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Revisiting BCG revaccination: Hopes, evidence, and the emerging verdict
[To cite: Agrawal A. Revisiting BCG revaccination: Hopes, evidence, and the emerging verdict (Selected Summary). Natl Med J India 2025;38: 294–5. DOI: 10.25259/NMJI_997_2025]
Schmidt AC, Fairlie L, Hellström E, Luabeya Kany Kany A, Middelkoop K, Naidoo K, Nair G, Gela A, Nemes E, Scriba TJ, Cinar A, Frahm N, Mogg R, Kaufman D, Dunne MW, Hatherill M; BCG REVAX Study Team (Gates Medical Research Institute, Cambridge, Massachusetts, USA; Wits Reproductive Health and HIV Institute, University of Witwatersrand, Johannesburg, South Africa; Be Part Yoluntu Centre, Paarl, South Africa; South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa; Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; South African Medical Research Council HIV-TB Pathogenesis and Treatment Research Unit, Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.) BCG revaccination for the prevention of Mycobacterium tuberculosis infection. N Engl J Med 2025; 392:1789–800.
SUMMARY
Bacille Calmette–Guérin (BCG) REVAX was a Phase 2b, double-blind, randomized, placebo-controlled study conducted across 5 sites in South Africa to confirm encouraging proof-of-concept findings from a previous South African adolescent trial, where BCG revaccination showed 45.4% efficacy in preventing sustained infection (95% CI 6.4%–68.1%). There was 90% power to detect a 45% efficacy signal, with 1836 HIV-negative, QuantiFERON-Tuberculosis (TB) Gold (QFT)-negative adolescents aged 10–18 years being randomized to receive either BCG Danish 1331 or placebo, with a median follow-up of 30 months. The results are, unfortunately, disappointing.1 The primary endpoint of prevention of sustained infection, defined as QFT conversion followed by persistent positivity at 3 and 6 months, was not met. The observed hazard ratio of QFT conversion in the revaccinated group compared to the placebo was 1.04 (95% CI 0.73–1.48), which argues strongly against any useful protection, being in the wrong direction. This is despite strong immunogenicity, evidenced by increased antigen-specific CD4+ T cells. Safety was acceptable, though local reaction was common, practically unblinding the revaccination arm to the observer.
COMMENTS
Vaccines have been one of the greatest successes in the history of medicine, with the potential to eliminate infectious diseases.2 While there have been isolated examples of partial successes through antimicrobials, such as synchronized mass treatment for some helminthic infections3, given the scale of the problem and toxicity of antitubercular therapy, the strongest hope for tuberculosis elimination remains effective vaccine-mediated prevention. Unfortunately, in the current absence of effective vaccines and a sparse pipeline, the WHO’s goal of eliminating tuberculosis by 2030, and the even more aspirational national goal of TB-Mukt Bharat by 2025, are likely to remain unmet.
Hopes
The widely used BCG vaccine elicits an immune response against Mycobacterium tuberculosis (M.tb) and confers some protection against severe childhood TB.4 BCG revaccination has thus attracted interest for reasons of plausibility coupled with pragmatism about cost, safety, and feasibility.5–7 While evidence for its ability to protect against TB has been marginal, whether during primary vaccination or after revaccination, there have been some recent causes for cautious optimism. In a South African adolescent trial, BCG revaccination showed 45.4% efficacy in preventing sustained infection (95% CI 6.4%–68.1%), although it did not prevent infection defined as QFT positivity.8 This suggested that the immune response may aid in clearing early infection, rather than preventing exposure or entry altogether. The immunological rationale was bolstered by Indian evidence from the Chingleput cohort, where retrospective reanalysis of the original Indian Council of Medical Research–National Institute for Research in Tuberculosis BCG trial yielded a hazard ratio of 0.64 (95% CI 0.46–0.89) for TB incidence amongst the small subgroup revaccinated with BCG, indicating a modest 36% protective efficacy.9
Evidence
So, is this the final word? While the trial design was quite robust, the study period overlapped with Covid-19 lockdowns, which likely altered exposure risks and artificially reduced TB transmission early on. Externally reduced risk of infection in both groups would reduce the power to detect vaccine efficacy. However, given an HR of 1.04, it seems unlikely that this had a significant influence on the results. The unblinding due to local reaction to BCG but not placebo is unlikely to have influenced QFT result interpretation and can be ignored. However, the reliance on QFT as a surrogate for infection is inherently flawed. QFT reflects immune sensitization to M.tb antigens that are absent in BCG (ESAT-6 and CFP10), not viable infection, and is thus subject to variability and spontaneous reversion. Notably, QFT reversion occurred in over 40% of converters in both arms, making it difficult to distinguish meaningful vaccine impact from immunological noise.10 Overall, while technically robust, the REVAX trial’s dependence on imperfect biomarkers limits the conclusiveness of otherwise clearly negative findings.
Emerging verdict
The negative results of the REVAX trial dampen hopes for BCG revaccination as a viable path for TB elimination. From early promise to cautious optimism and now to guarded realism, the trajectory has underscored the complexity of TB immunology. The evidence suggests that BCG revaccination, while safe and immunologically active, offers limited to no benefit in preventing sustained infection as currently measured. The realist in me concludes that it is unlikely to meaningfully alter TB epidemiology at the population level, while leaving room for optimism that this apparent failure was due to immunological noise, and that the Chingleput cohort analysis signal may yet turn out to be real rather than statistical noise. Both the realist and optimist in me agree that even if BCG revaccination is not the answer, the search for that answer is clearer now than it has ever been. India’s ongoing exploration of BCG revaccination will probably need re-evaluation, with perhaps a shift in priority towards newer vaccines.
Conflicts of interest:
None declared
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