesvirusRNAcouldbedetectedinsamplesfrom90%ofHIV‐infected
childrenonemonthafterrecoveryfromacutemeasles(104),butinthisstudynoattemptwasmadetoculturevirusfromanysamples.InregionsofhighHIV‐1prevalence,co‐infectionwithHIV‐1morethandoublestheoddsofdeathinhospitalizedchildrenwithmeasles(122)andmayslowtherateof
virusclearanceslightly,butthereisnoevidencethatHIV‐infectionleadstoanincreasedriskforpersistentmeaslesvirusinfection.NordoesHIVinfectionappeartopresentariskforpersistentinfectionwiththemeaslesvaccinevirus.Asearchforpersistentmeaslesmumpsandrubellavaccine
virusesinchildrenwithHIV‐1infectionfailedtodetectvirusinperipheralbloodmononuclearcells,polymorphonuclearleukocytes,orplasma(123).
ConclusionThereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe
sheddingofinfectiousvirusorplayanypartinmeaslestransmission.Asthenumberofacutemeaslesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthenumberofpotentialSSPEandMIBEcases.
AcutemeaslesinfectioninHIV‐infectedindividualstendstobemoresevere,lastlongerandresultinashorterlivedimmunitytore‐infection,butthereisnopublishedevidencetosuggestthatco‐
infectionincreasesthepotentialforestablishmentofpersistentmeaslesinfections,eitherwithwild‐typevirusorwithvaccine‐derivedvirus.
Riskassessment:Availableinformationsuggeststhattherelativelysmallnumberofpersistentmeaslesviruscases,includingthosethatmayresultfromco‐infectionwithHIV,poseaverylowriskforreintroductionofmeasles.
Riskfromnon‐humanprimatesAlargeproportionofourcurrentknowledgeofmeaslesandmeaslesinfectionmechanismshave
comefromexperimentalinfectionofnon‐humanprimates.In1911,GoldbergerandAndersondemonstratedthatmacaquesinoculatedwithfilteredsecretionsfrommeaslespatientsdevelopedmeasles,provingthecausativeagentwasavirus(124).Awiderangeofnon‐humanprimatespecies
aresusceptibletoexperimentalinfectionwithmeaslesvirus.TheseincludeMacacamulatta,M.fascicularis,M.radiata,M.cyclopis,Papiocristatus,Cercopithecusaethiops,Saimirisciureus,Colobusquereza,Pantroglodytes,Callithrixjacchus,Saguinusoedipus,S.fuscicollis,andAotustrivirgatus
andAtelesspecies(125,126,127).Aswouldbeexpectedfromaneffectiveanimalmodel,manyspeciesrespondtoinfectioninamannerverysimilartohumans(128,129,130).Inadvertent
transmissionofeithermeasles(fromhumans)orthecloselyrelatedcaninedistempervirus(fromdogs)tocaptivenon‐humanprimateshascausednumerousoutbreakswithsignificantmorbidityandmortality(131,127,132,133,134).Non‐humanprimatesinthewildappeartobefreefrommeasles,
onlycontractinginfectionwhentheycomeintocontactwithinfectedhumans(125).Human‐to‐primatediseasetransmissioncanpotentiallycausesignificantmorbidityandmortalityamongwildprimatepopulations.Serologicalevidenceofmeaslesinfectioninfree‐rangingpopulationsofnon‐
humanprimateshasbeenwelldocumented(135,136,137).Evidenceexistsofmeaslesinfectioninnon‐humanprimatepopulationswithfrequentcontactwithhumanpopulations,aswellasinwild
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populationswithminimalhumancontact(127).Across‐sectionalstudyofwildmacaques(Macacatonkeana)inSulawesi,Indonesia,foundserologicalevidenceofmeaslesevidencein5of15animals
surveyed(136).Becausehumanpopulationsrepresentthelargestreservoirofthemeaslesvirus,itismostlikelythat
measlesepizooticsinnon‐humanprimatepopulationsareinitiatedbyhumantonon‐humanprimatetransmissionandsubsequentlyspreadbyanimaltoanimaltransmission.Duetotheirrelativelysmallnumbers,itisunlikelythatnaturalpopulationsofnon‐humanprimatesaresignificantorsustainable
reservoirsofmeaslesvirus(127).
