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Presentation by Stefan Kaufmann [Max Planck Institute]

Presentation by Stefan Kaufmann [Max Planck Institute]

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  • 1. TB Vaccines Stefan H.E. KaufmannMax Planck Institute for Infection Biology Symposium on “A New Era for Vaccine Development” 5 September 2012 Wellcome Trust, London
  • 2. Agenda• The issue: TB• Immune response in TB• Current vaccine candidates in clinical trial• Future vaccination strategies• Biomarkers for accelerated vaccine development
  • 3. Kaufmann, unpublished
  • 4. Ottenhoff & Kaufmann, PLOS Path, 2012
  • 5. Kaufmann, unpublished
  • 6. Ottenhoff & Kaufmann, PLOS Path, 2012
  • 7. Kaufmann, unpublished
  • 8. Gengenbacher/Kaufmann,FEMS Microbiol. Rev., 2012
  • 9. Why is this important for TB vaccines? LTBI: Mtb hard to kill, dormancy antigens Active TB, “fresh” infection: Mtb “easier” to kill, active antigens Dormancy antigens: post-exposure, contain infection, prevent active TB BCG: low expression of dormancy antigens H56, ID93: multistage, post-exposure, adultsGengenbacher/Kaufmann,FEMS Microbiol. Rev., 2012
  • 10. BCG TodayProtection:• Against tuberculous meningitis and miliary TB in infantsCoverage:• High (> 80%); part of the expanded program on immunization (EPI) for infants• Ca. 100 million children BCG-vaccinated per year Ca. 4 billion vaccinations thus farSafety:• Very safe but adverse reactions possible• Risk for HIV+ newbornCost:• 0.1 – 0.5 US $ total (BCG, needle & syringe)But :• No reliable protection against adult tuberculosis / transmission (variable efficacies)
  • 11. Agenda• The issue: TB• Immune response in TB• Current vaccine candidates in clinical trial• Future vaccination strategies• Biomarkers for accelerated vaccine development
  • 12. Kaufmann, Trends Immunol, 2012
  • 13. Kaufmann, Trends Immunol, 2012
  • 14. Summary of clinical trials with MVA85A since 2002Helen McShane, UOXF
  • 15. Summary of clinical trials with MVA85A since 2002Helen McShane, UOXF
  • 16. In brief, MVA85A infant Phase IIb efficacy trial is in follow up phase, 2797 infants enrolled and we will unblind in Q1 2013. MVA85A HIV efficacy trial in South Africa and Senegal is ongoing, ~360 subjects (of 1400 total) enrolled to date. Helen McShane, UOXF
  • 17. Kaufmann, Trends Immunol, 2012
  • 18. SSI TB-vaccine fusion proteins H4 (Sanofi) H1 (1st generation) H56 (2nd generation) Ag85B TB10.4 Ag85B ESAT-6 Ag85B ESAT-6 Rv2660Boost an existing BCG- Prevent acute TB disease as well as re-induced immunity activation of existing latent infection• Infants – children • Adolescents• BCG vaccinated • With or without latent infection Peter Andersen, SSI
  • 19. The H56 multistage vaccine Early Ag´s “Latency Ag” Ag85B ESAT6 Rv2660c• ESAT-6 – Immunogenic secreted protein (not in BCG)• Ag85B – Immunogenic secreted protein (present in BCG)• Rv2660c – Weakly immunogenic – Highly expressed under in vitro stress and in late stage infection Peter Andersen, SSI
  • 20. Kaufmann, Trends Immunol, 2012
  • 21. Listeriolysin : A thiol-activated perforinPerforate cholesterol containing membraneIntracellular activityStringent pH optimum (5.5)Rapidly degraded in cytosol(contains PEST sequence)Apoptosis > necrosisNo cytotoxicityFurther info: A.L. Decatour & D.A. Portnoy, Science (2000), 290: 992;M. Palmer, Toxicon (2001), 39: 1681;N. Meyer-Morse et al., PLoS One (2010), 5: i8610
  • 22. Clinical trials with rBCGΔureC::hlyPhase I trial in Germany NCT 00749034: successfullycompleted December 2009Three escalating doses given to young adults (i.e., 10 4, 105,106 rBCGΔureC::hly, comparator 106 BCG)Phase I trial in South Africa NCT 01113281: successfullycompleted March 2011Three escalating doses given to young adults (i.e., 10 4, 105,106 rBCGΔureC::hly, comparator 106 BCG)Phase IIa trial in South Africa NCT 01479972: follow-upongoing, recruitment completed May 2012Three escalating doses given to newborn (i.e., 104, 105, 106rBCGΔureC::hly, comparator 106 BCG)
