measles, morbili

7/27/2019 measles, morbili

1/31

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


2/31

DrRaySanders.Measlesreintroductionriskanalysis

Page2

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


3/31


4/31


Page4

TableofContentsError!Bookmarknotdefined.


5/31


6/31


Page6

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?


7/31


Page7

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.


8/31


Page8

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.


9/31


Page9

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


10/31


Page10

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


11/31


Page11

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


12/31


Page12

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


13/31


Page13

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.


14/31


Page14

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


15/31


Page15

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


16/31


Page16

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(


17/31


Page17

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


18/31


Page18

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


19/31


Page19

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.


20/31


Page20

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


21/31


Page21

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.


22/31


Page22

Bibliography

1. AndersonRM.Biologicalchallengestoposteradication.Herdimmunityandthedesignofvaccinationprograms.InKnoblerS,

LederbergJ,PrayLA.ConsiderationsforviralDiseaseeradication.Lessonslearnedandfuturestrategies.Workshopsummary.

Washington:NationalAcademicPress;2002.p.6577.

2. BlackFL.Measlesendemicityininsularpopulations:criticalcommunitysizeanditsevolutionaryimplication.JournalofTheoretical

Biology.1966;11(2):p.207211.

3. KeelingMJ,GrenfellBT.Diseaseextinctionandcommunitysize:modellingthepersistenceofmeasles.Science.1997;275:p.6567.

4. KouadioIK,KamigakiT,OshitaniH.Measlesoutbreaksindisplacedpopulations:areviewoftransmission,morbidityandmortality

associatedfactors.BMCInternationalHealthandHumanRights.2010;10:5.

5. SzuszEK,GarrisonLP,BauchCT.Areviewofdataneededtoparameterizeadynamicmodelofmeaslesindevelopingcountries.BMC

ResearchNotes.2010;3:75.

6. TooleMJ,SteketeeRW,WaldmanRJ,NieburgP.Measlespreventionandcontrolinemergencysettings.BulletinoftheWorldHealth

Organization.1989;67:p.381388.

7. EdmostonMB,AddissDG,McPhersonJT,BergJL,CircoSR,DavisJP.Mildmeaslesandsecondaryvaccinefailureduringasustained

outbreakinahighlyvaccinatedpopulation.JAMA.1990;263:p.24672471.

8. HuissS,DamienB,SchneiderF,MullerCP.Characteristicsofasymptomaticsecondaryimmuneresponsestomeaslesvirusinlate

convalescentdonors.ClinicalandExperimentalImmunology.1997;109(3):p.416420.

9. OzanneG,DHalewynMA.Secondaryimmuneresponseinavaccinatedpopulationduringalargemeaslesepidemic.Journalof

ClinicalMicrobiology.1992;30:p.17781782.

10. HelfandRF,KimDK,GaryHEJ,EdwardsGL,BissonGP,PapaniaMJ,etal.Nonclassicmeaslesinfectionsinanimmunepopulation

exposedtomeaslesduringacollegebustrip.JournalofMedicalVirology.1998;56(4):p.337341.

11. VardasE,KreisS.Isolationofmeaslesvirusfromanaturallyimmune,asymptomaticallyre infectedindividual.JournalofClinical

Virology.1999;13(3):p.173179.

12. ChenRT,MarkowitzLE,AlbrechtP,StewartJA,MofensonLM,PrebludSR,etal.Measlesantibody:reevaluationofprotect ivetiters.

JournalofInfectiousDiseases.1990;162(5):p.10361042.

13. WhittleHC,AabyP,SambB,JensenH,BennettJ,SimondonF.Effectofsubclinicalinfectiononmaintainingimmunityagainst

measlesinvaccinatedchildreninWestAfrica.Lancet.1999;353(9147):p.98102.

14. LievanoFA,PapaniaMJ,HelfandRF,HarpazR,WallsL,KatzRS,etal.Lackofevidenceofmeaslesvirussheddinginpeoplewith

inapparentmeaslesvirusinfections.Journalofinfectiousdiseases.2004;189Suppl1:p.165170.

15. SonodaS,TN.Detectionofmeaslesvirusgenomeinlymphocytesfromasymptomatic healthychildren.JournalofMedicalVirology.

2001;65(2):p.381387.

16. CherryJD,FeiginRD,LobesLAJ,HinthornDR,ShackelfordPG,ShirleyRH,etal.Urbanmeaslesinthevaccineera:aclinical,

epidemiologic,andserologicstudy.JournalofPediatrics.1972;81(2):p.217230.

17. CherryJD,FeiginRD,LobesLAJ,ShackelfordPG.Atypicalmeaslesinchildrenpreviouslyimmunizedwithattenuatedmeaslesvirus

vaccines.Pediatrics.1972;50(5):p.712717.


23/31


Page23

18. SmithFR,CurranAS,RacitiKA,BlackFL.Reportedmeaslesinpersonsimmunologicallyprimedbypriorvaccination.Journalof

Pediatrics.1982;101(3):p.391393.

