Lecture 10 - Low Papillomavirus

Lecture 10 - Low Papillomavirus - Review series...

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Unformatted text preview: Review series Prophylactic human papillomavirus vaccines Douglas R. Lowy and John T. Schiller Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA. Humanpapillomavirus(HPV)infectioncausesvirtuallyallcasesofcervicalcancer,thesecondmostcommoncause ofdeathfromcanceramongwomenworldwide.ThisReviewexaminesprophylacticHPVsubunitvaccinesbasedon theabilityoftheviralL1capsidproteintoformvirus-likeparticles(VLPs)thatinducehighlevelsofneutralizing antibodies.Followingpreclinicalresearchbylaboratoriesinthenonprofitsector,MerckandGlaxoSmithKline aredevelopingcommercialversionsofthevaccine.BothvaccinestargetHPV16andHPV18,whichaccountfor approximately70%ofcervicalcancer.TheMerckvaccinealsotargetsHPV6andHPV11,whichaccountforapproximately90%ofexternalgenitalwarts.Thevaccineshaveanexcellentsafetyprofile,arehighlyimmunogenic,andhave conferredcompletetype-specificprotectionagainstpersistentinfectionandassociatedlesionsinfullyvaccinated women.Unresolvedissuesincludethemostcriticalgroupstovaccinateandwhenthevaccine'scostmaybelow enoughforwidespreadimplementationinthedevelopingworld,where80%ofcervicalcanceroccurs. Human papillomavirus infection and disease Ofthe10millioncasesofcancerthatdevelopannuallythroughouttheworld,morethan15%areestimatedtobeattributableto infectiousagents(1).Infectionbyhumanpapillomaviruses(HPVs) accountsforapproximately30%ofthesecancers(~5%ofallcancers),withhepatitisBandCvirusesand Helicobacter pyloritogether accountingforanother60%ofcancerswithaninfectiousetiology. HPVsinfectthestratifiedsquamousepitheliaofskinandmucous membranes,wheretheycausebenignlesions,someofwhichhave thepotentialtoprogresstoinvasivecancer.(24).HPVsaresmall, nonenvelopedviruseswhoseapproximately8-kbcirculargenome encodes2structuralproteins,L1andL2,thatformtheviralcapsid, plusseveralnonstructuralproteinsthatareimportantforthevirus lifecyclebutarenotincorporatedintovirions.Toestablishinfection, microtraumaorerosionoftheoverlyingepitheliallayersisthought toenableHPVstoinfectcellsofthebasalepitheliallayer,wherethe stemcellsandotherlong-livedcellsarefound(Figure1).HPVinfectionstendtolastmonthsoryearsbecausetheviralgenomesuccessfullyparasitizesthesecellsandbecausethevirusevadestheimmune systembylimitingmostviralgeneexpressionandviralreplicationto suprabasalcelllayers.Mostinfectionsareself-limited,presumably becausethehosteventuallymountsasuccessfulimmuneresponse. ThebenignlesionsinducedbyHPVsincludenongenitaland anogenitalskinwarts,oralandlaryngealpapillomas,andanogenitalmucosalcondylomata(Figure2).Anogenitalinfectionsare almostalwaystransmittedsexually.Long-terminfectionbyasubsetofHPVscanleadtomalignantanogenitaltumors,including cancersoftheanus,penis,vulva,vagina,andcervix(57).AproportionoforalcancerisalsoattributabletoHPV(8,9).WhileHPV infectionhasbeenassociatedonlimitedoccasionswithesophageal cancerandskincancer,afrequentcausallink,althoughplausible, remainsmoretenuous(6,10). AmongthecancersattributabletoHPVinfection,cervicalcancerhasreceivedthemostattention(11),asitaccountsforabout 10%ofallcancersinwomenworldwide.CervicalcanceristhesecNonstandardabbreviationsused:CIN,cervicalintraepithelialneoplasia;HPV, humanpapillomavirus;HSV,herpessimplexvirus;VLP,virus-likeparticle. Conflictofinterest:Theauthors,asemployeesoftheNationalCancerInstitute, NIH,areinventorsoftheHPVVLPvaccinetechnologydescribedinthisReview.The