TBVI the European Tuberculosis Vaccine Ininiative. Brigitte GICQUEL INSTITUT PASTEUR

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1 TBVI the European Tuberculosis Vaccine Ininiative Brigitte GICQUEL INSTITUT PASTEUR

2 Moving towards a TB free world in 2050 Foundation to facilitate European efforts Foundation to facilitate European efforts towardsthe the global global development development of of new new towards TBvaccines vaccines TB 5www.tbvi.eu March 2008

3 Discovery of the TB bacilli by Robert Koch (1882) However No extracts or killed TB bacilli confers protection against TB

4 1908, Calmette and Guerin isolate an attenuated culture of M. bovis that protects against tuberculosis

5 1921, vaccination starts

6 BCG Vaccine Most widely used vaccine (100 M doses/year) Recommended for widespread use by League of Nations in 1928 Prevents 30k meningitis and 11 k miliary TB cases in children/year

7 Retrospective study by Calmette: Data were obtained from 204 TB clinics Children born in 1925, 1926 and They were living in contact with TB patients Non vaccinated children 4854 BCG vaccinated children 2368 TB mortality 15,9% 3,4%

8 Efficacy of BCG as determined in controlled trials and observational studies in various populations 1 = Tuberculous meningitis 2 = Contact study 3 = Prospective cohort study Colditz GA JAMA (1994) 271: 698

9 BCG vaccination rate all children Children born in Sweden - Period of birth No. No./ 100,000 Cumulative incidence rate of tuberculosis below 5 years of age Swedish Parents 95% confidence interval No. No./ 100,000 Foreign Parents 95% confidence interval Relative risk Foreign/Swedish A. >95% 01/ / (0.3,1.9) (0.3,9.6) 3.4 (0.3,20) B. <5% / (2.3,6.1) (27,57) 10 (5.5,20) C. 7-17% 01/ / (1.5,5.1) 6 11 (4.2,25) 3.9 (1.2,11) Relative Risk B/A C/A (1.7,16) (1.2,13) (3.7,130) (0.8,43) Romanus V Bull Int Union Tuberc Lung Dis (1988) 63:34-8

10 History TBVI Tuberculosis Vaccine Cluster EU Framework Programme 5 Integrated Project TBVAC EU Framework Programme 6 Integrated Project 2000 Present 2007 EU R&D Commission Supports creation of a separate entity : TBVI Established

11 TuBerculosis Vaccine Initiative (TBVI) Integrated European effort to develop effective, safe, globally accessible & affordable TB vaccines > 40 of world s best universities, research institutes, and industries in TB vaccine development Responsibility and ownership for each candidate left with partner TBVI fills the TB vaccine pipeline with Priming vaccines Boosting vaccines TBVI builds on the success of EU TB vaccine research programs 4 new priming and boosting vaccines in clinical phase I to II stages 4 new priming and boosting vaccines in preclinical and non clinical stages 3 new adjuvants, one of which in clinical phase I studies 15 new biomarkers with potential to be used in monitoring of clinical trials

12 Working model TBVI Discovery Preclinical Clinical Phase I/IIa Phase IIb/III License/ Phase IV Product and Clinical development teams TBVI Aeras/Industry/EDCTP Facilitate discovery, preclinical and early clinical TB vaccine development Responsibility and ownership of candidate vaccine with individual project partners Guide and advice on development by tailor made product and clinical development teams (PDT/CDT) Stimulate late clinical development

13 Vaccine candidates TBVI Priming Phase I rbcg::hly Preclinical to nonclinical att. MTB:PhoP 6 rbcg 1 att. Mtb. Discovery 3 rbcg 6 att. Mtb 1 att. Mbovis Boosting Phase I/II (MVA/85A) (M72/AS01) H1/IC31 H1/CAF01 Preclinical to nonclinical HBHA 3 subunit/adjuvant 1 Lipid based 2 Viral delivery based Discovery 1 Subdominant antigens 1 Peptidome antigens 1 Lipid antigens 1 Reactivation antigens 1 Resuscitation antigens 2 Latency antigens

14 TBVI partners Argentinia Veterinary and Agriculture Research Centre National Institute for Agricultural Technology Belgium Université Libre de Bruxelles Institut Scientifique de Sante Publique GSK-Biologicals European Commission Denmark Statens Serum Institute European Malaria Vaccine Initiative (EMVI) Ethiopia Armauer Hansen Research Institute Finland FIT Biotech France Centre National de la Recherche Scientifique Institute National de la Santé et de la Recherche Médicale Institut Pasteur Paris Institut Pasteur Lille Institut Mérieux PX therapeutics The Gambia MRC The Gambia Germany University of Lübeck Technical University of Munich Max-Planck Institute for Infection Biology University of Tübingen University of Ulm University of Erlangen-Nürnberg Vakzine Projekt Management Italy National Institute for Infectious Diseases Lazzaro Spallanzani University of Palermo Istituto Superiore Di Sanita University of Padua Netherlands Central Veterinary Institute of Wageningen UR Biomedical Primate Research Centre BioMedical Research of Wageningen UR Leiden University Medical Center Free University of Amsterdam Netherlands Vaccine Institute European Developing Countries Clinical Trials Partnership Senegal Hospital Le Dantec South Africa University of Cape Town South Korea Institut Pasteur Korea Educational Foundation Yonsei University International Vaccine institute Portugal Gulbankian foundation University of Porto Spain Universidad de Zaragoza Facultad de Medicina Fundacio Institut De Investigado de Ciencies De La Salut Germans Trias I Pujol CZ Veterinaria/BIOFABRI Switzerland Institute for Research in Biomedicine University of Geneva University Hospital of Basel University of Zürich Centre Hospitalier Universitaire Vaudois STOP TB Partnership United Kingdom Health Protection Agency Porton Down University of Birmingham Aston University Manchester University Medical School, Imperial College of Science Technology and Medicine National Institute for Biological Standards University of Oxford London School of Hygiene and Tropical Medicine Veterinary Laboratory Agencies University College London USA Aeras Global TB vaccine Foundation Bill and Melinda Gates Foundation.

