Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever 英文参考文献.docVIP

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Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever 英文参考文献.doc

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Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever 英文参考文献

Pre-ClinicalEfficacyandSafetyofExperimentalVaccines BasedonNon-ReplicatingVacciniaVectorsagainst YellowFever BirgitScha¨fer1,GeorgW.Holzer1,AlexandraJoachimsthaler1,SogueCoulibaly2 ,Michael Schwendinger3,BrianA.Crowe3,ThomasR.Kreil4,P.NoelBarrett4,FalkoG.Falkner1* 1DepartmentofVirology,BaxterBioscience,BiomedicalResearchCenter,Orth/Donau,Austria,2DepartmentofAnimalHousing,BaxterBioscience,BiomedicalResearch Center,Orth/Donau,Austria,3DepartmentofImmunology,BaxterBioscience,BiomedicalResearchCenter,Orth/Donau,Austria,4GlobalRDVaccines,BaxterBioscience, BiomedicalResearchCenter,Orth/Donau,Austria Abstract Background: Currentlyexisting yellow fever(YF)vaccines arebased on theliveattenuatedyellow fevervirus 17Dstrain (YFV-17D).Although,agoodsafetyprofilewashistoricallyattributedtothe17Dvaccine,seriousadverseeventshavebeen reported,makingthedevelopmentofasafer,moremodernvaccinedesirable. Methodology/Principal Findings: Ageneencoding theprecursor of themembrane andenvelope(prME) proteinof the YFV-17D strain was inserted into the non-replicating modified vaccinia virus Ankara and into the D4R-defective vaccinia virus.Candidatevaccinesbasedontherecombinantvacciniaviruseswereassessedforimmunogenicityandprotectionina mouse model and compared to the commercial YFV-17D vaccine. The recombinant live vaccines induced c-interferon- secreting CD4- and functionally active CD8-T cells, and conferred full protection against lethal challenge already after a single low immunization dose of 105 TCID50. Surprisingly, pre-existing immunity against wild-type vaccinia virus did not negativelyinfluenceprotection.Unliketheclassical17Dvaccine,thevacciniavirus-basedvaccinesdidnotcausemortality followingintracerebraladministrationinmice,demonstratingbettersafetyprofiles. Conclusions/Significance:Thenon-replicatingrecombinantYFcandidatelivevaccinesinducedabroadimmuneresponse aftersingledoseadministration,wereeffectiveeveninthepresenceofapre-existingimmunityagainstvacciniavirusand demonstrateda