technologyhasbeenlicensedbytheNIHtothe2companies,MerckandGlaxoSmithKline,thataredevelopingthecommercialHPVvaccinesdescribedherein. Citationforthisarticle:J. Clin. Invest.116:11671173(2006).doi:10.1172/JCI28607. ondmostcommoncauseofdeathfromcancer,afterbreastcancer, amongwomenworldwide.Theintervalbetweentheacquisitionof HPVinfectionandmalignantprogressionusuallytakesatleast10 years(Figure3)andisfrequentlylonger(7,12).Cervicalcanceris thereforeveryuncommoninwomenunder25;theincidencerises progressivelyforwomenover25andishighestforwomenover40. About80%ofcervicalcancersoccurinless-developedcountries,primarilybecausetheylacksufficientresourcesforhigh-qualitycervicalcancerscreeningprogramsthatdetectcervicalabnormalitiesvia PapsmeartestingortestingforthepresenceofcervicalHPVDNA (13).Virtuallyallcasesofcervicalcancerareattributabletosexually acquiredHPVinfection(14),whileinfectionbyHPVaccountsfora variableproportionoftheothertumorsinwhichthevirushasbeen implicatedetiologically.Ofallcancercaseslinkedetiologicallyto HPV,cervicalcanceraccountsforabouttwo-thirdsofthem.This cancercanresultfrominfectionbyany1ofabout15oncogenic HPVtypes,butHPV16andHPV18predominate,accountingfor about50%and20%ofcervicalcancer,respectively(15).These2 typesaccountforanevenhigherproportionoftheothergenital andmucosalcancersattributabletoHPVinfection(6). GenitalHPVinfectionisbelievedtobethemostcommonsexuallytransmittedviralinfection,withanestimatedprevalenceof about2040%amongsexuallyactive20-year-oldwomen,anestimated3-yearcumulativeincidenceofmorethan40%instudiesof collegewomenintheUnitedStates,andanestimatedlifetimerisk forwomenofatleast75%foroneormoregenitalHPVinfections (16,17).MostgenitalHPVinfectionsarebenign,subclinical,and self-limited,andahighproportionofinfectionsassociatedwith low-gradecervicaldysplasias(Figure2)alsoregressspontaneously (7,17).Bycontrast,persistentcervicalinfection(oftendefinedas aninfectionthatisdetectedmorethanonceinanintervalof6 monthsorlonger)withanoncogenicHPVtype,especiallyHPV16 andHPV18,isthemostimportantriskfactorforprogressionto high-gradedysplasia(Figure2)(18),whichisrecognizedasaprecancerouslesionthatshouldbetreatedtopreventthedevelopmentofinvasivecancer.Locally,ablativetherapyisusedsuccessfullytotreathigh-gradedysplasia(13). Prophylactic HPV vaccine: development and efficacy studies IdentificationofaviralagentsuchasHPVasacauseofdisease(s) impliesthatsuccessfulprophylacticortherapeuticintervention 1167 TheJournalofClinicalInvestigation http://www.jci.org Volume116 Number5 May2006 review series Figure 1 Papillomavirus life cycle. To establish infection, the virus must infect basal epithelial cells that are long lived or have stem celllike properties. Microtrauma to the suprabasal epidermal cells probably enables the virus to infect the cell within the basal layer. The viral genome maintains itself as an episome in basal cells, where the viral genes are poorly expressed. Viral replication takes place in suprabasal layers and is tied to the epidermal differentiation process. The presence of the virus causes morphological abnormalities in the epithelium, including papillomatosis, parakeratosis, and koilocytosis. Progeny virus is released in desquamated cells. againsttheviralagentshouldpreventthedisease(s)itcauses.A preexistingviralinfectioncantheoreticallybetargetedbyanantiviraloratherapeuticvaccine.Successfulantiviralshavebeendevelopedforthetreatmentofsomeviralinfections,includingdiseases suchasHIVandinfluenza(19),butnotagainstvirusessuchas HPV.AtherapeuticvaccineagainstHPVinfectionwouldbehighly desirabletopreventthecancer-associatedcomplicationsofHPV infection,whichonlydevelopaftermanyyearsofinfection.However,despiteongoingeffortstodevelopeffectivetherapeuticvaccinesagainstHPVandotherviralinfections,nonehasbeenshown