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Immunogenicity of a low dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard dose diphtheria, tetanus, acellular pertussis when used as a pre school booster in UK children

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http://wrap.warwick.ac.uk

Original citation:

John, T., Voysey, M., Yu, L. M., McCarthy, N. D. , Baudin, M., Richard, P., Fiquet, A.,

Kitchin, N. and Pollard, A. J.. (2015) Immunogenicity of a low-dose diphtheria, tetanus

and acellular pertussis combination vaccine with either inactivated or oral polio vaccine

compared to standard-dose diphtheria, tetanus, acellular pertussis when used as a

pre-school booster in UK children : a 5-year follow-up of a randomised controlled study.

Vaccine, 33 (36). pp. 4579-4585.

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http://wrap.warwick.ac.uk/76174

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The Warwick Research Archive Portal (WRAP) makes this work of researchers of the

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A note on versions:

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be cited as it appears here.

(2)

ContentslistsavailableatScienceDirect

Vaccine

jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e

Immunogenicity

of

a

low-dose

diphtheria,

tetanus

and

acellular

pertussis

combination

vaccine

with

either

inactivated

or

oral

polio

vaccine

compared

to

standard-dose

diphtheria,

tetanus,

acellular

pertussis

when

used

as

a

pre-school

booster

in

UK

children:

A

5-year

follow-up

of

a

randomised

controlled

study

T.

John

a

,

M.

Voysey

b

,

L.M.

Yu

b

,

N.

McCarthy

c

,

M.

Baudin

d

,

P.

Richard

d,1

,

A.

Fiquet

d,1

,

N.

Kitchin

e,1

,

A.J.

Pollard

a,∗

aDepartmentofPaediatrics,UniversityofOxford,andtheNIHROxfordBiomedicalResearchCentre,Oxford,UK bNuffieldDepartmentofPrimaryCareHealthSciences,UniversityofOxford,Oxford,UK

cThamesValleyHealthProtectionUnit,Oxford,UK dSanofiPasteurMSDS.N.C.,Lyon,France eSanofiPasteurMSDLtd,Maidenhead,UK

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received27April2015

Receivedinrevisedform8June2015 Accepted29June2015

Availableonline10July2015

Keywords:

Low-dosediphtheriavaccine Pre-schoolbooster Immunogenicity

a

b

s

t

r

a

c

t

Thisserologicalfollowupstudyassessedthekineticsofantibodyresponseinchildrenwhopreviously participatedinasinglecentre,open-label,randomisedcontrolledtrialoflow-dosecomparedto standard-dosediphtheriaboosterpreschoolvaccinationsintheUnitedKingdom(UK).Childrenhadpreviouslybeen randomisedtoreceiveoneofthreecombinationvaccines:eitheracombinedadsorbedtetanus,low-dose diphtheria,5-componentacellularpertussisandinactivatedpoliovaccine(IPV)(Tdap–IPV,Repevax®; SanofiPasteurMSD);acombinedadsorbedtetanus,low-dosediphtheriaand5-componentacellular pertussisvaccine(Tdap,Covaxis®;SanofiPasteurMSD)givenconcomitantlywithoralpoliovaccine (OPV);oracombinedadsorbedstandard-dosediphtheria,tetanus,2-componentacellularpertussisand IPV(DTap–IPV,Tetravac®;SanofiPasteurMSD).Bloodsamplesforthefollow-upstudyweretakenat1, 3and5yearsafterparticipationintheoriginaltrial(median,5.07yearsofageatyear1),andantibody persistencetoeachvaccineantigenmeasuredagainstdefinedserologicalthresholdsofprotection.

Allparticipantshadevidenceofimmunitytodiphtheriawithantitoxinconcentrationsgreaterthan 0.01IU/mLfiveyearsafterboostervaccinationand75%,67%and79%ofchildrenwhoreceivedTdap–IPV, Tdap+OPVandDTap–IPV,respectively,hadprotectiveantitoxinlevelsgreaterthan0.1IU/mL.Long last-ingprotectiveimmuneresponsestotetanusandpolioantigenswerealsoobservedinallgroups,though polioresponseswerelowerintheseraofthosewhoreceivedOPV.

Low-dosediphtheriavaccinesprovidedcomparableprotectiontothestandard-dosevaccineandare suitableforuseforpre-schoolboostervaccination.

