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2. TB disease and infection: Do we have real news?
Martina Sester
Department of Transplant and Infection Immunology Saarland University; Germany

3. Overview – Facts and news…*
Worldwide epidemiology of tuberculosis
M. tuberculosis infection: continuum from latency to active disease
Implications for diagnosis of M. tuberculosis infection
Host-pathogen interactions
Role of innate immunity
The vaccine pipeline
*an immunologist´s view on 2011´s news…

4. Tuberculosis – the facts
7. position of leading causes of deaths
1/3 of the world's population could be infected
> 80% can be cured
prevention can be > 90% effective
Global tuberculosis control: WHO report 2011

5. Tuberculosis – the facts
1.45 million people died in 2010 due to TB
equally to 3800 deaths per day
8.8 million new cases of TB in 2010
Global incidence rate of 128/
Most cases occurred in
Asia (59%) and
Africa (26%)
WHO report 2011

6. Estimated TB incidence rates 2010
WHO report 2011

7. The global burden of TB in 2010 in relation to HIV co-infection
Estimated number of cases
Estimated number of deaths
All forms of TB
8.8 Mio (8.5–9.2 Mio)
1.45 Mio (1.2–1.5 Mio)
HIV-associated TB
1.1 Mio (13%)* (1.0–1.3 Mio)
0.35 Mio (0.32–0.39 Mio)
The proportion of TB cases coinfected with HIV is highest in countries in the African Region (Figure 2.4); overall, the African Region accounted for 82% of TB cases among people living with HIV.
*82% of TB cases among people living with HIV originate from the African region
WHO report 2011

8. Estimated HIV prevalence in new TB cases 2010
WHO report 2011

9. Trends in TB incidence rates
Lawn and Zumla (2011) Lancet 378: 57

10. Overview – Facts and news…
Worldwide epidemiology of tuberculosis
M. tuberculosis infection: continuum from latency to active disease
Implications for diagnosis of M. tuberculosis infection
Host-pathogen interactions
Role of innate immunity
The vaccine pipeline

11. Infection cycle of M. tuberculosis
from: Ulrichs und Kaufmann 2006 Monatsschrift Kinderheilkd 154: 133

12. TB disease and infection - definitions
Detection of M. tuberculosis and/or clinical symptoms compatible with tuberculosis
Latent infection with M. tuberculosis (LTBI)
Presence of an immune response in a skin test or an IFN-g release assay (IGRA)
Absence of clinical symptoms

13. Natural course of M. tuberculosis infection
Immunosuppression
exposure
Progression 1%
TB disease
Recent contacts
High TB prevalence
Old healed TB
Years after contact
Low TB prevalence
Successful TB/LTBI treatment
Latency 5%
2-5%
Latency 5%
2-5%
Latency 5%
2-5%
infection
Illustrate effect of MTB prevalence, illustrate effect of LTBI treatment in the various situations
LTBI
Protective immunity
Latency
90%
Never TB
Bacterium extinguished?
Live bacilli?
Chemoprophylaxis efficient
Chemoprophylaxis not necessary

14. Prevalence of latent infection with M
Prevalence of latent infection with M. tuberculosis and risk for progression
Prevalence of positive immune responses and relative risk for tuberculosis
Horsburg and Rubin (2011) N Engl J Med 364:1441

15. Immunodiagnosis of latent M. tuberculosis infection
APC
T cell
antigens/
peptides
IGRA
IFN-g release assay
PPD
ESAT-6/CFP-10/TB7.7
Negative controls
Positive controls, i.e. mitogens PHA/SEB
activation/ cytokine
induction
cytokine
induction
cytokine
induction
cytokine
induction
Skin test
ELISA
ELISPOT assay
Flow-cytometry
cytokine
activation marker
T.SPOT.TB
QuantiFERON TB gold

16. PPV and NPV of immune-based assays for the development of tuberculosis
Test
PPV
NPV
TST
99.7
QFT-G-IT
99.8
T-SPOT.TB
97.8
Diel et al. (2011) Eur Respir J 37: 88 16

17. Sensitivity and specificity of immune-based assays to diagnose active TB
Test
Sensitivity
Specificity
TST
0.65
0.75
QFT-G-IT
blood
0.80
0.79
extrasang.
0.48
0.82
T-SPOT.TB
0.81
0.59
0.88
summary of pooled values
Sester, Sotgiu et al. Eur Respir J (2011), 37: 100 17

18. New experimental tests LTBI
Antigen different from the commercial RD1 peptides
Markers different from IFN-g
Readouts different from ELISA or ELISPOT
Biological sample different from blood
More details in the following talk:
IGRA testing to diagnose TB disease and infection. What is new in clinical practice and for programmatic management? - D. Goletti, M Sester

