Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines

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

Use

of

the

nonavalent

HPV

vaccine

in

individuals

previously

fully

or

partially

vaccinated

with

bivalent

or

quadrivalent

HPV

vaccines

Pierre

Van

Damme

_,

_Paolo

_Bonanni

_,

_F.

_Xavier

_Bosch

_,

_Elmar

_Joura

_,

Susanne

Krüger

Kjaer

_,

_Chris

_J.L.M.

_Meijer

_,

_Karl-Ulrich

_Petry

_,

_Benoit

_Soubeyrand

_,

Thomas

Verstraeten

_,

_Margaret

_Stanley

a_{CentreforEvaluationofVaccination,VaccineandInfectiousDiseasesInstitute,UniversityofAntwerp,Antwerp,Belgium}

b_{DepartmentofHealthSciences,UniversityofFlorence,Florence,Italy}

c_{CancerResearchEpidemiologyProgram,CatalanInstituteofOncology,IDIBELL,Barcelona,Spain}

d_{DepartmentofObstetricsandGynecology,ComprehensiveCancerCenterVienna,MedicalUniversityofVienna,Vienna,Austria}

e_{DepartmentofGynaecology,JulianeMarieCentre,Rigshospitalet,CopenhagenUniversityHospitalandtheUniversityofCopenhagen,Copenhagen,}

Denmark

f_{DepartmentofPathology,FreeUniversityMedicalCenter,Amsterdam,TheNetherlands}

g_{DepartmentofGynaecologyandObstetrics,KlinikumWolfsburg,Wolfsburg,Germany}

h_{SanofiPasteurMSD,DepartmentofMedicalAffairs,Lyon,France}

i_{P95,EpidemiologyandPharmacovigilanceConsultingandServices,Leuven,Belgium}

j_{DepartmentofPathology,CambridgeUniversity,Cambridge,UK}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received7October2015

Receivedinrevisedform

22December2015

Accepted23December2015

Availableonline6January2016

Keywords:

Humanpapillomavirus

Cervicalcancer

Revaccination

a

b

s

t

r

a

c

t

Withtheavailabilityofthenonavalenthumanpapillomavirus(HPV)vaccine,vaccinees,parentsand

healthcareprovidersneedguidanceonhowtocompleteanimmunizationcoursestartedwiththebi-or

quadrivalentvaccineandwhethertorevaccinateindividualswhohavecompletedafullimmunization

coursewiththebi-orquadrivalentvaccine.Toanswerthesequestionsthreeparametersshouldbe

con-sidered:ageatthestartofvaccination(9to14yearsofageversus15yearsandolder,thecut-offfor2

or3dosesschedule),thenumberofdosesalreadyreceivedandthetimeintervalbetweendoses.Based

onanumberofscenarios,weproposethatthe9-valentvaccinecanbeusedtocompleteanincomplete

vaccinationregimenormightbeaddedtoapreviouscompletedscheduletoextendprotection.

©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND

license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ThenewnonavalentHPVvaccine(9vHPV,tradenameGardasil9) hasbeenapprovedforuseinUSA[1],Canada[2],Australia[3],and theEuropeanUnion[4].Thisvaccineincludeshigh-riskHPVtypes 16,18,31,33,45,52,and58inadditiontothelow-riskHPVtypes 6and11.

ThisnewvaccinecomesinadditiontotwoHPVvaccinesalready commerciallyavailableinalargenumberofcountries.Cervarix®is abivalentvaccine(2vHPV)thattargetsHPV16and18,twoHPV typesthat cause cervical cancer. Gardasil® (4vHPV)targetsthe sameoncogenictypes,aswellasHPV6and11,whichcauseexternal genitalwarts.Thusfar,millionsofwomenandasmallernumber ofmenhavebeenimmunizedwiththesetwoHPVvaccines,witha well-documentedsafetyprofile[5–9].Bothvaccinesprotectagainst HPVtype16/18relatedgenitaldiseases,essentiallyagainst50%of

∗ Correspondingauthor.Tel.:+3232652538;fax:+3232652640.

E-mailaddress:[email protected](P.VanDamme).

cervicalintraepithelialneoplasia(CIN)2/3and70%ofcervical can-cer[10].The5additionaltypesin9vHPVincreasetheprotection againstcervicalcancertoapproximately90%.ForCIN1,CIN2and CIN3lesions,theincreasesare20%,30%and30%,respectively[11], seeFig.1.

