measles, morbili
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7/27/2019 measles, morbili
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Riskanalysisformeaslesreintroductionpostglobalcertificationof
eradication
DrRaySanders.July2010
Summaryandconclusions
Measlesviruswillcontinuetoexistaftercertificationofglobaleradicationasvirusstocksand
infectiousmaterialsheldinlaboratories.Livevirusmayalsoexistinundetectedfocioftransmission
andinpersistentlyandchronicallyinfectedindividuals.Thisanalysisattemptstoidentifyand
evaluatethemainrisksforreintroductionofmeaslestransmissionpostcertificationoferadication
inaworldinwhichuniversalroutinemeaslesimmunizationisnolongerafeature.
Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumans
Thereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreedrequirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements
fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby
undetectedcontinuingtransmission.
Mildorasymptomaticmeaslesinfectionsareprobablyverycommonamongmeaslesimmune
personsexposedtomeaslescases,buttransmissionfromasymptomaticcasesislikelytobevery
rare.Ifitoccursitisunlikelytobeefficientenoughtosustaintransmission,especiallyinthehighly
vaccinatedpopulationsexpectedintheyearsimmediatelyfollowingglobalcertificationof
eradication.However,thepotentialroleofasymptomaticinfectionsinmaintainingtransmission
requiresfurtherinvestigation.
Ifthecriteriaforglobalcertificationoferadicationarefirmenough,andrequirerigorousvalidation,
thentheriskofundetectedmeaslestransmissionaftercertificationisverylow.Ifthecertification
criteriaarelax,orvalidationrequirementsareinadequate,theriskwillbehigher.
Riskoftransmissionofvaccinederivedvirus
Thecurrentlylicensedliveattenuatedmeaslesvaccinesaresafeandefficientandhavebeenused
successfullytoprotectmanymillionsofindividualsandpreventmeaslestransmission.Allcurrent
vaccinevirusesarecloselyrelatedandbelongtogenotypeA.Thereisnopublishedconclusive
evidenceforcurrentlylicensedliveattenuatedvaccinevirusesrevertingtowildtypetransmissibility
orvirulence.Onthecontrary,thevastmajorityofevidencepointstoanimpressivelevelofgenetic
stability.However,sincetheyarelivevirusesthatreplicatewithinvaccinerecipients,theremote
possibilitymustexistthattheycouldreverttowildtypecharacteristics.Thereisalsonoevidencefor
theestablishmentofvaccineescapemutants.Evenifvaccinevirusesweretoreverttowildtype
transmissibility,thereisnoreasontosuspectthattransmissioncouldnotbecontrolledusingcurrent
vaccines.
Riskfrompersistentinfections
Thereisnopublishedevidencethatcasesofpersistentmeaslesinfectionareassociatedwiththe
sheddingofinfectiousvirusorplayanypartinmeaslestransmission.Asthenumberofacute
measlesviruscasesdeclinesintheyearsleadingtoglobaleradication,wecanexpectadeclineinthe
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DrRaySanders.Measlesreintroductionriskanalysis
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numberofpotentialSSPEandMIBEcases.AcutemeaslesinfectioninHIVinfectedindividualstends
tobemoresevere,lastlongerandresultinashorterlivedimmunitytoreinfection,butthereisno
publishedevidencetosuggestthatcoinfectionincreasesthepotentialforestablishmentof
persistentmeaslesinfections,eitherwithwildtypevirusorwithvaccinederivedvirus.
Riskfromnonhumanprimates
Althoughnonhumanprimatescanbeexperimentallyandnaturallyinfectedwithmeaslesvirus,and
animalanimaltransmissionoccurs,populationsizesaretoosmalltomaintainepizootictransmission
orposeathreattohumanpopulations.
Riskoflaboratoryassociatedmeaslesinfection
Althoughthereisnodirectevidenceforlaboratoryacquiredmeaslesinfectionsitispossiblethat
theyhaveoccurredamongimmunelaboratorystaffandresultedinasymptomaticorverymild
infections.Thereisnopublishedevidencetosuggestthattheseasymptomaticormildinfections
resultinfurthertransmissionofvirus.Measlesviruslosesinfectivitywithinafewhoursatambient
temperatures,andinfectiousmaterialsstoredattemperaturesabove30 oCcanbeexpectedtolose
allinfectivityoverthecourseofonetotwoyears.Materialsstoredatorbelow70oC,orfreeze
dried,maintaininfectivityformanyyears.
Despitethelackofevidenceforlaboratoryacquiredmeaslesinfectionsorescapeofvirusintothe
community,thesemustbeconsideredpossibilitiesinaposteradicationworld.Anappropriate
systematiclaboratorycontainmentstrategyformeasles,learningfromtheexamplesetbythePolio
EradicationInitiative,shouldbedeveloped.
