expreswww.gegeshe.com

REVIEWARTICLEpublished:22August2014doi:10.
3389/fmicb.
2014.
00439TheinuenceofdeliveryvectorsonHIVvaccineefcacyBeatriceO.
Ondondo*NufeldDepartmentofMedicine,TheJennerInstitute,UniversityofOxford,Oxford,UKEditedby:ShuoLi,TheUniversityofMelbourne,AustraliaReviewedby:AndrewLucas,MurdochUniversity,AustraliaCodyCharlesAllison,WalterandElizaHallInstitute,Australia*Correspondence:BeatriceO.
Ondondo,NufeldDepartmentofMedicine,TheJennerInstitute,UniversityofOxford,ORCRB,RooseveltDrive,Oxford,OX37DQ,UKe-mail:beatrice.
ondondo@ndm.
ox.
ac.
ukDevelopmentofaneffectiveHIV/AIDSvaccineremainsabigchallenge,largelyduetotheenormousHIVdiversitywhichpropelsimmuneescape.
ThusnovelvaccinestrategiesaretargetingmultiplevariantsofconservedantibodyandTcellepitopicregionswhichwouldincurahugetnesscosttothevirusintheeventofmutationalescape.
Besidesimmunogendesign,thedeliverymodalityiscriticalforvaccinepotencyandefcacy,andshouldbecarefullyselectedinordertonotonlymaximizetransgeneexpression,buttoalsoenhancetheimmuno-stimulatorypotentialtoactivateinnateandadaptiveimmunesystems.
Todate,veHIVvaccinecandidateshavebeenevaluatedforefcacyandprotectionfromacquisitionwasonlyachievedinasmallproportionofvaccineesintheRV144studywhichusedacanarypoxvectorfordelivery.
Conversely,intheSTEPstudy(HVTN502)wherehumanadenovirusserotype5(Ad5)wasused,strongimmuneresponseswereinducedbutvaccinationwasmoreassociatedwithincreasedriskofHIVacquisitionthanprotectioninvaccineeswithpre-existingAd5immunity.
Thepossibilitythatpre-existingimmunitytoahighlypromisingdeliveryvectormayalterthenaturalcourseofHIVtoincreaseacquisitionriskisquiteworrisomeandahugesetbackforHIVvaccinedevelopment.
Thus,HIVvaccinedevelopmenteffortsarenowgearedtowarddeliveryplatformswhichattainsuperiorimmunogenicitywhileconcurrentlylimitingpotentialcatastrophiceffectslikelytoarisefrompre-existingimmunityorvector-relatedimmuno-modulation.
However,itstillremainsunclearwhetheritispoorimmunogenicityofHIVantigensorsubstandardimmunologicalpotencyofthesaferdeliveryvectorsthathaslimitedthesuccessofHIVvaccines.
ThisarticlediscussessomeofthepromisingdeliveryvectorstobeharnessedforimprovedHIVvaccineefcacy.
Keywords:HIV-1,vaccines,deliveryvectors,MVA,NYVAC,adenovirus,ALVAC,DNAINTRODUCTIONThirtyyearsafterthediscoveryofHIV/AIDS,thesearchforasafeandeffectivevaccinehasintensied,asanumberofpromis-ingcandidatevaccinesprogressingtophaseIIb/IIIclinicaltrialshavefailedtoshowefcacy.
OneofthegreatestbarrierstoHIVvaccinedevelopmentistheenormousviriondiversity(depictedbytheexistenceofnumerouscladesandsubtypesindistinctgeographicdemarcations)andthecontinuousevolutionwhichgeneratesnumerousquasi-specieswithinaninfectedindividual(Hemelaaretal.
,2011).
Thisnotonlymakesitchallengingtocreateimmunogenswhichareeffectivelymatchedtothecirculat-ingtargetviruses,butalsoprovidesroomforimmuneescapeofHIVfrompotentvaccine-inducedimmuneresponses.
Therefore,ithasemergedthatimmunogensderivedfromthemostcon-servedregionsofHIVandcoveringmultiplevariants(conservedmosaics)standoutasthemostsuitablecandidatesforT-cellbasedvaccines,whileimmunogenscoveringthemostpotentandbroadlyneutralizingandnon-neutralizingantibodyepitopesarebetterforantibody-basedvaccines(EminiandKoff,2004;RobinsonandAmara,2005;McMichael,2006;Letourneauetal.
,2007;ThornerandBarouch,2007;Sekaly,2008;Korberetal.
,2009;Barouchetal.
,2010;Santraetal.
,2010;Borthwicketal.
,2014).
However,thedevelopmentofavaccinebasedonconservedantibodyepitopestoprovideprotectiveglobalcoverageandtominimizeimmuneescapeishamperedbyinaccessibilityofthehighlyshieldedconservedenvelopedomains.
Furthermore,theobservationthatdevelopmentofbroadlyneutralizingantibod-iesrequiresprolongedstimulationwithhigherantigenicloadsfromdivergentvirusspecies(vanGilsandSanders,2013)impliesthatHIVvaccinestrategiesmustprovideacontinuoushighlevelexpressionofacocktailofimmunogens.
AlthoughtheuseofpolyvalentT-cellandB-cellmosaicconstructsorthecon-servedconsensussequencesmayeffectivelyovercomethechal-lengesofHIVdiversityandsignicantlyimprovevaccineefcacy(Santraetal.
,2010,2012),thelackofclearlydenedcorre-latesofefcacymeansthatitremainsunclearwhatimmuneresponsesanHIVvaccineshouldaimtoinduce.
Recently,anon-humanprimate(NHP)studybasedontheRhCMVvectorinducedexceptionallybroadandpersistentatypicalCD8+TcellswhicheffectivelyclearedSIVandmaintaineddurablesuppressionofvirusreplication(Hansenetal.
,2009,2011,2013),suggest-ingthatHIVvaccinedevelopmentresearchmayhavetoadaptimmunogendesignanddeliverystrategiesthatstimulatesimilarresponses.
Deliveryvectorsarevitalandintegralcomponentsofasuc-cessfulvaccineastheyplayanimportantroleinmodulatingbothinnateandadaptiveimmunity.
Therefore,vaccinevectorscansignicantlyinuencethemagnitudeandbreadth,aswellwww.
frontiersin.
orgAugust2014|Volume5|Article439|1OndondoChallengesofHIVvaccinedeliveryasthephenotypicandfunctionalqualitiesofvaccine-inducedimmuneresponses.
Moreover,asthetypeofdeliveryvector,inconjunctionwiththerouteofvaccineadministrationoftendeter-minewhetherornotvaccine-specicimmuneresponsespersistwithinthesystemicand/ormucosalcompartments(Masopustetal.
,2001;KiyonoandFukuyama,2004;Ranasingheetal.
,2007;CzerkinskyandHolmgren,2012),vectorchoiceremainsacrit-icaldeterminantoftheoverallefcacyofanygivenvaccine.
Apartfromtheimmunostimulatorypotentialtoinducestrongandpersistentimmunity,severalotherfactorssuchasstabilityandeaseoflargescalemanufacturing,safety,capacityfortransgeneinsertionandpre-existingimmunityalsoinuencevectorchoice.
Itisnowwell-documentedthatpre-existinganti-vectorimmu-nity(especiallyneutralizingantibodies)canpreventtransductionand/orexpressionofvaccinetransgenesthusreducingvaccine-specicimmuneinduction(Xiangetal.
,2002;Fitzgeraldetal.
,2003;LasaroandErtl,2009).
Thisisacommonphenomenon,clearlydemonstratedwithcertainvectorswhichshowsupe-riorimmunogenicityinanimalmodelsyetinduceonlymodestimmuneresponsesduetoneutralizationbypre-existingantibod-iesinhumans(McCoyetal.
,2007).
Additionally,pre-existingimmunitycanalterthenaturalcourseofinfectionleadingtocatastrophicconsequencessuchasenhancedHIVacquisitionandpossiblyaccelerateddiseaseprogression(Buchbinderetal.
,2008;McElrathetal.
,2008).
Thusstrategiesthatconcurrentlymaxi-mizevaccineimmunogenicitywhileminimizingsafetyconcernsremainanurgentpriorityinthedevelopmentofasafeandefcaciousvaccineforHIV/AIDS.
AgoodnumberofHIVvaccinecandidates(bothprophylac-ticandtherapeutic)employingabroadrangeofvaccinedeliveryvectorshavebeentestedandsomehaveprogressedtoevalua-tionofpotentialefcacyinphaseIIb/IIItrials.
OfsignicantrelevanceasfarassafetyistheSTEPtrialthatusedhumanadenovirusserotype5(Ad5)todeliverawell-designedHIVimmunogenexpressingGag/Pol/Nef,whichwasassociatedwithincreasedriskofHIVacquisitioninuncircumcisedmalevac-cineeswithpre-existingimmunitytoAd5(Buchbinderetal.
,2008;McElrathetal.
,2008).
Thisunexpectedandratherwor-risomendingpromptedtheprematurehaltingoftworelatedefcacytrialsduetofutility(Grayetal.
,2011;Hammeretal.
,2013).
Asdisappointingasthismighthavebeenatthetime,invaluablelessonshavebeenlearnedandthereisstillgreatopti-mismastheselessonsarenowtakenonboard.
FocussingonsomeofthepromisingHIVvaccinecandidatesinpreclinicalandclinicaldevelopment,thisreviewdiscussespertinentissuesrelatingtosafetyandimmunogenicityofreplicatingandnon-replicatingviralvectors,pre-existinganti-vectorimmunityandhowthesecanpotentiallyinuencethenaturalhistoryofHIVinfectionandprogression.
Inparticular,thisarticlehighlightsthesafetyproles,immuno-stimulatorypotentialandpossiblelimi-tationsofplasmidDNA,MVA(modiedvacciniavirusAnkara),ALVAC(canarypoxvirus),NYVAC(NewYorkattenuatedvac-ciniavirus),inuenzavirusandadenovirusvectoredvaccinesinpreclinicalandclinicalstudiesforHIVvaccines.
SomeofthedeliveryvectorsevaluatedinclinicalstudiesaresummarizedinTable1,whilethoseinpreclinicaldevelopmentaresummarizedinTable2.
RECOMBINANTDNAVACCINEVECTORSDNAplasmidvaccinescaninducebothTandBcellimmuneresponses,andarepopularfortheirsafety,stability,versatilityandeaseoflargescaleproduction.
Mostimportantlyisthefactthattheycanbeusedrepetitivelytoboostimmunity(Valentinetal.
,2010)withouttheriskofimmuneinterferenceasisthecasewithviralvectorswithhighprevalenceofpre-existingimmu-nity.
However,ontheirownDNAplasmidvaccineshaveexhibitedverylimitedimmunostimulatorycapacityandofteninducedsub-optimalimmuneresponses.
RecentadvancesinDNAdeliverysuchasintramuscular,skinorintradermalelectroporation(Selbyetal.
,2000;Wideraetal.
,2000;Braveetal.
,2010;Vasanetal.
,2011;Kopycinskietal.
,2012)oruseofotherphysicaldeliv-erymethodssuchasgenegunandbiojectordevices(Drapeetal.
,2006;Wangetal.
,2008a;Grahametal.
,2013),togetherwithconcurrentuseofcytokineadjuvantsincludingIL-2,IL-12,andIL-15(Winstoneetal.
,2011;Kalamsetal.
,2012,2013)havegreatlyimprovedtheimmunogenicpotentialofDNAvac-cines.
Inparticular,IL-12wasshowntosignicantlyaugmentthefrequency,magnitudeandbreadthofGag-specicimmuneresponsesinhealthyvolunteersimmunizedwitharecombinantDNAvaccineexpressingHIV-1Gag(Kalamsetal.
,2012,2013).
Similarly,whenmacaqueswereco-immunizedwithaplasmidencodingIL-12andaDNAplasmidexpressingSIV-Gag,strongantibodyandcellularresponseswhichcorrelatedwithabetterclinicaloutcomewereinduced(Boyeretal.
,2005;Chongetal.
,2007).
Moreimpressively,co-deliveryofaplasmidencodingGM-CSFwithaDNAvaccineexpressingSIVgenesinducedstrongneutralizingantibodyresponsesandADCC,whichprotectedagainstinfectionwithSIVsmE660(Laietal.
,2011).
TheuseofstrongadjuvantssuchasglucopyranosyllipidA(aTLR4agonist)inaDNA/MVA/proteinimmunizationregimenwasshowntoenhancebothantibodyandTcellresponses(McKayetal.
,2014),whileplasmidsencodingtheTLR5agonist,agellin,enhancedbothantibodyandTcellimmunitytoinuenzavirus(Applequistetal.