Withtheavailability ofthe9vHPV,vaccinees(andtheir par-ents)andhealthcareprovidersmaywonderhowtocompletean immunizationcoursestartedwiththebi-orquadrivalentvaccine andwhethertorevaccinateindividualswhohavecompletedafull immunization coursewiththe bi-or quadrivalent vaccine.The Europeansummary of product characteristicsof thethree HPV vaccinesstatesthatindividualswhoreceivedafirstdosewitha givenHPVvaccineshouldcomplete thevaccinationcoursewith thatsamevaccine[12–14].TheUSAdvisoryCommitteeon Immu-nizationPractices(ACIP)[15,16]ontheotherhand,statesthat“any availableHPVvaccineproductmaybeusedtocontinueorcomplete theseriesforfemalesforprotectionagainstHPV16and18”. Tak-ingtheaboveintoconsideration,weproposeapragmaticapproach http://dx.doi.org/10.1016/j.vaccine.2015.12.063

0264-410X/©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.

Fig.1.ContributionofhighriskHPVtypescoveredbythebi-andquadrivalentvaccinesandthenonavalentvaccinetocervicalcancerandprecancerouscervicallesions.

9vHPVtypesare:6,11,16,18,31,33,45,52,and58.TheoverallcontributionofHPVtoCIN1=73%,CIN2=86%,CIN3=93%,cervicalcancer=100%.Figureadaptedfrom

Hartwigetal.[11].

basedonlimitedexistingdata,andwheredataarenotyetavailable, onexpertopinion.Theproposedguidelinesaredraftedfora tran-sitionalperiod,andaddressthequestionsraisedonanindividual ratherthanonaprogrammaticlevel.Whiledraftingthedifferent scenarioswedidnottakeeconomicconsiderationsintoaccount, astheproposedschedules havenot beensufficientlyevaluated economically[15,16].

Apivotalrandomized,controlledclinicaltrial(RCT)[17] com-paring9vHPVwiththe4vHPVvaccinedemonstratedahighvaccine efficacyof 9vHPVagainsthigh-gradecervical,vulvar,or vaginal diseaserelatedtothenewHPVtypes31, 33,45, 52,and 58 of 96.7%(95%confidenceinterval,80.9%to99.8%).Simultaneously, antibodyresponsestoHPV-6,11,16,and18werenon-inferiorto thosegeneratedbythe4vHPVvaccine.Consequently,efficacyfor 9vHPVagainstpersistentinfectionanddiseaserelatedtoHPVtypes 6,11,16,or18canbeinferredtobecomparabletothatof4vHPV [17].Finally,immunizationwith9vHPVwasshowntobewell tol-eratedandsafeinthepivotalRCT,andalthoughitresultedinmore adverselocalreactionsthanvaccinationwiththe4vHPVvaccine,as expectedduetothehigherdoseofantigenand/oradjuvant,more than90%ofthesereactionsweremildtomoderateinintensity[17]. Subsequentinjection(using9vHPVtocomplete aHPV vacci-nationcourse initiated with a bi- or quadrivalent vaccine) has not been assessed in the clinical developmentprogram sofar. Similarly,nodataareavailableonrevaccinationwith9vHPV of subjects who completed an immunization course with 2vHPV.

Revaccinationwasinvestigatedinaclinicaltrial(studyV503-006, ClinicalTrials.gov Identifier: NCT01047345), which assessed the safetyandimmunogenicityofcomplete3doses9vHPV adminis-trationin 4vHPV recipients(3-dose schedule)witha minimum 12-monthinterval (with thethird doseof 4vHPV administered atleast oneyear prior tothefirst doseof9vHPV) [18]. 9vHPV wasfound tobe highly immunogenic withoutsafety concerns. In thegroupthat received3 dosesof 4vHPV and then3 doses of9vHPV,thegeometricmeantiters(GMTs)toHPVtypes6,11, 16,18werehigherthaninthe4vHPVvaccinenaïvepopulation fromotherstudies,whereastheGMTstoHPVTypes 31,33,45, 52and58werelowerthanin9vHPV-vaccinated,4vHPVvaccine naïvesubjects,seeFig.2[18].Theexpectationisthatthesegirls willbeprotectedagainstthe5newHPVtypes.Whether protec-tioniscomparabletothatagainstHPVtypes6,11,16,18isyet unknown.