©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗Correspondingauthor.A.J.PollardTel.:+441865234226. E-mailaddresses:Tessa.john@ouh.nhs.uk(T.John),

merryn.voysey@phc.ox.ac.uk(M.Voysey),ly-mee.yu@phc.ox.ac.uk(L.M.Yu),

Noel.McCarthy@phe.gov.uk(N.McCarthy),MBaudin@spmsd.com(M.Baudin),

pr.richard@laposte.net(P.Richard),anne.fiquet@pfizer.com(A.Fiquet),

Nicholas.Kitchin@pfizer.com(N.Kitchin),andrew.pollard@paediatrics.ox.ac.uk

(A.J.Pollard).

1 PR,AFandNKwereemployeesofSanofiPasteurMSDatthetimethestudywas

conducted.

1. Introduction

Children receivemultiple dosesof diphtheriavaccine in the United Kingdom (UK) immunisation schedule both as diph-theria toxoid antigen (5 doses by 15 years of age) and as a mutantdiphtheriatoxoidprotein,CRM197,acomponentof sev-eralprotein–polysaccharide conjugatevaccines (upto4 doses). The importance of maintaining diphtheria immunity through immunisation is emphasised byoutbreaks of diphtheria where immunisationprogrammesbreakdown,asseeninIndia[1]and Nigeria[2].However,diphtheriatoxoidcauseslocalreactionsand

http://dx.doi.org/10.1016/j.vaccine.2015.06.105

0264-410X/©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.

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4580 T.Johnetal./Vaccine33(2015)4579–4585

for this reason, to improve tolerability without compromising protection,severalvaccineshavebeendevelopedcontaininga low-doseoftheantigeninanattempttoreducereactogenicity.

In2001,theUKinfantimmunisationprogrammeprovided pro-tection against Haemophilus influenzae type b (Hib), diphtheria (D),tetanus(T),pertussiswith3dosesofawholecellpertussis (wP)combination vaccineadministeredin thefirst4monthsof lifetogetherwithoralpoliomyelitisvaccine(OPV).Atthattime, childrenreceivedtheirfirstboosterdoseofdiphtheriatoxoidin combinationwithtetanustoxoid(withOPVandmeasles,mumps andrubella(MMR)vaccines;DT+OPV+MMR)beforeschoolentry andatleast3yearsaftercompletionoftheinfant2-,3-and4-month primarycourse[3].

Concernsover localreactions(mainly erythemaand indura-tion)followingmultipleboosterdosesofdiphtheriaantigenduring childhoodhavebeenraised.Althoughatthetimeoftheprimary studylow-dosediphtheria(d)vaccinewasrecommendedinthe UKforchildrenovertheageof10yearsreceivingthevaccineas partoftheadolescentbooster,recommendationsforalow-dose diphtheriavaccinedidnotexistforyoungerchildren[3].

To ensure reduced reactogenicity and enhance population immunityagainstpertussis,acellularpertussis(aP/ap)vaccinewas addedtothepre-schoolboosterintheUKin2001;aPvaccinesare preferredoverwPvaccines,particularlyforboosters,becausethey areassociatedwithfewerlocalandsystemicadverseevents[4–6]. In2004inactivatedpoliovaccine(IPV)wasintroducedtoreplace theliveOPV[7].UnlikeOPV,IPVdoesnotcarryariskof vaccine-associatedparalysis[8].Inaddition,IPVcanbeincorporatedinto combinationvaccines,simplifyingimmunisationschedules[9].

Wecommencedastudyin2001comparingtheimmunogenicity andreactogenicityofonelow-doseandonestandard-dose diph-theriavaccinecombinedwithtetanus,acellularpertussisandIPV (Tdap–IPVandDTap–IPV)andofonelow-dosediphtheriavaccine combinedwithtetanusandacellularpertussisandgiven concomi-tantlywithOPV(Tdap+OPV)asapre-schoolboosterinUKchildren

[9].ThestudycomprisedVisit1(baselineblooddrawand vaccina-tion)andVisit2(post-vaccinationblooddraw28to42dayslater). Threehundredchildren,100childrenpervaccinegroup,were vac-cinatedatameanageof3.9years.Fullstudydetailsandresultshave beenreportedpreviouslyandshowedrobustimmueresponses fol-lowingimmunisationwithallthreevaccinesat1month[10].

