BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection

Background In a previous phase 2 trial, bacille Calmette-Guerin (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-gamma 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.) BCG Revaccination to Prevent M. tuberculosis InfectionMycobacterium tuberculosis continues to cause substantial illness globally. In this phase 2b randomized trial, BCG revaccination did not prevent sustained M. tuberculosis infection in IGRA-negative, HIV-negative adolescents.