Hope in the TB Vaccine Pipeline

1. Hope in the TB Vaccine Pipeline Sebastian Gelderbloem Aeras Global TB Vaccine Foundation 25 January 2011

2. Aeras Global TB Vaccine Foundation Mission To develop new, more effective TB vaccines and ensure their availability to all who need them Method Non-profit PDP; collaborate with academic, biotech, pharma and NGO partners to develop and test new TB vaccines Pursue a Prime-Boost strategy by developing a modern replacement for BCG plus booster vaccines Develop vaccines in our own lab and manufacturing plant

3. Existing TB Vaccine Ineffective BCG introduced in 1921

4. Children with HIV infection regardless of symptoms should not be BCG vaccinated All high risk infants need HIV screening Maternal antibody masks antibody tests Detection of virus required Very difficult to implement in many places WHO 2007 Recommendations on BCG • Disseminated BCG in HIV infected infants recently (2009) estimated to be 992 per 100,000 (Hesseling, et al)

5. Predicted Impact of 50% Effective New TB vaccine Young and Dye Cell 2006

6. Goals for Better TB Vaccines Eliminate TB as a public health threat Safe and effective in preventing TB in children, adolescents and adults, including people with HIV (for whom BCG is unsafe) Protect against all forms of TB – including MDR and XDR

7. TB Vaccine Pipeline As of November 2009 Preclinical Phase I Phase II Phase IIb Phase III AERAS-422Aeras Mtb [∆lysA ∆panCD ∆secA2]Albert Einstein College of Medicine MTBVAC01 [∆phoP, ∆fad D26]University of Zaragoza, Institute Pasteur, TuBerculosis Vaccine Initiative (TBVI) HBHAInstitute Pasteur of Lille, INSERM, TBVI Hybrid 56Statens Serum Institute (SSI), Aeras, Intercell, TBVI HG85 A/BShanghai H&G Biotech Hybrid-I+IC31SSI, TBVI, Intercell M72GSK, Aeras MVA85A/AERAS-485Oxford-Emergent Tuberculosis Consortium (OETC), Aeras AERAS-402/ Crucell Ad35Crucell, Aeras M vaccae*Immodulon, NIH VPM 1002Max Planck, Vakzine Projekt Mgmt, TBVI rBCG30*UCLA, NIH, NIAID, Aeras AdAg85AMcMaster University Hybrid-I+CAF01SSI Hyvac 4/ AERAS-404SSI, Sanofi-Pasteur, Aeras, Intercell RUTIArchivel Farma M smegmatis* Prime Boost Post-infection Immunotherapy Preclinical vaccine candidates 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. *indicates candidates that have been in clinical trials in the past, but are not currently being tested in clinical trials Source: Tuberculosis Vaccine Candidates – 2009; Stop TB Partnership Working Group on New TB Vaccines

8. Progress in TB Vaccine Development • 12 candidates have entered clinical trials; 9 currently being tested; 10th will enter trials this year • Robust pipeline of candidates in preclinical development • Capacity and infrastructure developed or being developed at several sites • Manufacturing capacity being developed and agreements explored, with particular emphasis on emerging economies • Regulatory pathways and market/economic impact research laying groundwork to accelerate adoption and uptake of new TB vaccines

9. Approach to a New TB Vaccine • Improve BCG – make a recombinant rBCG • Prime-Boost regimen • Give booster vaccinations in infants • Give booster vaccinations in adolescents who have received BCG at birth

10. Aeras TB Vaccine Candidates in Clinical Trials Potential Boost Vaccines

11. Clinical Trials: Field Site Development • Large-scale community-based clinical trials are conducted in high burden countries • Aeras partners with local research institutions to establish field sites and conduct clinical research • Build local infrastructure and health care/research capacity to perform future Good Clinical Practice (GCP) compliant Phase III clinical trials

12. Aeras Partnerships in Clinical Development –Africa and Asia St John’s Research Institute India CHC/GHC Cambodia Le Dantec Dakar Senegal KEMRI/CDC Kenya Manhiça Health Research Center Mozambique Makerere University Uganda AURUM Johannesburg South Africa SATVI/University of Cape Town South Africa

13. Site DevelopmentSouth Africa • Partnership with South African Tuberculosis Vaccine Initiative (SATVI) and AURUM • Field site developed in Worcester (~120 km from Cape Town); most advanced site in the world for TB vaccine trials • Infrastructure developed both for clinical and laboratory work

14. Aeras-Sponsored Trials in South Africa • SATVI is conducting Phase I, II and IIb studies of four vaccine candidates in Worcester • CIDRI will be conducting a Phase IIb in HIV positive adults in Kayalisha • UCT Lung Institute conducted a Phase II clinical trial in adults with active or previous TB in Cape Town • Aurum Institute isenrolling adults living with HIV in Phase IIb trial in Klerksdorp (mining community)

15. Key Accomplishments at Other Partner Sites State-of-the-art immunology and mycobacteriology laboratory established in South Africa and India GeneXeprt role-out for vaccine trials in South Africa, Mozambique, Uganda and Inida Mycobacterial and Immunology lab capacity is completed in Kenya and Uganda Local staff trained in clinical research in Kenya, Uganda and India Epidemiological cohort studies in Cambodia andKenya Quality management and data management infrastructure developed in Kenya , India and Uganda New state-of-the-art Clinical Research Center established at a District Hospital in western Kenya First multicenter TB vaccine clinical trial initiated in Kenya

16. Local Benefits of Clinical Research • Retain local talent and expertise • Raise awareness about TB in the community • Support and enhance local clinical research capacity • Community health and education • Infrastructure remains in the community • Leverage investment in infrastructure to use for clinical trials of other diseases

17. Drivers of Future Uptake • Wide recognition that TB is serious and neglected problem; MDR-TB threat • Widespread dissatisfaction with current BCG • Likely demand for partially effective vaccine better than BCG • Willingness to commit to rapid introduction • FDA or EMEA approval will speed adoption • Willingness to spend money out of existing budgets for prime-boost; private sector

18. Barriers to Future Uptake • Clarify expected benefits (20-30 years) • Fatalism about TB– competing priorities, e.g., HIV/AIDS • Funding • Waiting for strong efficacydata • Some resistance to adolescent boosting (transient populations) • Some skepticism about aerosol delivery

19. Lessons Learned • Heterogeneity of responses within and between countries • Strong efficacy datawill be a critical success factor for introduction, including in-country data • Cost, if kept low, not likely to be major issue; not an issue in private markets • Education and preparation will be necessary, but raising awareness and expectations too high needs to be avoided

20. Aeras gratefully acknowledges the support of the following major donors but also acknowledges the need for Government support to effectively fightTB Netherlands Ministry of Foreign Affairs US Food and Drug Administration

21. Thank You! For more information: www.aeras.org sgelderbloem@aeras.org