tobehighlyeffectiveclinically(20),probablybecausethevaccines havenotyetadequatelymimickedcriticalaspectsofacurative immuneresponse.Ontheotherhand,prophylacticvaccineshave beendevelopedagainstavarietyofhumanviralpathogensand areoftenacost-effectiveapproachtointerferewiththediseases causedbythesepathogens(21).Tobewidelyimplemented,aprophylacticvaccinegenerallyneedstoconferhigh-levelprotection foratleastseveralyearswithoutboostingandtobeparticularly safe,asitisgiventohealthyindividuals. TherecognitionofHPVasthecauseofcervicalcancerandother diseasesthereforeimpliedthataneffectiveHPVvaccineshould beabletointerferewiththebenignandmalignantconditions attributabletoHPVinfection.However,approvedprophylactic vaccineshavebeendirectedagainstinfectiousagentsthatcause systemicdisease,andeffortstodevelopvaccinesagainstsexually transmittedagentssuchasHPVwhosediseaseresultsfromlocal infectionhadnotprovensuccessful.Itisbelievedthatneutralizingantibodiesformthecornerstoneofmostprophylacticvaccines,andvirusesthatcausediseaseonlyafterpassingthrough thecirculationareaccessibletotheneutralizingantibodiespres1168 entintheblood(22).Anotherlimitationwasthatthepresence ofoncogenesinHPVssuggestedthatasubunitvaccineapproach wouldtheoreticallybepreferabletoaninactivatedvaccineoran attenuatedlive-virusvaccine,anditwasunclearwhetherasubunitHPVvaccinewouldhavethepotentialtobeeffectiveagainst thelocalinfectionscausedbygenitalHPVs. Despitetheseuncertainties,2pharmaceuticalcompanies,Merck andGlaxoSmithKline,haverecentlyreportedaremarkabledegree ofprotectionbycandidateprophylacticHPVvaccines(seebelow). Thevaccinesthatbothcompaniesaredevelopingaresubunit virus-likeparticle(VLP)vaccinescomposedofasingleviralprotein,L1,whichisthemajorstructural(capsid)proteinofthevirus andcontainstheimmunodominantneutralizationepitopesof thevirus.Thevaccinesarebasedprimarilyonpreclinicalresearch showingthat(a)whenexpressedincells,L1hastheintrinsicabilitytoself-assembleintoVLPs(Figure4)(2326)thatcaninduce highlevelsofneutralizingantibodies(23,27,28);(b)inanimal modelsofanimalpapillomavirusinfection,parenteralvaccination withL1VLPsprotectsfromhigh-dosechallengewithhomologousvirus(2931),whileanimalsarenotprotectedbysystemic immunizationwithdenaturedL1orL1VLPsfromaheterologous papillomavirusbecauseL1neutralizationepitopesareconformationallydependentandpredominantlytypespecific(29);and(c) protectioncanbepassivelytransferredbyimmuneIgG(29,30). TheVLPsfromtheMerckvaccineareproducedinyeast(3234), whiletheVLPsfromtheGlaxoSmithKlinevaccineareproduced ininsectcellsviarecombinantbaculovirus(35).Merckusesalum asanadjuvantinitsvaccine,whileGlaxoSmithKlineusesAS04, aproprietaryadjuvantcomposedofalumplusmonophosphoryl lipidA(adetoxifiedformoflipopolysaccharide).Bothvaccinesuse TheJournalofClinicalInvestigation http://www.jci.org Volume116 Number5 May2006 review series Figure 2 Progression from a benign cervical lesion to invasive cervical cancer. Infection by oncogenic HPV types, especially HPV16, may directly cause a benign condylomatous lesion, lowgrade dysplasia, or sometimes even an early high-grade lesion. Carcinoma in situ rarely occurs until several years after infection. It results from the combined effects of HPV genes, particularly those encoding E6 and E7, which are the 2 viral oncoproteins that are preferentially retained and expressed in cervical cancers; integration of the viral DNA into the host DNA; and a series of genetic and epigenetic changes in cellular genes. HSIL, highgrade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion. purifiedparticles,whicharegivenas3intramuscularinjections