19. ReyesMA,deBorreroMF,RoaJ,BergonzoliG,SaraviaNG.Measlesvaccinefailureafterdocumentedseroconversion.Pediatric

InfectiousDiseaseJournal.1987;6(9):p.848851.

20. AabyP,BukhJ,LeerhyJ,LisseIM,MordhorstCH,PedersenIR.Vaccinatedchildrengetmildermeaslesinfect ion:acommunitystudy

fromGuineaBissau.JournalofInfectiousDiseases.1986;154(5):p.858863.

21. LinnemannCCJ,RotteTC,SchiffGM,YoutseyJL.Aseroepidemiologicstudyofameaslesepidemicinahighlyimmunizedpopulation.

AmericanJournalofEpidemiology.1972;95(3):p.238246.

22. EndersJF,PeeblesTC.Propagationintissueculturesofcytopathicagentsfrompatientswithmeasles.ProceedingsoftheSocietyfor

ExperimentalBioliologyandMedicine.1954;86:p.277286.

23. MossWJ,ScottS.WHOImmunologicalBasisforImmunizationSeries.Module7:Measles.Geneva:WorldHealthOrganization;2009.

24. ParksCL,LerchRA,WalpitaP,WangHP,SidhuMS,UdemSA.Comparisonofpredictedaminoacidsequencesofmeaslesvirusstrains

intheEdmonstonvaccinelineage.JournalofVirology.2001;75:p.910920.

25. KrugmanS.FurtherattenuatedMeaslesVaccine:CharacteristicsandUse.ReviewsofInfectiousDiseases.1983;5:p.477481.

26. HirayamaM.MeaslesVaccinesUsedinJapan.ReviewsofInfectiousDiseases.1983;5:p.495503.

27. PeradzeTV,SmorodintsevAA.EpidemiologyandSpecificProphylaxisofMeasles.ReviewsofInfectiousDiseases.1983;5:p.487490.

28. XiangJ,ChenZ.MeaslesVaccineinthePeople'sRepublicofChina.ReviewsofInfectiousDiseases.1983;5:p.506510.

29. MakinoS.DevelopmentandCharacteristicsofLiveAIKCMeaslesVirusVaccine:ABriefReport.ReviewsofInfectiousDiseases.1983;

5:p.504505.

30. BorgesMB,CarideE,JaborAV,MalachiasJMN,FreireMS,HommaA,etal.StudyofthegeneticstabilityofmeaslesvirusCAM70

vaccinestrainafterserialpassagesinchickenembryofibroblastsprimarycultures.VirusGenes.2008;36:p.3544.

31. BorgesMBJ,MannGF,FreireMdS.BiologicalCharacterizationofClonesDerivedfromtheEdmonstonStrainofMeaslesVirusin

ComparisonwithSchwarzandCAM70VaccineStrains.MemInstOswaldoCruz,RiodeJaneiro.1996;91:p.507514.

32. TaminA,RotaPA,WangZD,HeathJL,AndersonLJ,BelliniWJ.Antigenicanalysisofcurrentwildtypeandvaccinestrainsofmeasles

virus.JournalofInfectiousDiseases.1994;170:p.795801.

33. ZhangY,ZhouJ,BelliniWJ,XuW,RotaPA.GeneticcharacterizationofChinesemeaslesvaccinesbyanalysisofcompletegenomic

sequencesJ.Journalofmedicalvirology.2009;81:p.14771483.

34. WardB,BoulianneN,RatnamS,GuiotMC,CouilardM,DeSerresG.Cellularimmunityinmeaslesvaccinefailure:demonstrationof

measlesantigenspecificlymphoproliferativeresponsesdespitelimitedserumantibodyproductionafterrevaccination.Journalof

InfectiousDiseases.1995;172:p.15911955.

35. CohenJI.Vaccineassociatedcasesduetoimmunizationwithlivevirusvaccines.InKnoblerS,LederbergJ,PrayLA.Considerations

forViralDiseaseEradication.LessonslearnedandFuturestrategies.Washington,DC:NationalAcademyPress;2002.p.9097.

36. RotaPA,KhanAS,DurigonE,YuranT,VillamarzoYS,BelliniWJ.DetectionofMeaslesVirusRNAinUrineSpecimensfromVaccine

Recipients.JournalofClinicalMicrobiology.1995;33:p.24852488.

37. LlanesRodasR,LiuC.Rapiddiagnosisofmeaslesfromurinarysedimentsstainedwithfluorescentantibody.NewEnglandJournalof

Medicine.1966;275:p.516523.


24/31


Page24

38. TakedaM.Measlesvirusbreaksthroughepithelialcellbarrierstoachievetransmission.JournalofClinicalInvestigation.2008;118:

p.23862389.

39. LeonardVHJ,SinnPL,HodgeG,MiestT,DevauxP,OezguenN,etal.Measlesvirusblindtoitsepithelialcellreceptorremainsvirulent

inrhesusmonkeysbutcannotcrosstheairwayepitheliumandisnotshed.JournalofClinicalInvestigation.2008;118:p.24482458.

