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2/12/2015 Varicellavaccine

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Varicellavaccine

SummaryandconclusionsPublichealthimpactThepathogenImmuneresponseThejustificationforvaccinecontrolVaricellavaccinesVaccineassociatedadverseeventsContraindicationsforvaricellavaccinationWHOpositiononvaricellavaccinesAdministrationsummaryReferencesOtherusefullinks

Summaryandconclusions

Varicella(chickenpox)isanacute,highlycontagiousviraldiseasewithworldwidedistribution.Whilemostlyamilddisorderinchildhood,varicellatendstobemoresevereinadults.Itmaybefatal,especiallyinneonatesandinimmunocompromisedpersons.Varicellazostervirus(VZV),thecausativeagent,showslittlegeneticvariationandhasnoanimalreservoir.Followinginfection,thevirusremainslatentinneuralganglia,anduponsubsequentreactivationVZVmaycausezoster(shingles),adiseasemainlyaffectingtheelderlyandimmunocompromisedpersons.Althoughindividualcasesmaybepreventedormodifiedbyvaricellazosterimmuneglobulinortreatedwithantiviraldrugs,controlofvaricellacanbeachievedonlybywidespreadvaccination.VaricellavaccinesbasedontheattenuatedOkastrainofVZVhavebeenmarketedsince1974,andthepositiveresultsofextensivesafety,efficacyandcosteffectivenessanalyseshavewarrantedtheintroductionofthesevaccinesintothechildhoodimmunizationprogrammesofseveralindustrializedcountries.Afterobservationofstudypopulationsforperiodsofupto20yearsinJapanand10yearsintheUnitedStates,morethan90%ofimmunocompetentpersonswhowerevaccinatedaschildrenwerestillprotectedfromvaricella.

Informationconcerningseveralaspectsofvaricellavaccinationisstillincomplete.Thedurationofprotectionagainstvaricellaandzosterwithoutnaturalexposuretothevirus,theepidemiologicalimpactofchildhoodvaccinationatvariouslevelsofcoverage,and

http://www.who.int/selection_medicines/en/http://archives.who.int/vaccines/index.shtmlhttp://www.who.int/vaccines/es/indexspanish.htmhttp://archives.who.int/vaccines/en/aboutus.shtmlhttp://www.who.int/search/http://www.who.int/vaccines/http://www.who.int/http://www.who.int/vaccines/fr/indexfrench.htmhttp://www.who.int/vaccines-surveillance/StatsAndGraphs.htmhttp://www.who.int/medicines_technologies/textonly.shtmlhttp://www.who.int/vaccines-documents/http://archives.who.int/vaccines/sitemap.shtml



thezosterpreventiveeffectofvaccinationofadultsandelderlypeoplewithahistoryofvaricellaneedtobebetterunderstood.Furthermore,thereislittleinformationfromdevelopingcountriesonthediseaseburdenofvaricellaandzoster,andontheincidenceandimpactofsecondaryinfections.Itisunlikely,however,thatvaricellawillbeamongthepriorityvaccinepreventablediseasesinmostdevelopingregions.

Decisionmakersconsideringtheuseofvaricellavaccineinroutineimmunizationprogrammesmusttakeintoaccounttheepidemiologyandthepublichealthandsocioeconomicimpactofvaricellarelativetootherhealthconcernscompetingforscarceresources.Thefollowingrecommendationsreflectcurrentevidence,andarelikelytobemodifiedasadditionalinformationbecomesavailable.

Mostdevelopingcountrieshaveothervaccinepreventablediseasesthatcausesignificantlygreatermorbidityandmortality,andvaricellavaccineisnotahighpriorityforroutineintroductionintotheirnationalimmunizationprogrammes.Routinechildhoodimmunizationagainstvaricellamaybeconsideredincountrieswherethisdiseaseisarelativelyimportantpublichealthandsocioeconomicproblem,wherethevaccineisaffordable,andwherehigh(85%90%)andsustainedvaccinecoveragecanbeachieved.(Childhoodimmunizationwithlowercoveragecouldtheoreticallyshifttheepidemiologyofthediseaseandincreasethenumberofseverecasesinolderchildrenandadults.)Additionally,thevaccinemaybeofferedinanycountrytoindividualadolescentsandadultswithoutahistoryofvaricella,inparticulartothoseatincreasedriskofcontractingorspreadingtheinfection.Thisuseinadolescentsandadultsentailsnoriskofanepidemiologicalshift,aschildhoodexposuretoVZVremainsunaffected.

