pneumococcal conjugate vaccine (pcv) product assessment€¦ · pneumococcal conjugate vaccine...
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PneumococcalConjugateVaccine(PCV)ProductAssessment April2017
OliviaCohen
Contact:KateO’Brien,MD,MPHExecutiveDirector,IVACJohnsHopkinsBloombergSchoolofPublicHealth415N.WashingtonStreet,Room563Baltimore,MD21231(240)[email protected]
AlternateContact:OliviaCohen,MPH
ResearchProgramCoordinator+41(0)[email protected]
Authoredby:InternationalVaccineAccessCenter
OliviaCohen,MSPHMariaKnoll,PhD
KateO’Brien,MD,MPHMeenaRamakrishnan,MD,MPH
DagnaConstenla,PhDLoisPrivor-Dumm&JulieBuss-Younkin
U.S.CentersforDiseaseControl JenniferFarrar,MPH
TamaraPilishvili,PhD,MPH CynthiaWhitney,MD,MPH
UniversityCollegeofLondon DavidGoldblatt,MB.ChB,MCRP,PhD
AgencedeMédecinePréventiveJenniferMoisi,PhD,MPH
WorldHealthOrganizationMonicadeCola,MPHThomasCherian,MD
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PCVProductAssessment
PrefaceThistechnicaldocumentprovidessummaryinformationregardingpneumococcalconjugatevaccine(PCV)products.Itsynthesizestheepidemiologicandbiologicevidenceaswellastheprogrammaticconsiderationssurroundingperformance,effectiveness,andimpactforcurrentPCVs:10-valent(PCV10)and13-valentproducts(PCV13).Theavailabilityofmultiplepneumococcalvaccines,withoverlappingbutnon-identicalcharacteristics,includingformulation,poseschallenges.Thereisaneedforcomprehensivedecision-makingframework,inclusiveofevidence-basedanalysesonproductperformance;todeterminewhichPCVproductsmaybestsuitdifferentcontextsincludingconsiderationsofsupply,logistics,price,coldchainrequirements,programimpact,andvendorcharacteristics.Theneedforsuchadecision-makingframework,populatedbyunbiasedevidencewillincreaseasadditionalpneumococcalvaccinesbecomelicensedandavailableforuse,increasingthecomplexityofproductchoices.ThisaddressesapressingpriorityforGavi,theWorldHealthOrganization(WHO),andcountriesonoptimizingandsustainingPCVuse.ThisdocumentprovidestechnicalinformationfromreviewoftechnicalandprogrammaticevidencethatmayhelpcountriesmakePCVproductchoicesandshouldnotbeviewedasformalWHOrecommendationsasithasnotyetundergoneformalWHOguidelinereview.ThedocumentwasdevelopedwithdirectsupportofGavifunds,andleveragedtheinfrastructureofthePCVReviewofImpactEvidence(PRIME)supportedbytheGatesFoundation.Materialsthatcanbeusedtoinformproductswitchesincludingthisdetailedtechnicalsummary:1. WHOPCVPositionPaper,2012(http://www.who.int/wer/2012/wer8714.pdf?ua=1)2. WHOConsiderationsforPCVProductChoice,2017(AvailablethroughWHORegionalandCountryOffices)3. WHOOperationalGuidanceonPCVProductSwitches,2017(AvailablethroughWHOCountryOffice)4. GaviFrequentlyAskedQuestions(FAQ)onPneumococcalConjugateVaccine(PCV)4-dosevial
presentations,2017(http://www.gavi.org/library/gavi-documents/guidelines-forms/)ThetechnicalevidenceprovidedinthisdocumentcomesfromacomprehensivereviewofpublisheddataonPCVimmunogenicityanddiseaseeffectivenessandimpactoflicensedPCVproducts(PCV10andPCV13)usedin3-doseschedules(2+1and3+0).Evidencefrombothobservationalstudiesandclinicaltrialsisincluded.Evidencereportingchangesindiseaseincidence(pre-andpost-PCVintroduction)wasprioritizedforsectionsonPCVeffectivenessandimpact.Caseseriesdataandstudiesprovidingdiseaseinformationfromonlythepost-PCVerainsectionswherethereisotherwiseseveredatapaucity,andotherwisearenotincluded.AsystematicevaluationofPCVproducts(i.e.allevidenceavailable,includingunpublisheddata)isunderwaytoinformthepolicyreviewprocessunderwaybytheStrategicAdvisoryGroupofExpertsonImmunization(SAGE)PCVWorkingGroup.Theresultsofthatevaluationwillbeusedtoupdatethesummariesalreadyincludedinthisreportandtoprovideadditionalanalyses.Thisincludesinformationnotpresentedhere,suchas:un-publisheddatafromsurveillancesites;4-,2-,and1-dosevaccineschedules;otitismedia;andpost-onlydata.Whatisthepurposeofthisdocument?• ToassistGaviinmakinginformeddecisionsaboutPCVproductrequests(includingswitches)bycountries• ToassistcountriesinmakinginformeddecisionsaroundPCVproductchoiceandrequeststoGavi
Howcancountriesusethisdocument?
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• AsatechnicaltooltoinformPCVdecision-makingonproductchoiceatthetimeofintroductionandwithinestablishedPCVprograms
• Asaresourcetoreadilyaccesskeyevidence,dataandtoolsforPCVproductchoice
HowcanGaviusethisdocument?• AsatechnicaltooltoinformPCVdemandforecastsincludingsupplyplanningforcountryallocation• Asaresourcetoreadilyaccesskeyevidence,dataandtoolsforPCVproductchoice• AsaresourcetocreatecountryguidanceonPCVproductchoices
ProductChoiceConsiderationsThedocumentprovidesinformationthatshouldbeconsideredinaproductchoicedecisionbutdoesnotitselfprovideanyrecommendationforproductchoice.Thisdocumentprovidesspecificinformationaboutthetwocurrentlyavailable,licensedPCVproductsalongwithadviceabouttheconsiderationsacountryshouldweighinmakingaproductchoice.Theinformationherefocusesonpre-qualifiedandgloballymarketedPCVs(i.e.PCV10andPCV13,seeTable2forkeydescriptorsofproductcharacteristics)butdoesnotincludeasystematicreviewofevidencefrompreviouslymarketedproducts(i.e.PCV7),orinformationonunlicensedproductsofthepast(i.e.PCV9,PCV11),orthosethatarecurrentlyunderevaluation.Theinformationispresentedinaframeworkthatcanbeupdatedasnewevidenceonexistingproductsandnovelpneumococcalvaccineproductsbecomesavailable.Thedocumentisnotintendedastheprimarysourceofinformationtosupportdecision-makingaboutwhethertoincludePCVinthevaccineprogramorondosingschedules;comprehensivedocumentsareotherwiseavailableforthosedecisions[1-6].Decision-makersconsideringaPCVproductchoiceshouldweightheevidenceaimingtoassureaPCVprogramthatisoptimizedfordiseaseimpactandsustainability.Thatevidenceshouldincludeanunderstandingof:• Pneumococcaldiseaseepidemiology(includingpneumococcalserotypeconsiderations)• PCVperformance,and• PCVprogrammaticconsiderations(includingproductavailability,cost,coldchainrequirements,product
presentation,wastage,productadministrationandtrainingrequirements)• PCVproductsupply• FinancialconsiderationsofPCVproducts
Vaccineperformancecharacteristicsareusuallyonesforwhichalargeamountofdataareavailableonindividualproducts,butfewdataexistthatofferdirectproductcomparisons.MostdatacomefromPCVimpactevaluationsinroutineusesettings,andbytheirnaturemostoftenincludeonlytheassessmentofasingleproduct.ThePCVperformancemeasuresincludeimmunogenicity,efficacyagainstdiseaseandcolonization(i.e.vaccineimpactwhengiveninidealcircumstances),effectivenessagainstdiseaseandcolonization(i.e.vaccineimpactwhengiveninroutineusecircumstances),durationofprotection,ageofadministration,indirecteffects(i.e.effectsonthosewhoarenotimmunized),serotypecross-protection,serotypereplacement,andsafety.EvidenceonPCVimpactonpneumococcalcolonizationanddiseasefromroutineimmunizationprogramsettingsisessentialfordecision-makerstoconsider,sincethequestionbeingaskediswhatvaccinetoimplementintheroutineuseprogram.Notallquestionsnotedherehavesufficientevidencetodrawconclusions;wheredataaresparseornotavailable,thislimitationisnoted.However,thereisarobust,andrapidlygrowingbodyofPCVevidencefrombothtrialsandofobservationalstudiesinroutineusesettingsthatpolicy-makerscanrelyontomakeaninformedproductchoice.Todate,althoughthebulkofevidenceremainsfromhigh-incomesettings,thereissubstantialevidencefrommiddle-andlow-incomesettings.
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TableofContents
Preface...............................................................................................................................................................2ProductChoiceConsiderations.............................................................................................................................3
ListofAbbreviations.....................................................................................................................................5
1. Contextandbackground......................................................................................................................61.1 PCVlicensureandrecommendations.......................................................................................................61.2 Pneumococcaldiseaseandserotypeepidemiology............................................................................6
2. VaccinecharacteristicsofcurrentlylicensedPCVproducts...................................................82.1 Serotypesincludedinproducts..................................................................................................................82.2 CarrierProtein.................................................................................................................................................82.3 Therapeuticindications................................................................................................................................92.4 FormulationsforPCV10andPCV13..........................................................................................................92.5SafetyProfile.........................................................................................................................................................9
3. Performance&impact........................................................................................................................113.1 LiteratureReviewMethods.......................................................................................................................113.2 Immunogenicity............................................................................................................................................12ImmunogenicityBackground...............................................................................................................................12ImmunogenicityFindings......................................................................................................................................133.3 NasopharyngealCarriage..........................................................................................................................14NPCarriageFindings..............................................................................................................................................153.4 Pneumonia......................................................................................................................................................19PneumoniaFindings...............................................................................................................................................203.5 InvasivePneumococcalDisease..............................................................................................................24IPDFindings:.............................................................................................................................................................243.6 Mortality..........................................................................................................................................................29MortalityFindings...................................................................................................................................................303.7 IndirectEffectsofPCVs...............................................................................................................................30IndirectEffectFindings..........................................................................................................................................31
3.8 Serotypes3,6A,19A..........................................................................................................................333.9 MixedPCV10-PCV13Regimens................................................................................................................37
4. EconomicandfinancialconsiderationsforPCVproducts......................................................374.1EconomicconsiderationsforPCVproducts............................................................................................384.2FinancialconsiderationsforPCVproducts.............................................................................................39
5. ProgrammaticconsiderationsforavailablePCVproducts....................................................40ProgrammaticFindings:........................................................................................................................................405.1 RecommendedPCVdosingschedules...................................................................................................415.2 Numberofinjectionsperroutineimmunizationvisit.....................................................................415.3 Currentandfutureproductpackaging,presentation,coldchainandstorage.......................415.3.1CurrentPCVpresentations.........................................................................................................................................415.3.24-DoseVialPCVpresentations.................................................................................................................................42
5.4 Trainingandsupervisionrequirements..............................................................................................436. SupplyconsiderationsforavailablePCVproducts...................................................................436.1 Supplyavailability&constraints............................................................................................................44
AppendixA…………………………………………………………………………………………………………………....……….i-lxxxiAppendixB………………………………………………………………………………………………………………………………...a-k
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ListofAbbreviationsACIP USAdvisoryCommitteeonImmunizationPracticesAMC AdvancedMarketCommitmentAMR AntimicrobialresistanceCEA CostEffectivenessAnalysesCRM CorynebacteriumdiphtheriaDT DiphtheriatoxoidDTaP Diphtheria-Tetanus-acellularPertussisvaccineEMA EuropeanMedicinesAgencyFDA USFoodandDrugAdministrationGACVS GlobalAdvisoryCommitteeonVaccineSafetyGSK GlaxoSmithKlineGSP GlobalSerotypeProjectHib HaemophilusinfluenzaetypeBICER IncrementalCost-EffectivenessRatioIgG ImmunoglobulinGIPD InvasivePneumococcalDiseaseMDVP MultiDoseVialPolicyNP NasopharyngealNRA NationalRegulatoryAuthorityNTHi non-typeableHaemophilusinfluenzaeOPA OpsonophagocyticActivityPCV PneumococcalConjugateVaccinePCV10 10-valentPneumococcalConjugateVaccinePCV13 13-valentPneumococcalConjugateVaccinePCV7 7-valentPneumococcalConjugateVaccinePD ProteinDPQ Pre-QualificationRCTs RandomizedcontroltrialsSAGE StrategicAdvisoryGroupofExpertsonImmunizationsSTs SerotypesTPP TargetProductProfileTT Tetanustoxoid,VE VaccineEffectivenessVT VaccineTypesVVM VaccineVialMonitoringWHO WorldHealthOrganization
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1. Contextandbackground
1.1 PCVlicensureandrecommendationsTheUSFoodandDrugAdministration(FDA)licensedthefirstPCVproduct(PCV7)foruseininfantsin2000.ArecommendationforinclusionofPCVintheroutineinfantimmunizationschedulewasmadebytheUSAdvisoryCommitteeonImmunizationPractices(ACIP)inJuly2000,andwasimplementedintheUSlaterthatyear[7].Manycountriesthenlicensedandadopteditsuse.In2007,WHOadoptedapolicy,asrecommendedbySAGE,thatallcountriesshouldincludePCVaspartoftheroutineinfantimmunizationschedule[8];WHOpre-qualification(PQ)forPCV7wasissuedthesameyear.TheWHOrecommendationwasmadewithevidencefromtwolargephaseIIIefficacytrialsinAfrica(theGambiaandSouthAfrica)confirmingthegeneralizabilityofefficacybeyondthatobservedintrialsfromNorthAmericaandEurope.Sincethen,twoadditionalPCVproducts(PCV10andPCV13)havereceivedWHOPQ,bothofwhichincludemoreserotypesthanthosefoundinPCV7;PCV7wasreplacedbyPCV13andisnolongeronthemarket[1].WHOPQhasbeengrantedforPCV102-dosevialsandPCV131-doseand4-dosevials.TheavailabilityoftwolicensedPCVproducts,whichdifferinseveralways,meansthatcountrieswithPCVneedtomakeproductselectiondecisionsforintroductionormaintenanceofPCVvaccineprograms.Thesedecisionsarebasedonacombinationoffactorsthatfallintofivecategories,including:diseaseepidemiology,productperformance,programmaticneeds,supply,andfinancialconsiderations.
1.2 PneumococcaldiseaseandserotypeepidemiologyWHOcountryspecificandglobalburdenofdiseaseestimatesareavailablefrom2000,2008andwillsoonbereleasedfor2015[9-11].IntheabsenceofPCVuse,pneumococcaldiseaseistheleadingvaccinepreventablecauseofmortalityofinfancyandchildhood.Moreover,insettingswheremortalityishigh,pneumococcusisresponsibleforanevengreaterfractionofmortalityandmorbiditythaninlowermortalitysettings.Plainlystated,wheremanychildrendieininfancyandearlychildhood,pneumococcaldiseaseisamainculprit.Insettingswheremortalityiscontrolled,pneumococcaldiseasemaynotcausedeathbutitisaubiquitouspathogenthatcausespneumonia,bloodstreaminfectionsandmeningitisthatrequireimmediate,appropriatetreatment.Pneumococcaldisease,evenwhennotfatal,incurssubstantialfinancialtreatmentcoststofamiliesandtogovernmenthealthcaresystems,andcanincurlong-termhealthconsequencestochildrenwhosurvive(e.g.sequelaeofmeningitisandcompromisedlungfunctionamongthosewhohadpneumonia).HavingdecidedtointroducePCV,policy-makerswillbeawarethatPCVscontainonlyalimitednumberofthemorethan96pneumococcalserotypes,andthatimmunitytooneserotypedoesnotnecessarilyconferimmunitytoothers(i.e.thereislimitedcross-protectionamongserotypes,andalwayswithinaserogroup).However,sinceonlyasmallsubsetoftheseserotypesareresponsibleforthevastmajorityofdiseaseanddeaths,theyweretargetedforinclusioninPCVstorepresentthosefoundacrossallepidemiologicsettings[12].BothPCVproductsonthemarketareconsideredglobalproducts,appropriateforanycountrysetting.TheserotypedistributionofpneumococcaldiseasepriortoPCVusewassystematicallyevaluatedforallregions.ThePneumococcalGlobalSerotypeProject(GSP)providesaserotype-by-serotypeestimateofthefractionofdisease,bygeographicregion,amongchildrenunder5yearsofage(Table1)[13].ThisanalysisformedthebasisforthepneumococcalvaccineAdvancedMarketCommitment(AMC)stipulationthateligiblepneumococcalvaccinesmustaccountfor,ataminimum,60%ofdiseasecausingstrains,andincludeserotypes1,5and14[14].TherationaleforthestipulationthatPCVsshouldaccountforatleast60%ofdiseasewaslaidoutintheTargetProductProfile(TPP)document.Serotypes1and5arecommoncausesofpneumococcaldiseaseoutbreaks,andareparticularlycommoninAfricaandAsiansettings;andserotype14wasfoundtobethemostcommoninallregions.Notedalsowasthatthe10serotypescausingthemajorityofdiseaseinAfrica
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werethesameasthoseinAsia,suggestingmoresimilaritiesthandifferencesbetweenpopulations.Thissystematicassessmentofserotypescausingdiseaseisconsideredthereferencedocumentforcountries.Table1.Serotypedistributionofthetop20globalserotypescausinginvasivepneumococcaldisease,byregion,pre-PCVamongchildrenunder-5yearsofage
BeyondtheconsiderationofserotypescausingdiseasepriortotheintroductionofPCV,policy-makersmayconsiderseveralotherfactorsregardingproductselectionandserotypes:• Antimicrobialresistance(AMR):Someserotypesaremorecommonlyfoundamongstrainsthatexhibit
AMR.Thesearelargelythoseincludedinavailablevaccines,butshiftsinthisepidemiologyarepossible.• Non-PCV7serotypesincludingtypes3,6A,and19A:Thisdocumentprovidesaspecificsectiononthe
impactofbothPCV13andPCV10ontypes3,6A,and19A;theformerincludestheseserotypesinthevaccineformulationwhilethelatterreliesonthepossibilityofcross-protectionfrom6Bfor6A,and19Ffor19A.ThisissueisoftenraisedforconsiderationbecauseoftheexperiencewiththefirstgenerationPCV7.FollowingtheuseofPCV7,anincreaseinthediseaseincidenceofserotypesnotincludedinthevaccine(i.e.serotypereplacement)wasobserved,butthemagnitudeofthatincreasewassmallrelativetothereductionindiseaseincidencefromvaccinetypes(VT).Overall,therewasasubstantialnetreductioninpneumococcaldiseasewiththeuseofPCV7.However,onenon-PCV7serotype,19A,wasobservedtoincreaseinincidenceinmanycountries,andwasaserotypecommonlyassociatedwithAMR.AttentiontoevidenceforPCV10regarding19Ainparticularisafocusforsomedecision-makers.
• Countryspecificserotypedistribution:Mostcountrieshavefewifanystudiestoinformlocalserotypedistributionofpneumococcaldiseaseininfantsandyoungchildren.Evenwheresuchdataexist,therearemanyreasonswhytheymaybeanunreliablesourcetoestimatethelong-termaverageserotypedistributionandshouldnotbeasubstantialdrivingfactorofproductchoice.TheregionalserotypedistributionsprovidedbytheGSPareconsideredamorerobustreflectionofthediseasecausingserotype
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distributionratherthanlocalstudieswithsmallnumbersofisolates,whosedistributionmaybesubstantiallybiasedrelativetothetruediseasedistributioninthecountry.
2. VaccinecharacteristicsofcurrentlylicensedPCVproductsTwoPCVproductsarecurrentlylicensed,pre-qualifiedbyWHO,globallymarketedandavailablewithGavisupport:PCV10manufacturedbyGlaxoSmithKline(GSK),marketedasSynflorix,andPCV13manufacturedbyPfizerInc.,marketedasPrevenar-13.
2.1 SerotypesincludedinproductsAlloftheserotypesincludedinPCV10arealsoincludedinthePCV13product.ThethreeadditionaltypesfoundinPCV13aretypes3,6A,and19A.Table2illustratesthecomparisonofserotypesinthetwoproducts(additionaldetailsonproductsareprovidedinTable3).Thereissomeevidenceofcross-protectionby6Bfor6Aandby19Ffor19AforPCV10,whichisdiscussedspecificallyinSection3.7.Table2:SerotypesincludedinandspecificationsofPCV10andPCV13productformulations
Product
FormulationSpecifications
Serotype&CarrierProtein
1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F
PCV10
VialSize:2-doseand4-dose*Preservative:None
1μgPD 3μg
PD1μgPD 1μg
PD1μgPD
1μgPD
1μgPD
3μgTT 3μg
DT
1μgPD
PCV13
VialSize:1-doseand4-dose
Preservative:None(for1-dose); 2- phenoxyethanol for4-dose
2.2μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
4.4μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
2.2μgCRM
PD=proteinDfromnon-typeableHaemophilusinfluenzae(NTHi),CRM=Corynebacteriumdiphtheria,TT=tetanustoxoid,DT=diphtheriatoxoid*WHOPQisexpectedfromlate2017andimplementationfrom2018onwards
Serotypeincludedinthevaccinesome evidenceofcrossprotection
2.2 CarrierProteinTable2describesthecarrierproteinsusedforeachproduct.PCV13usesCRM197proteinastheproteincarrierforeachofthe13-serotypes.CRM197isanon-toxicproteinderivedfromCorynebacteriumdiphtheriae.ThisisthesamecarrierproteinfoundinseveralHaemophilusinfluenzaetypeB(Hib)-conjugatevaccines.PCV10usesproteinD(derivedfromNTHi)asthecarrierforeightoftheserotypeswhileoneserotype(type18C)areconjugatedtotetanustoxoidandanother(type19F)isconjugatedtodiphtheriatoxoidprotein.
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2.3 TherapeuticindicationsPCV10andPCV13werelicensedandpre-qualifiedonthebasisofimmunogenicitynon-inferioritytoPCV7,whichwaslicensedonthebasisofdemonstratedefficacyagainstinvasivepneumococcaldisease(IPD).SincethetimeoflicensurebothPCV10andPCV13havegainedapprovalforindicationsbeyondpreventionofIPD.
Eachcountryinwhichtheproductislicensedformarketingapprovesthelabelingforthatcountry.TheWHOPQlabelinglargelymirrorsthatoftheresponsiblenationalregulatoryauthority(NRA);forPCV13thisistheEuropeanMedicinesAgency(EMA),andPCV10thisistheFederalAgencyforMedicinesandHealthProductsinBelgium[15,16].
TheWHOPQhasapprovedthetwovaccinesforthefollowingindications:• PCV10:forIPD,pneumococcalpneumonia,andotitismedia,withlabellingbytheEMAandWHOPQthat
includesthepreventionofserotypes19A[16].• PCV13:forIPD,pneumococcalpneumonia,andotitismediacausedbythe13serotypesinthevaccine[15].
Contraindications,specialwarningsandprecautionsforuseareoutlinedintheproductlabelingdocumentsandrelatespecificallytothosewhohaveallergiestocomponentsinthevaccine.Therearenosubstantivedistinctionsbetweentheproducts[15,16].
2.4 FormulationsforPCV10andPCV13AdescriptionoftheformulationsandpackagingcharacteristicsisprovidedinTable3.
2.5SafetyProfileThesafetyprofilesofbothPCV10andPCV13havebeenreviewedbymultiplenationalregulatoryauthoritiesduringthelicensureprocesses,theWHOprequalificationprocess,andtheGACVS[17].Bothproductshaveaccruedextensivepost-marketingsafetysurveillancedataandbothareassessedashavingexcellentsafetyprofiles.Therearenoissuesdistinguishingoneproductfromanotherfromasafetyperspective.
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Table3:WHOPrequalified,andanticipatedPCVproductformulationanddetails[3,4][15,16]
PCV Serotypesincluded
Manu-fact.
Tradename
Carrierproteins
YearPQbyWHO
Avail.FromUNICEF
Wast-agerate
Storageconditions Packaging
Volumeperdose
VVM
PCV101-dosevial,
preserv-ativefree
1,4,5,6B,7F,9V,14,18C,19F,and23F
GSK Synfl-orix
ProteinDfrom
NTHi,TTandDT
2009 No 5%
2-8°C,donotfreeze.
Cartonsof1,10and100vials
57.7,11.5
and9.7cm3perdose
VVM30:quitestableunderhigh
temperatures
PCV102-dosevial,
preserv-ativefree
1,4,5,6B,7F,9V,14,18C,19F,and23F
GSK Synfl-orix
ProteinDfrom
NTHi,TTandDT
2009 Yes 10% 2-8°C,donotfreeze.Anopened2-dosevialshouldnot
bereturnedto
therefrigerator
aftervaccinationsessionorafter6hours,
whichevercomesfirst.
Cartonsof100vials
4.8cm3
perdose
VVM30:quitestableunderhigh
temperatures
PCV104-dosevial,
preserv-ative2-PE*
1,4,5,6B,7F,9V,14,18C,19F,and23F
GSK Synfl-orix
ProteinDfrom
NTHi,TTandDT
Expect-edinlate2017
Expect-edin2018
10% 2-8°C,donotfreeze.
Info.NotYet
Available
2.4cm3
perdose
VVM30:quitestableunderhigh
temperatures
PCV11-dosevial
PCV10typesplustypes3,6Aand19A
Pfizer Prevnar13,
Prevenar13
CRM197protein
2010 Yes 5% 2-8°C,donotfreeze
Cartonsof50vials
12cm3
perdose
VVM30:quitestableunderhigh
temperatures
PCV134-dosevial,
Preserv-ative2-PE*
PCV10typesplustypes3,6Aand19A
Pfizer Prevnar13,
Prevenar13
CRM197protein
2016 Yes 10% 2-8°C,donotfreeze
Cartonsof25and50
vials
3cm3
perdose
VVM30:quitestableunderhigh
temperatures
PQ=WHOprequalified
*2-phenoxyethanol
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3. Performance&impactPerformancefactorsthatdecision-makersshouldconsiderforproductchoicedecisionsincludethevaccine’simmunogenicity;diseaseefficacy,effectiveness,impact,anddurationofprotection;theageatwhichitcanbeadministeredorismosteffective;addedbenefits,suchasindirect(herd)immunityandcross-protectionagainstotherserotypes;andthevaccine’ssafetyprofile.ExistingWHOdocumentsdescribetheseperformancemeasures[2,18].ForPCVproductchoice,thefocusisondiseaseandnasopharyngeal(NP)colonizationimpactsinceultimatelythesearetheoutcomesofmostclinicalandpolicyrelevance.Thissectionsummarizestheavailableinformationonefficacyfromrandomizedcontroltrials(RCTs)andobservationalstudiesoneachPCVproduct,effectivenessandimpactofPCVproductsonNPcarriageanddiseaseoutcomesincludingonmortality.
3.1 LiteratureReviewMethodsAsystematicreviewof14databases(AppendixC)wasconductedtoincluderelevantdatapublishedinEnglishfromJanuary1,2010-October9,2015,andad-hocadditionsthroughJanuary2017.Inaddition,allrelevantcitationsincludedinthesystematicPCVdosinglandscapereview(1994-2010)werebroughtintothisanalysisanddocument[19].• TypesofStudies:
o Included:RCTs,non-randomizedtrials,andobservationalstudiesreportingpre(baseline)andpostvaccineintroductionincidenceratesfordiseaseoutcomes
o Excluded:Postonlyincidencedata(i.e.nocomparisonbetweentimepoints,vaccineproducts,ordosingschedulesmade)andcase-seriesdata(pre-postorpostonly)
• Outcomes:o Included:Mortality(all-causeandpneumonia/IPDspecific),IPD,pneumonia,NPcarriage,and
immunogenicitymeasuredbyImmunoglobulinG(IgG)antibodyconcentrationso Excluded:otitismedia,immunogenicitymeasuredbyopsonophagocyticactivity(OPA)oravidity
• ProductsandSchedules:o Included:PCV10orPCV13ineither2+1or3+0dosingschedules
§ o Excluded:StudiesevaluatingotherPCVproductsanddosingschedulesweregenerallyexcluded
• Deduplication:Familiesofstudiesthatpublisheddataonthesamepopulation(s)overtimewereidentifiedand‘deduplicated’sothatthemostrecent,comprehensivedatawasincludedtoallowformaximumtimeforPCVimpacttobeevaluated
o Aparentpaperwaschosenandcitedforfamiliesofstudieswithinfiguresandtables• Citations:
o AllincludedstudiesaredescribedinAppendixA.o Allstudiesthatwereexcludedbasedoninsufficientevidencetodrawreliableconclusionson
impactaredescribedinAppendixB.
Specificmethodsfordirecteffectssection:Atleast1yearofpre-PCVand1yearofpost-PCVdatawasrequiredforobservationalstudies.Specificmethodsforindirecteffectssection:Atleast3yearsofpost-introductiondatawererequiredtobeincludedintheindirecteffectsassessment.Studieshadtoreportonanagegroupthatonlyrepresentedindirecteffects,notamixofdirectandindirecteffects.
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3.2 ImmunogenicitySummarySerotypes(STs)commontoPCV10andPCV13• PCV10andPCV13arebothhighlyimmunogenicininfantsforthe10STtheyhaveincommon,forall
dosingschedulesevaluated,andwithorwithoutconcomitantDiphtheria-Tetanus-acellularPertussis(DTaP)vaccineadministration.AtleastoneimmunogenicitystudyisavailablefromeveryWHOregion.Thisevidenceincludes6head-to-headstudies,whichdirectlycomparePCV10toPCV13withinasinglepopulationandusingthesameprotocol.
ST3,6Aand19A• PCV13isimmunogenic(i.e.induceshighconcentrationsoffunctionalantibody)againstST3,6Aand19A,
thethreeadditionalserotypesinthatvaccinebutnotinPCV10.• PCV10inducesincreasesinfunctionalantibodyagainstST6Aand19Afollowingtheprimaryseries,
althoughtheproportionofchildrenachievingthecorrelateofefficacyislowerthanthatobservedininfantsreceivingPCV13.Afteraboosterdose,>70%ofPCV10vaccinatedinfantshaveantibodyconcentrationsabovetheefficacycorrelateforbothserotypesbuttheabsoluteconcentrationsremainlowerthaninPCV13-vaccinatedinfants.
o PCV10receivedapositiveopiniononcross-protectionagainst19Aonthebasisofimmunogenicitydataandpost-marketingsurveillanceofIPDincidenceinEurope[15,16].
• ThereisinsufficientevidencetoevaluatetheimmunogenicityofPCV10againstserotype3,aserotypenotincludedinthevaccine.
Modifiersofimmunogenicity• Thenumberofprimarydoses,ageatfirstdose,dosinginterval,ageatlastdose,geographicregion,and
DTaPco-administrationallinfluencePCVimmunogenicity,whenconsideredoneatatime(i.e.inunivariateanalyses).Sincethesevariablesinteractwitheachother,additionalmultivariableanalysesareneededtounderstandtheindependenteffectsofeachvariableontheimmuneresponse.
Regionalrepresentationofdata• PCV10immunogenicitydatawereavailablefromallregions,thoughonlyAsiaandEuropehadstudies
usinga2-doseprimaryschedule.PCV13immunogenicitydatawerenotavailableforAfricaorSouthAmericaanddidnotincludeany2-doseprimaryschedulestudiesforOceania.
ImmunogenicityBackgroundInsupportoftheclinicaldevelopmentofextended-valencyPCVs(i.e.thoselicensedafterPCV7),theWHOdevelopedguidancefortheuseofthevaccinesbasedontheimmunologicoutcomescomparinganovelPCVwithalicensedPCVproductinhead-to-headstudies.Animmunologicalcorrelateofefficacy(%ofsubjectswithserotypespecificIgGabove0.35mcg/mLfollowinga3doseprimaryserieswhenIgGismeasuredusingthePfizerassaywithout22Sadsorption;basedonimmunogenicitybridgingstudies,whenIgGismeasuredusingtheGSKassaythecorrelateofefficacyhasbeenestablishedas0.22mcg/mL)wasestimatedfromlargerandomizedcontrolledefficacytrialsfromthelate1990’sandearly2000’sof7-and9-valentPCVwhichdemonstratedefficacyagainstinvasivepneumococcaldisease.Thiscorrelateofefficacyisnotanindividualcorrelate---inotherwords,individualchildrenwhoseantibodylevelisabove0.35mcg/mLdonotnecessarilyhaveprotectionfromdisease----butinsteadwhenapopulationimmunizedwithanovelPCVresultsinaproportionofindividualswithantibodyconcentrationsabove0.35mcg/mLthatisnon-inferiortotheproportionamongapopulationimmunizedwithalicensedPCVabovethissamevalue,thenitisinferredthat
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thenewPCVwouldhaveshownsimilarefficacyagainstdiseasetothatofthelicensedPCVhaditbeentestedforthatoutcome.Ofnote,thiscorrelateofefficacyisnotserotypespecificbutwasinsteadinferredbasedonoverallefficacyagainstallserotypestogether.Forsomeserotypesthecorrelateofefficacyislikelylowerandforothershigherthan0.35mcg/mL.Thisimmunogenicitybasedlicensureprocesshasbeenacceptedworldwide,andusedtolicensePCV10andPCV13withoutefficacytrials.BecausePCV10andPCV13RCTimmunogenicitydataresultedinproductlicensure,bydefinitiontheimmunogenicityresultsshowednon-inferioritytoPCV7.HereourfocusisonnotonlytheRCTdatabutalsoupdatedimmunologicaldatageneratedinpost-licensureimmunogenicitystudiesspanningbothvaccineproducts,differentregionsoftheworldanddifferingimmunizationschedules.Thepurposeoftheimmunogenicitysectionistolinktheimmunogenicitydatatodiseaseimpactandvaccineeffectiveness(VE)dataandtofocusonanyserotypespecificnuancesorproductnuancesthatmightinformproductchoice.
