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  1. 1. Thank you for viewing this presentation. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author. © 2012 by the author
  2. 2. May 23-26, 2012 in Bucharest, Romania “TB and M/XDR-TB: from clinical management to control and elimination” ERS School TB disease and infection: Do we have real news? Martina Sester Department of Transplant and Infection Immunology Saarland University; Germany
  3. 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. 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. 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 128/100 000 • Most cases occurred in – Asia (59%) and – Africa (26%) WHO report 2011
  6. 6. Estimated TB incidence rates 2010 WHO report 2011
  7. 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) WHO report 2011 *82% of TB cases among people living with HIV originate from the African region
  8. 8. Estimated HIV prevalence in new TB cases 2010 WHO report 2011
  9. 9. Trends in TB incidence rates Lawn and Zumla (2011) Lancet 378: 57
  10. 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. 11. TB disease and infection - definitions TB disease • 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-γ release assay (IGRA) • Absence of clinical symptoms
  12. 12. LTBI M. tuberculosis exposure infection Recent contacts High TB prevalence Old healed TB Years after contact Low TB prevalence Successful TB/LTBI treatment Protective immunity Latency 90% Never TB Natural course of M. tuberculosis infection Latency 5% 2-5% Progression 1% TB disease Bacterium extinguished? Live bacilli? Immunosuppression Immunosuppression Chemoprophylaxis efficient Chemoprophylaxis not necessary Latency 5% 2-5% Latency 5% 2-5%
  13. 13. Prevalence of latent infection with M. tuberculosis and risk for progression Horsburg and Rubin (2011) N Engl J Med 364:1441
  14. 14. APC T cell antigens/ peptides cytokine induction cytokine induction activation/ cytokine induction cytokine induction ELISA ELISPOT assay Flow-cytometry cytokine activationmarker Skin test Immunodiagnosis of latent M. tuberculosis infection T.SPOT.TBQuantiFERON TB gold IGRA IFN-γ release assayPPD ESAT-6/CFP-10/TB7.7 Negative controls Positive controls, i.e. mitogens PHA/SEB
  15. 15. Test PPV NPV TST 2.3-3.3 99.7 QFT-G-IT 2.8-14.3 99.8 T-SPOT.TB 3.3-10.0 97.8 Diel et al. (2011) Eur Respir J 37: 88 PPV and NPV of immune-based assays for the development of tuberculosis
  16. 16. Test Sensitivity Specificity TST 0.65 0.75 QFT-G-IT blood 0.80 0.79 extrasang. 0.48 0.82 T-SPOT.TB blood 0.81 0.59 extrasang. 0.88 0.82 Sester, Sotgiu et al. Eur Respir J (2011), 37: 100 Sensitivity and specificity of immune- based assays to diagnose active TB summary of pooled values
  17. 17. New experimental tests LTBI • Antigen different from the commercial RD1 peptides • Markers different from IFN-γ • 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
  18. 18. Diagnosis of active tuberculosis • Patient history • Chest X-ray • Culture • Acid-fast bacilli staining • Nucleic acid amplification testing
  19. 19. 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
  20. 20. 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
  21. 21. Pathogenesis and immune effector mechanisms Kaufmann (2010) Immunity 33: 567
  22. 22. Pathogenesis and immune effector mechanisms Kaufmann (2010) Immunity 33: 567 Apoptosis/necrosis of Macrophages affects bacterial growth and T- cell priming Immuno- pathogenesis of IRIS Macrophage activation Interplay IFN-γ/VitD signaling
  23. 23. Role of innate immunity • Controlling early pathogen growth • Instructing adaptive immunity infection time M.tuberculosisload normal immunity without innate immunity without adaptive immunity
  24. 24. 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
  25. 25. 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
  26. 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. 27. Suppression of apoptosis as innate defence mechanism of virulent strains 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 Increased bacterial load Delay in T-cell priming Decreased bacterial load Accelerated T-cell priming Interference with plasma membrane repair
  28. 28. Pathogenesis and immune effector mechanisms Kaufmann (2010) Immunity 33: 567 Macrophage activation Interplay IFN-γ/VitD signaling
  29. 29. 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