Toanswerthetwoquestionsonhowtocompletean immuniza-tioncoursestartedwiththebi-orquadrivalentvaccineandthe usefulnessofrevaccinatingindividualswhohavecompletedafull immunizationcoursewiththebi-orquadrivalentvaccine,three parametersshouldbeconsidered:age(9to14yearsofageversus 15yearsandolder,thecut-offfor2or3dosesschedule),the num-berofdosesalreadyreceivedandthetimeintervalbetweendoses. Forthosecountriesconsideringmalevaccination,our recommen-dationsforgirlsarealsovalidforboys,asimmunogenicityinboys issimilar,ifnothigher,comparedtogirls[19].

Table1

Scenariosandproposedapproaches,forgirls9–14yearsofage.

*Expectedaccordingtocurrentlyavailabledataandexpertjudgment,theroleofcross-protectionprovidedbythebi-andquadrivalentvaccineswasignored.

Wefirstconsiderthesituationingirlslessthan15yearsofage,

wherewecandistinguish4scenarios:

InscenarioA,revaccination,i.e.,agirlhasreceivedtwodoses

ofthebi-orquadrivalentHPVvaccinesixmonthsapart.Basedon

immunogenicityresults,twodosesofHPVvaccine,minimumsix

monthsapartshouldofferprotectionagainstthetwo,respectively,

fourtypesinthevaccine,ingirlsbetween9and14yearsofage

[20,21].Consequently,inviewoftheimmunogenicitydata,WHO changeditspreviousrecommendationofa 3-dosescheduletoa 2-doseschedulewitha6-monthintervalbetweendosesforboth thebi-andquadrivalentHPVvaccines,infemalesyoungerthan 15years[22].InmostEUcountriesthevaccinationschedulehas beenreducedfromthreetotwodosesintheadolescentpopulation. Aclinicaltrialisongoing comparingsafetyandimmunogenicity ofa2-dose9vHPVregimeninboysandgirls9to14yearsofage toa 3-dosescheduleof9vHPVinfemales16 to26yearsofage (V503-010,ClinicalTrials.govIdentifier:NCT01984697):available

immunogenicityandsafetydatasupporttheadministrationofa 2-doseregimenof9vHPV,wheretheseconddoseisadministered6to 12months(±1month)followingthefirstdose,asanalternativeto the3-doseregimenforgirlsandboys9to14yearsofage(dataon file).Basedontheseresults,andusingthesameapproachasthat previouslyacceptedforlicensureofa2-doseregimenof4vHPV, efficacyfindingsinyoungwomenwhoreceivedthe3doseregimen of9vHPVcanbeextendedtogirlsandboys9to14yearsofage whoreceivedthe2-dose(0,6)or(0,12)regimenincludingfull protectionagainstthe5additionaltypes.ForscenarioA,toachieve protectionagainstthenewtypes,thegirlwouldthereforehaveto bevaccinatedwiththe9vHPVvaccine,with2injections—6to12 monthsapart.

InscenarioB,agirlhasreceivedonlytwodosesofthebi-or quadrivalentHPVvaccinetwomonthsapartwhichisnotthe tim-ingrecommendedbyWHOfora2-dosevaccinationschedule[22]. Shemaythereforenotbefullyprotectedagainstthe2or4HPV

types[22].Thisislikelytoberemediedwithanextradoseof9vHPV betweenmonth6andmonth12–aftertheseconddoseofthe origi-nalvaccine–tobefullyprotectedagainsttheoriginaltypesshewas vaccinatedagainst(twoorfourHPVtypes,respectively).However, toachievesomeextraprotectionagainstthe7or5additionaltypes (dependingwhetherherinitialdoseswerethebi-orthe quadriva-lent,respectively),shewouldneedatleastaseconddoseof9vHPV vaccine6to12monthslater,asthereisnodatasupportingthat only1doseof9vHPVwillofferfullprotection.