40. LudlowM,AllenI,SchneiderSchauliesJ.Systemicspreadofmeaslesvirus:overcomingtheepithelialandendothelialbarriers.

ThrombosisandHaemostasis.2009;102(6):p.10501056.

41. HarrisonMS,SakaguchiT,SchmittAP.Paramyxovirusassemblyandbudding:Buildingparticlesthattransmitinfections.International

JournalofBiochemistryandCellBiology.2010;InPress(doi:10.1016/j.biocel.2010.04.005).

42. WorldHealthOrganization.Globaldistributionofmeaslesandrubellagenotypesupdate.WeeklyEpidemiologicalRecord.2006;81:

p.474479.

43. RiddellMA,RotaJS,RotaPA.Reviewofthetemporalandgeographicaldistributionofmeaslesvirusgenotypesintheprevaccineand

postvaccineeras.VirologyJournal.2005;2:p.87.

44. RotaPA,FeatherstoneDA,BelliniWJ.Molecularepidemiologyofmeaslesvirus.Currenttopicsinmicrobiologyandimmunology.

2009;330:p.129150.

45. RotaJS,WangZD,RotaPA,BelliniWJ.ComparisonofsequencesoftheH,F,andNcodinggenesofmeaslesvirusvaccinestrains.

Virusresearch.1994;31:p.317330.

46. BelliniWJ,RotaPA.Geneticdiversityofwildtypemeaslesviruses:implicationsforglobalmeasleseliminationprograms.Emerging

InfectiousDieases.1998;4(1):p.2935.

47. ChristensenLS,SchollerS,SchierupMH,VestergaardBF,MordhorstCH.Sequenceanalysisofmeaslesvirusstrainscollectedduring

thepreandearlyvaccinationerainDenmarkrevealsaconsiderablediversityofancientstrains.Actapathologica,microbiologica,et

immunologicaScandinavica.2002;110:p.113122.

48. RotaPA,BloomAE,VanchiereJA,BelliniWJ.Evolutionofthenucleoproteinandmatrixgenesofwildtypestrainsofmeaslesvirus

isolatedfromrecentepidemics.Virology.1994;198(2):p.724730.

49. RotaPA,RotaJS,ReddSB,PapaniaMJ,BelliniWJ.Geneticanalysisofmeaslesvirusesisolatedintheunitedstatesbetween1989and

2001:absenceofanendemicgenotypesince1994.Journalofinfectiousdiseases.2004;189Suppl1:p.S160164.

50. KremerJR,BrownKE,JinL,ale.Highgeneticdiversityofmeaslesvirus,WorldHealthOrganizationEuropeanRegion,20052006.

Emerginginfectiousdiseases.2008;14(1):p.107114.

51. ShulgaSV,RotaPA,KremerJR,NaumovaMA,MullerCP,TikhonovaNT,etal.Geneticvariability ofwildtypemeaslesviruses,

circulatingintheRussianFederationduringtheimplementationoftheNationalMeaslesEliminationProgram,20032007.Clinical

microbiologyandinfection.2009;15:p.528537.

52. ChiboD,BirchCJ,RotaPA,CattonMG.MolecularcharacterizationofmeaslesvirusesisolatedinVictoria,Australia,between1973

and1998.JournalofGeneralVirology.2000;81:p.25112518.

53. TipplesGA,GrayM,GarbuttM,RotaPA,ProgramCMS.GenotypingofmeaslesvirusinCanada:19792002.Journalofinfectious

diseases.2004;189Suppl1:p.S171176.

54. OutlawMC,PringleCR.SequencevariationwithinanoutbreakofmeaslesvirusintheCoventryareaduringspring/summer1993.

VirusResearch.1995;39(1):p.311.

55. ZhangY,ZhuZ,RotaPA,JiangX,HuJ,ale.MolecularepidemiologyofmeaslesvirusesinChina,19952003.VirologyJournal.2007

February;4(14).


25/31


26/31


Page26

hokkaidodistrict,Japan,2007.JapaneseJournalofInfectiousDiseases.2009;62(3):p.209211.

75. GrothC,BottigerB,PlesnerA,ChristiansenA,GlismannS,HoghB.NosocomialmeaslesclusterinDenmarkfollowinganimported

case,December2008January2009.EuroSurveillance.2009;14(8):p.19126.

76. CarrMJ,ConwayA,WatersA,MoranJ,HassanJ,HallWW,etal.MolecularepidemiologyofcirculatingmeaslesvirusinIreland2002

2007.JournalofMedicalVirology.2009;81(1):p.125129.

77. NigatuW,JinL,CohenBJ,NokesDJ,EtanaM,CuttsFT,etal.MeaslesvirusstrainscirculatinginEthiopiain19981999:molecular

characterisationusingoralfluidsamplesandidentificationofanewgenotype.JournalofMedicalVirology.2001;65(2):p.373380.