ConclusionAlthoughnon‐humanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,andanimaltoanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootic
transmission.
Riskassessment:Availableinformationsuggeststhatinfectionsinnon‐humanprimatespose
averylowriskforreintroductionofmeasles.
Riskoflaboratory‐associatedmeaslesinfectionRisksposedbylaboratory‐maintainedmeaslesviruses,throughaccidentalorintentionalrelease,arelargelydependentonwhetheruniversalimmunizationagainstmeaslesiscontinuedorifitisstopped
on,orsoonafter,globalcertification.Ifthedecisionismadetocontinueuniversalimmunization,possiblywithnon‐replicatingvaccines,theriskposedbylaboratory‐maintainedviruswillbeverylow,sincetherewillbealmostuniversalimmunity.If,however,universalimmunizationstopsafter
globalcertification,therisksposedbylaboratory‐maintainedmeasles‐infectiousmaterialswillprogressivelyincrease,asthenumberofmeasles‐susceptiblesinthepopulationincreases.Therisksincludenotonlyaccidentalreleaseoflivemeaslesvirusfromlaboratoriesandattenuatedvirus
vaccineproductionfacilities,butthreatofdeliberaterelease.
Whatistheevidenceforlaboratory‐acquiredmeaslesinfection?Aseriesofsurveysforlaboratory‐acquiredinfectionsconductedintheUK(138,139,140,141,142,143,144),theUSA(145,146,147,148,149)andJapan(150)failedtoinclude
measlesamongthelistedinfections.Arecentreviewofprinciplesforpreventionoflaboratory‐associatedinfectionsalsofailedtomakementionofmeasles(151).Anextensiveliteraturesearchfailedtofinddocumentedevidenceoflaboratory‐acquiredmeaslesinfection.Thisleavesthree
possibilities:laboratory‐acquiredmeaslesinfectionshavenotoccurred;theinfectionsthathaveoccurredhavebeenbelowthethresholdofsensitivityofthesurveillancesystems;or,measleshasbeenconsideredatrivialdiseaseandinfectionshavenotbeenreported(152,153).
Priortothe1970sitistobeexpectedthatalmostallstaffworkinginclinicalmicrobiologyandresearchlaboratorieswouldhavebeenexposedtomeaslesinfectionduringchildhood.Fromthe
1970sonwardsitistobeexpectedthatallnewstaffcomingtoworkintheselaboratorieswouldhavereceivedatleastonedoseofmeaslesvaccine.Itisunlikelytherefore,thatexposedlaboratorystaffwoulddevelopacutemeaslessymptomsfromlaboratory‐acquiredinfections.Butgiventhe
veryhightransmissibilityofmeaslesvirus,itispossiblethatexposuretoinfectiousvirus,and
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resultingasymptomaticinfections,orverymild,atypicalinfectionshaveoccurred.Iftheyhaveoccurred,itisprobablethattheseinfectionshavegoneundetected,orsimplyoverlookedas
unimportant.
Howstableismeaslesvirusintheenvironmentandinlaboratorymaterials?Measlesisnotaphysicallyrobustvirus.Itisviableforlessthan2hoursatambienttemperaturesonsurfacesandobjects,whiletheaerosolizedvirustypicallyremainsinfectiveforonly30minutesto2
hours,dependingonenvironmentalconditions(154,155).Itisverysensitivetoheatandisinactivatedafterlessthan40minutesat56°C,eveninmediumcontainingaproteinstabilizersuchas5%calfserum(156).Virusinmaintenancemediumlosesatleast2logsoftitrewhenstoredat+6oC
for14‐20weeksandlosesallinfectivityafter1yearatthistemperature.Additionofaproteinstabilizerimprovesviruslongevity,withalossofapproximately2logsoftitreafter1yearat+6oC.Interestingly,storageat‐30oCofferslittleadvantageoverstorageat+6oC,witha1‐2loglossoftitre
over1year.Storageat‐72oCorbelowresultsinverylittlelossofvirusinfectivity,andinfectiousmaterialsmaintainedatthistemperatureshouldretaininfectivityformanyyears(156).Thevirussurvivesfreeze‐dryingrelativelywelland,whenfreeze‐driedwithaproteinstabilizer,cansurvive
storagefordecadesat‐70oC(156,155).Incommonwithmanyotherenvelopedvirusesitisinactivatedbysolvents,suchasetherandchloroform,byacids(pH<5),alkalis(pH>10),andbyUVandvisiblelight.Itisalsosusceptibletomanydisinfectants,including1%sodiumhypochlorite,70%
alcoholandformalin.