,2005)OthersignicantimprovementsinDNAvaccinetechnologyincludecodonoptimization,useofstrongerpromoters/enhancersandsignalpeptidessuchasthetissueplasminogenactivator(tPA)andlysosomeassociatedmembraneprotein(LAMP1),allofwhichsignicantlyenhancetransgeneexpressionandtrafck-ing,thusleadingtoincreasedvaccineimmunogenicity(Wangetal.
,2006a;Yanetal.
,2007;Wallaceetal.
,2013).
Furthermore,easeofDNAmanipulationprovidesaplatformtodeliverpoly-valentormulti-genevaccinecomponentswhichcanincreasethebreadthanddepthofvaccine-inducedimmunitytoreduceimmuneescape.
Thisstrategyshowedremarkablesuccessinrabbitexperimentswhereapolyvalentgp120vaccineinducedbroadlyneutralizingantibodyresponsesasopposedtothemono-valentvaccine(Wangetal.
,2006b).
Similarly,polyvalentmosaicplasmidDNAvaccineshavedemonstratedenhancedimmuno-genicityinmice(Kongetal.
,2009)andrhesusmonkeys(Santraetal.
,2010).
SeveralstudiesindicatethatdeliveryofDNAvaccinesbyelectroporationinducesbothcellularandhumoralimmuneresponseswhicharelong-livedandcanpersistforseveralyearswithorwithoutsubsequentheterologousboosting(Cristilloetal.
,FrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|2OndondoChallengesofHIVvaccinedeliveryTable1|Representativeclinicalstudies.
StudynameandImmunogenVectors,regimenandrouteImmuneresponsesReferencesphaseofimmunizationgenerated(I)HETEROLOGOUSPRIME-BOOSTSTUDIESHIVCORE002(PhaseIstudy)HIVconsv(Tcellimmunogenbasedonconservedregions)ChAdV63/MVA(i.
m.
)DNA/ChAdV63/MVA(i.
m.
)DNA/MVA/ChAdV63(i.
m.
)-CD4+andCD8+Tcells-InvitrovirusinhibitionBorthwicketal.
,2014HVTN505(PhaseIIbstudy)VRC-HIVDNA016-00-VP/VRC-HIVADV014-00-VPDNA-prime(i.
m.
biojectordevice)/rAd5boost(i.
m.
needleandsyringe)-Tcellsandgp140bindingIgGantibodiesHammeretal.
,2013HVTN503/Phambili(PhaseIIbstudy)MRKAd5HIV-1Gag/Pol/NefDNA-prime(i.
m.
)/Ad5boost(i.
m.
)-CD8+andCD4+TcellsGrayetal.
,2011Phase1studyGagandEnvDNAandrecombinanttrimericEnvglycoproteinDNA-prime(i.
m.
)/ProteinboostwithMF59adjuvant-RobustBandTcells-StrongNAbstoSF162-ADCCandneutralizationoftier2strainsSpearmanetal.
,2011PhaseI/IIstudyMulti-clade,multigene:DNA/HIV-1gp160,p17/p24GagandMVA/HIV-1Gag/PolLowdose(i.
d.
)DNA-prime(x3)/MVA-boost(i.
m.
x2)(DDDMM)-HighmagnitudeandbroadCD4+andCD8+Tcellresponses-EnvantibodiesBakarietal.
,2011PhaseIstudyDP6-001Multigenepolyvalentgp120andGagDNAandpolyvalentgp120proteini.
m.
ori.
d.
PolyvalentDNA-prime/i.
m.
protein-boost(withQS21adjuvant)-HightiterbindingandBNAbs,ADCCandmultifunctionalTcellsBansaletal.
,2008;Vaineetal.
,2010RV144(PhaseIIIstudy)ALVAC-HIVvCP1521/AIDSVAXgp120B/EALVAC-prime(i.
m.
)/gp120protein-boost-Tcellsandnon-neutralizingantibodiestoV1/V2loopRerks-Ngarmetal.
,2009PhaseIstudyMultigenicHIVDNA(gp160-A/B/C;RevB,GagA/BandRT-BandHIV-MVAEnv/Gag/Pol)DNA-prime(i.
d.
withBiojector)/MVA-boost(i.
d.
/i.
m.
);withorwithoutGM-CSFadjuvant-BroadandpotentcellularimmuneresponsesSandstrometal.
,2008;Gudmundsdotteretal.
,2009HVTN502/STEPStudy(PhaseIIb)MRKAd5HIV-1Gag/Pol/NefDNA-prime(i.
m.
)/Ad5boost(i.
m.
)-StrongCD8+TcellresponsesBuchbinderetal.
,2008;McElrathetal.
,2008Phase1studyHIVA(HIV-1cladeAandaCTLepitopestring)DNA-prime(i.
m.
)/MVA-boost(i.
m.
)-MultifunctionalCD4+andCD8+TcellsMwauetal.
,2004;Goonetillekeetal.
,2006PhaseIstudy(EuroVacc:EV02)HIV-1cladeC-Env/Gag/Pol/Nef(DNA-CandNYVAC-C)DNA-prime(i.
m.
)/NYVAC-boost(i.
m.
)-Durable,broadandpoly-functionalCD4+andCD8+TcellsHararietal.
,2008;McCormacketal.
,2008PhaseIstudyALVAC-HIV(vCP300)gp120/gp41,Gag,Pro,Nef,PolandSF-2rgp120ALVAC-prime(i.
m.
)/i.
m.
Protein-boost(withMF59adjuvant)-DurableCTLs-AntibodyresponsesEvansetal.
,1999PhaseIstudyALVAC-HIV(vCP205)gp120/gp41,Gag,PolandSF-2rgp120ALVAC-prime(i.
m.
)/i.
m.
Protein-boost(withMF59adjuvant)-StrongCD8+TcellresponsesandNAbsBelsheetal.
,1998(Continued)www.
frontiersin.
orgAugust2014|Volume5|Article439|3OndondoChallengesofHIVvaccinedeliveryTable1|ContinuedStudynameandImmunogenVectors,regimenandrouteImmuneresponsesReferencesphaseofimmunizationgenerated(II)HOMOLOGOUSPRIME-BOOSTORSINGLEDOSESTUDIESHVTN-070and-080PhaseIstudiesPV(PENNVAX(R)-BDNAexpressingGag,Pol,EnvandDNA/IL-12DNA+IL-12(i.
m.
orbyelectroporation)-CD4+andCD8+TcellresponsesKalamsetal.
,2013IPCAVD-001Ad26.
ENVA.
01IntramusculardeliveryofrAd26-Bindingantibodies-MultipleCD8+andCD4+Tcellresponses-ADCCandvirusinhibitionBadenetal.
,2013;Barouchetal.
,2013HVTN090PhaseIastudyVSVINN4CT1Gag1(recombinantVSVexpressingHIV-1Gag)Dose-escalatingi.
m.
deliveryLowlevelTcellresponsesdetectedfollowinginitialdosingFuchsetal.
,2012,2013PhaseIstudyAd35-GRIN(Gag,RT,Integrase,Nef)andAd35-GRIN/ENVIntramusculardeliveryofAd35-GRIN/EnvorAd35-GRIN-Robust,broadandpolyfunctionalCD4andCD8+TcellsKeeferetal.
,2012PhaseI/IIstudy(RISVAC02)MVA-B(monomericgp120andcladeBGag/Pol/Nefpoly-protein)ThreedosesofMVA(i.
m.
)-DurableantibodyandcellularimmuneresponsesGarciaetal.
,2011;Gomezetal.
,2011PhaseIstudyADVAX(multigenicHIV-1DNAvaccine)DNAbyi.
m.
electroporation-CD4andCD8+TcellswithmultiplecytokinesVasanetal.
,2011VAX003(PhaseIIIstudy)Bivalentrecombinantgp120vaccine:AIDSVAXB/ESeveni.
m.
injections;withAlumadjuvant-Bindingandneutralizingantibodiestogp120Pitisuttithumetal.
,2006VAX004(MulticentrePhaseIIIstudy)Bivalentrecombinantgp120vaccine:AIDSVAXB/BSeveni.
m.
injections;withAlumadjuvant-Bindingandneutralizingantibodiestogp120Flynnetal.
,2005;Gilbertetal.
,2005i.
m.
,intramuscular;i.
n.
,intranasal;i.
d.
,intradermal;s.
c.
,subcutaneous;i.
p.
,intraperitoneal;ADCC,antibodydependentcytotoxicity;NAbs,neutralizingantibodies;BNAbs,broadlyneutralizingantibodies.
2008;Pateletal.
,2010;Jalahetal.
,2014).
Inparticular,thelevelofHIV-specicimmuneresponsestothemultigenicADVAXvac-cinewasincreasedbyupto70-foldwhenelectroporationwasusedfordelivery(Vasanetal.
,2011).
Nonetheless,DNAvac-cinesconsistentlyshowmuchbetterimmunogenicitywhenusedasprimingcomponentsinconjunctionwithviralvectorssuchasadenoviruses(Shiveretal.
,2002;Hammeretal.
,2013;Borthwicketal.
,2014),MVA(Sandstrometal.
,2008;Gudmundsdotteretal.
,2009;Bakarietal.
,2011;Borthwicketal.
,2014),fowlpox(Kentetal.
,1998),andNYVAC(Heletal.
,2001)inheterologousprimeboostregimensdeliveringthesamevaccineinserts,orinco-immunizationstrategiesthatcombineDNA-primewithproteinboosting(Kennedyetal.
,2008;Wangetal.
,2008b).
Asamat-teroffact,prime-boostregimensstillremainthemostsuccessfulstrategiesthatemphasizethepotentialofDNAvaccines.
ItwasrecentlyshownthataDNA-prime/protein-boostregimenwassig-nicantlybetterthaneitherDNA/DNAorprotein/proteinaloneregimensforgeneratinglong-termprotectionofmiceagainstLeishmaniadonovani(Mazumderetal.
,2011).
TheDNAandpro-teinco-immunizationmodalitiesareparticularlydesirableastheymaximizeinductionoflong-livedhumoralandcellularimmuneresponseswhichcandisseminatetomucosalsites,includingthegenito-rectalmucosae(Pateletal.
,2013;Jalahetal.
,2014).
Arecentstudyhasdemonstratedinsmallanimalmodelsthatconcurrent,multiple-routeDNAvaccinationscomprisingDNAprimebyelectroporation,followedwithintranasal,intramuscu-lar,subcutaneousortranscutaneoushomologousproteinboostinducedstrongHIV-specicBandTcellresponses(Mannetal.
,2014).
Independently,anotherstudyshowedenhancementofHIVgp120-specicIgAresponsesinserumandmucosalsecre-tionsfollowingaDNAenv-primeandgp120protein-boostdeliv-eredwithnovelcarbohydrate-basedadjuvants(Advax-MandAdvax-P)whichwerespecicallydesignedformucosalandsys-temicimmuneenhancement(Cristilloetal.
,2011).
Thetremen-douseffectofaDNAprimeinenhancingantibodyresponsestoproteinvaccineswasalsodocumentedinaPhase1clinicalstudy,whereintramusculardeliveryofaDNAprimingvac-cinefollowedwithrecombinantproteinbooststimulatedhigherfrequenciesofBandTcells,aswellashigherneutralizinganti-bodytitresandADCCincontrasttoimmunizationwithproteinalone(Spearmanetal.
,2011).
PerhapsthemostexcitingoftheDNA-prime/protein-booststudiesisthe6-plasmidpolyvalentFrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|4OndondoChallengesofHIVvaccinedeliveryTable2|Representativepreclinicalstudies.
AnimalsImmunogenVectors,regimenandImmuneresponsesOutcomesReferencesrouteofimmunizationgenerated(I)HETEROLOGOUSPRIME-BOOSTSTUDIESMiceandrabbitsHIVEnv/Gag-Pol-NefDNA,MVA-C(HIVEnv/Gag-Pol-NefandCN54gp140protein)IntramusculardeliveryofDNA/MVA/ProteinwithTLR4(GLA-AFadjuvant)forproteinboostAntibodyandTcellresponses–McKayetal.
,2014RhesusmacaquesSIVmac239Env/GagDNA,rmIL-12DNAandSIVmac239proteinvaccinesDNA-prime(byelectroporation)/i.
m.
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d.
Protein-boost,orDNAandproteinco-immunizationPersistentmucosalEnvelope-specicantibodyresponsesEnhancedimmunitybytheco-immunizationmodalityJalahetal.
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m.
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,2014RhesusmonkeysDNAexpressingSIVmac239antigens+rmIL-12andinactivatedSIVmac239virusparticlesasproteinDNAprime(i.
