Professional Documents
Culture Documents
Vaccine Design Strategies: What We Have Tried and What We Have Learned (Jerome Kim)
Vaccine Design Strategies: What We Have Tried and What We Have Learned (Jerome Kim)
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ClassicViralInfectionandImmunity
Ingeneral
Despitedifferencesinmanifestationsand
eradicationbytheimmunesystem
Peopleareprotectedagainstfutureinfection
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WhyisHIVDifferent?
HIVdiseaseprogressesrelentlesslyinallbut
afewcases,andspontaneousresolution doesnotoccur
Youdontgetbetter,thevirusnevergoes away
Theimmunitythatdevelopsdoesnot
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ScientificChallengestoHIVVaccineDevelopment
Insufficientknowledgeaboutimmunityrequiredtocontroland protectagainstinfection
Lackofaneffectivevaccine Lackofidealanimalmodel
HIVstrainvariationposesalargehurdleforanyvaccine(flu HIV strain variation poses a large hurdle for any vaccine (flu vaccine) HIVisamasterofdisguise
HIVtransmissioniscomplexandbehavioral IntegrationintohostcellDNAhidesthevirus
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AdaptedfromHaase,A(2005)
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Onlyafewvirusesescapethebottleneck
The risk of transmission of HIV via rectal mucosa ( (1/20 1/300) > genital mucosa ( ) g (1/200 1/3000) ) Usually only a single transmitted, founder virus establishes an infection and the transmitted founder founder viruses appear to have unique characteristics People acutely ( y recently) infected with HIV p y (very y) carry the highest risk of infecting others because most of the virus in their blood is a copy of the original transmitted founder g So, it may be possible to block transmission at the level of the single transmitted/founder infection, or perhaps to prevent that infection from spreading preventing the take
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X X
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Whatimmuneresponsescanblockinfection?
Antibody
Cellmediatedimmuneresponses
Innateimmuneresponses
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HowmightanHIV/AIDS vaccinework?
ImmuneAb Response?CTL CTL CTL CTL
1
PREVENT INFECTION
HIV
B A C
Vaccine Administered
A.LowerInitialPeakofViremia
2
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p B.Decreaseviralsetpoint C.DelayProgression C.
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Howdoweknowwhatvaccinestotest?
Animalmodels
ExamplesfromchronicHIVinfection
Intheabsenceofasuccessfulhumantrialandtruecorrelates ofprotection(orrisk)derivedfromthattrialtheinferences of protection (or risk) derived from that trial the inferences fromanimalandchronicinfectionmodelsmaybeincorrect Testofconcept(PhIIb)trialsmovethefieldforward
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Informedbyscience notashotinthedark
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HIVVaccineEfficacyTrials/Concepts
TRIAL Vax003 Vax004 Step Phambili VACCINE AIDSVAX B/E AIDSVAX B/B MRKrAd5 MRKrAd5 MRK rAd5 Antigen A244, MN,gD MNE8, MN,gD g Gag,Pol,Nef Gag,Pol,Nef Gag, Pol, Nef Clade B/E B/B B B Population ThaiIDU MSM MSM S.AfricanHigh S. African High incidence heterosexual Thailowrisk community MSM enrolling lli Vaccine Efficacy(VE) 0.1% (31, 24%) 6% 6% (17,24%) futility halted
RV144
92TH023gp120; LAIgag/pro, A244,MNgD Gag (D/A),Pol (D/A),Nef (D), (D/A) Nef (D) Env (D/A)
E/B
31.2% 31 2% (1,52)
HVTN505
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PreviewofAVM2011
DoesvaccinationchangetheappearanceofHIVdiseasein peoplewhohavebeenvaccinatedandbecomeinfected?
WorkonCorrelatesofProtection(Prof.BartHaynes)
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RV152:Breakthroughinfectionsafter vaccinationwithALVAC+AIDSVAXB/E
ImmuneAb Response?CTL Response ?CTL CTL CTL CTL
1
PREVENT PREVENT INFECTION
HIV
Vaccine Administered
KeyQuestion:DidvaccinationwithALVAC K Q i Did B i i i h ALVAC C A andAIDSVAXB/EreduceHIVdisease comparedtoplaceborecipientswho compared to placebo recipients who becameinfected?Ordidithavenoeffect? A.LowerInitialPeakofViremia 2
REDUCE REDUCE DISEASE B.Decreaseviralsetpoint B. Decrease viral set point C.DelayProgression C.
