Human papillomavirus (HPV) vaccine policy and evidence ...€¦ · cervical cancer’ (5). Similarly, the US CDC and the FDA claim that ‘ This [Garda sil] vaccine is an important

1Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave,

Vancouver, BC, V5Z 1L8, Canada and 2Program in Experimental Medicine and the Graduate Program in Neuroscience, University of British

Columbia, Vancouver, BC, Canada

Key messages

Todate,theefficacyofHPVvaccinesinpreventing•cervicalcancerhasnotbeendemonstrated,whilevaccinerisksremaintobefullyevaluated.CurrentworldwideHPVimmunizationpracticeswith•eitherofthetwoHPVvaccinesappeartobeneitherjustifiedbylongtermhealthbenefitsnoreconomicallyviable,noristhereanyevidencethatHPVvaccination(evenifproveneffectiveagainstcervicalcancer)wouldreducetherateofcervicalcancerbeyondwhatPapscreeninghasalreadyachieved.Cumulatively,thelistofseriousadversereactions•relatedtoHPVvaccinationworldwideincludesdeaths,convulsions,paraesthesia,paralysis,Guillain–Barrésyndrome(GBS),transversemyelitis,facialpalsy,chronicfatiguesyndrome,anaphylaxis,autoimmunedisorders,deepveinthrombosis,pulmonaryembolisms,andcervicalcancers.BecausetheHPVvaccinationprogrammehasglobal•coverage,thelongtermhealthofmanywomenmaybeatriskagainststillunknownvaccinebenefits.Physiciansshouldadoptamorerigorousevidencebased•medicineapproach,inordertoprovideabalancedandobjectiveevaluationofvaccinerisksandbenefitstotheirpatients.

All drugs are associated with some risks of adverse reactions. Because vaccines represent a special category of drugs, generally given to healthy individuals, uncertain benefits mean that only a small level of risk for adverse reactions is acceptable. Furthermore, medical ethics demand that vaccination should be carried out with the participant’s full and informed consent. This necessitates an objective disclosure of the known or foreseeable vaccination benefits and risks. The way in which HPV vaccines are often promoted to women indicates that such disclosure is not always given from the basis of the best available knowledge. For example, while the world ’s leading medical authorities state that HPV vaccines are an important cervical cancer prevention tool, clinical trials show no evidence that HPV vaccination can protect against cervical cancer. Similarly, contrary to claims that cervical cancer is the second most common cancer in women worldwide, existing data show that this only applies to developing countries. In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination. Future vaccination policies should adhere more rigorously to evidencebased medicine and ethical guidelines for informed consent.

Key words: Cervarix , cervical cancer, Gardasil, HPV vaccines, informed consent, vaccine adverse reactions

Annals of Medicine, 2011; Early Online, 1–12

© 2011 Informa UK, Ltd.

ISSN 0785-3890 print/ISSN 1365-2060 online

DOI: 10.3109/07853890.2011.645353

REVIEW ARTICLE

Human papillomavirus (HPV) vaccine policy and evidence-based medicine: Are they at odds?

Lucija Tomljenovic 1 & Christopher A. Shaw 1,2

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Introduction

In2002theUSFoodandDrugAdministration(FDA)statedthatvaccines represent a special category of drugs aimed mostly athealthyindividualsandforprophylaxisagainstdiseasestowhichan individualmayneverbeexposed (1).This, according to theFDA,places significant emphasis on vaccine safety (1). In otherwords,contrarytoconventionaldrugtreatmentsaimedatmanagementof existing,oftentimes severeand/oradvanceddiseaseconditions,inpreventativevaccinationacompromiseinefficacyfor the benefit of safety should not be seen as an unreasonableexpectation. Furthermore, physicians are ethically obliged to

provideanaccurateexplanationofvaccinerisksandbenefitstotheirpatientsand,whereapplicable,adescriptionofalternativecoursesoftreatment.Thisinturnenablespatientstomakeafullyinformeddecisionwithregardtovaccination.Forexample,theAustralianguidelines for vaccination emphasize that for a consent to belegallyvalid,thefollowingelementmustbesatisfied:‘it[consent]canonlybegivenaftertherelevantvaccine(s)andtheirpotentialrisksandbenefitshavebeenexplainedtotheindividual’(emphasis added) (2). Likewise, the United Kingdom (UK) guidelinespertainingtovaccinationpracticesstatethatsubjectsmustbegiven

Correspondence: LucijaTomljenovic,NeuralDynamicsResearchGroup,DepartmentofOphthalmologyandVisualSciences,UniversityofBritishColumbia,828W.10thAve,Vancouver,BC,V5Z1L8,Canada.Email:[email protected]

(Received 24 May 2011; accepted 31 October 2011)

2 L. Tomljenovic & C. A. Shaw

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adequateinformationonwhichtobasetheirdecisiononwhetherto accept or refuse a vaccine (3). This includes having a clearexplanationonvaccinerisksandsideeffects(3).

Surprisingly,intheUnitedStates(US),therearenogovernmentalrequirementsforinformedconsentforvaccination(4).Suchanomissionleavesthedooropentoafailuretoobtaininformedconsent. Nonetheless, there are regulatory agencies such as theUSFDAwhichareempoweredtoassurethatonlydemonstrablysafe and effective vaccines reach the market.In addition, healthauthorities (i.e.USCenters forDiseaseControlandPrevention(CDC)) are expected to provide expert advice concerning thebenefitsandrisksrelatedtoparticulardrugs,includingvaccines.Whentheseofficialbodiesarenotable toprovidetheirnormalregulatoryoversightand/oriffinancialintereststakeprecedenceoverpublichealth,significantproblemsintrueinformedconsentguidelinescanoccur.

What is known about the currently licensed human papillomavirus(HPV)vaccines?Whataretheirbenefits,andwhataretheirrisks?Whilemedicalauthoritiesinanumberofcountries,includingtheUS,stronglyadvocatetheiruse,somemembersofthepublichavebecomeincreasinglyscepticalforavarietyofreasons.Thekeyquestionposedbysuchscepticsisthis:IsitpossiblethatHPVvaccineshavebeenpromotedtowomenbasedoninaccurateinformation?Thepresentarticleexaminestheevidenceinordertoanswerthiscriticalquestion.

Can the currently licensed HPV vaccines prevent cervical cancer?

Gardasil’s manufacturer, Merck, states on their website that‘Gardasildoesmorethanhelppreventcervicalcancer,itprotects against other HPV diseases, too.’ Merck further claimsthat‘Gardasildoesnotpreventalltypesofcervicalcancer’(5).Similarly,theUSCDCandtheFDAclaimthat‘This[Gardasil] vaccine is an important cervical cancer prevention toolthatwillpotentiallybenefit thehealthofmillionsofwomen’(6)and‘Basedonalloftheinformationwehavetoday,CDCrecommends HPV vaccination for the prevention of mosttypesofcervicalcancer’(7).AllfourofthesestatementsareatsignificantvariancewiththeavailableevidenceastheyimplythatGardasilcanindeedprotectagainstsometypesofcervicalcancer.

