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Riskanalysisformeaslesreintroductionpostglobalcertificationof
eradication
DrRaySanders.July2010
Summaryandconclusions
Measlesviruswillcontinuetoexistaftercertificationofglobaleradicationasvirusstocksand
infectiousmaterialsheldinlaboratories.Livevirusmayalsoexistinundetectedfocioftransmission
andinpersistentlyandchronicallyinfectedindividuals.Thisanalysisattemptstoidentifyand
evaluatethemainrisksforreintroductionofmeaslestransmissionpostcertificationoferadication
inaworldinwhichuniversalroutinemeaslesimmunizationisnolongerafeature.
Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumans
Thereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreedrequirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements
fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby
undetectedcontinuingtransmission.
Mildorasymptomaticmeaslesinfectionsareprobablyverycommonamongmeaslesimmune
personsexposedtomeaslescases,buttransmissionfromasymptomaticcasesislikelytobevery
rare.Ifitoccursitisunlikelytobeefficientenoughtosustaintransmission,especiallyinthehighly
vaccinatedpopulationsexpectedintheyearsimmediatelyfollowingglobalcertificationof
eradication.However,thepotentialroleofasymptomaticinfectionsinmaintainingtransmission
requiresfurtherinvestigation.
Ifthecriteriaforglobalcertificationoferadicationarefirmenough,andrequirerigorousvalidation,
thentheriskofundetectedmeaslestransmissionaftercertificationisverylow.Ifthecertification
criteriaarelax,orvalidationrequirementsareinadequate,theriskwillbehigher.
Riskoftransmissionofvaccinederivedvirus
Thecurrentlylicensedliveattenuatedmeaslesvaccinesaresafeandefficientandhavebeenused
successfullytoprotectmanymillionsofindividualsandpreventmeaslestransmission.Allcurrent
vaccinevirusesarecloselyrelatedandbelongtogenotypeA.Thereisnopublishedconclusive
evidenceforcurrentlylicensedliveattenuatedvaccinevirusesrevertingtowildtypetransmissibility
orvirulence.Onthecontrary,thevastmajorityofevidencepointstoanimpressivelevelofgenetic
stability.However,sincetheyarelivevirusesthatreplicatewithinvaccinerecipients,theremote
possibilitymustexistthattheycouldreverttowildtypecharacteristics.Thereisalsonoevidencefor
theestablishmentofvaccineescapemutants.Evenifvaccinevirusesweretoreverttowildtype
transmissibility,thereisnoreasontosuspectthattransmissioncouldnotbecontrolledusingcurrent
vaccines.
Riskfrompersistentinfections
Thereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe
sheddingofinfectiousvirusorplayanypartinmeaslestransmission.Asthenumberofacute
measlesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthe
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numberofpotentialSSPEandMIBEcases.AcutemeaslesinfectioninHIVinfectedindividualstends
tobemoresevere,lastlongerandresultinashorterlivedimmunitytoreinfection,butthereisno
publishedevidencetosuggestthatcoinfectionincreasesthepotentialforestablishmentof
persistentmeaslesinfections,eitherwithwildtypevirusorwithvaccinederivedvirus.
Riskfromnonhumanprimates
Althoughnonhumanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and
animalanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootictransmission
orposeathreattohumanpopulations.
Riskoflaboratoryassociatedmeaslesinfection
Althoughthereisnodirectevidenceforlaboratoryacquiredmeaslesinfectionsitispossiblethat
theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymild
infections.Thereisnopublishedevidencetosuggestthattheseasymptomaticormildinfections
resultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinafewhoursatambient
temperatures,andinfectiousmaterialsstoredattemperaturesabove30 oCcanbeexpectedtolose
allinfectivityoverthecourseofonetotwoyears.Materialsstoredatorbelow70oC,orfreeze
dried,maintaininfectivityformanyyears.
Despitethelackofevidenceforlaboratoryacquiredmeaslesinfectionsorescapeofvirusintothe
community,thesemustbeconsideredpossibilitiesinaposteradicationworld.Anappropriate
systematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythePolio
EradicationInitiative,shouldbedeveloped.
Riskofintentionalreleaseofmeaslesvirus
Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthepast.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldbe
repeated,thethreatofmeaslesreleasewouldprobablybeveryeffectiveonceasizablepopulation
ofsusceptibleindividualshadaccumulated.Thisthreatcouldbecounteredbytheestablishmentofa
measlesvaccinestockpile,preferablyusinganew,easytomassadminister,nonreplicativemeasles
vaccine.Thesizeandnatureofanystockpileshouldbedefinedwithinasystematicand
comprehensiveposteradicationriskmanagementstrategy.
Risksforreintroductionofmeaslescanbesummarisedasfollows:
Risk Magnitude Tendencyovertime MitigatingactionsContinuingwildtype
measlestransmissionin
humans
Lowbutdependson
certificationcriteriaand
validationrequirements
Decreasing Basecertificationcriteria
andvalidationrequirements
ondynamicandstochastic
modellingdata
Transmissionofvaccine
derivedvirus
Verylow Dependsonlevelofvaccine
use
Developalternative,non
replicatingvaccines
Persistentinfections Verylow Decreasing Maintainsurveillance
Nonhumanprimates Verylow Decreasing Maintainsurveillance
Laboratoryassociated
infection
Verylowbutrisingpost
eradication
Increasing Developsystematic
laboratorycontainment
strategy
Intentionalrelease Verylowbutrisingpost
eradication
Increasing Developvaccinestockpiles
aspartofacomprehensive
riskmanagementstrategy
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TableofContentsError!Bookmarknotdefined.
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Theanalysisconcludeswithabriefdiscussionofactionsrequiredtoreducetheriskofaccidentalor
deliberatereleaseofmeaslesinaposteradicationworldandareasthatcouldbenefitfromfurther
research.
Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumansThereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreed
requirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements
fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby
undetectedcontinuingtransmission.However,basedoncurrentRegionalandGlobal
recommendationsoncertificationofRegionalmeasleselimination,itislikelythateradicationcriteria
willinclude:
1. Absenceofcirculatingmeaslesvirusforatleastoneyear;2. Adequatesurveillanceincludinggenotypedata.Adequatesurveillancemaybedefinedby:
Numberofreportedsuspectedmeaslescasesthatarediscardedasnonmeasles(targets:2/100,000populationnationally,1/100,000inatleast80%ofdistricts)
Percentageofreportedsuspectedcasesthathaveadequateinvestigationwithin48hoursofreport(target:80%ofreportedsuspectedcases)
Percentageofreportedsuspectedcasesthathaveadequatespecimenscollected(target:80%ofreportedsuspectedcases)
PercentageofdistrictswithaccesstoaWHOaccreditedmeaslesdiagnosticlaboratory(target:100%)
PercentageofspecimenswithIgMresultswithin7daysofreceiptinlaboratory(target:90%)
PercentageofchainsoftransmissionwithRNAsequenceanalysis(target:95%) Someuseofmeaslesavidityassaystodistinguishrecentfromlongstanding
immunologicalresponses
Somedemonstrationofalternativesurveillancemechanisms,routineorsupplementary,basedoncasedetection,investigationandreporting;
3. Achievementofhighpopulationimmunity.Populationimmunitymaybedemonstratedby: 95%coveragewithroutineMCV2inalldistricts,or 80%coveragewithroutineMCV1plus95%coveragewithSIAfollowupinall
districts,or
Someuseofextensiveserosurveydata.