The vaccines studied (Tdap–IPV, Tdap+OPV and DTap–IPV) wereallsufficientlyimmunogenicforuseasapre-schoolboosterin theUK,despiteTdap–IPVandTdapcontainingalowerdiphtheria dose,andcouldbeadministeredconcomitantlywithMMRvaccine. Allthreecombinationswerewelltolerated[10].

Theobjectiveofthisextendedfollow-upstudywastoevaluate thepersistenceofimmunity1,3and5yearsafteradministration ofthispre-schoolboostervaccine.

2. Methods

2.1. Participantsandvaccines

Studyvisitswereperformedatapproximately1,3and5years afterchildrenhadreceivedoneof3differentpre-schoolbooster vaccinesatanageof3.5–5yearsinasinglecentre(Oxford Vac-cineGroup,ChurchillHospital,Oxford,UK)open-label,randomised, controlled,PhaseIIIstudy.

Intheoriginalclinicaltrialchildrenaged3.5–5yearswere ran-domlyassignedtooneofthreestudygroups:acombinedadsorbed tetanus,low-dosediphtheria,5-componentacellularpertussisand IPV (Tdap–IPV, Repevax[®]; Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acel-lular pertussisvaccine (Tdap, Covaxis[®]; Sanofi Pasteur MSD) givenconcomitantlywithOPV;oracombinedadsorbed diphthe-ria,tetanus,2-componentacellularpertussisandIPV(DTap–IPV, Tetravac®;SanofiPasteurMSD).Inallgroups,MMRvaccinewas optionallygivenconcomitantly.

The two low-dose diphtheria vaccines (Tdap–IPV and Tdap) contained pertactin (PRN) and fimbriae (FIM) types 2+3, as wellasreduced quantitiesofpertussistoxoid(PT)and filamen-toushaemagglutinin(FHA).Thestandard-dosediphtheriavaccine (DTaP–IPV)containedonlyPTandFHA(Table1).

Allchildrenvaccinatedintheinitialstudyandwhohadnotbeen excludedorwithdrawnwereeligibleforinclusioninthefollow-up study.

Theobjectiveofthefollow-upstudywastoevaluatethe persis-tenceofantibodiestothevaccineantigens(diphtheria,tetanus, PT, FHA, PRN, FIM, and poliomyelitis types 1, 2, and 3) 1, 3, and5 yearsafterreceiptofthestudyvaccines.The 1yearvisit occurredbetweenJanuaryand November2003,year3 between December2004andNovember2005andyear5betweenJanuary andNovember2007,60to63monthsafterthedateoftheoriginal studyvaccineadministration.

Ateachvisita 5.0mLsample ofvenousblood wasobtained; participationateachtimepointwasoptionalandnon-participation atonetimepointwasnotanexclusioncriterionforfuture partic-ipation.Novaccineswereadministeredaspartofthefollow-up study,althoughanyoneidentifiedashavinglowantibodylevelsto aparticularantigenwereadvisedtoreceiveafurtherdoseofthe appropriatevaccine.

Table1

AntigenconcentrationsofTdap–IPV,Tdap+OPVandDTap–IPV.

Tdap–IPV Tdap+OPV DTap–IPV

Tdap OPV

Purifiedtetanustoxoid ≥20IU ≥20IU – ≥40IU

Purifieddiphtheriatoxoid ≥2IU ≥2IU – ≥30IU

Purifiedpertussistoxoid(PT) 2.5␮g 2.5␮g – 25␮g

Purifiedfilamentoushaemagglutinin(FHA) 5␮g 5␮g – 25␮g

Purifiedfimbriaetypes2+3(FIM) 5␮g 5␮g – –

Purifiedpertactin(PRN) 3␮g 3␮g –

Inactivatedpoliomyelitisvirustype1 40Dantigenunits - – 40Dantigenunits

Inactivatedpoliomyelitisvirustype2 8Dantigenunits – – 8Dantigenunits

Inactivatedpoliomyelitisvirustype3 32Dantigenunits – – 32Dantigenunits

Liveattenuatedtype1poliovirus – – ≥106TCID50

Liveattenuatedtype2poliovirus – – ≥105TCID50

Liveattenuatedtype3poliovirus – – ≥105.5TCID50

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Thestudywasconductedinaccordancewiththeprinciplesof theDeclarationofHelsinkiandhadtheapprovaloftheOxfordshire ResearchEthics Committee(C01.183). Signed,informedconsent wasobtainedfromaparentateachstudyvisitpriortoany pro-cedurebeingperformed.Verbalagreementwasobtainedfromthe participant.

