Figures
- FIGURE 1
Vaccine strategies along the natural history of tuberculosis (TB), according to the expected effect. Vaccines developed with the strategy to prevent infection (POI) are mostly targeted for populations not yet exposed to Mycobacterium tuberculosis (i.e. pre-infection). Vaccines developed for prevention of disease (POD) could be useful if administered post- or pre-TB infection to prevent development of symptomatic disease. Therapeutic vaccines could have effects both in treatment-shortening and/or prevention of recurrence. Vaccines primarily developed for a prevention of recurrence (POR) strategy could be given with the aim of prevention of either re-infection or recurrence of disease (true relapse).
- FIGURE 2
Hypothesised interferon gamma (IFN-γ) release assay (IGRA) dynamics after vaccination with a prevention of infection candidate. QuantiFERON-TB (QFT) negative participants receiving vaccine or placebo. Rates of acquisition of Mycobacterium tuberculosis infection (QFT conversion), established infection (sustained QFT conversion through 6 months post conversion) and transient infection (QFT reversion within 6 months post conversion) are compared between the study arms. Participants with sustained QFT conversion and QFT >4 IU·mL−1 are considered at higher risk of tuberculosis compared to non-converters and reverters. The dotted line represents the standard QFT cut-off at 0.35 IU·mL−1.
Tables
- TABLE 1
Advantages and disadvantages of possible end-point definitions for tuberculosis (TB) vaccine efficacy trials
Advantages Disadvantages POI IGRA (QTF) conversion (>0.35 IU·mL−1) ∼10-fold more frequent than TB disease
Widely used threshold in routine practice
Higher sensitivity for detecting MTB infection compared to higher thresholdsDoes not detect all true MTB infections
IGRA reversion is common, but of unclear clinical significance
Significance of protection unclear
Test performance in PLHIV, people with immune-mediated inflammatory diseases taking immunosuppressive treatment, and very young children is unclearIGRA (QTF) conversion (>4.0 IU·mL−1) Higher risk of progression to TB disease than conversion at manufacturer threshold
Higher specificity for detecting MTB infection than manufacturer thresholdLess frequent event than conversion at manufacturer threshold
Lower sensitivity for detecting MTB infection than manufacturer thresholdSustained IGRA conversion (6 months) Might represent sustained (persistent) MTB infection
Might be associated with higher risk of TB disease compared to a single conversion
Lower risk of false-positive result compared to a single testLess frequent event than initial IGRA conversion
Does not encompass IGRA conversion–reversion–conversion events
Need for TB preventive therapy precludes nested POI in POD efficacy trial designPOD MTB liquid culture (sputum) Gold standard (most sensitive) tool
Allows genotyping of MTB strainNeed for central laboratory
Variable contamination rate (largely laboratory-dependent)
Lower yield in pauci-bacillary TB disease:
- HIV-associated TB
- childhood TB- One sample Logistically simple
Lower sensitivityPotential false-positive results - Two or more separate samples (processed independently) Higher specificity (if both need to be positive) Logistically complex
Less frequent than single positive sample
Decreased sensitivity (if both need to be positive), especially in pauci-bacillary TB disease:
- HIV-associated TB
- childhood TB- Before treatment of the TB episode starts Not affected by effect of vaccination on response to TB therapy Logistically complex
Lower sensitivity than before or after treatment startsXpert Ultra (sputum) Does not need central laboratory
Available at district-level hospitals
Rapid turnaroundDoes not allow to genotype MTB strain
Lower sensitivity and specificity than culture (higher false-positive rate, especially among trace results)MTB liquid culture OR Xpert Ultra (sputum) - With symptoms Protection associated with direct health benefit No opportunity to assess vaccine efficacy against subclinical disease - Without symptoms Allows assessment of vaccine efficacy against subclinical TB disease Significance of clinical protection unclear
Need for TB treatment precludes subsequent assessment of vaccine efficacy against symptomatic TB diseaseDigital chest radiograph (with or without CAD) High sensitivity for TB, widely available and with high added value in populations with paucibacillary disease, such as:
- HIV-associated TB
- childhood TBLimited specificity Urine LAM High specificity in PLHIV with low CD4 counts Limited sensitivity with increasing levels of CD4 counts TB symptoms (clinical diagnosis) High sensitivity, especially in pulmonary TB among HIV-negative individuals, cheap, no laboratory infrastructure needed
Sometimes used to define unconfirmed TBLimited specificity
Subjective interpretation of symptomsPrevention of recurrence/therapeutic M. tuberculosis liquid culture (sputum) Gold standard
Allows genotyping of MTB strain (true relapse versus reinfection) if collected before treatmentNeed for central laboratory Xpert Ultra (sputum) Logistically simple at treatment start Cannot distinguish viable from non-viable MTB bacilli
No opportunity to genotype MTB strainCAD: computer-aided detection; IGRA: interferon gamma release assay; LAM: lipoarabinomannan MTB: Mycobacterium tuberculosis; PLHIV: people living with HIV; POD: prevention of disease; POI: prevention of infection; QFT: QuantiFERON-TB.
Jump To
- Article
- Abstract
- Abstract
- Introduction
- Prevention of infection (POI) approaches to accelerate candidate vaccines into prevention of disease (POD) efficacy trials
- Optimising TB disease end-points for future efficacy trials
- End-point definition in vaccine trials including PLHIV
- Conclusions
- Acknowledgements
- Footnotes
- References
- Figures & Data
- Info & Metrics