FromexperiencegainedthroughRegionalpolioeliminationandcertification,specificcriteriamaybe
usedtofulfilthethreegeneralcriteriaabove,butitisunlikelythatanysinglespecificindicatorwill
berequiredtopassorfailvalidation.Thestrictnessandextentofrequirementsforproviding
evidencethatcertificationcriteriahavebeenmetwilllargelydeterminethemagnitudeofriskposed
byundetectedcontinuingmeaslestransmission.Butevenwithrelativelylaxcriteriaandvalidation
requirements,howlikelyisitthatongoingmeaslestransmissionwillbeundetectedforaminimum
ofoneyearbeforecertification?
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Whatisthesmallestpopulationrequiredtomaintainmeaslestransmission?
Measlesepidemicshavegenerallybeencharacterisedbyexplosivecycleswithhighlycomplex
pathogenandpopulationlevelinteractionsthatinfluencetransmissiondynamics(1).Accurately
predictingthecriticalcommunitysize(CCS)requiredformaintainingmeaslesviruscirculationis
difficultduetothelargenumberofvariablesinvolved.Directobservationandarangeofboth
deterministicandstochasticmodelssuggestthatapopulationof250,000to400,000with5,000to
10,000birthsperyearisrequiredtomaintaintransmission(2,3).Highlevelsofimmunization,low
populationdensity,alowbirthrateandgoodpublichealthcarefacilitiesincreasetheCCS.Low
vaccineuptake,highpopulationdensity,highbirthrates,highlevelsofimmunodeficiencyandpoor
publichealthcarefacilitiesdecreasetheCCS(1,4,5).
AlthoughitmaybedifficulttoaccuratelyestimatetheCCSinlowincome,lowvaccinecoverage
populations,itiseasytoidentifythesepopulations.Ifdiseasesurveillanceandimmunization
activitiesaretargetedonthem,andonanynew,atriskpopulationsthatmayemergefollowing
displacementcausedbyconflictorclimatechange(6),thepotentialtooverlookcirculationofvirus
intheyearleadinguptoglobalcertificationwillbegreatlyreduced.
Whatroledoasymptomaticinfectionsplayinvirustransmission?
Measlescontrolstrategiesassumethatvirustransmissionoccursthroughchainsofclinically
recognizablemeaslescases,andthesurveillancesystemlargelyreliesontheidentificationofthese
casesfordetectingandrespondingtooutbreaks.Butasymptomaticinfectionscertainlyoccurand
mayplayanimportantroleinmeaslestransmission.Serologicalevidenceforacutemeaslesinfection
amongpeopleexposedtomeaslesvirusbutfailingtodevelopclassicalsymptomshasbeenwell
documented(7,8,9,10,11,12,13,14,15)andithaslongbeenrecognizedthatmeaslesviruscaninfect
previouslyimmunepersons,producingclassicsymptomsofmeaslesinsome,butmildorno
symptomsinmost(16,17,18,19,20).Theestimatedratesofmildorasymptomaticmeaslesinfections
afterexposuretomeaslescasesarevaried,however,inpartbecauseofdifferentdiagnostic
techniquesanddifferentcasedefinitionsused,orbecauseofthedifferenttypesofexposure.In
severalstudiestheratesofmildorasymptomaticinfectionweredeterminedduringoutbreaksin
whichpersonswerelikelytohavehadmultipleexposurestomeaslescases(16,21,12,8).Astudyof
mildorasymptomaticmeaslesinfectionsamong44personslikelytohavebeenexposedtoclassic
measlesduringa3daybustripconcludedthatinpopulationswithhighlevelsofimmunityto
measles,nonclassicmeaslesinfectionscanoccurinatleast20%ofpreviouslyimmunepersonswith
closeexposuretoapersonwithclassicmeasles(10).Itispossiblethatmildorasymptomatic
measlesinfectionsarecommonamongmeaslesimmunepersonsexposedtomeaslescasesandmaybethemostcommonmanifestationofmeaslesduringoutbreaksinhighlyimmunepopulations(10).
Althoughclinicallyunimportant,asymptomaticmeaslesvirusinfectionscouldbeepidemiologically
importantifinfectedpersonsarecapableoftransmittingvirus.Althoughatleastonestudyhas
reportedisolationofmeaslesvirusfromanasymptomaticindividualinclosecontactwithanacute
case(11),anotherstudyfailedtofindevidenceofvirussheddingfrom11seropositiveacutecase
contacts(14).Iftransmissionfromasymptomaticcasesdoesoccur,itislikelytobeveryrare,andis
unlikelytobeefficientenoughtosustaintransmission(11,15),especiallyinthehighlyvaccinated
populationsexpectedintheyearsimmediatelyfollowingglobalcertificationoferadication.
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Conclusion
Ifthecertificationcriteriaarefirmenough,andrequirerigorousvalidation,thentheriskof
undetectedmeaslestransmissionafterGlobalCertificationisverylow.Ifthecertificationcriteriaare
lax,orvalidationrequirementsareinadequate,theriskwillhigher.
Riskassessment:Theriskisintuitivelylow,butuntilthecriteriaforglobalcertificationofmeasleseradicationandtherequirementsforvalidationareestablisheditisnotpossibleto
estimatetheriskposedbycontinuingwildtypemeaslestransmissioninundetected
reservoirs.
Riskoftransmissionofvaccinederivedvirus
Thedevelopmentofliveattenuatedmeaslesvirusvaccinesbegansoonafterisolationofthevirusby
EndersandPeeblesin1954(22).ThefirstlicensedattenuatedmeaslesvaccinewasEdmonstonB,
usedbetween1963and1975butfrequentlyassociatedwithfeverandrash(23).Thefurther
attenuatedSchwarzandMoratenstrainswerederivedfromtheoriginalEdmonstonstrainthrough
additionalpassagesinchickembryofibroblasts(Figure1).Despitedifferencesintheirpassage
history,thesetwovaccinestrainshaveidenticalgenomicsequences(24).TheMoratenvaccineis
widelyusedintheUnitedStatesofAmerica;theSchwarzvaccineisusedinmanycountries
throughouttheworld,andtheEdmonstonZagrebvaccine,similarlyderivedfromtheEdmonstonB
strain,isthemostwidelyusedstrainindevelopingcountries.Otherattenuatedmeaslesvaccines
havebeenproducedfromlocallyderivedwildtypestrains,particularlyintheRussianFederation
(Leningrad16),thePeoplesRepublicofChina(Shanghai191)andJapan(CAM70,AIKC)(23).Allof
thecurrentvaccinevirusesarewelldocumentedandwellcharacterisedwithregardtoprovenance,
immunogenicity,thermalstabilityandgenomicstructure(25,26,27,28,29,30,31,32,33).Although
currentvaccinevirusesandtheirwildtypeprogenitorssharemorethan95%sequencehomology,
theycaneasilybedistinguishedgeneticallyfromcurrentlycirculatingwildtypeviruses.