2.2. Immunogenicityandsafetyassessments

Immuneresponsesweremeasuredbyseroneutralisation(SN) fordiphtheriaandpoliovirusantigensandbyenzyme immunoas-says (EIA) for tetanus and pertussis antigens (PT, FHA, PRN and FIM). Seroprotection wasdefined as a diphtheria antibody titre(SN)≥0.1IU/mL;tetanusantibodytitre(EIA)≥0.1IU/mL;and poliovirustypes 1, 2 and 3 antibody titre(SN)≥8 (1/dilution), respectively. In addition to seroprotection rates, basic clinical immunitytodiphtheriaandtetanusweredefinedasanantibody titre≥0.01IU/mL.Intheabsenceofanagreedcorrelateof protec-tion,nothresholdsofresponseforpertussisantigensweredefined butGMCswerecalculated.

Samplesobtainedatyear1wereanalysedinAventisPasteur lab-oratoriesinCanada.Fromyear3onwardsallassayswereperformed bytheGlobalClinicalImmunologyplatformofSanofiPasteurInc. (Swiftwater,PA,USA)Inordertocomparetheresultsobtainedat year1withthose obtainedatyear3anyear5,laboratory con-cordancestudieswereperformed.Asaconsequence,conversion factors were applied for the resultsof diphtheria, tetanus and poliomyelitistypes 1and 2at year1but this wasdeemednot necessaryfortheothervalences,i.e.fortype3poliomyelitisand pertussis.

Nosafetyassessmentswerecarriedoutduringthefollow-up study as novaccines were given. Only serious adverse events relatedtothebloodsamplingprocesswererecorded.

2.3. Statistics

Theimmunogenicityendpointsfor5-yearpost-booster persis-tencewerebasicclinicalimmunityand seroprotectionratesfor diphtheria,tetanusandtype1,2and3poliovirusantigens.

Immunogenicityanalyseswere performedfor the intention-to-treat (ITT)population. TheITTpopulationatthe5-year visit comprisedallchildrenincludedintheITTpopulationintheprimary studywhohadabloodsampleatyear5.Inaddition,theantibody dataatyear1andyear3,arealsopresentedforthesub-population ofparticipantsincludedintheITTpopulationatyear5.

Geometricmeanantibodyconcentrations/titres(GMCs/GMTs), andtheir2-sided95%confidenceintervals(CIs)werecalculated forimmunogenicitycriteria.In addition,theproportionsof par-ticipantswithantibodyconcentrations/titresagainstpre-defined acceptedthresholdswerecalculated.

The sample sizewas calculated for theprimary study.Only descriptive statistical analyses were performed in the follow-upstudy,which wasnot poweredfor antibodypersistence.No hypothesesrelatingtoexpectedresponserateswereformulated.

3. Results

3.1. Studypopulation

Randomisationandfollow-upofchildrenisshowninFig.1.In total,ofthe300childrenwhowereenrolledintotheinitialstudy, 219childrenparticipatedatyear1(73.0%),161(53.7%)atyear3 and146(48.7%)atyear5.140childrenwereincludedintheITT populationatyear5.Asubsetofthesechildrenalsohadresults availableatyear1(n=117)andyear3(n=113)andaretherefore includedinthisanalysis.

