Enhanced Protection against Ebola Virus Mediated by an Improved Adenovirus-Based Vaccine 英文参考文献.docVIP

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Enhanced Protection against Ebola Virus Mediated by an Improved Adenovirus-Based Vaccine 英文参考文献.doc

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Enhanced Protection against Ebola Virus Mediated by an Improved Adenovirus-Based Vaccine 英文参考文献

EnhancedProtectionagainstEbolaVirusMediatedbyan ImprovedAdenovirus-BasedVaccine JasonS.Richardson1.,MichelK.Yao1.,KaylieN.Tran1,2,MariaA.Croyle5,6,JamesE.Strong1,3,4 ,Heinz Feldmann1,3,GaryP.Kobinger1,3 * 1SpecialPathogensProgram,NationalMicrobiologyLaboratory,PublicHealthAgencyofCanada,Winnipeg,Manitoba,Canada,2DepartmentofMicrobiology,University ofManitoba,Winnipeg,Manitoba,Canada,3DepartmentofMedicalMicrobiology,UniversityofManitoba,Winnipeg,Manitoba,Canada,4DepartmentofPediatricsand ChildHealth,UniversityofManitoba,Winnipeg,Manitoba,Canada, 5DivisionofPharmaceutics,CollegeofPharmacy,TheUniversityofTexasatAustin,Austin,Texas, UnitedStatesofAmerica,6InstituteforCellularandMolecularBiology,TheUniversityofTexasatAustin,Austin,Texas,UnitedStatesofAmerica Abstract Background:TheEbolavirusistransmittedbydirectcontactwithbodilyfluidsofinfectedindividuals,elicitingdeathrates ashighas90%amonginfectedhumans.Currently,replicationdefectiveadenovirus-basedEbolavaccineisbeingstudiedin aphaseIclinicaltrial.AnotherEbolavaccine,basedonanattenuatedvesicularstomatitisvirushasshownefficacyinpost- exposure treatment of nonhuman primates to Ebola infection. In this report, we modified the common recombinant adenovirusserotype5-basedEbolavaccineexpressingthewild-typeZEBOVglycoproteinsequencefromaCMVpromoter (Ad-CMVZGP).Theimmuneresponseelicitedbythisimprovedexpressioncassettevector(Ad-CAGoptZGP)anditsabilityto affordprotectionagainstlethalZEBOVchallengeinmicewascomparedtothestandardAd-CMVZGPvector. Methodology/PrincipalFindings:Ad-CMVZGPwaspreviouslyshowntoprotectmice,guineapigsandnonhumanprimates from an otherwise lethal challenge of Zaire ebolavirus. The antigenic expression cassette of this vector was improved through codon optimization, inclusion of a consensus Kozak sequence and reconfiguration of a CAG promoter (Ad- CAGoptZGP). Expression of GP from Ad-CAGoptZGP was substantially higher than from Ad-CMVZGP. Ad-CAGoptZGP significantlyimprovedTandBcellresponsesatdoses10to100-