Publichealthimpact

Varicellaisahighlycommunicableviraldiseasewithworldwidedistribution.IntemperateclimatesoftheNorthernHemisphere,varicellaoccursmainlyintheperiodfromlatewintertoearlyspring.Secondaryattackratesreachcloseto90%insusceptiblehouseholdcontacts.Varicellazostervirus(VZV)isthecausativeagentandistransmittedbydroplets,aerosolordirectcontact,andpatientsareusuallycontagiousfromafewdaysbeforerashonsetuntiltherashhascrustedover.Onceacasehasoccurredinasusceptiblepopulation,itisveryhardtopreventanoutbreak.Assubclinicalinfectionisrare,thediseaseisexperiencedbyalmosteveryhumanbeing.Sometimes,mildclinicalinfectionsmaynotberecognizedormaybemisdiagnosed.Thus,intemperateregionsthemajorityofadultswithanegativehistoryforvaricellaareseropositivewhentested.

Intemperateclimatesmostcasesoccurbeforetheageof10.Theepidemiologyislesswellunderstoodintropicalareas,wherearelativelylargeproportionofadultsinsomecountriesareseronegative.Varicellaischaracterizedbyanitchy,vesicularrash,usuallystartingonthescalpandface,andinitiallyaccompaniedbyfeverandmalaise.Astherashgraduallyspreadstothetrunkandextremities,thefirstvesiclesdryout.Itnormallytakesabout710daysforallcruststodisappear.

Althoughvaricellaisusuallyabenignchildhooddisease,andrarelyratedasanimportantpublichealthproblem,thecoursemayoccasionallybecomplicatedbyVZVinducedpneumoniaorencephalitis,sometimesresultinginpersistentsequelaeordeath.Disfiguringscarsmayresultfromsecondarybacterialinfectionsofthevesicles,andnecrotizingfasciitisorsepticaemiamayoccurfromsuchinfections.InCanadaandtheUnitedStates,invasivegroupAstreptococcalinfectionscomplicatingvaricellahavebeendescribedwithincreasedfrequency.OtherseriousmanifestationsincludeVZV



inducedpneumonitis(morecommonlyinadults),therarecongenitalvaricellasyndrome(causedbyvaricelladuringthefirst20weeksofpregnancy)andperinatalvaricellaofnewbornswhosemothersdevelopchickenpoxfromfivedaysbeforedeliveryto48hoursafterwards.Inpatientssufferingfromimmunodeficiencies,includingHIVinfection,varicellatendstobesevereandzostermayberecurrent.Severeandfatalvaricellamayalsooccuroccasionallyinchildrentakingsystemicsteroidsfortreatmentofasthma.Ingeneral,complicationsaswellasfatalitiesfromvaricellaaremorecommonlyobservedinadultsthaninchildren.Casefatalityratios(deathsper100000cases)inhealthyadultsare3040timeshigherthanamongchildrenfivetonineyearsofage.Hence,ifavaccinationprogrammeisundertaken,itisimportanttoensurehighvaccinationcoverageinorderthatpreventionprogrammesdonotcausechangesintheepidemiologyofvaricellaresultinginhigherincidenceratesinadults.

Inabout10%20%ofthecases,varicellaisfollowedlaterinlifebyherpeszoster,orshingles,apainfulvesicularrashwithdermatomaldistribution.Mostcasesofzosteroccuraftertheageof50orinimmunocompromisedpersons.ItisarelativelycommoncomplicationinHIVpositivepersons.Zostermayoccasionallyresultinpermanentneurologicaldamagesuchascranialnervepalsiesandcontralateralhemiplegia,orinvisualimpairmentfollowingzosterophthalmia.Nearly15%ofzosterpatientshavepainorparasthesiasintheaffecteddermatomeforatleastseveralweeksandsometimespermanently(postherpeticneuralgia).Disseminated,sometimesfatalzostermayoccurinpatientssufferingfrommalignancies,AIDSorotherconditionsassociatedwithimmunodeficiency.TransmissionofVZVfromzosterpatientsmaycausevaricellainnonimmunecontacts.

