BackgroundRecent Mycobacterium tuberculosis (M.tb) infection predisposes to tuberculosis disease, the leading global infectious disease killer. We tested safety andefficacy of H4:IC31® vaccination or Bacille Calmette-Guerin (BCG) revaccination for prevention of M.tb infection. MethodsQuantiFERON-TB Gold In-tube (QFT) negative, HIV-uninfected, remotely BCG-vaccinated adolescents were randomized 1:1:1 to placebo, H4:IC31® or BCG revaccination (NCT02075203). Primary outcomes were safety and acquisition of M.tb infection, defined by initial QFT conversion tested 6-monthly over two years. Secondary outcomes were immunogenicity and sustained M.tb infection, defined by sustained QFT conversion without reversion three and six months post-conversion. Statistical significance for efficacy proof-of-concept was set at 1-sided p<0.10.Results990 participants were enrolled. Both vaccines had acceptable safety profiles and were immunogenic. QFT conversion occurred in 134 and sustained conversion in 82 participants. Neither H4:IC31® nor BCG prevented initial QFT conversion, with efficacy point estimates of 9.4% (95% confidence interval: -36.2, 39.7; one-sided p=0.32) and 20.1% (-21.0, 47.2; one-sided p=0.14), respectively. However, BCG did prevent sustained QFT conversion with an efficacy of 45.4% (6.4, 68.1; one-sided p=0.013); H4:IC31® efficacy was 30.5% (-15.8, 58.3; one-sided p=0.08). QFT reversion rate from positive to negative was 46% in BCG, 40% in H4:IC31 and 25% in placebo recipients. ConclusionsThis first proof-of-concept, prevention of M.tb infection trial showed that sustained infection can be prevented by vaccination in a high-transmission setting and confirmed feasibility of this strategy to inform clinical development of new vaccine candidates. Evaluation of BCG revaccination to prevent tuberculosis disease in M.tb- uninfected populations is warranted.
Summary Background Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Methods Adult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov , NCT02735590 . Findings 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25–6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3H...
MVA85A 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. NCT00679159.
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