78. LemmaE,SmitSB,BeyeneB,NigatuW,BabaniyiOA.GeneticcharacterizationandprogressionofB3measlesgenotypeinEthiopia:a

studyoffivemeaslesoutbreakcases.EthiopianMedicalJournal.2008;46(1):p.7985.

79. KokotasSN,BolanakiE,SgourasD,PogkaV,LogothetiM,KossivakisA,etal.CocirculationofgenotypesD4andD6inGreeceduring

the2005to2006measlesepidemic.DiagnosticMicrobiologyandInfectiousDisease.2008;62(1):p.5866.

80. ChironnaM,PratoR,SallustioA,MartinelliD,GerminarioC,LopalcoP,etal.Geneticcharacterizationofmeaslesvirusstrains

isolatedduringanepidemicclusterinPuglia,Italy20062007.VirologyJournal.2007Sept21;4:p.90.

81. WichmannO,HellenbrandW,SagebielD,SantibanezS,AhlemeyerG,VogtG,etal.LargemeaslesoutbreakataGermanpublic

school,2006.PediatricInfectiousDiseaseJournal.2007;26(9):p.782786.

82. JiY,XuS,ZhangY,ZhuZ,MaoN,JiangX,etal.GeneticcharacterizationofwildtypemeaslesvirusesisolatedinChina,20062007.

VirologyJournal.2010;7(1):p.105.

83. TruongAT,MuldersMN,GautamDC,AmmerlaanW,deSwartRL,KingCC,etal.GeneticanalysisofAsianmeaslesvirusstrainsnew

endemicgenotypeinNepal.VirusResearch.2001;76(1):p.7178.

84. GriffinDE.Measles.InKnipeDM,HowleyPM,GriffinDE,LambRA,MartinMA,RoizmanB,etal.,editors.FieldsVirology.5thed.

Philadelphia:LippincottWilliams&Wilkins;2007.p.15511585.

85. SchragSJ,RotaPA,BelliniWJ.SpontaneousMutationRateofMeaslesVirus:DirectEstimationBasedonMutationsConferring

MonoclonalAntibodyResistance.JournalofVirology.1999;73(1):p.5154.

86. HollandJJ,delaTorreJC,SteinhauerDA.RNAviruspopulationsasquasispecies.CurrentTopicsinMicrobiologyandImmunology.

1992;176:p.120.

87. deSwartRL,YkselS,OsterhausAD.Relativecontributionsofmeaslesvirushemagglutininandfusionproteinspecificserum

antibodiestovirusneutralization.JournalofVirology.2005;79(17):p.1154711551.

88. TatsuoH,OnoN,TanakaK,YanagiY.SLAM(CDw150)isacellularreceptorformeaslesvirus.Nature.2000;406:p.893897.

89. VeilletteA.ImmuneregulationbySLAMfamilyreceptorsandSAPrelatedadaptors.NatureReviewsImmunology.2006;6:p.5666.

90. HashiguchiT,KajikawaM,MaitaN,TakedaM,KurokiK,SasakiK,etal.Crystalstructureofmeaslesvirushemagglutininprovides

insightintoeffectivevaccines.ProceedingsoftheNationalAcademyofSciences.2007;104(49):p.1953519540.

91. SantibanezS,NiewieskS,HeiderA,SchneiderSchauliesJ,BerbersGA,ZimmermannA,etal.Probingneutralizingantibodyresponses

againstemergingmeaslesviruses(MVs):immuneselectionofMVbyHproteinspecificantibodies?JournalofGeneralVirology.

2005;86(Pt2):p.365374.

92. RuigrokRW,GerlierD.StructureofthemeaslesvirusHglycoproteinshedslightonanefficientvaccine.ProceedingsoftheNational

AcademyofSciences.2007;104(52):p.2063920640.


27/31


Page27

93. MossWJ,GriffinDE.Globalmeasleselimination.NatureReviews.Microbiology.2006;4(12):p.900908.

94. RimaBK,DuprexWP.Molecularmechanismsofmeaslesviruspersistence.VirusResearch.2005;111(1):p.132147.

95. ForthalDN,AarnaesS,BlandingJ,delaMazaL,TillesJG.Degreeandlengthofviremiainadultswithmeasles.JournalofInfectious

Diseases.1992;166(2):p.421424.

96. GresserI,KatzSl.Isolationofmeaslesvirusfromurine.NewEnglandJournalofMedicine.1960;263:p.452454.

97. DossetorJ,WhittleHC,GeenwoodBM.Persistentmeaslesinfectioninmalnourishedchildren.BritishMedicalJournal.1977;1:p.

16331635.

98. ScheifeleDW,ForbesCE.ProlongedgiantcellexcretioninsevereAfricanmeasles.Pediatrics.1972;50(6):p.867873.

99. MitusAEJF,MCJ,HollowayA.Persistenceofmeaslesvirusanddepressionofantibodyformationinpatientswithgiantcell

pneumoniaaftermeasles.NewEnglandJournalofMedicine.1959;261:p.882889.