Atyear1childrenwereagedbetween4.51and6.18years(mean age5.07),year3agedbetween6.50and8.09(meanage7.08years) andatyear5,childrenwereagedbetween8.56and10.13years

RANDOMISED n=300

n=100 TdaP-IPV & MMR

n=100 TdaP +OPV & MMR

n=100 DTaP-IPV & MMR

1 month Post vaccine Completed: 100

1 month Post vaccine Completed: 100

1 month Post Vaccine Completed: 99 •Blood sample traumac

for child: n=1

Consent given: 69 Completed: 68 •Blood sample traumac

for child: n=1

Consent given: 75 Completed: 75

Consent given: 75 Completed: 74 •Blood sample traumac

for child: n=1

Consent given: 48 Completed: 47 •Blood sample

unsuccessful: n=1

Consent given: 62 Completed: 60 •Blood sample

unsuccessful: n=2

Consent given: 51 Completed: 48 •Blood sample not

performed/refused: n=3

Consent given: 49 Completed: 48 •Blood sample

unsuccessful: n=1

Consent given: 56 Completed: 54 •Blood sample refused:

n=2

Consent given: 41 Completed: 38 •Blood sample refused:

n=3 1 year

3 years

5 years 1 month

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4582 T.Johnetal./Vaccine33(2015)4579–4585

Table2

Demographiccharacteristics(intention-to-treatpopulationateachVisit).

Year Tdap–IPV Tdap+OPV DTap–IPV

Age(years) Mean(SD) min–max

1 5.11(0.38) 5.05(0.32) 5.05(0.35) 4.54–6.18 4.57–5.90 4.51–6.09 3 7.1(0.35) 7.06(0.33) 7.09(0.30)

6.69–8.01 6.61–8.09 6.5–7.91 5 9.07(0.37) 9.05(0.27) 9.06(0.35)

8.59–9.96 8.56–9.71 8.65–10.13

Sex n(%)male 1 31(44.93%) 30(40.00%) 39(54.17%) 3 20(42.55%) 21(35.00%) 24(51.06%) 5 21(43.75%) 18(33.33%) 21(55.26%)

(meanage:9.06years).Atall3timepointsageofparticipantwas similaramongthethreegroups.Throughoutthestudyslightlymore girlsparticipatedthanboys(Table2).

3.2. Antibodypersistence

Antibodylevelswereloweratthefirstvisitinthisstudy(year1) thantheyhadbeenat1monthaftervaccinationintheinitialstudy

[10].Fiveyearsafterreceiptofvaccineallparticipantshad diph-theriaantitoxinconcentrations≥0.01IU/mL.Furthermore,75.00%, 66.67%and78.95%ofchildrenwhoreceivedTdap–IPV,Tdap+OPV andDTap–IPV,respectively,maintainedprotectiveantibodylevels fordiphtheriaconcentrations≥0.1IU/mL(Table3).

Allparticipantshadtetanusantitoxintitres≥0.01IU/mL;100%, 96.30%and89.47%ofchildrenwhoreceivedTdap–IPV,Tdap+OPV andDTap–IPV, respectively,had titres ≥0.1IU/mLatthe 5year followupvisit(Table3).TetanusGMCswereslightlylowerinthe DTap–IPVgroupthanintheother2groupsatalltimepointsbutCIs overlappedexceptatyear5(Table3).

Fiveyearsafterreceiptofthepre-schoolvaccine(s), seroprotec-tionratesfortype1poliomyelitiswere97.87%,96.23%and100% forTdap–IPV,Tdap+OPVandDTap–IPV,respectively.All partic-ipantshad a titreof ≥1:8for type 2 poliomyelitis inthe three vaccinegroups.Seroprotectionratesfortype3poliomyelitiswere 95.74%(45/47children)and97.37%(37/38children)forTdap–IPV andDTap–IPV,respectively.Incontrast,9childrenoutof53did notreachthethresholdintheTdap+OPVgroup,correspondingto aseroprotectionrateof83.02%(Table4).PolioGMTswerelowerat alltimepointsintheOPVgroupthanintheIPVgroups(Table4).

Persistingantibodyresponsesagainstpertussisantigenswere observedinallgroupsforPTandFHAandalsoforPRNandFIM intheTdap–IPVandTdap+OPVgroupsastheseantigensarenot containedintheDTap–IPVvaccine(Table5).

During the initial study 2 participants that received the Tdap+OPVvaccineswereidentifiedasnothavingachieved protec-tiveantibodylevelseitherfordiphtheriaorforpolio.Therelevant boostervaccinewasadministeredandtheindividualwithlowpolio titres,whoparticipatedatall3follow-upvisits,wasnotincludedin thepolioanalysisandtheindividualwithlowdiphtheriaantibody levels,whoparticipatedatthe1yeartimepoint,wasnotincluded inthediphtheriaandtetanusanalysis.Atyear3,threeyearsafter receiptoftheDTap–IPVvaccine,oneparticipant hadnot main-tainedprotectiveantibodylevelsfordiphtheriaandwasadvised toreceiveaboosterdoseofvaccineanddidnotparticipateatthe fiveyeartimepoint.

