Hepatitisbdiseaseandprevention：乙型肝炎疾病预防.ppt

Updateonmalariavaccine MarkR Withers M D MPH Director WRPKombewaClinic DrWalterOtienoMBChB M Med Paeds PhDWalterReedProject CentreforClinicalResearchKenyaMedicalResearchInstitute 2 2 WRP Kisumu 3 WRP Kisumu 4maincampuses KisumuHQ Kondele AdministrationBasicscience ELISA PCR flowcyt RDTsNewNyanzaProvincialGeneralHospital PGH Russian Children sHospital 65bedfacilityWard8 dedicatedin outpatientclinicalresearchcenter CenterofExcellence formalariamicroscopyKEMRI CenterforGlobalHealth Kisiantown Entomologymalariaculturelab monitorsdrugresistancepatterns KombewaClinicalResearchCenterDedicatedunitforlargeclinicaltrials Whyismalariasoimportant Severediseaseburden 300 500millioncases575000CM 19 mortality 1 42 5 66millionAnemia 13 mortality 1 12 1 99millionRDS 18 mortality InKombewa62 ofadmissionsinchildrenduetomalaria MalariaVaccineDevelopment OngoingforP falciparum P vivaxTheoreticalConcepts PregnantwomenprotectnewbornsLivinginendemicareasdevelopimmunityMalariavaccinestargetthelifecycle Pre erythrocyticstage sporozoite hepatic Erythrocytic asexual stageSexualstage transmissionblocking TARGETSOFMALARIAVACCINES Pre erythrocytic Preventinfection ReducediseaseBlood stage PreventdiseaseTransmissionblocking Preventtransmission RTS SProgramHistory Circumsporozoiteprotein MostabundantproteincoveringentiresporozoitesurfaceAlsoexpressedbymalarialiverstagesStructureofCSprotein OfallmalariaspecieshasacentraldomainwithseveralaminoacidrepetitionsAminoacidsequencethatcomposeseachrepetitioniscompletelydifferentforeachplasmodiumspecies Circumsporozoiteprotein StructureofCSprotein P falciparumCSproteinhaslimitedvariabilitythereforeidealforvaccinesP vivaxisolatesdisplayenormousvariation thereforenotidealformalariavaccinesAminoacidrepetitionstargetsforantibodiesN C terminalscontainepitopesrecognizedbyCD4 CD8TcellsTcellsspecificforepitopesofCSproteinconferprotectiveimmunityagainstliverstages RTS SMalariaVaccineDevelopment Pre erythrocyticstagevaccineCompositionofvaccineantigen SequenceofcircumsporozoiteproteinHepatitisBsurfaceantigen HBsAg Adjuvants ASO2 ASO1HBsAgisencodedwithhepatitisBvirusSproteingene thereforeprotectsagainsthepatitisB RTS SMalariaVaccineDevelopment Goal develop80 efficaciousvaccineby2025with 4yearprotectionCharacteristicsofanidealvaccine SafeEffectiveAffordableEasytodeliver EPIdeliverysystem WillnotinterferewithotherEPIvaccines DEVELOPMENTOFTHERTS SMALARIAVACCINE SPOROZOITESTAGEOFMALARIAPARASITE DEVELOPMENTOFRTS SMALARIAVACCINE R REPEAT S HEP B T T CELL R T S S SPOROZOITE HEP BVIRUS STRUCTUREOFTHECIRCUMSPOROZOITEPROTEIN CSP CENTRALREPEATREGION N TERMINAL C TERMINAL T CELLEPITOPES DEVELOPMENTOFRTS SMALARIAVACCINE SPOROZOITES ARECOATEDWITHASURFACEPROTEIN CIRCUMSPOROZOITEPROTEIN CSP ASEGMENTOFTHECIRCUMSPOROZOITEPROTEINCONTAININGREPEAT R ANDT CELLEPITOPES T ISFUSEDTOHEPATITISBSURFACEANTIGEN S TOPRODUCEFUSIONPROTEIN RTS RTSISCOMBINEDWITHASECONDUNFUSEDHEPATITISBSEGMENT S TOFORMASTABLERTS SANTIGEN RESULTSOFRTS SMALARIAVACCINETRIALS ManytrialshaveshownthatRTS SmalariavaccineissafeandimmunogenicRTS SefficacytrialinMozambique enrolled2022childrenaged1 4years50 protectionagainstseveremalariaandsevereanemiaat42monthspostvaccination RESULTSOFRTS SMALARIAVACCINETRIALS ManytrialshaveshownthatRTS SmalariavaccineissafeandstimulatestheimmunesystemRTS SefficacytrialinMozambique enrolled2022childrenaged1 4years50 protectionagainstseveremalariaandsevereanemiaMalariacauses1millionchildhooddeathsperyearinAfricaIfthisvaccinecouldreducebyhalfthecasesofseveredisease wewouldbesavingthousandsoflives MAINOBJECTIVES Toinvestigateefficacyagainstclinicaldiseaseinchildren5 17monthsofageandInfants6 12weeksofagewhoreceivethevaccineco administeredwithEPIvaccines ONGOINGRTS SVACCINETRIAL Amulti center PhaseIIItrialofthecandidatemalariavaccineRTS SThetrialhasbeendesignedtoaddresskeysafetyandefficacyinformationrequiredbeforeavaccinecanbelicensedAcross11sitesinAfricawithdifferentlevelsofmalariatransmission Kenya Tanzania Mozambique Gabon Ghana BurkinaFaso HowdoesRTS Swork RTS