TUBERCULOSIS VACCINE CANDIDATES 2010 Stop TB Partnership Working Group on New TB Vaccines

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1 TUBERCULOSISVACCINECANDIDATES 2010 StopTBPartnershipWorkingGrouponNewTBVaccines According to the Global Plan to Stop TB, , Encouraging and consistent scientific results from the laboratory and from early field trials indicate that the introduction of new, effective TB vaccines will be an essential component of any strategy to eliminate tuberculosis (TB) by New TB vaccines to prevent childhood and adult forms of tuberculosis, to reduce tuberculosis in persons co-infected with HIV, and to shorten drug treatment regimens will fundamentally alter our approach to TB control. A number of the new generation of TB vaccines may work best using a heterologous prime-boost strategy to complement the immune response induced by the current BCG. This prime-boost strategy could include administration of BCG or a new recombinant live replacement vaccine as the prime, followed by a booster inoculation with a different vaccine to infants and young children before they are exposed to TB (preexposure), as a separate booster to young adults, either before they are exposed or who may have already been exposed to TB (post-infection) or as an adjunct to chemotherapy (immunotherapy). TB vaccines under development could work in several ways: Prevent infection Prevent primary disease Prevent latent infection Prevent reactivation of latent infection Shorten the course and improve the response to chemotherapy TuberculosisVaccinePipeline2010 1

2 In the following table, tuberculosis vaccine candidates are presented in three categories: Candidates Tested in Clinical Trials (Section I): TB vaccine candidates that are in clinical studies in Certain candidates that have been in clinical studies but are not currently in clinical trials are listed as completed. Candidates in Preclinical Studies & GMP-2010 (Section II): TB vaccine candidates that as of 2010 are not yet in clinical trials, but have been manufactured under good manufacturing practice (GMP) for clinical use and have undergone some preclinical testing that meets regulatory standards. Next Generation Candidates-2010 (Section III): TB vaccine candidates that are in the research and development stage with some preclinical testing performed to show that they may confer protection. Vaccine candidates are further divided into specific Vaccine Types: Recombinant Live; Viral Vectored; Recombinant Protein or Other and a brief description is provided. The Table lists vaccines intended to be used as a Prime ( ) or Booster ( ) vaccine, as a Post-infection vaccine ( ) or in immunotherapy ( ). The information contained here was provided and updated by the vaccine developers unless otherwise indicated. In cases where an update regarding a previously listed vaccine candidate was not received in 2010, the 2009 listing was retained. TuberculosisVaccinePipeline2010 2

3 TUBERCULOSISVACCINECANDIDATES 2010 StopTBPartnershipWorkingGrouponNewTBVaccines SECTIONI:CandidatesTestedinClinicalTrials TypeofVaccine Products Productdescription Sponsor Indication VPM1002 rbcgpraguestrainexpressinglisteriolysinand carriesaureasedeletionmutation RecombinantLive rbcg30 rbcgticestrainexpressing30kdamtb antigen85b;phaseicompletedinu.s.. UCLA,NIH,NIAID,Aeras RecombinantBCGexpressingmutatedPfoA AERAS422 andoverexpressingantigens85a,85b,and Rv3407 ViralVectored Recombinant Protein WholeCell, Inactivatedor Disrupted OxfordMVA85A/ AERAS485 AERAS402/Crucell Ad35 AdAg85A M72+AS01 HybridI+IC31 HybridI+CAF01 HyVac4/AERAS404, +IC31 M.vaccae Mw[M.indicuspranii (MIP)] ModifiedvacciniaAnkaravectorexpressing Mtbantigen85A Replicationdeficientadenovirus35vector expressingmtbantigens85a,85b,tb10.4 Replicationdeficientadenovirus5vector expressingmtbantigen85a Recombinantproteincomposedofafusionof MtbantigensRv1196andRv0125&adjuvant AS01 Adjuvantedrecombinantproteincomposedof Mtbantigens85BandESAT6 Adjuvantedrecombinantproteincomposedof Mtbantigens85BandESAT6 Adjuvantedrecombinantproteincomposedof afusionofmtbantigens85bandtb10.4 InactivatedwholecellnonTBmycobacterium; phaseiiiinbcgprimedhiv+population completed;reformulationpending WholecellsaprophyticnonTBmycobacterium Statusas of2010 Citations MaxPlanck,VakzineProjekt ManagementGmbH,TBVI PhaseIb [14] PhaseI [completed] [59] Aeras PhaseI [1012] OxfordEmergentTubcerulosis Consortium(OETC),Aeras PhaseIIb [1317] Crucell,Aeras PhaseIIb [1011,18 20] McMasterUniversity PhaseI [2125] GSK,Aeras PhaseII [2629] StatensSerumInstitute(SSI), TBVI,EDCTP,Intercell PhaseI [3034] SSI PhaseI SSI,SanofiPasteur,Aeras, Intercell PhaseI [3537] NIH,Immodulon DepartmentofBiotechnology (MinistryofScience& Technology,Governmentof India),M/s.Cadila PharmaceuticalsLtd. PhaseIII [completed] [3842] PhaseIII [4345] TuberculosisVaccinePipeline2010 Prime, Boost, Postinfection, Immunotherapy 3