overa6-monthperiod. Ofcourse,itwouldbedesirableforanHPVvaccinetohavethe abilitytopreventallcasesofcervicalcancer.However,although the15oncogenictypesimplicatedincervicalcanceraremore closelyrelatedtoeachotherphylogeneticallythantheyaretothe HPVsthatcausenongenitalskinlesions(warts)(36),theimmunodominantepitopesinL1VLPsinduceneutralizingantibodiesthat arepredominantlytypespecific(37).Ithasthereforebeennecessary,atleastforthefirstgenerationHPVvaccines,tofocusonthe HPVtypesfoundmostfrequentlyincervicalcancer.ThisconsiderationhasledbothcompaniestofocusonHPV16andHPV18, which,asnotedabove,accountforabout70%ofcasesofcervical cancer.TheMerckvaccinealsotargetsHPV6andHPV11,which togetheraccountforabout90%ofexternalgenitalwarts(38);the latter2typesalsoinfectthecervix,butarenotimplicatedincervicalcancer.Thus,theGlaxoSmithKlinevaccinethatiscurrentlyin phaseIIItrialsisabivalentvaccinecomposedofVLPsfromHPV16 andHPV18,whilethevaccinethatMerckhasusedforitsphase IIItrialsisaquadrivalentvaccinethatcontainsVLPsfromHPV6, HPV11,HPV16,andHPV18. Whenconsideringappropriateendpointsfordeterminingvaccineefficacy,themostrelevantendpointsrecommendedbyan FDAvaccineadvisorypanel(39)wereareductionintheincidence ofvaccinetypespecificpersistentinfectionsandofassociated moderate-andhigh-gradecervicaldysplasiasandcarcinomasin situ,whichtogetherarereferredtoascervicalintraepithelialneoplasia2+(CIN2+;CINisgradedasCIN1,CIN2,andCIN3forlow-, moderate-,andhigh-gradedysplasia,respectively).HPVDNAtestingresultshavebeenshowntobesubstantiallymorereproducible thanthepathologicaldiagnosisofdysplasia(40),butmoderate- andhigh-gradedysplasiasrepresentclinicalendpointsthattriggertherapeuticintervention.Itisimportanttonotethatitwould beunethicaltousecervicalcancerasaprimaryendpointforvaccineefficacytrials,ascervicalcancerscreeningcanpreventthevast majorityofcancerthroughtheidentificationofprecancers,which arethentreated.Also,theintervalbetweeninfectionandthedevelopmentofinvasivecancerusuallytakesmorethan10years(7,12). Followingtheobservationsthatsystemicvaccinationwitha monovalentHPV16L1VLPvaccinewassafeandhighlyimmunogenic(41),evenwithoutadjuvant,aMerck-sponsoredproofof-principleefficacytrialofanHPV16L1VLPvaccinereported thatfullyvaccinatedwomenwhowereHPVnegativethroughout thevaccinationperiodwerecompletelyprotectedagainstthe developmentofpersistentincidentinfectionwithHPV16when followedforanaverageof17months(Table1andref.32).This vaccinecohorthasnowbeenfollowedforanaverageof3.5years, andthehighlevelofprotectionwasmaintainedthroughoutthis period(Table1andref.34).Aftertheinitialpeak,thelevelsof serumantibodiesappearedtodeclineapproximately10-foldover thefirst2yearsfollowingvaccinationbutthenremainedstable fortheremainderofthefollow-upperiod.Ifthelevelofserum antibodiesrepresentsasurrogateforprotectionagainstinfection, thestabilityoftheantibodytiterswouldsuggestthathigh-level protectionmaycontinuesubstantiallybeyond3.5years.PreliminaryefficacyresultsfromMerck'squadrivalentvaccinewerealso publishedandshowedexcellentprotectionagainstthevirusestargetedbythevaccine(Table1andref.33).Inunpublishedstudies, Merckhasreportedatscientificmeetingsontheclinicalefficacy ofthemultinationalphaseIIItrialoftheirquadrivalentvaccine, withanaveragefollow-upof1.5years(42,43).Whenfullyvaccinatedwomenwhoremainednegativeforinfectionthroughout thevaccinationperiodwereanalyzedagainstthecomparableplacebocohort,thevaccinewas100%effectiveinpreventingCIN2+ associatedwithHPV16orHPV18andalsoinpreventingexternal genitalwartsassociatedwithHPV6orHPV11.Evenwhenthe efficacywascomparedstarting1monthafterthefirstimmunization,protectionfortheseendpointswasgreaterthan90%.Thus systemicimmunizationwithasubunitHPVvaccinecanachievea highdegreeofprotectioninwomenagainstbenignandpremalignantdiseasesinducedbythissexuallytransmittedlocalinfection ofthegenitalmucosaorskin. 