Mark Hatherill

Dose-Finding Study of the Novel Tuberculosis Vaccine, MVA85A, in Healthy BCG-Vaccinated Infants

BACKGROUNDnBCG, the only licensed tuberculosis vaccine, affords poor protection against lung tuberculosis in infants and children. A new tuberculosis vaccine, which may enhance the BCG-induced immune response, is urgently needed. We assessed the safety of and characterized the T cell response induced by 3 doses of the candidate vaccine, MVA85A, in BCG-vaccinated infants from a setting where tuberculosis is endemic.nnnMETHODSnu2003Infants aged 5-12 months were vaccinated intradermally with either 2.5 × 10(7), 5 × 10(7), or 10 × 10(7) plaque-forming units of MVA85A, or placebo. Adverse events were documented, and T-cell responses were assessed by interferon γ (IFN-γ) enzyme-linked immunospot assay and intracellular cytokine staining.nnnRESULTSnThe 3 MVA85A doses were well tolerated, and no vaccine-related serious adverse events were recorded. MVA85A induced potent, durable T-cell responses, which exceeded prevaccination responses up to 168 d after vaccination. No dose-related differences in response magnitude were observed. Multiple CD4 T cell subsets were induced; polyfunctional CD4 T cells co-expressing T-helper cell 1 cytokines with or without granulocyte-macrophage colony-stimulating factor predominated. IFN-γ-expressing CD8 T cells, which peaked later than CD4 T cells, were also detectable.nnnCONCLUSIONSnMVA85A was safe and induced robust, polyfunctional, durable CD4 and CD8 T-cell responses in infants. These data support efficacy evaluation of MVA85A to prevent tuberculosis in infancy. Clinical Trials Registration.u2003NCT00679159.

Tuberculin skin test and QuantiFERON® assay in young children investigated for tuberculosis in South Africa.

SETTINGnAlthough the literature on interferon-gamma release assays on tuberculosis (TB) in children has increased, data pertaining to young children remain relatively limited.nnnOBJECTIVEnTo compare results from the tuberculin skin test (TST) and the QuantiFERON®-TB Gold In-Tube assay (QFT) in children aged <3 years investigated for TB disease.nnnDESIGNnTB suspects were evaluated by medical history and examination, TST, QFT, chest radiography, induced sputum and gastric washings for smear and culture for Mycobacterium tuberculosis.nnnRESULTSnA total of 400 children were enrolled. Among 397 children with both test results, 68 (17%) were QFT-positive and 72 (18%) were TST-positive (≥10 mm). Agreement between the tests was excellent (94%, κ = 0.79, 95%CI 0.69-0.89). TB disease was diagnosed in 52/397 (13%) participants: 3 definite, 35 probable and 14 possible TB. QFT sensitivity and specificity for TB disease were respectively 38% and 81%. TST sensitivity and specificity were respectively 35% and 84%.nnnCONCLUSIONnWhile TST and QFT had excellent concordance in this population, both tests had much lower sensitivity for TB disease than has been reported for other age groups. Our results suggested equivalent performance of QFT and TST in the diagnosis of TB disease in young children in a high-burden setting.

Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial

SETTINGnA high tuberculosis (TB) burden rural area in South Africa.nnnOBJECTIVEnTo compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age.nnnDESIGNnBCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations.nnnRESULTSnA total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs.nnnCONCLUSIONnHome visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.

Risky behaviour and psychosocial correlates in adolescents - is there a link with tuberculosis?

OBJECTIVEnReasons for the increase in incidence of tuberculosis (TB) in late adolescence are poorly understood. One hypothesis is that psychological and behavioural variables associated with adolescence may increase risk of developing TB. The study aimed to determine whether psychosocial and behavioural variables affect incidence of TB disease in adolescents.nnnMETHODSnA case-control study design was used in adolescents who were participants in a TB epidemiological study. Cases were adolescents diagnosed with TB disease. Approximately half of the controls had no TB disease but a positive TST indicative of latent TB. Half had neither TB disease nor latent TB. A self-administered questionnaire was completed by participants. The questionnaire consisted of a combination of standardised psychosocial instruments.nnnRESULTSnOf 292 participants, 62 were cases, 112 had latent TB and 118 neither TB disease nor latent TB. There were no significant differences in instrument scores between cases and controls. There was a trend for certain adverse life events to be more common in the TB-disease group.nnnCONCLUSIONnIn adolescents, a trend for association between TB incidence and psychosocial and behavioural variables was not statistically significant. Given the trend, research with larger samples, and more comprehensive assessment of the relationship between stressors and TB, is warranted.

Impact of isoniazid preventive therapy on the evaluation of long-term effectiveness of infant MVA85A vaccination

SETTING: South Africa. OBJECTIVE: To evaluate the long-term effectiveness of infant modified vaccinia Ankara virus-expressing antigen 85A (MVA85A) vaccination against tuberculosis (TB). DESIGN: We analysed data from a double-blind randomised placebo-controlled Phase 2b MVA85A infant TB vaccine trial (2009–2012), with extended post-trial follow-up (2012–2014). Isoniazid preventive therapy (IPT) was provided by public health services according to national guidelines. The primary outcome was curative treatment for TB disease. Survival analysis and Poisson regression were used for study analysis. RESULTS: Total follow-up was 10 351 person-years of observation (pyo). Median follow-up age was 4.8 years (interquartile range 4.4–5.2). There were 328 (12%) TB cases. TB disease incidence was 3.2/100 pyo (95%CI 2.8–3.5) overall, and respectively 3.3 (95%CI 2.9–3.9) and 3.0 (95%CI 2.6–3.5)/100 pyo in the MVA85A vaccine and placebo arms. A total of 304 children (11%) received IPT, with respectively 880 and 9471 pyo among IPT and non-IPT recipients. There were 23 (7.6%) TB cases among 304 IPT recipients vs. 305 (12.9%) among 2374 non-IPT recipients (P = 0.008). IPT effectiveness was 85% (95%CI 76–91). CONCLUSION: Extended follow-up confirms no long-term effectiveness of infant MVA85A vaccination, but a six-fold reduction in TB risk can be attributed to IPT. National TB programmes in high TB burden countries should ensure optimal implementation of IPT for eligible children.