100. BudkaH,UrbanitsS,LiberskiPP,EichingerS,PopowKrauppT.Subacutemeaslesvirusencephalitis:anewandfatalopportunistic

infectioninapatientwithAIDS.Neurology.1996;46(2):p.586587.

101. EndersJF,McCarthyK,MitusA,JCW.Isolationofmeaslesvirusatautopsyincasesofgiantcellpneumoniawithoutrash.New

EnglandJournalofMedicine.1959;261:p.875881.

102. MarkowitzLE,ChandlerFW,RoldanEO,SaldanaMJ,RoachKC,HutchinsSS,etal.Fatalmeaslespneumoniawithoutrashinachild

withAIDS.JournalofInfectiousDiseases.1988;158(2):p.480483.

103. NakataY,NakayamaT,IdeY,KizuR,KoinumaG,BambaM.Measlesvirusgenomedetecteduptofourmonthsinacaseofcongenital

measles.ActaPaediatrica.2002;91(11):p.12631265.

104. PermarS,MossWJ,RyonJJ,MonzeM,CuttsF,QuinnTC,etal.Prolongedmeaslesvirussheddinginhumanimmunodeficiencyvirus

infectedchildren,detectedbyreversetranscriptasepolymerasechainreaction.JournalofInfectiousDiseases.2001;183(4):p.532

538.

105. RiddellMA,ChiboD,KellyHA,CattonMG,BirchCJ.Investigationofoptimalspecimentypeandsamplingtimefordetectionof

measlesvirusRNAduringameaslesepidemic.JournalofClinicalMicrobiology.2001;39(1):p.375376.

106. vanBinnendijkRS,vandenHofS,vandenKerkhofH,KohlRH,WooninkF,BerbersGA,etal.Evaluationofserologicalandvirological

testsinthediagnosisofclinicalandsubclinicalmeaslesvirusinfectionsduringanoutbreakofmeaslesinTheNetherlands.Journalof

InfectiousDiseases.2003;188(6):p.898903.

107. RiddellMA,MossWJ,HauerD,MonzeM,GriffinDE.SlowclearanceofmeaslesvirusRNAafteracuteinfection.JournalofClinical

Virology.2007;39(4):p.312317.

108. PanCH,ValsamakisA,ColellaT,NairN,AdamsRJ,PolackFP,etal.Modulationofdisease,Tcellresponses,andmeaslesvirus

clearanceinmonkeysvaccinatedwithHencodingalphavirusrepliconparticles.ProceedingsoftheNationalAcademyofSciences.

2005;102(33):p.1158111588.

109. terMeulenV,StephensonJR,KrethHW.Subacutesclerosingpanencephalitis.InFraenkelConratH,WagnerRR,editors.

ComprehensiveVirology,vol.18.NewYork:PlenumPress;1983.p.105159.

110. CampbellH,AndrewsN,BrownKE,MillerE.ReviewoftheeffectofmeaslesvaccinationontheepidemiologyofSSPE.International

JournalofEpidemiology.2007;36:p.13341348.

111. YoungVA,RallGF.Makingittothesynapse:Measlesvirusspreadinandamongneurons.CurrentTopicsinMicrobiologyand

Immunology.2009;330:p.330.


28/31


Page28

112. PaulaBarbosaMM,CruzC.Nervecellfusioninacaseofsubacutesclerosingpanencephalitis.AnnalsofNeurobiology.1981;9:p.

400403.

113. CattaneoR,SchmidA,BilleterMA,SheppardRD,UdemSA.Multipleviralmutationsratherthanhostfactorscausedefectivemeasles

virusgeneexpressioninasubacutesclerosingpanencephalitiscellline.JournalofVirology.1988;62(4):p.13881397.

114. AyataM,KomaseK,ShingaiM,MatsunagaI,KatayamaY,OguraH.Mutationsaffectingtranscriptionalterminationinthepgeneend

ofsubacutesclerosingpanencephalitisviruses.JournalofVirology.2002;76(2):p.1306213068.

115. HottaH,NiheiK,AbeY,KatoS,JiangDP,NaganoFujiiM,etal.Fulllengthsequenceanalysisofsubacutesclerosingpanencephalitis

(SSPE)virus,amutantofmeaslesvirus,isolatedfrombraintissuesofapatientshortlyafteronsetofSSPE.Microbiologyand

Immunology.2006;50(7):p.525534.

116. JiangDP,IdeYH,NaganoFujiiM,ShojiI,HottaH.SinglepointmutationsoftheMproteinofameaslesvirusvariantobtainedfroma

patientwithsubacutesclerosingpanencephalitiscriticallyaffectsolubilityandsubcellularlocalizationoftheMproteinandcellfree

virusproduction.MicrobesandInfection.2009;11(4):p.467475.

117. BitnunA,ShannonP,DurwardA,RotaPA,BelliniWJ,GrahamC,etal.Measlesinclusionbodyencephalitiscausedbythevaccine

strainofmeaslesvirus.Clinicalinfectiousdiseases.1999;29:p.855861.