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Figure1.Relationshipsofmajorcurrentmeaslesvaccineviruses(fromMoss&Scott,2009(23)).
Measlesvirusisconsideredtobeoneofthemostcontagiousofhumanpathogens,withaveryhigh
leveloftransmissibility.Likewildtypevirus,measlesvaccinevirusreplicateseffectivelywithin
vaccinerecipients,inducingbothhumoralandcellularimmuneresponsessimilartonaturalmeasles
virusinfection,althoughtheseresponsesareoflowermagnitudeandshorterduration.
Approximately5%ofchildrendevelopfeverandrashafterreceivingmeaslesvaccine,andviralRNA
canbedetectedintheurineandrespiratorysecretionsforsomedayspostimmunization(34).
Vaccineviruscanbeisolatedfromthebloodofrecentvaccinerecipients,andhasbeendetectedin
samplesoflung,liver,bonemarroworbraintissuesintheveryrarecasesofsevereacutedisease
followingmeaslesvaccination(35).VirusRNAandantigencanbedetectedintheurineofvaccine
recipientsforupto1416dayspostimmunization(36,37),butthereisnopublishedevidenceforthe
transmissionofvaccinevirus.Obviouslythechangescausedbytheattenuationprocesseffectively
blocktransmissibility.Isitpossibleforvaccinevirustoregainthetransmissibilitycharacteristicsof
wildtypevirus?
Thereasonsfornontransmissionofvaccinevirusesarenotfullyunderstood,andarelikelytobe
complex.Ithasbeenproposedthatlossofabilitytointeractwithepithelialcellreceptorsisakey
factor(38,39,40).Itisalsopossiblethatmodificationofthevirusmatrix(M)protein,knowntobe
importantinvirusbuddingfrominfectedcells(41),contributestolossoftransmissibility.Theability
ofvaccinevirusestointerferewiththeinnateimmuneresponsemayalsobeakeyfactor.Whatever
thereason,itappearsthattheblockontransmissionofvaccinevirusesishighlyeffective.
Measlesvirusisserologicallymonotypicandisgeneticallycharacterizedintoeightclades(AH),
dividedinto23recognizedgenotypes(42,43,44).Allofthecurrentvaccines,whetherderivedfrom
Edmonstonornot,sharearemarkablenucleotidesequencesimilarityandallaremembersof
genotypeA(45,24).Duringthe1950sand1960s,onlymeaslesvirusesbelongingtogenotypeAwere
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isolatedandmayhavehadaworldwidedistributionbeforevaccinationstarted(46,47,48).Thisis
notthesituationtoday,whentheidentificationofnonvaccinerelatedgenotypeAvirusesisvery
unusual.Overthepastfifteenyearsamassiveamountofworkhasbeenputintocharacterizing
measlesvirusesassociatedwithoutbreaks.Althoughtherearestillgaps,virusesfrommostmajor
outbreaksandfromimportationsinareasthathaveeliminatedindigenousmeasles,arecurrently
beingsequencedandgeneticallycharacterizedthroughtheWHOLaboratoryNetworksactivities.
Wenowhaveareasonablycomprehensiveunderstandingofwhichvirusesarecirculatingwhere
(42,43,44,49,50,51,52,53).
Againstabackgroundofseveralthousandisolatescharacterized,veryfewgenotypeAviruseshave
beenidentifiedduringthepast20years.WiththepossibleexceptionofvirusesisolatedintheUKin
1993(54),nonehasbeenassociatedwithoutbreaks.Whendetectedtheyhavebeensporadiccases
withuncertainepidemiology,closelyassociatedwithveryrecentreceiptofvaccine,orqueriedas
laboratorycontaminants(43,55,56,57,58,59,60,61,62).
Table1summarizesthepublisheddocumentationonthedetectionofgenotypeAmeaslesviruses
since1990.
Yearofdetection Country State/Province/Region Numberofisolates Reference
1990 Japan Handai? 1 (62)
1991 Argentina BuenosAires 1 (63)
1993 UK Coventry,England 5 (54)
1995 SouthAfrica Johannesburg 1 (64)
1996 RussianFederation Novosibirsk,Siberia 3 (56)
1996 USA Delaware 1 (60)
1996 China Hunan 1 (55)
1996 UK ? 2 (58)
1996 SouthAfrica Johannesburg 1 (57)
1998 UK ImportationfromRussia 1 (58)
1999 Argentina BuenosAires 2 (63)
1999 China Henan 1 (55)
2000 UK ? 1 (58)
2001 Spain Ibiza 1 (59)
2002 Spain Madrid/Badajos 2 (59)
2003 Spain Almeria 3 (59)
2003 China Xinjiang 1 (55)
2005 Taiwan Taichung/Taipei 2 (61)
2007 Taiwan Tainan/Taipei 2 (61)
Table1.PublisheddocumentationonisolationandcharacterizationofgenotypeAmeaslesvirusesfrom1990
toMay2010.
Table1includesisolatesthatmayrepresentwildtypelineagesthathavesurvivedsincethepre
vaccinationera.Italsoincludesvirusesisolatedfromveryrecentvaccinerecipientspresentingwith
classicmeaslessymptoms.Butitmayalsoincludevaccinederivedisolatesthathavebeen
transmittedfromvaccinerecipientstounvaccinatedcontacts.AlthoughsomeofthesegenotypeA
viruseshavenucleotidesubstitutionsthatdistinguishthemfromvaccineviruses,thereisno
publisheddocumentationidentifyingadistinctsetofgeneticmarkersthatconsistentlydifferentiateswildtypevirusesfromattenuatedviruses(46).Measlesvaccinevirusesreisolatedfrom
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immunosuppressedpatientswithgiantcellpneumoniahavenucleotidesequencesalmostidentical
tothoseofthevaccinevirus,suggestingthatvaccinevirusesareverystableevenafterprolonged
replicationinahumanhost(46).
Numerouspublishedstudiesofseveralthousandsofisolatesfromacutemeaslescasesinvestigated
overthepast20yearshavefailedtodetectgenotypeAviruses(52,53,65,66,67,68,51,50,69,70)
(71,72,73,74,75,76,77,78,79,80)(81,82,83).Becauseoftheincreasingintensityofmeasles
immunizationprogrammes,genotypeAviruses,intheformofvaccineviruses,shouldbethemost
abundantmeaslesgenotypeonEarth.Giventhattheyaresoinfrequentlyisolatedfrommeasles
cases,themolecularepidemiologicaldataappearstosupportthecontentionthatvaccinevirusesdo
notreadilyreverttowildtypetransmissibility.
Whatistheriskofmeaslesvaccineescapemutants?