Riskofintentionalreleaseofmeaslesvirus
Measlesisahighlyinfectiousvirusthathashaddevastatingeffectsonsusceptiblepopulationsinthepast.Althoughitisunlikelythatthehighmortalitiesseenintheseisolatedcommunitieswouldbe
repeated,thethreatofmeaslesreleasewouldprobablybeveryeffectiveonceasizablepopulation
ofsusceptibleindividualshadaccumulated.Thisthreatcouldbecounteredbytheestablishmentofa
measlesvaccinestockpile,preferablyusinganew,easytomassadminister,nonreplicativemeasles
vaccine.Thesizeandnatureofanystockpileshouldbedefinedwithinasystematicand
comprehensiveposteradicationriskmanagementstrategy.
Risksforreintroductionofmeaslescanbesummarisedasfollows:
Risk Magnitude Tendencyovertime MitigatingactionsContinuingwildtype
measlestransmissionin
humans
Lowbutdependson
certificationcriteriaand
validationrequirements
Decreasing Basecertificationcriteria
andvalidationrequirements
ondynamicandstochastic
modellingdata
Transmissionofvaccine
derivedvirus
Verylow Dependsonlevelofvaccine
use
Developalternative,non
replicatingvaccines
Persistentinfections Verylow Decreasing Maintainsurveillance
Nonhumanprimates Verylow Decreasing Maintainsurveillance
Laboratoryassociated
infection
Verylowbutrisingpost
eradication
Increasing Developsystematic
laboratorycontainment
strategy
Intentionalrelease Verylowbutrisingpost
eradication
Increasing Developvaccinestockpiles
aspartofacomprehensive
riskmanagementstrategy
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TableofContentsError!Bookmarknotdefined.
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Theanalysisconcludeswithabriefdiscussionofactionsrequiredtoreducetheriskofaccidentalor
deliberatereleaseofmeaslesinaposteradicationworldandareasthatcouldbenefitfromfurther
research.
Riskofcontinuing,undetectedwildtypemeaslestransmissioninhumansThereare,asyet,nodefinitivecriteriaforcertificationofglobalmeasleseradicationoragreed
requirementsforvalidationofthesecriteria.Withoutthesecriteria,andthedetailedrequirements
fordemonstratingtheyhavebeenmet,itisnotpossibletoaccuratelyestimatetheriskpresentedby
undetectedcontinuingtransmission.However,basedoncurrentRegionalandGlobal
recommendationsoncertificationofRegionalmeasleselimination,itislikelythateradicationcriteria
willinclude:
1. Absenceofcirculatingmeaslesvirusforatleastoneyear;2. Adequatesurveillanceincludinggenotypedata.Adequatesurveillancemaybedefinedby:
Numberofreportedsuspectedmeaslescasesthatarediscardedasnonmeasles(targets:2/100,000populationnationally,1/100,000inatleast80%ofdistricts)
Percentageofreportedsuspectedcasesthathaveadequateinvestigationwithin48hoursofreport(target:80%ofreportedsuspectedcases)
Percentageofreportedsuspectedcasesthathaveadequatespecimenscollected(target:80%ofreportedsuspectedcases)
PercentageofdistrictswithaccesstoaWHOaccreditedmeaslesdiagnosticlaboratory(target:100%)
PercentageofspecimenswithIgMresultswithin7daysofreceiptinlaboratory(target:90%)
PercentageofchainsoftransmissionwithRNAsequenceanalysis(target:95%) Someuseofmeaslesavidityassaystodistinguishrecentfromlongstanding
immunologicalresponses
Somedemonstrationofalternativesurveillancemechanisms,routineorsupplementary,basedoncasedetection,investigationandreporting;
3. Achievementofhighpopulationimmunity.Populationimmunitymaybedemonstratedby: 95%coveragewithroutineMCV2inalldistricts,or 80%coveragewithroutineMCV1plus95%coveragewithSIAfollowupinall
districts,or
Someuseofextensiveserosurveydata.
FromexperiencegainedthroughRegionalpolioeliminationandcertification,specificcriteriamaybe
usedtofulfilthethreegeneralcriteriaabove,butitisunlikelythatanysinglespecificindicatorwill
berequiredtopassorfailvalidation.Thestrictnessandextentofrequirementsforproviding
evidencethatcertificationcriteriahavebeenmetwilllargelydeterminethemagnitudeofriskposed
byundetectedcontinuingmeaslestransmission.Butevenwithrelativelylaxcriteriaandvalidation
requirements,howlikelyisitthatongoingmeaslestransmissionwillbeundetectedforaminimum
ofoneyearbeforecertification?
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Whatisthesmallestpopulationrequiredtomaintainmeaslestransmission?
Measlesepidemicshavegenerallybeencharacterisedbyexplosivecycleswithhighlycomplex
pathogenandpopulationlevelinteractionsthatinfluencetransmissiondynamics(1).Accurately
predictingthecriticalcommunitysize(CCS)requiredformaintainingmeaslesviruscirculationis
difficultduetothelargenumberofvariablesinvolved.Directobservationandarangeofboth
deterministicandstochasticmodelssuggestthatapopulationof250,000to400,000with5,000to
10,000birthsperyearisrequiredtomaintaintransmission(2,3).Highlevelsofimmuniz