Download - Risk analysis for measles reintroduction post global certification of

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

DrRaySanders.Measlesre‐introductionriskanalysis

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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


Page17

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


Page18

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


Page19

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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