Safety and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine Given With Routine Pediatric Vaccination to Healthy Children in France

E Grimprel,1 F Laudat,2 SA Baker,3 MS Sidhu,3 C Sekaran,3 WC Gruber,3 EA Emini,3 DA Scott,3 on behalf of the 008 study group4

1Hôpital Armand Trousseau, Paris, France; 2Wyeth Vaccines Research, Paris, France; 3Wyeth Vaccines Research, Pearl River, NY, USA; 4Multiple investigational sites, France.

BACkGRounD

Presented at the 27th Annual Meeting of the European Society for Paediatric Infectious Disease (ESPID), June 9-13, 2009, Brussels, Belgium This study was supported by Wyeth Vaccines Research.

• Theincorporationof7-valentpneumococcalconjugatevaccine(PCV7,Prevenar®)intotheroutinechildhoodvaccinationscheduleintheUSandothercountrieshasbeenshowntobeeffectiveinpreventinginvasivepneumococcaldisease(IPD),pneumonia,andotitismediaininfantsandyoungchildren.

• Toincreaseserotypecoverageglobally,Wyethisdevelopinga13-valentpneumococcalvaccine(PCV13)thatcontainsthe7polysaccharideserotypesincludedinPCV7(4,6B,9V,14,18C,19F,23F)andanadditional6serotypes(1,3,5,6A,7F,19A).AllareconjugatedtothecarrierproteinCRM197.

• Itisestimatedthattheadditionofthese6serotypeswillincreasecoverageofvaccine-serotypeIPDto89%inEurope,92%intheUSandCanada,86%inOceania,87%inAfricaandLatinAmerica,and73%inAsia.1TheseestimatesarebasedonserotypedistributiondatapriortotheintroductionofPCV7vaccination.

• ThePCV13clinicaldevelopmentplanincludesstudiesofsafetyandtolerability,immunogenicityindifferentvaccinationschedules,andconcomitantvaccineantigenresponses.

• As part of this plan, the present phase 3, randomized, active-controlled, double-blind, multicenter study assessed the safety and anti-penumococcal immunogenicity of a toddler dose of PCV13 given at 12 months, following either a three-dose infant series of PCV13 or a three-dose infant series of PCV7. Immune responses to the common serotypes were also compared to recipients of a four-dose series of PCV 7.

SuBJECtS AnD MEtHoDS

• Healthyinfantswererandomlyassignedattheageof2months(2:1:1)toreceiveoneintramuscularinjectionof:

– either4dosesofPCV13at2,3,4,and12monthsofage

– or4dosesofPCV7at2,3,4,and12monthsofage– or3dosesofPCV7at2,3,4months,followed

by1doseofPCV13at12monthsofage– DTaP-IPV/Hibwasadministeredconcomitantly

at2,3,4,and12monthsofage

• Localreactions(redness,swelling,andtendernessatthePCVinjectionsite),systemicevents(fever,decreasedappetite,decreasedsleep,increasedsleep,andirritability),anduseofantipyreticstotreatorpreventsymptomswerecollectedwithin4daysofthe12-monthvaccinationusinganelectronicdiary.Adverseevents(AE)werecollectedthroughonemonthafterthetoddlerdose.

• Bloodsamplesforimmunogenicityassessmentwerecollectedpriortothe12-monthtoddlerdoseand1monthafter.

• Astandardizedimmunosorbantassay(ELISA)wasusedtomeasuretheconcentrationofIgGanti-polysaccharidebindingantibodiestothe13pneumococcalserotypesinallPCV7andPCV13recipients.

• GeometricmeanIgGantibodyconcentrations(GMC)andtheproportionofsubjectswhoachievedaserotype-specificIgGantibodyconcentration≥0.35μg/mLweredetermined(basedonWorldHealthOrganization[WHO]guidelineforthedeterminationofpotentiallyeffectiveanti-pneumococcalimmuneresponses).2,3

• Functionalopsonophagocyticassay(OPA)antibodydeterminationswereperformedonasubsetof100subjects/groupforthe6additionalserotypesafterthetoddlerdoseforthe2groupsinwhichthesubjectsreceivedPCV13forthisdose.

RESuLtS

• Privatepracticepediatricianslocatedat39sitesinFrancerandomized613infantsattheageof2months.Allchildrenwhocontinuedthestudyaftertheinfantseriesandreceivedthetoddlerdoseswereincludedinthesafetyanalysis.TheevaluablestudypopulationforpneumococcalimmunogenicityissummarizedinTable1.

table 1: Study Population at toddler Dose

PCV13/PCV13 Group

PCV7/PCV13 Group

PCV7/ PCV7 Group

total

Vaccinated 273 137 152 562Medianage(months) 12.1 12.1 12.0 —

Includedintheimmunogenicityanalysis*

241 121 133 495

Completed** 268 137 151 556*Theevaluableforimmunogenicitypopulationwasdefinedasfollows:metallinclusioncriteria;hadatleast1validanddeterminateassayresultfortheproposedanalysis;hadnomajorprotocolviolations.