4 RUTI FragmentedMtbcells ArchivelFarma,S.I. PhaseII [4650] M.smegmatis a Wholecellextract;phaseIcompletedinChina SECTIONII:CandidatesinPreclinicalStudies&GMP2010 PhaseI [completed] TypeofVaccine Products Productdescription Sponsor Indication Citations Mtb[lysApanCD Nonreplicating,Mtbstrainauxotrophicfor AlbertEinsteinCollegeof seca2] lysineandpantothenate;attenuatedforseca2 Medicine [5152] RecombinantLive LivevaccinebasedonattenuationofMtbby UniversityofZaragoza, MTBVAC[phoP,fad stableinactivationbydeletionofphopandfad InstitutePasteur,BIOFABRI, D26] D26genes TBVI [5357] Naturallymethylated21kDapurifiedprotein InstitutePasteurofLille, HBHA Recombinant fromm.bovisbcg INSERM,TBVI [5862] Protein Adjuvantedrecombinantproteincomposedof Hybrid56+IC31 Mtbantigens85B,ESAT6andRv2660 SSI,Aeras,Intercell Other HG85A/B ChimericDNAvaccines Ag85A/Ag85B ShanghaiH&GBiotech [6367] SpraydriedBCG b SECTIONIII:NextGenerationCandidates 2010 LiveattenuatedBCGDanishStrainspraydried fornasaladministration MEND [68] TypeofVaccine Products Productdescription Sponsor Indication Citations RecombinantLive HG856BCG rbcgoverexpressingchimericesat6/ag85a ShanghaiPublicHealthClinical [6365,69 DNAfusionprotein Center 70] IKEPLUSM.smegmatis LiveM.smegmatiswithdeletionofESX3 AlbertEinsteinCollegeof withesx3deletion/ encodinglocusandcomplementationwithmtb Medicine,Aeras complementation locus BCGwithreducedactivityofantiapoptotic pabcg microbialenzymesincludingsoda,glna1, VanderbiltUniversity [71] thioredoxin,andthioredoxinreductase a Candidate information communicated by the Wuhan Institute of Biological Products. b Candidate information communicated by TBVI. TuberculosisVaccinePipeline2010 Prime, Boost, Postinfection, Immunotherapy 4

5 ProapoptoticrBCG rbcg(mbtb)30 rbcgt+b rm.smegmatist+b rbcgtbmalaria rbcg38 RecombinantBCGexpressingmutatedPfoA andincludingmutationsshownataecomto inducemacrophageapoptosis rbcgwithlimitedreplicationoverexpressing the30kdamtbantigen85b rbcgandrm.smegmatisexpressingmultiplet andbepitopesofmtb ExpressesmultipleepitopesofMtbfusedto malarialepitopesandantigens rbcgticestrainoverexpressthe38kda protein Aeras,AlbertEinsteinCollege ofmedicine UCLA,NIH,NIAID [72] FinlayInstitute,UniversitiSains Malaysia [7375] UniversitiSainsMalaysia [76] UniversidadNacional AutónomadeMéxico [7780] Recombinant Protein ViralVectored rbcgmex38 rbcgoverexpressing L,DTranspeptidase Replicationdeficient rbcg rm.microti30 rm.microti38 Streptomyceslive vector ID93inGLASE adjuvant Latencyfusion proteins r30 R32Kda (recombinant85a) RecombinantLCMV pndvector rbcgmexicostrainoverexpressthe38kda protein RecombinantM.bovisBCGoverexpressingan MtbL,DTranspeptidase RecombinantBCGexpressingPfoAand classical,latency,andresuscitationantigens inlive,nonreplicatingbackground rm.microtistrainoverexpressthe30or38kda protein Recombinantstreptomycesexpressingmultiple TandBepitopesfromM.tb Subunitfusionproteincomposedof4Mtb antigens Recombinantfusionproteinscomposedof antigens85a85brv3407,rv3407rv1733c Rv2626c,Rv0867cRv1884Rv2389c 30kDaMtbAg85Bproteinpurifiedfrom rm.smegmatis Purifiedrecombinant85AproteinfromBCG Recombinantlymphocyticchoriomeningitis virusexpressingag85a,ag85b,orag85b ESAT6 pnd14vectorwithtpafactorexpressingesat6, cfp10,hspx,ag85a,ag85b,orag85c UniversidadNacional AutónomadeMexico [79,81] JohnsHopkinsUniversity [82] Aeras UniversidadNacional AutónomadeMexico [78,83] FinlayInstitute,Instituteof PharmacyandFood,Cuba [7475,84] InfectiousDiseaseResearch Institute [8586] Aeras UCLA,NIH,NIAID [8791] BhagawanMahavirMedical ResearchCenter,LEPRASociety BluePeterResearchCentre [9295] UniversityofGeneva HECPakistan TuberculosisVaccinePipeline2010 Prime, Boost, Postinfection, Immunotherapy 5