1169 TheJournalofClinicalInvestigation http://www.jci.org Volume116 Number5 May2006 review series Figure 3 Relationship among incidences of cervical HPV infection, precancer, and cancer. The HPV curve emphasizes the high incidence of infection that develops soon after women initiate sexual activity and subsequent lower incidence because a high proportion of infections are self-limited. The precancer incidence curve follows several years behind the HPV incidence curve and is substantially lower than that of HPV incidence, as there is generally a delay between the acquisition of HPV infection and precancer development, and only a subset of infected women develop precancers. The cancer incidence curve follows several years behind the precancer curve, reflecting the relatively long interval between precancer and progression to invasive cancer. As women approach 40 years of age, the incidence of cancer begins to approach the incidence of precancer. Figure modified with permission from the New England Journal of Medicine (53). TheMerck-sponsoredtrialshavenotreportedonthecomparativeincidenceofinfectionbyotherHPVtypesnotincludedin thevaccines.However,theproof-of-principlemonovalentHPV16 trialhasreportedonthetotalnumberofpatientswithvarious gradesofcervicaldysplasia,andwhetherthedysplasiaswereassociatedwithHPV16,forthefullyvaccinatedwomenwhowereHPV negativethroughoutthevaccinationperiod(32).Incontrastto thecompleteprotectionseenagainstHPV16-associateddysplasias,therewasnodifferencebetweentheplaceboandvaccinated groupsinthenumberofnonHPV16-associateddysplasiasinthe initialreportonthiscohort.Inthe3.5-yearfollow-upreport(34), therewasalsonoevidencethatnonHPV16-associateddysplasias inthevaccinatedgroupwerelessfrequentinnumberthanthose inthenonvaccinatedgroup.Theseresultsstronglysuggestthat theprotectionconferredbyMerckHPV16monovalentvaccinewas predominantlyHPVtypespecific. GlaxoSmithKlinehasalsosponsoredaproof-of-principleefficacytrialofanHPV16andHPV18bivalentvaccinesimilartothe onethatiscurrentlyinphaseIIItrials(Table1andref.35).Their placebo-controlledproof-of-principletrialhadasmallernumber ofparticipantswhowerefollowedforanaverageof18months. Inthegroupofwomenwhowerefullyvaccinatedandremained uninfectedthroughoutthevaccinationperiod,allsubsequentpersistentinfectionsassociatedwithHPV16andHPV18occurredin theplacebogroup,althoughtherewereonlyatotalof7cases(5 withHPV16and2withHPV18).Whenincidentpersistentinfectionwasmonitoredstarting1monthafterthefirstdoseofvaccine,combinedprotectionagainstHPV16andHPV18wasstill about90%.Anotherpotentiallyimportantresult,whichhasbeen presentedatmeetingsbutnotyetpublished,isthatthevaccine hasbeenassociatedwithsomecross-protectionagainstHPVtypes closelyrelatedtoHPV16andHPV18,althoughthisprotectionwas 1170 lesscompletethanthatofferedagainstHPV16andHPV18(44, 45).AsMerckhasnotreportedresultsanalyzedinthismanner, itisdifficulttoknowwhetherthecross-protectionrepresentsan activitythatmaybegreaterintheGlaxoSmithKlinevaccine.Itwill beimportantfortheongoinglarge-scaleefficacytrialstoanalyze thisparameter,ascross-protectionagainstHPVtypesnotinthe vaccinecouldenhanceitsoverallutility. Vaccine implementation issues Thenotableefficacyresults(Table1)havethusfarbeencorrelated withanexcellentsafetyprofile,whichmakeitlikelythatoneor bothvaccineswillbelicensedinthenearfuture.Infact,Merck