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TheSearchforCorrelates
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Whatisacorrelateofprotection?
Acorrelateisalaboratorytestorassaythatprovides appearstoberelated(statistically)totheriskofHIV pp ( y) infection Correlatesaremeasuredbylookingatimmuneresponsesin vaccinatedpersonsonly comparingHIV+casestoHIV i t d l i HIV+ t HIV vaccinatedcontrolsNOTagainstplaceborecipients Example:Iftheamountofantibodyagainsttheoutercoat p y g ofHIVishigh,therateofinfectionislow,andiftheamount ofantibodyislowtheinfectionrateishigh,itcould mean thattheantibodytotheHIVoutercoatprotectsagainst that the antibody to the HIV outer coat protects against infection
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Example:Acorrelatethatdecreasesinfectionrate Antibodytoviraloutercoatprotein
HIGH RateofInfection LOW
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HIGH
LOW
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Whyarecorrelatesimportant?
Vaccinescouldbedesignedtotrytomaximizethe amountofantibodytotheoutercoatprotein,this y p , wouldtellushowtomakebetterchangesmore rationallyandcouldspeedupthedevelopmentofa betterAIDSVaccine better AIDS Vaccine Ifanonhumanprimatestudywheremonkeysare vaccinatedandthenchallengedwithvirusidentifieda similarcorrelate,thenthemonkeymodelcouldbe usedtoaccelerateHIVvaccinedevelopmentby pointingoutthe best candidates pointing out the bestcandidates
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AretheredrawbackstouseofCorrelates?
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VaccinationandFollowupSchedule
V8 2wks postvax
CORRELATESANALYSIS: HOWDOESTHEIMMUNE HIVtest, HIV AT THIS RESPONSEATTHISPOINT RESPONSE test, POINT riskassessmentandcounseling RELATETOHIVINFECTIONS OVERTIME?
0.5 05
6monthvaccination schedule
2
3yearsoffollowup(every6mo.)
ALVACHIV (vCP1521)primingatweek0,4,12,24 AIDSVAX B/E gp120boostingatweek12,24 AIDSVAXB/E gp120 boosting at week 12, 24
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CriteriaforAdvancingAssaystotheCase ControlStudy
Criterion
1.Lowfalsepositiverate(judgedinplaceborecipientsand Week0responsesofvaccinees) 2.Vaccine inducedresponses withbroadvariability 2. Vaccineinduced responses with broad variability 3.Represents anicheinimmunologicalspace ( (nothighlycorrelatedwithotherassays) g y y) 4.Relativelylownoise(e.g., high reproducibilityonreplicatesamples) 5.Relativelylowspecimen volumerequirement 5 R l i l l i l i 6.Previouslyidentified asacorrelate inVax004
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RV144CorrelatesPrimaryImmunologicalVariables
Primary Variable 1.PlasmaIgA bindingscoreto an AntigenPanel[n=14 antigens]* 2.IgG avidity scoretoA244gD D11 3.ADCCluciferase 92TH023 4.NAb TZMbl +A3R5AUCMBtoan AntigenPanel[n 6] Antigen Panel [n=6]** 5.gp70V1V2 6.CD4+ TcellhelpICSmagnitude[% CD4+Tcellsexpressingatleastoneof IFNg,IL2,TNFa,CD154] AlternatePrimary ToggleVariable forSensitivity Analysis 1.PlasmaIgA bindingtoA244gD Delta11 2.IgG avidity scoretoMNgD 3.ADCCgp120coated CM243 4.TZMbl AUCMB[n=3targets] 5.TZM bl AUC MB[n 1target] 5. TZMbl AUCMB [n=1 target] 6.A3R5AUCMB[n=2targets] 7.V2 42aacyclicpeptide 8.AverageLuminex readoutfor9 cytokines[IL2, TNFa,IL10,IL13, MIP1b,GMCSF,IL4,TNFb] LabPI forPrimary/ PrimaryToggleVariable Tomaras/Tomaras Alam/Alam Evans/ Ferrari AFRIMs Sutthent [Siriraj hospital] Montefiori ZollaPazner/ZollaPazner McElrath/ McElrath
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CompleteSetofAssaysRecommendedfor AdvancementtotheCaseControlStudy