ImmunogenicityFindingsTherewasstrongevidencetosupporttheimmunogenicityofPCV10andPCV13,inallregions,forbothimmunizationschedules:2-primarydoseswithaboosteratorafter9-monthsofage(2+1)and3primarydoses(3+0).Basedondatafrom57PCV10and41PCV13studygroups(AppendixA.Table21),wecaninferthatbothproducts:- Induceasatisfactoryimmuneresponseaftertheprimaryseriesforboth2-doseand3-doseprimary
schedules;- Whenadministeredina2+1schedule,demonstrateastrongresponsetotheboosterdose.Becauseboth
productsalsoshowedantibodywaningbetweentheprimaryseriesandtheboosterdose,thisboosterdosemaybeimportantforlongerdurationofprotection.
- Performwellacrossregions.Althoughthisreviewwasnotintendedtodirectlycompareproducts,inthesixstudiesthatdid,PCV13inducedhigherantibodyaftera2or3-doseprimaryseriestosomeserotypescommontobothproducts(1,5,7F,23F)butevidencewasmixedforotherserotypes(6B,14,19F)[20,21].However,ahigherantibodyleveldoesnotnecessarilymeanbetterprotection;whencomparingtheproportionsofsubjectsachievingthecorrelateofefficacy,thetwovaccineswereequivalentforatleast8ofthe10commonserotypes.Differencesinantibodyresponseswerealsoseenbeforeandaftertheboosterdose:beforetheboosterdose,PCV13vaccineeshadhigherantibodytosomeserotypes(14,19F),PCV10vaccineeshadhigherantibodytootherserotypes(1,6B,23F)andevidencewasmixedfortheremainingserotypes(5,7F)[22,23];(aftertheboosterdose,PCV13inducedhigherantibodyforfourserotypes(1,7F,14,19F)andresultsweremixedforothers(5,6B,23F)[22-24][20].Again,therewasnosignificantdifferencebetweenproductswhencomparingtheproportionsofsubjectswithaconcentrationofantibodyabovethecorrelateforefficacy.Forserotypes3,6A,and19A,thosethatareincludedinPCV13butnotinthePCV10formulation,PCV13washighlyimmunogenic,meetingalloftheevaluationcriterialistedabove(i.e.non-inferiority,boostingandinductionoffunctionalantibodies).ForPCV10,therewasinsufficientevidencetoevaluateimmunogenicityforserotype3,sinceitwasalmostnevertestedforinPCV10immunogenicitystudies,presumablybecauseofPCV10’slackofanantigenthatcouldhaveanimpactonserotype3antibodyconcentrations,eitherdirectlyorthroughcross-protection.However,afterprimaryvaccinationwithPCV10,>50%ofsubjectshadantibodyconcentrationsto6Aand19Athatwereabovetheefficacycorrelate(range22-79%for6Aand22-87%for19A,basedon26studyarms).Thepercentrespondersimprovedto85%aftertheboosterdose(range72-99%and74-96%,respectively).Evidenceofboostingofantibodiesto6Aand19Awasalsoreflectedinantibodyconcentrations,which
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increased5-6foldforeachofthetwoserotypescomparedtopost-primarylevels(basedonevidencefrom19studies).TheseimmunogenicitydatasuggeststhatPCV10maydemonstratecross-protectiontotype6Aand/or19Adisease/colonizationwhichisdiscussedfurtherinsections3.2(NPcolonization),3.4(IPD)and3.7(3,6Aand19A).TherearelimitedOPAdataonthefunctionalactivityofthecross-reactingantibodiesfollowingPCV10primaryorboosterimmunizationbutofthosepublishedpostboosterOPAresponsestoPCV10aresignificantlylowerthanthosefollowingPCV13boost.Sincecountrieswhoareconsideringproductchoicesarenotallusingthesamevaccineschedule,wecomparedtheimmunogenicityofdifferentPCVschedules,investigatingtheeffectofthenumberofprimarydoses,ageatfirstdose,intervalbetweenprimarydosesandageatlastdoseonantibodylevels,byproduct.WealsoexaminedimmunogenicitybyregionandamongsubjectswithandwithoutconcomitantDTaPvaccinationsincetheconcomitantuseofwhole-cellpertussisvaccinesappeartoenhancetheimmunogenicityofPCV.Keyinferencesfromtheseanalysesinclude:• Forbothproducts,atwo-doseprimaryschedule(most,butnotallstudies,with8-weeksbetweendoses)†
elicitsacomparablepost-primaryimmuneresponsetoathree-doseprimaryschedule,exceptforserotypes6Band23F,forwhichtwo-doseschedulesaresignificantlylessimmunogenicthanthree-doseschedules.Atthepre-boostertimepoint,therearenosignificantdifferencesinproportionofchildrenwithantibodiesabovethecorrelateofefficacybetweenschedulesforanyoftheserotypes,howevertheGMC‘sdiddifferbetweenschedules,forsomeserotypesforbothPCV13andforPCV10.
• Forbothproducts,post-dose3antibodylevelsarehigherforchildrenreceivinga2+1schedulethanthosereceivinga3+0scheduleformostserotypes.However,thisdoesnotleadtosignificantdifferencesintheproportionofsubjectswithantibodylevelsabovethecorrelateofefficacyandmaythereforenothaveimplicationsintermsofpreventionofclinicaldisease.
• ImmuneresponsestoPCV10andPCV13aregenerallyhigherinAfricaandAsiathaninotherregions.However,thisfindingmaybeconfoundedbythefactthatchildrenintheseregionsreceivewhole-cellratherthanacellularpertussisvaccineconcomitantlywithPCV,thelatterlackingtheadjuvanteffectassociatedwithconcomitantwP.
• ForPCV13,antibodyresponsestomostserotypesincreasewithageatfirstdose,intervalbetweendosesandageatlastdose,producingdifferencesinantibodyconcentrationspost-primaryseriesandpost-dose3.TheeffectsoftheageatimmunizationontheimmuneresponseappeartobelessmarkedforPCV10.
Futureanalysesincludingmoredatawillenabledevelopmentofmultivariablemodelstoclarifytheadjustedeffectsofeachofthesecovariatesontheimmuneresponseandassessifanyofthesefindingsdifferacrossthetwoproducts.Todateweseenoevidenceofoneproductperformingdifferentlyfromtheotherwithrespecttovaccineschedulechoices,intervalbetweendosesorageatfirstdose.
3.3 NasopharyngealCarriageSummary:ImpactonNPcarriageofVT:• SignificantreductioninVTNPcarriagewasseeninbothroutineusesettingsandinclinicaltrials,andfor
bothPCV10andPCV13,forboth2+1and3+0schedules(n=14PCV10andn=15PCV13studies).(AppendixA,Table1)
• Reductionswereobservedwithinayearofroutinevaccineuse(e.g.inthefirstyearofintroduction20-30%carriagecomparedto60-80%priortoPCVintroduction);however,maximumimpactoncarriageisnot
†Among41studyarmsincluded,35had8weeksbetweendoses1and2,4hadonly4weeksand2had4months.
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realizeduntilafterseveralyearsofuse(e.g.,after5yearsinonecountry,VTcarriagewasobservedtobe1-2%).
• TherateofdeclineofNPcarriageisaffectedbyvaccinecoverage,useofabooster,implementationofcatch-upschedules,andpre-PCVprevalenceofpneumococcalcarriage,forexampleincommunitieswithhighHIVprevalence,(e.g.,VTcarriagewasstill22%inMalawiafter5yearsofPCV13use).
• PCV13impactwasalsoassessedincountriesthatswitchedfromPCV7toPCV13(n=10)andallobservedacontinueddeclineinPCV7-typecarriageaswellasadeclineincarriageofthe6serotypesinPCV13thatarenotinPCV7
• NoNPstudieswereconductedincountriesthatswitchedfromaPCV7toPCV10(usinga3-doseschedule).
ImpactonNPcarriageofSTs3,6Aand19A:• Duetolowbaseline(i.e.,pre-PCVintroduction)carriageratesoftheSTsthatareinPCV13butnotinPCV10
(i.e.,STs3,6Aand19A),theabilitytoassessproductspecificimpactontheseserotypeswaslimited.• NostudiesshowedimpactofPCV10onST3carriage,althoughabilitytoassesswaslimitedbyverylowST
3carriage.MoststudiesevaluatingPCV10impactonserotype6Aobservedsmalldeclines(e.g.,10-20%)butnoneweresignificant.StudiesevaluatingPCV10impacton19Ahadheterogeneousresults,withsomeshowingincreasesandsomedecreases.Astudyofa3+1scheduleshowednoimpactofPCV10onST19Aafter5yearsofuse,whichhadrisenafterpreviousintroductionofPCV7;duetolowcarriageof19Aonlyonestudyshowedasignificantchange,andthatstudyshowedanincreasein19A.
• StudiesevaluatingimpactofPCV13onST3wereinsufficientlypoweredtoevaluateanimpact.AllstudiesevaluatingimpactofPCV13onserotype6Aobserveddecreases,andtwowerestatisticallysignificant.Similarly,allstudieswithmeasureable(>2%)carriageofserotype19Aobserveddecreases,includingreturningcolonizationratesbacktopre-PCVratesinsettingswhereST19AincreasedfollowingPCV7use.However,inasettingwithhighpneumococcalcolonization(e.g.>80%pneumococcalcarriage),ST19Apersistedatlevelsof3%evenafter5yearsofPCV13use(Malawi).
Regionalrepresentationofdata:• AllWHOregionshaddataoncolonizationeffectsfrom3-doseschedulesforbothPCV10andPCV13except
PCV10intheMiddleEastandPCV13inLatinAmerica(AppendixA,Table1)
NPCarriageFindingsImpactonVTcarriagePCV13:Thirty-fourstudiesof3-dosescheduleswereassessed;15assessedtheimpactofPCVonVTcarriageandwereincludedinfurtheranalyses,andallshowedreductions(n=9evaluateda2+1scheduleandn=6evaluateda3+0schedule).AppendixATable2-9summarizesallstudiesreportingonVT,andserotypespecificpneumococcalcarriage.AppendixBTable1summarizesallstudiesthatwereassessedandnotincluded.
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Figure1.ImpactofPCV13onVTNPcarriage
ThreeofthestudieswereRCTs[20,25,26].Twoweretrialsof2+1schedulesthatcomparedPCV13tounvaccinatedchildren;alarge(91%)impactwasobservedinone(Polish)trial[25],andlessimpact(33%)wasobservedintheother(Vietnamese)[20].A3+0trialconductedinIsraelcomparedPCV13-vaccinatedchildrentochildrenwhoreceivedPCV7andfoundasignificant24%reductioninVTcarriage(notethatthemagnitudeofimpactobservedwouldhavebeengreaterifthecomparisongrouphadbeenunvaccinated)[26].Twelvestudieswereconductedinsettingsofroutine-use,nineincountriesthatswitchedfromPCV7toPCV13(4European,3African,1MiddleEasternand1Oceanian)andthreeincountriesthatintroducedPCV13denovo(2Africanand1Asian)[27-39].OfthesethreestudiesonlytwomeasuredachangeinVTcarriagepre-topost-PCV13,bothusing3+0schedules,andsignificantreductionswereseeninboth:twoyearsafterPCV13wasintroducedinBurkinaFaso,a40%reductioninVTcarriagewasobservedinchildren<5yearsofage(from33%preto20%post-PCV13)[29];a20%reductioninVTcarriagewasseenafterlessthan1yearpostintroductioninchildren<2yearsofageinCambodia(from53%to42%)[28].Athirdstudyofa3+0scheduleinMalawididnotevaluateimpactbyassessingcarriagebothpre-andpost-PCVbutratherassessedcarriage5yearspost-PCV13introductioninasettingwithhighvaccinecoverage(85%)thatusedacatch-upcampaigninchildren<1year.Inthatsetting,whichhadhighoverallcarriageasisfoundinmostAfricanstudies(81%carriedanypneumococcus),22%ofPCV13-vaccinatedHIV-negativechildren3-5yearsoldcarriedavaccinestrainindicatingsustainedcarriageofvaccine-typeslongafterintroductioninhigh-riskpopulations[27].ItisunknownhowhightheVTcarriagewaspriortotheintroductionofPCV13.OftheninestudiesreportingVTcarriageconductedincountriesthatswitchedfromPCV7toPCV13,sevenevaluateda2+1scheduleandtwoevaluateda3+0schedule.YearsofPCV13userangedfrom1to5yearsandallobservedreductionsinVTcarriageafterintroduction(Figure2).Carriageoftheadditional6STinPCV13
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thatarenotinPCV7wasreportedin10studiesandallobserveddeclines(measuredasagroup)aswellascontinueddeclinesinPCV7-VTcarriage.Figure2.ChangeinPCV13-typeNPcarriageafterPCV13introductionincountriesthatswitchedfromPCV7toPCV13
PCV10:Twenty-eightstudiesof3-dosescheduleswereassessed;14evaluatedVTcarriagefollowingPCV10immunizationandwereincludedintheanalysesthatfollowandallshowedreductions(n=3evaluateda2+1scheduleandn=11evaluateda3+0schedule).AppendixATable2-9summarizesallstudiesreportingimpactofPCV10onVT,andserotypespecificpneumococcalcarriage.AppendixBTable1summarizesallstudiesthatwereassessedandnotincluded.
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Figure3.ImpactofPCV10onVTNPcarriage
Sevenofthesestudieswereclinicaltrials(n=3evaluateda2+1scheduleandn=4a3+0schedule,plusonetrialalsoevaluatedcarriagepre-boosteraftera2-doseprimaryseries),butnoneoftheclinicaltrialswereconductedinsettingswithhighVTcarriage(allhad9-16%VTcarriageintheunvaccinatedcontrolgroup)[20,40-46].LowercarriagewasobservedinallPCV10-vaccinatedchildrencomparedtounvaccinatedcontrols,althoughnonewasstatisticallysignificantduetothelowVTcarriageinthecontrols,theaggregatedevidenceacrosstrialssuggestsPCV10doesreducecarriageagainstVTserotypes,howeveraformalmeta-analysishasnotyetbeenconducted.Anadditional4trialsevaluated3+1schedules,butthesewerealsoinlowcarriagesettingsandresultsweresimilar[41-44].Ofthe6studiesthatevaluated3-dosePCV10impactinroutine-use,allwereconductedincountriesthatusedPCV10denovo(i.e.didnotfirstusePCV7)[47-53].StudieswereconductedinAfrica,SouthAmerica,AsiaandOceaniaandalluseda3+0schedule.AllobservedadeclineinVTcarriage,asagroup,inchildrenwhoreceivedPCV10comparedtochildrenofasimilaragewhodidnot.VTcarriageinthesestudiesbeforePCV10introductionwaslowtomoderate,rangingfrom16%(Fiji)[48,49]to40%(Kenya)[47].YearsofPCV10useassessedrangedfrom1to4yearsandtwostudieswereinthecontextofacatch-upprogram.Thetwostudies(FijiandKenya)withthelargestimpact(>80%reductioninVTcarriageinchildren<2yearsofage)hadthelargestnumberofyearsofPCV10use(3-4years)andtheKenyastudyalsoimplementedPCV10catch-upimmunizationforchildren<5yearsatthetimeofvaccineintroduction.DeclineinVTcarriageintheotherstudiesrangedfrom30-52%afterpredominantly1-2yearsofPCV10use.A7thstudy,inEthiopia,assessedthedistributionofpneumococcalisolatesbefore(age6weeks)andafter(age9months)vaccinationandfoundthatalowerproportionofisolatescarriedwereVTaftervaccination(11%atage9monthscomparedto20%atage6weeks),suggestinganimpactofthevaccinesinceVTcarriagegenerallyincreaseswithageduringthisperiod[54].However,becausetherewasnounvaccinatedcomparisongroup,changesinSTdistributionduetonaturalacquiredimmunitycannotberuledoutinthisstudy.
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OnlyonestudyassessedtheimpactofPCV10onVTcarriagefollowing2-primingdoses[52];asignificant36%declineinvaccine-typecarriagepriortotheboosterdosewasobserved.Head-to-headtrialsofPCV10vs.PCV13:Althoughthisreviewwasnotintendedtodirectlycompareproducts,twotrialscomparedPCV10toPCV13,butVTcarriagewaslowingroupsthatreceivedPCV10andthosethatreceivedPCV13andnomeaningfuldifferenceswereobserved(PCV13-typewas13.5%inPCV10groupversus11.6%inPCV13groupinVietnamtrialmeasured12monthsaftera2+1schedule,and24%and23%,respectively,inPNGtrialmeasured9monthsaftera3+0schedule)[20,21].ThePNGtrialalsoassessedimpactonNTHi,theorganismfromwhichoneofthecarrierproteinsinPCV10isderived:infantswerefrequentlyco-colonizedwithNTHiwithnosignificantdifferencebetweenPCV10(54%)andPCV13(62%)immunizedinfants[21].
3.4 PneumoniaSummary• Thereisnosystematicevidencethatoneproducthasgreaterimpactonpneumoniaoutcomesthan
another;therangeofimpactwasbroad(-68%to-13%forclinicalpneumoniaand-66%to-34%forCXR-confirmedpneumonia)andvariablewithinoutcomesandproduct
• Crossstudycomparisonsareconfoundedbysubstantialdifferencesbetweenstudiesintheagegroupsstudied,thecasedefinitions,durationofPCVuse,studydesign,analyticapproachesandthenaturalseculartrendsinpneumoniahospitalizationrates.
Impactonall-causepneumoniacasedefinitions• 32studiesevaluating3-doseschedules(2+1or3+0)usingPCV10orPCV13wereavailableforreview(one
clinicaltrial[55],sixcase-controlstudies[56-61],and28pre/postobservationalstudies[56,61-86](AppendixA,Tables11-14).
ImpactonclinicalandCXR-confirmedpneumonia:• ThereviewfoundevidenceofimpactfrombothPCV10andPCV13forclinicalandCXR-confirmed
pneumonia,bothoutcomesthatarenotspecifictopneumococcus;theVEistheneteffectoftheproportionofcasesthatareduetopneumococcusandamongthose,theproportionthatareduetovaccinetypesorcross-reactingtypesaswellasserotypespecificVEofeachproductinthatpopulation.
Impactonpneumococcalpneumonia• Evidenceofimpactforpneumococcalpneumoniaandall-causeempyemawasonlyavailableforPCV13use
andtheevidenceregardingimpactonempyemawasmixed..TherewerenostudiesthatevaluatedPCV10useonpneumococcalpneumoniaorall-causeempyema.
Regionalrepresentationofdata• ThemajorityofstudieswerefromEurope(EUR)(n=12)[55,58,60,67,69,72,73,75,79,80,83,84]or
LatinAmerica(AMR)(n=10)[62,63,65,66,68,74,77,78,81,82];8studieswerefromAfrica(AFR)[56,59,61,64,76,85-87]andtwostudiesfromOceania(WPR),bothfromFiji[70,71].TherewerenostudiesidentifiedfromAsia(EMR,SEAR)orNorthAmerica(AMR);however,thereviewwaslimitedto3-doseschedules,excludingevidencefromcountriesusinga3+1schedule.
• TherewerenostudiesidentifiedfromAsia(EMR,SEAR)orNorthAmerica(AMR);however,thereviewwaslimitedto3-doseschedules,excludingevidencefromcountriesusinga3+1schedule.
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PneumoniaFindingsClinicaltrialsTherewasoneRCTevaluatingeitherPCV10orPCV13ina3-dosescheduleagainstpneumonia[55].TheFinnishstudyevaluatedPCV10usinga2+1scheduleandshowed28%(6%-45%)efficacyagainstclinicalpneumoniaand43%(19%-61%)efficacyagainstchestx-rayconsolidatedpneumonia.Case-controlstudiesAllsixcase-controlstudiesevaluatedPCV13[56,58-61,87];therewerenosuchstudiesthatevaluatedPCV10.FourofsixstudieswerefromAfrica(Table5).Threestudiesevaluated2+1schedulesandVErangedfrom20.1%to40.6%for≥2dosesagainstradiologicallyconfirmedpneumoniaand68%againstbacteremicpneumococcalpneumonia;allmeasuresofthesetwooutcomeswerestatisticallysignificantwiththeexceptionoftheVEfora2+1scheduleonradiologically-confirmedpneumoniacomparedtohospitalcontrolsinchildreninSouthAfrica[58-60].Threestudiesevaluated3+0schedules,allfromAfrica[56,61,87].TheVEfora3+0schedulerangedfrom58%to63%againstradiologicallyconfirmedpneumonia,butnoneweresignificant.ThestudyinTogofound80%VEfora3+0scheduleagainstseverepneumonia,butthiswasnotstatisticallysignificant[87].ThestudyinRwandashowed54%VEagainstseverepneumonia,whichwasstatisticallysignificant[61].Pre/postobservationalstudies,PCV10Clinicalpneumonia(Figure4):Twostudies(IcelandandSweden)evaluated2+1schedulesofPCV10againstclinicalpneumoniainchildren<2yearswithreductionsrangingfrom21%to36%comparedtothepre-PCVperiod[67,83];however,thestudyinSwedenshoweda3%increaseinclinicalpneumoniaintheperiodafterPCV7implementation,butpriortotheswitchtoPCV10[67].Threestudies(twofromFijiandonefromKenya)evaluated3+0scheduleswithchangesinclinicalpneumoniaincidencerangingfromreductionsof13.3%to32%comparedtothepre-PCVperiod;allreductionswerestatisticallysignificant[70,71,76].Radiologicalpneumonia(Figure6):Therewasonestudy(Kenya)usinga3+0schedulethatshowedastatisticallysignificantreductionof48%inradiologicallyconfirmedpneumonia.PneumococcalPneumoniaandempyema:NostudiesevaluatedPCV10againsteitherendpointPre/postobservationalstudies,PCV13Clinicalpneumonia(Figure4and5):Therewere9studiesusinga2+1schedulethatevaluatedaclinicalpneumoniaendpointandpriorPCV7varied[63,67,68,73,74,77,80,82,84].Forchildren<2years,reductionsrangedfrom27.3%to68.4%comparedtoapre-PCVbaselineperiodandallreductionswerestatisticallysignificant.ComparedtothePCV7period,changesinincidenceinchildren<2yearsrangedfrom+8%to-58%,withstatisticalsignificancevarying.Forchildren<5years,reductionsrangedfrom27.8%to49.7%comparedtoapre-PCVbaselineperiodandallreductionswerestatisticallysignificant.Changesinincidencerangedfrom+24%to-60.5%comparedtothePCV7periodandallmeasureswerestatisticallysignificant.OnestudyfromMalawievaluateda3+0scheduleonclinicalpneumoniaandfoundanon-significant47%increaseinWHO-definedclinicalpneumonia,buta47%significantdecreaseinhypoxemicpneumonia[86].ThisstudycompareddiseaseincidencetwoyearsafterPCV13implementationtothefirstsixmonthsafterPCV13implementationwithnotruecomparisontopre-PCVintroduction,butwasincludedduetopaucityofdatafromAfrica.Radiologicalpneumonia(Figure6and7):Therewere7studiesusinga2+1schedule[62,65,69,72,78,79,82]andonestudy[66]usinga3+0schedulethatevaluatedaradiologically-confirmedpneumoniaendpoint.For2+1schedules,inchildren<2years,reductionsrangedfrom34%to66.2%andallreductionsweresignificant.ComparedtothePCV7period,reductionsrangedfrom30%to85%andsignificancevaried.ThestudyfromUruguaywith85%reductionhadoneyearofbaselinedata,whichoccurredduringPCV7use[78].Inchildren
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<5years,changesinincidencerangedfroma15%increasetoa53%decrease;allreductionsweresignificant.ComparedtothePCV7period,reductionsrangedfrom36%to40%;allreductionsweresignificant.Forthestudythatevaluateda3+0schedule,significantreductions(range:26%to33%)wereseeninallagegroups.Pneumococcalpneumonia:Onestudyevaluatedpneumococcalpneumonia;thestudyfromArgentinaevaluateda2+1scheduleandfounda72.1%reductionindiseaseinchildren<5yearscomparedtothepre-PCVbaselineperiod[62].[62].Empyema:Threestudiesevaluated2+1schedulesagainstall-causeempyema;VEestimatesandsignificancevaried[65,80,84].Nostudiesevaluated3+0schedulesagainstempyemaPre/postobservationalstudies,PCV7/PCV13ClinicalPneumonia(Figure4and5):Therewere6studiesthatevaluatedtheimpactofPCV7introductionfollowedbyaswitchtoPCV13use[56,61,64,75,81,85].TwostudiesevaluatedPCV7/PCV13impactusing2+1schedulesagainstclinicalpneumonia[64,75];reductionsrangedfrom15%to44%inchildren<5years.Twostudies,bothfromAfrica,evaluateda3+0scheduleonclinicalpneumonia;onestudyfromTheGambiashowedsignificantreductionsinhypoxicpneumoniaacrossallagegroups(range:56%to72%)[56].Theotherstudy,fromRwanda,founda70%decreaseinseverepneumoniaanda7%increaseinclinicalpneumonia;however,thismeasureisonlyoneyearafterPCV13implementationandwasincludedduetopaucityofdatafromAfrica[61].Radiologicalpneumoniaandpneumococcalpneumonia(Figure6and7):TwostudiesevaluatedPCV7/PCV13againstradiologically-confirmedandpneumococcalpneumonia[56,81].Thestudyusinga2+1schedulefounda78%and97%significantreductionamongchildren<14yearsforpneumococcalpneumoniaandempyema,respectively[81].Thestudyusinga2+1schedulefounda78%and97%significantreductioninchildren<14yearsforradiologically-confirmedandpneumococcalpneumonia,respectively[81].Thestudyevaluatinga3+0schedulefoundsignificantreductionsrangingfrom22%to29%forradiologically-confirmedpneumoniaand57%to75%forpneumococcalpneumoniainchildren<5years[56].Empyema:TwostudiesevaluatedPCV7/PCV13usinga2+1scheduleagainstempyema[75,85].Onestudyfounda50%significantreduction[85].Theotherstudyfounda68%to78%increase,butthesewerenotstatisticallysignificant[75].Serotype-specificdataThisreviewdidnotidentifyanystudiesthatreportedtheimpactofPCV10orPCV13onserotype-specificpneumococcalpneumonia.
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Figure4.%Changeinincidenceofclinicalpneumonia(post-PCV10,PCV13,orPCV7and13v.pre-PCV),byproduct
*Russellstudyhas2datapointsfor2differentindigenousgroups;McCollumstudyisforclinicalpneumoniaandhypoxicpneumoniaFigure5.%Changeinincidenceofclinicalpneumonia(post-PCV10,PCV13,orPCV7and13v.pre-PCV),byproduct
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Figure6.%Changeinincidenceofradiologically-confirmedpneumonia(post-PCV10orPCV13v.pre-PCV),byproduct
Figure7.%Changeinincidenceofradiologically-confirmedpneumonia(post-PCV-10or-13v.PCV7period),byproduct
*IntheGivon-Lavistudy,the2datapointsareforJewishandBedouinchildren
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3.5 InvasivePneumococcalDiseaseSummary
• Therearenostudieswithhead-to-headcomparisonsofPCV10andPCV13orschedules(2+1vs.3+0)• ComparisonofimpactofPCV10andPCV13onVTIPDobservedacrossstudiesshouldbedonewith
cautionduetodifferencesindurationofPCV7/PCV10/PCV13use,agegroupsstudied,vaccinecoverage,andanalyticmethodsused
• Incountriesthathaveswitchedproducts(fromPCV7toPCV10/PCV13),themagnitudeofchangeinVTIPDshouldnotbeattributedentirelytoPCV10/13
ImpactonVTIPD
• SignificantreductioninIPDcausedbyvaccineserotypeswereobservedfollowingPCV10andPCV13introductionforboth2+1and3+0schedules
• IncountriesthathaveswitchedfromPCV7toPCV13,PCV13/non-PCV7typeIPDdeclinedfrom57to100%,withreductionsmeasured1to4yearspostPCV13introduction
• Vaccine-typeIPDdeclinedfrom47to87%incountriesintroducingPCV10following,withimpactmeasured1to3yearspostintroduction.
• VEstudiesdemonstratedthatbothPCV10andPCV13arehighlyeffectiveinpreventingVTIPD;oneclinicaltrialdemonstrateda92%efficacyofPCV10givenona2+1schedule
• TherewasnoevidencethatmagnitudeofreductioninVTIPDdiffersbetweenproductsImpactonIPDcausedbyST3,6A,and19A
• PCV13iseffectiveinreducingtype19Aand6Adisease;noconsistentimpactonST3diseasehasbeendemonstrated,withmoststudiesshowingnoimpact/lackofVEofPCV13againstST3IPD
• VerylimiteddataareavailableonPCV10impactonIPDcausedbythesethreeserotypes• PCV10appearseffectiveinreducingtype19Adisease;nodataonserotypes6Aand3
Regionalrepresentationofdata
• Thisreviewidentified39studiesevaluatingimpactofPCV10orPCV13onIPDcausebyvaccineserotypesusing3-doseschedules(2+1or3+0):oneclinicaltrial,ninecase-controlstudies[56,58-60,87][56,58-60,87][56,58-60,87][56,58-60,87][56,58-60,87][56,58-60,87][56,58-60,87]56,58-60,87][56,58-60,87][56,58-60,87][56,58-60,87][56,57,58-61,62,86,87]and29pre/postobservationalstudiesand29pre/postobservationalstudies.
• ThemajorityofstudieswerefromEurope(n=20),7fromAfrica,4fromLatinAmerica,3studiesfromeachAustralia/OceaniaandNorthAmerica,and2fromAsia.
• LimitedevidenceonPCV10comparedtoPCV13wasidentifiedthusfar;however,weanticipatemoredataonPCV10inthecomingyears.
• Whilethereviewwaslimitedto3-doseschedules,whichexcludedmanycountriesusinga3+1schedule,duetosparsedataonPCV10,weincludedstudiesconductedinsettingof3+1PCV10scheduleifserotype-specificinformationwasreported.
IPDFindings:Therewere42studiesavailableonPCV10orPCV13usinga3-doseschedulewithanIPDoutcome.Thenumberofstudiesbystudytype,regionandPCVproductisprovidedinAppendixATable16.
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PCV10ClinicaltrialsAclusterrandomizeddouble-blindtrialofPCV10inFinlanddemonstrateda92%(95%CI58–100)efficacyforVTIPDusinga2+1scheduleamongchildren<19monthold[88].Anextendedfollowupofthediseaseregisterforthistrialdemonstratedan80%(95%CI7-97)efficacyforacombined2+1/3+1schedule[89].Case-controlstudiesFourcase-controlstudieshavebeenconductedinasettingof3-dosescheduleevaluatedtheVEofPCV10againstvaccine-typeIPD.VEofPCV10againstPCV10-typeIPDrangedfrom77to97%forchildrenreceiving>1dose.Threeofthesestudieswereconductedinasettingofa2+1nationalschedule(Finland,Netherland,andCanada)[90-92],andonestudy(Pakistan)measuredtheVEinasettingofa3+0schedule[93].Noneofthesecase-controlstudiesmeasuredVEspecificallyforchildrenreceivinga2+1or3+0schedule.Acase-controlstudyconductedinBrazilinasettingof3+1schedule,estimatedVEof84%againstVTIPDforchildrenreceivingup-to-dateforageschedules[94].VEagainsttypes3,6A,and19AFourcase-controlstudiesevaluatedVEofPCV10againstindividualSTs.TheVEof>1doseagainsttype19AIPDrangedfrom61to82%,althoughtheestimateswerenotstatisticallysignificantinstudiesfromNetherlandsandBrazil(indirectcohortmethod)[92,94].TheVEofPCV10againstST3and6AIPDwasmeasuredonlyinonestudy(Brazil),withnon-significantVEof8%and15%,respectively[94].Pre/postobservationalstudiesSignificantreductionsinIPDcausedbyvaccineserotypeswereobservedfollowingPCV10introduction.IncountriesintroducingPCV10followingPCV7usinga2+1PCV10schedule,vaccine-typeIPDdeclinedfrom77to96%comparedtothePCV7period,withimpactmeasured2to4yearspostPCV10introduction(CanadaandNetherlands)[95,96].InFinlandandIceland,an87%and93%reductioninPCV10-typeIPDwasobserved3and5yearspostPCV10introductionusinga2+1schedule[97-99].A94%reductioninPCV10typeIPDwasobservedinonestudy(Kilifi,Kenya)fouryearsafterPCV10introductionona3+0schedule[100,101].A97%reductioninPCV10typeIPDwasobservedinBrazilfollowing2yearsofPCV10useon3+1schedule[102].Impactontypes3,6A,and19ATwostudiesreportedreductionsinIPDcausedbytype19AfollowingPCV7/PCV10introduction:a36%reductionwasreportedinCanadaanda62%reductioninNetherlands2and4yearspostintroductionusinga2+1schedule,respectively[95,96].InFinland,a93%reductionintype19Adiseaseanda100%reductionintype6Adiseasewasreported5yearspostPCV10introduction[103].Additionalserotype-specificdatafromcountriesusingPCV10arepending.PCV13Case-controlstudiesFivecase-controlstudieshavebeenconductedinasettingof3-dosenationalscheduleevaluatedtheVEofPCV13againstvaccine-typeIPD.TheVEofPCV13againstPCV13-typeIPDrangedfrom64to86%forchildrenreceiving>1dosesinthreestudieswith2+1nationalschedule(DominicanRepublic,UK,andCanada)[90,104-106].AstudyfromSouthAfricaestimatedtheVEfor>2dosesat85%[107].Onlyonestudy(UK)measuredtheVEofa2+1schedule(79%)[104,105].ThesamestudyestimatedVEagainstPCV13/non-PCV7serotypeIPDat73%forchildrenreceiving>1or>2doses.AcohortstudyinAustraliaestimatedtheVEofPCV133+0scheduleagainstPCV7-typeIPDat92%[108].Acase-controlstudyconductedinSpaininasettingof3+1scheduleestimatedVEof96%againstPCV13IPDand95%againstPCV13/non-PCV7typesforchildrenreceiving>1doses[109].
