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Progress in Developing New TB Vaccines Jerald C. Sadoff, MD

Progress in Developing New TB Vaccines Jerald C. Sadoff, MD Reversing the Tide: The End of Tuberculosis Columbia University March 7 th 2006. Potential Impact of 50-90% Effective Vaccines. Vaccines in combination with antibiotics could control the epidemic

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Progress in Developing New TB Vaccines Jerald C. Sadoff, MD

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  1. Progress in Developing New TB Vaccines Jerald C. Sadoff, MD Reversing the Tide: The End of Tuberculosis Columbia University March 7th 2006

  2. Potential Impact of 50-90% Effective Vaccines • Vaccines in combination with antibiotics could control the epidemic • Pre-exposure or post-exposure vaccines could eliminate about 1/3 of disease and death • A TB vaccine with pre- and post-exposure efficacy could achieve global control of TB Ziv et al, Emerging Infectious Diseases, Vol.10, No.9 September 2004 Lietman, T, Blower SM, Clin. Inf Dis.2000:30:S316-22 Lietman, T. Blower SM. Science. 1999:286:1300-01

  3. Aeras Global TB Vaccine Foundation Mission: To develop new TB vaccines and ensure their availability to all who need them Goals: - To obtain regulatory approval and ensure supply of a new TB vaccine regimen within 7-10 years - To introduce 2nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years

  4. Field Site Developed in the Breede River Valley of the Boland-Overberg Region of Western Cape Province, South Africa Boland-Overberg Region Ceres Breede River Valley

  5. India Site • Palamaner Taluk • Population of 350,000 • Mostly rural • ~ 3 hours from Bangalore • TB incidence rate in adults of 150-200/100,000 • St. Johns has long standing relationship with Emauss Leprosy Hospital in Palamner and has conducted large nutritional cohort studies in this community. St. John’s Medical College, Bangalore Palamaner Taluk

  6. Incidence of tuberculosis in 11,667 BCG vaccinated infants with a smear and/or culture positive for M.tb Total TB incidence = 3.1% 2-year TB incidence = 2.7%

  7. Preliminary Conclusions and Approach Conclusion: • Field trials of new TB vaccines feasible in this population Approach: • Large cohort studies in 9000 infants and 12000 adolescents in S. Africa and India to confirm high incidence

  8. Basis for New TB Vaccine Development • Humans are resistant to infection & disease • Only ~30% of exposed individuals are infected • Only ~10% of infected individuals get disease • Human resistance related to the immune system • Humans with INFγ and TNF genetic and pharmacologic pathway defects highly susceptible to TB

  9. Potential Uses of Effective TB Vaccine

  10. Prime Boost Strategies 24 Weeks 14 Weeks

  11. Protection in Eight BCG Trials Baily, G. V. J., et al, Indian Journal Medical Research 70, September 1979, pp. 349-363.

  12. rBCG30 over-expressing TB antigen 85B: Horwitz at UCLA which is not acceptable to regulatory authorities as a final product rBCGs escaping the endosome: Kaufmann at Max Planck Institute Aeras 403 rBCG – Aeras recombinant BCG combinesHorwitz and Kaufmann discoveries Recombinant attenuated TB: Bill Jacobs at Albert Einstein University BCG Replacements:Recombinant BCG & TB ready for Phase I

  13. Preliminary data from 17/30 subjects in trial

  14. Intracellular tropism of intracellular bacteria Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany

  15. PAg85B Ag85A Ag85B Ag 10.4 Phsp60 ureC R-flank MCS sacB EN pfo OriE pAF112 Pkan Ag85B leader peptide KanR oriM PAg85B ureC L-flank rBCG Aeras 403 Strain Construction BCG Danish 1331 PRv3130 pAF102 AFV102 oriE Pfo integration Plasmid for endosome escape AFV112 Aeras 403 Over-expression Plasmid

  16. rBCG Vaccine - Aeras 403 • New Fermentation and foam drying process developed which produces very high yield of room temperature stable vaccine • Aeras factory can produce the worlds needs for bulk vaccine- 150-300 million doses/year • Aeras bulk vaccine will be shipped to developing world manufacturers for foam drying, packaging and distribution • Phase I clinical trials scheduled for August 06