Thereisnoconclusivepublishedevidencefortheemergenceofmeaslesvaccineescapemutants
(84).MeaslesisatypicalRNAvirusinthatintrinsicerrorsoftheRNApolymeraseandlackof
proofreadingmechanismsresultsinamutationrateof9x10 5perbaseperreplicationandagenomic
mutationrateof1.4perreplication(85).Thisiswellwithinthetypicalrangeof103to10
6mutations
persiteperreplication(86).Asaconsequenceofthishighmutationrate,RNAviruspopulations,
eventhoseinitiatedbyasingleinfectiousunit,arenotclonalbutconsistofalargenumberof
geneticmicrovariantsreferredtoasquasispecies.Despitethehighmutationrate,andunlikeother
RNAvirusessuchasinfluenzaandHIV,measlesvirusremainsremarkablystable.Howcanlive
attenuatedvaccinesdevelopedfromwildtypemeaslesvirusesmorethanhalfacenturyagostillbe
effectiveagainstcirculatingviruses?
Theanswerisprobablyassociatedwithuseofthesignallinglymphocyticactivationmolecule(SLAM;
alsoknownasCD150)receptorbythemeasleshaemagglutinin(H)protein,whichisresponsiblefor
cellattachmentandisamajortargetforneutralizingantibodies(87).Theenvelopeofmeaslesvirus
hastwotypesofglycoproteinspikes,designatedhaemagglutinin(H)andfusion(F)proteins.TheH
proteinbindstospecificmolecules(receptors)ontargetcells,whiletheFproteinmediates
membranefusionbetweenthevirusenvelopeandthehostcellplasmamembranethrough
cooperationwiththeHprotein.In2000,SLAMwasidentifiedasacellreceptorformeaslesvirus
(88).SLAMisexpressedoncellsoftheimmunesystem,suchasactivatedlymphocytesanddendritic
cells(89).StudiesonthecrystallinestructureoftheHproteinhaveshownthatalthoughmostofthis
glycoproteiniscoveredbysugarchains,thelargesurfaceareathathoststheSLAMbindingsiteis
freefromsugarchains(90).Mutationsinthisregionarenotpermittedbecausetheyinterferewithreceptorbinding.Thisextremesequencerestrictionallowsforveryefficientproductionof
neutralizingantibodiesthatblockbindingofthevirustoitsreceptor.Sotheoriginalvaccinestrains,
developedinthe1960s,arestilleffectiveagainstcurrentwildtypeviruses(91).Analysisofavailable
sequencedatafromapproximately500isolatessuggeststhatdespitetheerrorproneviral
polymerase,theaminoacidsequenceofHisstronglyconserved,with60%oftheresiduesbeing
identicalorverysimilar(92).Itappearsthatanymutationthatchangesthenatureofthese
conservedresiduesresultsinnonviablevirus.
Conclusion
Thereisnocurrentpublisheddatatosupportevidenceforcurrentlylicensedliveattenuatedvaccinevirusesrevertingtowildtypetransmissibility.Onthecontrary,thevastmajorityofevidencepoints
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toanimpressivelevelofgeneticstability.However,sincetheyarelivevirusesthatreplicatewithin
vaccinerecipients,thepossibilitymustexistthattheycouldreverttowildtypetransmissibility.
Thereisstrongexperimentalevidenceforthemonotypicnatureandgeneticstabilityofmeasles
virusbeingbasedonuseoftheSLAMreceptor.Thereisalsonoevidencefortheestablishmentof
vaccineescapemutants.Evenifvaccinevirusesweretoreverttowildtypetransmissibility,thereis
noreasontosuspectthattransmissioncouldnotbecontrolledusingcurrentvaccines.
Riskassessment:Availableinformationsuggeststhattheriskofcurrentliveattenuated
vaccinevirusesrevertingtowildtypetransmissibilityisverylow,butitremainsapossibility.
Riskfrompersistentinfections
Howlongdoesmeaslesinfectionusuallypersist?
Inclassicmeaslescasesthereisa1014dayincubationperiodbetweeninfectionandtheonsetof
clinicalsignsandsymptoms,andinfectedpersonsareusuallycontagiousfrom23daysbeforeand
uptofourdaysafteronsetoftherash.Hostimmuneresponsestomeaslesvirusareessentialfor
viralclearance,clinicalrecoveryandtheestablishmentoflongtermimmunity.Earlyinnateimmune
responsesoccurduringtheprodromalphaseandincludeactivationofnaturalkiller(NK)cellsand
increasedproductionofinterferons(IFN)and(23,93,94).However,themechanismsandtiming
ofnormalmeaslesvirusclearancearepoorlyunderstood.Measlesvirushasbeenisolatedfrom
peripheralbloodmononuclearcells(PBMC)uptoaweek,andfromurineupto10days,after
appearanceoftherash(95,96).Delayedvirusclearancehasbeendocumentedincasesof
malnutrition(97,98,99)andpatientswithcellularimmunitydeficiencies(100,101,102).Detectionof
measlesvirusRNAhasbeenreportedforupto4monthsinacaseofcongenitalmeasles(103),for1
to4monthsafteruncomplicatedinfectionin90%ofHIV1infectedchildrenandmorethan50%of
HIVnoninfectedchildren(104,105,106,107).Thesedataareconsistentwithstudiesofrhesus
macaquesshowingthatvirusclearanceoccursover120150days(108),suggestingthatnormal
clearanceisaprolongedprocess.DespitethereportedpersistenceofviralRNA,therehavebeenno
reportsofinfectiousvirussheddingmorethan3to4weeksafterappearanceofsymptoms(98,99).
Persistentinfectionwithmeaslesvirushasdefinitivelybeenassociatedwithsubacutesclerosing
panencephalitis(SSPE),aprogressivefatalneurologicaldiseasewithhighlevelsofneuronalinfection
bymeaslesvirusinthecentralnervoussystem(94).Inimmunocompromisedpatients,persistent
measlesvirushasbeenlinkedtoanotherneurologicalinfection,measlesinclusionbodyencephalitis
(MIBE)(109).Multiplesclerosis,chronicallyactiveautoimmunehepatitis,Pagetsdisease,
otosclerosis,Crohnsdiseaseandautism,amongmanyotherdiseases,havealsobeensuggestedat
varioustimesaslongtermsequelaeofmeaslesvirusinfection.Noconfirmedevidencehasbeen
presented,however,tosubstantiatetheseassociations,letaloneproveacausativerelationship.
WhatistheriskfromSSPEcases?
SSPEisaslow,progressivediseasethatisinvariablyfatal.Theaverageperiodfrominitialmeasles
infectiontoSSPEsymptomonset(latency)usuallyrangesbetween4and10years,buthasbeen
reportedfrom2monthsto23years(110).Childrenarefarmorelikelytodevelopthiscomplication
thanadults.ReportedSSPEincidencevariesfromapproximately0.2to40casespermillion
populationperyear.Directcomparisonofdatafromdifferentcountriesisproblematicbecause
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methodsandqualityofdiagnosishavebeeninconsistent.AnalysesofdatafromtheUKandUSA
havecalculatedthetrueincidenceofSSPEtobeapproximately411casesofSSPEper100000cases
ofmeasles.Ahigherriskisassociatedwithearlierinfection:theriskfollowingmeaslesinfection
under1yearofageis18/100000comparedwith1.1/100000after5yearsofageintheUK(110).
Obviously,asthenumberofmeaslesinfectionsdeclines,sowillthenumberofpotentialSSPEcases.