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,2013MicepCCMp24rddVTT-CCMp24DNAprime/Tiantanboost(i.
m.
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,2010;Liuetal.
,2013RhesusmacaquesSIVSME543-Gag/Pol/EnvPrime-boost(i.
m.
)with:Ad26/MVA,Ad35/Ad26,DNA/MVA,MVA/Ad26-NAbs-Bindingantibodies-CellularresponsesProtectionfromSIVmac251acquisitionordiseaseprogressionBarouchetal.
,2012MiceAd35-GRIN/ENVandMVA-C(Gag/Env/Pol)Ad35-GRIN/ENV-prime(i.
m.
)/MVA-boost(i.
m.
)PolyfunctionalCD8+Tcells–Ratto-Kimetal.
,2012MacaquesSIVDNA/GM-CSF(SIV239Gag/PR/RT/Env/Tat/Rev)andMVA-SIVgpeDNA/GM-CSF-prime(i.
m.
)/MVA-boost(i.
m.
)-Neutralizingantibodyresponses-ADCCSterileprotectionafterSIVsmE660challengeLaietal.
,2011MurineDNA-Envandgp120proteinvaccinesDNAEnv-prime/gp120protein-boost(i.
m.
andi.
n.
)(Advax-MandAdvax-Padjuvants)-PersistentmucosalandsystemicAbs-Tcellresponses–Cristilloetal.
,2011New-bornandadultmiceBCG-HIVA,MVA-HIVAandHAdV5.
HIVABCG-prime(i.
p.
/i.
d.
/s.
c.
)followedwithi.
m.
MVA-orHAdV5-boost-Strong,cytotoxicCD8+Tcellresponses–Hopkinsetal.
,2011a;Saubietal.
,2011RhesusmacaquesVSVandSFVrepliconexpressingSIV-Gag/EnvVSV-prime(i.
m.
andi.
n.
)/SFVG-boost(i.
m.
)-HightiterNAbstoEnvproteinsandweakcellularresponses-SterilizingimmunityControlofSIVsmE660breakthroughinfectionsSchelletal.
,2011New-bornmacaquesVSV-SIVgpe(rVSV-Gag/Pol/Env)andMVA-SIVgpeVSV-prime(oral)/MVA-boost(i.
m.
)-SystemicAbs,bothsystemicandlocalcellularresponses–VanRompayetal.
,2010(Continued)www.
frontiersin.
orgAugust2014|Volume5|Article439|5OndondoChallengesofHIVvaccinedeliveryTable2|ContinuedAnimalsImmunogenVectors,regimenandImmuneresponsesOutcomesReferencesrouteofimmunizationgeneratedMice,rabbitsandmacaquesConsensusorPolyvalentmosaicDNAandprotein(gp120)vaccinesDNA-prime(i.
m.
)/i.
m.
andi.
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rVaccinia-boost.
DNA-prime(genegun)/Protein-boost(i.
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,2009RabbitsmacaquesHIV-1Envgp120DNA(electroporation)/gp120proteinboost-PersistentTh1,CTLandEnvresponsesNeutralizationofsensitiveSHIVisolatesCristilloetal.
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n.
withCholeratoxinadjuvant)-MucosalCD8+Tcells,mucosalandsystemicantibodies-Beta-chemokines–Gherardietal.
,2004RhesusmonkeysDNA,MVAandAd5vectorsexpressingSIVmac239GagDNAPrime(i.
m.
)/MVA-orAd5-boost(i.
m.
)-RobustCD8+TcellswithcytotoxicactivityPronouncedattenuationofSHIVinfectionandmitigateddiseaseprogressionShiveretal.
,2002MacaquesDNAandNYVACSIV-gpe(Gag/Pol/Env)DNA-prime(i.
m.
)/NYVAC-boost(i.
m.
)-DurableCD8+Tcellresponses–Heletal.
,2001(II)HOMOLOGOUSPRIME-BOOSTORSINGLEDOSESTUDIESMiceandrabbitsAd4Env160Ad4Env140Ad4Env120i.
m.
,i.
n.
,ors.
c.
deliveryofrAd4-TcellandantibodyresponsesNeutralizationoftier-1andtier-2pseudovirusesAlexanderetal.
,2013(Continued)FrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|6OndondoChallengesofHIVvaccinedeliveryTable2|ContinuedAnimalsImmunogenVectors,regimenandImmuneresponsesOutcomesReferencesrouteofimmunizationgeneratedMiceAd35-GRIN/ENVandMVA-Gag/Env/PolAd35-prime(i.
m.
)/Ad35-boosti.
m.
):MVA-prime(i.
m.
)/MVA-boost(i.
m.
)-PolyfunctionalCD8+Tcells–Ratto-Kimetal.
,2012RhesusmacaquesSIVSME543-Gag/Pol/EnvMVA-prime(i.
m.
)/MVA-boost(i.
m.
)-NeutralizingAbs,bindingantibodiesandcellularresponsesProtectionfromSIVmac251acquisitionordiseaseprogressionBarouchetal.
,2012RhesusmacaquesRhCMV-SIV/Gag,Rev/Nef/Tat,Pol,EnvRhCMVvectorsdeliveredbys.
c.
injection-Strongandpersisting,polyfunctionaleffectormemoryCD8+andCD4+cellsViralclearanceanddurableprotectionfromSIVmac239diseaseprogressionHansenetal.
,2009,2011RhesusmonkeysSIV-Gag,SIV-EnvandSIVRev-Tat-NeffusionproteinIntravenousdeliveryofrecombinantRhadinovirus-PersistenteffectormemoryCD8+TcellsControlofSIVmac239replicationBilelloetal.
,2011RhesusmacaquesRabiesvirus(RV)expressingSIVmac239Gag/PolorEnvIntramusculardeliveryofrRVconstructs-PolyfunctionalCD8+Tcellsinthemucosa-NAbsControlofSIVmac251-CXchallengeFauletal.
,2009RhesusandCynomolgusmacaquesSIV-GagDNA+rIL-12DNAvaccinesIntramuscularDNAdeliveryTcellandAntibodyresponsesImprovedclinicaloutcomeafterSHIV[89.
6P]challengeBoyeretal.
,2005;Chongetal.
,2007JuvenileandInfantRhesusmacaquesALVAC-SIVandMVA-SIVbothexpressingSIV-Gag/Pol/EnvMultipleimmunizationswithALVAC-SIV(i.
m.
)orMVA-SIV(i.
m.
)-Hightitresofbindingantibodies,low-levelTcellresponsesProtectionfromoralSIVmac251challenge,andreducedviremiainbreakthroughinfectionsVanRompayetal.
,2005MiceHIV-1EnvIIIBAg(DNA-EnvandMVA-Env)MVA-Env/MVA-EnvDNA-Env/DNA-Env(i.
n.
withCholeratoxinadjuvant)-MucosalCD8+Tcells,mucosalandsystemicantibodies-Beta-chemokines–Gherardietal.
,2004MiceInuenzavirusexpressingHIV-1ELDKWAepitopei.
n.
prime/boostwithchimericinuenzavirus,followedwithi.
p.
boostwithlivevirus-NeutralizingantibodiesNeutralizationofdistantlyrelatedHIV-1isolatesMusteretal.
,1994i.
m.
,intramuscular;i.
n.
,intranasal;i.
d.
,intradermal;s.
c.
,subcutaneous;i.
p.
,intraperitoneal;ADCC,antibodydependentcytotoxicity;NAbs,neutralizingantibodies;BNAbs,broadlyneutralizingantibodies.
DNAvaccineexpressinggp120andGag,followedbyQS21-adjuvantedpolyvalentgp120proteinboost(DP6-001study)inwhichmultifunctionalTcellsandhigh-titregp120-specicbind-ingandbroadly-neutralizingantibodiesaswellasADCCwereinduced(Grahametal.
,2006;Bansaletal.
,2008;Wangetal.
,2008b;Vaineetal.
,2010).
Apartfromeffectivedeliverystrategiesandroutesofimmu-nization,thereisevidenceshowingthatexpressionofDNAvaccinesandsubsequentimmunogenicityinhumansandotherprimatescanbelimitedbyserumamyloidPcomponent(SAP),aproteinfoundinbloodandknowntobindstronglytoDNA(Wangetal.
,2011,2012).
Insmallanimalsthisproteineitherbindsweaklyordoesnotexistatall.
Thus,depletionofSAPproteinpriortoadministrationofDNAvaccinesisanothernewstrategybeingtestedtoimproveDNAvaccineimmunogenic-ity.
Thisconcepthasbeenproveninmice,wheredepletionofSAPusingthebis-d-prolinecompoundCPHPC(Bodinetal.
,2010;Gillmoreetal.
,2010)wasshowntoaugmentantibodyandcellularimmuneresponsestoaDNAvaccineexpressingHepatitisBsurfaceantigens(Wangetal.
,2012).
Theconceptiscurrentlywww.
frontiersin.
orgAugust2014|Volume5|Article439|7OndondoChallengesofHIVvaccinedeliverybeingtestedinaPhase1clinicaltrial(HIVCORE003)ofhealthyadultsusingtheT-cellbasedHIVcandidatevaccine,HIVconsv.
AlthoughtheefcacyofanHIVDNAvaccineisyettobedemonstratedinhumans,variousstudies(prophylacticandther-apeutic)inthemacaquemodelhavereportedprotectiveimmuneresponseswhichcontrolledSIV/SHIVreplicationorprotectedfrominfection(Rosatietal.
,2005,2009;vonGegerfeltetal.
,2007;Valentinetal.
,2010;Pateletal.
,2013).
Inparticular,astudycombiningaDNA/MVAmucosaldeliveryofaDNAconstructexpressingreplication-defectiveSHIVparticlesandMVAexpress-ingSIV-Gag/PolandHIVEnv(MVA-SHIV)demonstratedsig-nicantprotectionfromdiseaseprogressionafteraSHIV89.
6Pchallenge(Wangetal.
,2004).
Furthermore,mucosalco-deliveryofaDNAprimingvaccinetogetherwithanIL-2encodingvec-tor,followedbyMVAboostalsoinducedprotectiveimmunityagainstSHIV89.
6Pchallenge(Bertleyetal.
,2004).
Theresultsinthesemacaquemodels,togetherwiththedocumentedefcacyofDNAvaccinesagainstanimaldiseases[e.
g.
,equineWestNileVirus(WNV)(Davisetal.
,2001),melanomaindogs(Bergmanetal.
,2003)andinfectioushematopoieticnecrosisvirus(IHNV)insalmon(Garveretal.
,2005;Kurathetal.
,2006)]raisehopesthatwiththerightimmunogenandeffectivedeliverystrate-gies(includingadjuvants),plasmidDNAvaccinesforHIV/AIDScouldachieveefcacyinclinicaltrials,whenusedalone,butmorerealisticallyinprime-boostcombinationswithliveviral-vectoredorproteinvaccines.
NON-REPLICATINGRECOMBINANTVIRALVECTORSADENOVIRUSVACCINEVECTORSAdenovirusesarethemostpowerfulvectorsforinducingbothantibodyandcell-mediatedimmunitytoinsertedtransgenesandareknowntoelicitbetween5-and10-foldstrongerTcellresponsescomparedtoconventionalnakedDNAorMVA/pox-likevirusvectors(Xiangetal.
,1996;Heetal.
,2000;Fitzgeraldetal.
,2003;Casimiroetal.
,2003a,2004;TatsisandErtl,2004;Catanzaroetal.
,2006).
TheAdenovirusvectorsuseeithertheCoxsackieandAdenovirusReceptor(CAR)orCD46receptors(Bergelsonetal.
,1997;Gaggaretal.
,2003)andcaninfectawidevarietyofcells,includingdendriticcells.
Inparticular,groupBadenovirusessuchasAd35recognizeCD46surfaceproteinandinfectDCsmoreefcientlythangroupCisolates.
Thesevectorsachievehigherlevelsoftransgeneexpressionwhichinturnresultsinstrongerandpersistentimmuneeffectorfunctions(Zhangetal.
,2001;Hutnicketal.
,2010;Sulemanetal.
,2011).
Severalstudiesindicatethatadenovirusespredominantlystimulateper-sistenteffectormemoryCD8+Tcellresponses(Yangetal.
,2003a,2007a;Tatsisetal.
,2007a)whicharemoresuitableforimmediatecontrolofinvadingpathogensatperipheralentrysitessuchasthegenitalmucosa(Cerwenkaetal.
,1999;Sallustoetal.
,2004;Husteretal.
,2006),andhaveshowntremendoussuccessinanimalstudies(Liuetal.
,2009).