Whichlaboratorymaterialspresentarisk?Measlesvirusinfectiousmaterialsincludeautopsyorclinicalsamples(e.g.pharyngealsecretions,urine,blood)frommeasles‐infectedpersonsorrecentlive‐attenuatedvaccinerecipients,and
laboratoryderivedmaterials(e.g.virusisolatesandreferencestocks,materialsderivedfrominoculatedcellcultures,laboratoryanimals).Measlesviruspotentialinfectiousmaterials,thosethataresuspectedtocontaininfectiousmeaslesviruses,includepharyngealsecretionsandblood
samplescollectedforanypurposeatatimeandinaplacewheremeaslesviruseswerecirculating,andstoredunderconditionsthatwouldpreservevirusinfectivity.Theyalsoincludeproductsofthesematerialsinmeaslesviruspermissivecellsoranimals(157).
Whattypesofriskdolaboratoriespresent?Riskspostmeasleseradicationwillexistattwolevels:
• occupationalriskofexposureamonglaboratorystaff,• communityriskoflaboratory‐associatedmeaslesexposure.
Thethreemostcommonroutesofexposuretoinfectiousagentsinthelaboratoryareingestion,inhalation,andinjection(153).Measlesviruscanremaininfectiousonsurfaces,suchasworkbenchesanddoorhandles,foruptotwohours.Iftransferredfromthehandtothemouth,noseor
conjunctiva,theycaninitiateinfectionofepithelialcells(158).Althoughtherearenorecordedincidentsoflaboratory‐acquiredmeaslesvirusinfections,severalsurveysdocumentthefrequent
occurrenceofingestingmorereadilyrecognizedpathogens,suchasShigellaandSalmonella(139,140,141,142,143,147,153).Themostcommonroutefornaturaltransmissionofmeaslesisbelievedtobebyinhalationofaerosolizedvirus;infectiousdropletsbeingproducedbytalking,
coughingandsneezingbyinfectedindividuals(158).Smallparticles(<5‐μdropletnuclei)ofsuspendedevaporatedresiduescanmoveaboutroomsandbuildingsonaircurrentsandwhen
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inhaleddepositprimarilyinthelowerrespiratorytract(159).Laboratoryactivitiesthatexposestafftoaerosolsgeneratedfrominfectiousmaterial(e.g.centrifugation,blending,vigorouspipetting,
etc.),andexposuretoinfectedlaboratoryanimals,presentariskforinfection.Themostcommonroutefordeliveryofcurrentmeaslesvaccinesisbyinjection.So,injectionandneedle‐stickinjuriesinvolvingmeaslesvirusinfectiousmaterialsobviouslypresentariskforinfection.
Communitymembersmaybeexposedtoinfectiousmeaslesvirusfrom:
• contaminatedlaboratoryworkers,
• infectedlaboratoryworkers,• contaminatedaireffluents,• transportofinfectiousmaterial,
• escapedinfectiousanimals.Again,nopublishedevidenceexistsfortheescapeofinfectiousmeaslesvirusfromthelaboratory
intothecommunity.Giventherapidinactivationofmeaslesvirusundernormalenvironmentalconditions,thelengthoftimeavailableforinfectiousvirustobecarriedoutofthelaboratoryandintothecommunity,eitheronthebodyorclothesofacontaminatedworker,orincontaminatedair
effluents,isprobablylimitedto2hours.Thisreducestherisktoaverylowlevel.Asdiscussedabove,availableevidencesuggeststhatimmunizedindividuals,whodevelopasymptomaticormildinfections,areunlikelytotransmitthevirus(10),reducingthecommunityrisk.Wecanassumethat
laboratoriesimplementinggoodlaboratorypractices(GLP)orgoodmanagementpractices(GMP)willminimizetherisksofreleasetotheenvironmentbyproperlypackagingandtransporting
infectiousmaterialsinaccordancewithcurrentinternationallawsandregulations.Giventhesecurityconcernsthatsurroundlaboratoryanimalhousesandresearchfacilities,thelikelihoodthatmeasles‐infectedanimalswouldescapeintothecommunitymustbeextremelysmall.