In scenario C, a girl has received only one dose of the bi-orquadrivalentHPVvaccine.Currentlythereis noHPVvaccine licensed for single dose administration and there is no robust clinicaldiseasedatasupportingprotectionagainst the2–4HPV typesafteronedoseofbi-orquadrivalentvaccine,althoughsome evidencehasbeen presentedthat a singledoseof thebivalent vaccine protectsagainst HPV16/18 infections for at least four years[23].Anextradoseof9vHPV given 6to12 monthsafter the first one should reasonably provide protection against the 2–4originaltypes.However,toachieveextraprotectionagainst theadditionaltypes, shewould needat leasta second doseof 9vHPV vaccine 6 to 12 months after, as described in scenario B.

ScenarioDrepresentsagirlwhohasfinishedherbi-or quadriva-lentHPVvaccinationschedulewith3doses.Sheisthereforefully protectedagainstHPVtypes16and18(andHPVtypes6and11 forthequadrivalentvaccine).Toachieveextraprotectionagainst thenewtypes,thegirlinthisscenarioshouldbevaccinatedwith the9vHPV vaccineatleast with2doses given 6to12 months apart(ifundertheageof15).Asdiscussedabove,thismayresult ina lowerimmuneresponse (expressedaslower GMTs)tothe additionalHPVtypes,withanasyetunknownclinicalsignificance [24].

Table1summarizes,foreachscenario,thevaccines,theinterval andnumberofdosesthatshouldbeconsidered,andtheexpected protectionresultingfromtheextradoses.

Ingirlsolderthan15yearsofagewhoseinitialserieswasgiven before15yearsofageandinwomen),asinscenarioDrevaccination shouldbeconsidered;3doses 9vHPVvaccine,accordingtoa 0, 2and6monthsscheduleshouldbeadministeredtoprovidefull protectionagainsttheextratypesin9vHPV.

Aspreviouslymentioned,thescenariosdescribedarenot neces-sarilylimitedtogirls,butmayalsoapplytoboys.Proposedguidance isbasedonavailableimmunogenicitydatasupportingthe admin-istrationofa2-doseregimenof9vHPV,wheretheseconddoseis administered6to13months(±1month)followingthefirstdose, asanalternativetothe3-doseregimenforgirlsandboys9to14 yearsofage.(Dataonfile;ongoingclinicaltrialV503-010, Clinical-Trials.govIdentifier:NCT01984697).

Wearefullyawarethattherearelimitationstothepresented scenarios,butsofarnoconcretedataexistasvaccinetrialswith theproposedscheduleshavenotbeenperformed.Theresultsof the9vHPV vaccinestudy infemales 12–26 years ofage, previ-ouslycompletelyvaccinated with4vHPV, showedthat thetime intervalbetweenbothserieshadnoimpactonthe9vHPV immuno-genicityat month 7 [24]; theauthors therefore do not expect a time interval to have anyimpact,but age at themoment of vaccineadministrationdoes.Wearealsoawarethatwhatis pro-posedinthispapershouldberegardedasvalidforatransitional periodintime.Inaddition,itis notproposedthatvaccines and visitstoexistingprograms(whichwouldbemajorprogrammatic challenges) should be made. With the proposed scenarios the authorsaim toaddress questions raised onan individual level (byahealthcareproviderorvaccinee),ratherthanrecommending thatcountriesamendtheirHPVimmunizationprogram.Finally,we needtotakeintoconsiderationthatthedurabilityoftheresponse and thelong-termefficacyof any2-dose HPVvaccineregimen

remains to be demonstrated, the impact onHPV, in particular onCIN2+,needstobemeasured,andsafetytobefurther docu-mented.

Inconclusion,theintroductionofthenew9vHPVvaccine offer-ingasignificantlybroaderprotectionraisesthequestionofwhatis themostappropriateandpracticalwayforcompletinga vaccina-tioncoursealreadystarted.Weproposethatthe9-valentvaccine canbeusedtocompleteanincompletevaccinationregimen (sce-nario Band C) or be added to a previous completedschedule (scenario A and D) toextend protection.The number of doses andtimingdepends onthedosesalreadygiven, andtheageof thevaccinee. Finally, for those countriesconsideringmale vac-cination,thispositioncan alsobeappliedtothevaccinationof boys.

Acknowledgments

Thispositionwasdefinedduringan expertmeeting heldby SanofiPasteurMSD.TheauthorsthankSandrineSamson(Sanofi PasteurMSD)fororganizingthisopportunity,andMarcBaay(P95) foreditorialassistancewiththemanuscript.

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