Thediseaseinitiallymanifestsassubtlecognitivelosses,progressingtomoreovertcognitive
dysfunction,followedbymotorloss,seizuresandeventualorganfailureinvirtuallyallaffected
individuals.Neuronsinboththegrayandwhitematterareinfected,andthediseaseishistologically
characterizedbythepresenceofcellularinclusionbodies(111).AserologichallmarkofSSPE,as
comparedtotheothercentralnervoussystemcomplications,istheelevationofmeaslesspecific
antibodiesinthebloodandcerebrospinalfluid(94).Mostimportantly,evidencefrombrainbiopsies
ofSSPEpatientsindicatesthatinfectedneuronsdonotreleasebuddingvirus(112).Basedon
sequencingstudiesofvirusfromthesespecimensandfromcellspersistentlyinfectedwithmeasles
virusisolatesfromSSPEpatients,ithasbeenproposedthatthefailureofinfectedneuronstoproducecompleteextracellularvirusmaybeduetodefectsinproteinexpressioncausedby
extensivepointmutationsintheH,fusion(F)andmatrix(M)genes(113,94,114,115,116).Thereis
noevidencefortransmissionofmeaslesvirusfromSSPEcases.
WhatistheriskfromMIBEcases?
Measlesinclusionbodyencephalitis(MIBE)isararecentralnervoussystemcomplicationfollowing
acuteMVinfection,hasbeendescribedinchildrenandadultsreceivingimmunosuppressivedrugs
andthereforeisthoughttochieflyaffectimmunocompromisedhosts.MIBEhasalsobeenreported
toresultfromreceiptofmeaslesvaccine(117).Theneurologicdiseaseusuallyappears3to6
monthsaftertheacutemeaslesrash(111),withamediantimeof4months(118).Measlesantigenispresentinthebrain,andvirushasbeenisolateddirectlyfromthebrainsofaffectedindividuals
(111,119).MIBEdiffersfromSSPEintheabsenceofelevatedserumandcerebrospinalfluid
neutralizingantibodies(94).Thediseasecourseisrelativelyshort,lastingfromdaystoweeks,
causingseizures,motordeficits,andstupor,oftenleadingtocomaanddeath.
Althoughonlyaverysmallpercentageofacutemeaslesinfectionswillgoontodeveloppersistent
complications,afewstudieshavedetectedmeaslesvirusRNAinvariousorgans,onautopsy,of
elderlyindividualswhodiedofnonviralcauses(120,121).Thesefindingssuggestthatmeaslesvirus
persistsinthebrains(andotherorgans)ofhealthyindividuals,andmaymanifestitselfincentral
nervoussystemdiseaseunderconditionsofimmunocompromiseorimmunosuppression.Thishas
beenunderlinedbythecaseofa13yearoldboythatdevelopedMIBEafterreceivingastemcell
transplant(119).Neitherthepatientnorthestemcelldonorhadapparentrecentmeaslesexposure
orvaccination,andneitherhadrecenttraveltomeaslesendemicregions.Thepatientwasbornin
Chicagoduringthemeaslesepidemicof19891991(birthyear1989).Anundiagnosedcaseof
measlesintheperiod19891991wouldsuggestalatencyperiodtoMIBEof12years,whichisnot
typical.CasesofMIBEwithoutclearmeaslesexposureorinfectionhavebeenreported.Inareview
ofMIBE,18%ofpatientshadnodocumentedmeaslesexposureorinfection(118);however,many
ofthesecasesoccurredinyearswhenmeasleswasmoreprevalent.Therearenopublishedreports
ofinfectiousmeaslesvirussheddingfromMIBEcases.
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DoesHIVcoinfectionpresentariskforpersistentmeaslesinfectionandtransmission?
Asdiscussedabove,measlesvirusRNAcouldbedetectedinsamplesfrom90%ofHIVinfected
childrenonemonthafterrecoveryfromacutemeasles(104),butinthisstudynoattemptwasmade
toculturevirusfromanysamples.InregionsofhighHIV1prevalence,coinfectionwithHIV1more
thandoublestheoddsofdeathinhospitalizedchildrenwithmeasles(122)andmayslowtherateof
virusclearanceslightly,butthereisnoevidencethatHIVinfectionleadstoanincreasedriskfor
persistentmeaslesvirusinfection.NordoesHIVinfectionappeartopresentariskforpersistent
infectionwiththemeaslesvaccinevirus.Asearchforpersistentmeaslesmumpsandrubellavaccine
virusesinchildrenwithHIV1infectionfailedtodetectvirusinperipheralbloodmononuclearcells,
polymorphonuclearleukocytes,orplasma(123).
Conclusion
Thereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe
sheddingofinfectiousvirusorplayanypartinmeaslestransmission. Asthenumberofacute
measlesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthe
numberofpotentialSSPEandMIBEcases.
AcutemeaslesinfectioninHIVinfectedindividualstendstobemoresevere,lastlongerandresultin
ashorterlivedimmunitytoreinfection,butthereisnopublishedevidencetosuggestthatco
infectionincreasesthepotentialforestablishmentofpersistentmeaslesinfections,eitherwithwild
typevirusorwithvaccinederivedvirus.
Riskassessment:Availableinformationsuggeststhattherelativelysmallnumberof
persistentmeaslesviruscases,includingthosethatmayresultfromcoinfectionwithHIV,
poseaverylowriskforreintroductionofmeasles.
Riskfromnonhumanprimates
Alargeproportionofourcurrentknowledgeofmeaslesandmeaslesinfectionmechanismshave
comefromexperimentalinfectionofnonhumanprimates.In1911,GoldbergerandAnderson
demonstratedthatmacaquesinoculatedwithfilteredsecretionsfrommeaslespatientsdeveloped
measles,provingthecausativeagentwasavirus(124).Awiderangeofnonhumanprimatespecies
aresusceptibletoexperimentalinfectionwithmeaslesvirus.Theseinclude Macacamulatta,M.
fascicularis,M.radiata,M.cyclopis,Papiocristatus,Cercopithecusaethiops,Saimirisciureus,Colobus
quereza,Pantroglodytes,Callithrixjacchus,Saguinusoedipus,S.fuscicollis,andAotustrivirgatus
andAtelesspecies(125,126,127).Aswouldbeexpectedfromaneffectiveanimalmodel,many
speciesrespondtoinfectioninamannerverysimilartohumans(128,129,130).Inadvertent
transmissionofeithermeasles(fromhumans)orthecloselyrelatedcaninedistempervirus(from
dogs)tocaptivenonhumanprimateshascausednumerousoutbreakswithsignificantmorbidityand
mortality(131,127,132,133,134).Nonhumanprimatesinthewildappeartobefreefrommeasles,
onlycontractinginfectionwhentheycomeintocontactwithinfectedhumans(125).Humanto
primatediseasetransmissioncanpotentiallycausesignificantmorbidityandmortalityamongwild
primatepopulations.Serologicalevidenceofmeaslesinfectioninfreerangingpopulationsofnon
humanprimateshasbeenwelldocumented(135,136,137).Evidenceexistsofmeaslesinfectioninnonhumanprimatepopulationswithfrequentcontactwithhumanpopulations,aswellasinwild
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populationswithminimalhumancontact(127).Acrosssectionalstudyofwildmacaques( Macaca
tonkeana)inSulawesi,Indonesia,foundserologicalevidenceofmeaslesevidencein5of15animals
surveyed(136).