19. Diagnosis of active tuberculosis
Patient history
Chest X-ray
Culture
Acid-fast bacilli staining
Nucleic acid amplification testing

20. New experimental tests active tuberculosis
Assays for childhood tuberculosis
Assays for smear negative tuberculosis
Faster assays
Improved NAAT tests (i.e. Xpert MTB/RIF assay)
More details in the following talk:
The new horizons of molecular diagnosis: do we still need conventional microbiology? - D. Cirillo

21. Overview – Facts and news…
Worldwide epidemiology of tuberculosis
M. tuberculosis infection: continuum from latency to active disease
Implications for diagnosis of M. tuberculosis infection
Host-pathogen interactions
Role of innate immunity
The vaccine pipeline

22. Pathogenesis and immune effector mechanisms
Kaufmann (2010) Immunity 33: 567

23. Pathogenesis and immune effector mechanisms
Macrophage activation
Interplay IFN-g/VitD signaling
Apoptosis/necrosis of
Macrophages affects bacterial growth and T-cell priming
Immuno-pathogenesis of IRIS
Kaufmann (2010) Immunity 33: 567

24. Role of innate immunity
Controlling early pathogen growth
Instructing adaptive immunity
without innate immunity
without adaptive immunity
M. tuberculosis load
normal immunity
infection
time

25. Role of innate immunity
Controlling early pathogen growth
Instructing adaptive immunity
Fremond et al. (2004) J Clin Invest 114: 1790; Feng et al. (2005) J Immunol 174: 4185

26. Apoptosis versus necrosis
Apoptotic macrophages decrease bacterial load and accelerate T-cell priming
Necrotic macrophages increase bacterial load and slow down T-cell priming
Divangahi et al. (2010) Nat Immunol 11: 751; Divangahi et al. (2009) Nat Immunol 10: 899

27. Apoptosis versus necrosis
Apoptotic macrophages decrease bacterial load and accelerate T-cell priming
Necrotic macrophages increase bacterial load and slow down T-cell priming
Divangahi et al. (2010) Nat Immunol 11: 751; Divangahi et al. (2009) Nat Immunol 10: 899

28. Suppression of apoptosis as innate defence mechanism of virulent strains
Interference with plasma membrane repair
Decreased bacterial load
Accelerated T-cell priming
Increased bacterial load
Delay in T-cell priming
Divangahi et al. (2010) Nat Immunol 11: 751; Divangahi et al. (2009) Nat Immunol 10: 899; Behar et al. (2010) Nat Rev Microbiol 8: 668

29. Pathogenesis and immune effector mechanisms
Macrophage activation
Interplay IFN-g/VitD signaling
Kaufmann (2010) Immunity 33: 567

30. Vitamin D deficiency and susceptibility to tuberculosis
Vitamin D3 at start of antimicrobial treatment, and after 14, 28, and 42 days
Martineau et al. (2011) Lancet 377: 242

31. Vitamin D deficiency and susceptibility to tuberculosis
Median time to culture conversion
36·0 days in the intervention group and
43·5 days in the placebo group
Adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14.
Vitamin D3 at start of antimicrobial treatment, and after 14, 28, and 42 days
Martineau et al. (2011) Lancet 377: 242

32. Vitamin D deficiency and susceptibility to tuberculosis
Effect of TaqI genotype
Enhanced response with
tt genotype (8.09, 95% CI 1.36–48.01; p=0.02)
Tt genotype (0.85, 95% CI 0.45–1.63; p=0.63)
TT genotype (1.13, 95% CI 0.60–2.10; p=0.71)
Median time to sputum culture conversion
36·0 days - intervention group
43·5 days - placebo group
Adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14.
Martineau et al. (2011) Lancet 377: 242

33. Active TB is associated with vitamin D deficiency
Patients from Cape Town
For the 75 nmol/L threshold for serum 25(OH)D concentration, proposed by some to denote optimal vitamin D status (23), a similar association was seen for HIV-infected participants (P = 0.001) but not for those without HIV infection (P = 0.45)
Effect of vitamin D deficiency is more pronounced in HIV infected patients
Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013

34. Seasonal variation in vitamin D status and tuberculosis notifications
Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013

35. Antimicrobial effect of vitamin D and T-cell derived IFN-g
Fabri et al. (2011) Sci Transl Med 3: 104ra102

36. Antimicrobial effect of vitamin D and T-cell derived IFN-g
Induction of autophagy
Fabri et al. (2011) Sci Transl Med 3: 104ra102

37. Antimicrobial effect of vitamin D and T-cell derived IFN-g
Induction of antimicrobial peptides
Fabri et al. (2011) Sci Transl Med 3: 104ra102

38. Mechanistic link - vitamin D deficiency and HIV-induced immunodeficiency
Antimicrobial effect via induction of antimicrobial peptides and autophagy
Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013
Fabri et al. (2011) Sci Transl Med 3: 104ra102

39. Pathogenesis and immune effector mechanisms
Immuno-pathogenesis of IRIS
Kaufmann (2010) Immunity 33: 567

40. HIV-associated IRIS Immune reconstitution inflammatory syndrome
May occur in up to 30% of HIV infected patients after start of ART
Tissue destructive inflammation
Microbial co-infections as risk factor
Recovering CD4 T cells as immediate effectors?
Pathological T cell responses?

