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.
Permanent WRAP url:
http://wrap.warwick.ac.uk/76174
Copyright and reuse:
The Warwick Research Archive Portal (WRAP) makes this work of researchers of the
University of Warwick available open access under the following conditions.
This article is made available under the Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 (CC BY-NC-ND 4.0) and may be reused according to the conditions of
the license. For more details see:
http://creativecommons.org/licenses/by-nc-nd/4.0/
A note on versions:
The version presented in WRAP is the published version, or, version of record, and may
be cited as it appears here.
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.
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) 2.5g 2.5g – 25g
Purifiedfilamentoushaemagglutinin(FHA) 5g 5g – 25g
Purifiedfimbriaetypes2+3(FIM) 5g 5g – –
Purifiedpertactin(PRN) 3g 3g –
Inactivatedpoliomyelitisvirustype1 40Dantigenunits - – 40Dantigenunits
Inactivatedpoliomyelitisvirustype2 8Dantigenunits – – 8Dantigenunits
Inactivatedpoliomyelitisvirustype3 32Dantigenunits – – 32Dantigenunits
Liveattenuatedtype1poliovirus – – ≥106TCID50 –
Liveattenuatedtype2poliovirus – – ≥105TCID50 –
Liveattenuatedtype3poliovirus – – ≥105.5TCID50 –
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
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
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:
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.
References
[1]ParandeMV,ParandeAM,LakkannavarSL,KholkuteSD,RoyS.Diphtheria
outbreakinruralNorthKarnataka,India.JMMCaseRep2014;1(3):e003558.
[2]BesaNC,ColdironME,BakriA,RajiA,NsuamiMJ,RousseauC,etal.
Diph-theriaoutbreakwithhighmortalityinnortheasternNigeria.EpidemiolInfect
2014;142(04):797–802.
[3]HMStationaryOffice.Immunisationagainstinfectiousdisease.London:HM
StationaryOffice;1996.http://www.immunisation.nhs.uk/pertussis.html.
[4]EdwardsKM,BradleyRB,DeckerMD,PalmerPS,VanSavageJ,TaylorJC,etal.
Evaluationofanewhighlypurifiedpertussisvaccineininfantsandchildren.J
InfectDis1989;160:832–7.
[5]BernsteinDI,SmithVE,SchiffGM,RathfonHM,BosciaJA.Comparisonof
acellularpertussisvaccinewithwholecellvaccineasaboosterinchildren
15to 18monthsand 4to6years ofage. PediatrInfectDisJ 1993;12:
131–5.
[6]HalperinSA,EastwoodBJ,BarretoL,FriesenB,MeddL,MeekisonW,etal.
Adversereactionsandantibodyresponsetofourdosesofacellularorwhole
cellpertussisvaccinecombinedwithdiphtheriaandtetanustoxoidsinthe
first19monthsoflife.Vaccine1996;14:767–72.
[7]ChiefMedicalOfficer,PLCMO.Newvaccinationsforthechildhood
immunisa-tionschedule.DepartmentofHealth;2004.p.3.
[8]TerryL.Theassociationofcasesofpoliomyelitiswiththeuseoftype3oral
poliomyelitisvaccines.Washington,DC:USDepartmentofHealth,Education
andWelfare;1962.
[9]KitchinN,etal.AntibodypersistenceinUKpre-schoolchildrenfollowing
pri-maryserieswithanacellularpertussis-containingpentavalentvaccinegiven
concomitantlywithmeningococcalgroupCconjugatevaccine,andresponse
toaboosterdoseofanacellularpertussis-containingquadrivalentvaccine.
Vaccine2009;13:5096–102.
[10]CollinsCL,SaltP,McCarthyM,ChantlerT,LaneL,HemmeF,etal.
Immuno-genicityandsafetyoflowdosediphtheria,tetanus,andacellularpertussis
combinationvaccinewitheitherinactivatedororalpoliovaccineasa
pre-schoolboosterinUKchildren.Vaccine2004;22:4262–9.
[11]Chantler TE, Lees A, Moxon ER, Mant D, Pollard AJ, Fiztpatrick R. The
rolefamiliaritywithscienceandmedicineplaysinparents’decision
mak-ing aboutenrollingachildinvaccineresearch.QualHealthRes2007;17:
311–22.
[12]MalletE,MatisseN,MathieuN,langueJ,BoisnardF,SoubeyrandB,etal.
haemophilusinfluenzatypeb(Hib)in5–6-year-oldchildrenafterprimary
vaccinationandfirstboosterwithpentavalentcombinedacellularpertussis
vaccine:immunogenicityandtoleranceofatetravalentcombinedacellular
pertussisvaccinegivenasasecondbooster.Vaccine2004;22:1415–22.
[13]ZeppF,HabermehlP,KnufM,Mannhardt-LaakmanW,HoweB,Friedland
LR.Immunogenicityofreducedantigencontenttetanus–diphtheria–acellular
pertussisvaccine in adolescentsasa sixthconsecutive dose ofacellular
pertussis-containingvaccine.Vaccine2007;25(29):5248–52.
[14]GalazkaAM.WHO/EPI/93.12.Theimmunologicalbasisforimmunizationseries.
Module2:diphtheriaGeneva:WorldHealthOrganisation;2001.
[15]GalazkaAM.WHO/EPI/GEN/93.13.Theimmunologicalbasisforimmunization