ConclusionAlthoughthereisnodirectevidenceforlaboratory‐acquiredmeaslesinfectionsitispossiblethattheyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymildinfections.Thereisnopublishedevidencetosuggestthatthesepossibleasymptomaticormild
infectionsresultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinacoupleofhoursatambienttemperaturesintheenvironment,andinfectiousmaterialsstoredattemperaturesabove‐30oCcanbeexpectedtoloseallinfectivityoverthecourseofonetotwoyears.
Despitethelackofevidenceforlaboratory‐acquiredmeaslesinfectionsorescapeofvirusintothecommunity,inapost‐eradicationworldthesemustbeconsideredpossibilitiesduetothehighlyinfectiousnatureofmeasles.
Riskassessment:Inameaslespost‐eradicationworldwithoutroutineuniversalimmunization,measleslaboratories(andmeasleslivevaccineproductionfacilities)willpose
averylowbutincreasingriskforreintroductionofmeasles.
RiskofintentionalreleaseofmeaslesvirusBioterroristthreatsdonotworkagainstpopulationsthathavebeenfullyimmunized.However,inapost‐eradicationworldinwhichuniversalroutineimmunizationhasceased,agrowingpopulation
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willbesusceptibletomeasles,andmeasleswill,eventually,becomeacredibleagentforbioterrorism.Thedevastatingeffectofmeaslesonsusceptiblepopulationsinthepre‐vaccination
erahasbeenwelldocumented(158).ThisisparticularlytruefortheislandsofthePacific.In1848inHawaii,10,000natives,about10percentofthepopulation,diedduringanepidemic(160,161,162).In1861onAneityumintheNewHebrides,thepopulationwasreducedbyabout60percentina
measlesepidemic(163).In1875inFiji,20,000natives,20to25percentofthepopulation,diedofmeasles(164).In1907,againinFiji,6percentof30,000casesdied,andin1911onRotuma16percentofthepopulationdiedofmeasles(165).In1936measlescaused100deathsand14,282casesin
theGilbertIslands(166),andin1937inHawaii,therewere205deathsfor13,680casesofmeasles(167).In1946intheBritishIslandsoftheSouthPacific,therewere1,000deathsfor15,000to20,000casesofmeasles(168).Therearemanyotheraccountsofsimilardevastatingmeasles
epidemicsinisolatedcommunitiesaroundtheworld.
Withadvancesinmodernmedicaltreatmentitisunlikelythatsimilarmortalityrateswouldbeinflictedoneortwogenerationspostmeasleseradication,butdeliberatereleasewouldcauseextensivedisruptiontomedical,publichealthandsocialservices,andprobablyincurenormous
containmentcosts.Thethreatofrelease,withtheknowledgeofthepotentialdisruptionandfinancialexpenseitcouldcause,wouldmakemeaslesaneffectiveagentforbioterroristsoncealargeenoughpopulationofmeasles‐susceptibleshadaccumulated.Measlesisnotcurrentlyincluded
intheCDCBioterrorismAgentCategories(169,170),butthissituationwillneedtobereviewedintheyearsfollowingeradication.
ConclusionMeaslesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthe
past.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldberepeated,thethreatofintentionalreleasewouldprobablybeveryeffectiveonceasizablepopulationofsusceptibleindividualshadaccumulated.
Riskassessment:Theriskofdeliberatereleaseofmeasleswillbeverylowatthetimeofglobaleradication,butwillriserapidlywithaccumulationofunvaccinatedmeasles
susceptibles.
ActionsrequiredtoreducetheriskofaccidentalordeliberatereleaseofmeaslesOneapproachtoreducingtheriskofmeaslesre‐introductionwouldbeadoptionofastrategytominimizeavailabilityofmeaslesvirus,throughremovaloflivevirusesfromlaboratoriesandsecurely
containingallinfectiousmaterialthatremains,andestablishinganinsurancepolicyintheformofavaccinestockpile.