Becausehumanpopulationsrepresentthelargestreservoirofthemeaslesvirus,itismostlikelythat
measlesepizooticsinnonhumanprimatepopulationsareinitiatedbyhumantononhumanprimate
transmissionandsubsequentlyspreadbyanimaltoanimaltransmission.Duetotheirrelativelysmall
numbers,itisunlikelythatnaturalpopulationsofnonhumanprimatesaresignificantorsustainable
reservoirsofmeaslesvirus(127).
Conclusion
Althoughnonhumanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and
animaltoanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootic
transmission.
Riskassessment:Availableinformationsuggeststhatinfectionsinnonhumanprimatespose
averylowriskforreintroductionofmeasles.
Riskoflaboratoryassociatedmeaslesinfection
Risksposedbylaboratorymaintainedmeaslesviruses,throughaccidentalorintentionalrelease,are
largelydependentonwhetheruniversalimmunizationagainstmeaslesiscontinuedorifitisstopped
on,orsoonafter,globalcertification.Ifthedecisionismadetocontinueuniversalimmunization,
possiblywithnonreplicatingvaccines,theriskposedbylaboratorymaintainedviruswillbevery
low,sincetherewillbealmostuniversalimmunity.If,however,universalimmunizationstopsafterglobalcertification,therisksposedbylaboratorymaintainedmeaslesinfectiousmaterialswill
progressivelyincrease,asthenumberofmeaslessusceptiblesinthepopulationincreases.Therisks
includenotonlyaccidentalreleaseoflivemeaslesvirusfromlaboratoriesandattenuatedvirus
vaccineproductionfacilities,butthreatofdeliberaterelease.
Whatistheevidenceforlaboratoryacquiredmeaslesinfection?
AseriesofsurveysforlaboratoryacquiredinfectionsconductedintheUK
(138,139,140,141,142,143,144),theUSA(145,146,147,148,149)andJapan(150)failedtoinclude
measlesamongthelistedinfections.Arecentreviewofprinciplesforpreventionoflaboratory
associatedinfectionsalsofailedtomakementionofmeasles(151).Anextensiveliteraturesearchfailedtofinddocumentedevidenceoflaboratoryacquiredmeaslesinfection.Thisleavesthree
possibilities:laboratoryacquiredmeaslesinfectionshavenotoccurred;theinfectionsthathave
occurredhavebeenbelowthethresholdofsensitivityofthesurveillancesystems;or,measleshas
beenconsideredatrivialdiseaseandinfectionshavenotbeenreported(152,153).
Priortothe1970sitistobeexpectedthatalmostallstaffworkinginclinicalmicrobiologyand
researchlaboratorieswouldhavebeenexposedtomeaslesinfectionduringchildhood.Fromthe
1970sonwardsitistobeexpectedthatallnewstaffcomingtoworkintheselaboratorieswould
havereceivedatleastonedoseofmeaslesvaccine.Itisunlikelytherefore,thatexposedlaboratory
staffwoulddevelopacutemeaslessymptomsfromlaboratoryacquiredinfections.Butgiventhe
veryhightransmissibilityofmeaslesvirus,itispossiblethatexposuretoinfectiousvirus,and
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resultingasymptomaticinfections,orverymild,atypicalinfectionshaveoccurred.Iftheyhave
occurred,itisprobablethattheseinfectionshavegoneundetected,orsimplyoverlookedas
unimportant.
Howstableismeaslesvirusintheenvironmentandinlaboratorymaterials?
Measlesisnotaphysicallyrobustvirus.Itisviableforlessthan2hoursatambienttemperatureson
surfacesandobjects,whiletheaerosolizedvirustypicallyremainsinfectiveforonly30minutesto2
hours,dependingonenvironmentalconditions(154,155).Itisverysensitivetoheatandis
inactivatedafterlessthan40minutesat56C,eveninmediumcontainingaproteinstabilizersuchas
5%calfserum(156).Virusinmaintenancemediumlosesatleast2logsoftitrewhenstoredat+6oC
for1420weeksandlosesallinfectivityafter1yearatthistemperature.Additionofaprotein
stabilizerimprovesviruslongevity,withalossofapproximately2logsoftitreafter1yearat+6oC.
Interestingly,storageat30oCofferslittleadvantageoverstorageat+6
oC,witha12loglossoftitre
over1year.Storageat72oCorbelowresultsinverylittlelossofvirusinfectivity,andinfectious
materialsmaintainedatthistemperatureshouldretaininfectivityformanyyears(156).Thevirus
survivesfreezedryingrelativelywelland,whenfreezedriedwithaproteinstabilizer,cansurvive
storagefordecadesat70oC(156,155).Incommonwithmanyotherenvelopedvirusesitis
inactivatedbysolvents,suchasetherandchloroform,byacids(pH10),andbyUV
andvisiblelight.Itisalsosusceptibletomanydisinfectants,including1%sodiumhypochlorite,70%
alcoholandformalin.
Whichlaboratorymaterialspresentarisk?
Measlesvirusinfectiousmaterialsincludeautopsyorclinicalsamples(e.g.pharyngealsecretions,
urine,blood)frommeaslesinfectedpersonsorrecentliveattenuatedvaccinerecipients,and
laboratoryderivedmaterials(e.g.virusisolatesandreferencestocks,materialsderivedfrominoculatedcellcultures,laboratoryanimals).Measlesviruspotentialinfectiousmaterials,thosethat
aresuspectedtocontaininfectiousmeaslesviruses,includepharyngealsecretionsandblood
samplescollectedforanypurposeatatimeandinaplacewheremeaslesviruseswerecirculating,
andstoredunderconditionsthatwouldpreservevirusinfectivity.Theyalsoincludeproductsof
thesematerialsinmeaslesviruspermissivecellsoranimals(157).
Whattypesofriskdolaboratoriespresent?
Riskspostmeasleseradicationwillexistattwolevels:
occupationalriskofexposureamonglaboratorystaff, communityriskoflaboratoryassociatedmeaslesexposure.
Thethreemostcommonroutesofexposuretoinfectiousagentsinthelaboratoryareingestion,
inhalation,andinjection(153).Measlesviruscanremaininfectiousonsurfaces,suchaswork
benchesanddoorhandles,foruptotwohours.Iftransferredfromthehandtothemouth,noseor
conjunctiva,theycaninitiateinfectionofepithelialcells(158).Althoughtherearenorecorded
incidentsoflaboratoryacquiredmeaslesvirusinfections,severalsurveysdocumentthefrequent
occurrenceofingestingmorereadilyrecognizedpathogens,suchasShigellaandSalmonella
(139,140,141,142,143,147,153).Themostcommonroutefornaturaltransmissionofmeaslesis
believedtobebyinhalationofaerosolizedvirus;infectiousdropletsbeingproducedbytalking,
coughingandsneezingbyinfectedindividuals(158).Smallparticles(
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inhaleddepositprimarilyinthelowerrespiratorytract(159).Laboratoryactivitiesthatexposestaff
toaerosolsgeneratedfrominfectiousmaterial(e.g.centrifugation,blending,vigorouspipetting,
etc.),andexposuretoinfectedlaboratoryanimals,presentariskforinfection.Themostcommon
routefordeliveryofcurrentmeaslesvaccinesisbyinjection.So,injectionandneedlestickinjuries
involvingmeaslesvirusinfectiousmaterialsobviouslypresentariskforinfection.