118. MustafaMMWSWNBWTCSJ.Subacutemeaslesencephalitisintheyoungimmunocompromisedhost:reportoftwocasesdiagnosed

bypolymerasechainreactionandtreatedwithribavirinandreviewoftheliterature.ClinicalInfectiousDiseases.1993;16(5):p.654

660.

119. FreemanAF,JacobsohnDA,ShulmanST,BelliniWJ,JaggiP,deLeonG,etal.Anewcomplicationofstemcelltransplantation:

measlesinclusionbodyencephalitis.Pediatrics.2004;114(5):p.e657660.

120. KatayamaYKKNATYHMHH.Detect ionofmeaslesvirusmRNAfromautopsiedhumantissues.JournalofClinicalMicrobiology.1998;

36(1):p.299301.

121. KatayamaY,HottaH,NishimuraA,TatsunoY,HommaM.DetectionofmeaslesvirusnucleoproteinmRNAinautopsiedbraintissues.JournalofGeneralVirology.1995;76(12):p.32013204.

122. MossWJ,FisherC,ScottS,MonzeM,RyonJJ,QuinnTC,etal.HIVtype1infectionisariskfactorformortalityinhospitalized

Zambianchildrenwithmeasles.ClinicalInfectiousDiseases.2008;46(4):p.523527.

123. FrenkelLMNKGACJ.Asearchforpersistentmeasles,mumps,andrubellavaccinevirusinchildrenwithhumanimmunodeficiency

virustype1infection.ArchivesofPediatricsandAdolescentMedicine.1994;148(1):p.5760.

124. GardnerMB,LuciwPA.Macaquemodelsofhumaninfectiousdisease.ILARJournal.2008;49(2):p.220255.

125. MacArthurJA,MannPG,OreffoV,ScottGB.Measlesinmonkeys:anepidemiologicalstudy.JournalofHygiene.1979;83(2):p.207

212.

126. ElMubarakH,YkselS,vanAmerongenG,MulderPG,MukhtarMM,OsterhausAD,etal.Infectionofcynomolgusmacaques

(Macacafascicularis)andrhesusmacaques(Macacamulatta)withdifferentwildtypemeaslesviruses.JournalofGeneralVirology.

2007;88:p.20282034.

127. JonesEngelL,EngelGA,SchillaciMA,LeeB,HeidrichJ,ChaliseM,etal.Consideringhumanprimatetransmissionofmeaslesvirus

throughtheprismofriskanalysis.AmericalJournalofPrimatology.2006;68(9):p.868879.

128. ZhuYD,HeathJ,CollinsJ,GreeneT,AntipaL,RotaP,etal.Experimentalmeasles.II.Infect ionandimmunityintherhesusmacaque.

Virology.1997;233(1):p.8592.

129. vanBinnendijkRS,vanderHeijdenRW,vanAmerongenG,UytdeHaagFG,OsterhausAD.Viralreplicationanddevelopmentofspecificimmunityinmacaquesafterinfectionwithdifferentmeaslesvirusstrains.JournalofInfectiousDiseases.1994;170(2):p.


29/31


Page29

443448.

130. deSwartRL.Measlesstudiesinthemacaquemodel.Currenttopicsinmiocrobiologyandimmunology.2009;330:p.5572.

131. ChoiYK,SimonMA,KimDY,YoonBI,KwonSW,WLK,etal.FatalmeaslesvirusinfectioninJapanesemacaques(Macacafuscata).

VeterinaryPathology.1999;36(6):p.594600.

132. WillyME,WoodwardRA,ThorntonVB,WolffAV,FlynnBM,HeathJL,etal.ManagementofameaslesoutbreakamongOldWorld

nonhumanprimates.LaboratoryAnimalScience.1999;49:p.4248.

133. YoshikawaY,OchikuboF,MatsubaraY,TsuruokaH,IshiiM,ShirotaK,etal.Naturalinfectionwithcaninedistempervirusina

Japanesemonkey(Macacafuscata).VeterinaryMicrobiology.1989;20(3):p.193205.

134. SunZ,LiA,YeH,ShiY,HuZ,ZengL.NaturalinfectionwithcaninedistempervirusinhandfeedingRhesusmonkeysinChina.

VeterinaryMicrobiology.2010;141(34):p.374378.

135. BhattPN,BrandtCD,WeissR,FoxJP,ShafferMF.ViralinfectionsofmonkeysintheirnaturalhabitatinsouthernIndia.II.Serological

evidenceofviralinfection.AmericanJournalofTropicalMedicineandHygiene.1966;15(4):p.561566.

136. JonesEngelL,EngelGA,SchillaciMA,BaboR,FroehlichJ.Detectionofantibodiestoselectedhumanpathogensamongwildandpet

macaques(Macacatonkeana)inSulawesi,Indonesia.AmericalJournalofPrimatology.2001;54(3):p.171178.

137. ShahKV,SouthwickCH.Prevalenceofantibodiestocertainvirusesinseraoffreelivingrhesusandofcaptivemonkeys.Indian

JournalofMedicalResearch.1965;53:p.488500.