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VEagainsttypes3,6A,and19AThreecase-controlstudiesevaluatedVEofPCV13againstindividualSTs.TheVEof>1doseagainsttype19AIPDwas74%(Canada)andrangedfrom67to94%for>2doses(UKandSouthAfrica)[90,104,105].Onestudy(UK)reportednosignificantVEofPCV13againsttype3IPDand98%VEagainsttype6A[105].Pre/postobservationalstudiesSignificantreductionsinIPDcausedbyvaccineserotypeswereobservedfollowingPCV13introduction.PCV13/non-PCV7typeIPDdeclinedfrom57to100%incountriesintroducingPCV13followingPCV7,ona2+1schedule,withreductionsmeasured1to4yearspostPCV13introduction(AppendixA,Table18).InAustralia,inasettingofa3+0PCV13schedule,a65%reductioninPCV13typeIPDwasobservedoneyearpost-introduction[110].InGambia,82%reductioninPCV13/non-PCV7typeIPDwasreported3yearspost-PCV13introductionusinga3+0schedule[111].Overall,reductionsinPCV13/non-PCV7typediseaseofgreatermagnitudewerereportedwhenstudiesreportedcomparisonstoPCV7periodasbaselinevs.whencomparisonstopre-PCV7periodweremade;thiswasduetoincreasesinPCV13uniqueserotypesreportedpostPCV7introduction.Therewerenopre-post-observational,3-dosestudiesreportingtheimpactofPCV13withoutprioruseofPCV7.Impactontypes3,6A,and19AIncountriesintroducingPCV13followingPCV7ona2+1schedule,sixstudiesreportedimpactonserotype-specificIPD.Significantreductionsintype19Adisease,rangingfrom69to91%werereportedinfourstudies(Israel,France,England,andSouthAfrica)with1to4yearspost-introduction[112-115].OnestudyinDenmarkreportednochangesintype19AdiseasecomparedtoPCV7period3yearspostPCV13introduction,withdiseaseincidenceincreasingduringPCV7periodcomparedtopre-PCVperiodandthendecliningtopre-PCV7levels[116].Nochangesintype3IPD1to3yearspostintroductionwerereportedinthreestudies(Denmark,Israel,andSouthAfrica).Twostudiesreportedsignificantreductionsof85%and68%(FranceandEngland)intype3disease1and4years,respectively,postPCV13introduction.Significantreductionsintype6Adiseaserangingfrom85%to100%werereportedinthreestudies(SouthAfrica,Israel,andEngland)post-PCV13comparedtoprePCVperiod,althoughmostofthesereductionsshouldbeattributedtoPCV7impact.Onlyonestudy(Australia)reportedimpactofPCV13ontype19Adiseaseinasettingof3+0schedule(77%reductionintype19AIPD)[110].
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Figure8(A-D).VaccineimpactincountriestransitionedfromPCV7toPCV10orPCV13
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Figure9.VaccineimpactincountriesintroducingPCV10withoutpriorPCV7use
3.6 MortalitySummary• DataonPCVimpactonmortalityfollowingPCV10orPCV13introductionina3-doseschedulearevery
limitedinnumber(9studies)andwithafewexceptionsarelargelyfromcountrieswithlowinfantandchildmortality
• Quantitativecomparisonsacrossstudiesshouldnotbeinterpretedtomeantherearetruedifferencesinimpactonmortality;theseobservationalstudiesarehighlyheterogeneousforfactorsthatthemselveswouldimpactonmortality(studymethod,analysisapproach,yearsofPCVuse,agestrata,outcome,seculartrends)
• Nevertheless,mostpublishedstudiesdemonstrateanimpactofPCVonmortalityinchildren;itisunknownhowmanystudieshavebeenconductedthatfoundnoimpactanddidnotpublishthefindings
• Nodifferencesinimpactonmortality,byproduct,areevidentfromthesedata
Mortalitychanges• Mortalityratesandabsolutenumbersofdeathareusedasoutcomesinstudies• Therangeofobservedreduction,acrossoutcomesofall-causemortality,IPDmortalityandpneumonia
mortality,isfrom6%-56%
CFRchanges• Threestudiesreportedthechangeincasefatalityratioforsevere/veryseverepneumonia[70],
pneumoniahospitalizations[117],and,all-causepneumonia[118].
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• Reductionsrangedfrom41%-57%,whichcouldreflectthelowerfractionofbacterialdiseaseamongthesecases,whichareknowntohaveahigherCFRthannon-bacterialcases
Regionalrepresentativeness• StudiesareavailablefromEUR(n=1foreachofPCV10andPCV13),AFR(n=1foreachofPCV10and
PCV13),AMR(n=2foreachofPCV10andPCV13)andWPR(n=1forPCV10)• NostudiesofmortalityforPCV10orPCV13for3-doseschedulesareavailablefromSEARorEMR
MortalityFindingsEvaluatingtheimpactofPCV10andPCV13onmortalityisofhighpriorityforpolicydecision-makersbutareamongthemosttechnicallydifficulttoconductbecauseoftherelativerarityofmortaloutcomes.FurthermoretherearemanyotherinterventionsthatcanaffectthemortalityrateabsentPCV,andtheseconfoundtheconclusionsfrommortalityanalyses.Allstudiesaretime-seriesstudieslookingatmortalityrates,ordeathcountsbeforeandafterPCVintroduction,leavingthesehighlysusceptibletoconfoundinggiventhatmortalityisverynon-specificforvaccineserotypepneumococcus.Thequantitativeestimatesofchangeinmortalityfromtheobservationalstudiesshouldthereforebecontextualizedwithinwhatwasobservedinthecourseofhighlycontrolledrandomizedtrials,whereconfoundingissubstantiallylessenedthroughtherandomizationandcontemporaneousevaluationofacontrolgroup.ThePCV9trialintheGambiawith3+0dosingscheduleconcludedthattherewasa16%reductioninall-causemortalityforinfants3-29monthsofagewiththeuseofPCV9[119].Thisallowssomebenchmarkingofthelowerboundforchangesthatmightbeexpectedinothersettings. Thereareninestudies(n=5PCV10;n=4PCV13)withmortalityoutcomefollowingtheuseofPCV10orPCV13ina3-doseschedule[66,86,118,120-125].Theoutcomesincludemortalityrates,mortalitycasesandchangesincasefatalityratio.Theseareassessedaccordingtoall-causemortality,IPDmortality,andpneumoniamortality(AppendixA,Table23).Theobservedreductionsarenotallstatisticallysignificantandtheirmagnitudeinsomecasesissurprisinglylarge,suggestingeitherthatpneumococcusisamuchgreatercontributortomortalitythanevidencedbyotherwork,thatherdeffectsarecontributingtotheoverallmeasuredbenefit,orthatthestudiessufferfromsomeofthemethodologicalissuesjustdescribed.Regardless,mostpublishedstudieshavedemonstratedanimpactonmortalityfollowingtheroutineuseofPCV,includinguseofbothproducts,inarangeofhighandlow-incomecountries,acrossgeographies.
3.7 IndirectEffectsofPCVsSummaryMostofthedataonindirecteffectsofPCV10/13isonIPD(n=22studies),withlimiteddataonNPcarriage(n=3studies)andpneumonia(n=6studies).VTNPColonization
• TherearelimitedbutconsistentdataontheindirecteffectsofPCV10(n=2studies)orPCV13(n=1study)onVTNPcarriageatleast3yearsaftervaccineintroduction.
• ThedataindicateareductioninVTcarriage,withrelativereductionrangingfrom35%to100%inpersonsofvariousages.
Pneumonia• Sixstudiesreportonpneumoniaincidenceingroupsnotdirectlyvaccinated.
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• Ingeneral,asthepneumoniaoutcomesbecomemorespecificforpneumococcalaetiology,thereisatrendtowardsagreaterobservedindirectimpactofPCV,butthedataarespotty.
• ComparedtothePCV7period,ifapplicable,orthepre-PCVperiod--inthesettingofdenovointroduction--clinicalpneumoniaincidencedecreasedby2%to40%inthePCV10/13period(n=5studies,reachingsignificancein2studies).
VTIPD• TherehasbeenasignificantreductioninVTIPDfollowingtheintroductionofPCV10orPCV13in
variousagegroupsstudied.• FollowingthetransitionfromPCV7toeitherPCV10orPCV13,therateofdiseaseduetotheadditional
serotypesincludedinthehighervalencyproducthasmostlydecreased,thoughthedataismorerobustforPCV13thanPCV10.
Regionalrepresentativeness• StudiesareavailablefromallregionsexceptAsia.• MostoftheincludeddataonindirecteffectsarefromEuropeancountriesusingPCV13ina2+1
schedule.
IndirectEffectFindingsPCVintroductionforinfantshasimpactedtheburdenofpneumococcaldiseaseinunvaccinatedpersonsofvariousagesbyreducingtheriskoftransmissionfromyoungchildren,theagegroupthoughttobethereservoirforpneumococcalcirculationatthecommunitylevel.YoungchildrenwhoreceivePCVarelesslikelytocarryvaccineserotypesintheirnasopharynxandthusarelesslikelytospreadtheseserotypestoolder,unvaccinatedindividualsandeveninfantstooyoungtobevaccinated.Withreducedexposuretovaccineserotypes,unvaccinatedpersonsarelesslikelytodevelopdisease,indirectlybenefitingfromPCVimplementationamonginfants.ThisphenomenonisreferredtoastheindirecteffectofPCVorherdimmunity.TheevidenceofPCV10andPCV13’simpactonindirecteffectssummarizedhereisbasedontheinclusionofstudieswithdatapriortoanyPCVuseandatleastthreeyearsofdatapostPCV10/13introduction(e.g.pre-poststudies).Thirty-onestudiesareincluded,mostlyrepresentingEuropeancountriesusingPCV13ina2+1schedule(AppendixA,Table8).MostofthedataonindirecteffectsisonIPD(n=22studies),withlimiteddataonNPcarriage(n=3studies)andpneumonia(n=6studies).Additionaldataonindirecteffectsisavailablefromcountriesusinga4-doseschedulebutwasnotincludedinthissummary.VTNPCarriage—IndirectEffectsTherearelimitedbutconsistentdataontheindirecteffectsofPCV10orPCV13’sintroductiononVTNPcarriageinolderchildrenandadults.DataarelimitedmainlybecausemostNPcarriagestudiesdonothaveatleastthreeyearsofpostintroductiondata(n=19studiesexcludedforthisreason;seeAppendixBTable27forexclusionreasons).ThreeNPcarriagestudieswereincluded:onestudyfromIsrael,withdataonthetransitionfromPCV7toPCV13,andtwostudiesonthedenovouseofPCV10fromFijiandKenya[47,48,126].(AppendixA,Table27).AllthreestudiesreportreductionofVTcarriageinvariousagegroupsnotdirectlyvaccinated,withtherelativereductioninVTcarriagerangingfrom35%to100%.InKenya,amongallpersonsover5yearsofage,therewasa65%reductioninPCV10VTcarriagethatwassignificantfouryearsaftervaccineintroduction[47].MorestudiesareneededtoassesstheindirectimpactofPCV10andPCV13overtime,particularlywithrespecttothemagnitudeandimportanceofNVTreplacementcarriage.
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Pneumonia—IndirectEffectsIndirecteffectdataonpneumoniaarestilllimitedandresultsaremorevariablethanforIPDandcarriage,inpartduetothevariabilityinpneumoniaoutcomesassessed.ManystudieswereexcludedbasedonhavingfewerthanthreeyearsofpostPCV10/13use(n=9)orbecausetheypresentdataonanagegroupthatincludedbothdirectandindirecteffectstogether(n=10,AppendixA,Table28).PCV13studiesbasedona3+1schedulewerealsoexcluded,thuscuttingouttheU.S.dataonthistopic.Sixstudiesreportonpneumoniaincidenceingroupsnotdirectlyvaccinated:threestudiesfromPCV10countries(Finland[127]andKenya[128,129]),twostudiesfromPCV13countries(Scotland[130]withprioruseofPCV7,andArgentina[131]withdenovoPCV13introduction),andonestudyfromacountrythatswitchedfromPCV7toPCV13andthentoPCV10(AppendixA,Table28;Sweden)[132].Fivestudiesreportonclinicalpneumoniainolderchildren(n=4studies)andadults(n=2).Themethodologyoftheclinicalpneumoniastudiesvariedsubstantially,makingcomparisonsbetweenstudiesverydifficult.
• Clinicalpneumonia:Twooffivestudiesreportastatisticallysignificantreductioninclinicalpneumonia,whilethreereportnosignificantchange.ComparedtothePCV7period,ifapplicable,orthepre-PCVperiod--inthesettingofdenovointroduction--clinicalpneumoniaincidencedecreasedby2%to40%inthePCV10/13periodinolderchildrenandadults.
• Radiographicallyconfirmedpneumonia:TwostudiesreportonCXRconfirmedpneumoniainolderchildrenandfoundan11%(notsignificant)and44%(significant)reduction[128,131].
• Pneumococcalpneumoniaandempyema:Onlyonestudyhasdataonpneumococcalpneumonia,reportingasignificantreductionof94%inthisoutcomeinpersonsover18years[129].Anotherstudyhasdataonall-causeempyemainolderchildrenbutfoundnosignificantdecrease[130].
Ingeneral,asthepneumoniaoutcomesbecomemorespecificforpneumococcaletiology,thereisatrendtowardsagreaterobservedindirectimpactofPCV,butthedataaresparseandfurtherstudiesareneededtoquantifytheseeffectsovertimeparticularlyinadultsandtheelderly.IPD—IndirectEffectsIPDstudiesrepresentthebulkoftheinformationthatisavailableontheindirecteffectsofPCV10andPCV13.Twenty-twostudieswereincluded,mostrepresentingEuropeancountriesusingPCV13ina2+1schedule.OnePCV10studyfromtheNetherlandsusinga3+1schedulewasincludedtobolstertheevidenceonPCV10andindividualserotypes.[133]Overall,therehasbeenareductioninall-causeIPDinthePCV10/13period(AppendixA,Table29A).IncountriesthatswitchedfromPCV7toPCV13,thisreductioncontinuedthetrendfromthePCV7period[30,109-111,116,134-140].InPCV10usingcountries(FinlandandtheNetherlands),thereissomeindicationtherehasbeenasmall,non-significantriseintheincidenceofIPDintheelderly,perhapsduetoreplacementwithNVTdisease,thatwarrantscontinuedsurveillance[133,141].WithrespecttoVTIPD,thedataareconsistentindocumentingasignificantindirecteffectofbothPCV10(n=2studies)andPCV13(n=6studies)ondiseaseinadultsandtheelderly.(AppendixA,Tables29Band29C)Specifically,followingthetransitionfromPCV7toeitherPCV10orPCV13,therateofdiseaseduetotheadditionalserotypesincludedinthehighervalencyproducthasdecreased,thoughthedataaremorerobustforPCV13thanPCV10.Intenoutof12studiesreportingonNVTIPD,therehasbeenanincreaseinNVTdiseasefromthePCV7orpre-PCVperiodtothePCV13orPCV10period,respectively.(Datanotshown.)OnlyfourstudiesreportedsignificantincreasesinNVTIPDbetween27%and96%invariousagegroups.
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TheobservedimpactofPCV10andPCV13useontypes3,6A,and19Aamongunimmunizedagestrataisdescribedinsection3.7below.Inbrief,thereisevidencethatPCV13resultsinreductionsofserotype3and6AIPDcomparedtothePCV7period.[114,116,138](AppendixA,Table29D)Serotype19AIPDalsodecreasedintheUKandDenmarkaftertransitionfromPCV7toPCV13butincreasedinIreland.[114,116,142]ForPCV10thereareverysparsedata,buttheytendtoshowsomereductionindiseaseduetoserotype6A(significancenotreported)inunvaccinatedpersons,andinanincreaseintherateofserotype3and19AIPD.[133,141]Thereisverylimiteddataonwhichtodrawfirmconclusionsone-wayortheother;thisisanimportantareaofongoingassessment.
3.8 Serotypes3,6A,19ASummaryPCV13:
• All3STarehighlyimmunogenicpostPCV13.• CarriageofST6Aand19AdeclineinthefaceofPCV13vaccination.Carriageprevalenceforserotype3
isgenerallylowprecludingrobustevaluationoftheimpactonST3.• IPD:PCV13iseffectiveinreducingST19Aand6Adisease;Somebutnotallcountriesdemonstratean
impactontype3disease• Indirecteffects:PCV13useresultsinreductionin6Adiseaseinadults.Animpacton19Ahasalsobeen
observedinsomebutnotallsettingswhileST3diseasehasdeclinedintheUKbutnotelsewhere.
PCV10:• SomeimmunogenicityisseentocrossreactiveST6Aand19Abutresponsesarelowertothoseseen
followingPCV13.Noresponsestoserotype3areseen.• CarriageofST6AinPCV10settingsisdifficulttoassessduetothelowprevalencebutsomereduction
hasbeenreported.Noimpacton19Aor3hasbeenseen.• IPD:PCV10appearseffectiveinreducingST6Aand19Adiseaseinvaccinatedchildren;noimpacton
ST3isseen.• Indirect:PCV10doesnotappeartoimpactconsistentlyonindirectdiseaseduetothesethreeST
ST3,6Aand19AFindingsSerotypes3,6Aand19AareincludedinPCV13butnotinPCV10.Howeverfortwooftheseserotypes(6Aand19A),closelyrelatedserotypes6Band19FareincludedinPCV10raisingthepossibilitythattheremaybesomebiologicaleffecton6Aand19AviacrossprotectionfollowingPCV10administration.FollowingtheuseofPCV7,whichcontainedserotype6Bbutnot6A,immuneresponsesandsomedirectprotectionagainstserotype6Adiseaseandcarriagewasnoted.PCV7includedserotype19Fbutresponsestotherelatedserotype19Aweregenerallypoorandlittleconsistentimpacton19AdiseaseandcarriagewasseenpostPCV7.ThedifferentproductiontechniquesandcarriercompositionofPCV10hasmeantthatpotentialcrossprotectionto6Aand19AfollowingPCV10meritsinvestigation.ImmunogenicityWhencomparingimmunogenicity,postprimaryandpreandpostboosterIgGgeometricmeanconcentrations(GMC’s)toserotypes6Aand19AwereinferiorpostPCV10comparedwithPCV13irrespectiveofwhether2or3primarydosesweregiven.Therewasoneexceptiontothis;onestudydemonstratedPCV10preboosterIgGconcentrationsfollowingthreeprimarydosesthatweresimilartoPCV13concentrations.
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Whenanalyzingtheresponseafterthethirddoseineithera3+0or2+1schedule,IgGGMC’sto6Aand19AwereconsistentlylowerfollowingPCV10thanPCV13intheequivalentschedule.Analysisofprimary,pre-boost,post-boostandpostdose3IgGGMC’sanalyzedbyageatfirstorlastdose,intervalbetweendosesorregiondidnotalterthegeneralfindingsindicatedabove.Analysisofproportionsabovecorrelatesofefficacy(i.e.0.35mcg/mLor0.22mcg/mL,dependingontheassayused)for6Aand19Ashowedthatproportionswereconsistentlylowerforallcomparisons(schedule,dosesetc.)comparingPCV10toPCV13immunization.However,afterprimaryvaccinationwithPCV10,>50%ofsubjectshadantibodyconcentrationsto6Aand19Athatwereabovethecorrelateofefficacy(range22-79%for6Aand22-87%for19A,basedon26studyarms).Thepercentrespondersimprovedto85%aftertheboosterdose(range72-99%and74-96%,respectively).Evidenceofboostingofantibodiesto6Aand19Awasalsoreflectedinantibodyconcentrations,whichincreased5-6foldforeachofthetwoserotypescomparedtopost-primarylevels,basedon19studies.Acomparisonofpostprimarypercentagesafter2or3primarydosesofPCV10waspossibleandrevealed10-15%greaterproportionsabovethethresholdforefficacyfollowing3comparedto2doses.WhileIgGGMC’stocrossreactiveserotypes6Aand19AandproportionsabovethecorrelateofefficacywerelowerfollowingPCV10thanPCV13thisdoesnotruleoutanimpacton6Aand19AcarriageanddiseasefollowingPCV10vaccination(seerelevantsectionsbelow).Onlytwostudiesmeasuredserotype3IgGGMC’spostPCV10andresponseswereextremelylow.Carriagea. ST3PCV13N=7studiesevaluateda3-dosePCV13scheduleonST3carriageandnoneprovidedevidenceofimpactonST3,butlowpowerduetoeitherlowbaselineST3carriageorinsufficienttimepost-PCV13introductionmakeconclusionsuncertainatthistime.N=5studiesevaluatedPCV13impactonST3incountriesthatswitchedfromPCV7toPCV13butconclusionsweredifficultduetolowST3carriage;however,mixedresults(i.e.,someincreasesandsomedecreases,nonesignificant),suggestonaveragenoimpactofPCV13onST3carriage.ThismaybesupportedbyaMalawistudythatdidnotevaluateimpactdirectlybutdidassesscarriageunderconditionsthatshouldhavemaximizedimpact(i.e.,5yearspost-PCV13introductioninPCV13-vaccinatedchildren3-5yearsoldwithoutHIVinasettingwith85%vaccinecoverageandthatusedacatch-upcampaigninchildren<1year).TheyfoundthatST3wasthemostcommonVTserotypecarried(4%),indicatingatbestsustainedcarriageofST3longafterPCV13introduction,andatworstnoimpactonST3.ST3carriagewasalsosimilarbetweenchildrenvaccinatedwithPCV13(16/881[1.8%])comparedtoPCV7-vaccinatedchildren(17/873[1.9%])inaclinicaltrialofa3+1schedule(i.e.,after4doseswhichwouldbeexpectedtohavealargerimpactthana3doseschedule),supportingthepossibilitythatPCV13maynotreducecarriageofST3;butST3carriagewaslowsotherewaslowpowertoassessimpact.PCV10:Althoughnoevidencewasfoundthat3-doseschedulesofPCV10reducecarriageofST3,abilitytoassessimpactwaslimitedbyverylowST3carriage.TwoclinicaltrialsobservedhigherST3carriageinPCV10-vaccinated(1-3isolates)comparedtounvaccinatedcontrols(0-1isolates).In1studyconductedinroutine-use,anincreasefrom3.7%to6%wasobserved;3otherstudiesevaluatedST3butbaselinecarriagewastoolowtoassessimpact.AnotherstudyintheNetherlandsofa3+1schedule(i.e.,4doses)thatswitchedfromPCV7toPCV10foundnochangeinST3carriageatanytime.
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b. ST6APCV13Evidencefrom9studiessuggestsPCV13reducescarriageofST6A.Twoclinicaltrialsshowed40%(Israel3+0,significant)and59%(Vietnam2+1)reductionincarriageofST6AinPCV13-vaccinatedchildrencomparedtoPCV7-vaccinatedchildrenandunvaccinatedchildren,respectively.In7studiesofroutine-useincountriesthatswitchedfromPCV7toPCV13,allobservedcontinueddeclinesfromthePCV7-eratopost-PCV13(1wasstatisticallysignificantbuttherestwerenotduetosmallnumbersof6Aisolates).Anotherstudyinahigh-riskpopulationinMalawi(describedabove)assessedcarriage5yearspost-PCV13introductionandfoundST6Acarriagewas2%indicatingcarriagewaslowbutpersistedlongafterPCV13introduction.PCV10:SeveralstudiessuggestthatPCV10maysomewhatreducecarriageofST6A,butnonehadlargeeffectsandnonewerestatisticallysignificantduetolowST6Acarriage.Non-significantdeclinesof10-20%wereobservedin3studiesthatevaluatedimpactafter2,3and4yearsofroutineuse;a4thstudyafter1yearofPCV10useobservedanon-significantincreasefrom0.9%(7/789)to4%(9/206).N=3clinicaltrialsevaluating3-doseschedulesallobservednon-significantlowerST6AcarriageinPCV10-vacinatedchildrencomparedtounvaccinatedcontrols.Childrenwhoreceivedonly2dosesalsohadlowercarriagecomparedtocontrolspre-booster.Twostudiesofa3+1(i.e.,4dose)schedulealsosuggestPCV10mayimpactST6Acarriage:asmall(non-significant)reductionwasobservedinaclinicaltrialandastudyintheNetherlandsevaluatingswitchingfromPCV7toPCV10foundthatdeclinesinST6Athatwereobservedpost-PCV7continuedtodeclineaftertheswitchtoPCV10.c. ST19APCV13N=5studiesevaluatedimpactofa3-dosePCV13scheduleonST19Acarriage,severalofwhichsuggestevidenceofimpact,butallhadinadequatesamplesizeand/orneedmoretimepost-PCV13.N=2clinicaltrialsassessedimpactofPCV13onST19A:carriagewastoolowtoassessinone(3/184inunvaccinatedcontrols)buttheothershowed37%lowercarriage(notsignificant)inPCV13-vaccinated(4.5%)comparedtoPCV7-vaccinatedcontrols(7%).OnestudyinFrancethatswitchedfromPCV7toPCV13foundthatthesignificantincreasesin19AthatwereobservedfollowingPCV7introductiondeclinedtobaselinelevels2yearsafterswitchtoPCV13,andTheGambiaisseeingasimilartrend.TheCambodiastudydescribedabovethatassessedimpactinchildren<5yearsofagetheyearPCV13wasintroduced(solittleimpactwouldbeexpectedsincethepercentofchildrenthatactuallyreceivedPCV13wouldhavebeenverylow),observedcarriageofST19Adecliningfrom7.4%pre-PCV13to4.3%(42%reduction).AndtheMalawistudydescribedabovefoundST19Acarriagewas3%5yearspost-PCV13introductionindicatingsustainedcarriageinhigh-riskpopulationslongafterPCV13introduction.PCV10:Therewere7studiesthatevaluatedtheimpactofPCV10onST19AandoverallitappearsthatthatPCV10hasnoimpact.N=5wereclinicaltrialsevaluating3-doseschedulesandconclusionsweredifficultduetolowST19Acarriage,butresultsweremixed(i.e.,3withincreasesand2withdecreases,nonesignificant),suggestingonaveragenoimpactofPCV10onST19Acarriage.N=3studieswereinthecontextofroutinePCV10useandallobservedincreasesin19Acarriage,generallygoingfrom1-3%to5-7%,oneofwhich(Kenya)wasstatisticallysignificant.OneadditionalstudyintheNetherlandsevaluateda3+1schedule(i.e.,4dosessoshouldhavealargereffect)andafterswitchingfromPCV7toPCV10foundthatthe5-foldincreasesin19AthatoccurredfollowingPCV7introductiondidnotreturntopre-PCV7levelsafter5yearsofPCV10use,providingfurtherevidencethatPCV10maynotreducecarriageofST19A.
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PneumoniaThisreviewdidnotidentifyanystudiesthatreportedtheimpactofPCV10orPCV13onserotype-specificpneumococcalpneumoniaInvasivePneumococcalDiseasePCV13:Threecase-controlstudiesevaluatedVEofPCV13againstindividualserotypes.TheVEof>1doseagainsttype19AIPDwas74%(Canada)andrangedfrom67to94%for>2doses(UKandSouthAfrica).TherewasnoVEofPCV13againsttype3IPDand98%VEagainsttype6Areportedinonestudy(UK).IncountriesintroducingPCV13followingPCV7ona2+1schedule,sixstudiesreportedimpactonserotype-specificIPD.Significantreductionsintype19Adisease,rangingfrom69to91%werereportedinfourstudies(Israel,France,England,andSouthAfrica)with1to4yearspost-introduction.OnestudyinDenmarkreportednochangesintype19AdiseasecomparedtoPCV7period3yearspostintroduction,withdiseaseincidencedecliningtopre-PCV7levels.Nochangesintype3IPD1to3yearspostintroductionwerereportedinthreestudies(Denmark,Israel,andSouthAfrica).Twostudiesreportedsignificantreductionsof85%and68%(FranceandEngland)intype3disease1and4years,respectively,postPCV13introduction.Significantreductionsintype6Adiseaserangingfrom85%to100%werereportedinthreestudies(SouthAfrica,Israel,andEngland)post-PCV13comparedtoprePCVperiod,althoughmostofthesereductionsshouldattributedtoPCV7impact.Onlyonestudy(Australia)reportedimpactofPCV13ontype19Adiseaseinasettingof3+0schedule(77%reductionintype19AIPD).PCV10:Fourcase-controlstudiesevaluatedVEofPCV10againstindividualserotypes.TheVEof>1doseagainsttype19AIPDrangedfrom61to82%,althoughtheestimateswerenotstatisticallysignificantinastudyfromNetherlandsandBrazil(indirectcohortmethod).TherewasnoVEofPCV10againsttypes3and6AIPD,althoughmeasuredonlyinonestudy(Brazil).Twopre/postobservationalstudiesreportedreductionsinIPDcausedbytype19AfollowingPCV7/PCV10introduction;a36%reductionwasreportedinCanadaand62%reductioninNetherlands2and4yearspostintroductionusinga2+1schedule,respectively.InFinland,a93%reductionintype19Adiseaseanda100%reductionintype6Adiseasewasreported5yearspostPCV10introduction.Additionalserotype-specificdatafromcountriesusingPCV10ispending.IndirecteffectsNPSomedataisavailableontheindirecteffectsofthePCV13-non-PCV10serotypes3,6Aand19A.NPcarriagedatafromKenyafouryearsafterPCV10introductionhasfoundthatserotypes3and6Ahavedecreasedamongadultssurveyedbuttheprevalenceof19Acarriagehasincreased2.5-fold,thoughthenumbersofpositivecarriersareverysmall(0.5%to1.4%)(AppendixA,Table2)[143].IPDWithrespecttoIPD,inFinland,therehasbeenan84%to116%increaseindiseasecausedby3,6Aand19Aasagroupinpersonsover18years,mostlydrivenbyalargeincreaseinserotype3and19Adiseaseintheelderlyinthe5yearssincePCV10use(AppendixA,Table4D)[141].Therehasbeennochangeintherateof6AIPD[141].Serotype6AIPDhasalsodecreasedinfourothercountries,onewithPCV10useandthethreewithPCV13use[114,116,133,138].Serotype3changeshavebeenmoredependentonthePCVproductinuse:diseaseincreasedintheNetherlands,likeFinland,inthesettingofPCV10useanddecreasedintheUKintheeraofPCV13use[114,133].
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Serotype19Atrendsaremoreerratic:inthreePCV13usingcountries,diseasehasdecreasedintheUKandDenmarkbutincreasedinIreland[142].Serotype19AIPDhasincreasedinbothofthePCV10countriesofFinlandandtheNetherlandsinpersons5-64yearsandover65yearsofage[133,141].IPDduetoserotype6CwasalsoreportedasincreasingmarkedlyintheNetherlandsintheelderlyinthePCV7andPCV10era[133].ContinuingsurveillanceofIPDandtrendsinserotypereplacementiswarrantedtoinformtheevolvingindirectimpactofPCVproductuseinvariouscountrysettings.
3.9 MixedPCV10-PCV13RegimensThecurrentWHOpositionpaperonpneumococcalvaccinesprovidesthefollowingstatementregardingtheuseofbothPCV10andPCV13toimmunizeanindividual(i.e.amixedproductregimen): Whenprimaryimmunizationisinitiatedwithoneofthesevaccines,itisrecommendedthatremainingdosesbeadministeredwiththesameproduct.InterchangeabilitybetweenPCV10andPCV13hasnotyetbeendocumented.However,ifitisnotpossibletocompletetheserieswiththesametypeofvaccine,theotherPCVproductshouldbeused[1].Sincethat2012WHOpositionstatementthreereports,fromtwostudies,havebeenpresentedinpublishedorabstractformontheuseofPCV10andPCV13mixedproductregimens.AnimmunogenicitystudyofPCV10boosterfollowingPCV13primingfoundlowerantibodyconcentrationsandopsonicactivityaswellaslackofmemoryB-cellinductionthanamongthosewhoreceivedPCV13booster[144,145].TheotherstudyassessedPCV13boosterfollowingPCV10orPCV13primingandfoundnodifferencesinimmunogenicityoftheboosterdoseforserotype19A,bytheproductusedforpriming[146].Theclinicalsignificanceofthesefindingsisnotclear,reinforcingtheWHO2012policystatement.