  • 23. Ottenhoff & Kaufmann, ERM, 2012
  • 24. Agenda• The issue: TB• Immune response in TB• Current vaccine candidates in clinical trial• Future vaccination strategies• Biomarkers for accelerated vaccine development
  • 25. Kaufmann, Lancet Infect Dis, 2011
  • 26. Targets for new TB vaccinesLevel 3.1:Post-exposure: Resuscitate dormant Mtb, then eradicate active MtbFuture approach:Benefit: Sterile Mtb eradicationRisk: Uncontrolled resuscitation → TB reactivation; collateraldamage by exaggerated immune responsePrinciple:Resuscitation of Mtb by immune modulation, followed by strongimmune response comprising CD4 Th1, Th17 effector response +CD8 CTL responseFocus on active antigens (low expression in BCG)
  • 27. Kaufmann, unpublished
  • 28. Targets for new TB vaccinesLevel 3.2:Pre-exposure: Prevent Mtb infectionFuture approach:Benefit: Sterile Mtb eradicationRisk: Collateral damage by exaggerated immune response No booster of memory by natural Mtb infectionPrinciple:AntibodiesInactivate Mtb survival factors (e.g. iron uptake)Increase Mtb uptake and killing by professional phagocytesPrevent Mtb uptake by non-professional phagocytesCD4 Th1 and Th17 effector and memory T cells; opsonizing IgGFocus on surface expressed antigens (not somatic, not secreted)
  • 29. Agenda• The issue: TB• Immune response in TB• Current vaccine candidates in clinical trial• Future vaccination strategies• Biomarkers for accelerated vaccine development
  • 30. Biomarkers: GoalsBiosignature for discrimination between active TBand LTBI (point of care diagnostic).Biosignature for understanding biology of infection,immunity & pathogenesis (reverse translation)Biosignature for prediction of risk of disease(correlate of protection & , stratification of studyparticipants).
  • 31. The Holy Grail of biomarker research•Prediction of risk of TB disease.•Stratification of study participants with high risk ofactive TB: reduce number of study participants andduration of clinical trials.•Monitoring of clinical trials: predict clinical endpointwith surrogate markers of vaccine efficacy
  • 32. Index: 850 HIV - newly diagnosed pulmonary TB patients Household contacts: 4500 Recruitment completed Q2 2010 Follow-up completed Q2 2012 Analysis to start Q1 2013 Expected household contacts with TB after 2 years follow-up: 112 (0% loss) TB cases 91 (20% loss) TB cases Current status: > 80 TB cases Protected >97%Exposure to TB 6 months 18 months 2 years Not protected <3%
  • 33. Index: 850 HIV - newly diagnosed pulmonary TB patients Household contacts: 4500 Recruitment completed Q2 2010 Follow-up completed Q2 2012 Analysis to start Q1 2013 Expected household contacts with TB after 2 years follow-up: generation vaccines 112 (0% loss) TB cases 91 (20% loss) TB cases generation vaccines rational design of next rational design of next Current status: > 80 TB cases can provide relevant info for can provide relevant info for Biomarkers from vaccine trials Biomarkers from vaccine trials Protected >97%Exposure to TB 6 months 18 months 2 years Not protected <3%
  • 34. Concluding remarks A dozen vaccine candidates in clinical trialAll: contain Mtb and prevent TBMost pre-exposure (active antigens), few post-exposure (stage-specific antigens)Future vaccination strategies Prevent infection Eradicate MtbBiomarkers Stratification of study participants Monitoring of study participants
  • 35. Hauptbahnhof CharitéMartin GengenbacherSteve Reece BundeskanzleramtChristiane Desel ReichstagJeroen MaertzdorfJanuary WeinerShreemanta Parida Brandenburger TorHans MollenkopfMarc Jacobsen
  • 36. Hauptbahnhof CharitéCollaborators:Gerhard Walzl, Martin Ota &the whole GC-6 team Bundeskanzleramt ReichstagBernd Eisele, VPMLeander Grode, VPM Brandenburger Tor Funding: MPS BMGF-GC 6/GC 12 EU-FP-6 /FP7 (NEW)TBVAC EDCTP