Communitymembersmaybeexposedtoinfectiousmeaslesvirusfrom:
contaminatedlaboratoryworkers, infectedlaboratoryworkers, contaminatedaireffluents, transportofinfectiousmaterial, escapedinfectiousanimals.
Again,nopublishedevidenceexistsfortheescapeofinfectiousmeaslesvirusfromthelaboratory
intothecommunity.Giventherapidinactivationofmeaslesvirusundernormalenvironmentalconditions,thelengthoftimeavailableforinfectiousvirustobecarriedoutofthelaboratoryand
intothecommunity,eitheronthebodyorclothesofacontaminatedworker,orincontaminatedair
effluents,isprobablylimitedto2hours.Thisreducestherisktoaverylowlevel.Asdiscussedabove,
availableevidencesuggeststhatimmunizedindividuals,whodevelopasymptomaticormild
infections,areunlikelytotransmitthevirus(10),reducingthecommunityrisk.Wecanassumethat
laboratoriesimplementinggoodlaboratorypractices(GLP)orgoodmanagementpractices(GMP)
willminimizetherisksofreleasetotheenvironmentbyproperlypackagingandtransporting
infectiousmaterialsinaccordancewithcurrentinternationallawsandregulations.Giventhesecurity
concernsthatsurroundlaboratoryanimalhousesandresearchfacilities,thelikelihoodthatmeasles
infectedanimalswouldescapeintothecommunitymustbeextremelysmall.
Conclusion
Althoughthereisnodirectevidenceforlaboratoryacquiredmeaslesinfectionsitispossiblethat
theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymild
infections.Thereisnopublishedevidencetosuggestthatthesepossibleasymptomaticormild
infectionsresultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinacoupleof
hoursatambienttemperaturesintheenvironment,andinfectiousmaterialsstoredattemperatures
above30oCcanbeexpectedtoloseallinfectivityoverthecourseofonetotwoyears.
Despitethelackofevidenceforlaboratoryacquiredmeaslesinfectionsorescapeofvirusintothe
community,inaposteradicationworldthesemustbeconsideredpossibilitiesduetothehighly
infectiousnatureofmeasles.
Riskassessment:Inameaslesposteradicationworldwithoutroutineuniversal
immunization,measleslaboratories(andmeasleslivevaccineproductionfacilities)willpose
averylowbutincreasingriskforreintroductionofmeasles.
Riskofintentionalreleaseofmeaslesvirus
Bioterroristthreatsdonotworkagainstpopulationsthathavebeenfullyimmunized.However,ina
posteradicationworldinwhichuniversalroutineimmunizationhasceased,agrowingpopulation
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willbesusceptibletomeasles,andmeasleswill,eventually,becomeacredibleagentfor
bioterrorism.Thedevastatingeffectofmeaslesonsusceptiblepopulationsintheprevaccination
erahasbeenwelldocumented(158).ThisisparticularlytruefortheislandsofthePacific.In1848in
Hawaii,10,000natives,about10percentofthepopulation,diedduringanepidemic(160,161,162).
In1861onAneityumintheNewHebrides,thepopulationwasreducedbyabout60percentina
measlesepidemic(163).In1875inFiji,20,000natives,20to25percentofthepopulation,diedof
measles(164).In1907,againinFiji,6percentof30,000casesdied,andin1911onRotuma16per
centofthepopulationdiedofmeasles(165).In1936measlescaused100deathsand14,282casesin
theGilbertIslands(166),andin1937inHawaii,therewere205deathsfor13,680casesofmeasles
(167).In1946intheBritishIslandsoftheSouthPacific,therewere1,000deathsfor15,000to
20,000casesofmeasles(168).Therearemanyotheraccountsofsimilardevastatingmeasles
epidemicsinisolatedcommunitiesaroundtheworld.
Withadvancesinmodernmedicaltreatmentitisunlikelythatsimilarmortalityrateswouldbe
inflictedoneortwogenerationspostmeasleseradication,butdeliberatereleasewouldcause
extensivedisruptiontomedical,publichealthandsocialservices,andprobablyincurenormous
containmentcosts.Thethreatofrelease,withtheknowledgeofthepotentialdisruptionand
financialexpenseitcouldcause,wouldmakemeaslesaneffectiveagentforbioterroristsoncea
largeenoughpopulationofmeaslessusceptibleshadaccumulated.Measlesisnotcurrentlyincluded
intheCDCBioterrorismAgentCategories(169,170),butthissituationwillneedtobereviewedin
theyearsfollowingeradication.
Conclusion
Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthe
past.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldberepeated,thethreatofintentionalreleasewouldprobablybeveryeffectiveonceasizable
populationofsusceptibleindividualshadaccumulated.
Riskassessment:Theriskofdeliberatereleaseofmeasleswillbeverylowatthetimeof
globaleradication,butwillriserapidlywithaccumulationofunvaccinatedmeasles
susceptibles.
Actionsrequiredtoreducetheriskofaccidentalordeliberatereleaseof
measlesOneapproachtoreducingtheriskofmeaslesreintroductionwouldbeadoptionofastrategyto
minimizeavailabilityofmeaslesvirus,throughremovaloflivevirusesfromlaboratoriesandsecurely
containingallinfectiousmaterialthatremains,andestablishinganinsurancepolicyintheformofa
vaccinestockpile.
Reducingtheriskofaccidentalrelease:alaboratorycontainmentstrategy
Asystematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythe
PolioEradicationInitiative(171),startingnowandcontinuingintotheposteradicationera,would
minimisetheriskofaccidentalreintroductionofmeaslesvirus.Thestrategyestablishedforpolio
outlinesthreedistinctphases.Phase1wouldlastfromthepresent,whenmeaslescontinuesto
circulate,tothetimewhenmeaslestransmissionceases.Phase2wouldcoverthecertification
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period,andPhase3wouldtakeplaceintheposteradication,postglobalcertificationperiod.These
threePhasesforpoliohavebeenclearlydescribedinaseriesofpublishedGlobalActionPlans
(172,173,157).
Thelaboratoryassociatedrisksposedbymeaslesareconsiderablylowerthanthoseposedbypolio,
andstrategiesforreducingtheriskevenfurthershouldnotsimplyduplicatetheactivitiesdeveloped
forpolio,butbeproportionateandappropriateformeasles.Thegeneralapproachtakenbythe
PolioEradicationInitiative,andlessonslearnedfromimplementingthepoliocontainmentstrategy,
shouldprovideasoundstartingpointformeasles.Strategiesforreducingtheriskinthepre
eradicationphaseshouldbebasedonthefollowingprinciples:
minimizingthenumberoflaboratoriesretainingmeaslesvirusinfectiousandpotentialinfectiousmaterials;
minimizingtherisksofoperationsinlaboratoryandmeasleslivevaccineproductionfacilities;
minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding; minimizingsusceptibilityofcommunitytomeaslesvirusspread.