At present there are no significant data showing that eitherGardasilorCervarix(GlaxoSmithKline)canpreventanytypeofcervicalcancersincethetestingperiodemployedwastooshorttoevaluate longtermbenefitsofHPVvaccination.The longestfollowupdatafromphaseIItrialsforGardasilandCervarixare5and8.4years,respectively(8–10),whileinvasivecervicalcancertakesupto20–40yearstodevelopfromthetimeofacquisitionofHPVinfection(10–13).Bothvaccines,however,arehighlyeffectiveinpreventingHPV16/18persistentinfectionsandtheassociatedcervicalintraepithelialneoplasia(CIN)2/3lesionsinyoungwomenwhohadnoHPVinfectionatthetimeoffirstvaccination(13–15). Nonetheless, although cervical cancer may be causedby persistent exposure to 15 out of 100 extant HPVs throughsexual contact (11), even persistent HPV infections caused by‘highrisk’HPVswillusuallynotleadtoimmediateprecursorlesions, letaloneinthelongertermtocervicalcancer.Thereasonforthisisthatasmuchas90%HPVinfectionsresolvespontaneouslywithin2yearsand,ofthosethatdonotresolve,onlyasmallproportion may progress to cancer over the subsequent 20–40years (10,11,16–18). Moreover, research data show that evenhigher degrees of atypia (such as CIN 2/3) can either resolveor stabilize over time (19). Thus, in the absence of longterm

followupdata, it is impossible toknowwhetherHPVvaccinescan indeed prevent some cervical cancers or merely postponethem.Inaddition,neitherofthetwovaccinesisabletoclearexistingHPV16/18infections,norcantheypreventtheirprogressiontoCIN2/3lesions(20,21).AccordingtotheFDA,‘Itisbelieved that prevention of cervical precancerous lesions is highly likely to result in the prevention of those cancers’ (emphasis added)(22).ItwouldthusappearthateventheFDAacknowledgesthatthe longtermbenefitsofHPVvaccinationrestonassumptionsratherthansolidresearchdata.

Gardasil and Cervarix: do the benefits of vaccination outweigh the risks?

Currently,governmentalhealthagenciesworldwidestatethatHPV vaccines are ‘safe and effective’ and that the benefitsof HPV vaccination outweigh the risks (6,23,24). Moreover,the US CDC maintains that Gardasil is ‘an important cervicalcancerpreventiontool’andtherefore ‘recommendsHPVvaccinationforthepreventionofmosttypesofcervicalcancer’ (6,7). However, the rationale behind these statements isunclear given that the primary claim that HPV vaccinationprevents cervical cancer remainsunproven.Furthermore, inthe US, the current agestandardized death rate from cervical cancer according to World Health Organization (WHO)data (1.7/100,000) (Table I), is2.5 times lower than the rateof serious adverse reactions (ADRs) from Gardasil reportedto the Vaccine Adverse Event Reporting System (VAERS)(4.3/100,000dosesdistributed)(TableII).IntheNetherlands,thereportedrateofseriousADRsfromCervarixper100,000doses administered (5.7) (Table II) is nearly 4fold higherthan the agestandardized death rate from cervical cancer(1.5/100,000)(TableI).

Although it may not be entirely appropriate to comparedeaths alone from cervical cancer to serious ADRs from HPVvaccines, it should be reemphasized that (in accordance withFDA guidelines) the margin of tolerance for serious ADRs fora vaccine with uncertain benefits needs to be very narrow, especiallywhensuchvaccineisadministeredtootherwisehealthyindividuals (1).HPV vaccination, even if proven effective asclaimed,istargeting9–12yearoldgirlstopreventapproximately70%ofcervicalcancers,someofwhichmaycausedeathatarateof1.4–2.3/100,000womenindevelopedcountrieswitheffectivePap smear screening programmes (Table I). For a vaccine designedtopreventadiseasewithsuchalowdeathrate,theriskto those vaccinated should be minimal. Further, according tosomeestimates,HPVvaccinationwoulddolittletodecreasethealreadylowrateofcervicalcancerincountrieswithregularPapscreening (10).Thus, anyexpectedbenefit fromHPVvaccination will notably drop in the setting of routine Pap screening.Accordingly, the risktobenefit balance associated with HPVvaccinationwillthenalsobecomelessfavourable.Ontheotherhand, indevelopingcountrieswherecervicalcancerdeathsaremuchhigherandPapscreeningcoveragelow(TableI),thepotentialbenefitsofHPVvaccinationaresignificantlyhamperedbyhighvaccinecosts(25).

It shouldbenoted that foranyvaccine thenumberofdosesthat are eventually administered is lower than the number ofdosesthataredistributed.Thus,calculationsbasedonthelattertendtounderestimatetherateofvaccineassociatedADRs(Figure 1). Supporting this interpretation, we show in Table II andFigure1thatforanyofthetwoHPVvaccines,thereportedrateofADRsper100,000dosesadministeredisverysimilaracrossdifferentcountriesandapproximatelyseventimeshigherthanthat

HPV vaccines and evidence-based medicine 3

TableI.Keydataoncervicalcancer,HPV16/18prevalence,andcervicalcancerpreventionstrategiesin22countries.DatasourcedfromtheWorldHealthOrganization(WHO)/InstitutCatalad’Oncologia(ICO)InformationCentreonHPVandcervicalcancer(105).

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HPV16/18prevalencein

Incidenceper Mortalityper Mortalityranking womenwithlow/100,000women 100,000women amongallcancers highgradelesions/ HPVvaccine

Country (agestandardized) (agestandardized) (allages) Papscreeningcoverage(%) cervicalcancer(%) introduced

Australia

Netherlands

US

France

Canada

Spain

UKandIreland

Israel

Germany

China

VietNam

Russia

Brazil

Thailand

4.9

5.4

5.7

7.1

6.6

6.3

7.2

5.6

6.9

9.6

11.5

13.3

24.5

24.5

1.4

1.5

1.7

1.8

1.9

1.9

2

2.1

2.3

4.2

5.7

5.9

10.9

12.8

17th

16th

15th

15th

14th

15th

16th

14th

13th

7th

4th

7th

2nd

2nd

60.6(Allwomenaged20–69yscreenedevery2y)

59.0(Allwomenaged> 20yscreenedevery5y)

83.3(Allwomenaged> 18yscreenedevery3y)