15 Sub-unit and monovalent vaccines

16 Bacterial numbers in organs of vaccinated mice after challenge with virulent M. tuberculosis Immunization a Spleen Result for expt 1 b Lung Result of expt 2 b Spleen Control BCG 4.00 (P = ) 2.94 (P = ) 2.96 (P = ) ST-CF-PBS ND PBS-DDA ST-CF-DDA 4.17 (P = ) 2.93 (P = ) 3.46 (P = ) Andersen P (1994) Infect Immun 62:

17 Protection in naive and sensitised mice after vaccination and aerosol challenge with M. tuberculosis Vaccine Group Exp. 1 Log 10 CFU Lung Log 10 resistance Control 6.36 (+/-0.08) Naive BCG 5.83 (+/-0.06) 0.53* ESAT (+/-0.09) 0.60* Control 6.18 (+/-0.08) Sensitised BCG 6.27 (+/-0.07) <0.05 ESAT (+/-0.16) 0.44* Exp.2 Naive Control Ag85B-ESAT (+/-0.12) 6.03 (+/-0.12) 0.85* Sensitised Control Ag85B-ESAT (+/-0.08) 5.37 (+/-0.14) 0.93* Olsen AW et al. Infect Immun (2001) 69: *Significantly different compared to naive mice

18 Pre-clinical results DNA-MVA protection equivalent to BCG with various antigens in mice (McShane et al, 2001 Infect Immun (2001) 69:681-6) BCG-MVA85A immunogenic and protective in guinea pigs (Williams A Infect Immun (2005) 73:3814-6)

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20 McShane H, et al. Nat Med. (2004) 10:

21 Live attenuated vaccines

22 RD1 mic versus RD1 bcg region M. tuberculosis H37Rv RD1 bcg Rv3863 Rv3865 Rv3867 Rv3864 Rv3866 Rv3868 Rv3869 Rv3870 Rv3871PE/PPE Rv3874 esat6 Rv3876 Rv3877 Rv3878 RD1 mic Rv3879 Rv3880/81 Pym A S et al. Nat Med (2003) 9:

23 RD1 mic versus RD1 bcg region M. tuberculosis H37Rv RD1 bcg Rv3863 Rv3865 Rv3867 Rv3864 Rv3866 Rv3868 Rv3869 Rv3870 Rv3871PE/PPE Rv3874 esat6 Rv3876 Rv3877 Rv3878 RD1 mic Rv3879 Rv3880/ CFU in the lungs unvaccinated BCG vaccinated BCG::RD CFU in the spleen at sacrifice unvaccinated BCG vaccinated BCG::RD1

24 Naive BCG Pasteur BCG P urec Listeria Hly CD8 BCG P urec Hly 5.5 M. tuberculosis CD4 (Th1), CD8 4.5 M. bovis BCG CD4 (Th1) Low CD8 3.5 M. bovis BCG +listeriolysin M. bovis BCG urec+listeriolysin Improved CD8? Improved CD8? Days post-challenge Grode L et al. J Clin Invest( 2005) 115:

25 Gonzalo-Asensio J et al. PLoS ONE (2008) 3:e3496.

26 Liver Spleen 1,E+07 1,E+07 cfu/liver 1,E+06 1,E+05 cfu/spleen 1,E+06 1,E+05 1,E+04 1,E ,E Days Days Lungs 1,E+07 1,E+06 cfu/lung 1,E+05 1,E+04 1,E+03 1,E Days Perez E et al. Mol Microbiol (2001) 41:

27 Protection of phop MUTANT against iv challenge with M. tuberculosis H37Rv Spleen Lung CFU Control BCG phop CFU Control BCG phop 100 Control BCG phop Martin C et al. Vaccine (2006) 24:

28 Martin C et al. Vaccine (2006) 24:

29 Cardon PJ et al. Vaccine (2009) 27:

30 Effectiveness of TBVAC in promoting the initial development of EU vaccine candidates Candidate -vaccines Developer Initial cgmp Production Regulatory Assessm. Phase I Clinical Trials Clinical Trials in PPD+ Clinical Trials in PPD+ & HIV+ MVA-Ag85A, (VV, Pr-b) UOXF Done (lot1) Done (lot1) On-going UOXF UOXF 2006 UOXF 2009 Senegal Gambia South Africa Mtb72f hybrid recag + AS02 GSKbio Done (lot1) Done (lot1) Initiated Feb 2004 USA Lausanne 2007 Lausanne Planned 2010 Ethiopia Ag85B-ESAT6 recag + IC31 SSI Done 2004 Done(lot1) 09/ 2005 Leiden 2008 Leiden Planned 2010 Ethiopia rbcg-urec-hly MP- VPM/BPR Done 2007 Done 2007 Done 2009 Mtb- PhoP HBHA UNIZAR INSERM/ ULB Pre-PDT exploratory meetings Planned 2010 Planned 2011