Reducingtheriskofaccidentalrelease:alaboratorycontainmentstrategyAsystematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythePolioEradicationInitiative(171),startingnowandcontinuingintothepost‐eradicationera,would
minimisetheriskofaccidentalre‐introductionofmeaslesvirus.Thestrategyestablishedforpoliooutlinesthreedistinctphases.Phase1wouldlastfromthepresent,whenmeaslescontinuestocirculate,tothetimewhenmeaslestransmissionceases.Phase2wouldcoverthecertification
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period,andPhase3wouldtakeplaceintheposteradication,postglobalcertificationperiod.ThesethreePhasesforpoliohavebeenclearlydescribedinaseriesofpublishedGlobalActionPlans
(172,173,157).
Thelaboratory‐associatedrisksposedbymeaslesareconsiderablylowerthanthoseposedbypolio,andstrategiesforreducingtheriskevenfurthershouldnotsimplyduplicatetheactivitiesdevelopedforpolio,butbeproportionateandappropriateformeasles.Thegeneralapproachtakenbythe
PolioEradicationInitiative,andlessonslearnedfromimplementingthepoliocontainmentstrategy,shouldprovideasoundstartingpointformeasles.Strategiesforreducingtheriskinthepre‐eradicationphaseshouldbebasedonthefollowingprinciples:
• minimizingthenumberoflaboratoriesretainingmeaslesvirusinfectiousandpotential
infectiousmaterials;• minimizingtherisksofoperationsinlaboratoryandmeasleslivevaccineproduction
facilities;
• minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding;• minimizingsusceptibilityofcommunitytomeaslesvirusspread.
Thehighestrisksarepresentedbythoselaboratoryoperationsinvolvingmeaslesvirusreplication,
includingthegrowthofvaccinestrainsforlivevaccineproduction.Thelowestrisksarenon‐replicative,biosafety‐appropriateoperationsperformedwithpotentiallyinfectiousclinicalmaterials.Intheyearsleadinguptoglobaleradicationallworkwithwildmeaslesvirusesshouldrequire
biosafetylevel‐2(174),withadditionalrequirementsforrestrictinglaboratoryaccess,andmaintenanceofaccuraterecordsofmeaslesvirusmaterials.Establishingnationalmeasles
inventories,andcallstosafelydisposeofallunwantedmeaslesinfectiousandpotentialinfectiousmaterials,ashasbeenaccomplishedforpolio,wouldalsoberequired.
Thesecondphaseofriskreductionwouldconsistessentiallyofvalidatingthecontainmentactivitiesatnational,regionalandgloballevelsasarequirementforGlobalCertification.Stoppinguniversal
measlesimmunizationpostcertification(thirdphase)willaltertherelativeweightsoftheprinciplesonwhichminimizingtheriskfromthelaboratoryisbased(157):
• minimizingsusceptibilityofcommunitiestomeaslesvirusspreadwillnolongerapplyinthosecountriesthatelecttostopmeaslesimmunization;
• minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding,intheabsenceofanon‐infectiousvaccine,willrelysolelyonpreventionofinfection;
• minimizingthenumberoflaboratoriesretainingmeaslesvirusmaterialsandminimizingthe
risksofoperationsinthoselaboratoriesbecomesmuchmoreimportant.Wearecurrentlyconsideringtheprospectofglobalcessationofmeaslestransmissionapproximately
adecadefromnow,allowingreasonabletimetodevelopanappropriatemeasleslaboratorycontainmentstrategyandforlaboratoryresearchonmeaslesvirusestocontinueundercurrent,biosafetylevel‐2,conditions.Italsoallowstimeforcontinueddevelopmentofalternativemeasles
vaccinesandspecificantivirals.