74.9(Allwomenaged20–69yscreenedevery2y

72.8(Allwomenaged18–69yscreenedevery3y;Annualifat

highrisk)75.6(Allwomenaged18–65y

screenedevery3y80(Allwomenaged25–64y

screenedevery5y)34.7(Allwomenaged18–69y

screenedevery3y)55.9(Womenaged20–49y






everscreened

3.8/44.6/76.2

1.5/61.6/87.9

7.7/55/76.6

7.6/63.4/75.6

11.8/56.2/74.3

2.3/46.9/55.9

2.4/61.9/79.1

2.2/44.8/68.5

1.4/54.1/76.8

2.3/45.7/71

2.1/33.3/72.6

9.3/56/74

4.3/54/70.7

4.1/33.3/73.8

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Pakistan

SouthAfrica

India

CambodiaNepal

NigeriaGhana

Uganda

19.5

26.6

27

27.432.4

3339.5

47.5

12.9

14.5

15.2

16.217.6

22.927.6

34.9

2nd

2nd

1st

1st1st

2nd1st

1st


13.6(Allwomenaged18–69yscreenedevery3y


None2.4(Allwomenaged18–69y

screenedevery3yNone


None

6/59.3/96.7

3.6/58.4/62.8

6/56/82.5

3.2/33.3/72.66/59.3/82.3

4.7/41.3/504.6/41.3/50

6.7/37.9/74.1

Yes

Yes

Yes

YesNo

YesYes

Yes

calculatedfromthenumberofdistributeddoses.Thelattercalcu Accordingtosomeestimates,only1–10%oftheADRsintheUSlationsalsoshowacomparablerangeacrossseveralcountries(Fig arereportedtoVAERS(27).ure1).Giventhatgovernmentofficialvaccinesurveillancepro ThelackofdataonseriousADRsincountrieswhereroutinegrammesroutinelyrelyonpassivereporting(26),therateofADRs HPVvaccinationforyoungwomenisrecommendedandstronglyfromHPVandothervaccinesmaybe furtherunderestimated. promoted(TableII)greatlyhampersourunderstandingaboutthe

TableII.Summaryofadversereactions(ADRs)fromHPVvaccinesGardasilandCervarix.NotethattheUSFDACodeofFederalRegulationdefinesaseriousadversedrugeventas‘anyadversedrugexperienceoccurringatanydosethatresultsinanyofthefollowingoutcomes:death,alifethreateningadversedrugexperience,inpatienthospitalizationorprolongationofexistinghospitalization,apersistentorsignificantdisability/incapacity,oracongenitalanomaly/birthdefect’(106).

Total n

Vaccine Country Totaln ADRs(ref.) Dosesn(ref.)ADRs/100,000

dosesTotal n serious

ADRs(ref.)Total n serious

ADRs/100,000doses

Gardasil

Cervarix

USFranceAustraliaIrelandNetherlandsUK

18,727(7)1,700(34)1,534(39)

314(33)575(32)

8,798(23)

35,000,000a(7)4,000,000a(34)6,000,000a (39)

90,000b(33)192,000b(32)

3,500,000b(23)

544326

349299251

1,498(7)na

91c(26,28,29)na

575(32)na

4.3–1.5c

–5.7–

na= notavailable.aDosesdistributed.bDosesadministered.cExcluding2010data(unavailableatthetimeofwritingofthisreport).


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Figure1.Therateofadversereactions(ADRs)fromGardasilandCervarixreported through various governmentofficial vaccine surveillanceprogrammes.Forthedatasource,seeTableII.

overallsafetyofthevariousHPVvaccinationprogrammes.Nonetheless, analysis of the UK Medicines and Healthcare productsRegulatoryAgency(MHRA)vaccinesafetydatashowsthattheremay be valid reasons for concern. For example, the total numberofADRsreported forCervarixappears tobe24–104 timeshigher than that reported for any of the other vaccines in theUKimmunizationschedule(Figure2).

Official reports on adverse events following immunization(AEFI) inAustralia also raise concerns (26). In2008,Australiareported an annual AEFI rate of 7.3/100,000, the highest since2003, representing an 85% increase compared with AEFI ratefrom2006(26).This increasewasalmostentirelyduetoAEFIsreportedfollowingthecommencementofthenationalHPVvaccinationprogrammeforfemalesaged12–26yearsinApril2007(705 out of a total of 1538 AEFI records). Thus, nearly 50% ofallAEFIsreportedduring2007wererelatedtotheHPVvaccine.Moreover, HPV vaccine was the only suspected vaccine in 674(96%) records, 203 (29%) had causality ratings of ‘certain’ or‘probable’,and43(6%)weredefinedas‘serious’.ThemostsevereAEFIsreportedfollowingHPVvaccinationwereanaphylaxisandconvulsions.Notably,in2007,10outof13reportedanaphylaxis(77%) and 18 out of 35 convulsions (51%) occurred in womenfollowingHPVvaccination(26).During2008,theHPVvaccine

wasstillthenumberonevaccineonthelistofAEFIsinAustralia,with497records(32%ofallAEFIs),andaccountablefornearly30%ofconvulsions(13outof43)(28).During2009,theAustralianreportedAEFIrateforadolescentsdecreasedbyalmost50%(from10.4 to5.6/100,000) (29).Thisdecline inAEFI rateswasattributedtoareductioninthenumbersofHPVvaccinerelatedreports, following cessation of the catchup component of theHPV programme(29). Namely, the percentage of AEFIs relatedto HPV vaccines was only 6.4 in 2009 (29) compared to 50 in2007(26).InspiteoftheoverallsignificantdecreaseinAEFIrate,the percentage of convulsions attributable to the HPV vaccineremainedcomparablebetween2007and2009(51%(26)and40%(29),respectively).

Cumulatively,thelistofseriousADRsrelatedtoHPVvaccinationintheUS,UK,Australia,Netherlands,France,andIrelandincludes deaths, convulsions, syncope, paraesthesia, paralysis,Guillain–Barrésyndrome(GBS),transversemyelitis,facialpalsy,chronic fatigue syndrome, anaphylaxis, autoimmune disorders,deep vein thrombosis, pulmonary embolisms, and pancreatitis(23,24,26,28–35).

Itmaybethusappropriatetoaskwhetheritisworthriskingdeathoradisabling lifelongneurodegenerativeconditionsuchasGBSatapreadolescentageforavaccinethathasonlyatheoreticalpotentialtopreventcervicalcancer,adiseasethatmaydevelop20–40yearsafterexposuretoHPV,when,asHarpernoted,thesamecanbepreventedwithregularPapscreening(36)?

Itisalsoofnotethatinthepostlicensureperiod(2006–2011),theUSVAERSreceived360reportsofabnormalPapsmears,112reports of cervical cancer dysplasia, and 11 reports of cervicalcancersrelatedtoHPVvaccines(35).InareporttotheFDA(37),Merckexpressedtwo‘importantconcerns’regardingadministration of Gardasil to girls with preexisting HPV16/18 infection.One was ‘the potential of Gardasil to enhance cervical disease’,andtheother‘wastheobservationsofCIN2/3orworsecasesduetoHPVtypesnotcontainedinthevaccine’.AccordingtoMerck,‘Thesecasesofdiseasedue tootherHPVtypeshave thepotentialtocountertheefficacyresultsofGardasil fortheHPVtypescontainedinthevaccine.’Table17inMerck’sreporttotheFDAshows that Gardasil had an observed efficacy rate of –44.6% insubjectswhowerealreadyexposedto ‘relevantHPVtypes’(37).If,asimpliedbyMerck’sownsubmission,Gardasilmayexacerbate

Figure2.Therateofadversereactions(ADRs)fromCervarixcomparedtothatofothervaccinesintheUKimmunizationschedule.DatasourcedfromthereportprovidedbytheUKMedicinesandHealthcareproductsRegulatoryAgency(MHRA)fortheJointCommitteeonVaccinationandImmunisationinJune2010(23).