Thepathogen

VZVisadoublestrandedDNAvirusbelongingtotheherpesvirusfamily.Onlyoneserotypeisknown,andhumansaretheonlyreservoir.VZVentersthehostthroughthenasopharyngealmucosa,andalmostinvariablyproducesclinicaldiseaseinsusceptibleindividuals.Theincubationperiodisusually1416(1021)days.Followingvaricella,theviruspersistsinsensorynerveganglia,fromwhereitmaylaterbereactivatedtocausezoster.Serumantibodiesagainstviralmembraneproteinsandglycoproteinsareutilizedindiagnostictests,butarelessreliableascorrelatesofimmunity,particularlytozoster.Aswithotherhumanherpesviruses,nucleosideanaloguessuchasacyclovirinhibitthereplicationofVZV,althoughlessefficientlythaninthecaseofHerpessimplex.

Immuneresponse

Naturalinfectioninduceslifelongimmunitytoclinicalvaricellainalmostallimmunocompetentpersons.Newbornbabiesofimmunemothersareprotectedbypassivelyacquiredantibodiesduringtheirfirstmonthsoflife.Temporaryprotectionofnonimmuneindividualscanbeobtainedbyinjectionofvaricellazosterimmuneglobulinwithinthreedaysofexposure.TheimmunityacquiredinthecourseofvaricellapreventsneithertheestablishmentofalatentVZVinfection,northepossibilityofsubsequentreactivationaszoster.Althoughantibodyassaysareconvenientlyusedasanindicationofpreviousinfectionorresponsetovaccination,failuretodetectantibodiesagainstVZVdoesnotnecessarilyimplysusceptibility,asthecorrespondingcellmediatedimmunitymaystillbeintact.Ontheotherhand,about20%ofpersonsaged5565shownomeasurablecellmediatedimmunitytoVZVinspiteofpersistingantibodies,andahistoryofpreviousvaricella.ZosteriscloselycorrelatedtoafallinthelevelofVZVspecificTcells,andanepisodeofzosterwillreactivatethespecificTcellresponse.



Thejustificationforvaccinecontrol

Exceptforvaccination,nocountermeasuresarelikelytocontrolthedisseminationofvaricellaorthefrequencyofzosterinasusceptiblecommunity.Varicellazosterimmuneglobulinandantiherpesviraldrugsareverycostly,andmainlyappliedforpostexposureprophylaxisorthetreatmentofvaricellainpersonsathighriskofseveredisease.Duetoitsextremelycontagiousnature,varicellaisexperiencedbyalmosteverychildoryoungadultintheworld.Eachyearfrom1990to1994,priortoavailabilityofvaricellavaccine,about4millioncasesofvaricellaoccurredintheUnitedStates.Ofthesecasesapproximately10000requiredhospitalizationand100died.Althoughvaricellaisnotcommonlyperceivedasanimportantpublichealthproblem,thesocioeconomicconsequencesinindustrializedcountriesofadiseasethataffectspracticallyeverychildandcausesthecarertobeabsentfromworkshouldnotbeunderestimated.

Therecentlymarketedvaricellavaccineshavebeenshowntobesafeandeffective.Fromasocietalperspective,arecentcostbenefitanalysisintheUnitedStatesshowedthatroutinechickenpoxvaccinationislikelytosavefivetimestheinvestment.Evenwhenonlydirectcostswereconsidered,benefitsalmostbalancedthecosts.Similarstudiesfromdevelopingcountriesarenotavailable.However,thesocioeconomicaspectofvaricellaislikelytobeoflessimportanceincountrieswithadifferentsocialorganization.Ontheotherhand,thepublichealthimpactofvaricellaandzostermaybeincreasinginregionswithhighratesofHIVendemicity.

