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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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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