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the very disease it is supposed to prevent, why do the US FDAand the CDC allow for preadolescent girls and young womento be vaccinated with Gardasil without prescreening them forHPV16/18infections?

Side-effects from HPV vaccines: are they a minor concern?

Accordingtogovernmentalhealthagenciesworldwide,includingtheUSCDC,HealthCanada,theAustralianTherapeuticGoodsAdministration(TGA),theUKMHRA,andtheIrishMedicinesBoard(IMB), thevastmajorityofadversereactionsfromeitherGardasilorCervarixarenonserious(6,23,24,38,39).Thesesourcesfurtherstatethatmostparticipantsreportbriefsorenessattheinjectionsite,headache,nausea,fever,andfainting(6,23,24,38,39).Moreover,theUKMHRAandtheUSFDAandtheCDCmaintain that fainting is common with vaccines (especially amongadolescents)andhencenotareasonforconcern(6,23).Specifically,theUKMHRAstatesthat‘“Psychogenicevents”includingvasovagal syncope, faints and panic attacks can occur with anyinjectionprocedure’andthat‘sucheventscanbeassociatedwithawiderangeoftemporarysignsandsymptomsincludinglossofconsciousness, vision disturbances, injury, limb jerking (oftenmisinterpreted as a seizure/convulsion), limb numbness or tingling,difficultyinbreathing,hyperventilationetc.’(23).

TheVAERSdata show that since2006when itwasfirst approved,Gardasilhasbeenassociatedwith18,727adversereactionsintheUSalone,8%ofwhichwereserious(1498)including68deaths(TableII).AreporttoanypassivevaccinesurveillancesystemdoesnotbyitselfprovethatthevaccinecausedanADR.

Systematic,prospective,controlledtrialsareneededtoestablishorrejectcausalrelationshipswithregardtodrugrelatedadversereactionsofanytype.Nevertheless,theunusuallyhighfrequencyofreportsofADRsrelatedtoHPVvaccines(Figure2),aswellastheirconsistentpattern(i.e.withonlyminordeviations,nervoussystemrelateddisordersrankthehighestinfrequencyacrossdifferentcountries,followedbygeneral/administrationsiteconditionsandgastrointestinaldisorders)(Figure3),indicatesthattherisksofHPVvaccinationmaynothavebeenfullyevaluatedinclinicaltrials.Indeed,intheiranalysisofADRsofpotentialautoimmuneaetiologyinalargeintegratedsafetydatabaseofASO4adjuvantedvaccines(anoveladjuvantsystemcomposedof3Odesacyl4monophosphoryllipidAandaluminumsaltsusedinCervarix),Verstraetenetal.(40)acknowledgethat‘Itisimportanttonotethatnoneofthesestudiesweresetupprimarilytostudyautoimmunedisorders.’IfthepurposeofthestudywasindeedtoassessADRsof‘potentialautoimmuneaetiology’,asthetitleitselfclearlystates(40),thenthestudyshouldhavebeendesignedtodetect them. All of the eight authors of the ASO4 safety studyareemployeesofGlaxoSmithKline(GSK), themanufacturerofCervarix(40).Theseauthorsnotedthat‘oursearchoftheliteraturefoundnostudiesconductedbyindependentsourcesonthissubject’and‘AllstudiesincludedinthisanalysiswerefundedbyGSKBiologicals,aswastheanalysisitself.GSKBiologicalswasinvolvedinthestudydesign,datacollection,interpretationandanalysis,preparationofthemanuscriptanddecisiontopublish’(40).

Giventhatvaccinescantriggerautoimmunedisorders(41–44),a more rigorous safety assessment than that provided by theGSKsponsoredstudywouldappeartohavebeenwarranted.

Figure3.PercentagesofreportedADRsassociatedwithHPVvaccinesforeachsystemorganclass.DatasourcedfromtheDatabaseoftheNetherlandsPharmacovigilanceCentreLareb(32),theUKMedicinesandHealthcareproductsRegulatoryAgency(MHRA)(62),andtheIrishMedicinesBoard(IMB)(24).ThemostcommonlyreportedADRsinthenervoussystemandpsychiatricdisordersclasswereheadache,syncope,convulsions,dizziness,hypoaesthesia,paraesthesia,lethargy,migraine,tremors,somnolence,lossofconsciousness,dysarthria,epilepsy,sensorydisturbances,facialpalsy,grandmalconvulsion,dysstasia,dyskinesia,hallucination,andinsomnia.


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Meanwhile, independent scientific reports have linkedHPV vaccination with serious ADRs, including death (45,46),amyotrophic lateral sclerosis (ALS) (45), acute disseminatedencephalomyelitis (ADEM) (47–49), multiple sclerosis (MS)(50–52),opsoclonusmyoclonussyndrome(OMS)(whichischaracterized by ocular ataxia and myoclonic jerks of the extremities)(53), orthostatic hypotension (54), brachial neuritis (55),visionloss(56),pancreatitis(57),anaphylaxis(58),andposturaltachycardiasyndrome(POTS)(59).

ADEMandMSareseriousdemyelinatingdiseasesofthecentralnervoussystemthattypicallyfollowafebrileinfectionor vaccination(49,50,60).Bothdisordersarealsothoughttobetriggeredbyanautoimmunemechanism(50).Clinicalsymptomsincluderapidonset encephalopathy,multifocalneurologicdeficits,demyelinatinglesions,opticneuritis,seizures,spinalconditions,andvariablealterationsofconsciousnessormentalstatus(47,49,60).RegardingPOTS,thereportedcasehadnootherrelevantfactorsoreventsprecedingthesymptomsonsetapartfromGardasilvaccination(59).POTSisdefinedasthedevelopmentoforthostaticintolerance(61).According to Blitshteyn, ‘It is probable that some patients whodevelopPOTSafterimmunizationwithGardasilorothervaccinesare simply undiagnosed or misdiagnosed, which leads to underreporting and a paucity of data on the incidence of POTS aftervaccinationinliterature’(59).PatientswithPOTStypicallypresentwithcomplaintsofdiminishedconcentration,tremulousness,dizzinessandrecurrentfainting,exerciseintolerance,fatigue,nauseaandlossofappetite(59,61).Suchsymptomsmaybeincorrectlylabelledaspanicdisordersorchronicanxiety.Notably,symptomsofPOTSappeartobeamongthemostfrequentADRsreportedaftervaccinationwithHPVvaccines(6,23,24,39).Inspiteofthis,healthauthoritiesworldwidedonotregardtheseoutcomesascausallyrelatedtothevaccine(6),butratheras‘psychogenicevents’(23,39).