  30. 30. Vitamin D deficiency and susceptibility to tuberculosis Vitamin D3 at start of antimicrobial treatment, and after 14, 28, and 42 days 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. Martineau et al. (2011) Lancet 377: 242
  31. 31. Vitamin D deficiency and susceptibility to tuberculosis 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 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)
  32. 32. Active TB is associated with vitamin D deficiency Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013 Effect of vitamin D deficiency is more pronounced in HIV infected patients Patients from Cape Town
  33. 33. Seasonal variation in vitamin D status and tuberculosis notifications Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013
  34. 34. Antimicrobial effect of vitamin D and T-cell derived IFN-γ Fabri et al. (2011) Sci Transl Med 3: 104ra102
  35. 35. Antimicrobial effect of vitamin D and T-cell derived IFN-γ Fabri et al. (2011) Sci Transl Med 3: 104ra102 Induction of autophagy
  36. 36. Antimicrobial effect of vitamin D and T-cell derived IFN-γ Fabri et al. (2011) Sci Transl Med 3: 104ra102 Induction of antimicrobial peptides
  37. 37. Mechanistic link - vitamin D deficiency and HIV-induced immunodeficiency Fabri et al. (2011) Sci Transl Med 3: 104ra102 Antimicrobial effect via induction of antimicrobial peptides and autophagy Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013
  38. 38. Pathogenesis and immune effector mechanisms Kaufmann (2010) Immunity 33: 567 Immuno- pathogenesis of IRIS
  39. 39. 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?
  40. 40. Mouse model for lymphopenia-induced IRIS Barber et al. (2012) Nat Rev Microbiol 10: 150 IRIS develops in context of • Chronic microbial infection • CD4 T cell deficiency
  41. 41. Model for IRIS involving a dysregulated innate immune response Barber et al. (2012) Nat Rev Microbiol 10: 150
  42. 42. 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
  43. 43. Characteristics of successful vaccines Rappuoli & Aderem (2011) Nature 473: 463 CMV
  44. 44. 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
  45. 45. 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
  46. 46. Adjuvants used for fusion proteins Kaufmann (2011) Lancet Infect Dis 11: 633 • Serve to improve immunogenicity • i.e. ligands for pattern recognition receptors
  47. 47. Vaccines – where they should act • Pre-exposure vaccination • Post-exposure vaccination • Therapeutic vaccination Kaufmann (2011) Lancet Infect Dis 11: 633
  48. 48. Therapeutic vaccine candidates
  49. 49. Pre-/post-exposure vaccines
  50. 50. Most advanced vaccine candidates Kaufmann (2011) Lancet Infect Dis 11: 633 12 candidates have reached clinical trials Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis (to replace BCG) (after BCG)
  51. 51. Most advanced vaccine candidates Kaufmann (2011) Lancet Infect Dis 11: 633 12 candidates have reached clinical trials Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis (to replace BCG) (after BCG)
  52. 52. Most advanced vaccine candidates Kaufmann (2011) Lancet Infect Dis 11: 633 12 candidates have reached clinical trials Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis (to replace BCG) (after BCG)
  53. 53. Most advanced vaccine candidates Kaufmann (2011) Lancet Infect Dis 11: 633 12 candidates have reached clinical trials Animal models: Prevention of tuberculosis, no eradication of M. tuberculosis (to replace BCG) (after BCG)
  54. 54. Post-exposure vaccines
  55. 55. 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
  56. 56. Effective vaccine for pre- and post-exposure H56 vaccine • Pre-exposure Aagaard et al. (2011) Nat Med 17: 189 6 weeks after challenge 24 weeks after challenge • T cells induced are polyfunctional
  57. 57. Effective vaccine for pre- and post-exposure H56 vaccine • Post-exposure Aagaard et al. (2011) Nat Med 17: 189 35 weeks p.i. blood 35 weeks p.i. spleen
  58. 58. Effective vaccine for pre- and post-exposure H56 vaccine • Post-exposure Aagaard et al. (2011) Nat Med 17: 189 35 weeks p.i. blood 35 weeks p.i. spleen 2 vaccinations 3 vaccinations 2 vaccinations 2 vaccinations 2 vaccinations 2 vaccinations Analysis between 23 and 43 weeks p.i.
  59. 59. Future candidates? • Up to now, no vaccine candidate has achieved sterilising immunity
  60. 60. 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

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