1. TB vaccines: what is on the horizon? Tom Evans, MD Chief Scientific Officer, Aeras IAC, Washington, D.C., July 27, 2012

2. Global Plan will not eliminate TB by 2050 Chris Dye, WHO; London 2009

3. Predicted Impact of a 60% Efficacious TB Vaccine Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME Proc Natl Acad Sci USA. 2009 39% 52% 37% 80% 92%

4. Key Challenges –Lack of validated animal models or clear correlates of protection of immunity Covered by existing vaccine No coverage or impact from existing vaccine Active Disease Latent Pre- infection InfantsAdolescentsAdultsHIV+ All Ages BCG –Large and expensive trials needed to prove efficacy –Diversity of BCG, populations, and environmental factors may require more than one vaccine

5. Better TB Vaccines: Reasons to be Optimistic ‒ Most people (80-90%) do not get disease when infected ‒ Evidence of BCG vaccine efficacy in children ‒ New TB vaccine candidates protect in animal models ‒ There are clinical clues to guide immunologic hypotheses Low CD4+ T cells are more susceptible to M.tb infection Anti-TNF treatment is associated with reactivation ‒ New TB vaccines boost cellular immune responses in multiple clinical studies

6. Strategies for TB Vaccine Development ‒ Pre-infection: to prevent infection Improved priming vaccines Novel booster vaccines Block Initial Infection Prevent Early Disease Prevent Latent Infection Prevent Reactivation Disease ‒ Post-infection: to prevent disease Develop novel booster vaccines to extend and enhance immune protection ‒ Immunotherapeutic: treatment Shorten the course of chemotherapy for active TB Improve efficacy of MDR/XDR/TDR- TB treatment

7. Why conduct TB vaccine studies in HIV+ patients?  PROS ‒ 1/3 of all deaths from HIV in Africa ‒ Incidence ~ 2% annually despite ART and INH preventative Rx ‒ Population with high mortality ‒ Able to access through the medical system ‒ Easier “downstream” population to vaccinate  CONS ‒ Immune response may be modified, with possible negative results ‒ Use of preventative INH as recommended by WHO is not uniformly followed ‒ May be a greater rate of re-infection as opposed to reactivation ‒ Continually changing treatment and prevention landscape for trials lasting 3-4 years ‒ Possible issues of safety, especially with live vaccines

8. Reality of TB vaccine trials in HIV+ Samandari et al., 2011, Botswana ‒ The increased incidence is made almost entirely from those that are skin test + ‒ There is a lag between INH preventative therapy and this increased incidence ‒ If given preventative therapy, on ART and CD4>200, incidence is not highly differentiated from the general population Should trials be first done in the general population, and only then bridged back to the HIV+ population?

9. M. Vaccae Phase IIPhase IIIPhase IIb Global Clinical TB Vaccine Pipeline – 2000

10. Clinical trials in HIV+ patients Global Clinical TB Vaccine Pipeline – 2012 ID93 + GLA-SE IDRI, Aeras IN hu Ad5 Ag85A McMaster CanSino VPM 1002 Max Planck, VPM, TBVI Hybrid-I + IC31 SSI, TBVI, EDCTP, Intercell RUTI Archivel Farma, S.L Mw DBY, India, M/s. Cadila Phase IIPhase IIIPhase IIb Mycobacterial – whole cell or extract rBCG Viral vector Protein/adjuvant Hyvac 4/ AERAS- 404 + IC31 SSI, sanofi-pasteur, Aeras, Intercell H56 + IC31 SSI, Aeras, Intercell M72 + AS01 GSK, Aeras MVA85A/AERAS- 485 OETC, Aeras AERAS- 402/Crucell Ad35 Crucell, Aeras M. Vaccae Anhui Longcom, China

