UpdateonmalariavaccineMarkR.Withers,M.D.,MPH,Director,WRPKombewaClinicDrWalterOtieno

MBChB,M.Med(Paeds),PhD

WalterReedProject-CentreforClinicalResearchKenyaMedicalResearchInstituteUpdateonmalariavaccineMark22WRP-Kisumu22WRP-Kisumu3WRP-Kisumu:4maincampuses

KisumuHQ(“Kondele”)

AdministrationBasicscience:ELISA,PCR,flowcyt,RDTsNewNyanzaProvincialGeneralHospital(PGH,Russian)Children’sHospital:65bedfacilityWard8:dedicatedin-outpatientclinicalresearchcenter“CenterofExcellence”formalariamicroscopy

KEMRI“CenterforGlobalHealth”(Kisiantown)

Entomologymalariaculturelab(monitorsdrugresistancepatterns)KombewaClinicalResearchCenterDedicatedunitforlargeclinicaltrials3WRP-Kisumu:4maincampusesWhyismalariasoimportant?Severediseaseburden300-500millioncases575000CM(19%mortality)1.42–5.66millionAnemia(13%mortality)1.12–1.99millionRDS(18%mortality)

InKombewa62%ofadmissionsinchildrenduetomalariaWhyismalariasoimportant?SMalariaVaccineDevelopment

OngoingforP.falciparum&P.vivaxTheoreticalConcepts:PregnantwomenprotectnewbornsLivinginendemicareasdevelopimmunityMalariavaccinestargetthelifecycle:Pre-erythrocyticstage

(sporozoite/hepatic)Erythrocytic(asexual)stageSexualstage(transmissionblocking)MalariaVaccineDevelopment

OTARGETSOFMALARIAVACCINESPre-erythrocytic -Preventinfection -ReducediseaseBlood-stage -PreventdiseaseTransmissionblocking -PreventtransmissionTARGETSOFMALARIAVACCINESPrHepatitis-b-disease-and-prevention：乙型肝炎疾病預防Hepatitis-b-disease-and-prevention：乙型肝炎疾病預防RTS,SProgramHistoryRTS,SProgramHistoryCircumsporozoiteproteinMostabundantproteincoveringentiresporozoitesurfaceAlsoexpressedbymalarialiverstagesStructureofCSprotein:OfallmalariaspecieshasacentraldomainwithseveralaminoacidrepetitionsAminoacidsequencethatcomposeseachrepetitioniscompletelydifferentforeachplasmodiumspeciesCircumsporozoiteproteinMostaCircumsporozoiteproteinStructureofCSprotein:P.falciparumCSproteinhaslimitedvariabilitythereforeidealforvaccinesP.vivaxisolatesdisplayenormousvariation-thereforenotidealformalariavaccinesAminoacidrepetitionstargetsforantibodiesN-&C-terminalscontainepitopesrecognizedbyCD4&CD8TcellsTcellsspecificforepitopesofCSproteinconferprotectiveimmunityagainstliverstagesCircumsporozoiteproteinStrucRTS,SMalariaVaccineDevelopment

Pre-erythrocyticstagevaccine

Compositionofvaccineantigen:SequenceofcircumsporozoiteproteinHepatitisBsurfaceantigen(HBsAg)Adjuvants:ASO2&ASO1

HBsAgisencodedwithhepatitisBvirusSproteingene,thereforeprotectsagainsthepatitisB.RTS,SMalariaVaccineDevelopmRTS,SMalariaVaccineDevelopment…

Goal:develop80%efficaciousvaccineby2025with≥4yearprotection

Characteristicsofanidealvaccine:

SafeEffectiveAffordableEasytodeliver(EPIdeliverysystem)WillnotinterferewithotherEPIvaccinesRTS,SMalariaVaccineDevelopmDEVELOPMENTOFTHERTS,SMALARIAVACCINESPOROZOITESTAGEOFMALARIAPARASITEDEVELOPMENTOFTHERTS,SMALARDEVELOPMENTOFRTS,SMALARIAVACCINER(REPEAT)+S(HEP-B)+T(T-CELL)R

TSSSPOROZOITEHEP-BVIRUSDEVELOPMENTOFRTS,SMALARIAVSTRUCTUREOFTHECIRCUMSPOROZOITEPROTEIN(CSP)CENTRALREPEATREGIONN-TERMINALC-TERMINALT-CELLEPITOPESSTRUCTUREOFTHECIRCUMSPOROZODEVELOPMENTOFRTS,SMALARIAVACCINESPOROZOITES–ARECOATEDWITHASURFACEPROTEIN–CIRCUMSPOROZOITEPROTEIN(CSP)

ASEGMENTOFTHECIRCUMSPOROZOITEPROTEIN

CONTAININGREPEAT(R)ANDT-CELLEPITOPES(T)ISFUSEDTOHEPATITISBSURFACEANTIGEN(S)TOPRODUCEFUSIONPROTEIN,RTS

RTSISCOMBINEDWITHASECONDUNFUSEDHEPATITISBSEGMENT(S)TOFORMASTABLERTS,SANTIGEN

DEVELOPMENTOFRTS,SMALARIAVRESULTSOFRTS,SMALARIAVACCINETRIALSManytrialshaveshownthatRTS,SmalariavaccineissafeandimmunogenicRTS,SefficacytrialinMozambique–enrolled2022childrenaged1-4years50%protectionagainstseveremalariaandsevereanemiaat42monthspostvaccinationRESULTSOFRTS,SMALARIAVACCIRESULTSOFRTS,SMALARIAVACCINETRIALSManytrialshaveshownthatRTS,SmalariavaccineissafeandstimulatestheimmunesystemRTS,SefficacytrialinMozambique–enrolled2022childrenaged1-4years50%protectionagainstseveremalariaandsevereanemiaMalariacauses1millionchildhooddeathsperyearinAfricaIfthisvaccinecouldreducebyhalfthecasesofseveredisease,wewouldbesavingthousandsoflivesRESULTSOFRTS,SMALARIAVACCIHepatitis-b-disease-and-prevention：乙型肝炎疾病預防MAINOBJECTIVESToinvestigateefficacyagainstclinicaldiseaseinchildren5-17monthsofageandInfants6-12weeksofagewhoreceivethevaccineco-administeredwithEPIvaccinesMAINOBJECTIVESToinvestigateONGOINGRTS,SVACCINETRIALAmulti-center,PhaseIIItrialofthecandidatemalariavaccineRTS,SThetrialhasbeendesignedtoaddresskeysafetyandefficacyinformationrequiredbeforeavaccinecanbelicensedAcross11sitesinAfricawithdifferentlevelsofmalariatransmission;Kenya,Tanzania,Mozambique,Gabon,Ghana,BurkinaFasoONGOINGRTS,SVACCINETRIALAHowdoesRTS,Swork?