Inadditiontotheeffectormem-oryTcells,stablecentralmemoryCD8+Tcellpopulationsarealsogenerated,thusprovidingsurveillanceinbothperipheralandlymphoidsites.
Althoughpersistingadenovirus-drivenimmuneresponsescouldalsobeduetothelong-termpresentationofantigensbynon-haematopoieticcellsservingasunlimitedanti-gendepot(Finnetal.
,2009;Kimetal.
,2010;Bassettetal.
,2011),long-livedimmunityislargelyattributedtopersistinglow-levelexpressionofinsertedimmunogens.
Adenovirusgenomesareknowntopersistforprolongedperiodsinvariouscelltypes(includingthoseatinoculationsites)wheretheyremaintran-scriptionallyactiveandcontinuouslyproducelow-levelsofanti-gentoprimenaveTcellswhilealsomaintainingtheeffectormemoryTcells(Yangetal.
,2006,2007b;Tatsisetal.
,2007a).
Furthermore,thearisingeffectormemoryTcellsexpresstheIL-7receptor(CD127)whichallowstheirprolongedsurvivalintheabsenceofantigen.
Besidesinductionofpotentadaptiveimmuneresponses,adenovirusesalsostimulateinnateimmunityviahighlyinammatoryresponseswhichinvolveTLR2,TLR9,NOD-likereceptorsandthetype1interferonpathwaysthatresultinabundantcytokineandchemokinesecretion(Hensleyetal.
,2005;NazirandMetcalf,2005;Appledornetal.
,2008;Muruveetal.
,2008).
Anotherattractivefeatureofadenovirusvectorsistheirabilitytoinducebothsystemicandmucosalimmuneresponsesfollowingparenteraldelivery,aswellastheirsuitabil-ityformucosalimmunization(Sharpeetal.
,2002;Xiangetal.
,2003;BangariandMittal,2006;Hautetal.
,2010).
Themostwell-characterizedoftheadenovirusvectorsishumanAd5,successfullyusedasadeliveryvectorforarabiesvaccineandfoundtobeverygoodatinducingprotectivevirusneutralizingantibodiesconcurrentlywithCD8+andCD4+Tcells(Xiangetal.
,1995,1996).
IntheHIVeld,Ad5wasusedasaboosterimmunizationfollowingDNAprimingandinducedstrongCD8+TcellresponsesinalargeproportionoftheSTEPstudyvaccinees(Buchbinderetal.
,2008;McElrathetal.
,2008).
However,clinicalefcacymayhavebeensignicantlycompro-misedbypre-existingneutralizingantibodies(rangingfrom40to70%indevelopedcountriesandgreaterthan90%indevel-opingcountries)andcellularimmunity(Fitzgeraldetal.
,2003;Holtermanetal.
,2004;BangariandMittal,2006;Xiangetal.
,2006;LasaroandErtl,2009;Erschingetal.
,2010;Mastetal.
,2010;Barouchetal.
,2011).
Theseresultswererecapitulatedinanon-humanprimatestudyusinglow-dosepenileexposuretoSIVmac251inAd5seropositiveanimalsimmunizedwithSIV-Gag/Pol/Nef(Qureshietal.
,2012).
Possibly,adenovirusvacci-nationboostedthenumbersofactivatedCD4+TcellswhicharetargetsforHIV-1(Benlahrechetal.
,2009).
Whilethismightseemaplausibleexplanation,especiallywhenconsideringthepotentialofsuchactivatedtargetstotrafctothegenito-rectalmucosae(Tatsisetal.
,2007a;Benlahrechetal.
,2009),thisargu-mentisstronglycontestedbyobservationsthatothervaccinecarrierssuchasDNAandMVAdostimulateCD4+Tcellactiva-tionbuthavenotbeenassociatedwithincreasedHIVacquisition.
However,itisworthnotingthatDNA/MVAvaccinesareyettobetestedforefcacyinlargeclinicaltrialsandassuchtheirpoten-tialtoenhanceHIVacquisitionhasneverassessed.
Furthermore,DNA/MVAvaccinescombinationshavenotbeenassociatedwithlong-termpersistenceofactivatedTcellsormucosalhoming.
Anotherpostulatedtheoryistheformationofadenovirus-specicantibodyimmunecomplexesthatactivatebothdendriticandCD4+Tcellshencefuellinginfection(Perreauetal.
,2008).
Inthisstudy,Ad5immunecomplexeswerestronglycorrelatedwithhigherHIVinfectionintheinvitrocultures,thussupportingastrongerlikelihoodofenhancedHIVacquisition.
ShouldeitherFrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|8OndondoChallengesofHIVvaccinedeliveryorbothofthesetheoriesbetrue,thiswouldhavedireconse-quencesforotherclinicaltrialsusingAd5todelivernon-HIVimmunogenssuchasmalaria(Sedegahetal.
,2011;Tammingaetal.
,2011;Chuangetal.
,2013)andTB(Smailletal.
,2013)vac-cineswhichwillinducesimilarphenotypesandpre-disposethevaccineestoincreasedHIVacquisitionrisk,althoughthismaynotbeapparentlydetectableasthesestudiesmaynotmonitorHIVacquisition.
Apartfromtheissueofpre-existingimmunity,immunizationwithAd5caninduceneutralizingantibodiesinnaveindivid-ualswhichcanbeahindranceforsuccessiveimmunizationswiththesameorcross-reactiveadenoviralvectors(Casimiroetal.
,2003b;BangariandMittal,2006).
Thusnewrareaden-ovirusvectorswithlowerpre-existingimmunitysuchasAd26andAd35arebecomingmoreattractive(Holtermanetal.
,2004;Abbinketal.
,2007;Barouchetal.
,2012;Zhangetal.
,2013),althoughthesearerelativelylessimmunogeniccomparedtoAd5(Collocaetal.
,2012).
Besidesthelowersero-prevalence,Ad26neutralizingantibodytitresareusuallyverylowcomparedtoAd5(Abbinketal.
,2007;Chenetal.
,2010;Mastetal.
,2010).
AsanHIVvaccinedeliveryvector,Ad26wasshowntoinducebroadlyfunctionalcellularandantibodyresponseswithviralinhibitorycapacityinarst-in-human(IPCAVD-001)clinicaltrialofanHIVenvelopeimmunogen(Ad26.
ENVA.
01)(Badenetal.
,2013;Barouchetal.
,2013).
Inthisstudy,adose-dependentexpan-sionofthemagnitude,breadth,andepitopicdiversityofEnv-specicbindingantibodyresponseswereobserved.
TheresponsescomprisedmultipleCD8+andCD4+Tcellmemorysubpopu-lationsandcytokinesecretionphenotypes.
Antibody-dependentcell-mediatedphagocytosisanddegranulationfunctionalactivitywerealsoobserved.
Ad35hasalsoshownhighimmunogenicityinhealthyvolunteers,elicitingrobustandpolyfunctionalCD8+andCD4+TcellsinamajorityofvolunteersimmunizedwithAd35-GRIN(animmunogenbasedonGag,RT,integraseandnef)orAd35-GRIN/ENV(premixedAd35-GRINandAd35-ENVvaccines)(Keeferetal.
,2012).
Similarly,inBALB/cmice,anAd35-GRIN/ENV-primefollowedbyaboostwithrMVAcon-tainingGag/Env/PolgenesfromvariousHIV-1cladesinducedpolyfunctionalCD8+Gag-speciccentralandeffectormem-oryTcellswhichweresuperiortothoseelicitedinhomologousAd35/Ad35orMVA/MVAprimeboosts(Ratto-Kimetal.
,2012).
OtherrareadenovirusvectorsincludehumanAd6,chim-panzeeAd3,Ad63,andAd68(Barnesetal.
,2012;Collocaetal.
,2012;Dicksetal.
,2012;O'Haraetal.
,2012;Roshormetal.
,2012).
Thechimpanzeeadenovirusesremainattractiveinparticularduetotheirhighimmunologicalpotencyandlowsero-prevalence,aswellasextremelyloworvirtuallyabsentcross-reactivitywithhumanadenoviruses(Xiangetal.
,2006;Chenetal.
,2010;Collocaetal.
,2012).
Furthermore,chimpanzeeadenovirusesinducestrongerTandBcellresponsesinheterologousprime-boostregimenseveninthepresenceofpre-existingimmunitytoAd5(Tatsisetal.
,2009).
Apartfromusingthesenaturallyoccur-ringhumanandchimpanzeeadenoviruses,newderivativesofadenovirusvectorsthathaveequivalentimmunogenicitybutwithsignicantlylowerpre-existingantibodiesarecurrentlybeingdeveloped(Dicksetal.
,2012;Lopez-Gordoetal.
,2014).
However,itisworthnotingthatpre-existingcellularimmunity(CD8+andCD4+Tcells)maybeamajordeterrentasunlikeantibodies,thesecellsarehighlycross-reactiveacrossadenovirusserotypesbecausetheyaredirectedtoconservedsequencesofadenovirus(Oliveetal.
,2002;Fitzgeraldetal.
,2003;Frahmetal.
,2012).
Nevertheless,somestudiesindicatethatAd5andAd26vectorscanstillelicitsignicantsystemicandmucosalresponseseveninpeoplewithpre-existingimmunity(Barouchetal.
,2013;Smailletal.
,2013).
Immunogenicadenovirusesfacedwithsignicantpre-existingimmunityproblemscanbeimprovedbymodica-tionoftheantibody-bindingsites,especiallywithinthevariablehexonloopsinordertoreduceNAbbindingwhilstmaintainingimmunogenicity(Bruderetal.
,2012).
Thiscanbeachievedviapointmutationsorcompletereplacement(Robertsetal.
,2006;Abeetal.
,2009;Pichla-Gollonetal.
,2009;Bruderetal.
,2013).
Besidestheirimmunogenicitywhenusedalone,adenovirusvaccinesarealsoveryimmunogenicwhenusedtoprimeresponseswhicharethenboostedbyothervaccinevectors(Tatsisetal.
,2007b;Ratto-Kimetal.
,2012).
Inparticular,adenovirus-primefollowedwithMVA-boostcaninducehighfrequenciesofmuchmorelong-lived,potentTcells(Reyes-Sandovaletal.
,2008,2010;Caponeetal.
,2010;Hilletal.
,2010).
APhaseIclinicaltrialofaT-cellHIVvaccinebasedontheconservedregionswasrecentlyshowntoelicitexceptionallyhighmag-nitudeandpolyfunctionalTcellresponses(circa5000IFN-γELISPOTSFU/millioncells)inHIV-negativehealthyvolun-teerswhenprimedwithchimpanzeeAd63(ChAdV63-HIVconsv)followedwithMVA-HIVconsvboost(Borthwicketal.
,2014).
Thevaccine-inducedCD8+Tcellsexhibitedpotentinvitroantiviralactivity.
Thisstudyalsodemonstratedthatthemag-nitudeandfunctionalcapacityofTcellsinducedinaregi-mencomprisingthreeprimingdosesofDNAfollowedwithChAdV63andMVA(DDDCM)didnotdiffersignicantlyfromthoseinasimpliedChAdV63-primeandMVA-boost(CM)regimen.
ThesuperiorimmunogenicityofthisregimenisnotuniquetoHIVimmunogens,asithasalsobeendemon-stratedinpreclinicalandclinicalstudiesofexperimentalmalariavaccines(Dunachieetal.
,2006;Draperetal.
,2010).
Suchrepeatedheterologousimmunizationswiththesametransgeneareknowntoincreaseboththemagnitudeandfunctionalqualityofvaccine-specicTcellsandtoallowmoreefcientmigra-tiontomucosal-associatedtissues(Tatsisetal.
,2007b).
ThisisimportantinHIVinfection,aseffectorimmunecellsinmucosalsitescouldblockHIVtransmission.
IthasalsobeenshownthatDNAprimingfollowedwithadenovirusboost-ingcanreducethelevelofanti-vectorantibodiesandincreasetransgene-specicimmuneresponses(Xiangetal.
,1999;Yangetal.
,2003b),althoughthisisquestionablewhenconsideringtheSTEPstudywhichemployedaDNA-prime/Ad5-boostregi-men.
However,itispossiblethatthisregimeneffectivelyreducedtheanti-vectorantibodyeffect,thuscurtailingapotentiallyworseoutcomeintheabsenceofDNApriming.
Furthermore,prime-boostregimenswithvariouscombinationsofadenovirusvectorswereshowntoinducerobustfrequenciesofHIV-1Gag-specicCD8+Tcellsinnonhumanprimates(Reyes-Sandovaletal.