4. EconomicandfinancialconsiderationsforPCVproductsSummary
• Manycosteffectivenessanalyses(CEA)havebeenconductedforPCV10andPCV13,virtuallyallshowinghighICERwhencomparedtoacceptedstandards
• MostCEstudiesofPCV10andPCV13usevaccineimpactdataextrapolatedfromPCV7observations,assumingadifferentialhealthimpactofthetwoproductsbecauseofthemarginalincreaseinserotypecoverageofPCV13beyondPCV10;PCV10haslowerCEgenerallythanPCV13becauseoftheseassumptions
• Onlyveryfewstudiesincludetheherdeffectsinthemodelledestimates• TogetherwiththeEligibilityandTransitionpolicy,theco-financingpolicyisattheheartofGavi’s
catalyticfundingmodel.AsGavi-supportedcountriesprogressonatrajectoryofincreasingGNIpercapitatowardsphasingoutofGavisupport,theyincreasinglytakeonhigherlevelsofco-financing.Formoreinformation,pleaserefertothelatestCo-financingpolicyattheGaviwebsite:http://www.gavi.org/about/governance/programme-policies/co-financing/.
o TheAdvancedMarketCommitmenttailpriceasof2017orPCV10is$3.05perdose(for2doseand4dosevials)andforPCV13is$3.05perdosein4-dosevialand$3.30in1dosevial.Forcurrentpricingpleasesee:https://www.unicef.org/supply/files/PCV.pdf
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4.1EconomicconsiderationsforPCVproductsEconomicevaluationsfocusonmeasuringtheimpactofdiseaseontheeconomichealthoffamilies,communities,governmentsandsocietiesasawhole.Avarietyofhealtheconomicquestionscanbeaddressedincludingsuchquestionsas:Howmuchisthepreventionofpneumococcaldiseasecostingthegovernmentandhealthsystem?Howmucharehouseholdsspendingout-of-pockettopayformedicalcarerelatedtopneumococcaldisease,redirectingfundsthatcouldbeusedelsewhere?Howmuchmoneyislosttotheeconomywhenproductivitydecreasesbecauseofthisdisease?Whichinterventionorprogramisthemostcost-effective?Theanswerstothesequestionswilldifferbyproductiftherearesubstantialdifferencesinhealthimpact(addressedinsection3)orinproduct/programcostsacrosstheavailableproducts.Thesehealtheconomicanalysesareusuallynotsufficienttodrivepolicydecisions,buttheyhavebecomeanecessarypieceofevidencetomakeinformeddecisionsonhowtoallocateresourcesinatransparentway.Cost-effectivenessofPCV:FindingsfromselectedstudiesMeasuringvaccineimpactfromaneconomicperspectivehasusuallybeendoneusingcost-effectivenessanalyses(CEAs)comparingPCVtonovaccine,comparingdifferentPCVproducts,orcomparingdifferentdosingschedules.Theconclusionaboutwhetheravaccineisacost-effectiveanchoroncomparingthecostperdisabilitylife-yearaverted(cost/DALY)tosomechosenthreshold,oftenusingtheWHOthresholdofbasedonthenationalannualGDPpercapita.ThereisagrowingbodyofliteratureontheeconomicevaluationofPCVinavarietyofsettings(AppendixA,Table26)[147,148][149][150][151][152][153,154][155][156,157][158].Studiesdifferonkeyinputvariables—suchascostofvaccine,estimatedvaccineeffectiveness,perspectiveandinclusionofindirecteffects—thusmakingdirectcomparisonsoftheirresultsacrossstudiesilladvised.However,thevastmajorityofstudiesshowincrementalcosteffectivenessratiosintherangeconsideredhighlycost-effective.Studieshavegenerallybeenconsistentintheendpointoutcomesselected,butthereislittleconsistencyintheinclusionofindirecteffectsandserotypereplacement.Ofstudiesthatincludedthese,therewasawiderangeofparametersselected.ManystudiesusedserotypereplacementdatafromtheU.S.,whichmaynotbeapplicabletosettingswithdifferentserotypedistributions[147,155,159].Additionally,itisdifficulttoextrapolateresultsofPCVCEAstoothersettingsbecauseofdifferencesinthehealthsystem,vaccinefinancing(i.e.,Gavieligiblevs.non-eligible),anddiseaseepidemiology.A2006-2014systematicreviewofCEAstudiesgloballyhighlightssomeofthechallengesinestimatingthecost-effectivenessofPCVproducts[159].Twenty-eightstudieswereincludedinthereviewbasedontheirinclusionofPCV10orPCV13asoneofthevaccinesevaluated.Thestudiesvariedwidelyinvaccinecostperdose,andmoststudiesdidnotperformsensitivityanalysesonvaccinecost,whichcanbehighlyinfluential.Ofthe28studies,17studieswerefundedbyindustry(allthePfizer-fundedstudiesfoundPCV13toyieldfavorablecost-effectivenessresults,andalltheGSK-fundedstudiespreferredPCV10;somestudiescomparedPCV13andPCV10directlyhoweverthecomparatorforcost-effectivenessinmoststudieswasno-vaccination).Thisdifferencemainlyliesintheassumptionsforthemodel.Ofthe11studiesthatwerenotfundedbytheindustry,allconcludedthatPCV13andPCV10werelikelytoperformfavorablytothecurrentsituation(i.e.oftenPCV7)butthedecisionofwhichofthesetwovaccinecandidatestochoosefromwaslessclear,duetouncertaintiesonserotypereplacementandherdeffects,serotypecross-protectionandNTHiAOMprotection.Theauthorsconcludedthatcost-effectivenesswashighlydependentonthepriceusedinthemodels,andtheweightpolicymakersattachedtopreventingIPDcasesversusAOMcasesthroughPCVuse[159].LimitationsoftheeconomicevaluationofPCV10vs.PCV13areimportanttoconsider.TheindirecteffectsofPCVusedwereahighlyinfluentialparameterinsensitivityanalysesoftenincreasingthecost-effectivenessbyseveralfolds,butmanystudiesdidnotaccountforherdeffectsorserotypereplacement.
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TasslimiandcolleaguesprovideaCEAofPCV10andPCV13usinga3p+0schedulecomparedtonovaccineinGavi-eligiblecountries[148].TheauthorsconcludethatPCVwouldbehighlycosteffectivein69of73Gavi-eligiblecountriesbasedontheWHOGNIpercapitathresholds.Thisfindingwasrobustwhenassumptionsregardingdiseaseepidemiologyandvaccine-relatedeffectswerevariedinsensitivityanalyses[148].Thisstudyaccountsforindirecteffects,herdimmunityandserotypereplacement,andtakesa10-yearsocietalperspective.Outcomesincludedinthemodelare:pneumococcalpneumonia,pneumococcalmeningitisandnon-pneumonia,non-meningitisIPDinchildrenU5years;andpneumococcalmeningitis,pneumococcalsepsisandall-causepneumoniainolderchildrenandadults.Theauthorsobservedanotableimprovementinpooledcosteffectiveness,allothervariablesbeingequal,whenmovingfromPCV7toPCV10,butlittleadditionalimprovementfromPCV10toPCV13(AppendixA,Table25-26)[148].AstudyofPCVcost-effectivenessin77middle-incomecountriesfoundPCV10andPCV13tobecost-effectiveforallcountriescomparedtonovaccine[149].
4.2FinancialconsiderationsforPCVproductsSince2007,allcountriesapplyingtoGaviforNewVaccineSupportco-financeaportionofthecost.Theco-financingrequirementforindividualcountriesdependsontheirtransitionphasepertheEligibilityandTransitionpolicy.Intheinitialself-financingphase,thegovernment’scontributionisaflatamount:US$0.20perdoseofanyGavi-supportedvaccinethatisusedinroutineimmunizationprograms.Thiscontributionisintendedprimarilytoreinforcecountryownershipandbuildprocurementcapacity,withoutdiscouragingnewvaccineadoption.Whenacountryentersthepreparatorytransitionphase,thegovernment’scontributionincreasesby15percentperyear.Inthisphase,theco-financingrequirementisapercentageofthepriceofvaccines,andtheabsoluteamountwillthusvaryfromvaccinetovaccine.Whenacountryentersacceleratedtransition,thegovernment’sshareofvaccinecostsincreasesfromthelevelithadreachedduringthepreviousphaseto100%ofthecostoveraperiodoffiveyears[149].In2009thepilotAdvancedMarketCommitment(AMC)forPCVwasestablished.TheAMCprovidesaninnovativefinancemechanismtoincentivizethescalingupofPCVproductiontomeetdevelopingcountryneeds.BothGSK(themanufacturerofPCV10)andPfizer(themanufacturerofPCV13)areAMC-eligiblemanufacturers.AccordingtothetermsoftheAMC,thepriceofPCV10andPCV13toGavi-supportedcountrieswillbenomorethanthe“tailprice,”intendedtocovertheincrementalproductioncostofvaccine[160].In2017thetailpriceofPCV102dosevialandPCV134dosevialtoUS$3.05perdoseandthetailpriceofPCV13singledosevialis$3.30perdose[149].149].AsofDecember31,2016,59outof73Gavi-eligiblecountrieshavebeenapprovedforAMCsupportedintroductionofPCV,and57countrieshaveintroducedPCV,with2countriesplanningtointroducethevaccinewithGavisupportin2017(IndiaandHaiti)[149].TheAMCTermsandConditionsprovideaccesstoAMC-supplyandpricesforPCVtothe73countriesthatwereGavi-eligiblein2003,eveniftheyarenolongerGavi-supported.Thesecountrieswillpaythetailprice[161].Otherstrategiesforreducingvaccinecostincludepooledprocurementandsupply-sideapproaches,whicharemostlyrelevantforcountriesnoteligibletoaccessAMCsupplyandprices.ProcurementofvaccineatreducedcostismadepossiblethroughthePanAmericanHealthOrganization(PAHO)revolvingfundandthroughtheUNICEFSupplyDivision[166].Thereisalsoanexampleofatechnologytransferagreementbetweenamiddle-incomecountryandamanufacturer.BrazilhasagreedtopurchaseUS$2.2billionofPCV10fromGlaxoSmithKlineoveran8-yearperiodinexchangefortechnologytransferthatwilleventuallyallowBraziltomanufacturethevaccineforitself[166].
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InadditiontothetwoPCVsthatareWHOpre-qualifiedandhaveestablishedsupplyagreementsundertheAMC,twoothermanufacturershaveregisteredpublicallyforinclusionintheAMC.ThesetwomanufacturersarePanaceaBiotecLimited(India)andSerumInstituteofIndia.SeveralPCVproductsfrombothmultinationalanddevelopingcountrymanufacturersareindevelopment,andtheirentranceintothemarketwillimprovethebalanceofsupplyanddemandandcouldeventuallyprovidecompetitivepressuresinthemarket.However,asPCVsarecomplicatedproductstomanufacture,thepriceswilllikelyreflectcostsofmanufacturingthatareinthesamerangecurrentprices.Onemanufacturer,SerumInstituteofIndiahaspublicallystatedapriceof$2.00perdose[167].
5. ProgrammaticconsiderationsforavailablePCVproductsSummary
• BothPCV10andPCV13willbeavailablein4-dosevialswithpreservativeo PCV13,4-dosevialsareavailableinearly2017o PCV10,4-dosevialsareexpectedtobeavailablein2018pendingWHOpre-qualification
• ThecoldchainvolumeperdoseofPCV104dv(2.4cm3)istwothirdsofPCV134dv(3.6cm3).• PCV13willalsocontinuetobeavailablein1-dosevials;PCV10in2-dosevialswillnolongerbe
availableoncePCV104-dosevialsareavailableand,asthecasemaybe,haveattainedlocalregistrationincountries.
• CountriesmaybeentitledtoaproductswitchgrantuptoUS$0.25perchildinthebirthcohortoralumpsumofUS$30,000whicheverishigher,iftheymeettherequiredcriteria.Inordertorequestaproductswitchgrant,countriesshouldsubmittheirrequest,alongwithaproductswitchbudget,throughtheGavicountryportalatthetimeoftheNVSrenewalrequest.ThedetailsoftheproductswitchpolicycanbefoundonGavi'swebsiteat:http://www.gavi.org/about/governance/programme-policies/health-system-and-immunisation-strengthening-support-framework/.
• Thereisalmostnoinformationontheperformanceofmixedproductregimensinindividualchildren
ProgrammaticFindings:CarefulconsiderationshouldbegiventotheprogrammaticissuesandimplicationsaroundPCVproductchoice,andwhenweighingaswitchbetweenPCVproducts.Anychangeinproductusedwillhaveimportantcostsandprogramimplications,bothpositiveandnegative:
• Retrainingofhealthworkersisrequired,particularlyaroundthemulti-dosevialpolicytoreviewhowlongtheproductcanbekeptanddiscusspoliciesregardingbothwastageandavoidingmissedopportunities.
• Productavailability• Operationalissues–finishingoutandswitchingsupplyofvaccines,coldchainspaceor
transportationrequirements• Evidenceonmixedproductregimens(SeeSection3.9)
Asof2017,countriesmaychooseamongoneandfour-dosevialsforPCV13andfrom2018willhaveaccessonlyto4-dosevialsforPCV10(seeTableinSection5.3.2below).Aswitchtoeithervaccines4-dosevialwilltriggersomeprogrammaticprocessesincludingstaffretrainingandplanningfortheswitchtomanageexistinginventory.Currently,threepresentationsofPCVareavailabletoAMCeligiblecountries.Futurechoicesareexpectedtoalsobeavailableinmulti-dosevialswithpreservative.
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5.1 RecommendedPCVdosingschedulesForcountriesusing3dosesofPCV,WHOhasrecommendedeitheroftwodosingschedules–3p+0or,alternatively,2p+1–eachrequiring3dosesofeitheravailablePCVproduct(10Vor13V)[1].Therearetrade-offsinchoosingbetweenthesetwoschedules,butthechoiceofscheduleisnotinfluencedbyproduct.Forthisreasonwedonotprovideanindepthdiscussionofproductchoice,byscheduleinthisdocument.SchedulepreferencesareunderreviewbyaSAGEPCVWorkingGroup(WG).WHOconvenedtheSAGEWGonPCVsinDecember2016.InJune2017theWGwillreviewtheevidenceonPCVimmuneresponse,VE,andimpacttoinformtheirproposedrecommendationstotheWHOpositiononPCVusetoSAGEinOctober2017(asappropriate).
5.2 NumberofinjectionsperroutineimmunizationvisitGiventhatthenumberofdosesadministeredofeitherPCV10orPCV13shouldbe3perchildandthatWHO’srecommendedschedulesforadministrationofthesedosesarethesameforbothproducts,thenumberofinjectionsgivenatanimmunizationvisitshouldnotchangebasedontheproductchosen.
5.3 Currentandfutureproductpackaging,presentation,coldchainandstorageVialscontaining4-dosesofPCV13areavailableand4-dosePCV10vialsareexpectedin2018.Insomecases,Gavi-eligiblecountrieswillberequiredtoswitchpresentations(PCV10willonlybeavailableina4-dosepresentationstartingafterPCV104-dosepresentationhasattainedlocalregistrationinGavicountriesin2018).Section5.3.1describesthecurrentproductsavailableand5.3.2providesdetailsontheforthcoming4-dosepresentationsforbothPCV10andPCV13.Theselectionofproductpresentationshouldbemadebyweighingtherelativeadvantagesanddisadvantagesofeachproduct.Forexample,whilesingle-dosepresentationsshouldminimizewastageofunusedvaccine,thecoldchainandstoragerequirementsaregreater.Inaddition,new4-dosepreservative-containingPCV10andPCV13productswillbesubjecttotheguidancelaidoutintheWHOMultidoseVialPolicy[168].Countrieswillneedtoensureclearlyarticulatedpoliciesandcarefultrainingforhealthworkerstominimizewastageofunusedvaccinedosesinopenvials,andtomaximizeopportunitiestovaccinatechildren.ThisisespeciallyimportantinsettingswhereimmunizationsessionsmayconsistofsmallnumbersofchildrenandespeciallyimportantforPCV10usingcountriesswitchingoverfromthe2-dosevialwhichdoesnotcontainpreservativeandisdiscardedafter6hours.
5.3.1CurrentPCVpresentationsCurrently,PCV10isavailablein100-vialcartons;eachvialcontainstwo-doses,correspondingtoavolumeof4.8cm3perdose.Atpresent,PCV13isavailablein50-vialcartons;eachvialisasingle-dose,corresponding12cm3perdose,or2.5timesthevolumeofPCV10.Thesingle-dosePCV13vialrequiresmorespaceforcoldchainstorageanddistribution,butitreducesvaccinewastage(5%estimated)comparedtoatwo-dosevialthatifopenedandnotusedinthesamedaymustbediscarded(10%estimatedwastage)(Table3,Section2.4).PCV134-dosevialsarenowavailableforuse(asof2017).PCV13isavailableasaliquidvaccineinsingle-dosevials(Gaviandnon-Gavicountries),orprefilledsyringes(non-Gavicountries).The4-dosePCV13isavailabletoGavicountriesinpackagesof50vials(200doses)[169].OfthecurrentlyavailablePCVproductsorformulationsbothPCV10andPCV134-dosevialscontainapreservative.PCV10ispresentedinasingle-dose(non-Gavicountries)ortwo-dosevialwithoutpreservative(Gavicountries).TheWHOspecificallyassessedthesafetyofthetwo-dosePCV10formulationinaKenyanstudypriortoreceivingfullpre-qualification.Inthisstudy,theriskratioforabscessfollowinginjectionwiththesecondvs.firstvialdoseofPCV10wasnotsignificantlyincreasedcomparedtoanotherEPIvaccine(pentavalentvaccine),lendingsupporttothefeasibilityofsafelyusingthisformulationinAfricaandlow-incomesettings[170].
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PCV10 in a 2-dose vial presentation will no longer be available once the PCV10 4-dose presentation has been prequalified and attained local registration within your country. Countries currently supported for PCV10 2-dose vials need to submit a request to indicate to which presentation they want to switch through the Gavi country portal during the annual reporting cycle in May 2017, or if urgent through a letter to Gavi outside that date.
5.3.24-DoseVialPCVpresentationsPCV13 4-dose vials have become available to Gavi countries in 2017 and PCV10 4-dose vials are forecasted to become available in 2018 [162]. The availability of PCV10 4-dose vials is pending its prequalification by WHO, expected in late 2017, and, as the case may be, its local registration. PCV13presentationina4-dosevialwithapreservativehasreceivedWHOPQandisavailableglobally.Both4-dosevialpresentationsarecurrentlyavailableasproductoptionsthroughtheGavicountryportalintheMay2017reportingcycle.Productpackagingandpresentation:4-dosevials[171]PCV10:CountriesthatcurrentlyhavePCV102-dosevialsintheirroutineimmunizationwillhavetoswitchtoPCV104-dosevials(ortoanotherPCVproductoftheirpreference)from2018onwards.IfacountrywishestoswitchtoapresentationotherthanPCV104-dose,theywillneedtoindicatetheirpreferencethroughtheGavicountryportalintheMay2017reportingcycle,orifurgentthroughalettertoGavioutsidethatdate.• 2017:
o Single-dosevials(non-Gavi)o Two-dosevials:cartonsof100vials(availabletoGavicountries)
• 2018onwards(assumingWHOPQachieved):Insteadof1-dosevial,4-dosevialswillbeavailablethroughGavitocountriesusingPCV10.(Note:PCV102-dosewillremainavailableuntilPCV104-dosepresentationhasattainedlocalregistrationinGavicountries.)
o New4-dosevials:§ Preservative:Containspreservative(2-Phenoxyethanol)§ Shelflife:36months§ Volume:2.4cm3/dose§ Wastagerateneedstobeconfirmed.Currentassumptionis10%assameascurrent2-dose
presentation†§ EMAapprovalandWHOpre-qualificationanticipatedinfourthquarterof2017with
productavailablesometimeinearly2018§ Subjecttopre-establishedWHOMulti-dosevialpolicy(MDVP)forusageafteropening§ Willcontainavaccinevialmonitor(VVM)
†InformationprovidedforPCV104-dosevialisbasedonassumptionsanddiscussionswithWHO.However,finalopenvialpoliciesandwastageassumptionswillbereviewedandrevisedafterWHOpre-qualification.WHOpolicyontheuseofopenedmulti-dosevaccinevials(2014Revision)canbeconsultedat:http://www.who.int/immunization/documents/general/WHO_IVB_14.07/en/PCV13:PCV13isavailableina4-dosevialasofearly2017andwillcontinuetobeavailabletoGavicountriesinasingle-dosevialfortheforeseeablefuture.Theslightlylowerper-dosecostofthe4-dosePCV13productascomparedthesingle-dosePCV13maybeoffsetbyhigherwastagecomparedtotheslightlymoreexpensive
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single-dosepresentationandthesetrade-offsshouldbeconsideredcarefully.Whenconsideringstandardwastageadjustments,thepercoursecostofthe1dosevialis$9.90comparedwithacostof$9.15forthe4-dosevialforPCV13.[172]• 2017onwards:
o Single-dosevials:cartonsof50vialso New4-dosevialsarealsoavailabletoGavicountries
§ Preservative:containspreservative(2-Phenoxyethanol)§ Shelf-life:24months§ Packaging:availableincartonsof50vials/200dosesthatarethesamesizeascurrent1d
product(thusrequiressamestoragespaceascurrentpackagingof50single-dosevials)§ Volume:3cm3/dose§ Subjecttopre-establishedWHOMulti-dosevialpolicy(MDVP)forusageafteropening(i.e.
presentationcanbeusedovera28-dayperiodfollowingitsfirstuse,givenstorageat2-8degreesCelsius)
§ Willcontainavaccinevialmonitor(VVM)
5.4 TrainingandsupervisionrequirementsPCV10:Thecurrentlyavailableproductsdonotcontainapreservative.The2-dosepreservative-freepresentationavailabletoGavicountriesrequiresspecifictrainingforhealthworkers:openedvialsofthisPCVproductmustbediscardedattheendoftheimmunizationsessionorsixhoursafteropening,whichevercomesfirst.Additionaldetailscanbefoundinsection3oftheWHOPCV10IntroductionHandbook[3].OthertrainingandadministrationrequirementsforPCV10aresimilartothoseforPCV13.Theforthcoming4-dosepresentationofPCV10isexpectedtobepre-qualifiedinlate2017andavailablein2018.ThisistheonlypresentationthatwillbeavailabletoGavicountriesexceptduringtransitionperiodfromthecurrent2-doseformulationtothenew4-dosepresentationforPCV10.TheproductwillcontainapreservativeandwillbesubjecttotheguidanceprovidedinWHO’sMDVP.Openvialsofvaccineneedtobecarefullymanagedsoastominimizewastageandmustbediscardedafter28days.Inaddition,thepoliciesaboutopeningofvialsforsmall-sizeimmunizationsessionsshouldbecarefullyarticulatedtoastoavoidinadvertentmissedopportunitiestovaccinate.PCV13:Thesingledosepresentationdoesnotcontainapreservative.ThetrainingrequirementsforthispresentationavailabletoGavicountriescanbefoundinsection3oftheWHOPCV13IntroductionHandbook[4].The4-dosepresentationofPCV13isWHOpre-qualifiedandavailableasof2017.Thenew4-dosepresentationcontainsapreservativeandissubjecttotheguidanceprovidedinWHO’sMDVP.Openvialsofvaccineneedtobecarefullymanagedsoastominimizewastageandmustbediscardedafter28days.Inaddition,thepoliciesaboutopeningofvialsforsmall-sizeimmunizationsessionsshouldbecarefullyarticulatedtoastoavoidinadvertentmissedopportunitiestovaccinate.
6. SupplyconsiderationsforavailablePCVproductsUnderthetermsoftheAdvanceMarketCommitment(AMC),PCVistobeprocuredbyGavicountriesthroughUNICEFSupplyDivision.Thisisdifferentfromprocurementoptionsforotherproducts,whichincludeself-procurementoptionsandeventransitionedGavicountriesmustprocurethroughUNICEFtogetaccesstotheAMCprice[2,173].
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AccurateforecastingofdoseprocurementisalsocriticalandcountriescanusetheWHOVaccineForecastingTool.Countriescanselectfromoneoftwoavailableprequalifiedproducts(PCV102-dosevial)(PCV13,1-doseand4-dosevial).A4-dosePCV10vialisexpectedtobepre-qualifiedinlate2017.Forcountrieswishingtoswitchfromthesingledosepresentationtothe4-dosepresentation,theymustindicatethroughtheGavicountryportalduringtheannualreportingcycleinMay[171].Storageandlogisticsrequirementsshouldbeconsideredandthe4-dosevialwillreducestoragerequirementssignificantlyasdescribedinsection5.3.2.Wastageratesforcountriesswitchingfromasingledosepresentationtoa4-dosepresentationwillalsoincreasefrom5%to10%sothatwillneedtobetakenintoaccount.ShelflifewillbesimilarforbothPCVproductsin4-dosevials(36months).
6.1 Supplyavailability&constraintsAccordingtoUNICEF,supplyavailabilityisnolongerconsideredconstrained.BothsuppliersofPCVhaveincreasedproductioncapacity,anditissufficienttomeetnewapprovedGavicountrydemand.UNICEFhasa10-yearAMCsupplyagreementswithPfizer(740milliondosesthrough2023)andGSK(720milliondosesthrough2024).Demandreached164milliondosesin2016[174, 175].India,whichisplanningintroductionin2017,willaddanadditional8.9milliondosesin2017ontopofincreasesinotherGavicountries.TheseadditionalquantitieswillbemetthroughtheexistingSupplyAgreements.However,asIndiaandothercountriesincreasedemandinfutureyears,therecouldbeshort-termriskstothesupply-demandbalancepriortoentryofnewmanufacturers.Additionally,asthe4-dosevialfromPfizer(alreadyprequalified)hasbeenintroducedin2017andthe4-dosevialfromGSKisexpectedtobeintroducedin2018[176],demandwillshiftfromsingledosePCVtomulti-dosevial(MDV)PCV.TheuncertaintyofcountrypreferenceanddemandforMDVpresentationscouldhaveanimpactondemandforecastsandthereforeavailabilityofpreferredpresentationinthefuture.
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105. Andrews,etal.,Serotype-specificeffectivenessandcorrelatesofprotectionforthe13-valentpneumococcalconjugatevaccine:Apostlicensureindirectcohortstudy.TheLancetInfectiousDiseases,2014.14(9):p.839-846.
106. Tomczyk,S.,etal.,EFFECTIVENESSOF13-VALENTPNEUMOCOCCALCONJUGATE(PCV13)INTHEDOMINICANREPUBLIC:PRLEIMINARYRESULTSFROMAMATCHED-CASECONTROLSTUDY.ISPPD-10,2016.
107. Gottberg,A.v.,etal.,EFFECTIVENESSOFTHE13-VALENTPNEUMOCOCCALCONJUGATEVACCINEAGAINSTINVASIVEPNEUMOCOCCALDISEASEINSOUTHAFRICANCHILDREN:ACASE-CONTROLSTUDY.ISPPD-10,2016.
108. Gidding,H.,etal.,POPULATION-BASEDESTIMATESOFPNEUMOCOCCALCONJUGATEVACCINEEFFECTIVENESSINAUSTRALIA.ISPPD-10,2016.
109. Guevara,M.,etal.,Direct,indirectandtotaleffectsof13-valentpneumococcalconjugatevaccinationoninvasivepneumococcaldiseaseinchildreninNavarra,Spain,2001to2014:cohortandcase-controlstudy.EuroSurveill,2016.21(14).
110. Jayasinghe,S.,etal.,ACOMPARISONOFPOPUATIONIMPACTOF13VPCVAND7VPCVTHREEYEARSPOSTINTRODUCTIONUSINGA“3+0”SCHEDULEINAUSTRALIA.ISPPD-10,2016.
111. Mackenzie,G.A.,etal.,EffectoftheintroductionofpneumococcalconjugatevaccinationoninvasivepneumococcaldiseaseinTheGambia:apopulation-basedsurveillancestudy.LancetInfDis,2016.16:p.703-11.
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113. Lepoutre,etal.,ImpactofthepneumococcalconjugatevaccinesoninvasivepneumococcaldiseaseinFrance,2001-2012.Vaccine,2015.33(2):p.359-366.
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126. Ben,etal.,Pneumococcalnasopharyngealcarriageinchildren<5yearsofagevisitingthepediatricemergencyroominrelationtoPCV7andPCV13introductioninsouthernIsrael.HumVaccinImmunother,2015:p.0.
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130. Nath,etal.,HastheincidenceofempyemainScottishchildrencontinuedtoincreasebeyond2005?ArchivesofDiseaseinChildhood,2015.100(3):p.255-258.
131. Papucci,S.L.,etal.,IMPACTOFUNIVERSALIMMUNIZATIONWITHPNEUMOCOCCALCONJUGATEVACCINE13-V(PCV13V)ONHOSPITALIZATIONSFORPNEUMONIAANDBACTERIALMENINGITISINVILELACHILDREN’SHOSPITAL,ROSARIO(SANTAFE)ARGENTINA.ISPPD-10,2016.
132. Kostenniemi,U.J.andS.A.Silfverdal,PNEUMOCOCCALVACCINATIONEFFECTIVEONOTITISBUTFAILAGAINSTPNEUMONIA–AREGISTERBASEDSTUDYOFRESPIRATORYTRACTINFECTIONSINANORTHERNSWEDISHCOUNTY.ISPPD-10,2016.
133. Knol,M.J.,etal.,INCIDENCEOFINVASIVEPNEUMOCOCCALDISEASEINTHENETHERLANDSUPTOFOURYEARSAFTERINTRODUCTIONOF10-VALENTPNEUMOCOCCALCONJUGATEVACCINATION.ISPPD-10,2016.
134. Steens,etal.,Pneumococcalvaccinationinolderadultsintheeraofchildhoodvaccination:PublichealthinsightsfromaNorwegianstatisticalpredictionstudy.Epidemics,2015.11:p.24-31.
135. Collins,S.,etal.,TRENDSININVASIVEPNEUMOCOCCALDISEASEOVERTIME:ENGLANDANDWALES2000/01TO2014/15.ISPPD-10,2016.
136. Ricketson,L.,etal.,PNEUMOCOCCALSEROTYPESCAUSINGINVASIVEDISEASEPOST-PCV13:ATALEOFTWOCANADIANCITIES.ISPPD-10,2016.
137. Ramirez-Cardoce,M.,J.Villalobos-Vindas,andJ.Castro-Cordero,INVASIVEPNEUMOCOCCALDISEASEINANADULTPOPULATIONINCOSTARICABEFOREANDAFTERINTRODUCTIONOFPNEUMOCOCCALCONJUGATEVACCINES.ISPPD-10,2016.
138. Gottberg,A.v.,etal.,ONGOINGPNEUMOCOCCALDISEASEDECLINESANDANINDIRECTEFFECTOFVACCINATION,SOUTHAFRICA,2005-2015.ISPPD-10,2016.
139. Plessis,M.d.,etal.,Non-vaccinepneumococcalserotypesinadultsaged>25yearspreandpostpneumococcalconjugatevaccineintroductioninSouthAfrica.ISPPD-10,2016.
140. Moberley,S.,etal.,EpidemiologyofinvasivepneumococcaldiseaseinIndigenousAustralianadults.ISPPD-10,2016.
141. Nuorti,P.,etal.,EVIDENCEOFHERDPROTECTIONANDSEROTYPEREPLACEMENTINADULTSAFTERUNIVERSAL10-VALENTPNEUMOCOCCALCONJUGATEVACCINATIONOFINFANTSINFINLAND.ISPPD-10,2016.
142. Corcoran,M.,etal.,THEPERSISTENCEOFSEROTYPE19A–DESPITETHEINTRODUCTIONOFPCV13VACCINE.ISPPD-10,2016.
143. Hammitt,L.,IndirectImpactofPneumococcalConjugateVaccineinKilifi,Kenya,M.Ramakrishnan,Editor.2016.
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144. Truck,J.,etal.,DivergentMemoryBCellResponsesinaMixedInfantPneumococcalConjugateVaccineSchedule.PediatrInfectDisJ,2016.
145. Truck,J.,etal.,TheAntibodyResponseFollowingaBoosterWithEithera10-or13-valentPneumococcalConjugateVaccineinToddlersPrimedWitha13-valentPneumococcalConjugateVaccineinEarlyInfancy.PediatrInfectDisJ,2016.35(7):p.787-93.
146. Prymula,R.,etal.,ABOOSTERDOSEOFPCV13INCHILDRENPRIMEDWITH2OR3-DOSESOFPHID-CV–POSSIBLEALTERNATIVEIMMUNIZATIONSTRATEGY?ISPPD-10,2016.
147. Sinha,A.,etal.,Cost-effectivenessofpneumococcalconjugatevaccinationinLatinAmericaandtheCaribbean:aregionalanalysis.RevPanamSaludPublica,2008.24(5):p.304-13.
148. Tasslimi,A.,etal.,CosteffectivenessofchildpneumococcalconjugatevaccinationinGAVI-eligiblecountries.IntHealth,2011.3(4):p.259-69.
149. Nakamura,M.M.,etal.,Costeffectivenessofchildpneumococcalconjugatevaccinationinmiddle-incomecountries.IntHealth,2011.3(4):p.270-81.
150. Kim,S.Y.,G.Lee,andS.J.Goldie,EconomicevaluationofpneumococcalconjugatevaccinationinTheGambia.BMCInfectDis,2010.10:p.260.
151. TourayMML,H.R.,AcharyaA.,ThecosteffectivenessofpneumococcalconjugatevaccineintheroutineinfantimmunisationprogrammeofTheGambia..JournalPharmHealthServicesRes.,2011.2:p.175-84.
152. Ayieko,P.,etal.,Assessmentofhealthbenefitsandcost-effectivenessof10-valentand13-valentpneumococcalconjugatevaccinationinKenyanchildren.PLoSOne,2013.8(6):p.e67324.
153. Tate,J.E.,etal.,ProjectedhealthbenefitsandcostsofpneumococcalandrotavirusvaccinationinUganda.Vaccine,2011.29(17):p.3329-34.
154. Kieninger,M.P.,etal.,Cost-effectivenessanalysisofpneumococcalconjugatevaccineintroductioninParaguay.Vaccine,2015.33Suppl1:p.A143-53.
155. Kulpeng,W.,etal.,Cost-utilityanalysisof10-and13-valentpneumococcalconjugatevaccines:protectionatwhatpriceintheThaicontext?Vaccine,2013.31(26):p.2839-47.
156. Sartori,A.M.,P.C.deSoarez,andH.M.Novaes,Cost-effectivenessofintroducingthe10-valentpneumococcalconjugatevaccineintotheuniversalimmunisationofinfantsinBrazil.JEpidemiolCommunityHealth,2012.66(3):p.210-7.
157. Castaneda-Orjuela,C.,etal.,Cost-effectivenessofpneumococcalconjugatevaccinesof7,10,and13valencesinColombianchildren.Vaccine,2012.30(11):p.1936-43.
158. Mezones-Holguin,E.,etal.,Cost-effectivenessanalysisof10-and13-valentpneumococcalconjugatevaccinesinPeru.Vaccine,2015.33Suppl1:p.A154-66.
159. Wu,D.B.,etal.,Choosingbetween7-,10-and13-valentpneumococcalconjugatevaccinesinchildhood:areviewofeconomicevaluations(2006-2014).Vaccine,2015.33(14):p.1633-58.
160. Snyder,C.M.,W.Begor,andE.R.Berndt,Economicperspectivesontheadvancemarketcommitmentforpneumococcalvaccines.HealthAff(Millwood),2011.30(8):p.1508-17.
161. Gavi,t.V.A.,2015PneumococcalAMCAnnualReport.2015,Gavi,theVaccineAlliance:Geneva,Switzerland.
162. Gavi,t.V.A.PCV4-doseVialsFAQs.2017.163. UNICEFSupply:PCV2017.164. Pfizer,250millionpneumococcalconjugatevaccinedosesdeliveredinGavicountries.2017:
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165. CohenOG,G.K.,MuralidharanK,O'BrienKL,KnollMD,GapAnalysisofPCVImpactEvaluationsinSettingsofRoutineUse.2016,JohnsHopkinsUniversity:Baltimore,MD.
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167. Roy,M.CyrusPoonawalla&AffordableVaccines.TheBorgenProject,2013.