  17. Prime Boost Strategies 24 Weeks 14 Weeks

  18. Candidates for boosting infants and adolescents in or about to start Phase I • Recombinant fusion proteins in adjuvant • M72 fusion GSK/Aeras • Ag85B::ESAT6 SSI/TBVAC • Ag85B::10.4 fusion SSI/Aeras • Vectored vaccines • rMVA-Ag85A Oxford • rAd35-Ag85A-Ag85B-TB10.4 fusion Aeras/Crucell • Oral Shigella dsRNA capsids Aeras

  19. rBCG prime with rAd35 Aeras 403 BoosterFold rise in CD8+T cells

  20. Prime Boost Strategies 24 Weeks 14 Weeks

  21. EM of procapsids in S. flexneri MPC51

  22. mRNA Completion of second strand triggers mRNA synthesis and secretion P2 catalyzes synthesis of mRNA, which is passively secreted back through P4 hexamers on capsid surface for translation L M S Nucleocapsid (NC)

  23. Delivery of rdsRP by Shigella vectors to host antigen presenting cells Shigella-rdsRP vector Induction of TB-specific CD4+ and CD8+ T cells Presentation of TB antigens in the context of HLA class I&II Invasion Nucleus EF2-independent translation of TB antigens • Access cytoplasm • Lysis due to murI • Release of rdsRP Synthesis of recombinant segment-S and segment-M mRNA by RNA-dependent RNA polymerase activity of rdsRP

  24. rdsRP encoded antigen mRNA expression by HeLa cells HeLa cell 14 hr post-invasion by MPC51 carrying rdsRP LSMtb4 (85A-85B-10.4 encoded on rSeg-M) Probed with anti-85A IgY

  25. Mouse Dose Response/Immunogenicity Study Cellular immune responses of BALB/c mice vaccinated intranasally with varying doses of the Shigella-vectored nucleocapsid LSMtb4 (expresses Ag85A-85B-10.4 fusion) or Ad35 TBS administered IM

  26. Vaccine Development Timelines 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Field Site Preparation & Epidemiology Phase III Aeras 403 Prime Aeras 402 Boost Infants & Adolescents Aeras Crucell Preclin. Aeras 402 & Aeras 403 Phase I and II Aeras 403/402 Phase III Aeras 403 Prime Aeras 404 Boost Infants & Adolescents Preclinical Aeras Aeras 404 (oral) Phase I and II Aeras 403/404 Aeras Aeras 402 = Crucell Ad35 vectored TB vaccine Aeras 403 = rBCG with overexpression & endosome escape Aeras 404 = capsids In shigella for oral delivery

  27. Summary • A moderately effective vaccine + drug control could virtually eliminate the TB epidemic • Based on 20 years of research, a prime-boost vaccine strategy has great potential • This new vaccine regimen could be licensed and available in 7-10 years • The potential of rBCG prime given at birth followed by viral vector, capsid or protein boost to induce high levels of cellular immunity make this a very attractive vaccine regimen for TB, malaria and HIV

  28. Contact Information Jerald C. Sadoff, MD President & Chief Executive Officer Aeras Global TB Vaccine Foundation 7500 Old Georgetown Road, Suite 800 Bethesda, MD 20814 +1-301-547-2912 jsadoff@aeras.org

  29. Jerald Sadoff led or contributed to the development of these vaccines • Licensed • Hepatitis A –Vaqta • H. Influenza conjugate –Liquid Pedvax • Varicella- 4 degree stable Varivax • Combination Hep B & H. Influenza – Comvax • Combination D, T, aP, Polio, H. Influ, Hep B –Hexavac • Measles, Mumps, Rubella, Varicella – MMRV • Rotavirus – Rotatech • Zoster – Zostovac • HPV – (license 06) • Cholera (Killed Whole cell +B -SBL) • In phase IIB or III • Malaria (Army-GSK-RTSS) • HIV (Merck) • Cholera –Peru 14 • Shigella conjugate (NIH) • In phase I • TB rBCG & M72

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