BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.

BACKGROUND In a previous phase 2 trial, bacille Calmette-Guérin (BCG) revaccination was not shown to provide protection from primary Mycobacterium tuberculosis infection but prevented sustained M. tuberculosis infection, defined by an initial conversion on a QuantiFERON-TB (QFT) test (an interferon-γ release assay) from negative to positive, followed by two additional positive QFT tests at 3 and 6 months after the initial conversion (a secondary end point). A vaccine efficacy of 45% (95% confidence interval [CI], 6 to 68) was observed. METHODS We performed a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of BCG revaccination, as compared with placebo, for the prevention of sustained QFT test conversion (primary end point) in QFT test-negative, human immunodeficiency virus (HIV)-negative adolescents. Adverse events were assessed in a secondary analysis, and immunogenicity was assessed in an exploratory analysis. Vaccine efficacy was evaluated in the modified intention-to-treat population, which included all the participants who had undergone randomization, received the BCG vaccine or placebo, and had a negative QFT test 10 weeks after receipt of BCG vaccine or placebo; the last criterion was added to exclude participants with M. tuberculosis infection around the time that the vaccine or placebo was administered. Hazard ratios and 95% confidence intervals were estimated from a stratified Cox proportional-hazards model. RESULTS A total of 1836 participants underwent randomization; 918 received the BCG vaccine, and 917 received placebo. After a median 30 months of follow-up, a sustained QFT test conversion was observed in 62 of 871 participants in the BCG-vaccine group and 59 of 849 participants in the placebo group. The hazard ratio for a sustained QFT test conversion (BCG vaccine vs. placebo) was 1.04 (95% CI, 0.73 to 1.48), for a vaccine efficacy point estimate of -3.8% (95% CI, -48.3 to 27.4). Adverse events occurred more frequently in the BCG-vaccine group than in the placebo group, and most were due to injection-site reactions (pain, redness, swelling, and ulceration). BCG revaccination induced cytokine-positive type 1 helper CD4 T cells. CONCLUSIONS BCG revaccination in QFT-test negative, HIV-negative adolescents did not provide protection from sustained M. tuberculosis infection. (Funded by the Gates Foundation; ClinicalTrials.gov number NCT04152161.).