In summary, it appears that many medical authorities mayhave been too quick to dismiss a possible link between HPVvaccinesandseriousADRsbyrelyingheavilyondataprovidedby the vaccine manufacturers rather than from independentresearch.TheUKMHRAstates that ‘Thevastmajorityof suspected ADRs reported to MHRA in association with Cervarixvaccinecontinuetoberelatedtoeitherthesignsandsymptomsof recognized side effects listed in the product information ortotheinjectionprocessandnotthevaccineitself(i.e.“psychogenic”innaturesuchasfaints)’(23).ItisinterestingtonotethattheentiregroupofsystemclassdisordersshowninFigure3 isregarded as unrelated to the HPV vaccine by the MHRA. AccordingtotheAgency,‘ThesesuspectedADRsarenotcurrentlyrecognisedassideeffectsofCervarixvaccineandtheavailableevidencedoesnotsuggestacausallinkwiththevaccine.Th eseare isolated medical events which may have been coincidentalwithvaccination’(23,62).However,thefactthatasimilarpatternofsystemclassADRstothatintheUKhasalsobeenobservedinatleasttwoothercountriesarguesagainsttheMHRAconclusionandsuggeststheopposite,namelyacausalrelationshipwiththeHPVvaccine(Figure3).

Safety assessment of HPV vaccines in clinical trials: was it adequate?

Adoubleblinded,placebocontrolledtrialisconsideredthe‘goldstandard’forclinicaltrialsasitisthoughttopreventpotentialresearchers’biasesfromdistortingtheconductofatrialand/ortheinterpretationoftheresults(63).Biases,however,maystilloccurdue to selective publication of findings from within such trials,subject selection factors (inclusion/exclusion criteria), as well asplacebochoices.Withregardtothelatter,accordingtotheFDA,aplacebois‘aninactivepill,liquid,orpowderthathasnotreatmentvalue’(63).Itisthereforesurprisingthustonotethatnoregulationsgovernplacebocomposition,giventhatcertainplaceboscaninfluencetrialoutcomes(64).Specifically,placebocompositioncan,inprinciple,bemanipulatedtoproduceresultsthatarefavourabletothedrugeitherintermsofsafetyorefficacy(64).

TheclinicaltrialsforGardasilandCervarixusedanaluminumcontaining placebo (15,20,40,65–69). Both HPV vaccines, likemanyothervaccines,areadjuvantedwithaluminuminspiteofwell documented evidence that aluminum can be highly neurotoxic (70–72). Moreover, current research strongly implicatesaluminum adjuvants in various neurological and autoimmunedisordersinbothhumansandanimals(41,73–80).Itisthusbecomingincreasinglyclearthattheroutineuseofaluminumasaplaceboinvaccinetrialsisnotappropriate(80,81).

Notably, safety data for Gardasil presented in Merck’s packageinsertandtheFDAproductapprovalinformation(82)showthatcomparedtothesalineplacebo,thosewomenreceivingthealuminumcontainingplaceboreportedapproximately2–5timesmore injectionsite ADRs. On the other end, the proportion ofinjectionsiteADRsreportedintheGardasiltreatmentgroupwascomparable to thatof thealuminum‘control’group(Table III).Thus,Merck’sowndataseemtoindicatethatalargeproportionofADRsfromtheHPVvaccinewereduetotheeffectofthealuminumadjuvant.

For the assessment of serious conditions, the manufacturerpooledtheresultsfromthestudyparticipantswhoreceivedthesalineplacebowiththosewhoreceivedthealuminumcontainingplaceboandpresentedthemasone‘control’group.Theoutcomeof thisprocedurewas thatGardasiland thealuminum ‘control’group had exactly the same rate of serious conditions (2.3%)(TableIV).

InarecentmetaanalysisofsafetyandefficacyofHPVvaccines,seventrialsenrollingatotalof44,142femaleswereevaluated(83).Twomainpopulationsofwomenweredefinedinthesetrials:thosewho received three doses of the HPV vaccine or the aluminumcontainingplacebowithinayear(denotedastheperprotocolpopulation(PPP)),andthosewhoreceivedat leastoneinjectionofthevaccine or the placebo within the same period (intentiontotreatpopulation (ITT)). While HPV vaccine efficacy was evaluated inbothPPPandITTcohorts,vaccinesafetywasprimarilyevaluatedintheITTcohort(83).AlthoughITTanalysis is ‘conservative’ forassessment of treatment benefits (since dropouts may occur), it is‘anticonservative’forassessmentofADRs,becauseADRswilloccur

Table III. Injectionsite adverse reactions (ADRs) reported in Gardasil clinical trials among 8878 female participants aged 9–26 years, 1–5 dayspostvaccination(82).

Aluminum(AAHS)a SalineplaceboADRtype Gardasil(n =5088)% (n =3470)% (n =320)% Gardasil/saline Gardasil/AAHS AAHS/saline

Pain 83.9 75.4 48.6 1.7 1.1 1.6Swelling 25.4 15.8 7.3 3.5 1.6 2.2Erythema 24.7 18.4 12.1 2.0 1.3 1.5Pruritus 3.2 2.8 0.6 3.5 1.1 4.7Bruising 2.8 3.2 1.6 1.8 0.9 2.0aAAHSControl= amorphousaluminumhydroxyphosphatesulfate.


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Table IV. Number of girls and women aged 9–26 years who reported acondition potentially indicative of a systemic autoimmune disorder afterenrolmentinGardasilclinicaltrials(82).

Aluminum(AAHS)Gardasil(n =10,706) a(n =9412)

Condition n(%) n(%)

Arthralgia/arthritis/arthropathy 120(1.1) 98(1.0)Autoimmunethyroiditis 4(0.0) 1(0.0)Coeliacdisease 10(0.1) 6(0.1)Insulindependent 2(0.0) 4(0.0)Diabetesmelitusinsulindependent 2(0.0) 2(0.0)Erythemanodosum 27(0.3) 21(0.2)Hyperthyroidism 35(0.3) 38(0.4)Hypothyroidism 7(0.1) 10(0.1)Inflammatoryboweldisease 2(0.0) 4(0.0)Multiplesclerosis 2(0.0) 5(0.1)Nephritis 2(0.0) 0(0.0)Opticneuritis 4(0.0) 3(0.0)Pigmentationdisorder 13(0.1) 15(0.2)Psoriasis 3(0.0) 4(0.0)Raynaud’sphenomenon 6(0.1) 2(0.0)Rheumatoidarthritis 2(0.0) 1(0.0)Scleroderma/morphea 1(0.0) 0(0.0)Stevens–Johnsonsyndrome 1(0.0) 3(0.0)Sytemiclupuserythematosus 3(0.0) 1(0.0)Uveitis 3(0.0) 1(0.0)Total 245(2.3) 218(2.3)

lessfrequentlyiffewerdosesofthevaccineareadministered.Th us,suchaselectionproceduremayexplainwhythemetaanalysisfoundtherisktobenefitratiotobeinfavouroftheHPVvaccines(83).