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DevelopingavaccinestockpileLiveattenuatedmeaslesvaccineshavebeenhighlysuccessfulinprotectingpopulationsagainst
measlesandstoppingmeaslestransmission.Asdiscussedabove,thesevaccinesareverysafe,andposeonlyasmallpotentialriskforestablishingtransmissionofvaccine‐derivedvirusesinaposteradicationworld.Toremovethisriskanewvaccinethathasnocapacityforreplicationor
transmissionisrequired(175).Theidealmeaslesvaccinewouldbeinexpensive,safe,heat‐stable,immunogenicinneonatesorveryyounginfants,andadministeredasasingledosewithouttheneedtouseaneedleorsyringe(93),be100%effectiveand100%incapableoftransmission.Whilesucha
vaccinewouldhaveclearbenefitsfortheeradicationofmeasles,itwouldbeasavaccineforstockpilingposteradicationthatitwouldcomeintoitsown.Severalvaccinecandidateswithsomeofthesecharacteristicsareundergoingdevelopmentandtesting.Featuresofthesenew,potential
measlesvaccineshavebeenextensivelyreviewed(175,176).
Howlargeameaslesvaccinestockpilewouldberequiredisverydifficulttopredictwithoutmodelling.Requirementswouldobviouslybedynamic,dependingonsomefairlycomplexvariables,includingthenumberofsusceptiblesaccumulatinginthecommunity,theeffectivenessofthe
vaccine,transmissiondynamicsofthevirusandtheeffectivenesswithwhichanyeventrequiringanimmunizationresponsewasdetected,reportedandrespondedto.Decisionsonsuchbig,expensiveitemsasestablishingameaslesvaccinestockpileshouldnotbetakeninisolation,butconsidered
systematicallyandincludedinaconsensusriskmanagementstrategy,ashasbeenachievedforpolio(177,178,179,180,181,182).Developmentofapostmeasleseradicationriskmanagementstrategyshouldbeginassoonaspossible.
AreasrequiringfurtherresearchTherisksofre‐introductionofmeaslespostglobaleradicationmaybereducedbyapplyingknowledgeacquiredthroughkeyareasofresearchconductedintheyearsleadinguptoeradication.Thesekeyareasincludethefollowing:
GreaterunderstandingofthetransmissiondynamicsofmeaslesIndrawingupthecertificationcriteriaandvalidationrequirementsitwillbenecessarytoengage
expertsfamiliarwiththedevelopmentofdynamicandstochasticmodelsofmeaslestransmission,persistenceandelimination.Thiswillbeparticularlyimportantfordeterminingthecertificationandvalidationrequirementsforlow‐income,highdensitypopulations.Basedontheexperiencegained
inpolioeradication,thiswillbemostrelevantforselectedpopulationsinAfrica,theIndiansub‐continentandlargerefugee/migrantpopulationcamps.
Importantinformationcanalsoprobablybegainedfromdetailedepidemiologicalandmolecular
analysisofoutbreaks,particularlythoseoccurringinhighlyimmunizedpopulations,high‐densitypopulations,andingenerallyhighly‐immunizedpopulationswithinadequatelyimmunizedsub‐
populations.
Withtherapidincreaseinthenumberofhighlyimmunizedpopulations,opportunitiesforstudyingasymptomaticandatypicalinfectionsandtheirpotentialroleintransmissionshouldbetaken.
Greaterunderstandingofthechangesbroughtaboutbytheattenuationprocess
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Ifcurrentlylicensedattenuatedmeaslesvaccinesaretobeusedinapost‐eradicationworld,moreinformationonthenatureofthechangescausedbyattenuationandthepotentialforreversionto
wild‐typecharacteristicswillberequired.Analternativewouldbetospeedupdevelopment,testingandintroductionofnewmeaslesvaccinesthatarenotdependentonliveattenuatedvirus.
Moreunderstandingofthenatureofthecomplexinteractionbetweenmeaslesvirusandthehostimmunesystem,includingbothhumoralandcell‐mediatedresponses,wouldprobablybenefit
continueduseofexistingvaccinesanddevelopmentofnewvaccines.
Intheyearsleadinguptoglobaleradication,allgenotypeAvirusesdetectedinassociationwithacutecasesofmeaslesshouldbethoroughlyscrutinized.Fullepidemiologicalinformationwillberequired,andadditionalsequencedatafrombothclinicalsamplesandcorrespondingviralisolates
willbenecessarytoruleoutthepossibilityoftransmissionofvaccine‐derivedvirus.Thoroughgeneticanalyses,includingfullgenomicsequencing,shouldbeperformedonselectedvaccinevirusesthatareassociatedwithcommonvaccinereactionsaswellasthosedetectedintheveryrare
severreactionstovaccination.
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