appliedtotheFDAinDecember2005foralicensetoselltheir quadrivalentvaccine.ItisanticipatedthatapplicationforlicensurewillalsocomefromGlaxoSmithKlineiftheirphaseIIItrial resultsaresimilarlypositive. Severalissuesaboutthevaccineremaintobeaddressed.Itwillbe importanttoconfirmthatthestrongsafetyprofileremainsintact asmoreindividualsreceivethevaccine.Asnotedabove,itremains tobedeterminedhowlongthehighleveloftype-specificprotectionismaintained,asthisissuewillhaveimplicationsforwhether andwhenboosterinjectionsmightbeadvisableandwillalsocontributetothecost-effectivenessofthevaccine.Itremainstobeseen whetherthecross-protectionagainstHPVtypesnotinthevaccine, asnotedintheGlaxoSmithKlineproof-of-principletrial,willbe confirmedinthelarge-scaletrialsofthisvaccineandwhetherthe Merckvaccinepossessessimilarproperties.Asubstantialdegree ofcross-protectioncouldincreasethepotentialimpactofthe vaccinebyfurtherreducingtheincidenceofseriousgenitalHPV infectionsandbyreducingthenumberofabnormalPaptestsand thecostoftheirfollow-up.Ontheotherhand,protectionagainst heterologousHPVtypesislikelytowanemorequicklythanthat TheJournalofClinicalInvestigation http://www.jci.org Volume116 Number5 May2006 review series tiveinwomenbutnotinmen,whichraisesthepossibilitythatan analogousdifferencemightbeseenwiththeHPVvaccine(47).As HSVinfectionismorelikelytobemucosalinwomenandcutaneousinmen,itwasspeculatedthatthedifferenceinprotectionfrom theHSVvaccinemightbeattributabletohigherantibodytitersin mucosathaninskin.EvenifthisexplanationisrelevanttoHSV,the highlevelofprotectionoftheMerckvaccineagainstcutaneousgenitalwartsinwomenwouldbeexpectedtoapplytomenaswell,since thesewartsappearoncornifiedskininbothsexes.Itmayalsobe relevantthattheprotectioninducedinwomenbytheHSVvaccine waslessrobustthanthatinducedbytheHPVvaccine(47).Efficacy trialsoftheHPVvaccineinmenwilldirectlyaddressthisissue. Akeyquestionwillbewhomtovaccinate.IntheUnitedStates, themainnationaladvisorycommitteewillbetheAdvisoryCommitteeonImmunizationPracticesattheCentersforDiseaseControlandPrevention.Untiltherearedatathatshowthevaccine isprotectiveinmen,itwouldseemmostlogicaltofocuspublic healtheffortsprimarilyonvaccinatingwomen.Iftheprincipal activityofthevaccineisthepreventionofincidentHPVinfection, thegreatestreductioninthenumberofinfectionswouldlikely resultfromimmunizinggirlsorwomenbeforetheybecomesexuallyactive.IntheUnitedStates,thisconsiderationwouldimply thatpre-oryoungadolescentgirlswouldbeprimecandidatesfor thevaccine.Ofcourse,oldergirlsandwomenwithnopriorsexual exposureshouldalsoachievemaximumbenefitfromthevaccine, whichimpliesthat"catch-up"vaccinationforthesegroupsshould beseriouslyconsidered.Givingthevaccinetowomenwhohave hadsomepriorsexualactivitycouldalsoreducetheirnumber ofinfections,althoughtheirdegreeofbenefitfromthevaccine wouldprobablybeinverselyrelatedtotheirdegreeofpriorsexual activity.Ifthevaccinesareshowntobehighlyeffectiveinmen,it willbelogicaltoincludetheminvaccinationprogramsinhighresourcesettingssuchastheUnitedStates,especiallyiftheMerck vaccineisabletoprotectmenagainstgenitalwarts.Fromapublichealthperspective,however,thedegreetowhichvaccination ofmaleswouldcontributetoherdimmunityisunclear.Insome modelsofsexuallytransmittedinfections,ifahighproportionof onegenderisvaccinatedandthevaccineiseffectiveinpreventing transmission,vaccinatingtheothergenderachievesarelatively Figure 4 Electron micrograph of HPV16 L1 VLPs. Original magnification, 14,500. Image courtesy of Yuk-Ying Susana Pang (Laboratory of Cellular Oncology, National Cancer Institute). againsttheHPVtypesspecificallytargetedbythevaccine,which