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168. Organization,W.H.,WorldHealthOrganizationPolicyStatement:Multi-doseVialPolicy(MDVP)Handlingofmulti-dosevaccinevialsafteropening.2014:Geneva,Switzeralnd
169. Inc.,P.,PfizerReceivesEuropeanApprovalforNewMulti-DoseVialPresentationofPrevenar13®,inFour-DoseVialWillHelpAddressInfrastructureChallengesinDevelopingCountries,P.Inc.,Editor.2016,PfizerInc.:http://www.pfizer.com.
170. Burton,D.C.,etal.,RiskofInjection-SiteAbscessamongInfantsReceivingaPreservative-Free,Two-DoseVialFormulationofPneumococcalConjugateVaccineinKenya.PLoSOne,2015.10(10):p.e0141896.
171. Gavi,t.V.A.,PneumococcalConjugateVaccine(PCV)4-dosevialpresentations:FrequentlyAskedQuestions(FAQs)March2016,t.V.A.Gavi,Editor.2016,Gavi,theVaccineAlliance.
172. Gavi,t.V.A.VaccineSupply&Procurement.2016.173. Gavi,t.V.A.,2017APPLICATIONGUIDELINESFORPNEUMOCOCCALVACCINESFORCOUNTRIESTHAT
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174. Division,U.S.,PneumococcalConjugateVaccine:Supply&DemandUpdate,UNICEF,Editor.2016.175. Gavi,t.V.A.,PneumococcalAMCReport,inAMCAnnualReport2016.2016:
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i
AppendixA.
TABLE1.CharacteristicsofincludedstudiesinNPCarriageAnalysis
PCV10 PCV13CharacteristicN=37
2+1N=4(11%)
3+0N=14(38%)
3+1N=1(2%)
TotalN=19(51%)
2+1N=13(35%)
3+0N=8(22%)
TotalN=21(57%)
Studytype Clinicaltrial 4 6 0 10 3 2 5
Pre/postsurvey 0 4 1 5 10 3 13Postsurvey 0 1 0 1 0 3 3
Case-control/indirectcohort
0 3 0 3 0 0 0
Region Africa 0 4 0 4 2 3 5Asia 2 3 0 5 2 1 3
Australia/Oceania 0 3 0 3 0 3 3Europe 1 3 1 5 9 1 10
LatinAmerica 1 1 0 2 0 0 0NorthAmerica 0 0 0 0 0 0 0
PreviousOtherPCVProductUse
PCV7 0 1 1 2 10 3 13PCV10 - - - - 1 1 1
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ii
TABLE2.ObservationalstudiesestimatingpercentrelativereductionagainstvaccineserotypeNPCarriageamongthegeneralpopulation
StudyInformation %RelativeReduction(95%ConfidenceInterval)Comparedto
Region Country(Reference)
StudyDesign
DosingSchedule
PCVIntroductionYear(s)
NumberofYearsPostIntroductionCarriageEvaluated
AgeGroup(s)(Population)
Baseline(noPCV)
PCV7Period
PCV10
AFR Mozambique(Sigaque;Moiane2016)
PrePostSurvey
3+0 PCV10:2013
PCV10:2 0-23months(HIV-)0-59months(HIV-)
42.7%(19,60)30.1%(12,44)
PCV7NotUsed
AFR Kenya,Kilifi(Hammitt2014;2016)
PrePostSurvey
3+0 PCV10:2011
PCV10:4 <2years(General)<5years(General)
83.8%(76,89)97.1%(94,99)
PCV7NotUsed
AFR Kenya,Nairobi(Kim2016;2014)
PrePostSurvey
3+0 PCV10:2011
PCV10:2 <5years(General)
51.7%(40,61) PCV7NotUsed
AFR Ethiopia(Tsegaye2016)
Cohort 3+0 PCV10:2011
PCV10:1 9months(General)
45%(p=0.037)(17,64)
PCV7NotUsed
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iii
AMR Brazil(Andrade2014)
Cross-Sectional
3+0 PCV10:2010
PCV10:1 7-11months(General)
44.0%(14,64)
PCV7NotUsed
EUR Netherlands(Vissers2016;Bosch2015;2014)
PrePostSurvey
2+1 PCV7:2006PCV10:2011
PCV7:5PCV13:5
<2years(General)
88.8%(84,92) 97.9%(72,100)
SEAR Pakistan(Ali;Nisar2016)
PrePostSurvey
3+0 PCV10:2013
PCV10:3 <2years(General)
30%(9,46) PCV7NotUsed
WPR Fiji(Dunne;Russell2016)
PrePostSurvey
3+0 PCV10:2012
PCV10:2 5wk-23months(General)5wk-6years(General)
84.4%(76,90)95.6%(92,97)
PCV7NotUsed
WPR Australia(Leach2016;2016)
PostSurvey
3+0 PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2PCV13:2
<6years(Aboriginal)
ReductionnotReported.CarriagemeasuredinPCV10periodonly(nocomparisontoabaselinemeasure).
Reductionnotreported.CarriagemeasuredinPCV10period(noPCV7periodmeasure).
PCV13
AFR Gambia(Roca2014;2015)
PrePostSurvey
3+0
PCV7:2009PCV13:2011
PCV7:2PCV13:1
6-11months(General)
NotReported 45%(28,58)
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iv
AFR SouthAfrica,Soweto(Nzenze2014;2015)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)
<48months(General)
8.5%(-3,19)NotReported
41.7%(32,50)62.0%(56,67)
AFR SouthAfrica,Mpumalanga(Nzenze2013;2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)<5years(General)
36.3%(29,43)28.7%(24,33)
55.9%(45,65)55.2%(47,62)
AFR BurkinaFaso(Moisi2016)
PrePostSurvey
3+0 PCV13:2013
PCV13:2 <5years(General)
40.9%(28,51) PCV7NotUsed
AFR Malawi(Swarthout2016)
PostSurvey
3+0 PCV13:2011
PCV13:5 3-5years(General)
NotReported PCV7NotUsed
EMR Cambodia(SuyKuong2016)
PrePostSurvey
3+0 PCV13:2015
PCV13:0.5 0-23months(General)<5years(General)
28.0%(15,39)11.4%(0.5,21)
PCV7NotUsed
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v
EUR Norway(Steens2015;Vestrheim2008;2010)
PrePostSurvey
2+1
PCV7:2006PCV13:2011
PCV7:2PCV13:2
<2years(DayCare)
<59months(DayCare)
60.3%(42,73)45.9%(41,51)
73.9%(44,88)75.2%(67,82)
EUR France(Dunais2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:2PCV13:2
3-40months(DayCare)
72.7%(64,80) 78.2%(59,89)
EUR Israel(BenShimol2015;Danino2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:5
7-23months
<5years
NotReported25.3%(21,29)
56.5%(48,64)75.1%(70,79)
EUR Israel(Porat2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:4
<5years(General)
NotReported NotReported
EUR UK(Devine2016;Jones2016;Gladstone2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:4PCV13:5
<4years(General)
59%(54,63) 84.1%(44,96)
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vi
EUR UK(VanHoek2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:3PCV13:3
<5years(General)
NotReported 94.3%(78,99)
EUR Sweden(Galanis2016)
PrePostSurvey
2+1
PCV7:2007PCV13:2010
PCV7:3PCV13:4
<6years(General)
19.8%(NS) 46.2%(NS)
EUR Italy(Mameli2015;Zuccotti2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:6PCV13:2
3-59months(General)
2.9%(1,5) 51.6%(-6,78)
WPR Australia(Hoskins2014;2012;Collins2013)
PostSurvey
3+0
PCV7:2005PCV13:2011
PCV7:6PCV13:2
<5years(Aboriginal)
Notreported. Notreported.
WPR Australia(Leach2016;2016)
PostSurvey
3+0
PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
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TABLE3.Observationalstudiesestimatingpercentrelativereductionagainstserotype3NPCarriageamongthegeneralpopulation
StudyInformation %RelativeReduction(95%ConfidenceInterval)Comparedto
Region Country(Reference)
StudyDesign
DosingSchedule
PCVIntroduction
Year(s)
NumberofYearsPostIntroductionCarriageEvaluated
AgeGroup(s)(Population)
Baseline(noPCV)
PCV7Period
PCV10
AFR Mozambique(Sigaque;Moiane2016)
PrePostSurvey
3+0 PCV10:2013 PCV10:2 0-23months(HIV-)0-59months(HIV-)
NotReportedNotReported
PCV7NotUsed
AFR Kenya,Kilifi(Hammitt2014;2016)
PrePostSurvey
3+0 PCV10:2011 PCV10:4 <2years(General)<5years(General)
-9.1%(-403,76)42.3%(p=0.228)
PCV7NotUsed
AFR Kenya,Nairobi(Kim2016;2014)
PrePostSurvey
3+0 PCV10:2011 PCV10:2 <5years(General)
-62.2%(-177,5) PCV7NotUsed
AFR Ethiopia(Tsegaye2016)
Cohort 3+0 PCV10:2011 PCV10:1 9months(General)
NotReported PCV7NotUsed
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AMR Brazil(Andrade2014)
Cross-Sectional
3+0 PCV10:2010 PCV10:1 0-18months(General)
NotReported PCV7NotUsed
EUR Netherlands(Vissers2016;Bosch2015;2014)
PrePostSurvey
2+1 PCV7:2006PCV10:2011
PCV7:5PCV13:5
<2years(General)
-12.5%(-158,51) 50%(-33,81)
SEAR Pakistan(Ali;Nisar2016)
PrePostSurvey
3+0 PCV10:2013 PCV10:3 <2years(General)
NotReported PCV7NotUsed
WPR Fiji(Dunne;Russell2016)
PrePostSurvey
3+0 PCV10:2012 PCV10:2 5wk-23months(General)5wk-6years(General)
NotReportedNotReported
PCV7NotUsed
WPR Australia(Leach2016;2016)
PostSurvey 3+0 PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2PCV13:2
<6years(Aboriginal)
NotReported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
NotReported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
PCV13
AFR Gambia(Roca2014;2015)
PrePostSurvey
3+0
PCV7:2009PCV13:2011
PCV7:2PCV13:1
6-11months(General)
NotReported -200%(-23619,100)
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AFR SouthAfrica,Soweto(Nzenze2014;2015)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)
<48months(General)
NotReportedNotReported
-60%(-354,44)49.2%(-16,78)
AFR SouthAfrica,Mpumalanga(Nzenze2013;2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)<5years(General)
NotReportedNotReported
NotReportedNotReported
AFR BurkinaFaso(Moisi2016)
PrePostSurvey
3+0 PCV13:2013 PCV13:2 <5years(General)
NotReported PCV7NotUsed
AFR Malawi(Swarthout2016)
PostSurvey 3+0 PCV13:2011 PCV13:5 3-5years(General)
NotReported PCV7NotUsed
EMR Cambodia(SuyKuong2016)
PrePostSurvey
3+0 PCV13:2015 PCV13:0.5 0-23months(General)<5years(General)
NotReported64.7%(3,87)
PCV7NotUsed
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EUR Norway(Steens2015;Vestrheim2008;2010)
PrePostSurvey
2+1
PCV7:2006PCV13:2011
PCV7:2PCV13:2
<2years(DayCare)
<59months(DayCare)
NotReported-10.3%(13,8)
NotReported60.5%(26,79)
EUR France(Dunais2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:2PCV13:2
3-40months(DayCare)
NotReported NotReported
EUR Israel(BenShimol2015;Danino2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:5
7-23months
<5years
NotReportedNotReported
NotReportedNotReported
EUR Israel(Porat2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:4
<5years(General)
NotReported NotReported
EUR UK(Devine2016;Jones2016;Gladstone2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:4PCV13:5
<4years(General)
NotReported NotReported
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EUR UK(VanHoek2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:3PCV13:3
<5years(General)
NotReported NotReported
EUR Sweden(Galanis2016)
PrePostSurvey
2+1
PCV7:2007PCV13:2010
PCV7:3PCV13:4
<6years(General)
-54%(-133,-2) -5%(-47,25)
EUR Italy(Mameli2015;Zuccotti2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:6PCV13:2
3-59months(General)
Notreported. -50%
WPR Australia(Hoskins2014;2012;Collins2013)
PostSurvey
3+0
PCV7:2005PCV13:2011
PCV7:6PCV13:2
<5years(Aboriginal)
Notreported. Notreported.
WPR Australia(Leach2016;2016)
PostSurvey
3+0
PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
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TABLE4.Observationalstudiesestimatingpercentrelativereductionagainstserotype6ANPCarriageamongthegeneralpopulation
StudyInformation %RelativeReduction(95%ConfidenceInterval)Comparedto
Region Country(Reference)
StudyDesign
DosingSchedule
PCVIntroduction
Year(s)
NumberofYearsPostIntroductionCarriageEvaluated
AgeGroup(s)(Population)
Baseline(noPCV)
PCV7Period
PCV10
AFR Mozambique(Sigaque;Moiane2016)
PrePostSurvey
3+0 PCV10:2013 PCV10:2 0-23months(HIV-)0-59months(HIV-)
NotReported PCV7NotUsed
AFR Kenya,Kilifi(Hammitt2014;2016)
PrePostSurvey
3+0 PCV10:2011 PCV10:4 <2years(General)<5years(General)
16.5%(NS)10.3%(NS)
PCV7NotUsed
AFR Kenya,Nairobi(Kim2016;2014)
PrePostSurvey
3+0 PCV10:2011 PCV10:2 <5years(General)
18.6%(-27,48)
PCV7NotUsed
AFR Ethiopia(Tsegaye2016)
Cohort 3+0 PCV10:2011 PCV10:1 9months(General)
NotReported PCV7NotUsed
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AMR Brazil(Andrade2014)
Cross-Sectional
3+0 PCV10:2010 PCV10:1 0-18months(General)
NotReported
PCV7NotUsed
EUR Netherlands(Vissers2016;Bosch2015;2014)
PrePostSurvey
2+1 PCV7:2006PCV10:2011
PCV7:5PCV13:5
<2years(General)
92.3%(86,96)
84.4%(20,97)
SEAR Pakistan(Ali;Nisar2016)
PrePostSurvey
3+0 PCV10:2013 PCV10:3 <2years(General)
20.8%(-26,50)
PCV7NotUsed
WPR Fiji(Dunne;Russell2016)
PrePostSurvey
3+0 PCV10:2012 PCV10:2 5wk-23months(General)5wk-6years(General)
NotReportedNotReported
PCV7NotUsed
WPR Australia(Leach2016;2016)
PostSurvey
3+0 PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:PCV13:2
<6years(Aboriginal)
NotReported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
NotReported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
PCV13
AFR Gambia(Roca2014;2015)
PrePostSurvey
3+0
PCV7:2009PCV13:2011
PCV7:2PCV13:1
6-11months(General)
62.7%(39,77)
NotReported
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AFR SouthAfrica,Soweto(Nzenze2014;2015)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)
<48months(General)
71.8%(50,84)NotReported
NotReported67.1%(47,80)
AFR SouthAfrica,Mpumalanga(Nzenze2013;2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)<5years(General)
NotReported
NotReported
AFR BurkinaFaso(Moisi2016)
PrePostSurvey
3+0 PCV13:2013 PCV13:2 <5years(General)
NotReported
PCV7NotUsed
AFR Malawi(Swarthout2016)
PostSurvey
3+0 PCV13:2011 PCV13:5 3-5years(General)
NotReported PCV7NotUsed
EMR Cambodia(SuyKuong2016)
PrePostSurvey
3+0 PCV13:2015 PCV13:0.5 0-23months(General)<5years(General)
NotReported28.8%(5,46)
PCV7NotUsed
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EUR Norway(Steens2015;Vestrheim2008;2010)
PrePostSurvey
2+1
PCV7:2006PCV13:2011
PCV7:2PCV13:2
<2years(DayCare)
<59months(DayCare)
NotReported44.6%(42,47)
NotReported91.7%(70,98)
EUR France(Dunais2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:2PCV13:2
3-40months(DayCare)
NotReported
NotReported
EUR Israel(BenShimol2015;Danino2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:5
7-23months
<5years
NotReported13.7%(12,16)
NotReported97.7%(93,99)
EUR Israel(Porat2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:4
<5years(General)
6.25%(p>0.05)
76.7%(p<0.05)(72,81)
EUR UK(Devine2016;Jones2016;Gladstone2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:4PCV13:5
<4years(General)
NotReported
NotReported
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EUR UK(VanHoek2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:3PCV13:3
<5years(General)
NotReported
NotReported
EUR Sweden(Galanis2016)
PrePostSurvey
2+1
PCV7:2007PCV13:2010
PCV7:3PCV13:4
<6years(General)
12%(-70,54)
34%(-29,66)
EUR Italy(Mameli2015;Zuccotti2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:6PCV13:2
3-59months(General)
Notreported.
23.5%(-325,86)
WPR Australia(Hoskins2014;2012;Collins2013)
PostSurvey
3+0
PCV7:2005PCV13:2011
PCV7:6PCV13:2
<5years(Aboriginal)
Notreported.
Notreported.
WPR Australia(Leach2016;2016)
PostSurvey
3+0
PCV7:2001PCV10:2009PCV13:2011
PCV7:12PCV10:2PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
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TABLE5.Observationalstudiesestimatingpercentrelativereductionagainstserotype19ANPCarriageamongthegeneralpopulation
StudyInformation %RelativeReduction(95%ConfidenceInterval)Comparedto
Region Country(Reference)
StudyDesign
DosingSchedule
PCVIntroduction
Year(s)
NumberofYearsPostIntroductionCarriageEvaluated
AgeGroup(s)(Population)
Baseline(noPCV)
PCV7Period
PCV10
AFR Mozambique(Sigaque;Moiane2016)
PrePostSurvey
3+0 PCV10:2013 PCV10:2 0-23months(HIV-)0-59months(HIV-)
NotReportedNotReported
PCV7NotUsed
AFR Kenya,Kilifi(Hammitt2014;2016)
PrePostSurvey
3+0 PCV10:2011 PCV10:4 <2years(General)<5years(General)
-343.8%(p=0.005)(-1269,-44)-369.2%(p=0.001)(-1178,-72)
PCV7NotUsed
AFR Kenya,Nairobi(Kim2016;2014)
PrePostSurvey
3+0 PCV10:2011 PCV10:2 <5years(General)
-900%(-3357,-189)
PCV7NotUsed
AFR Ethiopia(Tsegaye2016)
Cohort 3+0 PCV10:2011 PCV10:1 9months(General)
NotReported PCV7NotUsed
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AMR Brazil(Andrade2014)
Cross-Sectional
3+0 PCV10:2010 PCV10:1 0-18months(General)
NotReported
PCV7NotUsed
EUR Netherlands(Vissers2016;Bosch2015;2014)
PrePostSurvey
2+1 PCV7:2006PCV10:2011
PCV7:5PCV13:5
<2years(General)
-437.5%(-677,-272)
82.6%(75,88)
SEAR Pakistan(Ali;Nisar2016)
PrePostSurvey
3+0 PCV10:2013 PCV10:3 <2years(General)
NotReported
PCV7NotUsed
WPR Fiji(Dunne;Russell2016)
PrePostSurvey
3+0 PCV10:2012 PCV10:2 5wk-23months(General)5wk-6years(General)
NotReportedNotReported
PCV7NotUsed
WPR Australia(Leach2016;2016)
PostSurvey 3+0 PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV13:2
<6years(Aboriginal)
NotReported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
NotReported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
PCV13
AFR Gambia(Roca2014;2015)
PrePostSurvey
3+0
PCV7:2009PCV13:2011
PCV7:2PCV13:1
6-11months(General)
NotReported
24.1%(-30,56)
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AFR SouthAfrica,Soweto(Nzenze2014;2015)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)
<48months(General)
NotReportedNotReported
NotReportedNotReported
AFR SouthAfrica,Mpumalanga(Nzenze2013;2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)<5years(General)
NotReported
NotReported
AFR BurkinaFaso(Moisi2016)
PrePostSurvey
3+0 PCV13:2013 PCV13:2 <5years(General)
NotReported
PCV7NotUsed
AFR Malawi(Swarthout2016)
PostSurvey 3+0 PCV13:2011 PCV13:5 3-5years(General)
NotReported PCV7NotUsed
EMR Cambodia(SuyKuong2016)
PrePostSurvey
3+0 PCV13:2015 PCV13:0.5 0-23months(General)<5years(General)
NotReported-20.2%(-324,66)
PCV7NotUsed
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EUR Norway(Steens2015;Vestrheim2008;2010)
PrePostSurvey
2+1
PCV7:2006PCV13:2011
PCV7:2PCV13:2
<2years(DayCare)
<59months(DayCare)
NotReported17.6%(16,19)
NotReported-35.7%(-209,40)
EUR France(Dunais2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:2PCV13:2
3-40months(DayCare)
-159.2%(-468,-18)
57.3%(14,79)
EUR Israel(BenShimol2015;Danino2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:5
7-23months
<5years
NotReportedNotReported
NotReportedNotReported
EUR Israel(Porat2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:4
<5years(General)
NotReported
NotReported
EUR UK(Devine2016;Jones2016;Gladstone2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:4PCV13:5
<4years(General)
NotReported
NotReported
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EUR UK(VanHoek2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:3PCV13:3
<5years(General)
NotReported
NotReported
EUR Sweden(Galanis2016)
PrePostSurvey
2+1
PCV7:2007PCV13:2010
PCV7:3PCV13:4
<6years(General)
-94%(-231,-14)
33%(-4,56)
EUR Italy(Mameli2015;Zuccotti2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:6PCV13:2
3-59months(General)
51.5%(50,53)
52.8%(-133,90)
WPR Australia(Hoskins2014;2012;Collins2013)
PostSurvey
3+0
PCV7:2005PCV13:2011
PCV7:6PCV13:2
<5years(Aboriginal)
NotReported
NotReported
WPR Australia(Leach2016;2016)
PostSurvey
3+0
PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
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TABLE6.ObservationalstudiesestimatingpercentrelativereductioninPCV7-typeNPCarriageamongthegeneralpopulationinsettingswherePCV7waspreviouslyused
StudyInformation %RelativeReduction(95%ConfidenceInterval)Region Country
(Reference)
StudyDesign
DosingSchedule
PCVIntroduction
Year(s)
NumberofYearsPostIntroductionCarriageEvaluated
AgeGroup(s)(Population)
ComparedtoBaseline(noPCV)
ComparedtoPost-PCV7Period
PCV10
EUR Netherlands(Vissers2016;Bosch2015;2014)
PrePostSurvey
2+1 PCV7:2006PCV10:2011
PCV7:5PCV10:5
<2years(General)
91.4%(87,94) 97.2%(63,100)
WPR Australia(Leach2016;2016)
PostSurvey 3+0 PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2
<6years(Aboriginal)
Nodatareported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
Nodatareported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
PCV13
AFR Gambia(Roca2014;2015)
PrePostSurvey
3+0
PCV7:2009PCV13:2011
PCV7:2PCV13:1
6-11months(General)
47.9%(8,71) NotReported
AFR SouthAfrica,Soweto(Nzenze2014;2015)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)
<48months(General)
37.7%(24,49)NotReported
NotReported61.2%(53,68)
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AFR SouthAfrica,Mpumalanga(Nzenze2013;2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)<5years(General)
47.2%(30,60)39.1%(35,46)
NotReported47.1%(35,57)
EUR Norway(Steens2015;Vestrheim2008;2010)
PrePostSurvey
2+1
PCV7:2006PCV13:2011
PCV7:2PCV13:2
<2years(DayCare)
<59months(DayCare)
85.7%(48,96)52.3%(48,59)
NotReported88.1%(80,93)
EUR France(Dunais2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:2PCV13:2
3-40months(DayCare)
100%(-27,100) NotReported
EUR Israel(BenShimol2015;Danino2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:5
7-23months
<5years
58.9%(46,69)42.9%(40,48)
NotReported64.6%(55,72)
EUR Israel(Porat2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:4
<5years(General)
NotReported NotReported
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EUR UK(Devine2016;Jones2016;Gladstone2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:4PCV13:5
<4years(General)
92%(88,95) 99.4%(89,100)
EUR UK(VanHoek2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:3PCV13:3
<5years(General)
86.8%(80,92) 90.5%(31,99)
EUR Sweden(Galanis2016)
PrePostSurvey
2+1
PCV7:2007PCV13:2010
PCV7:3PCV13:4
<6years(General)
59%(50,66) 66%(56,74)
EUR Italy(Mameli2015;Zuccotti2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:6PCV13:2
3-59months(General)
52.8%(51,56) 79.8%(11,95)
WPR Australia(Hoskins2014;2012;Collins2013)
PostSurvey
3+0
PCV7:2005PCV13:2011
PCV7:6PCV13:2
<5years(Aboriginal)
NotReported NotReported
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WPR Australia(Leach2016;2016)
PostSurvey
3+0
PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods.
Nochangereported.CarriagemeasuredinPCV10andPCV13periods
Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
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TABLE7.ObservationalstudiesestimatingpercentrelativereductionagainstNPCarriageofthe3additionalserotypesinPCV10orthe6additionalserotypesinPCV13amongthegeneralpopulationinsettingswherePCV7waspreviouslyused
StudyInformation %RelativeReduction(95%ConfidenceInterval)Region Country
(Reference)
StudyDesign
DosingSchedule
PCVIntroduction
Year(s)
NumberofYearsPostIntroductionCarriageEvaluated
AgeGroup(s)(Population)
ComparedtoBaseline(noPCV)
ComparedtoPost-PCV7Period
PCV10
EUR Netherlands(Vissers2016;Bosch2015;2014)
PrePostSurvey
2+1 PCV7:2006PCV10:2011
PCV7:5PCV10:5
<2years(General)
-13.1%(-235,62) 100%(NS)
WPR Australia(Leach2016;2016)
PostSurvey 3+0 PCV7:2001PCV10:2009PCV13:2011
PCV7:10PCV10:2PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(nobaselinemeasure).
Nochangereported.CarriagemeasuredinPCV10andPCV13periods(noPCV7periodmeasure).
PCV13
AFR Gambia(Roca2014;2015)
PrePostSurvey
3+0
PCV7:2009PCV13:2011
PCV7:2PCV13:1
6-11months(General)
NotReported 42.7%(21,59)
AFR SouthAfrica,Soweto(Nzenze2014;2015)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)
<48months(General)
-240.3%(-368,-147)NotReported
75.3%(66,82)68.7%(59,76)
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AFR SouthAfrica,Mpumalanga(Nzenze2013;2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2011
PCV7:2PCV13:2
<2years(General)<5years(General)
1.9%(-29,26)0.9%(NS)
69.7%(52,81)68.6%(55,78)
EUR Norway(Steens2015;Vestrheim2008;2010)
PrePostSurvey
2+1
PCV7:2006PCV13:2011
PCV7:2PCV13:2
<2years(DayCare)
<59months(DayCare)
43.8%(-21,74)27.9%(25,31)
55.6%(-24,84)50.9%(26,68)
EUR France(Dunais2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:2PCV13:2
3-40months(DayCare)
-56.8%(-156,4) 74.9%(52,87)
EUR Israel(BenShimol2015;Danino2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:5
7-23months
<5years
NotReported2.3%(-1,5)
54.3%(41,65)82.9%(78,87)
EUR Israel(Porat2016)
PrePostSurvey
2+1
PCV7:2009PCV13:2010
PCV7:2PCV13:4
<5years(General)
NotReported NotReported
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EUR UK(Devine2016;Jones2016;Gladstone2015)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:4PCV13:5
<4years(General)
-13159%(p=0.0381) 50%(p=0.0381)(-103,88)
EUR UK(VanHoek2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:3PCV13:3
<5years(General)
43.3%(38,49) 96%(73,99)
EUR Sweden(Galanis2016)
PrePostSurvey
2+1
PCV7:2007PCV13:2010
PCV7:3PCV13:4
<6years(General)
-26%(-44,43) 23%(17,37)
EUR Italy(Mameli2015;Zuccotti2014)
PrePostSurvey
2+1
PCV7:2006PCV13:2010
PCV7:6PCV13:2
3-59months(General)
-61.8%(-63,-61) 15%(-132,69)
WPR Australia(Hoskins2014;2012;Collins2013)
PostSurvey
3+0
PCV7:2005PCV13:2011
PCV7:6PCV13:2
<5years(Aboriginal)
NotReported 18%(0.4,33)
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WPR Australia(Leach2016;2016)
PostSurvey
3+0
PCV7:2001PCV10:PCV13:2011
PCV7:12PCV10:PCV13:2
<6years(Aboriginal)
Nochangereported.CarriagemeasuredinPCV10andPCV13periods.
Nochangereported.CarriagemeasuredinPCV10andPCV13periods.
Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
TABLE8.RandomizedControlledTrialsestimatingpercentrelativereductionagainstNPCarriageoftheVaccine-TypeSerotypes,Serotype3,Serotype6A,andSerotype19Aamongthegeneralpopulation
StudyInformation PCV10orPCV13 Serotype3 Serotype6A Serotype19A
Region Country(Reference) DosingSchedule
Baseline %Reduction
Baseline %Reduction
Baseline %Reduction
Baseline %Reduction
PCV10
SEAR Nepal(Hamaluba2015)
2+0 9 6(118,60)
1 -245(-3165,64)
6 43(-85,82)
3 43(-85,82)
SEAR Nepal(Hamaluba2015)*combined2+1and3+0groupsformorestatpower
2+0&3+0 9 6(-92,54)
1 -130(-1932,74)
6 43(-49,78)
3 71(-54,95)
EUR Finland(Jokinen2016) 2+1 13 61(35,76)
NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
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WPR Vietnam(Temple2016,Smith-Vaughan2016)
2+1 9 51(-1,77)
0 -140(-11326,69)
7 32(-54,70)
2 -94(-647,50)
AMR COMPAS(Borys2012) 2+1 14 26(NS)
NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
SEAR Nepal(Hamaluba2015)
3+0 9 6(-118,60)
1 -15(-1714,93)
6 43(-85,82)
3 100(NS)
WPR Vietnam(Smith-Vaughan2016)
3+0 9 15(-79,60)
NotReported
NotReported
7 89(11,99)
2 -194(-1061,26)
EUR CzechRepublic(Prymula2011)
3+0 16 34(4,55)
NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
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EUR CzechRepublic(Prymula2012)
3+0 16 49(11,70)
NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
EUR Netherlands(vandenBergh2013)
3+0 NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
7 -23(-111,29)
WPR Vietnam(Smith-Vaughan2016)
3+1 9 52(-18,81)
NotReported
NotReported
7 23(-91,69)
2 100(NS)
EUR Netherlands(vandenBergh2013)
3+1 NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
7 5(-61,45)
PCV13
WPR Vietnam(Temple2016)
2+1 17 33(-8,59)
0 0(NS)
7 59(-6,84)
2 -13(-399,75)
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EUR Poland(Grzesiowski2014)*ST19Aincreasedfrom3to4cases
2+1 16 91(78,96)
NotReported
NotReported
NotReported
NotReported
NotReported
NotReported
EUR Israel(Dagan2013)*Carriagemeasuresnewacquisition
3+0 29 24(11,35)
NotReported
NotReported
5 40(4,63)
7 36(5,56)
EUR Israel(Dagan2013)*Carriagemeasuresnewacquisition
3+1 57 29(21,35)
2 5(-87,52)
13 42(22,56)
23 45(32,56)
*Negativereductionindicatesanincreaseincarriage
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TABLE9.HeadtoHeadRandomizedControlledTrialscomparingNPCarriageinPCV10andPCV13amongthegeneralpopulation
Region Country(Reference) DosingSchedule
Product %Carriage
AllCarriage PCV10 PCV13 3,6A,19A
WPR PapauNewGuinea(Pomat2016,Orami2016)*DatatakenfromtheOramipaper9mosgroup
3+0 PCV13 89.0% 22% 30.0% 8
PCV10 90.0% 19% 32.0% 14
AllCarriage PCV10 PCV13 3 6A 19A
WPR Vietnam(Temple2016) 2+1 PCV10 24.0% 4.5% 14.0% 2.0% 5.0% 3.0%
PCV13 25.0% 7.1% 12.0% 0.0% 3.0% 2.0%
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TABLE10.Characteristics0fStudiesincludedinPneumoniaAnalysis
Characteristic PCV10N=6
PCV13N=27
TotalN=32
Studytype*Clinicaltrial 1 0 1
Case-control 0 6 6Observational 5 23 28
RegionAfrica 1 7 8Asia 0 0 0
Australia/Oceania 2 0 2Europe 3 10 12
LatinAmerica 0 10 10NorthAmerica 0 0 0
PCVdosingschedule2+1 3 22 243+0 3 5 8
EndpointClinicalpneumonia
(includingLRTI)6 15 20
Radiologically-confirmedpneumonia
2 13 15
Pneumococcalpneumonia 0 4 4Empyema 0 5 5
*OnestudyevaluatesPCV10andPCV13(Berglund,Sweden)andhasbeencountedinbothPCV10andPCV13columns.Twostudies(Mackenzie,Gambia;Moisi,Rwanda)evaluatePCVimpactusingacase-control/indirectcohortdesignandapre/postobservationalstudydesign.