Therewerenoseriousadverseeventsassociatedwiththeblood samplingprocedurecarriedoutatanyofthe3followupvisits.

4. Discussion

This study reports on the persistence of antibody up to 5

yearsfollowingreceiptofoneof3pre-schoolboostervaccinations Table

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T.

John

et

al.

/

Vaccine

33

(2015)

4579–4585

4583

Antibodyresponsestopoliovirustypes1,2,and3at1,3and5yearsafteraboosterdoseofTdap–IPV,Tdap+OPVorDTap–IPV(intention-to-treatpopulationatyear5).

Tdap–IPV Tdap+OPV DTap–IPV

Timepost booster

1Year 3Year 5Year 1Year 3Year 5Year 1Year 3Year 5Year

N 37 36 47 46 47 53 32 29 38

Polio1 %≥1:8[95%CI] 100* [90.59–100] 100[90.36–100] 97.87[88.89–99.62] 100* [92.29;100] 100* [92.44–100] 96.23[87.25–98.96] 100* [89.28–100] 100[88.30–100] 100[90.82–100] GMT[95%CI] 338.74* [267.04–429.69] 284.59[195.41–414.45] 101.85[73.86–140.43] 112.42* [89.95–140.52] 112.09* [81.16–154.80] 64.01[46.87–87.42] 322.89* [234.85–443.94] 357.74* [243.40–525.80] 124.55[90.01–172.34]

Polio2 %≥1:8[95%CI] 100* [90.59–100] 100[90.36–100] 100[92.44–100] 100* [92.29–100] 100* [92.44–100] 100[93.24–100] 100* [89.28–100] 100[88.30–100] 100[90.82–100] GMT[95%CI] 471.59* [356.21–624.35] 341.72[252.84–461.84] 202.19[164.58–248.39] 167.23* [135.32–206.67] 153.91* [115.16–205.69] 106.58[84.37–134.64] 531.83* [363.84–777.38] 393.60[257.25–602.21] 211.37[144.17–309.90]

Polio3 %≥1:8[95%CI] 100[90.59–100] 97.22[85.83–99.51] 95.74[85.75–98.83] 100[92.29–100] 97.87[88.89–99.62] 83.02[70.77–90.80] 100[89.28–100] 96.55[82.82–99.39] 97.37[86.51–99.53] GMT[95%CI] 1043.37[711.24–1530.58] 414.27[248.34–691.09] 147.26[101.81–213.00] 98.33[71.42–135.38] 38.19[28.85–50.56] 16.75[13.07–21.47] 1104.65[770.60–1583.50] 389.05[239.04–633.19] 145.43[101.79–207.76]

Abbreviations:CI:confidenceinterval;GMT:geometricmeantitres.Tdap–IPV:combinedadsorbedtetanus,low-dosediphtheria,5-componentacellularpertussisandinactivatedpoliovaccine(Repevax®;SanofiPasteurMSD); Tdap+OPV:combinedadsorbedtetanus,low-dosediphtheriaand5-componentacellularpertussisvaccine(Covaxis®;SanofiPasteurMSD)givenconcomitantlywithoralpoliovaccine;DTap–IPV:combinedadsorbed standard-dosediphtheria,tetanus,2-componentacellularpertussisandinactivatedpoliovaccine(Tetravac®;SanofiPasteurMSD)

%percentageofsubjects;*converteddata;CI,confidenceinterval;GMT,geometricmeantitres.

Table5

Geometricmeanconcentrationsofpertussisantibodiesat1,3and5yearsafteraboosterdoseofTdap–IPV,Tdap+OPVorDTap–IPV(intention-to-treatpopulationatyear5).

