Presentation by Stefan Kaufmann [Max Planck Institute]

1. TB Vaccines
Stefan H.E. Kaufmann
Max 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

4. Kaufmann, unpublished

5. Ottenhoff & Kaufmann, PLOS Path, 2012

6. Kaufmann, unpublished

7. Ottenhoff & Kaufmann, PLOS Path, 2012

8. Kaufmann, unpublished

9. Gengenbacher/Kaufmann,
FEMS Microbiol. Rev., 2012

10. 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,
adults
Gengenbacher/Kaufmann,
FEMS Microbiol. Rev., 2012

11. BCG Today
Protection:
• Against tuberculous meningitis and miliary TB in infants
Coverage:
• 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 far
Safety:
• Very safe but adverse reactions possible
• Risk for HIV+ newborn
Cost:
• 0.1 – 0.5 US $ total (BCG, needle & syringe)
But :
• No reliable protection against adult tuberculosis / transmission
(variable efficacies)

12. Agenda
• The issue: TB
• Immune response in TB
• Current vaccine candidates
in clinical trial
• Future vaccination strategies
• Biomarkers for accelerated
vaccine development

15. Kaufmann, Trends Immunol, 2012

16. Kaufmann, Trends Immunol, 2012

17. Summary of clinical trials with MVA85A since 2002
Helen McShane, UOXF

18. Summary of clinical trials with MVA85A since 2002
Helen McShane, UOXF

19. 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

20. Kaufmann, Trends Immunol, 2012

21. SSI TB-vaccine fusion proteins
H4 (Sanofi)
H1 (1st generation) H56 (2nd generation)
Ag85B TB10.4 Ag85B ESAT-6 Ag85B ESAT-6 Rv2660
Boost 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

22. 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

23. Kaufmann, Trends Immunol, 2012

26. Listeriolysin : A thiol-activated perforin
Perforate cholesterol containing membrane
Intracellular activity
Stringent pH optimum (5.5)
Rapidly degraded in cytosol
(contains PEST sequence)
Apoptosis > necrosis
No cytotoxicity
Further 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

28. Clinical trials with rBCGΔureC::hly
Phase I trial in Germany NCT 00749034: successfully
completed December 2009
Three 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: successfully
completed March 2011
Three 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-up
ongoing, recruitment completed May 2012
Three escalating doses given to newborn (i.e., 104, 105, 106
rBCGΔureC::hly, comparator 106 BCG)

29. Ottenhoff & Kaufmann, ERM, 2012

30. Agenda
• The issue: TB
• Immune response in TB
• Current vaccine candidates
in clinical trial
• Future vaccination strategies
• Biomarkers for accelerated
vaccine development

31. Kaufmann, Lancet Infect Dis, 2011

35. Targets for new TB vaccines
Level 3.1:
Post-exposure: Resuscitate dormant Mtb, then eradicate active Mtb
Future approach:
Benefit: Sterile Mtb eradication
Risk: Uncontrolled resuscitation → TB reactivation; collateral
damage by exaggerated immune response
Principle:
Resuscitation of Mtb by immune modulation, followed by strong
immune response comprising CD4 Th1, Th17 effector response +
CD8 CTL response
Focus on active antigens (low expression in BCG)

37. Kaufmann, unpublished

38. Targets for new TB vaccines
Level 3.2:
Pre-exposure: Prevent Mtb infection
Future approach:
Benefit: Sterile Mtb eradication
Risk: Collateral damage by exaggerated immune response
No booster of memory by natural Mtb infection
Principle:
Antibodies
Inactivate Mtb survival factors (e.g. iron uptake)
Increase Mtb uptake and killing by professional phagocytes
Prevent Mtb uptake by non-professional phagocytes
CD4 Th1 and Th17 effector and memory T cells; opsonizing IgG
Focus on surface expressed antigens (not somatic, not secreted)

39. Agenda
• The issue: TB
• Immune response in TB
• Current vaccine candidates
in clinical trial
• Future vaccination strategies
• Biomarkers for accelerated
vaccine development

40. Biomarkers: Goals
Biosignature for discrimination between active TB
and 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 study
participants).

41. The Holy Grail of biomarker research
•Prediction of risk of TB disease.
•Stratification of study participants with high risk of
active TB: reduce number of study participants and
duration of clinical trials.
•Monitoring of clinical trials: predict clinical endpoint
with surrogate markers of vaccine efficacy

42. 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%

43. 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%

44. Concluding remarks
A dozen vaccine candidates in clinical trial
All: contain Mtb and prevent TB
Most pre-exposure (active antigens), few post-
exposure (stage-specific antigens)
Future vaccination strategies
Prevent infection
Eradicate Mtb
Biomarkers
Stratification of study participants
Monitoring of study participants

45. Hauptbahnhof Charité
Martin Gengenbacher
Steve Reece Bundeskanzleramt
Christiane Desel
Reichstag
Jeroen Maertzdorf
January Weiner
Shreemanta Parida Brandenburger Tor
Hans Mollenkopf
Marc Jacobsen

46. Hauptbahnhof Charité
Collaborators:
Gerhard Walzl, Martin Ota &
the whole GC-6 team Bundeskanzleramt
Reichstag
Bernd Eisele, VPM
Leander Grode, VPM
Brandenburger Tor
Funding:
MPS BMGF-GC 6/GC 12
EU-FP-6 /FP7 (NEW)TBVAC EDCTP