Thehighestrisksarepresentedbythoselaboratoryoperationsinvolvingmeaslesvirusreplication,
includingthegrowthofvaccinestrainsforlivevaccineproduction.Thelowestrisksarenon
replicative,biosafetyappropriateoperationsperformedwithpotentiallyinfectiousclinicalmaterials.
Intheyearsleadinguptoglobaleradicationallworkwithwildmeaslesvirusesshouldrequire
biosafetylevel2(174),withadditionalrequirementsforrestrictinglaboratoryaccess,and
maintenanceofaccuraterecordsofmeaslesvirusmaterials.Establishingnationalmeasles
inventories,andcallstosafelydisposeofallunwantedmeaslesinfectiousandpotentialinfectious
materials,ashasbeenaccomplishedforpolio,wouldalsoberequired.
Thesecondphaseofriskreductionwouldconsistessentiallyofvalidatingthecontainmentactivities
atnational,regionalandgloballevelsasarequirementforGlobalCertification.Stoppinguniversal
measlesimmunizationpostcertification(thirdphase)willaltertherelativeweightsoftheprinciples
onwhichminimizingtheriskfromthelaboratoryisbased(157):
minimizingsusceptibilityofcommunitiestomeaslesvirusspreadwillnolongerapplyinthosecountriesthatelecttostopmeaslesimmunization;
minimizingthesusceptibilityofworkerstomeaslesvirusinfectionandshedding,intheabsenceofanoninfectiousvaccine,willrelysolelyonpreventionofinfection;
minimizingthenumberoflaboratoriesretainingmeaslesvirusmaterialsandminimizingtherisksofoperationsinthoselaboratoriesbecomesmuchmoreimportant.
Wearecurrentlyconsideringtheprospectofglobalcessationofmeaslestransmissionapproximately
adecadefromnow,allowingreasonabletimetodevelopanappropriatemeasleslaboratory
containmentstrategyandforlaboratoryresearchonmeaslesvirusestocontinueundercurrent,
biosafetylevel2,conditions.Italsoallowstimeforcontinueddevelopmentofalternativemeasles
vaccinesandspecificantivirals.
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Developingavaccinestockpile
Liveattenuatedmeaslesvaccineshavebeenhighlysuccessfulinprotectingpopulationsagainst
measlesandstoppingmeaslestransmission.Asdiscussedabove,thesevaccinesareverysafe,and
poseonlyasmallpotentialriskforestablishingtransmissionofvaccinederivedvirusesinapost
eradicationworld.Toremovethisriskanewvaccinethathasnocapacityforreplicationor
transmissionisrequired(175).Theidealmeaslesvaccinewouldbeinexpensive,safe,heatstable,
immunogenicinneonatesorveryyounginfants,andadministeredasasingledosewithouttheneed
touseaneedleorsyringe(93),be100%effectiveand100%incapableoftransmission.Whilesucha
vaccinewouldhaveclearbenefitsfortheeradicationofmeasles,itwouldbeasavaccinefor
stockpilingposteradicationthatitwouldcomeintoitsown.Severalvaccinecandidateswithsomeof
thesecharacteristicsareundergoingdevelopmentandtesting.Featuresofthesenew,potential
measlesvaccineshavebeenextensivelyreviewed(175,176).
Howlargeameaslesvaccinestockpilewouldberequiredisverydifficulttopredictwithout
modelling.Requirementswouldobviouslybedynamic,dependingonsomefairlycomplexvariables,
includingthenumberofsusceptiblesaccumulatinginthecommunity,theeffectivenessofthe
vaccine,transmissiondynamicsofthevirusandtheeffectivenesswithwhichanyeventrequiringan
immunizationresponsewasdetected,reportedandrespondedto.Decisionsonsuchbig,expensive
itemsasestablishingameaslesvaccinestockpileshouldnotbetakeninisolation,butconsidered
systematicallyandincludedinaconsensusriskmanagementstrategy,ashasbeenachievedforpolio
(177,178,179,180,181,182).Developmentofapostmeasleseradicationriskmanagementstrategy
shouldbeginassoonaspossible.
AreasrequiringfurtherresearchTherisksofreintroductionofmeaslespostglobaleradicationmaybereducedbyapplying
knowledgeacquiredthroughkeyareasofresearchconductedintheyearsleadinguptoeradication.
Thesekeyareasincludethefollowing:
Greaterunderstandingofthetransmissiondynamicsofmeasles
Indrawingupthecertificationcriteriaandvalidationrequirementsitwillbenecessarytoengage
expertsfamiliarwiththedevelopmentofdynamicandstochasticmodelsofmeaslestransmission,
persistenceandelimination.Thiswillbeparticularlyimportantfordeterminingthecertificationand
validationrequirementsforlowincome,highdensitypopulations.Basedontheexperiencegained
inpolioeradication,thiswillbemostrelevantforselectedpopulationsinAfrica,theIndiansubcontinentandlargerefugee/migrantpopulationcamps.
Importantinformationcanalsoprobablybegainedfromdetailedepidemiologicalandmolecular
analysisofoutbreaks,particularlythoseoccurringinhighlyimmunizedpopulations,highdensity
populations,andingenerallyhighlyimmunizedpopulationswithinadequatelyimmunizedsub
populations.
Withtherapidincreaseinthenumberofhighlyimmunizedpopulations,opportunitiesforstudying
asymptomaticandatypicalinfectionsandtheirpotentialroleintransmissionshouldbetaken.
Greaterunderstandingofthechangesbroughtaboutbytheattenuationprocess
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Ifcurrentlylicensedattenuatedmeaslesvaccinesaretobeusedinaposteradicationworld,more
informationonthenatureofthechangescausedbyattenuationandthepotentialforreversionto
wildtypecharacteristicswillberequired.Analternativewouldbetospeedupdevelopment,testing
andintroductionofnewmeaslesvaccinesthatarenotdependentonliveattenuatedvirus.
Moreunderstandingofthenatureofthecomplexinteractionbetweenmeaslesvirusandthehost
immunesystem,includingbothhumoralandcellmediatedresponses,wouldprobablybenefit
continueduseofexistingvaccinesanddevelopmentofnewvaccines.
Intheyearsleadinguptoglobaleradication,allgenotypeAvirusesdetectedinassociationwith
acutecasesofmeaslesshouldbethoroughlyscrutinized.Fullepidemiologicalinformationwillbe
required,andadditionalsequencedatafrombothclinicalsamplesandcorrespondingviralisolates
willbenecessarytoruleoutthepossibilityoftransmissionofvaccinederivedvirus.Thorough
geneticanalyses,includingfullgenomicsequencing,shouldbeperformedonselectedvaccine
virusesthatareassociatedwithcommonvaccinereactionsaswellasthosedetectedintheveryrare
severreactionstovaccination.
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