WHO对HPV疫苗的指导原则

WHO/BS/06.2050-FinalENGLISHONLYEXPERTCOMMITTEEONBIOLOGICALSTANDARDIZATIONGeneva,23to27October2006GUIDELINESTOASSURETHEQUALITY,SAFETYANDEFFICACYOFRECOMBINANTHUMANPAPILLOMAVIRUSVIRUS-LIKEPARTICLEVACCINES©WorldHealthOrganization2006Allrightsreserved.PublicationsoftheWorldHealthOrganizationcanbeobtainedfromWHOPress,WorldHealthOrganization,20AvenueAppia,1211Geneva27,Switzerland(tel.:[phone];fax:[phone];e-mail:[e-mail]).RequestsforpermissiontoreproduceortranslateWHOpublications–whetherforsaleorfornoncommercialdistribution–shouldbeaddressedtoWHOPress,attheaboveaddress(fax:[phone];e-mail:[e-mail]).ThedesignationsemployedandthepresentationofthematerialinthispublicationdonotimplytheexpressionofanyopinionwhatsoeveronthepartoftheWorldHealthOrganizationconcerningthelegalstatusofanycountry,territory,cityorareaorofitsauthorities,orconcerningthedelimitationofitsfrontiersorboundaries.Dottedlinesonmapsrepresentapproximateborderlinesforwhichtheremaynotyetbefullagreement.Thementionofspecificcompaniesorofcertainmanufacturers’productsdoesnotimplythattheyareendorsedorrecommendedbytheWorldHealthOrganizationinpreferencetoothersofasimilarnaturethatarenotmentioned.Errorsandomissionsexcepted,thenamesofproprietaryproductsaredistinguishedbyinitialcapitalletters.AllreasonableprecautionshavebeentakenbytheWorldHealthOrganizationtoverifytheinformationcontainedinthispublication.However,thepublishedmaterialisbeingdistributedwithoutwarrantyofanykind,eitherexpressedorimplied.Theresponsibilityfortheinterpretationanduseofthemateriallieswiththereader.InnoeventshalltheWorldHealthOrganizationbeliablefordamagesarisingfromitsuse.Thenamedauthors[editors]aloneareresponsiblefortheviewsexpressedinthispublication.Adoptedbythe57thmeetingoftheWHOExpertCommitteeonBiologicalStandardization,23-27October2006.Adefinitiveversionofthisdocument,whichwilldifferfromthisversionineditorialbutnotscientificdetails,willbepublishedintheWHOTechnicalReportSeries.WHO/BS/06.2050-FinPage2IntroductionGeneralconsiderationsSpecialconsiderationsPartA.GuidelinesonmanufacturingA.1DefinitionsA.2GeneralmanufacturingrecommendationsA.3ControlofsourcematerialsA.4ControlofHPVantigenvaccineproductionA.5ControlofpurifiedmonovalentantigenbulkA.6AdsorbedmonovalentantigenbulkA.7FinalvaccinebulkA.8FillingandcontainersA.9ControltestsonfinalvaccinelotA.10RecordsA.11RetainedsamplesA.12LabellingA.13DistributionandtransportA.14Stabilitytesting,storageandexpirydatePartB.NonclinicalevaluationofrecombinantHPVVLPvaccinesB.1PharmacologicalstudiesB.2SafetyPharmacologystudiesB.3ToxicologystudiesPartC.ClinicalevaluationofrecombinantHPVVLPvaccinesC.1ImmuneresponsestothevaccineC.2StudiesofprotectiveefficacyC.3BridgingefficacybymeansofimmunogenicitydataC.4VaccinesafetyC.5Post-marketingstudiesandsurveillancePartD.GuidelinesfornationalregulatoryauthoritiesD.1GeneralD.2ReleaseandcertificationAuthorsAcknowledgementsReferencesAppendix1Modelsummaryprotocolformanufacturingandcontrolofrecombinanthumanpapillomavirusvirus-likeparticlevaccineAppendix2Modelcertificateforthereleaseofrecombinanthumanpapillomavirusvirus-likeparticlevaccineWHO/BS/06.2050-FinPage3IntroductionWHOconvenedtwomeetingsinGeneva,23-24Marchand28-30August,2006,wherescientificexperts,regulatoryprofessionalsandotherstakeholdersmettodevelopguidelinesforprophylactichumanpapillomavirus(HPV)vaccines.Thisdocumentisintendedtoprovidebackgroundandguidancetonationalregulatoryauthorities(NRAs)andvaccinemanufacturersontheproduction,qualitycontrolandevaluationofthesafetyandefficacyofrecombinantHPVvirus-likeparticle(VLP)vaccines.ThisdocumentsetsouttheguidanceonproductmanufactureandqualityassessmentinpartA.Inaddition,guidancespecifictothenonclinicalandclinicalevaluationofrecombinantHPVvaccinesisprovidedinPartBandPartC,respectively.ThisdocumentshouldbereadinconjunctionwithallrelevantWHOguidelinesincludingthoseonnonclinical(1)andclinicalevaluation(2)ofvaccines.Thefollowingtextiswrittenintheformofguidelinesinsteadofrecommendations.Guidelinesallowgreaterflexibilitythanrecommendationswithrespecttoexpectedfuturedevelopmentsinthefield.Thisguidanceisbasedontheexperienceoftheproductsdevelopedsofar,asdescribedbelow,andmayneedtobeupdatedinviewoffuturedevelopments.GeneralconsiderationsHPVisasmall,non-envelopeddeoxyribonucleicacid(DNA)virus.Thecircular,double-strandedviralgenomeisapproximately8-kbinlength.Thegenomeencodesfor6earlyproteinsresponsibleforvirusreplicationand2lateproteins,L1andL2,whicharetheviralstructuralproteins.L1isthemajorstructuralprotein.L1proteinsassociatetoformpentamericstructurescalledcapsomers.Maturevirusparticlesarecomprisedof72capsomersarrangedinicosahedralsymmetry.Theminorcapsidprotein,L2,ispresentinasmanyas72moleculespermaturevirusparticle.L2isnotrequiredforparticleformation.HPVinfection,replicationandparticlematurationoccursinthestratifiedsquamousepitheliaofskinandmucousmembranes,withvirusspreadoccurringbyskin-to-skincontact.Over100differenttypesofHPVhavebeenidentifiedandmolecularlycharacterized.TheseHPVscauseavarietyofd