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TABLE11.SummaryCharacteristicsOfControlledTrialsEvaluatingAPneumoniaEndpoint,BySchedule
Country Reference Studydesign
Vaccineproduct
Dosingschedule
EndpointandCaseDefinition
VaccineEfficacy(95%CI)Comments
IntenttoTreat PerProtocol
Finland KilpiISPPD2016
RandomizedControlled
trialPCV10
Doses>8weeksapart;
boosterat>11
months
Hospital-diagnosedclinical
pneumonia
28%(6to45) Vaccineefficacyfora2+1schedule
Consolidatedpneumonia 43%(19to61)
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TABLE12.SummaryCharacteristicsAndFindingsOfCase-ControlStudiesEvaluatingAPneumoniaEndpoint
Country(Reference)
Studydesign
PopulationPCVproductanddosingschedule
Endpoint Comparisongroup
VEcomparedtonoPCV(95%CI)Comments
2+1 3+0 ≥1dose ≥2doses
2+1
Israel(Givon-Lavi,ISPPD2014)
Case-control 2-12months
PCV7/PCV13(2,4,12months)
CXR-confirmedpneumonia
Childrenwithrotavirus-negative
gastroenteritis
40.6(11.1-
60.3)49.5%ofdoseswerePCV13
Spain(Madrid)(Tagarro,J
Pediatr2016)
Case-control
2-12monthsPCV13(2,4,12months)
Bacteremicpneumonia
Childrenwithbacterial
pneumonia
86.0(70.0-95.0)
(comparedto<1doses)
68.0(60.0-96.0)
(comparedto<2doses)
SouthAfrica(Madhi,
Thorax2015)
Case-control 8-103weeks
PCV13(6,14,39weeks)
CXR-confirmedpneumonia(WHO)
Hospital20.1(-9.3-41.6)
(adjusted)
Community32.1(4.6-51.6)
(adjusted)
3+0
TheGambia(Mackenzie,unpublished)
Case-control
3-11monthsPCV13(2,3,4months)
CXR-confirmedpneumonia(WHO)
Community 63(-8to
70)
-8(-83to37)
(1dose)
17(-50to54)
(2doses)
≥12months Community 7(-264to76)
-29(-536to74)
(1dose)
26(-216to83)
(2doses)Rwanda(Gatera,
Vaccine2016)
Indirectcohort
<5yearsPCV7/PCV13(6,10,14weeks)
Severepneumonia
Mildpneumonia
54(42to63)
Earlypostintroduction
Togo(Moisi,ISPPD
2016)
Indirectcohort
<5yearsPCV13
(6,10,14weeks)
CXRpneumonia
non-CXRpneumonia
58(-100to99)
Earlypost-introductionandsmallsamplesize
Severepneumonia(WHO)
non-severepneumonia
80(-90to100)
PneumoniawithCRP>40
mg/L
pneumoniawithoutCRP>40mg/L
-2%(-30to80)
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TABLE13.SummaryCharacteristicsAndFindingsOfPre/PostObservationalStudiesEvaluatingAPneumoniaEndpoint,PCV10
Country ReferenceCase
DefinitionStudydesign
Dosingschedule
Agegroupsevaluated
Surveillanceyearsreported*
Baselinemeasure(per100,000)
%changeatpost-PCVintroductionperiodcomparedto†¶
Comments
Pre-PCV
Post-PCV7/Pre-PCV10
Post-PCV10 Pre-PCV
Post-PCV7/Pre-PCV10
Pre-PCV
Post-PCV7/Pre-PCV10
Clinicalpneumonia2+1
Iceland Kristinsson,ISPPD2014
Notstated Pre/post 3,5,12months
<15months
3 - 1.5 2,800 -36%¶
SwedenBerglund,PLoSOne2014
ICD-10codes(J12-J18)
Pre/post 3,5,12months
<2years 11 1 2 654.7504.4per
100,000-21%¶ +3%
3+0
FijiTuivaga,
ISPPD2016
ICD-10codes
(includingbronchiolitis)
Pre/post6,10,14weeks <2years 5 - 2
Notreported -18%¶
ICD-10codes
(excludingbronchiolitis)
Notreported
-32%¶
Fiji Russell,ISPPD2016
ICD-10codes(iTaukei)
Pre/post 6,10,14weeks <2years 5 - 1.5
4,250 -19%¶ %changecalculatedfromIRs
giveningraphICD-10codes
(FID) 1,500 -13.3%¶
KenyaSilaba,
ISPPD2016
WHOdefinition-severe/very
severe
Pre/post6,10,14weeks
2-59months 9 - 4 2,170 -27%¶
Baselinemeasurefor2002/2003
Radiologically-confirmedpneumonia3+0
KenyaSilaba,
ISPPD2016 WHO Pre/post6,10,14weeks
2-59months 9 - 4
Notreported -48%¶
*Yearsofpre-PCVdataexcludetheyearofPCVintroduction†Negativepercentchangeindicatesapercentreduction;Positivepercentchangeindicatesapercentincrease¶Significanceofp<0.05
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Table14.SummaryCharacteristicsAndFindingsOfPre/PostObservationalStudiesEvaluatingAPneumoniaEndpoint,PCV13
Country Reference CaseDefinition
Studydesign
Dosingschedule
Agegroups
evaluated
Surveillanceyearsreported*
Baselinemeasure(per100,000)
%changeatpost-PCVintroduction
periodcomparedto†¶
Comments
Pre-PCV
Post-PCV7/Pre-PCV13
Post-PCV13 Pre-PCV
Post-PCV7/Pre-PCV13
Pre-PCV
Post-PCV7/Pre-PCV13
Clinicalpneumonia2+1
Argentina(Pilar)
Gentile,ISPPD2016(#99)
Clinicaldiagnosis
Pre/post
2,4,12months
<12months
3 - 2
Notreported
-50.4%¶
12-23months
Notreported
-68.4%¶
24-59months
Notreported -36.1%¶
<5yearsNot
reported -49.7%¶
Argentina(Rosario)
LopezPapucci,ISPPD2016
Notstated Pre/post
2,4,12months
<1year
4 - 2
Notreported 0
1year Notreported
-43.2%¶
2-4years Notreported
-38.2%¶
ArgentinaVizzotti,ISPPD2016
Notstated(NESSdata)
Pre/post
2,4,12months
<1year2 - 3
3,295 -27.3%¶
<5years 5,545 -27.8%¶
CostaRicaCastro,ISPPD2016
Notstated Pre/post
2,4,15months
<2years 4 2 2 1,180 850 -35.0%¶ -9%¶
MexicoPalaciosISPPD2016
ICD-10codesPre/po
st2,4,12months ≤4years 0 6 4 2,443 -60.5%
PCV10usedfor8monthsin2010andchangedtoPCV13;
significanceunknown
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Spain(Galicia)
Rivero-Calle,ISPPD2016
ICD-9codes(480-486,
487)
Pre/post
2,4,12months
<2years
6 5 2
Notreported
-23.1%¶ -58.0%¶Notclearinabstractif
Post-PCV13%changeis
comparedtopre-vaccineorpost-PCV7
2-4years Notreported
-9.7% -54.8%¶
SwedenBerglund,PLoSOne2014
ICD-10codes(J12-J18)
Pre/post
3,5,12months <2years 11 1 2 654.7 504.4 -37%¶ -18%
PCV13v.PCV7%changeborderlinesignificant
UKSaxena,JInfect2015
ICD-10codes(J12-J18)
Pre/post
2,3,13months
<2years
5 4 4
-20%¶ +8% Post-PCVperiods
includeyearofintroduction2-4years -12%¶ +24%¶
UK(Scotland)
Nath,ArchDisChild,2015
ICD-10codes(J12-J18)
Pre/post
2,3,13months
<1year
24 4 4
Baselinemeasureonly
availablefor<14years
-13%¶ -6%Post-PCVperiods
includeyearofintroduction
1-4years +1% -12%¶
3+0
MalawiMcCollum,PLoS
One,2017
WHOclinicalpneumonia
Post6,10,14weeks <5years 0 - 2.5
1,067(hospital,2012)
+47 Post-PCV
comparedtoearlypost-PCVWHOclinical
pneumonia+hypoxemia
119(hospital,2012)
-46.8¶
Radiologicallly-confirmedpneumonia2+1
Argentina
Gentile,ISPPD2016(#100)
Notstated Pre/post
2,4,12months <5years 5 - 2 Not
reported -32.9%¶
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Argentina(Rosario)
LopezPapucci,ISPPD2016
Culture-negativeplus
pneumococcal
consolidatepneumonia
Pre/post
2,4,12months
1year
4 - 2
Notreported
-66.2%¶
2-4yearsNot
reported -45.5%¶
Argentina(Concordia
)
Rearte,ISPPD2016
Chestradiograph
Pre/post
2,4,12months <5years 4 - 2 732 -53.3%¶
IsraelGivon-
LaviISPPD2016
NotstatedPre/po
st2,4,12months
<2yearsBedouin
4 2 2
2,840 2,660 -51%¶ -48% PCV7periodincludes
PCV13yearofintroduction;PCV13v.
PostPCV7%change
calculated
<2yearsJewish 1,650 1,410 -49%¶ -40%
IsraelGreenberg,Vaccine
2015WHO Pre/po
st2,4,12months
<12months
7 2 2
1,870 2,020 -34%¶ -38%¶PCV7periodincludes
PCV13yearofintroduction
12-23months 990 930 -34%¶ -30%¶
24-59months 390 730 -27%¶ -36%¶
Israel
Greenberg
ISPPD2016
Notstated Pre/post
2,4,12months
<5years 4 2 2 Notreported
Notreported
+15%¶ -40%¶
RelatedtoGreenberg,Vaccine2015article;PCV7
periodincludes
PCV13yearofintroduction
UruguayLaurani,ISPPD2014
WHO Cohort 2,4,12months
<2years 1 4
-69.3%amongchildrenvaccinatedwith3doses
-85%amongchildrenvaccinatedwith3doses
Significanceunknown;timeperiodfor%
changeunknown;
PCV13period
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includesyearof
introduction;only1yearofbaselinedata
3+0
NicaraguaBecker-Dreps,
PIDJ2014
Physiciandiagnosis
Pre/post
2,4,6months
<12months
3 - 26,400 -33%¶
12-23months 2,500 -26%¶
Pneumococcalpneumonia2+1
Argentina
Gentile,ISPPD2016(#100)
NotstatedPre/po
st2,4,12months <5years 5 - 2
Notreported -72.1%¶
Empyema2+1Argentina(Concordia
)
Rearte,ISPPD2016
pleuraleffusion
Pre/post
2,4,12months <5years 4 - 2 103 -84.5%¶
UK(Scotland)
Nath,ArchDisChild,2015
ICDcodes(J86.9andA156-165)
Pre/post
2,3,13months
<1year
24 4 4
Baselinemeasureonly
availablefor<14years
+72% -53%Post-PCVperiods
includeyearofintroduction
1-4years +126%¶ -8%
UKSaxena,JInfect2015
ICD-10codes(J86.0,J86.9)
Pre/post
2,3,13months
<2years5 4 4
-41%¶ -42%¶ Post-PCVperiods
includeyearofintroduction2-4years -20% +22%
*Yearsofpre-andpost-PCVdataexcludetheyearofPCVintroduction,unlessstatedotherwise†Negativepercentchangeindicatesapercentreduction;Positivepercentchangeindicatesapercentincrease¶Significanceofp<0.05Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
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TABLE15.SummaryCharacteristicsandFindingsofPre/PostObservationalStudiesEvaluatingaPneumoniaEndpoint,PCV7/13
Country ReferenceCase
DefinitionStudydesign
Dosingschedule
Agegroups
evaluated
Surveillanceyearsreported*
Baselinemeasure(per100,000)
%changeatpost-PCVintroductionperiodcompared
to†¶Comments
Pre-PCV
Post-PCV7/Pre-PCV13
Post-PCV13
Pre-PCV
Post-PCV7/Pre-PCV13
Pre-PCV
Post-PCV7/Pre-PCV13
Clinicalpneumonia2+1
SouthAfrica
IzuISPPD2016
Notstated Pre/post
6,14weeks;
9months;
<5years,HIV-
uninfected
3 2 4 Notstated
-44%¶
Significantreductionsin0-3m,3-12m,2-5y,not1-2y;PCV13periodincludesyearofintroduction
SwedenLindstrand,Pediatr2014
ICD-10codes(J13-J18) Pre/post
3,5,12months
<2years
4 2 3
450 -19%¶ PCV13periodincludesyearofintroduction2-<5
years250 -15%¶
3+0
TheGambia
MacKenzie,unpublished
Hypoxicpneumonia Pre/post
2,3,4months
2-11months
1 1 2
1,310 -57%¶
Only1yearofbaselinedata
12-23months 680 -72%¶
24-59months 130 -56%¶
RwandaGatera,Vaccine2016
Severepneumonia
Pre/post6,10,14weeks <5years 7 1 1
67.1 -70.3%¶ Changeisforlatestyear;only1yearpost-
PCV13introduction
Mildpneumonia 331.5 +7.6%¶
Radiologicallly-confirmedpneumonia2+1
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Uruguay Pirez,PIDJ2014
Clinicalsigns+radiograph
(clinicalreading)
Pre/post 2,4,12months
<14years 5 2 2 8,791 -78.1%¶
Changeisforlatestyear;%Post-PCV7
periodsincludesPCV13yearofintroduction
3+0
TheGambia
MacKenzie,unpublished WHO Pre/post
2,3,4months
2-11months
1 1 2
2,100 -23%¶
Only1yearofbaselinedata
12-23months 1,600 -29%¶
24-59months
500 -22%¶
Pneumococcalpneumonia2+1
Uruguay Pirez,PIDJ2014
Isolationofpneumococc
usfrombloodor
pleuralfluid
Pre/post 2,4,12months
<14years 5 2 2 662
608(PCV13add.6st)
-90.4%¶
-97.1%¶for
PCV13add.6st
Changeisforlatestyear;Post-PCV7
periodsincludesPCV13yearofintroduction
3+0
TheGambia
MacKenzie,unpublished
pneumococcalpneumonia
Pre/post 2,3,4months
2-11months
1 1 2
290 -58%¶
Only1yearofbaselinedata
12-23months
260 -75%¶
24-59months
110 -57%¶
Empyema2+1
SouthAfrica
Zampoli,PIDJ2015
pleuraleffusionwithpurulentorturbidpleural
tap
Pre/post6,14
weeks;9months;
<12years 2 2 3
1,040pneumoniaadmissions
(2007-2011;PCV7introducedin
2009)
-50%¶
92%ofchildrenin“pre”cohortunimmunizedwithfullseries
SwedenLindstrand,Pediatr2014
ICD-10codes(J86) Pre/post
3,5,12months <2years 4 2 3 2.5 +78%
PCV13periodincludesyearof
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*Yearsofpre-andpost-PCVdataexcludetheyearofPCVintroduction,unlessstatedotherwise†Negativepercentchangeindicatesapercentreduction;Positivepercentchangeindicatesapercentincrease¶Significanceofp<0.05Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.
2-<5years 1.8 +68%
introduction
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TABLE16.CharacteristicsofincludedstudiesinIPDAnalysis
Characteristic 2+1N=(%)
3+0N=(%)
TotalN=(%)
StudytypeClinicaltrial 1 0 1
Pre/postsurveillance 25 4 30*Case-control/indirect
cohort7 2 11*
RegionAfrica 5 2 7Asia 1 1 2
Australia/Oceania 3 3Europe 20 21*
LatinAmerica 4 6*NorthAmerica 3 3
PCVproductPCV10 9 3 12*PCV13 24 3 30*
EndpointVTIPD 30 6 39*
VTMeningitis 2 0 2VTBacteremicPneumonia 1 0 1
*Twocase-controlstudiesandonepre-poststudyconductedinasettingofa3+1scheduleincluded
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Clinicaltrialssummary:
Aclusterrandomizeddouble-blindtrialofPCV10inFinlanddemonstrateda92%(95%CI58–100)efficacyfor2+1scheduleamongchildren<19monthold(Palmuetal.Lancet2013).Anextendedfollowupofthediseaseregisterforthistrialdemonstratedan80%(95%CI7-97)efficacyforacombined2+1/3+1schedule(PalmuetalISPPD2016).
TABLE17.ObservationalstudiesestimatingvaccineeffectivenessagainstVT-IPDbyschedule
Study VEcomparedtonovaccine(95%CI)
Country(Reference)
StudyDesign Population
age
PCVproduct
(CountrySchedule)
VTgroup 2+1 3+0 >1dose >2doses
PCV13
UnitedKingdom
(Milleretal.,2011)
(Andrewsetal.,2014)
Indirectcohort 2.5-<24
months
PCV13(2+1) PCV13+6C
PCV13/non-PCV7
PCV7
79%(25-94%)
69%(37-85%)
73%(57-83%)
83%(35-96%)
73%(55-84%)1
90%(34-98%)1
Canada(Deceunincket
al.,2015)
Case-control 2-59months PCV13(2+1),catch
upfor<5years
PCV13 86%(62-95%)
SouthAfrica
(VonGottbergetal.
ISPPD2016)
Case-control 6weeks-9
months
PCV13(2+1) PCV13 85%(37-96%)
DominicanRepublic
(Tomczyketal.ISPPD
Case-control PCV13(2+1) PCV13 64%(-47-94%)
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47
2016)
Australia(Giddingetal.
ISPPD2016)
Cohort <2months PCV7/PCV13(3+0) PCV7 92%(86-93%)
Spain
(Guevaraetal.,2016)
Case-control 2-13.5months PCV13(3+1) PCV13
PCV13/non-PCV7
96%(43-100%)
95%(30-100%)
PCV10
Finland
(Auranenetal.ISPPD
2014)
Rinta-Kokkoetal.
ISPPD2016)
Indirectcohort
Indirectcohort
Case-control
Cohort
>3months,
PCV10eligible
<5years
PCV10(2+1) PCV10
95%(42-100%)
78%(17-94%)
93%(76-98%)
95%(47-99%)
Netherlands(Knoletal.
ISPPD2016)
Indirectcohort 2-54months PCV10(2+1) PCV10 89%(41-98%)
Canada(Deceunincket
al.,2015)
Case-control 2-59months PCV10(2+1)
PCV10+6A
97%(84-99%)
Pakistan(Alietal.
Unpublished)
Case-control <5years PCV10(3+0) PCV10 76.5%(NS) 80.3(NS)
Brazil(Dominguesetal Case-control <5years PCV10(3+1),catch PCV10 84%(66-92%)2
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2014)
(Veranietal2015)
Indirectcohort
upfor12-23
months
74%(42-88%)2
1VEforatleast2dosesbeforeage12monthsoronedoseonorafterage12months
2VEforuptodateforagenumberofdoses
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TABLE18.ObservationalstudiesdocumentingimpactofPCVintroductiononallIPD,VT-IPD,meningitisorbacteremiaamongyoungchildrenbeforeandaftervaccineintroduction,byPCVdosingschedule
Reference Outcome,
agegroups
Country PCV
product(s)
Surveillanceyearsreported Baselineincidence(cases/100,000) Percentchangeatmaximum
yearspost-introduction
comparedto
PrePCV Post-
PCV7/pr
e-
PCV10/
13
Post-
PCV10/1
3
VTgroup PrePCV Post-
PCV7/pre-
PCV10/13
Pre-PCV Post-
PCV7/pre-
PCV10/13
PCV7-PCV10(2+1)
DeWalset
al.Vaccine
2014
VTIPD,<2
years
Canada
(Quebec)
PCV7,
PCV10
4 5 2 PCV7
PCV10
57.0
5.6
-98
-77
Knoletal,
EID2015
VTIPD,<5
years
Netherlands PCV7,PCV10 3 5 4 PCV10/non
-PCV7
-96(-99,–73)
PCV7-PCV13(2+1)
Harboeet
al.CID
2014
VTIPD,
<2years
Denmark PCV7,PCV13 7 3 3 PCV7
PCV13/non
36.4(32.9–
40.3)
14.4(11.1–
-99
-84(-67,-93)
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-PCV7 18.7)
Ben-Shimol
etal
Vaccine
2014
VT-IPD,<5
years
Israel PCV7,PCV13 4 1 1 PCV7
PCV13/non
-PCV7
30.5
14.8
3.2
21.7
-95(-91,-97)
-70(-56,-79)
-53(-7,-77)
-79(-70,-85)
Ben-Shimol
etalPIDJ
2015
VT-
Bacteremic
Pneumonia
(BP)vs
otherIPD
(non-BP
IPD),<5
years
Israel PCV7,PCV13 4 1 1 PCV7
PCV13/non
-PCV7
9.6(BP)
20.9(non-BP
IPD)
6.8(BP)
8.0(non-BP
IPD)
0.9(BP)
2.5(non-BP
IPD)
13(BP)
8.4(non-BP
IPD)
-96(-88,-99)
-95(-90,-97)
-62(-37,-77)
-75(-56,-86)
-59(+59,-89)
-55(0,-79)
-80(-69,-88)
-77(-60,-77)
Gabarrot
etal,
PLosOne
2014
VTIPD,<2
years,2-4
years
Uruguay PCV7,PCV13 5 2 3 PCV7
PCV13/non
-PCV7
38.0(<2)
7.0(2-4)
24.8(<2)
16.1(2-4)
-92(-74,-97)
-83(-86,-98)
-75(-39,-90)
-56(-72,+6)
Pirezetal.
PIDJ2014
VTCAP,<15
years
Uruguay PCV7,PCV13 5 2 3 PCV7
30.4per10,000
discharges
-91
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PCV13/non
-PCV7
PCV13
36.4
60.8
-95
-97
Lepoutre
etal,
Vaccine
2015
VTIPD,<2
years,2-4
years
France PCV7,PCV13 2 2 1 PCV7
PCV13/non
PCV7
20.8(<2)
5.3(2-4)
15.5(<2)
7.6(2-4)
-95(-91,-87)
-91(-96,-82)
-84(-89,-76)
-61(-71,-47)
Galaniset
al.
EurRespirJ
2016
VTIPD,
<2years
Sweden PCV7,PCV13 2 1 3 PCV7
PCV13
22.71
4.42
5.22
-92(-68,-98)
-71(-92,13)
-75(-94,-2)
Slotvedet
al.
Vaccine
2016
VTIPD,
<5years
Denmark PCV7,PCV13 8 2 3 PCV7
PCV13
2.34
0.99
-80(-96,-14)
-77(-98,193)
Diawaraet
al.
IntJInfect
Dis2015
VTIPD,
<2years,
>2-5years
Morocco PCV13
replacedby
PCV10
3
3 PCV7
PCV10/non
-PCV7
18.0(<2)
0.6(3-5)
5.7(<2)
0.3(3-5)
-74(-100,-41)
-54(-82,128)
-78(-94,-22)
-4(-81,128)
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PCV13/non
-PCV10
5.7(<2)
0.2(3-5)
-83(-100,-28)
-35(-87,585)
Rudnicket
al.Vaccine
2013
VTIPD,<5
years
Canada
(Ontario)
PCV7(3+1),
PCV10(3+1),
PCV13(2+1)
1 1 PCV13 11.6 -41(p=0.07)
Waightet
al.Lancet
InfDis
2015
VT-IPD;
<2years
2-4years
Englandand
Wales
PCV7,
PCV13
5 4 4 PCV7
PCV13/non
-PCV7
1.58(<2)
0.78(2-4)
12.67(<2)
4.98(2-4)
-76(-7,-94)
-80(-96,+12)
-89(-78,-94)
-91(-75,-96)
Shirietal,
ISPPD2014
VTIPD,<2
years
SouthAfrica PCV7,
PCV13
4 2 1 PCV7
PCV13/non
-PCV7
149
32.1
-90(-83,-94)
-74(-45,-88)
Dalbyetal,
ISPPD2014
VTIPD,<2
years
Denmark PCV7,PCV13 7 3 2 PCV13/non
-PCV7
N/A N/A -85(-64,-95)
Changet
al,Valuein
Health
2014
VTIPD,<5
years
Taiwan PCV7,PCV13 3 6 2 PCV7
PCV13
- - -71(p=0.012)
-80(p=0.001)
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Steenset
al,Vaccine
2013
VTIPD,<2
years,2-4
years
Norway PCV7,PCV13
2 5 1 PCV7
PCV13/non
PCV7
64(<2)
15(2-4)
10(<2)
6(2-4)
-77(-87,-61)
-45(-74,+11)
-100(-100,-72)
-52(-89,+79)
Von
Gottberg
etal,NEJM
2014
VTIPD,<2
years
SouthAfrica PCV7,PCV13
4 2 2 PCV7
PCV13/non
PCV7
32.1
7.5
-89(-92,-86)
-57(-68,-42)
Mooreet
al,
JID2014
VTIPD,<2
years
UK PCV7,PCV13 9 4 3 PCV7
PCV13/non
PCV7
33.4-46.5
8.3-9.9
-76(-86,-59)
-64(-84,-20)
von
Gottberg
etal.,
ISPPD-10
2016
VTIPD,<2
years
SouthAfrica PCV7
PCV13
3 4 PCV7
PCV13
33.6
14.4
-97(-96,-98)
-70(-65,-74)
Gentileet
al.,ISPPD-
Meningitis,
<1year
Argentina PCV13 4 1 PCV13 1.2 -55(-10,-77)
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102016
Collinset
al.,ISPPD-
102016
Meningitis,
<5years
UK(England,
Wales)
PCV7
PCV13
6 2 4 PCV7
PCV13/non
-PCV7
3.4
1.5
-99
-77
PCV7-PCV13(3+0)
Jayasinghe
etal.,
ISPPD-10
2016
VTIPD,
<2years
Australia
PCV7
PCV13
2 3 1 PCV7
PCV13
-96(-94,-98)
-65(-52,-76)
Mackenzie
etal.,
LancetInf.
Dis2016
VTIPD,<2
years,2-4
years
Gambia PCV7,PCV13 N/R 2 3 PCV7
PCV13/non
-PCV7
122(<2)
44(2-4)
78(<2)
58(2-4)
-83(-93,-57)
-74(-91,-26)
-82(-94,-44)
-62(-83,-15)
PCV10(2+1)
Jokinenet
al,
ISPPD2012
VT-IPD,<1
years
Finland PCV10 5 1 PCV10 33.8 -46.7
Rinta- VT-IPD,3- Finland PCV10 5 5 PCV10 38.8 -93(-90,-96)
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Kokkoet
al.ISPPD
2016
66months
Haraldsson
etal,ISPPD
2014
VTIPD,<2
years
Iceland
PCV10 3 3 PCV10 51.8 -87(p<0.001)
PCV10(3+0)
Scottetal,
ISPPD2012
VT-IPD,<5
years
Kenya PCV10 7 <1 PCV10 50.8 -70(-91,-30)
Russellet
al.,ISPPD-
102016
IPD(overall
IPD?),
<2years
Fiji
PCV10 3 1 ? -51(-10,-76)
PCV10(3+1)
Santoset
al.,Vaccine
2013
VTIPD,<2
years
Brazil PCV10 4 2 PCV10 16.5 -97
(p=0.0002)
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TABLE19.ObservationalstudiesestimatingvaccineeffectivenessagainstIPDbyserotypeandbyschedule
Study VEcomparedtonovaccine(95%CI)
Country(Reference)
StudyDesign Populationage PCVproduct
(CountrySchedule)
Serotype >1dose >2doses
PCV13
UnitedKingdom
(Andrewsetal.,2014)
Indirect
cohort
2.5-<24months PCV13(2+1) 1
3
6A
7F
19A
84%(54-95%)1
26%(–69-68%)1
98%(64-99%)1
91%(70to98)1
67%(33to84)1
Canada(Deceunincket
al.,2015)
Case-control 2-59months PCV13(2+1) 19A 74%(11-94%)
SouthAfrica
(VonGottbergetal.
ISPPD2016)
Case-control 6weeks-9
months
PCV13(2+1) 19A 94%(44-100%)
PCV10
Finland
(Auranenetal.ISPPD
2014)
Indirect
cohort
>3months,
PCV10eligible
PCV10(2+1) 19A
29%(-631-93%)
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Netherlands(Knoletal.
ISPPD2016)
Indirect
cohort
2-54months PCV10(2+1) 19A
7F
61%(-79-92%)
87%(13to98)
Canada(Deceunincket
al.,2015)
Case-control 2-59months PCV10(2+1)
19A
7F
71%(24–89%)
93%(23–99%)
Brazil(Dominguesetal
2014)
(Veranietal2015)
Case-control
Indirectcohort
<5years PCV10(3+1),catch
upfor12-23
months
3
6A
19A
6A
19A
7·8%(–272-77%)2
15%(–312-82%)2
82%(11-96%)2
62%(−42-89.9%)2
63%(−17-88.6%)2
51%(−52-84%)
71%(17-90%)
1VEforatleast2dosesbeforeage12monthsoronedoseonorafterage12months
2VEforuptodateforagenumberofdoses
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TABLE20.ObservationalstudiesdocumentingimpactofPCVintroductiononallIPD,meningitisorbacteremiaamongyoungchildrenbeforeandaftervaccineintroduction,byPCVdosingscheduleandbyserotype
Reference Outcome,
agegroups
Country PCV
product(s)
Surveillanceyearsreported Baselineincidence(cases/100,000) Percentchangeatmaximum
yearspost-introduction
comparedto
PrePCV Post-
PCV7/p
re-
PCV10/
13
Post-
PCV10/1
3
Serotype PrePCV Post-
PCV7/pre-
PCV10/13
Pre-PCV Post-
PCV7/pre-
PCV10/13
PCV7-PCV10(2+1)
DeWalset
al.Vaccine
2014
VTIPD,<2
years
Canada
(Quebec)
PCV7,
PCV10
4 5 2 19A 21.1 -36
Knoletal,
EID2015
VTIPD,<5
years
Netherlands PCV7,PCV10 3 5 4 19A -62(-81,–23)
PCV7-PCV13(2+1)
Harboeet
al.CID
2014
VTIPD,
<2years
Denmark PCV7,PCV13 7 3 3 1
3
19A
1.3
1.3
3.8
Nochange
Nochange
Decreasedto
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pre-PCV7level
Ben-Shimol
etal
Vaccine
2014
VT-IPD,<5
years
Israel PCV7,PCV13 4 1 1 1
3
19A
3.8
0.3
5.1
5.2
0.8
5.0
-88(-95,-71)
+13(-62,+237)
-68(-83,–41)
-84(-94,–58)
+145(-36,+130)
-69(-84,–42)
Lepoutre
etal,
Vaccine
2015
VTIPD,<2
years,2-4
years
France PCV7,PCV13 2 2 1 19A
7F
1
3
-83(-72,-90)
-77(-59,-87)
-96(-73,-100)
-85(-36,-96)
Poratetal.