41. HIV-associated IRIS
Sester et al. (2010) Eur Respir J 36: 1242

42. Mouse model for lymphopenia-induced IRIS
IRIS develops in context of
Chronic microbial infection
CD4 T cell deficiency
Barber et al. (2012) Nat Rev Microbiol 10: 150

43. Model for IRIS involving a dysregulated innate immune response
Barber et al. (2012) Nat Rev Microbiol 10: 150

44. Overview – Facts and news…
Worldwide epidemiology of tuberculosis
Infection cycle
M. tuberculosis infection: continuum from latency to active disease
Implications for diagnosis of M. tuberculosis infection
Host-pathogen interactions
Role of innate immunity
The vaccine pipeline

45. Characteristics of successful vaccines
CMV
Rappuoli & Aderem (2011) Nature 473: 463

46. BCG vaccine Developed 1921 120 Mio doses administered/year
Provides 80% protection against severe and disseminated disease in children
50% risk reduction in adults (0-80% efficacy)
Genetic divergence
Differences in T-cell response

47. Vaccine candidates Subunit and live viral vectors
Antigens: ESAT-6, TB10.4, Ag85A, Ag85B, Mtb32 and 39 and fusions thereof
Adjuvants: IC31, AS01, AS02, CAF01
Live viral vectors: Adenovirus, Vaccinia
Live attenuated or killed bacteria
rBCG
M. tuberculosis
M. vaccae

48. Adjuvants used for fusion proteins
Serve to improve immunogenicity
i.e. ligands for pattern recognition receptors
Kaufmann (2011) Lancet Infect Dis 11: 633

49. Vaccines – where they should act
Pre-exposure vaccination
Post-exposure vaccination
Therapeutic vaccination
Kaufmann (2011) Lancet Infect Dis 11: 633

50. Therapeutic vaccine candidates

51. Pre-/post-exposure vaccines

52. Most advanced vaccine candidates
12 candidates have reached clinical trials
(to replace BCG)
(after BCG)
Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis
Kaufmann (2011) Lancet Infect Dis 11: 633

53. Most advanced vaccine candidates
12 candidates have reached clinical trials
(to replace BCG)
(after BCG)
Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis
Kaufmann (2011) Lancet Infect Dis 11: 633

54. Most advanced vaccine candidates
12 candidates have reached clinical trials
(to replace BCG)
(after BCG)
Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis
Kaufmann (2011) Lancet Infect Dis 11: 633

55. Most advanced vaccine candidates
12 candidates have reached clinical trials
(to replace BCG)
(after BCG)
Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis
Kaufmann (2011) Lancet Infect Dis 11: 633

56. Post-exposure vaccines

57. Effective vaccine for pre- and post-exposure
H56 vaccine
Early antigen Ag85B
Early antigen ESAT-6
Latency antigen Rv2660c
expressed during starvation
Vaccination of mice
Aagaard et al. (2011) Nat Med 17: 189

58. Effective vaccine for pre- and post-exposure
H56 vaccine
Pre-exposure
6 weeks after challenge
24 weeks after challenge
T cells induced are polyfunctional
Aagaard et al. (2011) Nat Med 17: 189

59. Effective vaccine for pre- and post-exposure
H56 vaccine
Post-exposure
35 weeks p.i.
blood
35 weeks p.i.
spleen
Aagaard et al. (2011) Nat Med 17: 189

60. Effective vaccine for pre- and post-exposure
H56 vaccine
Post-exposure
2 vaccinations
2 vaccinations
2 vaccinations
2 vaccinations
35 weeks p.i.
blood
35 weeks p.i.
spleen
3 vaccinations
2 vaccinations
Analysis between 23 and 43 weeks p.i.
Aagaard et al. (2011) Nat Med 17: 189

61. Future candidates?
Up to now, no vaccine candidate has achieved sterilising immunity

62. Future candidates?
Sweeney et al. (2011) Nat Med 17: 1261

63. Conclusions
Understanding the continuum from latency to active disease will lead to improved diagnosis of patients at risk and targeted therapy
Knowledge of the role of innate immunity will lead to improved understanding of host-pathogen interactions
Rationale vaccine design has achieved success, but clinical studies are still proceeding at slow pace