AssaysRecommended toInclude [SufficientDatatoSupportaDecisionNow] BailerPeptideMicroarrays BermanV2loopELISA BermansCD4blockingELISA ZollaPazner ELISAgp70V1V2,severallinearV2 peptides,V3binding Haynes/ParkscompetitionELISAmAb A32 H /P k titi ELISA Ab DeVico CompetitionELISAmAb A32 LewisCD4iepitope assaybyflow Afrims + Siriraj TZM bl NAb +Siriraj TZMbl MontefioriTZMbl +A3R5NAb RaoSPRbindingtocyclicV2 andV3peptides TomarasLuminex f forIgA,IgG,IgM,IgG subclass b l EvansADCC Ferarri ADCCgp120coatedcells Alam SPR binding Ab avidity SPRbindingAb avidity gD Ab levels(Tomaras,Alamavidity,FerrariADCC)
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McElrathBcell ElISpot McElrathEnvspecific ICS McElrathEnvspecific cytokines(Luminex) McElrath CFSEassay,Envonly92TH023 McElrathNK/DC/Tcellphenotypepanel M El th NK/DC/T ll h t l McElrathBcell ElISpot McElrathenvspecific ICS McElrathenvspecific cytokines(Luminex) McElrath env specific cytokines (Luminex)
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Summary:A244gp120andinducedimmuneresponses
330
S I T I R T G 310 T P N V N G H N E S L Q 320 N P S K S R V V V I N C T R F I Y R I I E C Y A K R T 340 I N I D G I I D G 350 E G E E A L S G N L L L T Q 290 200 N G E F T 280 T W 360 K L D I V P N 420 260 Y S N G F K I A N G V L S V P K 270 T S I Q A E D A L K Q V I C N C T V C V H D H G C K N P E I K T T V N K 250 T C Y G N P E K 240 H L N C I N I A Y G A K Q D 210 370 N F P H E K L K 190 S I L G F K P 410 R N E S I K D N D Y Q V 230 R F I T 380 N L E P S R I S T T 220 T C K K P I L 430 T T K P L I L N V N M P T F I N C C P C P N Q C K P C 180 F 130 Y S P P L K T V GG 140 I K L F S S 170 D Q H I 390 L F C Q I T I N N 400 E C E G D E V R D N 440 G I I 120 T T MH H F N C R W M I Q E N M D V L W N Q V C N I S A E I N S 460 I Q T S V N T G G I V 150 L M 110 G A L G N N K W M N F N E T V N T N S 450 L K A Q E T I 160 90 Y M N A T R P A L 100 L R D N N P 470 P V W A T H A T G G P V T V N D C A T H N D PN Q E I 80 N A L A V A C F Y N D S 490 L T K E D A T K I N A 70 S L T N D G T K D 480 N K M A G A E W R A D H G R N P 40 V G E G H L N P R F T E N G V R K 60 I V F E A P V R COOH R W R E K 510 G V 50 F L G K D V V E L T L PV L D Q L L E V P I Y L V R V 500 K Y K V V Q I E P A K R R A 520 G L R NH2 A A A G G M
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T N N A K T I L I
47bs LDI
V2
V3 BindingantibodytoV2 VaccineserashowblockingAb signaturetargeting V2,V2V3,C1 V2 V2V3 C1 Env andV2specificBab decreaseaftervaccination V4 MonoclonalantibodiesfromsortedBcellsare specificforV2andothergp120epitopes CellularimmuneresponsesgeneratedtoV2
V1
gD
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Acknowledgements
RV144volunteersandcommunitymembers AFRIMS USandThaiComponent DivisionofAIDS,NationalInstituteofAllergyandInfectiousDiseases,NIH Division of AIDS National Institute of Allergy and Infectious Diseases NIH FacultyofTropicalMedicine,Mahidol University GlobalSolutionsforInfectiousDiseases HenryM.JacksonFoundationfortheAdvancementofMilitaryMedicine MinistryofPublicHealth,Thailand sanofi pasteur TheBill&MelindaGatesFoundationsCollaborationforAIDSVaccineDiscovery (CAVD) CenterforHIV/AIDSVaccineImmunology(CHAVI) RoyalThaiArmy HIVVaccineTrialsNetwork(HVTN) FredHutchinsonCancerResearchCenter,SCHARP U.S.MilitaryHIVResearchProgram,WalterReedArmyInstituteofResearch;U.S. ArmyMedicalResearchandMaterielCommand
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