**Therewere6withdrawals,5inGroupPCV13/PCV13(2protocolviolations;1failedtoreturn;1parentalrequest;1other)and1inGroupPCV7/PCV7(protocolviolation).

Safety and tolerability

Figure 1. Percent of infants experiencing local reactions after toddler dose

Mild swelling or redness, 0.5 – 2.0 cm; moderate swelling or redness, 2.5 – 7.0 cm; severe swelling or severe redness >7cm. Significant tenderness = present and interfered with limb movement.

PCV7/PCV7PCV7/PCV13PCV13/PCV13

0 20 40 60 80

Mild Swelling

Moderate Swelling

Severe Swelling

Mild Redness

Moderate Redness

Severe Redness

Any Tenderness

Significant Tenderness

Figure 2. Percent of infants experiencing systemic events after toddler dose

Fever ≥38 but ≤39º

Fever >39 but ≤40º

Fever >40º

Decreased appetite

Decreased sleep

Increased sleep

Irritability

Antipyretics preventive

Antipyretics treatment

PCV7/PCV7PCV7/PCV13PCV13/PCV13

0 10 20 30 40 50 60

• TherewerenodifferencesinunsolicitiedAEs,orseriousAEsbetweenthe3groups.

SuMMARy

• Thesedatashowthatinchildrenwhoreceived3dosesofPCV7followedbyadoseofPCV13inthesecondyearoflife,theimmuneresponsestothe7commonserotypeswerecomparablewiththoseseeninsubjectsboostedwithPCV7.

• ThePCV13toddlerdoseafteraninfantserieswithPCV7alsoelicitedrobustresponsestothe6additionalserotypesthatwerecomparablewiththeimmuneresponsesobservedaftera3-doseinfantserieswithPCV13,althoughsomewhatlessthanthetoddlerresponseseeninchildrenwhohadcompletedtheinfantserieswithPCV13.

(Theposttoddlerresponsestoserotype3werecomparableirrespectiveofwhetherthesubjectshadreceivedPCV7orPCV13intheinfantseries.)

• ThehigherGMCsinthePCV13/PCV13groupsuggestthatmemorywasestablishedfortheadditionalserotypesduringtheinfantseries.

• AtoddlerdoseofPCV13iswelltoleratedandsafeafteraninfantserieswithPCV7orPCV13.

• ThesedataindicatethatonlyasingledoseofPCV13isnecessarywhengivenafteraninfantserieswithPCV7toelicitappropriatelevelsof

anti-polysaccharideantibodiesagainstthe6additionalserotypes.

• Giventhatthe7commonserotypeconjugatesareidenticalbetweenthe2vaccines,andgiventhattheimmunogenicityprofileofPCV13hasbeenshowntobesimilarfortheseserotypes,itcanberecommendedthatswitchingtoPCV13canoccuratanytimeinthescheduleforinfantswhohavenotcompletedthePrevenarseries(infantseriesandtoddlerdose).

REFEREnCES1. GSPSummaryReport(Stage1,Version1)forSAGEmeetingNovember6-8,2007;October18,2007version

(publicdocument).

2. WorldHealthOrganization.Recommendationsfortheproductionandcontrolofpneumococcalconjugatevaccines.WHOTechnicalReportSeries,No.927,2005.

3. JodarL,ButlerJ,CarloneG,etal.Serologicalcriteriaforevaluationandlicensureofnewpneumococcalconjugatevaccineformulationsforuseininfants.Vaccine.July4,2003;21(23):3265-3272.

4. GrimprelE,ScottD,LaudatF,BakerS,GruberW.SafetyandImmunogenicityofa13-valentPneumococcalConjugateVaccineGivenwithRoutinePediatricVaccinationtoHealthyInfantsinFrance.2ndVaccineCongress.Boston,MA,2008.

5. KieningerD,KueperK,SteulK,JuergensC,AhlersN,BakerS,etal.SafetyandImmunologicNon-inferiorityof13-valentPneumococcalConjugateVaccineComparedto7-valentPneumococcalConjugateVaccineGivenasa4-DoseSerieswithRoutineVaccinesinHealthyInfantsandToddlers.46thAnnualICAACIDSAMeeting.Washington,DC,2008.

