BCG Revaccination Fails to Prevent TB Infection in HIV-Negative Adolescents: NEJM

A recent phase 2b clinical trial in South Africa found that Bacille Calmette-Guérin (BCG) revaccination did not prevent sustained Mycobacterium tuberculosis infection in initially uninfected, HIV-negative adolescents. These findings were published in The New England Journal of Medicine contrast with earlier signals of benefit in youth from a prior phase II trial but align with negative results seen in adults.

The study builds on a previous phase 2 trial where BCG revaccination was shown to reduce the rate of sustained tuberculosis (TB) infection, not by preventing initial infection, but by curbing its persistence, as evidenced by a series of positive interferon-γ release assays (IGRAs) known as QuantiFERON-TB (QFT) tests over a six-month period. That earlier study reported a vaccine efficacy of 45% (95% CI, 6 to 68) in preventing sustained infection, giving hope for a relatively low-cost tool in TB prevention.

However, the new randomized, double-blind, placebo-controlled trial enrolled 1,836 adolescents who tested negative on the QFT assay and were also HIV-negative. The participants were randomly assigned to receive either the BCG vaccine (918 individuals) or a placebo (917 individuals). Also, final inclusion in the vaccine efficacy analysis required a negative QFT test 10 weeks post-vaccination, to exclude participants with potential latent infections already developing at the time of vaccination.

After a median follow-up of 30 months, 62 out of 871 participants in the BCG group and 59 out of 849 in the placebo group demonstrated sustained QFT conversion, which was defined as 3 consecutive positive QFT test results at baseline, 3 months, and 6 months. The calculated hazard ratio was 1.04 (95% CI, 0.73 to 1.48), by indicating essentially no difference between the vaccine and placebo groups. This translates to a point estimate of vaccine efficacy at –3.8%, with a confidence interval ranging from –48.3% to 27.4%, suggesting no statistically significant protective effect.

While the vaccine did stimulate an immune response, particularly type 1 helper CD4 T cells producing cytokines, this did not translate into clinical efficacy. The BCG group also experienced a higher rate of adverse events, though these were primarily mild and localized injection-site reactions such as redness, swelling, pain, and occasional ulceration. Overall, these results cast doubt on the utility of BCG revaccination as a preventive measure for TB in adolescents, highlighting the need for more effective vaccine candidates. 

Source:

Schmidt, A. C., Fairlie, L., Hellström, E., Luabeya Kany Kany, A., Middelkoop, K., Naidoo, K., Nair, G., Gela, A., Nemes, E., Scriba, T. J., Cinar, A., Frahm, N., Mogg, R., Kaufman, D., Dunne, M. W., & Hatherill, M. (2025). BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection. The New England Journal of Medicine, 392(18), 1789–1800. https://doi.org/10.1056/nejmoa2412381