Tdap–IPV Tdap+OPV DTap–IPV

Timepostbooster 1Year 3Year 5Year 1Year 3Year 5Year 1Year 3Year 5Year

PT N 37 36 38 46 47 41 32 28 33

GMC(EU/mL)[95%CI] 26.51[16.89–41.61] 5.83[4.08–8.34] 7.98[4.88–13.05] 32.96[22.28–48.77] 7.88[4.99–12.44] 8.06[4.76–13.66] 12.86[8.40–19.67] 6.24[3.98–9.79] 4.98[3.23–7.67]

FHA N 37 36 46 47 45 54 33 29 38

GMC(EU/mL)[95%CI] 22.76[16.01–32.35] 16.99[11.39–25.34] 26.86[20.64–34.95] 29.69[21.96–40.14] 32.13[21.46–48.10] 38.77[28.53–52.71] 36.85[26.11–52.01] 38.99[24.19–62.86] 41.29[29.71–57.38]

PRN N 37 36 47 47 48 54 33 29 38

GMC(EU/mL)[95%CI] 40.16[24.72–65.24] 18.51[12.60–27.18] 18.13[12.95–25.39] 54.33[33.36–88.48] 30.89[21.21–44.99] 26.82[18.14–39.67] 2.98[2.16–4.11] 3.64[2.74–4.82] 3.84[2.90–5.08]

FIM N 36 36 47 47 48 52 33 29 34

GMC(EU/mL)[95%CI] 126.00[65.45–242.56] 66.56[46.05–96.21] 63.62[42.93–94.28] 154.86[96.78–247.79] 90.43[64.42–126.95] 74.32[52.39–105.42] 14.70[10.11–21.39] 11.56[6.81–19.62] 10.21[6.39–16.33]

PT,pertussistoxoid;FHA,filamentoushaemagglutinin;PRN,pertactin;FIM,fimbriaetypes2+3;CI,confidenceinterval;GMC,geometricmeanconcentrations.Abbreviations:PT:pertussistoxoid;FHA:filamentoushaemagglutinin; PRN:pertactin;FIM:fimbriaetypes2+3;CI:confidenceinterval;GMC:geometricmeanconcentrations.Tdap–IPV:combinedadsorbedtetanus,low-dosediphtheria,5-componentacellularpertussisandinactivatedpoliovaccine (Repevax®;SanofiPasteurMSD);Tdap+OPV:combinedadsorbedtetanus,low-dosediphtheriaand5-componentacellularpertussisvaccine(Covaxis®;SanofiPasteurMSD)givenconcomitantlywithoralpoliovaccine;DTap–IPV:

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4584 T.Johnetal./Vaccine33(2015)4579–4585

administeredinaclinicaltrialofchildrenaged3.5to5yearsin 2001.Followingarapiddeclinein thefirstyearforall antibod-ies[10], thedatafrom thisstudy demonstratethat a low-dose diphtheriatoxoid-containing vaccine(Tdap–IPV and Tdap) pro-videslong-lastingimmuneresponsesforallantigenswithlevelsof immunitybeingbroadlysimilartothoseachievedwith standard-dosediphtheriatoxoidvaccines(DTap–IPV).All3vaccinesstudied intheprimarystudyaresuitableforuseasapre-schoolboosterto provideafourthdoseofthecontainedantigens.

Overalltherewereslightlymorefemalesthanmalesinthestudy butthisreflectedtheoriginalstudypopulation(55%versus45%). 300children participatedin theinitialstudyofwhich 219,161 and146participatedat1,3and5years,respectively.The reten-tionrateisnotdissimilartootherstudiesconductedincohortsof childreninOxford(unpublishedobservations).Bythe5-yeartime pointitwasknownthatseveralfamilieshadmovedawayfrom theareabutreasonsfornon-participationamongstthe remain-ingchildren are largelyunknown.A separatequalitative study, conductedwiththecohortofchildrenapproachedfortheinitial vaccinestudy,identifiedanxietyofbloodsamplingand temper-amentofchildasreasonsfornon-participation[11].Whilethese viewswereexpressedinrelationtoastudyinvolvinganew vac-cineitislikelytheissuesremainrelevantwhenmakingadecision whetherornottoparticipateinastudyinvolvingjustablood sam-ple.