Vaccine
2016
VTIPD,
<2years
Israel PCV7,PCV13 8 2 3 6A
6B
7.1
7.1
-86(9,-98)
-86(9,-98)
-36(-96,921)
-36(-96,921)
Waightet
al.Lancet
InfDis
2015
VT-IPD;
<2years
2-4years
Englandand
Wales
PCV7,
PCV13
5 4 4 1
3
6A
7F
19A
-91(-98,–68)
-68(-89,–6)
-100(-100,–62)
-91(-97,–74)
-91(-97,–75)
Von
Gottberg
etal,NEJM
VTIPD,<2
years
SouthAfrica PCV7,PCV13
4 2 2 6A
1
3
6.3
1.5
0.6
-85(-91,-76)
-57(-79,-16)
-41(-79,+54)
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2014 5
7F
19A
0.7
0.2
4.5
+22(-60,+63)
-100(-100,
+132)
-70(-81to-55)
PCV7-PCV13(3+0)
Jayasinghe
etal.,
ISPPD-10
2016
VTIPD Australia,
<2years
PCV7
PCV13
2 3 1 19A -77(-87,-65)
PCV10(3+0)
PCV10(2+1)
Rinta-
Kokkoet
al.ISPPD
2016
VT-IPD,<2
years
Finland PCV7,PCV10 N/R 5 5 19A
6A
3
6.8
2.8
0.4
-93(-90,-96)
-100(-68,-100)
+192(NS)
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TABLE21.SummaryofincludedImmunogenicitystudyarmsinAnalyses
PCV10(n=44) PCV13(n=18)
2dose 3dose 2dose 3dose
(n=10) (n=34) (n=11) (n=7)
Region
Africa 0 2 0 0
Asia 6 10 2 0
Europe 4 18 9 3
NAmerica 0 1 0 2
Oceania 0 2 0 2
SAmerica 0 1 0 0
ConcomitantDTaP
DTaP 9 18 4 3
NoDTaP 1 16 7 4
Agedose1
1m 0 2 0 2
1.5-1.75m 2 7 0 0
2m 5 21 8 5
3m 3 4 3 0
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Dose1-2interval
0.5m 0 0 0 0
1m 2 25 1 4
1.25-1.5m 0 1 0 0
2m 7 8 10 3
4m 1 0 0 0
Dose2-3interval
1m NA 23 NA 4
2m NA 10 NA 3
3m NA 1 NA 0
Ageatlastdose
3-3.5m 4 8 1 2
4-4.5m 2 11 7 2
5m 3 6 3 0
6m 1 9 0 3
Ageatbooster
None 2 13 0 3
9m 4 1 2 0
11-14m 4 12 9 4
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15-24m 0 8 0 0
TABLE22.CharacteristicsofincludedMortalitystudiesincludedinAnalysis
Characteristic PCV10N=5(56%)
PCV13N=4(44%)
StudytypeClinicaltrial 0 0Pre/postsurveillance 5(100%) 4(100%)Case-control/indirectcohort 0 0
RegionAfrica 1(20%) 1(25%)Asia 0 0Australia/Oceania 1(20%) 0Europe 1(20%) 1(25%)LatinAmerica 2(40%) 12(50%)NorthAmerica 0 0
DosingSchedule2+1 2(40%) 2(50%)3+0 2(40%) 2(50%)3+1* 1(20%) 0
EndpointCFR 2(40%) 1(25%)MortalityRateorCases 3(60%) 3(75%)*Includedduetopaucityofdataonmortality
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TABLE23.StudiesReportingonMortalityPreandPostPCVIntroduction
Country(Reference) Endpoint AgeGroup
%RelativeReduction(95%CI)
PCV10
Finland(Palmu2015)
AllIPD/sepsis 3-42m
51%(-94,93)35%(-181,90)
Colombia(Carrasquilla2016)
PneumoniaAllCause
<5y
Bogota:56.80%(49.2,63.3)Nationwide:33.4%(27.6-38.8)Bogota:22.1%(19.4-24.7)Nationwide:25.3%(23.8-26.8)
Brazil(Simonsen2016) Pneumonia 3-24m 6%Kenya(Verani2016)
PneumoniarelatedCFR <5y 43%(0,68)
Fiji(Tuigava2016)
Severe/veryseverepneumoniaCFRCXRPneumoniaCFR <2y
50%57%
PCV13
Denmark(Harboe2014)
IPDrelated30-daymortality All 28%(18,37)
Nicaragua(Becker-Dreps2014) Allcause <1y 33%(20,43)CostaRica(Castro2016) Pneumonia <2y 34.9%Malawi(McCollum2017)
PneumoniaHospitalizationsCFR <5y 41%(21,63)
CFR=CaseFatalityRate
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TABLE24.ICER(US$/DALYaverted)byU5mortalitystratainGavi-eligiblecountries(23)
Underfivemortalitystrata
<25deaths/1000livebirths
25-99deaths/1000livebirths
100-149deaths/1000livebirths
>=150deaths/1000livebirths
PCV7 $1078 $283 $103 $65PCV10 $582 $152 $66 $41PCV13 $471 $125 $60 $37
TABLE25.SummaryofselectedCEAsofPCV
Vaccine Country/regionVaccinepriceperdose
Numberofdoses Vaccineefficacy Perspective ICER Notes
PCV7 GAVI-eligiblecountries(n=72)
AMCprice+$1administrationcostperdose
3 85% Societal 2005US$146/DALYaverted
Includesindirecteffectsandserotypereplacement,discounting3%
PCV10 GAVI-eligiblecountries(n=72)
AMCprice+$1administrationcostperdose
3 85% Societal 2005US$88/DALYaverted
Includesindirecteffectsandserotypereplacement
PCV13 GAVI-eligiblecountries(n=72)
AMCprice+$1administrationcostperdose
3 85% Societal 2005US$77/DALYaverted
Includesindirecteffectsandserotypereplacement
PCV7 Middle-incomecountries(n=77)
$10or$20+$5administrationcostperdose
3 85% Societal 2005US$1,600/DALY
averted
Includesindirecteffectsandserotypereplacement,discounting3%
PCV7 Lowermiddle-incomecountries(n=35)
$10+$5administrationcostperdose
3 85% Societal 2005US$1,500/DALY
averted
Includesindirecteffectsandserotypereplacement
PCV7 Uppermiddle-incomecountries(n=42)
$20+$5administrationcostperdose
3 85% Societal 2005US$1,900/DALY
averted
Includesindirecteffectsandserotypereplacement
PCV10 Middle-incomecountries(n=77)
$10or$20+$5administrationcostperdose
3 85% Societal 2005US$1,000/DALY
averted
Includesindirecteffectsandserotypereplacement
PCV10 Lowermiddle-income
$10+$5administration
3 85% Societal 2005US$920/DALYaverted
Includesindirecteffectsandserotypereplacement
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countries(n=35)
costperdose
PCV10 Uppermiddle-incomecountries(n=42)
$20+$5administrationcostperdose
3 85% Societal 2005US$1,300/DALY
averted
Includesindirecteffectsandserotypereplacement
PCV13 Middle-incomecountries(n=77)
$10or$20+$5administrationcostperdose
3 85% Societal 2005US$900/DALYaverted
Includesindirecteffectsandserotypereplacement
PCV13 Lowermiddle-incomecountries(n=35)
$10+$5administrationcostperdose
3 85% Societal 2005US$800/DALYaverted
Includesindirecteffectsandserotypereplacement
PCV13 Uppermiddle-incomecountries(n=42)
$20+$5administrationcostperdose
3 85% Societal 2005US$1,100/DALY
averted
Includesindirecteffectsandserotypereplacement
PCV7 LatinAmericaandCaribbean
countries(n=45)
$20 3 97% Societal 2005US$1,747/DALY
averted
Doesnotincludeindirecteffects
PCV7 LatinAmericaandCaribbean
countries(n=45)
$20 3 97% Societal 2005US$59,000/life
saved
Doesnotincludeindirecteffects
PCV7 TheGambia $3.50 3 26%againstall-cause
pneumonia,16%againstSpn
meningitis/sepsis
Societal 2005US$910/DALYaverted
Directeffectsonlyinbasecasescenario,addingindirecteffects
reducedICERto$830/DALYaverted
PCV10 TheGambia $3.50 3 35%againstall-cause
pneumonia,22%againstSpn
meningitis/sepsis
Societal 2005US$670/DALYaverted
Directeffectsonlyinbasecasescenario,addingindirecteffects
reducedICERto$550/DALYaverted
PCV13 TheGambia $3.50 3 41%againstall-cause
pneumonia,26%againstSpn
meningitis/sepsis
Societal 2005US$570/DALYaverted
Directeffectsonlyinbasecasescenario,addingindirecteffects
reducedICERto$480/DALYaverted
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PCV9 TheGambia $5 3 35-37%againstpneumonia,77%againstVT-IPDand16%against
all-causemortality
Publichealthcare
$30/DALYaverted Directeffectsonly,costsofillnessandVEfromPCV9clinicaltrialinThe
Gambia(26)
PCV10 Kenya $3.50 3 77%againstpneumonia,92%againstsepsisandmeningitis
Societal 2010US$59/DALYaverted
InclusionofindirecteffectsreducedICERto$32/DALYaverted
PCV10 Kenya $3.50 3 77%againstpneumonia,92%againstsepsisandmeningitis
Societal 2010US$1,958/lifesaved
InclusionofindirecteffectsreducedICERto$1158/lifesaved
PCV13 Kenya $3.50 3 77%againstpneumonia,92%againstsepsisandmeningitis
Societal 2010US$47/DALYaverted
InclusionofindirecteffectsreducedICERto$25/DALYaverted
PCV13 Kenya $3.50 3 77%againstpneumonia,92%againstsepsisandmeningitis
Societal 2010US$1,558/lifesaved
InclusionofindirecteffectsreducedICERto$888/lifesaved
PCV10 Uganda $3.50programcostperdose
3 85%inHIV-negativechildren
Publichealthcare
US$38.50/DALYaverted
Onlydirecteffectsanddirectmedicalcostsincluded.PCV10wouldbecost-savingatco-financingcostof$0.15per
dosePCV10 Thailand $61.90 3 89%againstIPD,
6%againstpneumonia,6%againstAOM
Societal 2013US$45,183perQALYgained
PCV10vs.novaccinationwithoutinclusionofherdeffects
PCV10 Thailand $61.90 3 89%againstIPD,6%against
pneumonia,6%againstAOM
Societal 2013US$17,173perQALYgained
PCV10vs.novaccinationwithherdeffects:40%againstIPDin20-39yearolds,14%againstIPDin40-64yearolds,and29%againstIPDin>65year
oldsPCV13 Thailand $46.20 3 89%againstIPD,
6%againstpneumonia,6%
Societal 2013US$49,220perQALYgained
PCV13vs.novaccinationwithoutinclusionofherdeffects
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againstAOMPCV13 Thailand $46.20 3 89%againstIPD,
6%againstpneumonia,6%againstAOM
Societal 2013US$17,437perQALYgained
PCV13vs.novaccinationwithherdeffects:40%againstIPDin20-39yearolds,14%againstIPDin40-64yearolds,and29%againstIPDin>65year
oldsPCV10 Brazil $19.60 4 94%againstIPD
in0-5yearolds,87.5%againstVTpneumoniain0-2yearolds,
57.5%againstVTAOMin0-2year
olds
Healthcare,societal
2013US$11,815perDALYaverted
UniversalPCV10vaccinationvs.high-riskPCV10vaccination
PCV10 Colombia $16.20 3 74%againstSpnmeningitis,21%againstCXR
pneumonia,34%againstAOM
Societal 2013US$1,892perLYGgained
PCV10vs.novaccination
PCV13 Colombia $17.90 3 83%againstSpnmeningitis,24%againstCXR
pneumonia,9%againstAOM
Societal 2013US$9,801perLYGgained
PCV13vs.novaccination
PCV10 Peru $14.24 3 13%againstAOM,81%againstIPDmultipliedbyserotype
coverageof71%
Government 2011US$1,605perDALYaverted
PCV10vs.novaccination,highlycost-effective
PCV13 Peru $16.34 3 8%againstAOM,81%againstIPDmultipliedbyserotype
coverageof81%
Government 2011US$1,304perDALYaverted
PCV13vs.novaccination,highlycost-effective
PCV10 Paraguay $14.85 3 34%againstAOM,6%against
all-causepneumonia,80%
againstIPD
Government,societal
2009US$3,851perDALYaverted
(gov’t),US$1,920perDALYaverted
(societal)
PCV10vs.novaccination,cost-effectivefromgovernmentperspectiveandhighlycost-effectivefromsocietal
perspective
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multipliedby80%VTcoverage
PCV13 Paraguay $20 3 6%againstAOM,6%againstall-
causepneumonia,80%
againstIPDmultipliedby
85%VTcoverage
Government,societal
2009US$4,901perDALYaverted
(gov’t),US$3,657perDALYaverted
(societal)
PCV13vs.novaccination,cost-effectivefrombothgovernmentand
societalperspective
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TABLE26.CharacteristicsOfIndirectEffectsStudies
Characteristic PCV10N=(%)
PCV13N=(%)
TotalN=31
Region
Africa 3 3 6
Asia 0 0 0
Australia/Oceania 1 3 4
Europe1 5 14 18
LatinAmerica 0 2 2
NorthAmerica2 1 1 1
PCVdosingschedule
2+11,2 5 19 22
3+0 4 4 8
3+1 1 0(notincluded) 1
Outcome
NPCarriage 2 1 3
Pneumonia1 4 3 6
IPD2 4 19 221OnepneumoniaarticlereportsonbothPCV13and10usedsequentiallyinSweden.
2OneIPDarticlereportsonbothPCV13andPCV10inCanada.
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TABLE27:IndirectEffectsOnNpCarriagePrevalence
Reference Agegroup
Country PCVproduct(s)
Numberofyears Prevalence Percentchangeatmaximumyearspost-PCV10/13introduction
comparedtoPrePCV
surveillancePCV7use PCV10/
PCV13PrePCV(dates)
PCV7(dates) PCV10/13(dates)
Pre-PCV PCV7
PCV7VT
Ben-ShimolHumVaccImmunother2016
7-59mo,unvaccinated
Israel PCV7,PCV132+1
-- 5 4 -- 16.7%(2009-Jun2011)
9.0%(Jul2011-2014)
-- -46%
PCV13-nonPCV7VT(1,3,5,6A,7F,19A)
Ben-ShimolHumVaccImmunother2016
7-59mo,unvaccinated
Israel PCV7,PCV132+1
-- 5 4 -- 13.4%(2009-Jun2011)
4.5%(Jul2011-2014)
-- -66%
PCV10VT
DunneISPPD102016
5-8wks Fiji PCV103+0
1 -- 3 9.4%(2012)
-- 0%(2015)
-100% --
DunneISPPD102016
Adults Fiji PCV103+0
1 -- 3 2.2%(2012)
-- 0%(2015)
-100% --
HammittISPPD102016
>5yrs Kenya PCV103+0
2 -- 4 8%(2009-2010)
-- 3%(2011-2015)
-65%(sig) --
HammittISPPD102016
5-9yrs Kenya PCV103+0
2 -- 4 16.9%(2010)
-- 9.1%(2015)
-46% --
HammittISPPD102016
10-14yrs
Kenya PCV103+0
2 -- 4 9.5%(2010)
-- 4.6%(2015)
-52% --
HammittISPPD102016
15-19yrs
Kenya PCV103+0
2 -- 4 15.4%(2010)
-- 0%(2015)
-100% --
HammittISPPD102016
20-39yrs
Kenya PCV103+0
2 -- 4 5.1%(2010)
-- 3.3%(2015)
-35% --
Hammitt 40-49 Kenya PCV10 2 -- 4 5.2% -- 0% -100% --
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ISPPD102016 yrs 3+0 (2010) (2015)
HammittISPPD102016
50-59yrs
Kenya PCV103+0
2 -- 4 9.8%(2010)
-- 0%(2015)
-100% --
HammittISPPD102016
>60yrs Kenya PCV103+0
2 -- 4 5.3%(2010)
-- 0%(2015)
-100% --
Serotype3
Hammitt,personalcommunication2016
>18yrs Kenya PCV103+0
2 -- 4 1.3%(2010)
-- 0.5%(2015) -62%
Serotype6A
Hammitt,personalcommunication2016
>18yrs Kenya PCV103+0
2 -- 4 1.8%(2010)
-- 0.9%(2015)
-50%
Serotype19A
Hammitt,personalcommunication2016
>18yrs Kenya PCV103+0
2 -- 4 0.4%(2010)
-- 1.4%(2015)
250%
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TABLE28:IndirectEffectsOnPneumoniaIncidence
Country Ref CaseDefinition
Agegroupsevaluate
d
NumberofyearsBaselinemeasure
(peryear)1
%changeatpost-PCV10/13
introductionperiodcomparedto
CommentsPre-PCVsurveillance
PCV7use
PCV10/PCV13use Pre-PCV
Post-PCV7/Pre-
PCV10/13
Pre-PCV PCV7
Clinicalpneumonia
PCV102+1
FinlandOkashaISPPD102016
All-causepneumoniahospitalizati
ons
>18yrs 6.5 -- 4 548 -- -5.3%(sig)
%changeinexpectedvs.
observedratein2014basedoninterruptedtimeseriesanalysis.
Pneumoniatrendhadbeenincreasing
pre-PCV.
FinlandOkashaISPPD102016
All-causepneumoniahospitalizati
ons
50-64yrs 6.5 -- 4 NR -- -21%(sig)
FinlandOkashaISPPD102016
All-causepneumoniahospitalizati
ons
>65yrs 6.5 -- 4 1752 ---7.3%(sig)
PCV103+0
KenyaSilabaISPPD102016
Severeorveryseverepneumoniahospitalizati
ons
5-12yrs 9 -- 4 NR ---5%(not
sig) IRR=0.95(95%CI
0.56,1.59)
PCV132+1
UK(Scotland)
NathArchDisChild2015
PneumoniahospitalizationsbyICDcodes
10-14yrs 6 4 3 NR NR NR -2%(notsig)
IRR=0.98(95%CI0.87,1.11)
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Argentina
LopezPapucciISPPD102016
Clinicalpneumoniahospitalizati
ons
5-12yrs 4 -- 4
499per10,000hospitaldischarge
s
---40%(sig) Datafrom1hospital
PCV13àPCV102+1
SwedenKostenniemiISPPD102016
ClinicalpneumoniahospitalizationsbyICDcodes
6-17yrs 4 1 4 418 600 +7% -25%
VasterbottenCounty:introduced
PCV7in2009,PCV13in2010andthenPCV10in2011
SwedenKostenniemiISPPD102016
ClinicalpneumoniahospitalizationsbyICDcodes
18-64yrs 4 1 4 825 1,004 +8% -12%
SwedenKostenniemiISPPD102016
ClinicalpneumoniahospitalizationsbyICDcodes
>65yrs 4 1 4 4,010 4,141 -3% -6%
CXRpneumonia
PCV103+0
KenyaSilablaISPPD102016
CXRpneumoniahospitalizati
ons
5-12yrs 5 -- 3 NR ---11%
(notsig) IRR=0.89(95%CI
0.47,1.69)
PCV132+1
Argentina
LopezPapucciISPPD102016
CXRpneumoniahospitalizati
ons
5-12yrs 4 -- 4
261per10,000hospitaldischarge
s
---44%(sig) Datafrom1hospital
Pneumococcalpneumonia
PCV103+0
Kenya BigogoISPDD10
Pneumococcal
>18yrs,genpop
3 -- 3 112 -- -94%(sig)
Basedonbloodorurineantigen
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1unlessotherwisenotedthedenominatorisrateper100,000NR=notreported
2016 pneumoniasurveillance
testingofARIcases.Moresevereillnesswaslesslikelytobe
tested.Kenya
BigogoISPDD102016
Pneumococcal
pneumoniasurveillance
>18yrs,HIVneg
3 -- 3 59 -- -100%
Empyema
PCV132+1
UK(Scotland)
NathArchDisChild2015
EmpyemahospitalizationsbyICDcodes
10-14yrs 6 4 3 NR NR NR-37%
(notsig)IRR=0.63(95%CI
0.34,1.12)
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TABLE29:IndirectEffectsOnIPDIncidence
4a29A:All–causeIPD
Reference Agegroup
Country PCVproduct(s)
Numberofyears Baselineincidence(cases/100,000) Percentchangeatmaximumyearspost-PCV10/13introduction
comparedtoPrePCV
surveillancePCV7use PCV10/
PCV13use
PrePCV(dates)
PCV7(dates) PCV10/PCV13(dates)
Pre-PCV PCV7
AllPneumococcalSerotypesPCV102+1NuortiISPPD102016
18-49yrs
Finland PCV10 5 -- 5 8(2005-2008)
10.1(2008)
-- 6.56(2012-2015)
6.8(2015)
-18%(sig)
-33%
NuortiISPPD102016
50-64yrs
Finland PCV10 5 -- 5 17.63(2005-2008)
22.1(2008)
-- 17.29(2012-2015)
18.1(2015)
-2%
-18%
NuortiISPPD102016
>65yrs
Finland PCV10 5 -- 5 31.17(2005-2008)
36.8(2008)
-- 33.64(2012-2015)
38(2015)
8%
3%
NuortiISPPD102016
>18yrs
Finland PCV10 5 -- 5 15.9(2005-2008)
-- 16.1(2012-2015)
1%(notsig)
PCV103+1à2+1KnolISPPD102016
5-64yrs Netherlands
PCV7,PCV10
NR2
5 5 NR
7.2(2005-2006)
NR(2009-2011)
7.9(2010-2011)
NR(2014-2016)
7.2(2015-2016)
0%
-8%(notsig)
-9%KnolISPPD10
>65yrs
Netherlands
PCV7,PCV10
-- 5 5 NR
NR(2009-2011)
NR(2014-2016)
4%(notsig)
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2016 63(2005-2006)
50.9(2010-
2011)
51.3(2015-
2016)
-19%
1%PCV132+1SteensEpidemics2015
>65yrs Norway PCV7,PCV13
2 5 3 73 54 34 -53% -37%
HarboeCID2014
5-17yrs Denmark PCV7,PCV13
8 3 3 2.5(2000-2007)
1.9(2008-2010)
2.4(2011-2013)
-5%(notsig) 29%(notsig)
HarboeCID2014
18-49yrs Denmark PCV7,PCV13
8 3 3 7.1(2000-2007)
6.8(2008-2010)
5.7(2011-2013)
-20%(sig) -16%(sig)
HarboeCID2014
50-64yrs
Denmark PCV7,PCV13
8 3 3 23.6(2000-2007)
21.6(2008-2010)
19(2011-2013)
-20%(sig) -12%(sig)
HarboeCID2014
>65yrs Denmark PCV7,PCV13
8 3 3 66.5(2000-2007)
60.0(2008-2010)
49.4(2011-2013)
-25%(sig) -18%(sig)
GalanisEurRespJ2016
18-65yrs Sweden PCV7,PCV13
3 2 4 11.72(2005-2007)
9.9(2007)
8.47(2009-2010)
8.2(2009)
7.22(2011-2014)
4.9(2014)
-38%(sig)
-51%
-25%(notsig)
-40%GalanisEurRespJ2016
>65yrs Sweden PCV7,PCV13
3 2 4 38.0(2005-2007)
35.6(2007)
37.6(2009-2010)
37.4(2009)
34.2(2011-2014)
35.4(2014)
-10%(notsig)
-1%
-9%(notsig)
-5%GuevaraEuroSurv2016
75days-59mo
Spain PCV7,PCV13
4 3 4 75(2001-2004)
41(2008-2010)
16(2011-2014)
-79% -61%
CollinsISPPD102016
15-44yrs UK PCV7,PCV13
6 4 5 7.8(2005/200
6)
4.3(2009/2010)
2.9(2014/2015
)
-63% -33%
CollinsISPPD102016
45-64yrs UK PCV7,PCV13
6 4 5 17.7(2005/200
6)
9.7(2009/2010)
9.3(2014/2015
)
-47% -4%
CollinsISPPD102016
>65yrs UK PCV7,PCV13
6 4 5 32.2(2005/200
6)
26.1(2009/2010)
25.2(2014/2015
)
-22% -3%
RicketsonISPPD10
>15yrs Canada(Toronto)
PCV7,PCV10,
4 4 5 11.2(1998-2001)
8.4(2002-2010)
6.7(2011-2015)
-40% -20%
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2016 PCV13RicketsonISPPD102016
>15yrs Canada(Calgary)
PCV7,PCV13
4 8 5 10.4(1998-2001)
11.3(2002-2010)
8.8(2011-2015)
-15% -22%
VillalobosISPPD102016
Adults CostaRica PCV7,PCV13
1 NR 5 3.9 -- 2.3 -41%
VillalobosISPPD102016
Adults<65yrs
CostaRica PCV7,PCV13
1 NR 5 1.8(2007) -- 0.93(2015) -48%
VillalobosISPPD102016
>65yrs CostaRica PCV7,PCV13
1 NR 5 23.6(2007) -- 10.3(2015) -56%
VonGottbergISPPD102016
10-14yrs SouthAfrica
PCV7,PCV13
4 2 4 2.6(2008) 2.1(2010) 1.0(2015) -62% -52%
VonGottbergISPPD102016
15-24yrs SouthAfrica
PCV7,PCV13
4 2 4 3.2(2008) 3.1(2010) 1.5(2015) -53% -52%
VonGottbergISPPD102016
25-44yrs SouthAfrica
PCV7,PCV13
4 2 4 12.3(2008) 11.2(2010) 6.2(2015) -50% -45%
VonGottbergISPPD102016
45-64yrs SouthAfrica
PCV7,PCV13
4 2 4 8.9(2008) 9.4(2010) 6.7(2015) -25% -29%
VonGottbergISPPD102016
>64yrs SouthAfrica
PCV7,PCV13
4 2 4 6.3(2008) 6.9(2010) 6.4(2015) 2% -7%
duPlessisISPPD102016
>25yrs SouthAfrica
PCV7,PCV13
4 2 4 28(2005-2008)
NR 19(2012-2015)
-33%(sig)
PCV133+0JayasingheISPPD102016
15-49yrs Australia PCV7,PCV13
3 6 3.5 4.9(2002-2004)
-- 2.8(2014) -45%(sig) --
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JayasingheISPPD102016
50-64yrs Australia PCV7,PCV13
3 6 3.5 9.5(2002-2004)
-- 7.6(2014) -19%(sig)
JayasingheISPPD102016
>65yrs Australia PCV7,PCV13
3 6 3.5 25.1(2002-2004)
25(2004)
--
15.9(2010
15(2014)
12.4(2015)
-40%(sig)
-50%
-22%MoberleyISPPD102016
15-24yrsNon-
indigenous
Australia PCV7,PCV13
5 6 3 2.6(2002-2006)
1.7(2007-2010)
1.5(2011-2014)
-42% -12%
MoberleyISPPD102016
25-34yrsNon-
indigenous
Australia PCV7,PCV13
5 6 3 4.3(2002-2006)
2.9(2007-2010)
2.7(2011-2014)
-37% -7%
MoberleyISPPD102016
35-49yrsNon-
indigenous
Australia PCV7,PCV13
5 6 3 5.4(2002-2006)
4.4(2007-2010)
4.8(2011-2014)
-11% 9%
MoberleyISPPD102016
50-64yrsNon-
indigenous
Australia PCV7,PCV13
5 6 3 8.9(2002-2006)
7.7(2007-2010)
7.6(2011-2014)
-15% -1%
MoberleyISPPD102016
>65yrsNon-
indigenous
Australia PCV7,PCV13
5 6 3 22.6(2002-2006)
17(2007-2010)
16.8(2011-2014)
-26% -1%
MackenzieLancetID2016
5-14yrs TheGambia
PCV7,PCV13
1 2 3 12(2008-2010)
8.6(2011) 10(2013-2014)
-16%(notsig) 16%
MackenzieLancetID2016
>15yrs TheGambia
PCV7,PCV13
1 2 3 9(2008-2010)
11.7(2011) 4(2013-2014)
-59%(notsig) -66%
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29B:VT-IPDinPCV10countries
Reference Agegroup
Country PCVproduct(s)
Numberofyears Baselineincidence(cases/100,000) Percentchangeatmaximumyearspost-PCV10introduction
comparedtoPrePCV
surveillancePCV7use PCV10 PrePCV
(dates)PCV7(dates) PCV10
(dates)Pre-PCV PCV7
PCV10VT
NuortiISPPD102016
18-49yrs Finland PCV10 5 -- 5 5.62(2005-2008)
6.9(2008)
-- 2.81(2012-2015)
1.7(2015)
-51%(sig)
-75%
--
NuortiISPPD102016
50-64yrs Finland PCV10 5 -- 5 10.7(2005-2008)
11.6(2008)
-- 6.3(2012-2015)
4.0(2015)
-41%(sig)
-66%
--
NuortiISPPD102016
>65yrs Finland PCV10 5 -- 5 19.2(2005-2008)
22.2(2008)
-- 10.1(2012-2015)
6.7(2015)
-47%(sig)
-70%
--
PCV7VT
KnolISPPD102016
5-64yrs Netherlands
PCV7,PCV10
2 5 5 3.2(2005-2006)
1.9(2010-2011)
0.7(2015-2016)
-78%
-63%
KnolISPPD102016
>65yrs Netherlands
PCV7,PCV10
2 5 5 29.6(2005-2006)
7.6(2010-2011)
3.2(2015-2016)
-89%
-58%
PCV10-nonPCV7VT(1,5,7F)
KnolISPPD102016
5-64yrs Netherlands
PCV7,PCV10
2 5 5 1.5(2005-2006)
2.7(2010-2011)
1.3(2015-2016)
-13% -52%
KnolISPPD102016
>65yrs Netherlands
PCV7,PCV10
2 5 5 9.5(2005-2006)
9.1(2010-2011)
4.8(2015-2016)
-49% -47%
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29C:VT-IPDinPCV13countries
Reference Agegroup
Country PCVproduct(s)
Numberofyears Baselineincidence(cases/100,000) Percentchangeatmaximumyearspost-PCV13introduction
comparedtoPrePCV
surveillancePCV7use PCV13 PrePCV
(dates)PCV7(dates) PCV13
(dates)Pre-PCV PCV7
PCV7VT
HarboeCID2014
>65yrs Denmark PCV7,PCV13
8 3 3 29.2(2007) 14(2009)
2.4(2013) -92% -83%
CollinsISPPD102016
15-44yrs UK PCV7,PCV13
6 4 5 2.5(2005/200
6)
0.3(2009/2010)
0.1(2014/2015
)
-96% -67%
CollinsISPPD102016
45-64yrs UK PCV7,PCV13
6 4 5 7.1(2005/200
6)
1.0(2009/2010)
0.2(2014/2015
)
-97% -80%
CollinsISPPD102016
>65yrs UK PCV7,PCV13
6 4 5 15.9(2005/200
6)
3.2(2009/2010)
0.9(2014/2015
)
-94% -72%
GalanisEurRespJ2016
18-65yrs Sweden PCV7,PCV13
3 2 4 6.1(2005-2007)
4.7(2007)
2.6(2009-2010)
2.9(2009)
0.94(2011-2014)
0.4(2014)
-84%(sig)
-91%
-63%(sig)
-86%GalanisEurRespJ2016
>65yrs Sweden PCV7,PCV13
3 2 4 22.3(2005-2007)
18.4(2007)
10.1(2009-2010)
12.1(2009)
3.24(2011-2014)
2.4(2014)
-85%(sig)
-87%
-68%(sig)
-80%
vonGottbergISPPD102016
10-14yrs SouthAfrica
PCV7,PCV13
4 2 4 1.0(2008) 0.5(2010) 0.2(2015) -80% -60%
vonGottbergISPPD102016
15-24yrs SouthAfrica
PCV7,PCV13
4 2 4 0.9(2008) 0.7(2010) 0.2(2015) -78% -71%
vonGottbergISPPD102016
25-44yrs SouthAfrica
PCV7,PCV13
4 2 4 4.3(2008) 3.2(2010) 0.7(2015) -84% -78%
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vonGottbergISPPD102016
45-64yrs SouthAfrica
PCV7,PCV13
4 2 4 3.3(2008) 2.8(2010) 0.9(2015) -73% -68%
vonGottbergISPPD102016
>64yrs SouthAfrica
PCV7,PCV13
4 2 4 2.1(2008) 2.2(2010) 0.7(2015) -67% -68%
MackenzieLancetID2016
5-14yrs TheGambia
PCV7,PCV13
1 2 3 -- 2.1(2011) 1.0(2013-2014)
-- -52%
MackenzieLancetID2016
>15yrs TheGambia
PCV7,PCV13
1 2 3 1.0(2008-2010)
1.35(2011) -- -- --
JayasingheISPPD102016
5-64yrs Australia PCV7,PCV13
3 6 4 4.1(2004) 0.5(2010) 0.3(2015) -93% -40%
JayasingheISPPD102016
>65yrs Australia PCV7,PCV13
3 6 4 17.3(2004) 1.9(2010) 1.1(2015) -94% -42%
PCV13VT
SteensEpidemics2015
>65yrs Norway PCV7,PCV13
2 5 3 58(2004-2006)
27.5(2010/2011)
8.8(2013/2014
)
-85% -68%
SlotvedVaccine2016
5-64yrs Denmark PCV7,PCV13
9 3 4 NR 0.46(2008-2010)
0.29(2011-2014)
-- -38%(notsig)
SlotvedVaccine2016
>65yrs Denmark PCV7,PCV13
9 3 4 NR 2.7(2008-2010)
1.41(2011-2014)
-- -48%(notsig)
MackenzieLancetID2016
5-14yrs TheGambia
PCV7,PCV13
1 2 3 10(2008-2010)
-- 10(2013-2014)
5%(notsig) --
MackenzieLancetID2016
>15yrs TheGambia
PCV7,PCV13
1 2 3 7.0(2008-2010)
-- 4.0(2013-2014)
-50%(notsig) --
PCV13-nonPCV7VT(1,3,5,6A,7F,19A)
HarboeCID2014
>65yrs Denmark PCV7,PCV13
8 3 3 17.6(2007) 20/7(2009) 11.4(2013) -35% -45%
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CollinsISPPD102016
15-44yrs UK PCV7,PCV13
6 4 5 3.4(2005/200
6)
2.4(2009/2010)
0.7(2014/2015
)
-79% -71%
CollinsISPPD102016
45-64yrs UK PCV7,PCV13
6 4 5 5.8(2005/200
6)
4.4(2009/2010)
1.7(2014/2015
)
-71% -61%
CollinsISPPD102016
>65yrs UK PCV7,PCV13
6 4 5 8.6(2005/200
6)
10.4(2009/2010)
5.1(2014/2015
)
-41% -51%
GalanisEurRespJ2016
18-65yrs Sweden PCV7,PCV13
3 2 4 2.96(2005-2007)
3.2(2007)
3.25(2009-2010)
3.2(2009)
2.52(2011-2014)
1.4(2014)
-15%(notsig)
-56%
-22%(notsig)
-56%GalanisEurRespJ2016
>65yrs Sweden PCV7,PCV13
3 2 4 7.75(2005-2007)
7.4(2007)
12.1(2009-2010)
13.4(2009)
9.65(2011-2014)
8.6(2014)
25%(notsig)
16%
-20%(notsig)
-36%vonGottbergISPPD102016
10-14yrs SouthAfrica
PCV7,PCV13
4 2 4 1.2(2008) 1.0(2010) 0.3(2015) -75% -70%
vonGottbergISPPD102016
15-24yrs SouthAfrica
PCV7,PCV13
4 2 4 1.4(2008) 1.4(2010) 0.3(2015) -79% -79%
vonGottbergISPPD102016
25-44yrs SouthAfrica
PCV7,PCV13
4 2 4 4.1(2008) 4.4(2010) 1.3(2015) -68% -70%
vonGottbergISPPD102016
45-64yrs SouthAfrica
PCV7,PCV13
4 2 4 3.3(2008) 3.7(2010) 1.5(2015) -55% -59%
vonGottbergISPPD102016
>64yrs SouthAfrica
PCV7,PCV13
4 2 4 1.8(2008) 2.6(2010) 0.9(2015) -50% -65%
Mackenzie 5-14yrs The PCV7, 1 2 3 10(2008- 6.4(2011) 9.0(2013- -5%(notsig) 41%
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LancetID2016
Gambia PCV13 2010) 2014)
MackenzieLancetID2016
>15yrs TheGambia
PCV7,PCV13
1 2 3 7.0(2008-2010)
7.3(2011) 4.0(2013-2014)
-48%(notsig) -45%
JayasingheISPPD102016
5-64yrs Australia PCV7,PCV13
3 6 4 0.7(2004) 2.1(2010) 0.8(2015) 14% -62%
JayasingheISPPD102016
>65yrs Australia PCV7,PCV13
3 6 4 3.6(2004) 5.7(2010) 2.2(2015) -39% -61%
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29D:Serotype3,6A,6Cand/or19AIPD
Reference Agegroup
Country PCVproduct(s)
Numberofyears Baselineincidence(cases/100,000) Percentchangeatmaximumyearspost-PCV10/13
introductioncomparedtoPrePCV
surveillancePCV7use PCV10/
PCV13PrePCV(dates)
PCV7(dates) PCV10/PCV13(dates)
Pre-PCV PCV7
3,6A,19A
PCV10
NuortiISPPD102016
>18yrs Finland PCV10 5 -- 5 2.05(2005-2008)
-- 4.43(2012-2015)
116% --
NuortiISPPD102016
18-49yrs Finland PCV10 5 -- 5 0.93(2005-2008)
-- 1.79(2012-2015)
92% --
NuortiISPPD102016
50-64yrs Finland PCV10 5 -- 5 2.46(2005-2008)
-- 4.52(2012-2015)
84% --
NuortiISPPD102016
>65yrs Finland PCV10 5 -- 5 4.68(2005-2008)
-- 9.71(2012-2015)
107% --
Serotype3
PCV10
NuortiISPPD102016
>65yrs Finland PCV10 5 -- 5 1.36(2005-2008)
-- 4.94(2012-2015)
263% --
KnolISPPD102016
5-64yrs Netherlands
PCV10 2 5 5 0.37(2005-2006)
0.37(2010-2011)
0.39(2015-2016)
5% 5%
KnolISPPD102016
>65yrs Netherlands
PCV10 2 5 5 3.24(2005-2006)
4.16(2010-2011)
4.81(2015-2016)
48% 16%
PCV13
WaightLancet
15-44yrs UK PCV7,PCV13
6 4 4 0.18(2005/200
0.13(2009-2010)
0.07(2013-2014)
-61% -46%
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lxxxvii
2015 6)
WaightLancet2015
45-64yrs UK PCV7,PCV13
6 4 4 0.85(2005/200
6)
0.8(2009-2010)
0.33(2013-2014)
-61% -59%
WaightLancet2015
>65yrs UK PCV7,PCV13
6 4 4 2.7(2005/200
6)
2.8(2009-2010)
1.6(2013-2014)
-41% -43%
HarboeCID2014
>65yrs Denmark PCV7,PCV13
8 3 3 4.2(2000-2007)
4.4(2008-2010)
4.5(2011-2013)
7% 2%
Serotype6A
PCV10
NuortiISPPD102016
>65yrs Finland PCV10 5 -- 5 2.22(2005-2008)
-- 1.96(2012-2015)
-12% --
KnolISPPD102016
5-64yrs Netherlands
PCV7,PCV10
2 5 5 0.13(2005-2006)
0(2010-2011)
0(2015-2016)
-100% --
KnolISPPD102016
>65yrs Netherlands
PCV7,PCV10
2 5 5 1.6(2005-2006)
0.66(2010-2011)
0.17(2015-2016)
-89% -74%
PCV13