138. GristNR.Hepatitisandotherinfectionsinclinicallaboratorystaff,1979.JournalofClinicalPathology.1981;34(6):p.655658.

139. GristNR.InfectionsinBritishclinicallaboratories198081.JournalofClinicalPathology.1983;36(2):p.121126.

140. GristNR,EmslieJ.InfectionsinBritishclinicallaboratories,19823.JournalofClinicalPathology.1985;38(7):p.721725.

141. GristNR,EmslieJA.InfectionsinBritishclinicallaboratories,19845.JournalofClinicalPathology.1987;40(8):p.826829.



144. WalkerD,CampbellD.AsurveyofinfectionsinUnitedKingdomlaboratories,19941995.JournalofClinicalPathology.1999;52(6):

p.415418.

145. SulkinSE,PikeRM.Surveyoflaboratoryacquiredinfections.AmericanJournalofPublicHealthandtheNation'sHealth.1951;41(7):

p.769781.

146. PikeRM,SulkinSE,SchulzeML.Continuingimportanceoflaboratoryacquiredinfections.AmericanJournalofPublicHealthandthe

Nation'sHealth.1965;55:p.190199.

147. PikeRM.Laboratoryassociatedinfections:summaryandanalysisof3921cases.HealthLaboratoryScience.1976;13(2):p.105114.

148. PikeRM.Laboratoryassociatedinfections:incidence,fatalities,causes,andprevention.AnnualReviewofMicrobiology.1979;33:p.

4166.

149. VesleyD,HartmannHM.Laboratoryacquiredinfectionsandinjuriesinclinicallaboratories:a1986survey.AmericanJournalof

PublicHealth.1988;78(9):p.12131215.


30/31


Page30

150. ShimojoH.VirusinfectionsinlaboratoriesinJapan.BibliothecaHaematologica.1975;(40):p.771773.

151. KimmanTG,SmitE,KleinMR.Evidencebasedbiosafety:areviewoftheprinciplesandeffectivenessofmicrobiologicalcontainment

measures.ClinicalMicrobiologyReviews.2008;21(3):p.403425.

152. CollinsCH.Laboratoryacquiredinfections:history,incidence,causes,andprevention.3rded.Oxford:ButterworthHeinemannLtd;

1993.

153. SewellDL.LaboratoryAssociatedInfectionsandBiosafety.ClinicalMicrobiologyReviews.1995;8(3):p.398405.

154. GershonAA.MeaslesVirus(Rubeola).InMandellG,DouglasR,BennettJ,editors.PrinciplesandPracticeofInfectiousDiseases.3rd

ed.NewYork:ChurchillLivingstone;1990.p.1279.

155. ReddS,MarkowitzE,KatzS.Measlesvaccine.InPlotkinSA,OrensteinWA,editors.Vaccines.3rded.Philadelphia:Saunders;1999.p.

222266.

156. MusserSJ,UnderwoodGE,WeedSD,OssewaardeJL.StudiesonMeaslesVirus.II.PhysicalPropertiesandInactivationStudiesof

MeaslesVirus.JournalofImmunology.1960;85:p.292297.

157. DowdleW,vanderAvoortH,deGourvilleE,DelpeyrouxF,DesphandeJ,HoviT,etal.Containmentofpoliovirusesaftereradication

andOPVcessation:characterizingriskstoimprovemanagement.RiskAnalysis.2006;26(6):p.14491469.

158. NorrbyE,OxmanMN.MeaslesVirus.InFieldsBN,KnipeDM,ChanockR,HirschMS,LMJ,PMT,etal.,editors.Virology.2nded.New

York:RavenPressLtd;1990.p.10131044.

159. HatchTF.Distributionanddepositionofinhaledparticlesintherespiratorytract.BacteriologicalReviews.1961;25:p.237240.

160. DamonSC.DecreaseofPolynesianRaces.TheFriend.1849;7(3):p.20.

161. LeeWS.TheIslandNewYork:Holt,RinehartandWinston;1966.

162. ThrumTG.HawaiianEpidemics.InThrumTG,editor.HawaiianAlmanacandAnnual.Honolulu:PressPublishingCompany;1897.p.

97.

163. MumfordEP,MohrJL.ManualontheDistributionofCommunicableDiseasesandTheirVectorsintheTropics,PacificIslandsSection,

PartI.SupplementtoAmericanJournalofTropicalMedicine.1944;24:p.126.

164. HirschA.Handbookofgeographicalandhistoricalpathology.In.London:NewSydenhamSociety;1983.p.154170.

165. CorneyBG.ANoteonanEpidemicofMeaslesatRotuma,1911.ProceedingsoftheRoyalSocietyforMedicine.1913;6:p.138142.

166. SimmonsJS,WhayneTF,AndersonGW,HorackHM.PartTwo,ThePacificArea.InGlobalEpidemiology. Philadelphia:JBLippincottCo.;1944.p.264and437.