6 Other Ac 2 SGLDiacylated Sulfoglycolipid HG856A HG856SeV HspDNAvaccine HVJEnvelope/HSP65 DNA+IL12DNA LiporaleBCG Mycobacterial liposomesandproteo somes NasL3/AM85B conjugate NasL3/HtkBCG (BCGadjuvant) PSconjugate pumvc6/7dna c RecombinantB/HPIV MycobacteriallipidswithAc 2 SGL,anovel glycolipidantigen ChimericDNAvaccines ESAT6/Ag85A; Ag85A/Ag85B RecombinantSendaivirusoverexpressing chimericesat6/ag85aprotein CodonoptimizedheatshockproteinfromM. leprae,acpgisland CombinationofDNAvaccinesexpressing mycobacterialheatshockprotein65&il12 LiveattenuatedBCGDanishStraininanovel lipidadjuvantanddeliverysystemforanoral vaccine LiposomesfromM.smegmatisandproteo liposomesfrombcgandm.smegmatis NasalvaccinewithmancappedArabinoman nanoligosaccharideconjugatedtoag85bin EurocineL3 TM adjuvant IntranasalheatkilledwholeBCGCopenhagen strainineurocinel3 TM adjuvant SubunitMtbpolysaccharideproteinconjugate DNAvaccineplasmidvectorspUMVC6or pumvc7expressingrv3872,rv3873,rv3874, Rv3875orRv3619c RecombinantB/HPIVvectorencodingfusionof antigens85a85brv3407,rv3407rv1733c Rv2626c,Rv0867cRv1884Rv2389c InstitutdePharmacologieet BiologieStructuraleduCNRS [96] ShanghaiH&GBiotech [97] ShanghaiH&GBiotech CardiffUniversity,Sequella [98101] OsakaUniversity [102106] ImmuneSolutionsLtd. [107111] FinlayInstitute UniversitiSainsMalaysia KarolinskaInstitute [112116] KarolinskaInstitute [117119] AlbertEinsteinCollegeof Medicine KuwaitUniversity [120] NIH,Aeras TBioVax HeatshockHspCproteinantigencomplexes ImmunoBiologyLtd. [121122] TBVax TcellepitopebasedDNAprime/peptideboost vaccine EpiVax,Inc. [123125] c Candidate information acquired from published literature. TuberculosisVaccinePipeline2010 Prime, Boost, Postinfection, Immunotherapy 6

7 Key: Prime Boost Candidateisindicatedpostinfection Candidateisindicatedforimmunotherapy BCG BacilleCalmetteGuérin IL Interleukin GMP GoodManufacturingPractices GSK GlaxoSmithKlineBiologicals M.bovis Mycobacteriumbovis Mtb Mycobacteriumtuberculosis NIAID NationalInstituteofAllergyandInfectiousDiseases NIH NationalInstitutesofHealth OETC OxfordEmergentTuberculosisConsortium,Ltd. SSI StatumSerumInstitute TBVI TuberculosisVaccineInitiative UCLA UniversityofCaliforniaLosAngeles TheaimoftheStopTBWorkingGrouponNewVaccinesistobringtogetherthewiderangeofinternationalgroupswithan interestintbvaccinedevelopment,actingasa"broker"topromotesynergyandtoaccelerateidentificationandintroductionofthe mosteffectivevaccinationstrategy.thisisachievedbyrepresentationofnationalandinternationalpublichealthorganisms,major fundingorganizations,tbendemiccountries,commercialandnonprofitinstitutionsinvolvedintbvaccinedevelopment,aswellas expertsinregulatoryissuesassociatedwithvaccinedevelopment. TuberculosisVaccinePipeline2010 7

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