couldalsohaveimplicationsforboosting. Anotherunansweredquestioniswhethervaccinationmightalter thenaturalhistoryofprevalentHPVinfectionbyreducingtheincidenceofpersistentinfectionorcytologicalabnormalities.Thelarge vaccinetrialsmayhaveasufficientnumberofprevalentinfections attributabletotheHPVtypesinthevaccinetoaddressthisquestion.Ifsucha"therapeuticeffect"wereseen,itcouldprovidean addedrationaletovaccinatesexuallyactivewomenwhomighthave prevalentinfectionwithoneofthetypesinthevaccine.Themost likelyexplanationforsuchaneffectwouldbethatthevaccinehad reducedtheefficiencyoftransmissionofanearlyinfectionfromone genitalsitetoothergenitalsites,presumablyviaspecificantibodies inthegenitaltract(46).Itisalsopossiblethatthevaccinecouldhave directtherapeuticeffectsagainstestablishedlesions.However,this possibilityseemslesslikely,aspersistentinfectionisusuallyattributedtothepresenceoftheviralgenomeinlong-livedbasalepithelialcells,whichdonotexpressL1.Theexperimentalevidencealso doesnotsupportthispossibility:whentheeffectoftheVLPvaccine wastestedonestablishedlesionsinananimalmodel(bovinepapillomavirustype4[BPV-4], whichinducedbenignoral Table 1 mucosallesions),itdidnot induce their regression, Proof-of-principle HPV VLP prophylactic efficacy trials although the vaccine was very effective when given Study Koutskyetal.(32) Harperetal.(35) Villaetal.(33) Maoetal.(34) prophylactically(31). HPV VLP type 16 16, 18 6, 11, 16, 18 16 Although the immune Adjuvant Alum AS04 Alum Alum Sponsor Merck GSK Merck Merck response of men to the Trial site United States United States, United States, United States vaccine is similar to that Canada, Brazil European Union, Brazil ofwomen(41),itisnotyet Subject age 1623 1525 1623 1623 knownwhetherthevaccine No. subjects (ATP) 1,533 721 468 1,505 will be protective in men. Vaccination schedule (mo) 0, 2, 6 0, 1, 6 0, 2, 6 0, 2, 6 Many vaccines have comFollow-up (yr) 1.5 1.5 2.5 3.5 parable efficacy in males Persistent infectionsA 42/0 (100) 7/0 (100) 36/4B (90) 111/7C (94) and females. However, a CIN1+D 9/0 (100) 6/0 (100) 3/0 (100) 24/0 (100) subunitvaccinefortype2 Shown are according-to-protocol (ATP) analyses for the HPV types included in the vaccines. AValues are shown as herpessimplexvirus(HSV number of controls versus number of vaccinees with persistent infections; values in parentheses indicate percent effigDvaccine),anothersexucacy. BTen of 36 controls and 3 of 4 vaccinees were HPV DNA positive only at the last visit. CNineteen of 111 controls allytransmittedviralinfecand 7 of 7 vaccinees were HPV DNA positive only at the last visit. DValues are shown as number of controls versus number of vaccinees that were CIN1+; values in parentheses indicate percent efficacy. GSK, GlaxoSmithKline. tion,wasfoundtobeeffec TheJournalofClinicalInvestigation http://www.jci.org Volume116 Number5 May2006 1171 review series smallincreaseinherdimmunity(48).Inaddition,morethan80% ofcancersattributabletoHPVinfectionoccurinwomen(1).These considerationssuggestthatvaccinationofwomenshouldprobablyhavethehighestpriorityinsettingswithlimitedresources. Anticipated impact of vaccination Theprevioussectionhasnotedseveralimportantunanswered questionsthatmakeitdifficulttopredicttheactualimpactofa vaccineonHPVinfectionanddisease.However,itispossibleto givesomeestimatesifitisassumedthatthevaccinewillprovide atleast90%type-specificefficacy,withboostersasnecessaryto ensurethatthisprotectionisoflongduration.Underthosecircumstances, the greatest short-term impact in industrialized nationssuchastheUnitedStateswouldbeareductioninthe overallnumberofCIN2+casestoaboutone-thirdtoone-halfas