Acknowledgements: Thankstoalltheinvestigatorswhoparticipatedinthestudy:

Pr.EGrimprel,Paris,andDoctors:RAlt,Strasbourg;OArwani,Illkirch;PAttal,GargeslèsGonesses;SBarrois,Lyon;BBaszanger,BourgSaintMauriceCedex;SBenoit,Tours;BBlanc,Maromme;BCaurier,JouéLesTours;FCeccato,

Tresses-Melac;FChateil,Blanquefort;ACosti,Strasbourg;TDavid,Ecully;VFournier,Lyon;JLuGasnier,LesSablesd’Orlonne;MGuy,NogentsurMarne;FJeannerot-Meens,Villeneuved’Ascq;KKassmann,Draguignan;ZKlink,Thionville;FLaine,

LeHavre;XLanse,LeHavre;JCLeveque,ChâlonsenChampagne;J-FLienhardt,Bondues;BLogre,Floirac;MLuppi,LePontet;SMenuGuillemin,ChâlonsenChampagne;MNavel,Ancenis;FNourmamode,Talence;AOudin,Nancy;HPflieger,Strasbourg;HPorcheret,Challans;DSomerville,Brest;DSror,Lingolsheim;BSzelechowski,VitrysurSeine;FThirion,VillerslesNancy;

FThollot,Essey-les-Nancy;PMTran,Nice;J-LVuillemin,Vandoeuvre-les-Nancy;R-RWisnewsky,Creteil.

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Immunogenicity• ImmuneresponsesbeforeandafterthetoddlerdoseareshowninFigure3andFigure4.

Figure 3. Comparisons of Pneumococcal IgG GMCs (mg/mL) for the 7 Common Serotypes Before and After the Toddler Dose

0

2

4

6

8

10

12

4 6B 9V 14 18C 19F 23C 4 6B 9V 14 18C 19F 23C 4 6B 9V 14 18C 19F 23C

Pre-toddler Post-toddler

GM

C (

g/m

L)

PCV7/PCV7PCV7/PCV13PCV13/PCV13

Figure 4. Comparisons of Pneumococcal IgG GMCs (mg/mL) for the 6 Additonal Serotypes Before and After the Toddler Dose

Pre-toddler Post-toddler

PCV7/PCV13PCV13/PCV13

0123456789

10

1 3 5 6A 7F 19A 1 3 5 6A 7F 19A

GM

C (

g/m

L)

• Forthe7commonserotypes,IgGGMCsweresimilarinallgroups.

• Forthe6additionalserotypes:– IgGGMCswerehigherfor5ofthe6serotypesinPCV13/PCV13recipientsvs.PCV7/PCV13;serotype3GMCswere

comparablebetweenthetwogroups.– Importantly,GMCsforthe6additionalserotypesinPCV7/PCV13recipientsweresimilartotheGMCsobtainedaftera3-dose

infantserieswithPCV13.4,5

• Forthecommonserotypes,theproportionsofchildrenwithanIgGconcentration≥0.35µg/mLwere>97%acrossallthreegroups(Table2).

table 2: Percent of Subjects Achieving Pneumococcal IgG Concentrations ≥0.35 µg/mL to the 7 Common Serotypes 1 Month After the toddler Dose.

PCV7 Serotype

PCV13/PCV13 % ≥0.35 μg/mL

n=230-236

PCV7/PCV13 % ≥0.35 μg/mL

n=108-113

PCV7/PCV7 % ≥0.35 μg/mL

n=111-1274 100.0 99.1 100.06B 99.6 98.1 99.29V 100.0 100.0 100.014 99.6 99.1 100.018C 99.6 98.2 99.219F 97.9 97.3 97.623F 99.6 99.1 99.2

• Fortheadditionalserotypes,theproportionsofresponderswithanIgGconcentration≥0.35µg/mLweregenerallycomparablebetweenthesubjectswhoreceivedPCV13followinganinfantserieswithPCV7andthesubjectswhoreceivedPCV13followingaPCV13infantseries(Table3).

• Importantly,theproportionsofOPArespondersandOPAGMTswerealsocomparablebetweenthe2studygroups.Therewasnoconsistentpatternofarelativelygreaterresponsewithineithergroup.

table 3: Serum IgG and Functional (oPA) Responses to the 6 Additional Serotypes 1 Month After the toddler Dose

Additional Serotype

PCV13/PCV13 PCV7/PCV13

% ≥0.35 μg/mL n=230-236

oPA n=86-88 % ≥0.35 μg/mL

n=108-113

oPA n=89-90

% titer ≥1:8 GMt % titer ≥1:8 GMt1 100.0 100.0 126.0 95.5 98.9 61.63 94.8 100.0 345.3 93.8 97.8 428.95 100.0 100.0 244.2 90.1 97.8 131.06A 100.0 100.0 1346.8 89.9 98.9 891.47F 100.0 100.0 8126.2 100.0 100.0 17034.619A 100.0 98.8 804.1 100.0 97.8 1072.4GMC=geometricmeanconcentration;OPA=opsonophagocyticassay;GMT=geometricmeantiter