Itisnotyetsufficientlydocumentedthatthevaricellavaccine,administeredeitherinchildhoodorinadultpopulations,willprotectagainstzoster.However,severalindications,includingtheresultsofvaccinationstudiesincertainimmunodeficientgroups,areencouraginginthisregard.Thepublichealthaswellasthesocioeconomicimpactofthisvaccinewouldincreasedrasticallyifitwasprovedtoprotectagainstzosterinthegeneralpopulation.Inindustrializedcountriesconsiderableamountsarespentonmedicalcareincomplicatedcasesofzosterinimmunocompromisedorelderlypersons,andtheincreasingincidenceofzosterinHIVaffectedareasiswelldocumented.

Varicellavaccines

ThecurrentlymarketedvaricellavaccinesarebasedonthesocalledOkastrainofVZV,whichhasbeenmodifiedthroughsequentialpropagationindifferentcellcultures.Variousformulationsofsuchlive,attenuatedvaccineshavebeentestedextensivelyandareapprovedforuseinJapan,theRepublicofKorea,theUnitedStatesandseveralcountriesinEurope.Someformulationsareapprovedforuseatninemonthsofageandolder.

Followingasingledoseoftheabovementionedvaccines,seroconversionisseeninabout95%ofhealthychildren.Fromalogisticaswellasanepidemiologicalpointofview,theoptimalageforvaricellavaccinationis1224months.InJapanandseveralothercountriesonedoseofthevaccineisconsideredsufficient,regardlessofage.IntheUnitedStates,twodoses,fourtoeightweeksapart,arerecommendedforadolescentsandadults,inwhom78%werefoundtohaveseroconvertedafterthefirst,and99%aftertheseconddoseofthevaccine.Childrenbelow13yearsofagereceiveonlyonedose.

Smallstudies,usingformulationsdifferenttothatcurrentlylicensedintheUnitedStates,showthatwhenthevaccineisadministeredwithinthreedaysafterexposuretoVZV,apostexposureprotectiveefficacyofatleast90%maybeexpected.Varicellain



personswhohavereceivedthevaccine("breakthroughvaricella")issubstantiallylessseverethanthediseaseinunvaccinatedindividuals.Furtherstudiesareneededtoclarifythepostexposureefficacyofthecurrentlylicensedproduct,especiallyinoutbreaksituations.

Whengivenatseparatesitesandwithseparatesyringes,simultaneousvaccinationofvaricellawithothervaccinesisassafeandimmunogenicaswhenthevaccinesaregivenatintervalsofseveralweeks.However,inordertoinducethesameimmuneresponseasthemonovalentvaricellavaccine,thedoseofthevaricellacomponenthadtobeincreasedwhenincludedinatetravalentvaccinewiththecombinedmeaslesmumpsrubellavaccine.Amultivalentvaccineisnotyetlicensed.

AsjudgedfromtheJapaneseexperience,immunitytovaricellafollowingvaccinationlastsforatleast1020years.IntheUnitedStates,childhoodvaccinationagainstvaricellaprovides70%90%protectionagainstinfection,andmorethan95%protectionagainstseveredisease710yearsafterimmunization.Frominvestigationofavaricellaoutbreakinadaycarecentre,postlicensureefficacywasfoundtobe100%inpreventingseverediseaseand86%inpreventingalldisease.Theattackrateinunvaccinatedsusceptiblechildrenwas88%.Itislikely,butasyetnotproved,thatsomeprotectionisalsoachievedagainstzoster.However,inJapanaswellasintheUnitedStates,thevaccinecoverageinthepopulationisquitelimited,andthecontinuedcirculationofwildtypeVZVislikelytocausepostvaccinationboosting.Hence,thelongtermprotectioninducedbythevaccinealoneisdifficulttoassessatthistime.

Inimmunocompromisedpersons,includingpatientswithadvancedHIVinfection,varicellavaccinationiscurrentlycontraindicatedforfearofdisseminatedvaccineinduceddisease.VaccinesafetyishoweverbeingevaluatedinasymptomaticHIVinfectedchildrenwithCD4countsofmorethan1000,andakilledvaricellavaccinehasbeenstudiedinVZVpositivebonemarrowtransplantpatientswhereamultipledoseschedulehasbeenshowntoreducetheseverityofzoster.Furthermore,incarefullysupervisedtrials,patientswithleukaemiainremissionorsolidtumoursbeforechemotherapy,anduraemicpatientswaitingfortransplantation,havereceivedthevaccine.Inmostcases,onetotwodosesresultedinhighratesofprotection,withonlymoderatesideeffects.Asignificantreductionintherateofzosterhasalsobeenrecordedinthesepatients.

