1 / 20

TB vaccines: what is on the horizon?

TB vaccines: what is on the horizon? . Tom Evans, MD Chief Scientific Officer, Aeras IAC, Washington, D.C., July 27, 2012. Global Plan will not eliminate TB by 2050. Chris Dye, WHO; London 2009. Predicted Impact of a 60% Efficacious TB Vaccine. 39% 52% 37% 80% 92%.

stewart-johns
Download Presentation

TB vaccines: what is on the horizon?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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 39% 52% 37% 80% 92% Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME Proc Natl Acad Sci USA. 2009

  4. Key Challenges • Lack of validated animal models or clear correlates of protection of immunity Active Disease Latent • Large and expensive trials needed to prove efficacy BCG • Diversity of BCG, populations, and environmental factors may require more than one vaccine Pre-infection Infants Adolescents Adults HIV+ All Ages Covered by existing vaccine No coverage or impact from existing 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 • Post-infection: to prevent disease • Develop novel booster vaccines to extend and enhance immune protection Prevent Latent Infection Prevent Early Disease Prevent Reactivation Disease • 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. Global Clinical TB Vaccine Pipeline – 2000 Phase I Phase II Phase IIb Phase III M. Vaccae

  10. Global Clinical TB Vaccine Pipeline – 2012 Phase I Phase II Phase IIb Phase III MVA85A/AERAS-485OETC, Aeras VPM 1002Max Planck, VPM, TBVI Mw DBY, India, M/s. Cadila IN hu Ad5 Ag85A McMaster CanSino M72 + AS01GSK, Aeras AERAS-402/Crucell Ad35Crucell, Aeras Hybrid-I + IC31SSI, TBVI, EDCTP, Intercell ID93 + GLA-SE IDRI, Aeras M. Vaccae Anhui Longcom, China Mycobacterial – whole cell or extract Hyvac 4/ AERAS-404 + IC31SSI, sanofi-pasteur, Aeras, Intercell RUTIArchivel Farma, S.L Clinical trials in HIV+ patients Viral vector H56 + IC31SSI, Aeras, Intercell rBCG Protein/adjuvant

  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. vaccaevs 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. INFg ELISPOT Responses in HIV+Scriba et al. AJRCCM, 2012 • 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: 1.5x108- 1x1011 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 1010 or placebo) administered to 26 patients and showed the vaccine to be immunogenic and safe with no change in VL or CD4 count

  15. 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. Decade of progress • $600 million invested since 2005 • Robust pipeline of discovery and preclinical candidates • 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

  17. 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.

More Related