,2004),althoughithastobeappreciatedthatthelevelofpre-existingAd5immunityinNHPswouldbelowerorabsent.
www.
frontiersin.
orgAugust2014|Volume5|Article439|9OndondoChallengesofHIVvaccinedeliveryAdenovirusesareonlyassociatedwithbenignhumanpatholo-gies,buttheirgreatestlimitationispre-existingimmunitywhichdampensvaccine-specicimmunitybylimitingtransgeneexpres-sion,whilepotentiallyexacerbatingHIVacquisition.
However,allelseconsidered,Adenovirusesremainbyfarthemostpromis-ingvaccinecarriersforHIV-1,becauseunlikeothervectors,theyinduceexceptionallyhighandpersistentfrequenciesofvaccinespecicTcells,whichisarequirementforsustainedHIVcon-trol.
Althoughtheirefcacyhasprobablybeenhamperedbyhighsero-prevalence,thisnolongerseemsaninsurmountablehur-dleinlightoftheenormousamountofresearcheffortsdirectedatndingstrategiestocircumventtheproblemsofpre-existingimmunity(Gabitzschetal.
,2009).
Additionally,replicatingade-novirusessuchasAdH4andAdHu7whichcanbedeliveredorallyintheformofediblecapsulesmighthelptoovercomepre-existingimmunity(Xiangetal.
,2003).
Moreover,intranasalororaldeliveryofadenoviruseshasbeenshowntoprovidesupe-riorprotectioninanimalmodels,andmighttriggermucosalimmuneresponseswell-situatedforpreventingHIVacquisition.
PerhapsadenovirusvectorsengineerednottoinduceCD4+TcellscouldbeanalternativetoovercomeincreasedHIV-1acqui-sitionrisk,althoughlackingCD4+TcellhelpfortheCD8+TcellsmightcompromisethedifferentiationandstabilityandthusefcacyofbothCD8+Tcellsandantibodyresponses(Yangetal.
,2007b).
RECOMBINANTMVA(rMVA)VECTORSApartfromtheirexcellentsafetyprole,inherentadjuvantprop-ertiesandeaseoflargescaleproduction,recombinantvacciniavirusvectorsarealsopopularfortheirlargegenomeswhichfacilitateinsertionoflargerimmunogens(SmithandMoss,1983).
MVAdoesnotreplicateinhumans(CarrollandMoss,1997)duetoserialpassaginginchickembryobroblastswhichresultedinlossofmorethan10%ofitsgenome(Meyeretal.
,1991),anditssafetywaswell-documentedduringthesmallpoxeradicationcampaign(MahnelandMayr,1994).
MVA'spotentimmunostimulatorypropertiesareachievedinacascadeofeventsinvolvinginductionoftype1interferons,variouschemokinesforcellmigrationandactivationofseveralcellularsignalingpathways(Priceetal.
,2013).
TheimmunostimulatorypotencyofMVAislargelyattributedtotheabsenceofgenesinvolvedinimmuneevasion(suchasthosethatinterferewithIFN-α,IFN-β,andTNF-α),thusallowingforstrongerinnateimmu-nitytobegenerated(Antoineetal.
,1998).
MVAvectorsareparticularlyimportantforgeneratingstrongTcellimmunityagainstintracellularpathogensandcancers,buthavealsobeenshowntoinducepotent,hightitreantibodiesinavarietyofdis-easemodelsincludingSIVandmalaria(Gherardietal.
,2003;Draperetal.
,2008,2013;Barouchetal.
,2012).
However,itisnowwellestablishedthatMVAvectorsaremoresuitedforboostingratherthanpriming,anddependingontheprimingvector(e.
g.
,DNAorlivevectorssuchasfowlpoxandaden-oviruses),MVAcaninducevariousphenotypesofTcells,eitherpredominatedbyCD4+orCD8+subsetsoracombinationofboth.
Inpre-clinicalandclinicalstudiesofmalaria,recombinantMVAwasshowntobehighlyimmunogenicasitinducedstrong(andprotective)cellularandantibodyresponsestomalariaanti-gens,eitheronitsownorwhenusedtoboostresponsesprimedbyvectorssuchasDNA,fowlpoxorAdHu5(Schneideretal.
,1998,1999;Gilbertetal.
,1999,2002;McConkeyetal.
,2003;Andersonetal.
,2004;Websteretal.
,2005;Bejonetal.
,2007;Sheehyetal.
,2011).
RecombinantMVA85A(expressingthemycobacterialanti-genAg85A)wasalsoshowntoinducestronganddurableTcellresponsesinvariousclinicalstudies(Scribaetal.
,2012;Tamerisetal.
,2013,2014).
Furthermore,itwasdemonstratedthatMVAexpressinginuenzaAvirusantigens(MVA-NP+M1)efcientlyboostedCD8+Tcellresponsestoachieveclinicalefcacyinhumans(Berthoudetal.
,2011;Lillieetal.
,2012).
Asatherapeu-ticvaccineforcancer,recombinantMVAexpressingthehumanpapillomavirusantigensE2,E6,orE7,withorwithoutIL-12wasshowntoinduceTandBcellimmunityresultingincontrolledHPVloadandsubsequentregressionorcompleteeliminationofprecancerouslesionsinamajorityofvaccinees(CoronaGutierrezetal.
,2004;Garcia-Hernandezetal.
,2006;Albarranetal.
,2007).
Additionally,MVAexpressing5T4antigen(TroVax)induced5T4-specicantibodyandcellularresponseswhichcorrelatedwithtumorregressioninaclinicaltrialofpatientswithadvancedcolorectalcancer(Harropetal.
,2006).
AlthoughthereiscleardemonstrationoftheclinicalefcacyofprophylacticandtherapeuticMVA-vectoredvaccinesformalaria,TB,inuenzavirusandcancer,MVAvaccinesforHIVareyettobeevaluatedforclinicalefcacy.
However,PhaseIandIIstud-iesofMVAexpressingHIVantigens,eitheraloneorinvariousprime-boostcombinationsindicatemodesttostrongimmuno-genicity(Guimaraes-Walkeretal.
,2008;Howlesetal.
,2010;Bakarietal.
,2011;Garciaetal.
,2011;Goepfertetal.
,2011;Gomezetal.
,2011).
Inparticular,theMVA-BcandidateHIVvaccineexpressingmonomericgp120andGag-Pol-Nefpoly-proteinofcladeBwhereMVAwasadministeredwithoutpriorpriming,inducedlong-lastingrobustandpolyfunctionaleffectormem-oryTcellandantibodyresponsesinPhaseI/IIstudies(Garciaetal.
,2011;Gomezetal.
,2011).
Furthermore,MVAhasshownmuchhigherimmunogenicitywhencombinedinprime-boostregimenswithotherprimingvectorssuchasDNA,fowlpoxoradenovirus(Goepfertetal.
,2011;Keeferetal.
,2011;Borthwicketal.
,2014).
InPhase1studiesoftheHIVAimmunogen(basedonHIVcladeAandastringofCTLepitopes),primingwithDNA(pTHr.
HIVA)followedwithMVAboosting(MVA.
HIVA)wasfoundtobeimmunogenic,inducingmultifunctionalandprolif-erativeCD8+andCD4+Tcellresponsesingreaterthan70%ofthevaccinees(Mwauetal.
,2004;Goonetillekeetal.
,2006).
Asdiscussedearlier,aPhaseIstudycombiningDNA-and/orChAdV63-primefollowedwithMVAboosttodeliveranHIV-1TcellimmunogeninducedhighmagnitudeTcellresponseswithpotentantiviralcapacity(Borthwicketal.
,2014).
Thisstudyandsimilarstudiesofmalariavaccines(Sheehyetal.
,2011,2012;O'Haraetal.
,2012)showedthatthemagnitudeofTcellresponsesinducedbyChAdV63aloneweremodest,butsig-nicantboostingwasachievedfollowingMVAadministration,thushighlightingthesuperiorimmunogenicpotentialofMVAwhencombinedwithappropriateprimingvectorssuchasBCG(Whelanetal.
,2009;Scribaetal.
,2012),naturalinuenzaAvirus(Berthoudetal.
,2011)orChAdV63(Collocaetal.
,2012).
FrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|10OndondoChallengesofHIVvaccinedeliveryRemarkably,aDNA/MVAprimeboostofavaccineexpress-ingmultipleHIVantigensinducedresponsesinabout90%ofvolunteersanddemonstratedstrongimmunogenicitydespitepre-existingimmunitytovacciniavirus(Sandstrometal.
,2008).
AsatherapeuticHIVvaccinevector,rMVAwasfoundtobesafeandtosignicantlyaugmentHIV-specicCD4+andCD8+TcellresponsesinHAART-treatedHIV-infectedvolunteersimmu-nizedwiththeMVA.
HIVAcandidatevaccine(Dorrelletal.
,2006;Ondondoetal.
,2006;Yangetal.
,2007c).
FurthermoreMVAwasfoundtobesafeinneonatesinaPhase1trialwhereMVA.
HIVAwasadministeredtoinfantsborntoHIV-infectedoruninfectedmothers(Afolabietal.
,2013).
TherapeuticadministrationofMVAprimefollowedwithfowlpoxboostexpressingEnv,Gag,Tat,Rev,andNef-RTfusionantigensincreasedthefrequenciesandbreadthofTcellresponsesinyoungadults(Greenoughetal.
,2008).
OneveryattractivefeatureofrMVA(andotherpoxvirusvectors)istheirabilitytoinducemucosalimmuneresponseswhenadministeredviamucosalroutes(GherardiandEsteban,1999,2005).
Inparticular,murineandmacaquesstudiesusingrMVAvectorsdemonstratedinductionofprotectiveHIV-specicimmuneresponseswithinthegenito-rectalmucosae,whichinsomecasescorrelatedwithreduceddiseaseprogression(Belyakovetal.
,1998a;Makitaloetal.
,2004;Wangetal.
,2004).
EnhancedimmunogenicityofrMVAincombinationwithDNAprimingwasalsoachievedbyusingthenon-toxicBsubunitofcholeratoxin(CTB)asmucosaladjuvant(Gherardietal.
,2004).
Thus,eventhoughMVAmaybeinadequateasastand-alonedeliveryplatform,itdenitelyshowsgreaterpotentialasaboostingvec-tor(especiallyforthechimpanzeeadenoviruses)andshouldbeevaluatedforefcacyinadvancedHIVvaccinetrials.
RECOMBINANTNYVACVACCINEVECTORSNYVACvectorisalsoavaccinia-basedvectorwhichwashighlyattenuatedbydeletionof18genesinvolvedinhostrangevir-ulence.
IthasbeenshowntoinducemainlyCD4+Tcellresponses,incontrasttoMVAwhichhasastrongerimmunos-timulatorypotentialandisknowntoinducebothCD8+andCD4+responses(Mooijetal.
,2008).
However,inatrialofchronicallyinfectedpatientsonHAART,aNYVAC-basedvac-cineexpressingGag/Pol/Nef/EnvfromanHIV-1cladeBisolate(NYVAC-B)wasfoundtobehighlyimmunogenicandinducedhighmagnitude,broadandpolyfunctionalCD4+andCD8+Tcells(Hararietal.
,2012).
SimilartoMVA,NYVACelicitsgreaterimmuneresponseswhenusedinprime-boostcombina-tionsratherthanonitsown(Hararietal.
,2008;McCormacketal.
,2008).
IntheseEuroVaccstudies,primingwithDNA-CfollowedwithNYVAC-Cboostelicitedbroad,polyfunctionalanddurableCD4+Tcellresponsesingreaterthan90%ofvolunteers,comparedtoonly40%whenNYVACwasusedalone(Hararietal.
,2008).
Moreover,inapreclinicalstudywithaDNAprimefollowedwithNYVACboost,responsestoavaccineexpressingSIV-Gag/Pol/Envwereboosted10-foldwithimprovedqualityandquantityofTcellresponses(Heletal.
,2001).
ANYVAC/SIV-gpevaccine(expressingSIVGag/Pol/Env)alsoelicitedmucosalimmuneresponsesinmacaquesfollow-ingbothmucosalandsystemicdelivery(Stevcevaetal.
,2002).
DespitetheskewingtowardCD4+Tcellresponses,NYVAChaspotentialtostimulateandboostmorebalancedimmuneresponseswhencombinedwithothervectors,anditspotentialshouldbefullyexplored,especiallyfortherapeuticHIVvaccineswhichrequirere-invigorationofCD4+Tcellfunctions(andfrequencies).
CANARYPOX(ALVAC)VACCINEVECTORSALVACisanattenuatedderivativeofthecanarypoxvirusthatwasrepeatedlypassagedinchickembryobroblastsandthushasrestrictedtropismwithveryminimalpathogenicityinhumans(Yuetal.