11. M. vaccae: DarDar study of TB prevention in newly diagnosed HIV in Tanzania von Reyn et al. AIDS, 2010 Study was the first to have a signal of possible TB vaccine efficacy Phase III, RCT in Tanzania; Eligibility: CD4≥ 200, prior BCG 5 doses of heat killed M. vaccae vs placebo (compliance 84%) Median CD4~400/µl, VL~ 4.1 Log10 31% INH x 6 mos for TST ≥ 5 mm; 28% ART during trial Low loss to f/u (18%) Safe, no adverse effect on CD4 or VL

12. MVA85A ‒ Oxford Emergent TB Consortium (OETC)/Wellcome Trust/Aeras ‒ Modified Vaccinia Ankara (MVA) expressing M.tb antigen 85A Attenuated poxvirus, replication deficient in mammalian cells Administered to  120,000 vaccinees (smallpox eradication) ‒ Protects animals in multiple models from M.tb challenge after BCG prime-MVA85A boost administered intradermally ‒ 14 clinical trials completed or ongoing involving >2000 participants ‒ Acceptable safety profile in all populations studied Site of injection reactions in most subjects ‒ Preferentially induces CD4+ (vs. CD8+) T cell responses Appears more immunogenic in adults, two doses needed in HIV+ No effect of vaccination on CD4 count or viral load (Scriba et al. 2012)

13. INF  ELISPOT Responses in HIV+ Scriba et al. AJRCCM, 2012 12 Less robust than HIV uninfected Persist (and can be boosted) Minimally affected by ART Exhibited CD4+ T cell polyfunctionality in ICS assays Phase 2b, randomized, double-blind, controlled trial (supported by EDCTP) ‒ HIV-infected adults (South Africa, Senegal, N=1400) initiated ‒ Both ART and non-ART enrolled, all PPD+ given INH for 6 mo prior to enrollment ‒ Over 400 subjects enrolled

14. AERAS-402 / Crucell human Ad35 ‒ Human adenovirus 35 encoded 3 M.Tb antigens ‒ Multiple Phase I/IIa trials completed and ongoing, including in: Adults with/without latent TB infection; Adults with active TB; Infants ‒ Dosing range: 1.5x10 8 - 1x10 11 viral particles administered IM Acceptable safety profile; no SAEs related to AERAS-402 Immunogenic (CD8+ T cell responses preferentially) ‒ Phase IIb proof-of-concept study in infants ongoing Phase 2, HIV infected, BCG vaccinated; Aurum Institute, South Africa First dose (3 x 10 10 or placebo) administered to 26 patients and showed the vaccine to be immunogenic and safe with no change in VL or CD4 count

15. 14 VPM1002 in HIV-exposed infants BCG is not recommended by WHO for HIV-infected infants, although this recommendation is not followed in practice. ‒ rBCG that expresses listeriolysin to induce endosomal perforation, apoptosis induction, and cross presentation to increase CD8+ responses ‒ Safer than BCG in the SCID mouse model ‒ Showed superior protection to BCG in some animal studies ‒ Studied in healthy adults, TB infected adults, and infants Presently in a trial in HIV uninfected infants in South Africa in preparation for a Proof of Concept trial in HIV exposed newborns

16. 15 Decade of progress ‒ $600 million invested since 2005 ‒ Rich pipeline of 15 new vaccine candidates entered clinical trials ‒ Promising activities for development of new biomarkers emerged ‒ Capacity for vaccine production and carrying out large-scale clinical trials established ‒ Better understanding of safety and immunogenicity ‒ Robust pipeline of discovery and preclinical candidates

17. 16 Decade to come ‒ First efficacy data from proof-of-concept trials that are underway ‒ Better understanding of correlates of immunity, accelerating the testing of future vaccines ‒ Start of multiple phase III studies ‒ Possibility of TB vaccine licensure

18. Aeras gratefully acknowledges the volunteers in our clinical trials, hard work of many partners, and support of the following major donors: Netherlands Ministry of Foreign Affairs US Food and Drug Administration

19. Global TB vaccine development collaboration

20. Thank You! For more information: www.aeras.org An ounce of prevention is worth a pound of cure.