WaightLancet2015
15-44yrs UK PCV7,PCV13
6 4 4 0.07(2005/200
6)
0.05(2009-2010)
0(2013-2014)
-100% -100%
WaightLancet2015
45-64yrs UK PCV7,PCV13
6 4 4 0.22(2005/200
6)
0.15(2009-2010)
0(2013-2014)
-100% -100%
WaightLancet2015
>65yrs UK PCV7,PCV13
6 4 4 1.1(2005/200
6)
0.77(2009-2010)
0.03(2013-2014)
-97% -96%
HarboeCID2014
>65yrs Denmark PCV7,PCV13
8 3 3 2.0(2000-2007)
1.5(2008-2010)
0.3(2011-2013)
-85% -80%
vonGottbergISPPD102016
10-14yrs SouthAfrica
PCV7,PCV13
4 2 4 0.2(2008) 0.1(2010) 0.1(2015) -50% 0%
vonGottberg
15-24yrs SouthAfrica
PCV7,PCV13
4 2 4 0.2(2008) 0.2(2010) 0(2015) -100% -100%
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lxxxviii
ISPPD102016vonGottbergISPPD102016
25-44yrs SouthAfrica
PCV7,PCV13
4 2 4 0.6(2008) 0.7(2010) 0.1(2015) -83% -86%
vonGottbergISPPD102016
45-64yrs SouthAfrica
PCV7,PCV13
4 2 4 0.7(2008) 0.9(2010) 0.2(2015) -71% -78%
vonGottbergISPPD102016
>64yrs SouthAfrica
PCV7,PCV13
4 2 4 0.2(2008) 0.2(2010) 0.1(2015) -50% -50%
Serotype6C
PCV10
KnolISPPD102016
5-64yrs Netherlands
PCV7,PCV10
2 5 5 0(2005-2006)
0(2010-2011)
0.21(2015-2016)
-- --
KnolISPPD102016
>65yrs Netherlands
PCV7,PCV10
2 5 5 0.11(2005-2006)
0.42(2010-2011)
1.26(2015-2016)
1045% 200%
Serotype19A
PCV10
NuortiISPPD102016
>65yrs Finland PCV10 5 -- 5 1.1(2005-2008)
-- 2.9(2012-2015)
164%
KnolISPPD102016
5-64yrs Netherlands
PCV7,PCV10
2 5 5 0.58(2005-2006)
1.09(2010-2011)
1.33(2015-2016)
129% 22%
KnolISPPD102016
>65yrs Netherlands
PCV7,PCV10
2 5 5 2.11(2005-2006)
4.72(2010-2011)
4.98(2015-2016)
136% 6%
PCV13
CorcoranISPPD10
>65yrs Ireland PCV7,PCv13
1 3 5 1.12(2007) 1.85(2010) 3.28(2015) 193% 77%
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lxxxix
2016
WaightLancet2015
15-44yrs UK PCV7,PCV13
6 4 4 0.13(2005/200
6)
0.4(2009-2010)
0.17(2013-2014)
31% -58%
WaightLancet2015
45-64yrs UK PCV7,PCV13
6 4 4 0.49(2005/200
6)
1.1(2009-2010)
0.41(2013-2014)
-16% -63%
WaightLancet2015
>65yrs UK PCV7,PCV13
6 4 4 1.5(2005/200
6)
3.6(2009-2010)
1.1(2013-2014)
-27% -63%
HarboeCID2014
>65yrs Denmark PCV7,PCV13
8 3 3 1.6(2000-2007)
3.3(2008-2010)
2.9(2011-2013)
81% -12%
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a
AppendixB.Table1.Excludedstudies
StudyCharacteristicsCountry,Reference StudyDesign Population
agePCVproductandCountrySchedule
ExclusionReason
NPCarriage Australia,Leach,JournalofPaediatricsandChildHealth,2011
Postsurvey children PCV7,PCV10,3+0 Onlyreportsallcarriage,noserotypingdone
Germany,Linden,EurJPediatr,2015
Postsurvey children PCV7,PCV10,PCV13,
3+1,2+1ReportsPCV10andPCV13together,cannotdistinguishdatabyproductreceived
Italy,Camili,PLoSONE,2013
Postsurvey children PCV7,PCV13,2+1 ReportsPCV10andPCV13together,cannotdistinguish
databyproductreceivedItaly,Martinelli,ISPPD-10,2016
Postsurvey Seniors PCV7,PCV13,2+1 Onlyreportsonagesover65
France,Cohen,PediatricInfectiousDiseaseJournal,2012
Postsurvey children PCV7,PCV13,2+1 NPCarriagesurveyedonlyamongAOMcases
France,Cohen,Vaccine,2015
Pre/Postsurvey children PCV7,PCV13,3+1,2+1 NPCarriagesurveyedonlyamongAOMcases
France,Angoulvant,BMCInfectiousDiseases,2015
Postsurvey children PCV7,PCV13,2+1 NPCarriagesurveyedonlyamongAOMcases
Isreal,Greenberg, Pre/Postsurvey children PCV7,PCV13,2+1 NPCarriagesurveyedonlyamongAOMcases
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b
ISPPD-10,2016Colombia,Morales,ISPPD-10,2016
Postsurvey children PCV10,2+1 Nodatesprovidedforsurveyandonlyestimatesfor
prevalencegivenTanzania,Ndossa,JournalofHealthResearch,2015
Cohort children PCV10,3+0 Onlyreportsonallpneumococcalcarriage
Iceland,Quirk,ISPPD-10,2016
Pre/Postsurvey children PCV10,2+1 Agesofchildrensampledwasnotreported
Iceland,Sigurðsson,ISPPD-10,2016
Pre/Postsurvey children PCV10,2+1 Onlyreportsonallpneumococcalcarriage
Ethiopia,Assefa,PediatricsandNeonatology
Postsurvey children PCV10,3+0 Onlyreportsonallpneumococcalcarriage
Malawi,Kamng'ona,BMCInfectiousDiseases
Pre/Postsurvey children PCV13,3+1 DoesnotdistinguishbetweenPreandPost-Introduction
periodsorvaccinatedandunvaccinatedgroups
Togo,Tall,ISPPD-10,2016
Pre/Postsurvey Both PCV10,3+0 NPCarriagesurveyedonlyamongpneumoniacases
Australia,Beissbarth,ISPPD-10,2016
RCT children PCV10,PCV13,3+1,3+0 Doesnotdistinguishbetweenschedules
Pakistan,Kerai,ISPPD-10,2016
Postsurvey children PCV10,3+0
Lowcoverageinstudypopulationandreportscarriage6Aand19Atogether.UsesthesamedataasTsegaye2016,whichwillbeincluded
Fiji,Russell,ISPPD-10,2016
Pre/Postsurvey Both PCV10,3+0 Onlyreportsonallpneumococcalcarriage
Portugal,Rodrigues,ISPPD-10,2016
Postsurvey children PCV7,PCV10,PCV13,
2+1 Doesnotdistinguishbetweenschedules
Fiji,Russell,ISPPD-10,2016
Pre/Postsurvey Both PCV10,3+0 Onlyreportsonallpneumococcalcarriage
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c
USA,Shea,ISPPD-10,2016 Pre/Postsurvey children PCV7,PCV13,
3+1 Onlyreportsallpneumococcalcarriage
Korea,Ahn,InfectiousDiseases Pre/Postsurvey children PCV7,PCV10,PCV13,
2+1
Reportsamongpatientswithrespiratoryinfections,includingpneumonia,notrepresentativeofgeneralpopulation
Iceland,Erlendsdottir,ISPPD-9,2014 Postsurvey children PCV10
2+1Noimpactassessment,childrenreportedonunlikelytobevaccinated
Pneumonia Israel,BenShimol,PIDJ2015
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
Uruguay,Gabarrot,PLoSONE2014
Pre/Postobservation allages PCV13,2+1 MainoutcomeIPDwithproportionofIPDcasesthatwere
pneumoniaItaly,Martinelli,HumanVac&Immuno2014
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
Morocco,Jroundi,JTropPed2014
Post-onlyobservation children PCV10,2+1 Onlypost-data
UnitedKingdom(UK),Moore,JID2014
Pre/Postobservation allages PCV13,2+1
PapermentionsproportionofIPDcasesthatwerepneumoniaorbacteremia,butoverallratesareforIPDingeneral
Israel,Weinberger,EID2013
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1.5years)
UnitedKingdom(UK),Elemraid,DiagMicro&InfectDis2013
Post-onlyobservation allages PCV13,2+1 Insufficientnumberofyearspost-introduction(1.5years);
studyisondiagnostics,notimpact
Brazil,Afonso,EID2013
Pre/Postobservation children PCV10,3+0 Insufficientnumberofyearspost-introduction(1year)
Uruguay,Hortal,ISPPD2012
Pre/Postobservation children PCV13,2+1 Duplicatedata
Argentina,Bakir,ISPPD2014
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year);no
pre-PCVdata,onlyyearofintroArgentina,Bakir, Pre/Post children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
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d
ISPPD2014 observationArgentina,Rearte,ISPPD2014
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
Argentina,Ranca,ISPPD2014
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
Gambia,Ikumapayi,ISPPD2014
Pre/Postobservation allages PCV13,3+0 Casedataonly;etiologyofpnacases
Gambia,Ebruke,ISPPD2014 casecontrol children PCV13,3+0 Nopneumoniaoutcome
Uruguay,Giachetto,ISPPD2014
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
Madagascar,Rabezanahary,ISPPD2014
casecontrol children PCV10,3+0 Pre-PCVdataonly
Ireland,O'Connell,ISPPD2014
Pre/Postobservation children PCV13,2+1 MainoutcomeofinterestisIPD;statesreductionin
incidenceofcomplicatedpneumonia,butnodatashownArgentina,Badano,ISPPD2014
Pre/Postobservation children PCV13,2+1 Insufficientnumberofyearspost-introduction(1year)
MultipleCountries(PleaseSpecify),PERCHStudyGroup,ISPPD2014
casecontrol children PCV10/PCV13,2+1,3+0 Etiologyofpneumonia,notimpact
Brazil,Oliveira,Vaccine2016 cohort children PCV10,2+1 Norelevantoutcomeofinterest-studyfocuseson
complicationsofARIsandriskfactorsforARIFrance,Noel,JPediatrInfectDisSoc2016
Pre/Postobservation children PCV13,2+1 EDvisitsonly;allotherdatapresentedinreportisfor
hospitalizedcasesSouthAfrica,Zar,LancetRespirMed2016
casecontrol children PCV13,2+1 Studyonetiology,notPCVimpact
Sweden,JohanssonKostenniemi,ISPPD2016
Pre/Postobservation allages PCV10/PCV13,2+1 Onlyqualitativedata
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e
MultipleCountries,Tregnaghi,ISPPD2016
RandomizedControlledTrial
children PCV10,3+0 3+1schedule
Iceland,Sigurðsson,ISPPD2016
Pre/Postobservation children PCV10,2+1 Nopneumoniadata
Italy,Martinelli,ISPPD2016
Post-onlyobservation allages PCV13,2+1 Nopneumoniadata;onlypostdata
Venezuela,delNogal,ISPPD2016 casecontrol children PCV13,2+1 Cross-sectionalstudynestedincohortstudy;noincidence
Togo,Tall,ISPPD2016 Pre/Postobservation allages PCV13,3+0 Nopneumoniadata
Argentina,Rearte,ISPPD2016
Pre/Postobservation children PCV13,2+1 Caseseries
Argentina,Rearte,ISPPD2016
Pre/Postobservation children PCV13,2+1 Duplicate
Fiji,Russell,ISPPD2016
Pre/Postobservation allages PCV10,3+0 Duplicate
MultipleCountries,Tregnaghi,ISPPD2016
RandomizedControlledTrial
children PCV10,3+0 3+1schedule
Mortality
Sweden,Luthander,ActaPaediatrica
Pre/Postobservation allages PCV7,PCV10,2+1
Aetiologystudythatbreaksdowndeathsintopre/postperiods,howevertherewasanotherinterventioninPCVtimeperiod
UnitedKingdom,Slack,ISPPD,2012
IndirectCohort children PCV7,PCV10,2+1 Nopre/postcomparisonjustacompleteserotype
distributionofthedeathsoccurredoverstudyperiodIceland,Haraldsson,ISPPD,2014
Pre/Postobservation allages PCV10,2+1 Onlycasenumbers(notincidenceorreduction);Toosmall
samplesize
Australia,Kluyver Pre/Postobservation allages PCV7,PCV13,3+1
Numberofdeathsinreportedperiodofsurveillance,butnopre/postcomparisonpossible;Toosmallsamplesize
SouthAfrica,Zar, casecontrol children PCV13,2+1 DrakensteinChildHealthstudy.NocomparisonofPCVvs.
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f
LancetofRespiratoryMedicine,2016
noPCVgroup
Argentina,Gentile,ISPPD,2016
Pre/Postobservation children PCV13,2+1 Onlycasenumbers(notincidence)
UnitedKingdom,Collins,ISPPD,2016
Pre/Postobservation children PCV7,PCV10,2+1
Postonlymeasureofdeaths,bySTgroup,nocomparisonpreandpostabletobemade
CzechRepublic,Stock,PLoSONE,2015
Pre/Postobservation allages PCV10,PCV13,3+1 CasefatalityrateforallIPDonly
Brazil,Grando,Cadernosdesaudepublica,2015
Pre/Postobservation children PCV13,3+1 Casefatalityrateforpneumococcalmeningitisonly
Canda,Rudnick,Vaccine,2013
Pre/Postobservation allages PCV7,PCV10,PCV13,2+1,3+1 Casefatalityrateforadultsonly
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g
Table2:IndirectEffectsStudiesExcludedfromReview
StudyCharacteristicsCountry,Reference
StudyDesign Populationage
PCVproductandCountrySchedule
ExclusionReason
NPC
ItalyAnsaldiHumVacImmunother2013
Postsurvey >60yrs PCV132+1
Lessthan3yearspostdataNopre-PCVcomparisonperiod
ItalyAzzariHumVacImmunother2016
Postsurvey <5yrs PCV132+1
Excludedbasedonagegroup,mostlydirecteffects
AustraliaBeissbarthISPPD102016
RCT <1yr PCV10,PCV133+0,4+0
NocomparisonperiodforpostPCV10/13Excludebasedonstudydesign
NetherlandsBoschVaccine2016
Prepostsurvey
Adults PCV103+1
Lessthan3yearspostdata
ItalyCamilliPLoSOne2013
Postsurvey <5yrs PCV132+1
Lessthan3yearspostdata
SouthAfricaDubeISPPD102016
Postsurvey <5yrs PCV132+1
Excludebasedonagegroup,mostlydirecteffects
ItalyDurandoISPPD92014
Postsurvey >60yrs PCV132+1
OnlydataonallpneumococcalcarriageLessthan3yearspostdata
IcelandErlendsdottir
Prepostsurvey
2-6yrs PCV132+1
OnlydataonallpneumococcalcarriageLessthan3yearspostdata
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h
ISPPD92014
SwedenGalanisEurRespJ2016
Prepostsurvey
<6yrs PCV132+1
Excludedbasedonagegroups,mixeddirecteffects
UKHamalubaArchDisChild2012
Postsurvey Adults>65yrs
PCV132+1
Lessthan3yearspostdata
KenyaHammittLancetGlobalHealth2014
Prepostsurvey
>5yrs PCV103+0
Lessthan3yearspostdata
AustraliaHoskinsISPPD92014
Postsurvey >5yrs PCV133+0
Lessthan3yearspostdata
FinlandJokinenISPPD102016
RCT 5-9yrs PCV102+1,3+1
Excludebasedonstudydesign
FinlandJokinenISPPD92014
RCT 3-7yrs PCV102+1,3+1
Excludebasedonstudydesign
KenyaKimISPPD102016
Prepostsurvey
Adults,HIV+ PCV103+0
Lessthan3yearspostdataHIV+highriskgroup
NetherlandsKronePloSOne2015
Postsurvey >60yrs PCV103+1
Lessthan3yearspostdata
ItalyMartinelliISPPD102016
Postsurvey >65yrs PCV132+1
NocomparisonperiodforpostPCV13
BurkinaFasoMoisiISPPD102016
Prepostsurvey
>5yrs PCV133+0
Lessthan3yearspostdata
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i
SouthAfricaNzenzeISPPD92014
Prepostsurvey
15-45yrs PCV132+1
Lessthan3yearspostdata
SouthAfricaNzenzeISPPD102016
Postsurvey >5yrs PCV132+1
Lessthan3yearspostdata
ItalyPasinatoVaccine2014
Postsurvey <5yrs PCV132+1
Lessthan3yearspostdata
ItalyPrincipiJMedMicro2014
Postsurvey 15-19yrs PCV132+1
Lessthan3yearspostdata
FijiRussellISPPD102016
Prepostsurvey
Adults PCV103+0
Onlyreportdataonallpneumococcalcarriage
FijiRussellISPPD102016
Prepostsurvey
Adults PCV103+0
Onlyreportdataonallpneumococcalcarriage
MozambiqueSigauqueISPPD102016
Prepostsurvey
<5yrs PCV103+0
Lessthan3yearspostdata
IcelandSigurossonISPPD102016
Prepostsurvey
<4yrs PCV102+1
Excludebasedonagegroup
NorwaySteensPIDJ2015
Prepostsurvey
>5yrs PCV132+1
Lessthan3yearspostdata
TogoTallISPPD102016
Prepostsurvey
>5yrs PCV133+0
Lessthan3yearspostdata
UKvanHoekVaccine2014
Prepostsurvey
>5yrs PCV132+1
Lessthan3yearspostdata
NetherlandsVissersISPPD10
Prepostsurvey
Adults PCV103+1
Allpneumococcalcarriagedataonly
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j
2016
IPD
FranceAlexandreActaPaediatrica2010
Prepostinc 2-18yrs PCV132+1
PostPCV7dataonly
UruguayAlgortaISPPD102016
Prepostinc Adults PCV132+1
PCV7andPCV13datareportedtogether
BrazilAzevedoISPPD92014
Prepostinc >50yrs PCV103+1
OnlyallSpnincidence,3+1schedule
BrazilCaieraoPLoSOne2014
PrePostcases >6yrs PCV103+1
Excludedbasedonstudydesign
SpainCamaraISPPD102016
Prepostinc >18yrs PCV132+1
LowcoverageofPCV13inprivatemarket
TaiwanChangValueinHealth2014
Prepostinc <18yrs PCV10,PCV13
Excludebasedonagegroups,mixeddirecteffects
AustraliaDeKluyverCDI2015
Postcaseseries
>5yrs PCV133+0
Excludedbasedonstudydesign
CanadaDeWalsVaccine2014
Prepostinc >5yrs PCV10,PCV132+1
Lessthan3yearspostdata
MoroccoDiawaraISPPD92014
Prepostinc Generalpopulation
PCV13,PCV102+1
Agegroupwithmixeddirecteffects,noincidencedataLessthan3yearspostdata
BrazildosSantos
Prepostinc >15yrs PCV133+1
Lessthan3yearspostdata,3+1schedule
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k
Vaccine2013
SpainErcibengoaISPPD102016
Prepostcases >5yrs PCV132+1
Excludedbasedonstudydesign
IcelandErlendsdottirISPPD92014
Prepostinc >2yrs PCV102+1
Lessthan3yearspostdata
UruguayGabarrotPLoSOne2014
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
UruguayGabarrotISPPD92014
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
ArgentinaGentileISPPD102-16
Prepostinc 5-15yrs PCV132+1
Lessthan3yearspostdata
DenmarkHarboeISPPD92014
Prepostinc Genpop PCV132+1
Excludedbasedonagegroups,mixeddirecteffects
CanadaHelfertyIntJCircumpolarHealth2013
Prepostinc >2yrs PCV10,PCV132+1
Lessthan3yearspostdata
FranceJanoirPLoSOne2014
Prepostcases >16yrs PCV132+1
Excludedbasedonstudydesign
NetherlandsKnolEmergingInfDis2015
Prepostinc >18yrs PCV103+1
DatacoveredinKnolISPPD102016
FranceLepoutreVaccine2015
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
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l
UKMartinLancet2014
Prepostinc >65yrs PCV132+1
Lessthan3yearspostdata
SwitzerlandMeichtryVaccine2014
Caseseries >16yrs PCV132+1
CasesonlyforPCV13period
UKMooreISPPD92014
Prepostinc Generalpop PCV132+1
Excludedbasedonagegroups,mixeddirecteffects
SouthAfricaNzenzeISPPD92014
Prepostinc 15-45yrs PCV132+1
Lessthan3yearspostdata
FinlandPalmuISPPD92014
Clinicaltrial >5yrs PCV102+1
Excludedbasedonstudydesign
FinlandPalmuISPPD102016
Prepostinc <7yrs PCV102+1
Historicalcontrol,agegroupfordirecteffects
SpainPicazoPIDJ2013
Postinc >5yrs PCV132+1
Excludebasedonstudydesign,postonly
UruguayPirezPIDJ2014
Prepostinc <15yrs PCV132+1
Excludedbasedonagegroup,mixeddirecteffectsLessthan3yearspostdata
FinlandPolkowskaISPPD102016
Prepostinc >5yrs PCV102+1
DatesnotreportedforcomparisonperiodpreandpostPCV
CostaRicaRamirezISPPD102016
Prepostinc >65yrs PCV132+1
MixedoutcomeofIPDandpneumoniareportedtogether
IsraelRegev-YochayISPPD102016
Postinc >18yrs PCV132+1
StartedinyearofPCV7introduction,sopostonly
CanadaRicketsonISPPD92014
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
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m
CanadaRudnickVaccine2013
Prepostinc >5yrs PCV10,PCV132+1
Lessthan3yearspostdata
FijiRussellISPPD102016
Prepostinc <4yrs PCV103+0
Excludedbasedonagegroups
CanadaSahniCanJPublicHealth2012
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
DenmarkSlotvedISPPD92014
Prepostinc <90days PCV132+1
PCV7andPCV13datareportedtogether
NorwaySteensVaccine2013
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
NorwaySteensBMCInfDis2014
Prepostinc >5yrs PCV132+1
PostPCV7dataonly
Finland,USASuayaISPPD102016
Prepostinc >5yrs PCV10,PCV132+1
SamedataasreportedinNuortiISPPD102016
GermanyvanderLindenPLoSOne2015
Prepostcases >5yrs PCV132+1
Excludedbasedonstudydesign
GermanyvanderLindenISPPD102016
Prepostcases >16yrs PCV132+1
Excludedbasedonstudydesign
SouthAfricavonGottbergNEJM2014
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
NetherlandsWagenvoortISPPD102016
Prepostinc >5yrs PCV103+1,2+1
Malesandfemalesreportedseparately
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n
Pneumonia
NicaraguaBecker-DrepsPIDJ2014
Prepostinc 5-14yrs PCV133+0
Lessthan3yearspostdata
NicaraguaBecker-DrepsVaccine2015
Prepostinc >50yrs PCV133+0
Lessthan3yearspostdata
VenezueladelNogalISPPD102016
Prepostcases <10yrs PCV132+1
Excludedbasedonstudydesignandagegroup
ArgentinaGentileISPPD92014
Prepostinc <18yrs PCV132+1
Excludedbecauseofagegroups,mixeddirecteffects
ArgentinaGentileISPPD102016
Prepostinc 5-15yrs PCV132+1
Lessthan3yearspostdata
IsraelGreenbergVaccine2015
Prepostinc <18yrs PCV132+1
Excludedbecauseofagegroups,mixeddirecteffects
SwedenLindstrandPediatrics2014
Prepostinc 5-18yrs PCV132+1
Lessthan3yearspostdata
ItalyMartinelliISPPD102016
Postcases >65yrs PCV132+1 Excludedbasedonstudydesign
UKMcDonaldDiabeticMed2013
Prepostinc >65yrs PCV132+1
Excludedbecausehighriskgrouponly:diabeticpatients
PolandPatrzalekCurrMedResOpin2016
Prepostinc >30yrs PCV132+1
Lessthan3yearspostdata
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o
UruguayPirezPIDJ2014
Prepostinc <15yrs PCV132+1
Excludedbecauseofagegroups,mixeddirecteffectsLessthan3yearspostdata
UruguayPirezISPPD92014
Prepostinc <14yrs PCV132+1
Excludedbecauseofagegroups,mixeddirecteffectsLessthan3yearspostdata
SpainRivero-CalleISPPD102016
Prepostinc >5yrs PCV132+1
Lessthan3yearspostdata
FijiRussellISPPD102016
Prepostinc <2yrs PCV103+0
Excludedbasedonagegroups
FijiRussellISPPD102016
Prepostinc <2yrs PCV103+0
Excludedbasedonagegroups
UKSaxenaJInf2015
Prepostinc <16yrs PCV132+1
Excludedbecauseofagegroups,mixeddirecteffects
TogoTallISPPD102016
Prepostinc <4yrs PCV133+0
Excludedbasedonagegroups,mixeddirecteffects
SpainTagarroJPeds2015
Casecontrol <14yrs PCV132+1
Excludedbasedonstudydesign
IsraelVeraniISPPD92014
Casecontrol <5yrs PCV132+1
Excludedbasedonstudydesign
SouthAfricaZampoliPIDJ2015
Prepostinc <12yrs PCV132+1
Excludedbasedonagegroups,mixeddirecteffects
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AppendixC.
SearchStrategy:Librarians at the Johns Hopkins Medical Institutes, Welch Library, will work with the PRIME coordinator to refresh the literature search strategy developed for the PCV dosing landscape in 2010. Electronic searches were conducted in EMBASE, PubMed, Biological Abstracts (BA), Pascal Biomed, Global Health, BioAbst/Reports, Reviews, Meetings, Cochrane Library, African Index Medicus (AIM), Western Region Index Medicus (WPRIM), Index Medicus for Eastern Med. Region (IMEMR), Index Medicus for South-East Asia Region (IMSEAR), Latin America and Caribbean Health Sciences Info. (LILACS), Pan-American Health Org. (PAHO), and, IndiaMed (IndMed). The terms listed in Appendix 1 will be used to identify all potentially relevant articles for this review. Each article must include a minimum of one “narrow vaccine term” and one “Pneumococcal term” to be identified in the search. Terms may be listed as Medical Subject Headings (MeSH) or other categories specific to each database. Only studies published in the English language will be considered for review because of the low likelihood that such studies have been published in non-English journals1. It is our assessment that the vast majority of reports will be reported in English, and the effort required to search in other languages will yield little if any additional data. Other resources will also be considered: “Gray literature” (national surveillance data, congress and conference proceedings and annals (especially the international symposium of pneumococcus and pneumococcal disease (ISPPD)); hand-searching from reference lists of included studies; contact with authors of included studies and with experts, vaccine manufacturers and associations related to the topic
SearchtermsPneumococal Terms: 1. Pathogen terms
“Streptococcus pneumoniae”[mesh] (“Diplococcus”[all fields] AND “pneumoniae”[all fields]) (“micrococcus”[all fields] AND “pneumoniae”[all fields]) “Pneumococcus”[all fields] “pneumococcal”[all fields] “s. pneumoniae”[all fields] “pneumococci”[all fields] Pneumococc*[all fields] “Streptococcus” [mesh] “Streptococcal”[mesh] 2. Outcome-related terms
“Pneumonia, Pneumococcal”[mesh] “Meningitis, Pneumococcal”[mesh] “Meningitis, Streptococcal”[mesh]
Narrow Vaccine Terms: “Vaccines, conjugate”[mesh] “Pneumococcal Vaccines”[mesh] “streptococcal vaccines”[mesh] ((“conjugate” OR “conjugated” OR “pneumococcal”[all fields] OR “streptococcal”[all fields]) AND (“vaccine”[tiab] OR “vaccines”[tiab] OR “vaccination”[tiab] OR “vaccinated”[tiab] OR “immunization”[tiab] OR “immunisation”[tiab] OR “immunized”[tiab] OR “immunised”[tiab])) ((“Pneumococcal”[all fields] OR “pneumococcus”[all fields] OR “capsular”[all fields]) AND
1 Articles that have been translated into English will be included.
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“Pneumococcal Infections”[mesh] “Streptococcal Infections”[mesh] “Otitis Media”[mesh] (“lobar”[all fields] AND “pneumonia”[all fields]) (“Nasopharyngeal”[all fields] AND “carriage”[all fields]) (“Nasopharyngeal”[all fields]AND “colonization”[all fields]) (“ nasopharyngeal”[all fields] AND “colonisation”[all fields]) (“Community acquired”[all fields] AND “pneumonia”[all fields]) (“community acquired”[all fields] AND “pneumonias”[all fields]) (“Bacteraemic”[all fields] AND “pneumonia”[all fields]) (“bacteraemic”[all fields] AND “pneumonias”[all fields]) (“Bacteremic”[all fields] AND “pneumonia”[all fields]) (“bacteremic”[all fields] AND “pneumonias”[all fields]) “Anti-pneumococcal”[all fields] “antipneumococcal”[all fields] (“lower respiratory tract infection”[all fields]) (“lower respiratory tract infections”[all fields]) (“Invasive disease” [all fields]) (“invasive pneumococcal disease” [all fields]) (“invasive bacterial disease” [all fields]) (“Bacterial pneumonia”[all fields]) (“Bacterial pneumonias”[all fields]) (“Otitis Media”[all fields]) (“inner ear infection”[all fields]) (“inner ear infections”[all fields])
(“polysaccharide”[all fields]) AND (“vaccine”[tiab] OR “vaccines”[tiab] OR “vaccination”[tiab] OR “vaccinated”[tiab] OR “immunization”[tiab] OR “immunisation”[tiab] OR “immunized”[tiab] OR “immunised”[tiab])) “PncCRM197”[all fields] “PCV”[all fields] “Pneumovax”[all fields] “Pnu-Imune” [all fields] “Pnu Imune”[all fields] “PnuImune”[all fields] “pneu immune”[all fields] “pnu immune”[all fields] “pneumo 23”[all fields] “pneumopur”[all fields] “streptopur”[all fields] “streptorix”[all fields] “PncOMPC vaccine” [Substance Name] “PncOMPC”[all fields] (“Pneumococcal”[all fields] AND “polysaccharide”[all fields] AND “meningococcal”[all fields] AND “outer”[all fields] AND “membrane”[all fields] AND “protein”[all fields] AND “complex”[all fields]) “five-valent pneumococcal conjugate vaccine” [Substance Name] “five-valent”[all fields] “5-valent”[all fields] “PCV5”[all fields] “PCV-5”[all fields] “heptavalent pneumococcal conjugate vaccine” [Substance Name] “heptavalent”[all fields] “PNCRM7”[all fields] “PNCRM-7”[all fields] “PCV7”[all fields] “PCV-7”[all fields] “seven-valent”[all fields] ” 7-valent”[all fields] “Prevenar”[all fields] “Prevnar”[all fields] “10-valent pneumococcal vaccine” [Substance Name] “Ten-valent”[all fields] “10-valent”[all fields] “PCV10”[all fields] “PCV-10”[all fields] “13-valent pneumococcal vaccine” [Substance Name] “Thirteen-valent”[all fields] “13-valent”[all fields] “PCV13”[all fields] “PCV-13”[all fields] “nine-valent”[all fields] “9-valent”[all fields] “PCV9”[all fields] “PCV-9”[all fields]
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“two-valent”[all fields] “2-valent”[all fields] “PCV2”[all fields] “PCV-2”[all fields] “three-valent”[all fields] “3-valent”[all fields] “PCV3”[all fields] “PCV-3”[all fields] “four-valent”[all fields] “4-valent”[all fields] “PCV4”[all fields] “PCV-4”[all fields] “six-valent”[all fields] “6-valent”[all fields] “PCV6”[all fields] “PCV-6”[all fields] “7vPnC”[all fields] “7vCRM”[all fields] “PHiD-CV”[all fields] ((“23-valent”[all fields] “23vPPV”[all fields] “PPV23”[all fields] “PPSV23”[all fields] “23-valent pneumococcal capsular polysaccharide vaccine”[substance name] “pneumococcal surface protein” [all fields] “pneumococcal surface proteins”[all fields] “pneumococcal protein”[all fields] “pneumococcal proteins”[all fields] “streptococcal surface protein”[all fields] “streptococcal surface proteins”[all fields] “streptococcal protein”[all fields] “streptococcal proteins”[all fields]
Additional search elements: Additional controlled vocabulary used in EMBASE (pathogen/outcome terms):
• ‘streptococcus pneumonia’[EMTREE term] • ‘lower respiratory tract infection’ [EMTREE term] • ‘bacterial pneumonia’ [EMTREE term] • ‘lobar pneumonia’ [EMTREE term] • ‘community acquired pneumonia’ [EMTREE term]
Additional controlled vocabulary in EMBASE (vaccine terms):
• ‘Pneumococcus vaccine’ [EMTREE term] • ‘Streptococcus vaccine’ [EMTREE term] • ‘Pneumococcus polysaccharide’ [EMTREE term]
Adjacency Searching (near 5) used in: EMBASE Global Health Biological Abstracts Biological Abstracts/RRM
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Pascal BioMed Cochrane Library Animal Limits used in: PubMed EMBASE Biological Abstracts Biological Abstracts/RRM Other limits: English language Date: 1994 – December 31, 2016 Not needed – pneumococcal/streptococcal finds that did not yield additional material: Pneumococcal Pneumonia Pneumococcal Pneumonias Pneumococcal Meningitis Pneumococcal Infection Pneumococcal Infections Pneumococcal mortality Pneumococcal mortalities Streptococcal infection Streptococcal infections