manysuchlesionsinvaccinatedwomencomparedwithnonvaccinatedwomen,giventhatHPV16andHPV18togetheraccount for6070%ofsuchlesions.Thisprotectionwouldtranslateto asubstantialreductioninmedicalandpsychologicalmorbidity andtreatmenttogetherwithareductionintherelatedcosts.The anticipatedeventualreductionintheincidenceofcervicalcancers anditsconsequenceswouldbeanticipatedtobeatleastasgreat. Ifthevaccinewerewidelyadministeredtopopulationsthathistoricallyarelesslikelytobescreenedregularly,thevaccinecould preventmostofthoseseriousinfectionsthatcurrentlyarenot detectedbecauseofalackofscreening(49).Theimpactonsubclinicalandlow-gradedysplasiaswouldbeexpectedtobemore modest,asonlyaminorityoftheseinfectionsareattributableto HPV16andHPV18(ortoHPV6/11/16/18,whenconsideringthe quadrivalentMerckvaccineinfection)(50).AlthoughtheseanticipatedreductionsinCIN2+andinvasivecervicalcancerwouldbe impressive,itmustbenotedthattherewouldstillbemanyserious 1.Pisani,P.,Parkin,D.M.,Munoz,N.,andFerlay,J. 1997.Cancerandinfection:estimatesoftheattributablefractionin1990.Cancer Epidemiol. Biomarkers Prev.6:387400. 2.Lowy,D.R.,andHowley,P.H.2001.Papillomaviruses.InFields virology.D.M.KnipeandP.H.Howley,editors.Lippincott,Williams,&Wilkins.Philadelphia,Pennsylvania,USA.22312264. 3.ZurHausen,H.2002.Papillomavirusesandcancer: frombasicstudiestoclinicalapplication.Nat. Rev. Cancer.2:342350. 4.Bosch,F.X.,Schiffman,M.,andSolomon,D.,editors.2003.Futuredirectionsinepidemiologicand preventiveresearchonhumanpapillomaviruses andcancer.J. Natl. Cancer Inst. Monogr.31:131. 5.Frisch,M.2002.Ontheetiologyofanalsquamous carcinoma.Dan. Med. Bull.49:194209. 6.Gillison,M.L.,andShah,K.V.2003.Chapter9:role ofmucosalhumanpapillomavirusinnongenital cancers.J. Natl. Cancer Inst. Monogr.31:5765. 7.Schiffman,M.,andKjaer,S.K.2003.Chapter2: naturalhistoryofanogenitalhumanpapillomavirusinfectionandneoplasia.J. Natl. Cancer Inst. Monogr.31:1419. 8.Gillison,M.L.,andLowy,D.R.2004.Acausalrole forhumanpapillomavirusinheadandneckcancer.Lancet.363:14881489. 9.Szentirmay,Z.,etal.2005.Humanpapillomavirus inheadandneckcancer:molecularbiologyand clinicopathologicalcorrelations.Cancer Metastasis Rev.24:1934. 10.Pfister,H.2003.Chapter8:humanpapillomavirus andskincancer.J. Natl. Cancer Inst. Monogr.31:5256. 11.Yang,B.H.,Bray,F.I.,Parkin,D.M.,Sellors,J.W.,and Zhang,Z.F.2004.Cervicalcancerasapriorityfor 1172 HPVinfectionsagainstwhichthevaccinewouldnotprotect.For thisreason,itwillbeessentialtoeducatehealthcareprovidersand patientsaboutthislimitationofthevaccineandtoemphasizethat itwillbenecessaryforvaccinatedwomentofollowcurrentcervical cancerscreeningguidelines. Whataboutvaccinationindevelopingcountries,where80%of cervicalcancersoccur,butwheremedicalresourcesarerelatively scarce?Thevaccineprobablyhasthepotentialtopreventseveral hundredthousandcancersannually,manyofwhichaffectrelativelyyoungwomenandthereforehaveanenormousimpacton theirlifeexpectancies(11).However,vaccinationinlow-resource settingswouldprobablybecost-effectiveonlyiftheexpenseof vaccinationweremodest,especiallyinviewofthelonginterval betweeninfectionandthedevelopmentofinvasivecancer.The historyofhepatitisBvaccinationsuggeststhatitmaytakemany yearstoachieveacost-effectivevaccinationprogramindeveloping areas(51).Thusreducingthecostofvaccinationwouldbeapriorityforthedevelopingworld.Intheinterim,asubstantialreductionintheincidenceofcervicalcancermightbeachievableinthese settings,inlesstimethanvaccinationwouldleadtoareduction, bythealternatemodalityofalow-costonce-ortwice-in-a-lifetime screen-and-treatapproachtocervicalcancerprevention(52,53). 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