Vaccineassociatedadverseevents

Inhealthychildrentheadverseeffectsofthevaccinationarelimitedtosomelocalswellingandrednessatthesiteofinjectionduringthefirsthoursfollowingvaccination(27%),andinafewcases(fewerthan5%)thevaccineesexperienceamildvaricellalikediseasewithrashwithinfourweeks.Inaplacebocontrolledstudyinvolving900healthychildrenandadolescents,painandrednessatthesiteofvaccinationweretheonlydocumentedadverseeventsfollowingvaccination.Thevaccinewassimilarlywelltoleratedbyalreadyimmunepersonswhowereinadvertentlyimmunized.Rareoccasionsofmildzosterfollowingvaccinationshowthatthecurrentlyusedvaccinestrainsmayinducelatency,withthesubsequentriskofreactivation.Sincelicensureanddistributionofmorethan10milliondosesofvaccineintheUnitedStates,theVaccineAdverseEventReportingSystem(VAERS)hasreceivedreportsofencephalitis,ataxia,pneumonia,thrombocytopenia,arthropathyanderythemamultiformeoccurringaftervaccination.Theseeventsmaynotbecausallyrelatedandtheyoccuratmuchlowerratesthanfollowingnaturaldisease.

Contraindicationsforvaricellavaccination

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Theseincludeahistoryofanaphylacticreactionstoanycomponentofthevaccine(includingneomycin),pregnancy(duetotheoreticalrisktothefetuspregnancyshouldbeavoidedforfourweeksfollowingvaccination),ongoingsevereillness,andadvancedimmunedisordersofanytype.Exceptforpatientswithacutelymphaticleukaemiainstableremission,ongoingtreatmentwithsystemicsteroids(foradultsmorethan20mg/day,forchildrenmorethan1mg/kg/day)isconsideredacontraindicationforvaricellavaccination.Ahistoryofcongenitalimmunedisordersinclosefamilymembersisarelativecontraindication.Fortunately,bothvaricellazosterimmuneglobulin(VZIG)andantiviraldrugsareavailableshouldpersonsintheimmunocompromisedcategoriesreceivethevaccinebymistake.Administrationofblood,plasmaorimmunoglobulinlessthanfivemonthsbeforeimmunizationorthreeweeksafterwardsislikelytoreducetheefficacyofthevaccine.DuetothetheoreticalriskofReyesyndrome,theuseofsalicylatesisdiscouragedforsixweeksfollowingvaricellavaccination.

WHOpositiononvaricellavaccines

ThecurrentvaricellavaccinesseemtomeettheaboveWHOguidelinesasfarastheiruseinindustrializedcountriesisconcerned.However,fromtheglobalperspective,therearelimitationsintermsofpriceandstorage.Forexample,oneofthecurrentlyavailablevaccinesrequiresstorageat15Candusewithin30minutesofreconstitution.

Thelikelihoodthateverychildwillcontractvaricella,combinedwithasocioeconomicstructurethatimplieshighindirectcostsforeachcase,makevaricellarelativelyimportantinindustrializedcountrieswithtemperateclimates.Routinechildhoodvaccinationagainstthisdiseaseisestimatedtobecosteffectiveinsuchareas.Limitedseroprevalencestudieshavesuggestedthatsusceptibilitytovaricellaismorecommonamongadultsintropicalthanintemperateclimates.Thus,fromthepublichealthpointofview,varicellacouldprovetobemoreimportantintropicalregionsthanpreviouslyassumed,inparticularinareaswhereHIVishighlyendemic.Theimpactofvaricellaintheglobalcontextrequiresfurtherinvestigation.Ontheotherhand,inmostdevelopingcountries,othernewvaccines,includinghepatitisB,rotavirus,aswellasconjugatedHibandpneumococcalvaccines,havethepotentialforamuchgreaterpublichealthimpact,andshouldthereforebegivenpriorityovervaricellavaccines.Hence,atthepresenttimeWHOdoesnotrecommendtheinclusionofvaricellavaccinationintotheroutineimmunizationprogrammesofdevelopingcountries.