Theproportionofchildrenmaintainingpersistenceof antibod-iesaboveacceptedseroprotectionlevelsfordiphtheria,tetanus, and poliomyelitis weresimilar tothose reportedin a previous study,in which seroprotectiveantibodylevelsagainst diphthe-ria, tetanus, types 1–3 poliomyelitis and Hib were maintained 4–5yearsafterprimaryvaccinationandafirstboosterwiththe DTap–IPV–HibvaccinePentavac®[12].Furthermore,whilea Ger-manstudydemonstratedthatdiphtheriaantitoxintitreswaneover thefirstyearfollowingvaccinationirrespectiveoftheinitialtitre, ithasbeensuggested thattheprotectionafforded bylow-dose diphtheriacontainingcombinationsmaystillpersistthroughto adolescence[13].Thisfollow-upstudysupportslastingprotection againstdiphtheriaforupto5yearsfollowingreceiptofapre-school boostervaccine.Itisnoteworthythat,althoughthepointestimates forthelowdosediphtheriavaccine-inducedanti-toxin concentra-tionsareslightlylowerateachtimepointthanthestandarddose vaccinelevels,noneoftheseconcentrationsweresignificantly dif-ferentasconfidenceintervalsoverlappedsubstantially.

Whiletherearewidelyacceptedreferencelevelsforfull pro-tectionagainstdiphtheria (antitoxinconcentrations≥0.1IU/mL)

[14]andtetanus(antitoxinconcentrations≥0.1IU/mL)[15]there remainnoclearserologicalcorrelatesofprotectionforpertussis fromlargescalefieldstudies,whichmakesitdifficulttointerpret theimmunogenicityofthepertussiscomponentsofthevaccinesin theoriginalstudy[10].AntibodiestoPT,FHA,PRNandFIMwere therefore measuredby EIAusing in-housereference standards. Despitesomewaning,thedatafromthestudyshowpersistence ofantibodyresponsesagainstPTandFHApertussisantigensinall groupsandalsoforPRNandFIMinthe2groupsthatreceiveda 5-componentacellularpertussisvaccine.

Asthestudywasnotpoweredtoshowanyintergroup statis-ticaldifferencesacomparativeanalysisofresultsacrossthethree treatmentgroupsinthisfollow-upantibodypersistencestudywas notattempted.However,serumpolioresponsesweremorerobust inthegroupsreceivingIPVthantheOPVgroupatalmostalltime points(non-overlapping CIs).Sincemucosalresponseswerenot measured,differencesinprotectioninducedbythesedifferent vac-cinestrategiescannotbedetermined.Wealsonotedthatthethere isariseinsomeofthepertussisantibodyconcentrationsbetween the3and5yeartimepoints,whichweproposemayreflectnatural boosting.

Inconclusion,apre-schoolboostervaccinecontaininga low-dosediphtheria toxoid(Tdap–IPV or Tdap+OPV) demonstrates comparablepersistentimmunityfordiphtheria,tetanusand per-tussis antigens to a standard-dose diphtheria toxoid vaccine (DTap–IPV)5yearsafteradministrationtochildrenagedasyoung as3.5yearslivingintheUK.

Fundingandconflictofintereststatement

The study was sponsored by Sanofi PasteurMSD. Withthe exceptionoftheauthorsemployedbySanofiPasteurMSD(M.B, P.R,A.FandN.K),noauthorshavereceiveddirectpaymentfrom Sanofi Pasteur MSD. The sponsor funded the study and devel-oped the studyprotocol in collaboration withA.J.P. Employees of the sponsor reviewed themanuscript beforesubmission for publication.Developmentofthismanuscriptwasalsosupported by theOxford Partnership Comprehensive BiomedicalResearch CentrewithfundingfromtheNIHRBiomedicalResearchCentre Programme (T.J.).A.J.P. haspreviously acted as chief investiga-torfor clinical trials conductedon behalfof Oxford University, sponsored by vaccine manufacturers including Sanofi Pasteur MSD.

Acknowledgements

We would like to thank the participants of this study and theirfamilymembers.Weacknowledgethecontributionsof mem-bers of Oxford Vaccine Groupwho were involved in thestudy overthe5yearperiod,particularlyRebeccaBeckley,ClinicalTrials Assistant,whoassistedwiththevisits.CommunigenLtd,Oxford, UK (supported by Sanofi Pasteur MSD, Lyon, France) provided an early outlinemanuscript withthe overall paper written by T.J.

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