167. EnrightJR.SeasonalIncidenceofCommunicableDiseasesinHawaii.TheHawaiiHealthMessenger.1949.

168. BabbotFL,GordonJE.ModemMeasles.AmericanJournalofMedicalSciences.1954;228:p.334361.

169. CentersforDiseaseControlandPrevention.EmergencyPreparednessandResponse.[Online].;2007[cited2010June10.Available

from:HYPERLINK"http://www.bt.cdc.gov/bioterrorism/overview.asp" http://www.bt.cdc.gov/bioterrorism/overview.asp .

170. RotzLD,KhanAS,LillibridgeSR,OstroffSM,HughesJM.Publichealthassessmentofpotentialbiologicalterrorismagents.Emerging

InfectiousDiseases.2002;8(2):p.225230.


31/31


171. DowdleWR,WolffC,SandersR,LambertS,BestM.Willcontainmentofwildpoliovirusinlaboratoriesandinactivatedpoliovirus

vaccineproductionsitesbeeffectiveforglobalcertification?BulletinoftheWorldHealthOrganization.2004;82(1):p.5962.

172. WorldHealthOrganization.WHOglobalactionplanforlaboratorycontainmentofwildpolioviruses.Geneva:WorldHealth

Organization,VaccinesandBiologicals;1999.ReportNo.:WHO/V&B/99.32.

173. WorldHealthOrganization.WHOglobalactionplanforlaboratorycontainmentofwildpolioviruses.Secondedition.Geneva:World

HealthOrganization,VaccinesandBiologicals;2004.ReportNo.:WHO/V&B/03.11.

174. WorldHealthOrganization.Laboratorybiosafetymanual.3rded.Geneva:WorldHealthOrganization;2004.

175. PtzMM,BoucheFB,deSwartRL,MullerCP.Experimentalvaccinesagainstmeaslesinaworldofchangingepidemiology.

InternationalJournalforParasitology.2003;33(56):p.525545.

176. GriffinDE,PanCH.Measles:oldvaccines,newvaccines.CurrentTopicsinMicrobiologyandImmunology.2009;330:p.191212.

177. AylwardRB,SutterRW,CochiSL,ThompsonKM,JafariH,HeymannD.Riskmanagementinapoliofreeworld.RiskAnalysis.2006;

26(6):p.14411448.

178. FinePE,RitchieS.Perspective:determinantsoftheseverityofpoliovirusoutbreaksintheposteradicationera.RiskAnalysis.2006;

26(6):p.15331540.

179. SangrujeeN,DuintjerTebbensRJ,CceresVM,ThompsonKM.Policydecisionoptionsduringthefirst5yearsfollowingcertif ication

ofpolioeradication.MedscapeGeneralMedicine.2003;5(4):p.35.

180. ThompsonKM,TebbensRJ,PallanschMA,KewOM,SutterRW,AylwardRB,etal.Therisks,costs,andbenefitsofpossiblefuture

globalpoliciesformanagingpolioviruses.AmericanJournalofPublicHealth.2008;98(7):p.13221330.

181. TebbensRJD,PallanschMA,AlexanderJP,ThompsonKM.Optimalvaccinestockpiledesignforaneradicateddisease:Applicationto

polio.Vaccine.2010;28:p.43124327.

182. TebbensRJD,PallanschMA,KewOM,CaceresVM,JafariH,CochiSL,etal.RisksofParalyticDiseaseDuetoWildorVaccineDerived

PoliovirusAfterEradication.RiskAnalysis.2006;26(6):p.14711505.

measles, morbili

Documents

askep morbili

morbili ppt

lapkas morbili

Laporan Morbili 1212

Untitled-1 [] dikenal juga sebagai Morbili atau Measles, ... Pada saat tertentu adanya peningkatan kasus di suatu wilayah ... di provinsi di Pulau Jawa pada Bulan Agustus

Lapsus Morbili

Morbili, Varicella Rubella

case morbili san

Refkas Morbili Dian

Pendahuluan morbili

Morbili Sent

morbili rin_024.ppt

Makalah Morbili

Jurnal Morbili Lp

Morbili ririn

morbili presentasi

Morbili Ferry

morbili ikhsan.ppt

MT Morbili

Laporan Kasus Morbili

Bab 2 Morbili

Refreshing Morbili April

Case Morbili Arin

Case 4 Morbili

CURRICULUM VITAE - pediatricfkuns.ac.id in children (Rustam Siregar).pdf · Morbili / Measles / Campak Sumber: “The Color Atlas of Pediatric, 2015” Sumber “Pediatric Practice

Slide Morbili lapkas dan laporan kasus pada pasien morbili

· PDF filePenyakit Campak dikenal juga sebagai Morbili atau Measles. ... Imunisasi Massal d Rubdla dib.ikan pada anak usia 9 bulan kuraeri 15 tahun

Morbili Fix

kasus morbili

Case Morbili Taufiq

morbili makalah

LAPORAN MORBILI

PPT Morbili

Case Morbili

Presus Morbili