Varicellavaccinemaybeusedeitheratanindividualleveltoprotectsusceptibleadolescentsandadults,oratapopulationlevel,tocoverallchildrenaspartofanationalimmunizationprogramme.Vaccinationofadolescentsandadultswillprotectatriskindividuals,butwillnothaveasignificantimpactontheepidemiologyofthediseaseonapopulationbasis.Ontheotherhand,extensiveuseasaroutinevaccineinchildrenwillhaveasignificantimpactontheepidemiologyofthedisease.Ifsustainedhighcoveragecanbeachieved,thediseasemayvirtuallydisappear.Ifonlypartialcoveragecanbeobtained,theepidemiologymayshift,leadingtoanincreaseinthenumberofcasesinolderchildrenandadults.Hence,routinechildhoodvaricellaimmunizationprogrammesshouldemphasizehigh,sustainedcoverage.

Althoughobservationsinselectedimmunodeficientgroupsindicatethatchildhoodvaricellavaccinationalsoreducestheriskofzoster,theperiodofobservationsinceintroductionofthevaccineistooshorttopermitfirmconclusionsaboutitszosterpreventiveeffectinthegeneralpopulation.Moreover,carefullyconductedvaccinationstudiesinadultsandtheelderlyarerequiredbeforerecommendationsmaybemadeconcerningtheuseofvaricellavaccinesforthepreventionofzosterinthoseagegroups.

Recommendationsonpossibleuseofthisvaccineforpersonsincertainstatesofimmunodeficiencyarebeyondthescopeofthisarticle.Adviceisprovidedbyseveral



expertpanelssuchastheAdvisoryCommitteeonImmunizationPractices(ACIP)intheUnitedStates.

ThischapterwaslastpublishedasaWHOpositionpaper:Varicellavaccines:WHOpositionpaper.WeeklyEpidemiologicalRecord,1998,73:241248,andontheInternetathttp://www.who.int/wer/pdf/1998/wer7332.pdf.

Administrationsummary

Typeofvaccine

Numberofdoses

Schedule

Contraindications

Adversereactions

Specialprecautions

Liveattenuatedvirus,Okastrain

Onedoseforpersonsagedunder13yearstwodosesinadolescentsandadultsfourtoeightweeksapart,subcutaneous

1224monthsofageforearlychildhoodimmunization*

Pregnancyreactiontopreviousdose(includingreactiontoacomponentsuchasgelatin)anyadvancedimmunedisorderorcellularimmunedeficiencysymptomaticHIVinfectionsevereillness

Mildlocalreactionmildillnesswithrash

Bewareofconfusionbetweenvaccineandvaricellazosterimmuneglobulin

*Notrecommendedfordevelopingcountries

Keyreferences

AmericanAcademyofPediatrics,CommitteeonInfectiousDiseases.Varicellavaccineupdate.Pediatrics,2000,105:136141.

CentersforDiseaseControlandPrevention.Preventionofvaricella.UpdaterecommendationsoftheAdvisoryCommitteeonImmunizationPractices.MorbidityandMortalityWeeklyReport,1999,48:RR6.

CentersforDiseaseControlandPrevention.OutbreakofinvasivegroupAstreptococcusassociatedwithvaricellainachildcarecenterBoston,Massachusetts,1997.MorbidityandMortalityWeeklyReport,199746:944948.

CentersforDiseaseControlandPrevention.Preventionofvaricella.RecommendationsoftheAdvisoryCommitteeonImmunizationPractices(ACIP).MorbidityandMortalityWeeklyReport,1996,45(RR11):137.

EndersG,MillerE,CradockWatsonJ,etal.Consequencesofvaricellaandherpeszosterinpregnancy:prospectivestudyof1739cases.Lancet,1994,343:15481551.

WiseRP,SalivaME,BraunMM,TerraccianoMootreyG,SewardJF,RiderLG,KrausePR.Postlicensuresafetysurveillanceforvaricella.JournaloftheAmericanMedicalAssociation,2000,284:12711279.

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