Theseventrialsincludedinthemetaanalysiswereallsponsoredbythevaccinemanufacturers(14,15,20,65–69).InalengthyreportofpotentialconflictsofinterestsoftheFUTUREIItrialstudygroup(15),themajorityofauthorsdeclared‘receivinglecturefeesfromMerck,SanofiPasteur,andMerckSharp&Dohme’.Inaddition,‘IndianaUniversityandMerckhaveaconfidentialagreementthatpaystheuniversityonthebasisofcertainlandmarksregardingtheHPVvaccine.’Inthe2009JAMAeditorial(11),Haugnotedthat‘Whenweighingevidenceaboutrisksandbenefits,itisalsoappropriatetoaskwhotakestherisk,andwhogetsthebenefit.Patientsandthepubliclogicallyexpectthatonlymedicalandscientificevidenceisputonthebalance.Ifothermattersweighin,suchasprofitforacompanyorfinancialorprofessionalgainsforphysiciansorgroupsofphysicians,thebalanceiseasilyskewed.Thebalancewillalsotiltiftheadverseeventsarenotcalculatedcorrectly.’

Are there safe and effective alternatives to HPV vaccination?

Although approximately 275,000 women die annually fromcervicalcancerworldwide,almost88%ofthesedeathsoccurindevelopingcountries. Suchdisproportionof cancerdeathsmaybesurprisinggiventhattheprevalenceofHPV16/18inwomenwithcervicalcancer isequal inbothdevelopinganddevelopedcountries(71.0%and70.8%,respectively)(TableV).Furthermore,HPV16andHPV18arethemostoncogenicofallHPVsubtypesand increasingly dominant with increasing severity of cervicalcancerlesions(TableI)(84).Nonetheless,analysisofWHOdatain Figure 4 shows that HPV16/18 prevalence in women withhighgrade lesionsaswellascervicalcancer isnota significantpromoterofhighcervicalcancermortality indevelopingcountries (P = 0.07–0.19), but rather it is the lack of or insufficientPapscreeningcoverage(P < 0.0001).Thesedatadonotdisputethat HPV16/18 infection is a primary prerequisite for cervicalcancer.However, theydopoint toothercofactorsasnecessarydeterminantsofbothdiseaseprogressionandoutcome(85).

TheefficacyofregularPapscreeningproceduresindevelopedcountriesisfurtheremphasizedbythefactthatsuchprogrammeshelped to achieve a 70% reduction in the incidence of cervicalcancer over the last five decades (10,12,86,87). Conversely, inFinland,whenwomenstoppedattendingPapscreens,a4foldincreaseincervicalcanceroccurredwithin5yearsfromscreeningcessation(88,89).

ItshouldbeemphasizedthatHPVvaccinationdoesnotmakePapscreeningobsolete,especiallysincethecurrentHPVvaccinesguardonlyagainst2outof15oncogenicHPVstrains.HarpernotedthatifHPVvaccinatedwomenstoppedgoingforPapsmears,the incidence rate of cervical cancer would increase (36,86). AsimilarconcernwasalsoraisedbyFrenchandCanadianresearcherswhosuggestedthepossibilitythatvaccinatedwomenmightbelessinclinedtoparticipateinscreeningprogrammes(87,90).Suchoutcomeswouldinturncompromisetimelyspecialistreferralofcasesharbouringprecancerouslesions,especiallythoserelatedtoHPVgenotypesotherthan16/18(90).

Are HPV vaccines cost-eff ective?

ThecurrentlylicensedHPVvaccinesareamongthemostexpensivevaccinesonthemarket(i.e.GardasilcurrentlycostsUS$400forthethreerequireddoses)(87),makingitunlikelythatthosecountries with the heaviest burden of cervical cancer mortality (i.e. Uganda, Nigeria, and Ghana) would ever benefit fromthem.ThatisundertheassumptionthatthelongtermbenefitsfromHPVvaccination(i.e.cancerprevention)wereproven.Forexample, preadolescent HPV vaccination in Thailand is costeffectiveonlywhenassuming lifelongefficacyandacostof10international dollars (I$, a currency that provides a means oftranslatingandcomparingcostsamongcountries)pervaccinatedgirl(approximatelyI$2/dose)orless(91).ThecosteffectivenessanalysisofHPVvaccinationforEasternAfricashowsasimilaroutcome(25).Incountrieswherepricingislessofanissue,suchas theUS,HPVvaccination isonlycosteffectivebasedon theassumption of complete and lifelong vaccine efficacy and 75%coverageofthetargetedpreadolescentpopulation(92,93).IntheNetherlands,HPVvaccinationisnotcosteffectiveundersimilarassumptions(e.g.thattheHPVvaccineprovideslifelongprotectionagainst70%ofallcervicalcancers,hasnosideeffects,andisadministeredtoallwomenregardlessoftheirriskofcervicalcancer)(94).Notethatthereasonwhyhighcoverageisneededfor a vaccine to be costeffective in the developed countrysetting is the very low incidence of cervical cancer (due to effectivenessofPapscreeningprogrammes).Forexample,topreventasingleoutof5.7/100,000cervicalcancercases (oroneoutof1.7/100,000cervicalcancerdeaths) intheUS,nearlyeverygirlwouldneedtobevaccinatedfortheHPVvaccineprogrammetobecosteffective.

The increased pressure to make the HPV vaccines mandatory forallpreadolescentgirlsmakes thecostof theHPVvaccinationprogrammeasignificant issue.Forexample,accordingtoa2006report in The New York Times (95), tomakeGardasilmandatorywouldprobablydoublethecostoftheUSvaccinationprogramme: ‘North Carolina, for instance, spends $11 millionannuallytoprovideeverychildwithsevenvaccines.Gardasilalonewouldprobablycostatleastanother$10million.’UndertheassumptionthattheHPVvaccineoffersfullprotectionagainstHPVinfectionfor5years,an11yearoldgirlwouldneed13boostershotsifsheweretolivetotheageof75.AtacurrentcostofUS$120perdose,thetotalcostforvaccinatingonegirlwouldthusexceedUS$1500.Accordingtosomeestimates,tovaccinateevery11and12yearoldgirlintheUSwouldcostUS$1.5billionandto


TableV.Keycervicalcancerstatisticsaccordingtothe2010WorldHealthOrganization(WHO)/InstitutCatalad’Oncologia(ICO)reportonHPVandrelatedcancers(107).

