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 thresholds | Does 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 unclear |
| IGRA (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 threshold | Less frequent event than conversion at manufacturer threshold Lower sensitivity for detecting MTB infection than manufacturer threshold |
| Sustained 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 test | Less 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 design |
| POD | ||
| MTB liquid culture (sputum) | Gold standard (most sensitive) tool Allows genotyping of MTB strain | Need 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 sensitivity | Potential 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 starts |
| Xpert Ultra (sputum) | Does not need central laboratory Available at district-level hospitals Rapid turnaround | Does 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 disease |
| Digital 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 TB | Limited 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 TB | Limited specificity Subjective interpretation of symptoms |
| Prevention of recurrence/therapeutic | ||
| M. tuberculosis liquid culture (sputum) | Gold standard Allows genotyping of MTB strain (true relapse versus reinfection) if collected before treatment | Need for central laboratory |
| Xpert Ultra (sputum) | Logistically simple at treatment start | Cannot distinguish viable from non-viable MTB bacilli No opportunity to genotype MTB strain |
CAD: 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.