,2006).
Despitethecomparativelylowerimmunogenic-itywithrespecttootherpoxvirusvectorssuchasMVA(Zhangetal.
,2007)andNYVAC,thefactthatALVAChasnopoten-tialpre-existingimmunityinhumansmakesitamoreattractiveHIVvaccinedeliveryvector.
TheALVACvector(vCP205)wasshowntobesafeandtoinducestrongCD8+CTLandantibodyresponsestoanHIVvaccineexpressinggp120/41andGag/Polsequences[ALVAC-HIV(vCP205)]inaPhase1clinicaltrialintheUSAinthe1990s(Belsheetal.
,1998).
ArelatedALVAC-basedvaccineexpressingmultipleHIVantigenscomprisingGag,Env,Nef,PolandPro[ALVAC-HIV(vCP300)]alsoinduceddurableCTLresponsesinhealthyvolunteers(Evansetal.
,1999).
Inpre-clinicalstudies,ALVACexpressingSIVGag/Pol/Envprotectedagainstlow-doseoralSIVmac251challengeofneonaterhesusmacaquesinastudydesignaimingtomimicHIVtransmissionthroughbreastmilk(VanRompayetal.
,2005).
MorerecentlyALVAC-basedHIVvaccineshavebeentestedinbothadultsandinfants,wheretheyhaveshownmodestimmunogenicity(Kintuetal.
,2013;Kaleebuetal.
,2014)andintheRV144trialofALVACprime[ALVAC-HIV(vCP1521)]andproteinboost(AIDSVAXB/Ergp120),theonlyHIVvaccinecandidatetoshowefcacy(Rerks-Ngarmetal.
,2009,2013).
WhileitisunclearwhetherthemodestsuccessofRV144wasduetotheimmunostimulatorypotentialofcanarypoxvirusvec-tororimmunogenicityofthevaccineinserts,thefactthattheimmunogensintheRV144trialvaccinesarenotsignicantlydis-tinctfromthoseusedinotherHIVvaccinesintheeldeliminatesthe"immunogeneffect,"thusleavingthevectorsanddeliverymethodsaspossibleexplanations.
But,astheAIDSVAXvaccine(recombinantgp120)showednoefcacyinearliertrials(VAX003andVAX004),thesuccessofRV144pointstothedeliveryvec-tor(ALVAC)andpossiblythebenetsofacombinedviralvectorandproteinimmunizationregimenasopposedtohomologousboosts.
Thismightsuggestthatcombinedlivevector-primingandprotein-boostimmunizationmodalitiescouldbefurtherrenedtoachievegreaterpotentialforincreasedefcacy.
Alternatively,protectionbythecombinedvaccinescouldbeattributedtoTcellhelpfortheantibodyresponses.
ItmusthoweverbenotedthatunliketheRV144study,VAX003,andVAX004wereconductedinhigh-riskpopulations,whichmightbeastrongconfound-ingfactor,althoughthismightaswellbereectiveoftheverylimitedefcacyofstand-aloneproteinsubunitvaccinesforHIV.
DespitethemodestefcacyofRV144,theimmuneresponseswanedwithinashorttimeindicatingthatALVACmaynotbeaparticularlysuitablevectortoinducelong-livedanti-HIVimmunity,unlessitiscombinedwithotherpowerfulvectors.
Inwww.
frontiersin.
orgAugust2014|Volume5|Article439|11OndondoChallengesofHIVvaccinedeliverydirectcomparisonofimmunogenicity,ALVACwasfoundtobelessimmunogenicthanMVA,possiblyduetoMVA'senhancedantigenexpressionwithindendriticcells(Zhangetal.
,2007).
Nonetheless,ALVACisstillquitepromisingforHIVvaccinedeliv-ery,asitisalsoalreadylicensedfordeliveryofseveralveterinaryvaccinesincludingthefelineleukemiavirus(FeLV)andfelinerabiesvaccine(PUREVAX)andRECOMBITEKvaccinewhichprotectsagainstcaninedistemper,equineinuenzaandWestNileVirus.
MYCOBACTERIUMBOVISBACILLUSCALMETTE-GUERIN(BCG)VACCINEVECTORSPreventionofbreastmilktransmissionofHIV-1remainsanimportantgoalforHIVvaccineresearchers.
BCGisanattenuatedvaccineproventobesafeandhasformanyyearsbeenadmin-isteredtonew-bornbabiestoimmunizeagainstMycobacteriumtuberculosis(Mtb).
Assuch,BCGprovidesaplatformtoco-deliverHIVimmunogensinneonatestopotentiallyprotectagainstmother-to-childtransmissionofHIV-1.
ThepotentialuseofBCGasanHIVvaccinevectorwasexploredinpreclinicalstud-iesofadultandnew-bornBALB/cmiceusingtheHIV-1cladeAGagimmunogen(HIVA)(Mwauetal.
,2004).
PrimingwithrecombinantBCGexpressingHIVA(BCG.
HIVA)inducedHIV-specicTcellresponseswhichwereefcientlyboostedwithrMVA(MVA.
HIVA)(Hopkinsetal.
,2011a,b;Saubietal.
,2011,2012).
Infurtherrelatedstudies,primingwithBCG.
HIVAandboostingwithacombinationvaccineexpressingHIVAandtheMtbanti-gen85A(mMVA.
HIVA.
85A)inducedrobustIFN-γ-producingTcellstobothHIV-1andMtbantigens.
Moreover,inadultmice,BCG.
HIVAprimedweakHIV-1-specicCD8+Tcellresponses,whichwerestronglyboostedwitheitherAd5(HAdV5.
HIVA)orrMVA(MVA.
HIVA).
Thus,immunizationofneonateswithrecombinantBCGexpressingHIV-1immunogens,followedwithanMVAboostexpressingthesameHIVimmunogenmightcon-currentlyprotectagainstMtbandHIV-1.
ItremainstobeseenhowtheserBCG-vectoredHIV-1vaccineswillperforminclinicalstudies.
REPLICATION-COMPETENTVIRALVECTORSTheunprecedentedsuccessoftheSIVmac239nefexperimen-talvaccineinrhesusmacaques(Reynoldsetal.
,2008,2010)givesahintthatpossibly,asuccessfulHIVvaccinewillrequirealivedeliveryvector,astheseareknowntoinducehighmag-nitude,durableandbroadlyeffectiveimmunity.
Butasexcitingasthismaysound,therearesignicantchallengesintermsofbalancingthesafetyandimmunogenicityvs.
replicativecapacity.
Oftheadenoviruses,Ad4andAd7havebeentestedinclin-icalstudies(byoraldelivery)andweresuccessfullyusedforthepreventionofrespiratoryandentericillnesses(HokeandSnyder,2013).
Thesereplicationcompetentadenovirusesnat-urallyinfectandreplicateinmucosaltissues(PattersonandRobert-Guroff,2008)andcouldthusbequiterelevantforHIVvaccines.
PreclinicalstudiesofrecombinantAd4expressingHIV-1cladeCenvelopegp160(Ad4Env160),gp140(Ad4Env140),andgp120(Ad4Env120)demonstratedinductionofenvelope-specicTcellsinmiceandantibodyresponsesinrabbits(Alexanderetal.
,2013).
Serumfromtherabbitswasabletoneutralizeatier1cladeCpseudovirusandtoalesserextent,homologousandheterologoustier2pseudoviruses.
AreplicatingCMVvectoredSIVvaccine(RhCMV-SIV/Gag,Rev/Nef/Tat,Pol,Env)wasshowntopersistinvaccinatedrhesusmacaquesandconferreddurableprotectionfromdiseasepro-gressionowingtoinductionofhighmagnitudeeffectormemoryCD8+Tcells,despitepre-existingCMVimmunity(Hansenetal.
,2009,2011,2013).
Otherreplication-competentvirusesinclinicaldevelopmentincludetheTianTanvacciniavirus(TT),Vesicularstomatitisvirus(VSV),aderivativeofNYVAC(NYVAC-C-KC)andSendaivirus(SeV).
TheTianTanvacciniaviruswasusedinaDNA-prime(pCCMp24)/Tiantanboost(rddVTT-CCMp24)reg-imenwhereitwasshowntoinduceantibodyandHIV-specicTcellresponses(includingmemoryphenotypes)followingintra-musculardeliveryandhasnowbeenadvancedtoPhaseIIclinicalstudyinChina(Excleretal.
,2010;Liuetal.
,2013).
TheNYVAC-C-KCvectorshaveshownsuperiorcellularandhumoralimmu-nitycomparedtothenon-replicatingNYVAC,atleastinmice(Kibleretal.
,2011;Gomezetal.
,2012).
ASendaivirusvectorexpressingSIVGag(SeV-Gag)admin-isteredintranasallyasaboostfollowingintramuscularprimingwithanenvelope-independentDNAvaccine(CMV-SHIVdEN)demonstratedverystrongsuppressionofintravenousSIVmac239challengeinrhesusmacaques,whichwasextendedovera3-yearperiod(Matanoetal.
,2001;Takedaetal.
,2003;Kawadaetal.
,2007).
ClinicalinvestigationsofaSeV-basedcandidateHIVvaccineexpressingGag[SeV-G(NP)]areongoinginRwanda,KenyaandtheUK,anditisexpectedthatresultsofthesetri-alswillprovideafeelofthepotentialofSendaivirusasanHIVvaccinevector.
AttenuatedVSVisanon-pathogenic,lowsero-prevalencevectorthatwasalsofoundtobequitepromis-ingasitachievedviruscontrolduringSHIV89.
6PchallengeexperimentsinrhesusmacaquesimmunizedwithrVSVexpress-ingGagandEnv(Roseetal.
,2001).
RecombinantVSVvectorwasshowntoinducestrongmemoryCTLresponsestoHIV-1GagandEnvinmice,whichweresignicantlyampliedbyboostingwithheterologousrecombinantvacciniavirusvectors(Haglundetal.
,2002).
ItispostulatedthatintranasaldeliveryofrVSVvaccinesincombinationwithIL-12administeredduringDNAprimingmayelicitmucosalimmunityforHIV(Eganetal.
,2004,2005).
PrimingwithrVSV-Gag/Pol/Env(VSV-SIVgpe)fol-lowedwithMVA-Gag/Pol/Env(MVA-SIVgpe)boostwasshowntoinducestrongandlong-livedantibodyandcellularresponsesthatachievedlong-termcontrolofSHIVreplication(Schelletal.
,2009;VanRompayetal.
,2010).
Anongoingphase1trialofrVSV-HIV-1Gagvaccine(HVTN090)hasdemonstratedclini-calsafetyandTcellimmunogenicityfollowingintramusculardelivery(Fuchsetal.
,2012,2013),althoughthemagnitudeofresponseswaslimitedandwillmostlikelyrequirepriming(orboosting)withsuitablevectors.
Othervectorsbeingexploredincluderhadinovirus(Bilelloetal.
,2011),yellowfevervirus(Bonaldoetal.
,2010),rabiesvirus(Fauletal.
,2009),Venezuelanequineencephalitisvirus(VEEV)(Caleyetal.
,1997)andSemlikiForrestvirus(Schelletal.
,2011),allofwhichhaveshownstrongimmunogenic-ity,withsomeachievingefcacyinNHPchallengeprotec-tionmodels.
InuenzavirusvaccinevectorshavealsobeenFrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|12OndondoChallengesofHIVvaccinedeliverystudiedextensivelyandhavebeensuccessfullyusedasdeliveryvehiclesforseveralexperimentalHIVvaccines(Lietal.
,1993a,2013;Musteretal.
,1994,1995;Garcia-SastreandPalese,1995;Paleseetal.
,1997;Sextonetal.
,2009).
Asnaturalmucosalpathogens,inuenzavirusvectorsarewell-adaptedforstimulat-ingrobustmucosalandsystemicimmunitycomprisingbothanti-bodyandcellularimmuneresponses(Garcia-SastreandPalese,1995;Paleseetal.
,1997;Lietal.
,2013).
Mucosalimmuniza-tionofmicewithchimericinuenzavirusvectorsexpressingtheHIV-1gp120V3looppeptide(IHIGPGRAFTYTT)(Lietal.
,1993a)orthegp41epitope(ELDKWA)(Musteretal.
,1993,1994,1995)wasshowntoinducepersistentantibodyandCTLresponses.
Inuenzavirusvectorsmightbesuccessfullycom-binedinprime-boostregimensasdemonstratedininuenzavirus-primeandMVA-booststudiesinmice(Gherardietal.
,2003),althoughtheyhavealimitedcapacityforimmunogeninsertion.