WorldDevelopingcountries

(%total)Developedcountries

(%total)

Womenatriskforcervicalcancer(aged�15y)AnnualnumberofnewcasesofcervicalcancerAnnualnumberofcervicalcancerdeathsPrevalence(%)ofHPV16and/orHPV18amongwomenwithcervicalcancer

2,336,986

529,828275,128

70.9

1,811,867(77.5)

453,321(85.6)241,969(87.9)

71.0

525,120(22.5)

76,507(14.4)33,159(12.1)

70.8

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protectonlythesegirlsforalifetimewouldcostUS$7.7billion(96). If we were to estimate just the cost of initial vaccinationexcludingtheboostershotsfor11and12yearoldgirls,intenyearstheUSwouldspendatleast15billionoflimitedhealthcaredollarsonGardasilalone(96).WhothenreapsthebenefitatnoriskfrommakingtheHPVvaccinemandatory?Thecustomerorthemanufacturer?

AltogethertheaboveobservationsdonotsupporttheclaimmadebytheUSCDCandtheFDA,thatis,‘This[Gardasil]vaccine is an important cervical cancer prevention tool that willpotentiallybenefitthehealthofmillionsofwomen’(6)and,instead,appeartosuggest thatcurrentworldwide immunizationcampaigns (Table I) with either of the two HPV vaccines areneitherjustifiedbylongtermhealthbenefitsnoreconomicallyviable.

How does HPV vaccine marketing and promotion line up with international ethical guidelines for informed consent?

The medical profession’s ethical duty is to provide a full andaccurateexplanationofthebenefitsaswellastherisksassociated

withaparticulardrugsothatapatientisabletomakeaninformeddecisionregardingatreatment.Ifaphysicianfailstodosoand/oriffinancial interests takeprecedenceoverpublichealth,breachesofinformedconsentguidelinesmayoccur.Forinstance,presentinginformationinawaywhichpromotesfearofadiseasewhileundervaluingpotentialvaccinerisksislikelytoencouragepatientstogiveconsenttothetreatment,evenwhenthelatterhasnoprovensignificanthealthbenefit.

Both Gardasil and Cervarix were approved by the US FDA,whichin2006wasfoundtobe‘...notpositionedtomeetcurrentoremergingregulatoryresponsibilities’,because‘itsscientificbasehaserodedanditsscientificorganizationalstructureisweak’(97).AccordingtotheScienceandMissionatRiskReportpreparedbytheFDAScienceBoardin2006(97),therisksofan‘underperforming’FDAarefarreachingfortwomainreasons.First,‘TheFDA’s inability to keep up with scientific advances means thatAmerican livesareat risk’, and second,‘ Theworld looks to theFDAasaleaderinmedicineandscience.Notonlycantheagencynotlead,itcan’tevenkeepupwiththeadvancesinscience’(97).

If the FDA’s decisions to approve certain drugs could by itsown admission be unreliable, then the only other gatekeeperforconsumersafetyistheexpertadviceprovidedbyotherhealth

Figure4.CorrelationbetweencervicalcancermortalityratesandA:Paptestscreeningcoverage;B:HPV16/18prevalenceinwomenwithhighgradelesions(CIN2/3,carcinoma in situ (CIS),andhighgradecervicalsquamous intraepithelial lesions(HSIL));C:HPV16/18prevalence inwomenwithcervicalcancer.Dataweresourcedfor22countriesfromWorldHealthOrganization(WHO)/InstitutCatalad’Oncologia(ICO)InformationCentreonHPVandcervicalcancer(TableI).ThecorrelationanalysiswascarriedoutusingGraphPadPrismstatisticalsoftwaretoderivePearsoncorrelationcoefficients(r).Thelevelofsignificancewasdeterminedusingatwotailedtest.ThecorrelationwasconsideredstatisticallysignificantatP <0.05.


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authorities. The history of how HPV vaccines came to market,however, indicates that such advice was not always given fromthebasisofthebestavailableevidence.A2009SpecialCommunication from JAMA by Rothman and Rothman (98) providescompelling evidence that Gardasil manufacturer Merck fundededucational programmes by professional medical associations(PMAs)asamarketingstrategytopromotetheuseoftheirvaccine.Themarketingcampaignproceeded‘flawlessly’,accordingtoMerck’schiefexecutiveofficer,andin2006Gardasilwasnamedthepharmaceutical ‘brandoftheyear’ forbuilding‘amarketoutofthinair’(98).ThereasonwhythemarketingcampaignforGardasilwassosuccessfulwasthat‘Bymakingthisvaccine’stargetdiseasecervicalcancer,thesexualtransmissionofHPVwasminimized,the threat of cervical cancer to all adolescents maximized, andthesubpopulationsmostatrisk[womenindevelopingcountries]practicallyignored’(98).ThattheseargumentsweredeliveredbythePMAsiscauseforconcern,sincePMAsareobligatedtoprovidememberswithevidencebaseddatasothattheyinturnareabletopresentrelevantrisksandbenefitstotheirpatients(98).

India’smedicalauthoritieshavealsobeenpubliclycondemnedafteracivilsocietyledinvestigationrevealedthattrialsforHPVvaccines in the states of Andhra Pradesh and Gujarat violatedestablishednationalandinternationalethicalguidelinesonclinicalresearchaswellaschildren’srights(99).Theseeventsapparentlyoccurredasaresultof‘aggressive’promotionalpracticesofthedrugcompaniesandtheiruncriticalendorsementbyIndia’smedicalassociations(99).Althoughproclaimedasapostlicensure observational study of HPV vaccination against cervicalcancer,theprojectwasinfactaclinicaltrialand,assuch,shouldhaveadheredtoprotocolsmandatedbytheDrugsandCosmeticsAct(DCA)andtheIndianCouncilforMedicalResearch(ICMR)(100).Instead,thetrialwasfoundinseriousbreachofboththeDCA’sandtheICMR’sguidelinesforinformedconsentandwasterminated in April 2010, following six postHPV vaccinationdeaths (99). The report in the 2011 issue of Lancet Infectious DiseasesfurtherrevealsthatbothICMRandDCAsubsequentlydenied information on the study protocols as a ‘trade secretand commercial confidence of third party’ (100). According tothe authors, ‘It remains unclear how information from a studydoneincollaborationwithgovernmenthealthorganisationscanberegardedasatradesecret’(100).ItisworthemphasizingthattheterminationofHPVvaccinetrialsinIndiaoccurreddespiteanannualcervicalcancermortalityrateof15.2/100,000women,whichisover7–10timesgreaterthanthatinthedevelopedworld(TableI).Suchanoutcomeindicatesthatevensituationsofunmetmedicalneedscannotberesolvedattheexpenseofabandoningethicalrequirementsforinformedconsent.

QuestionableHPVvaccinemarketingstrategieswerealsoseeninFranceandwereeventuallystoppedbytheactionofgovernment health authorities who found the sponsorship of severalGardasiladvertisementstobeindirectviolationofFrenchpublichealthcodes(101).Theseviolationsincluded,butwerenotlimitedto:1)Claiminglongerefficacythanwasactuallyproven(8.5versus4.5years)and2)Makingfalseclaims(theadsinquestionreplacedtheofficiallyapproveduseofGardasilfor‘thepreventionoflowgradelesions’withstatementsindicatingGardasilshouldbe used for ‘the prevention of premalignant genital lesions,cancersofthecervixandexternalgenitalwarts’).

