In a disappointing outcome, the Bacille Calmette-Guérin (BCG) revaccination didn’t help prevent sustained Mycobacterium tuberculosis infection in initially uninfected adolescents without HIV in a South African phase 2b randomised trial.
The trial couldn’t rule out an impact on subsequent tuberculosis disease, however, which it was not powered to assess.
Getting the BCG shot in the trial did induce T-cell response but without an impact on sustained conversion to a positive QuantiFERON-TB (QFT) test indicating M. tuberculosis infection that could lead to TB disease, reported the researchers led by Alexander Schmidt, MD, PhD, of the Gates Medical Research Institute in Massachusetts, in the New England Journal of Medicine.
A prior phase 2 trial had shown that BCG revaccination in teens led to 45.4% efficacy in reversion from positive to negative QFT compared with placebo, substantially more than seen with an experimental vaccine candidate for this secondary endpoint in the trial.
As this “could indicate successful immune control or clearance of M. tuberculosis infection, thus decreasing the risk of progression to disease”, Schmidt and colleagues’ BCG REVAX trial was designed as a confirmatory study.
However, reports Medpage Today, it showed no such trend. The hazard ratio for the primary endpoint of sustained QFT test conversion was 1.04 (95% CI 0.73-1.48) with revaccination versus placebo, for a vaccine efficacy point estimate of -3.8% (95% CI, -48.3 to 27.4) at the median 30 months of follow-up.
The researchers noted a similar lack of BCG revaccination efficacy in prevention of sustained M. tuberculosis infection in a large trial of adult healthcare workers in Brazil both for initial and sustained QFT test conversion.
“Given that a lack of vaccine efficacy was observed in two randomised, controlled trials that involved participants with different ancestry and age range and were conducted in locations with a different force of infection, geography, climate, and environmental mycobacteria exposure, the evidence supporting BCG revaccination for the prevention of M. tuberculosis infection appears to have weakened,” Schmidt's group concluded.
“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,” they added, noting that a trial under way in India to evaluate prevention of disease with BCG revaccination could provide the final answer.
As to the difference from the hypothesis-generating phase 2 study, “the inclusion of clinical sites with a lower prevalence of TB than the sites in the previous trial and the Covid-19-related school shutdowns probably contributed to the lower overall incidence of (interferon-γ release assay) conversion (6.5 to 6.9% vs 9.9% per person-year)”, noted an accompanying editorial.
The way forward for new tuberculosis vaccines isn’t clear, wrote editorialists Stephen Carpenter, MD, PhD, and Henry Boom, MD, both of University Hospitals Cleveland Medical Centre.
“Increasing evidence suggests that antigens presented by infected macrophages are key to the development of vaccines that elicit protective T-cell responses,” they noted. “Identification of the antigens that are successfully presented by M. tuberculosis-infected macrophages – and the T cells that are able to recognise them – is likely to be important in the development of protective tuberculosis vaccines.”
The trial included 1 836 adolescents aged 10 to 18 years (median 13) enrolled at five sites in South Africa, where TB disease incidence is among the highest in the world and where adolescents have a fast rise in M. tuberculosis infection of up to 10% per year.
The modified intent-to-treat population narrowed to 1 720 after excluding those who didn’t receive the BCG vaccine or placebo as randomised or who didn’t have a negative QFT test 10 weeks after receipt of BCG vaccine or placebo – a criterion “added to exclude participants with M. tuberculosis infection around the time that the vaccine or placebo was administered”, the researchers explained.
Initial QFT test conversion after day 71 of follow-up occurred in 135 participants (15.5%) in the BCG-vaccine group and 125 participants (14.7%) in the placebo group.
Sustained test conversion occurred in 62 of 871 (7.0%) participants in the BCG-vaccine group and 59 of 849 (7.1%) participants in the placebo group.
This primary endpoint outcome was defined by an initial conversion on the M. tuberculosis-specific interferon-γ release assay QFT from negative to positive, followed by two additional positive QFT tests at three and six months after the initial conversion.
Further analyses by percentage of participants with a sustained QFT test conversion and cumulative incidence of a sustained QFT test conversion over time were likewise similar between groups.
Laboratory-confirmed TB disease developed in three participants in each treatment group.
Study details
BCG revaccination for the prevention of Mycobacterium tuberculosis infection
Alexander Schmidt, Lee Fairlie, Elizabeth Hellström, et al.
Published in the NEJM on 7 May 2025
Abstract
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, randomised, 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 randomisation; 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.
NEJM comment – To BCG or Not Two BCG (Open access)
Medpage Today article – BCG Revaccination Hopes Dim for Tuberculosis Prevention (Open access)
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Century-old BCG vaccine prevents TB in children, not adults – Boston meta-analysis
SA clinical trial finds TB vaccine well tolerated
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