HETEROLOGOUSPRIME-BOOSTSTRATEGIESFORENHANCEDHIVVACCINEEFFICACYRepeatedvaccinationinheterologousprimeboostapproachesemployingdifferentvectorcombinationsinaspecicorderiswidelyacceptedasthemostefcientmeanstoinducesupe-riorqualityandquantityofvaccine-specicimmuneresponses(Lietal.
,1993b;RamshawandRamsay,2000;Estcourtetal.
,2002;McShane,2002;Newman,2002).
Heterologousprimeboostregimesallowimmuneboostingwithoutcreatingproblemsofanti-vectorimmunity.
Furthermore,heterologousprime-boostsresultinincreasedfrequenciesofmemoryTcells,andithasbeenshownthatthenumberofimmunizationscansignicantlyinuencethephenotypeofvaccine-specicmemoryTcells,withsecondaryandtertiaryimmunizationsgeneratingeffector-likememoryTcellswhichpreferentiallyaccumulateinnon-lymphoidorgans(Masopustetal.
,2006;NolzandHarty,2011).
Thesendingshavehugeimplicationsonthequalityandpotentialofmucosalsurveillanceofcellsinducedinprime-boostvaccinationprotocols.
Distinctliveviralvectorscanbecombinedinprime-boostregimestomaximizeimmuneresponses.
InmoststudiesDNAhasbeenusedforpriming,butrecentlyanumberofvirusvectorsincludingAdenoviruses,inuenzavirusesaswellasfowlpoxandcanarypoxhavebeentestedinprime-boostregi-mens.
Prime-boostregimenscomprisingAdenovirusandMVAorheterologousAdenovirusstrainshaverecentlybeenshowntoinducebothcellularandhumoralimmuneresponsestoSIVandmalariaantigens(Draperetal.
,2008;Liuetal.
,2009;Tatsisetal.
,2009;Barouchetal.
,2012).
Inparticular,impres-siveprotectionagainstSIVacquisitioninrhesusmonkeyswasachievedfollowingimmunizationwithaSIVSME543-Gag/Pol/EnvvaccinedeliveredbyAd26/MVAandAd35/Ad26prime-boostregimenswhichinducedamixtureofneutralizingandbindingantibodyaswellascellularimmuneresponses(Barouchetal.
,2012).
Thisstudyfurtherdemonstratedinductionofbothsys-temicandmucosalimmuneresponsesandachievedprotectionfrombothacquisitionanddiseaseprogression,thusprovidingproofofconceptthatHIV-1acquisitionandpost-infectioncon-trolmightbeachievedbyimprovedimmunogendesignanddeliverystrategies.
Heterologousorhomologousregimenscom-prisingDNA/MVA,MVA/Ad26,andMVA/MVAwerecompar-ativelylessefcaciousthanAd26/MVAorAd35/Ad26,whichreducedviralloadset-pointsbygreaterthan100-fold.
APhase1clinicaltrial(B003/IPCAVD-004)assessingtheimmunogenic-ityofvariousprime-boostcombinationsofAd26andAd35isongoing,andwillinformtheeldontheclinicalutilityofthesetwopromisinghumanadenovirusvectorcombinations.
AnotherNHPstudyemployingthreedosesofplasmidDNAfollowedwithAd5todelivervariousimmunogenscomprisingSIV-Gag,SIV-EnvmosaicimmunogensorSIVmac239Envalsoinducedcellularandantibodyresponses(neutralizingantibodiesandADCC)andachievedsignicantprotectionagainstintra-rectalchallengeofrhesusmacaqueswithSIVsmE660thatwasamismatchofthevaccinestrain(Roedereretal.
,2014).
Moreover,superiorimmunogenicityofprime-boostcombinationsusingDNA/ChAdV63/MVAorChAdV63/MVAhasbeendemonstratedinaPhaseIstudy(Borthwicketal.
,2014).
ThesuccessofaviralvectorforpriminghasalreadybeendemonstratedintheRV144studywhichusedALVACtoprimeantibodyandTcellresponses,followedwithaproteinboost(Rerks-Ngarmetal.
,2009).
AlthoughprimingwithDNAhasalwaysseemedabetterstrategyasitfocusestheimmuneresponsetotheimmunogentransgene,asopposedtoviralvectorswhichcarrymultitudesofimmunogenicantigenswithintheirback-bones,theefcacyofviral-vectorprimingfollowedbyproteinboostingintheRV144studyandthesuperiorimmunogenicityofvirus-prime/virus-boostinthestudiesdiscussedabovesup-porttheuseofviralvectorsforbothprimingandboosting.
Therefore,heterologousprime-boostregimenscombiningDNA,AdenovirusandMVAorALVACarelikelytoachieveefcacyagainstHIVinclinicaltrials,althoughthiswillrequirethatHIVEnvorgenesencodingNAbepitopesareincludedintheimmuno-genformulations(Barouchetal.
,2012,2013).
Preclinicalstudiesinvestigatingthepotentialofcombinedchimpanzeeadenovirus,MVAandproteinprime-boostregimenstodeliverimmuno-genswhichcanstimulatebroadlyneutralizingantibodiessuchasBG505areunderway.
ThesuccessofrecombinantadenovirusvectorprimingfollowedwithMVAboostininducinghigh-titreantibodieseitherontheirownorinconjunctionwithmolecu-laradjuvantshasalreadybeenproveninpreclinicalstudiesofmalaria(Draperetal.
,2008).
Possiblythepersistenceofaden-ovirusensurescontinuousantigensupplywhichissuitableforBcellpriming.
ItisenvisagedthatoptimaldeliverymodalitieswhichcombineHIVimmunogenselicitingBNAbswiththosethatstimulatestrongTcellimmunitywillachieveenhancedvac-cineefcacy.
OfcourseamajorcaveatofcombiningstrongTcellvectorswithantibody-producingimmunogensisthepossi-bleimmuneinterferenceofantibodyproductionbythesevectors.
Nevertheless,thiscanbeoptimizedperhapsbyemployingsev-eralproteinboostswithpowerfuladjuvantsinordertodeliverthemostbalancedimmuneresponses.
POTENTIALVACCINE-ASSOCIATEDRISKOFHIVACQUISITIONTheincreasedriskofHIV-1acquisitionintheSTEPandHVTN505trialvaccineesdespitestrongimmuneresponseshaswww.
frontiersin.
orgAugust2014|Volume5|Article439|13OndondoChallengesofHIVvaccinedeliveryraisedmanyunansweredquestionsastowhetherthevaccinedeliverymodalities,suboptimalpotencyoftheHIVimmuno-gensorotherunknownexternalfactorsareresponsibleforvaccinefailure.
Asfarasimmunogendesign,thevaccinecon-structusedintheSTEP,PhambiliandHVTN505studiesrepre-sentsoneofthemostcomprehensiveimmunogenswithbroadcoverage,asitcompriseda6-plasmidDNAandrAd5vec-torsexpressingGag/Pol/Nef/Envproteinsfrommultipleclades.
Otherimmunogensbasedonsimilarorfarlesscomprehen-siveHIVproteincoveragehavealsobeentestedandshowedvarieddegreesofimmunogenicity.
Thus,anunderstandingonwhethertheoutcomesoftheSTEP/Phambili/HVTN505studies(efcacy,immunogenicityorincreasedriskofacquisition)wouldhavebeendifferentifotherdeliveryvectors(suchasDNA/MVA,DNA/ALVACorDNA/Ad35/Ad26orevenareplicatingCMVvec-tor)hadbeenusedtodeliverthesameimmunogensinthesetrialsiskeyforfurtherprogressionintheeld.
AnAlternativewaytolookatthisistoaskwhethertheresultsofRV144trialwouldhavebeenworseifAd5wasusedinsteadofALVAC,assumingthattheprevalenceofAd5neutralizingantibodiesintheRV144pop-ulationdoesnotdiffersignicantlyfromtheSTEPandPhambilistudypopulations.
Thendingthatthevaccinewasnotatallefcaciousamongstmenwhowerecircumcisedorinuncircumcisedmenwhodidnothavepre-existingAd5immunityraisesdoubtsastowhetheref-cacywasgenuinelyhinderedbyAd5serostatus.
ThisisfurthersupportedbytheresultsofHVTN505studywhichtestedonlycircumcisedindividualswithoutAd5antibodies,yetnoprotec-tionwasobserved.
Moreover,theabsenceofAd5antibodiesintheHVTN505studyparticipants(whichshouldintheoryallowforhigherimmunogenicity)wasnotassociatedwithanysignicantenhancementofthemagnitudeandqualityofimmuneresponsesoverthoseseenintheSTEPandPhambilistudies.
Therefore,Ad5serostatuscanbesafelyremovedfromtheequation,leav-ingtheonlyplausibleexplanationforvaccinefailuretobethequalityandquantityofimmuneresponses.
IfthiscanbefullydocumentedbeyonddoubtthenitimpliesthateithertheAd5deliveryvectorortheHIV-1antigensusedwerenotimmunogenicenoughtoaffordprotectionfrominfectionorpost-infectionviruscontrol.
However,consideringthatAd5isoneofthemostimmunogenicvectorscurrentlyavailable,(andthattheimmuno-genusedinthesestudieswascomprehensiveandwell-designed),thiswouldhaveseriousimplicationsforvaccinedesign,asitsetsthebarreallyhighfornewcandidatevaccineswhichwouldbeexpectedtostimulateresponsesofextremelyhighermagnitudesandsuperiorqualitativepropertiesinordertoachieveeventheminimalefcacy.
Onabrighterside,thiswouldperhapsinsti-gateintensescrutinyofthecurrentmethodsusedforassessingvaccineimmunogenicityinordertostandardizeandsynchronizewiththoseforefcacymeasurements.
Oneotherinterestingquestioniswhether(andhow)Ad5sero-positivityisintrinsicallyassociatedwithHIVacquisition.
AlthoughstudiesofuncircumcisedmendocumentincreasedriskofnaturalHIVacquisitionduetoahighfrequencyofCD4+CCR5+targetcellsintheforeskin(Prodgeretal.
,2012),howthisrelatestheirAd5sero-positivityandtitrelevelswithinfectionriskisnotveryclear.
However,thefactthattheriskofHIV-1acquisitionintheSTEPstudydiminishedwithtimeafterimmunization,andeventuallyleveledupwithplaceborecip-ients(Buchbinderetal.
,2008)mightinactualfactsupportaroleforvaccine-inducedimmuneactivationinHIVacquisition(Tenbuschetal.
,2012).
Perhapsthiscouldbeasaresultofgeneralizedimmuneactivationorinductionofactivatedvaccine-specicHIV-1targetswithmucosal-homingproperties.
Shouldthisbethecase,thenthiswouldnotbeuniquetoAd5vectorsaloneanditwouldthereforebeexpectedtoequallyaffectotherdeliveryvectorscapableofinducingactivatedmucosal-homingtargetcells.
However,astherewerenonotabledifferencesinactivatedcirculatingTcellsbetweenvaccineesandplacebos,itisunlikelythatgeneralizedvaccine-inducedimmuneactivationplayedarole,althoughitremainspossiblethattherecouldhavebeensignicantdifferencesinactivatedtargetsatmucosalsiteswhichwerenotmeasured.
ThisthenraisesanotherinterestingquestionastowhethertheoutcomeoftheSTEP/Phambili/HVTN505studieswouldhavebeensignicantlyworse(orbetter)hadthevaccinesbeenadmin-isteredmucosally.
Thisquestionmighthavetwosidestoit,inthesensethatmucosaldeliverywouldprobablyhavegeneratedhigherfrequenciesofactivatedHIVtargetsatthegenitalmucosae,henceincreasingthepotentialoffuellinginfection.
Ontheotherhand,inductionofrobustandpolyfunctionaleffectorimmuneresponsesatmucosalportalsofHIVentrywouldprobablyhaveclearedtheincomingHIVbeforeinfectionbecameestablished.
Althoughthesequestionshavenoclearcutanswersandcannotbeaddressedretrospectivelyinthecontextoftheclinicaltrialstheyrelateto,theyhoweverhighlighttheextremechallengesinHIVvaccinedelivery,andnewstudiesdesignedtodirectlytackletheseissueswillbequiteinformativeforfuturevaccinedevelopmentresearch.
Studieslookingatwhetherthemostpromisingdeliv-eryvectors(andtherespectiveimmunogens)canconcurrentlyinduceactivatedHIV-1targetcellsthatpreferentiallyhometoandpersistinthegenito-rectalandGALTmucosae,andwhetherornotsuchvaccine-inducedcellsbecomehighlypermissivetoHIVinfectionwillbeofparticularinterestineffortsaimedatlimit-ingtheriskofvaccine-inducedHIV-1acquisitionandaccelerateddiseaseprogression.