IntheUS,Merckhasbeenheavilycriticizedforthefactthatit spentvast sums in lobbying tomake thevaccinemandatory(12,98). According to an editorial from The American Journal of Bioethics,eventhosewhostronglyfavouredthevaccinewere‘stunnedatthedegreetowhichMerckhaspushedits$400vaccineasamandatorymeasure’(102).Nonetheless,what ismore

disconcertingthantheaggressivemarketingstrategiesemployedbythevaccinemanufacturersisthepracticebywhichthemedical profession has presented partial information to the public,namely,inawaythatgeneratesfear,thuslikelypromotingvaccineuptake.Forexample, theUSCDCandtheFDAstate that‘Worldwide,cervicalcanceristhesecondmostcommoncancerinwomen,causinganestimated470,000newcasesand233,000deaths per year’ (6). The Telethon Institute for Child HealthResearch in Australia made a similar statement in 2006 whilerecruiting volunteers for a HPV vaccine study. In the openingparagraphthepointwasalsomadethatcervicalcancerwasoneofthemostcommoncausesofcancerrelateddeathsinwomenworldwide (103). A crucial fact was omitted in both instanceswhichisthatwhileitiscertainlytruethatapproximatelyaquarterofamillionofwomendieofcervicalcancereachyear,88%ofthesedeathsoccurinthedevelopingcountriesandcertainlynotintheUSnorAustralia(TableV),wherecervicalcanceristhe15thand17thcauseof cancerrelateddeaths, respectively,and where mortality rates from this disease are the lowest onthe planet (1.4–1.7/100,000) (Table I). Finally, contrary to theinformationprovidedbytheCDCandtheFDA,thereisnoevidencethatGardasilis‘animportantcervicalcancerpreventiontool’(6).

Itthusappearsthattothisdate,medicalandregulatoryentitiesworldwidecontinuetoprovideinaccurateinformationregardingcervicalcancerriskandtheusefulnessofHPVvaccines,therebymaking informed consent regarding vaccination impossible toachieve.

Concluding remarks

Regulatory authorities are responsible for ensuring that newvaccinesgothroughproperscientificevaluationbeforetheyareapproved.Anequalfiduciaryresponsibilityrestswiththemedicalprofessiontoonlypromotevaccinationswiththosevaccineswhose safety and efficacy have been thoroughly demonstrated.Theavailableevidence,however,indicatesthathealthauthoritiesinvariouscountriesmayhavefailedtoprovideanevidencebasedrationaleforimmunizationwithHPVvaccinesand,indoingso,mayhavebreachedinternationalethicalguidelinesforinformedconsent.ContrarytotheinformationfromtheUSCDC,HealthCanada, Australian TGA, and the UK MHRA, the efficacy ofGardasilandCervarixinpreventingcervicalcancerhasnotbeendemonstrated,andthelongtermrisksofthevaccinesremaintobefullyevaluated.

CurrentworldwideHPVimmunizationpracticeswitheitherofthetwoHPVvaccinesappeartobeneitherjustifiedbylongterm health benefits nor economically viable, nor is there anyevidencethatHPVvaccinationwouldreducetherateofcervicalcancerbeyondwhatPapscreeninghasalreadyachieved.Furthermore, the frequency, the severity, as well as the consistency ofthepatternsofADRsreportedtovariousgovernmentalvaccinesurveillanceprogrammesforbothGardasilandCervarix(Figures2and3)raisesignificantconcernsabouttheoverallsafetyofHPVvaccinationprogrammes.Becausetheseprogrammeshaveglobalcoverage(TableI),thelongtermhealthofmanywomenmaybeunnecessarilyatriskagainststillunknownvaccinebenefits.Altogethertheseobservationssuggestthatareductionintheburdenof cervical cancer globally might be best achieved by targetingotherriskfactorsforthisdisease(i.e.smoking,useoforalcontraceptives,chronicinflammation)(85)inconjunctionwithregularPap test screening. The latter strategy has already been provensuccessful indevelopednationswhere the incidenceofcervicalcancerisverylow(TableI).


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According to the Helsinki Declaration and the InternationalCode of Medical Ethics (104), the wellbeing of the individualmust be a physician’s top priority, taking precedence over allotherinterests.AlthoughtheDeclarationisaddressedprimarilyto physicians, the World Medical Association encourages otherparticipants in medical research involving human subjects toadoptthesesameprinciples(104).Greatereffortsshouldthusbemadetominimizetheunduecommercialinfluencesonacademicinstitutionsandmedical research,given that thesemay impedeunbiased scientific inquiry into important questions aboutvaccinescienceandpolicy.

Thealmostexclusiverelianceonmanufacturers’sponsoredstudies,oftenofquestionablequality,asabaseforvaccinepolicymakingshouldbediscontinued.SoshouldbethedismissalofseriousADRsas coincidental or ‘psychogenic’ in spite of independent researchsuggestingotherwise. Itcanhardlybedisputed inviewofall theevidence(i.e.casereportsandvaccineADRsurveillanceinvariouscountries)thatHPVvaccinesdotriggerseriousADRs.Whatdoesremain debatable, however, is the true frequency of these eventsbecauseallsystemsofmonitoringforvaccineADRscurrentlyinplacerelyonpassivereporting.PassiveADRsurveillanceshouldthusbereplacedbyactivesurveillancetobetterourunderstandingoftruerisksassociatedwithparticularvaccines(especiallynewvaccines).ThepresentationofpartialandnonfactualinformationregardingcervicalcancerrisksandtheusefulnessofHPVvaccines,ascitedabove, is, inourview,neitherscientificnorethical.Noneofthesepracticesservepublichealthinterests,noraretheylikelytoreducethelevelsofcervicalcancer.IndependentevaluationofHPVvaccinesafetyisurgentlyneededandshouldbeapriorityforgovernmentsponsored research programmes. Any future vaccination policiesshouldadheremorerigorouslytoevidencebasedmedicineaswellasstrictlyfollowethicalguidelinesforinformedconsent.

Declaration of interest: ThisworkwassupportedbytheDwoskin, Lotus and Katlyn Fox Family Foundations. L.T. and C.A.S.conductedahistologicalanalysisofautopsybrainsamplesfromaGardasilsuspecteddeathcase.C.A.S. isa founderandshareholderofNeurodynCorporation,Inc.Thecompanyinvestigatesearlystate neurological disease mechanisms and biomarkers.Thisworkandanyviewsexpressedwithin itaresolely thoseoftheauthorsandnotofanyaffiliatedbodiesororganizations.

AportionofthisinformationwaspresentedattheVaccineSafetyConference,3–8January2011(www.vaccinesafetyconference.com).

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Documents

Human papillomavirus (HPV) vaccine policy and evidence ...€¦ · cervical cancer’ (5). Similarly, the US CDC and the FDA claim that ‘ This [Garda sil] vaccine is an important