BCG Revaccination Ineffective in Preventing Mycobacterium Tuberculosis Infection

In a significant phase 2b clinical trial, researchers have found that Bacille Calmette-Guérin (BCG) revaccination does not effectively prevent sustained Mycobacterium tuberculosis infections in adolescents when compared to a placebo. The study, led by Dr. Alexander Schmidt of the Gates Medical Research Institute in Cambridge, Massachusetts, involved 1,836 adolescents aged 10 to 18 years in South Africa, who were followed over a median period of 30 months. All participants tested negative for HIV and showed negative QuantiFERON-TB (QFT) test results at the beginning of the trial.

The primary objective of the study was to assess the efficacy of BCG revaccination in preventing sustained M. tuberculosis infection, defined as the conversion of a QFT test from negative to positive, confirmed by subsequent positive tests at three and six months. The results indicated no significant protective effect from the BCG vaccine, with conversion rates being statistically similar between the BCG and placebo groups (hazard ratio 1.04, P = .58), resulting in a negative vaccine efficacy of -3.8% (95% CI, -48.3 to 27.4).

These findings are critical as previous studies had suggested the BCG vaccine might reduce sustained infections, prompting the need for further investigation. Notably, the study's authors cautioned that the absence of efficacy in preventing infection decreases the likelihood of BCG revaccination offering protection against tuberculosis disease itself.

Dr. Schmidt emphasized the importance of this research in understanding tuberculosis prevention strategies, stating, “Although this trial does not allow us to draw firm conclusions on the efficacy of BCG revaccination for the prevention of disease, the lack of vaccine efficacy with respect to prevention of infection probably decreases the likelihood of BCG revaccination conferring protection against disease.”

The study's implications are significant for public health strategies, particularly in regions where tuberculosis remains a pressing health concern. Tuberculosis is currently one of the leading infectious disease killers globally, as reported by the World Health Organization (WHO). The organization has highlighted the urgent need for effective vaccination strategies to combat this disease, especially among high-risk populations.

Moreover, the study faced limitations, including a four-month pause in enrollment due to the COVID-19 pandemic, which may have contributed to a lower incidence of QFT test conversions among participants. Despite this, the study did report that most adverse events related to the vaccine were mild to moderate, with serious adverse events occurring in only 0.3% of participants across both groups, and no deaths or treatment discontinuations were reported.

This clinical trial adds to a growing body of evidence questioning the efficacy of BCG revaccination in preventing tuberculosis infection. As public health policymakers continue to seek effective interventions against tuberculosis, these findings may necessitate a reevaluation of vaccination strategies in high-burden regions.

The results of this study were published on May 7, 2025, in the New England Journal of Medicine, underscoring the importance of ongoing research in the fight against tuberculosis. The Gates Foundation funded the study, and some authors disclosed affiliations with pharmaceutical companies, including GSK and Pfizer, raising discussions about the influence of industry funding on research outcomes.