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PneumococcalConjugateVaccine(PCV)ProductAssessment April2017

OliviaCohen

Contact:KateO’Brien,MD,MPHExecutiveDirector,IVACJohnsHopkinsBloombergSchoolofPublicHealth415N.WashingtonStreet,Room563Baltimore,MD21231(240)-472-6655klobrien@jhu.edu

AlternateContact:OliviaCohen,MPH

ResearchProgramCoordinator+41(0)78-632-0721ocohen3@jhu.edu

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

28

29

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

43

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].

44

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.

45

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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

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

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)

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

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)

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.

vii

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

viii

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)

ix

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

x

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

xi

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.

xii

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

xiii

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

xiv

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

xv

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

xvi

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.

xvii

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

xviii

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)

xix

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

xx

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

xxi

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.

xxii

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)

xxiii

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

xxiv

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

xxv

WPR Australia(Leach2016;2016)

PostSurvey

3+0

PCV7:2001PCV10:2009PCV13:2011

PCV7:10PCV10:2PCV13:2

<6years(Aboriginal)

Nochangereported.CarriagemeasuredinPCV10andPCV13periods.

Nochangereported.CarriagemeasuredinPCV10andPCV13periods

Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.

xxvi

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)

xxvii

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

xxviii

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)

xxix

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

xxx

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

xxxi

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)

xxxii

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

xxxiii

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%

xxxiv

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.

35

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)

36

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)

37

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

38

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

39

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%¶

40

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

41

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.

42

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

43

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

44

*Yearsofpre-andpost-PCVdataexcludetheyearofPCVintroduction,unlessstatedotherwise†Negativepercentchangeindicatesapercentreduction;Positivepercentchangeindicatesapercentincrease¶Significanceofp<0.05Studieshighlightedingreydidnotmeetfullinclusioncriteria,butwereincludedduetopaucityofdata.

2-<5years 1.8 +68%

introduction

45

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

46

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%)

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

48

2014)

(Veranietal2015)

Indirectcohort

upfor12-23

months

74%(42-88%)2

1VEforatleast2dosesbeforeage12monthsoronedoseonorafterage12months

2VEforuptodateforagenumberofdoses

49

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)

50

-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

51

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)

52

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)

53

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)

54

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)

55

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)

56

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%)

57

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

58

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

59

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)

60

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)

61

62

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

63

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

64

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

65

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

66

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

67

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

68

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

69

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

70

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

71

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.

lxxii

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% --

lxxiii

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%

lxxiv

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)

lxxv

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

lxxvi

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)

lxxvii

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)

lxxviii

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%

lxxix

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) --

lxxx

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%

lxxxi

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%

lxxxii

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%

lxxxiii

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%

lxxxiv

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%

lxxxv

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%

lxxxvi

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%

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%

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%

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%

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

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

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)

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

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.

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

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

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

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

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

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

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

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

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

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

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.

“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]

“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

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