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 2012 by the author
“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
May 23-26, 2012 in Bucharest, Romania
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…
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
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
Estimated TB incidence rates 2010
WHO report 2011
The global burden of TB in 2010
in relation to HIV co-infection
All forms of TB
HIV-associated
TB
Estimated
number of cases
8.8 Mio
(8.5–9.2 Mio)
1.1 Mio (13%)*
(1.0–1.3 Mio)
*82% of TB cases among people living
with HIV originate from the African region
Estimated number
of deaths
1.45 Mio
(1.2–1.5 Mio)
0.35 Mio
(0.32–0.39 Mio)
WHO report 2011
Estimated HIV prevalence
in new TB cases 2010
WHO report 2011
Trends in TB incidence rates
Lawn and Zumla (2011) Lancet 378: 57
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
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-g release assay (IGRA)
• Absence of clinical symptoms
Natural course of
M. tuberculosis infection
M. tuberculosis
Immunosuppression
exposure
1%
infection
Progression
Latency
90%
Latency
Years after
contact
Recent
contacts
Low TB
High
TB prevalence
prevalence
Successful
treatment LTBI
Old
healedTB/LTBI
TB
TB disease
5%
2-5%
Live bacilli?
Immunosuppression
Chemoprophylaxis efficient
Protective immunity
Never TB
Bacterium extinguished?
Chemoprophylaxis not necessary
Prevalence of latent infection with
M. tuberculosis and risk for progression
Horsburg and Rubin (2011) N Engl J Med 364:1441
Immunodiagnosis of
latent M. tuberculosis infection
antigens/
peptides
APC
PPD
ESAT-6/CFP-10/TB7.7
Negative controls
Positive controls, i.e. mitogens
PHA/SEB
Skin test
IFN-g release assay
T cell
cytokine
induction
activation/
cytokine
induction
cytokine
induction
ELISA
ELISPOT assay
QuantiFERON TB gold
T.SPOT.TB
Flow-cytometry
activation marker
cytokine
induction
IGRA
cytokine
PPV and NPV of immune-based assays
for the development of tuberculosis
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
Sensitivity and specificity of immunebased assays to diagnose active TB
Test
Sensitivity
Specificity
TST
0.65
0.75
0.80
0.79
extrasang. 0.48
0.82
0.59
0.82
QFT-G-IT
blood
0.81
T-SPOT.TB
extrasang. 0.88
blood
summary of pooled values
Sester, Sotgiu et al. Eur Respir J (2011), 37: 100
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
Diagnosis of active tuberculosis
•
•
•
•
•
Patient history
Chest X-ray
Culture
Acid-fast bacilli staining
Nucleic acid amplification testing
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
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
Pathogenesis and
immune effector mechanisms
Kaufmann (2010) Immunity 33: 567
Pathogenesis and
immune effector mechanisms
Macrophage activation
Interplay IFN-g/VitD signaling
Apoptosis/necrosis of
Macrophages affects
bacterial growth and Tcell priming
Immunopathogenesis
of IRIS
Kaufmann (2010) Immunity 33: 567
Role of innate immunity
• Controlling early pathogen growth
• Instructing adaptive immunity
without innate immunity
M. tuberculosis load
without adaptive immunity
normal immunity
infection
time
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
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
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
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
Pathogenesis and
immune effector mechanisms
Macrophage activation
Interplay IFN-g/VitD signaling
Kaufmann (2010) Immunity 33: 567
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
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
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
Active TB is associated with
vitamin D deficiency
Patients from Cape Town
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
Seasonal variation in vitamin D status
and tuberculosis notifications
Martineau et al. (2011) Proc Natl Acad Sci U S A 108: 19013
Antimicrobial effect of
vitamin D and T-cell derived IFN-g
Fabri et al. (2011) Sci Transl Med 3: 104ra102
Antimicrobial effect of
vitamin D and T-cell derived IFN-g
Induction of autophagy
Fabri et al. (2011) Sci Transl Med 3: 104ra102
Antimicrobial effect of
vitamin D and T-cell derived IFN-g
Induction of antimicrobial peptides
Fabri et al. (2011) Sci Transl Med 3: 104ra102
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
Pathogenesis and
immune effector mechanisms
Immunopathogenesis
of IRIS
Kaufmann (2010) Immunity 33: 567
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?
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
Model for IRIS involving a
dysregulated innate immune response
Barber et al. (2012) Nat Rev Microbiol 10: 150
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
Characteristics of successful vaccines
CMV
Rappuoli & Aderem (2011) Nature 473: 463
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
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
Adjuvants used for fusion proteins
• Serve to improve immunogenicity
• i.e. ligands for pattern recognition receptors
Kaufmann (2011) Lancet Infect Dis 11: 633
Vaccines – where they should act
• Pre-exposure vaccination
• Post-exposure vaccination
• Therapeutic vaccination
Kaufmann (2011) Lancet Infect Dis 11: 633
Therapeutic vaccine candidates
Pre-/post-exposure vaccines
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
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
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
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
Post-exposure vaccines
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
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
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
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
Future candidates?
• Up to now, no vaccine candidate has
achieved sterilising immunity
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