PERSPECTIVESANDCONCLUSIONIdeally,vectorsforHIV-1vaccinesshoulddirectlytargetanti-genpresentingcells(APCs)orotherimmunecellstoinducelong-lived,strongantibodyandcellularresponsesthatcanbroadlydisseminatetosystemicandmucosalcompartments.
Thevaccine-specicTcellsinparticularshouldbebroadandcontainactivatedeffector,effectormemoryandcentralmem-oryphenotypesinvariousproportionsinordertoachieveaproperbalancebetweenimmediatevirusclearanceandsus-tainedimmune-surveillanceforlong-termprotection,asdemon-stratedbytheRhCMV-SIVvaccinewhichcontrolledandclearedpathogenicSIVinfection(Hansenetal.
,2009,2011,2013).
Furthermore,vectorswhichcanstimulatepolyfunctionalCD4+andCD8+TcellsthatactinconcertwithBcellstoinhibitHIVreplicationthroughavarietyofmechanismswouldbemoresuc-cessfulthanthoseinducingonlymono-functionalTcellsofeithersubsetalone.
FrontiersinMicrobiology|MicrobialImmunologyAugust2014|Volume5|Article439|14OndondoChallengesofHIVvaccinedeliveryOfparticularrelevancetoprotectionfrominfectionwouldbevaccinevectorsassociatedwithhomingandlong-termpersistenceofvaccine-inducedimmuneresponsivecellsatthegenito-rectalmucosae(ChanzuandOndondo,2014)aswellasothermucosalsitesservingasHIVreservoirs.
ThisremainsaveryimportantpriorityinconsiderationofthesignicantrapidCD4+TcelldepletionintheintestinalmucosadespitesuccessfulHAART(Brenchleyetal.
,2004;Mehandruetal.
,2004).
Thus,vac-cinevectorswhichnaturallyinfectcellswithinmucosalinduc-tivesites,especiallythereplication-competentvirusessuchasadenovirusandinuenzavirusvectors(Gherardietal.
,2003;Sextonetal.
,2009)whichcanbeadministeredmucosallytotriggermucosalimmunity,wouldbemoresuitedforHIVvac-cinedelivery.
Alternatively,deliveryofvaccinesviarouteswhichenhancemucosalimmunity(Holmgrenetal.
,2003;HolmgrenandCzerkinsky,2005;CzerkinskyandHolmgren,2012)orvec-torspossessinganinherentabilitytoinducemucosalimmunityinadditiontosystemicimmuneresponsesfollowingparenteralormucosalvaccinedelivery(Moseretal.
,2007)maybeemployed.
Virosomevectorsforinstance,possessintrinsicadjuvantprop-ertiesandauniqueabilitytotargetantigenpresentingcells,hencehavebeenverysuccessfulatinducingprotectivemucosalimmunityinSHIVchallengemodels(Moseretal.
,2007;Bomseletal.
,2011;Leroux-Roelsetal.
,2013).
OthervectorssuitableformucosalvaccinedeliveryincludeVEEV(Caleyetal.
,1997).
Intheabsenceofmucosaldeliveryvectors,newdeliverytechnolo-giessuchasthe"primeandpull"approachmaybeutilizedinconjunctionwithsystemicdeliverymethodstoenhancemucosalhomingandsubsequentimmunity(Azizietal.
,2010;ShinandIwasaki,2012;Tregoningetal.
,2013).
Inthisapproach,spe-cializedchemokinesareadministeredinmucosalcompartmentsfollowingparenteralimmunizationinordertochemo-attracttheactivatedvaccine-specicimmunecellsfromthesystemiccompartments.
Furthermore,useofmucosaladjuvantssuchasCTBandLT-B(Albuetal.
,2003;YukiandKiyono,2003),pro-inammatorycytokines(IL-1α,IL-12,andIL-18)(Belyakovetal.
,1998b;Bradneyetal.
,2002;Albuetal.
,2003)orimmunostim-ulatoryCpGmotifs(Horneretal.
,2001;Dumaisetal.
,2002;Daftarianetal.
,2003;Jiangetal.
,2005)whichtargetrecruitmentofimmunecellstothemucosalsiteswouldbeuseful.
Co-deliveryofvaccineswithgenesencodingCCL19andCCL28wasalsoshowntoenhanceHIV-1-specicTandBcellresponsesinthesystemicaswellasmucosalcompartments(Huetal.
,2013).
Inconsiderationofbothsafetyandimmunogenicitygoalsasalreadydiscussed,andwithparticularemphasisonthepivotalroleofCTLresponsesincontrollingHIVreplication,itseemsthatnon-replicatingviralvectorswithlowersero-prevalencewouldbehighlydesirable,mainlyduetoexcellentsafetyprolesandpotentadjuvanteffectallowingforinductionofverystrong,highqualityandlong-livedcellularandhumoralimmunity.
However,althoughsafetyandreducedimmuneinterferencewouldbeguar-anteed,amajorcaveatwouldbethattheselowersero-prevalencevectorsmaynotbeadequatelyimmunogenic.
Perhapsthesevec-torscanbere-engineeredtoimprovetheirimmunogenicpoten-tial.
Forinstance,theimmunogenicityofvectorssuchasMVAandNYVACcanbeimprovedbyremovalofgenesassociatedwithimmuneevasionwhichcounteractimmuneresponsestothevaccine(Kibleretal.
,2011;Gomezetal.
,2012;Garcia-Arriazaetal.
,2013).
Inothercases,additionofcytokine-encodinggenessuchastype1interferons,IL-12orGM-CSFcanenhancevac-cineefcacy(Gherardietal.
,1999,2000;Rodriguezetal.
,1999;RamshawandRamsay,2000;Bayeretal.
,2011).
Furthermore,chemokinessuchasCCL3whichrecruitsprofessionalAPCscanbeco-deliveredwithHIVantigenstoenhancevaccineimmuno-genicity(Lietzetal.
,2012).
Alternatively,vectorscapableofinducingsubstantialimmuno-genicityinthepresenceofpre-existingnaturalorvaccine-inducedanti-vectorimmunitymaybeworthconsidering,althoughitisexpectedthatndinghighlyattenuatedvectorswhicharesafeandremainimmunologicallypotentwillbeequallychalleng-ing.
Asdiscussedearlier,combiningsomeofthemostpromisingvectorsinheterologousprime-boostregimenswillsignicantlyenhancethequantity,qualityandprotectiveefcacyofimmuneresponses.
However,inconsiderationofthepossiblecatastrophiceffectsofelevatedimmuneactivationlikelytoarisefromvar-iousvectorcombinations,itwouldbeexpectedthatsuitableHIVvaccinevectorsmaintainlowerlevelsofimmuneactiva-tiontolimitthenumbersofactivatedHIV-1targets(Perreauetal.
,2008;Benlahrechetal.
,2009)likelytofuelinfectionintheeventofexposure.
Furthermore,itisdocumentedthatintheabsenceofaverystrongprotectiveimmuneresponsestocoun-teracttheincomingvirus,thepresenceofvaccine-specicTcellswhichareactivatedandhencemoresusceptibletoinfectionmayincreasetheriskofacquisition(Tenbuschetal.
,2012).
Whetheritispossibletoachievepotentimmunostimulatorycapacitybutwithminimalimmuneactivationstillremainsasubjectofintenseinvestigation.
Whensafetyandversatilityareconsidered,andinfullviewoftheenormoustechnologyadvancementsinDNAplasmidformu-lationsanddelivery,inconjunctionwithotherimmunomodula-toryinterventionssuchasSAPdepletionanduseofmolecularadjuvants,recombinantDNAvaccinesremainveryattractive,althougheffortstoimprovestimulationoflong-livedeffec-tor/memoryCD8+Tcellphenotypesarestillneededtoachievelong-termefcacy.
Undoubtedly,repeatedimmunizationsorcombiningDNAvaccineswithpersistent(replicating)vectorsorvectorswithslowimmunogenreleasefeatureswouldinducedurableimmunity.
Nonetheless,replicatingvectorswithlowersero-prevalenceandminimalpathogenicity(Roseetal.
,2001;Kawadaetal.
,2007;Fuchsetal.
,2013;Liuetal.
,2013)arebeingconsideredastheywouldprovideapersistentpoolofHIVvaccine-speciceffectormemoryphenotypecytotoxicTcellswhicharecriticalforlong-termprotectionfromdiseaseprogres-sion(Hansenetal.
,2009,2011,2013).
Sucheffectormemoryresponseswouldotherwisebeexpectedtowanewithtime,intheabsenceofantigen.
Replicatingvectorsmayalsobebetter-suitedforinductionofbroadlyneutralizingantibodiessincepersistingexpressionoftheEnvantigensislikelytodrivehighlevelsofsomaticmutationsrequiredforafnitymaturationoftheseanti-bodies(vanGilsandSanders,2013).
AnewstrategythathasbeenproventoinducedurableandprotectiveantibodyresponsesinhumanizedmicechallengedwithhighdosesofdiverseHIVstrainsisvectoredimmunoprophylaxis,whichinvolvesinser-tionofimmunoglobulingenesintoviralvectorssuchasthewww.
frontiersin.
orgAugust2014|Volume5|Article439|15OndondoChallengesofHIVvaccinedeliveryadeno-associatedvirus(AAV)toprovidelong-termexpressionofneutralizingantibodies(Balazsetal.
,2012,2014).
Moreover,inclusionofTh2cytokinessuchasIL-4,IL-5,andIL-6whichenhanceBcellmaturationintolong-livedantibodysecretingcellsisyetanotherstrategyalreadyshowntoinducehightitresofneutralizingantibodieswhichprotectedmicefromFriendVirus(Ohsetal.
,2013).
Otherpossiblestrategiesincludeuseoflentivi-ralvectorsexpressingBcellreceptorgenesencodingneutralizingantibodiestoHIV-1totransducehaematopoieticstemcells(Luoetal.
,2009).
Sinceoptimuminductionofimmuneresponsestovaccinesstronglydependsoninnateimmunetriggeringaswellasthelevelsoftransgeneexpression,vectorswithnaturaladjuvantproper-tiesandthereforecapableofstronglyinducinginnateimmu-nityareparticularlyimmunogenicandthushighlydesirable.
However,caremustbetakentobalancebetweenstronginnatefunctionstimulationandthepotentialriskofinducingpotentstimulationofimmuno-pathologicaleffects,includingimmunehyper-activation.
Inconclusion,asuccessfulvaccineforHIVwillhavetostimu-latepotentantibodyandCTLresponsesbroadenoughtocovermultipleHIVvariantsandwithpotentialtoneutralize,bindorsuppressHIV-1replicationforsustained(possiblyinnite)lengthsoftime.
Ofutmostimportance,howeverisgenerationofvaccine-specicimmuneresponsesinthegenito-rectalmucosae,themajorportalsofHIVentry.
Emergingevidencestronglysuggeststhatnon-pathogenic,low-levelreplicatingviralvectorswhichcanmimicliveattenuatedvaccines,butwithlowsero-prevalencemightbethebestwaytoachieveHIVvaccineefcacy.
Asthesevectorspersistlongafterimmunization,theyarecapableofinducingandmaintainingeffector/memoryCTLsforcontin-uedimmunesurveillancethatisnecessarytoprotectfrominfec-tion,diseaseprogressionandtoclearorpreventestablishmentoflatentreservoirs.
Thus,toachieveprotectiveefcacyHIVvaccinedevelopmentwillneedingeniousstateofthearttechnologiestocreatetheverybestofTcellandantibodyimmunogens,deliv-eredbythemostpotentbutsafevectorspossessingremarkablyhighcapacitytoinducebothsystemicandmucosalimmunity,butwithoutsignicantimmuneactivationlikelytofuelHIVacquisi-tion.
RecentsignicantadvancesinvaccinedeliverytechnologiesandHIVimmunogendesignprovidehopethatthisisnotfarfromreality.
ACKNOWLEDGMENTSBeatriceO.
OndondoisaseniorHIVvaccinedevelopmentimmu-nologistemployedonaresearchgrantsupportedbyMRCUK.
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0329ConictofInterestStatement:Theauthordeclaresthattheresearchwascon-ductedintheabsenceofanycommercialornancialrelationshipsthatcouldbeconstruedasapotentialconictofinterest.
Received:30June2014;accepted:03August2014;publishedonline:22August2014.
Citation:OndondoBO(2014)TheinuenceofdeliveryvectorsonHIVvaccineefcacy.
Front.
Microbiol.
5:439.
doi:10.
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00439ThisarticlewassubmittedtoMicrobialImmunology,asectionofthejournalFrontiersinMicrobiology.
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