Second BCG Dose to Prevent Tuberculosis in Adolescents
August 1, 2025 4 minutes read
By Philip R. Fischer, MD, DTM&H
Synopsis: Despite a previous study raising the hope that giving Bacille Calmette-Guérin (BCG) vaccine to adolescents who previously had received BCG as newborns would better prevent sustained tuberculosis (TB) infections, a new study conclusively demonstrates that revaccination with BCG during adolescence has no statistically significant effect on the incidence of subsequent TB infection or sustained positivity of interferon gamma release assay tests.
Source: Schmidt AC, Fairlie L, Hellström E, et al. BCG revaccination for the prevention of Mycobacterium tuberculosis infection. N Engl J Med. 2025;392(18):1789-1800.
Tuberculosis (TB) is still common, with approximately 21% of the world’s 8.2 billion people being infected. Of these, approximately 56 million were recently infected and are at particular risk of progressing to active disease. Ten million new cases are reported each year; 13% involve children younger than 15 years of age. Worldwide, approximately 1.3 million people die of TB each year, and 13% of those also are infected with the human immunodeficiency virus (HIV).
Schmidt and an international team supported by the Gates Foundation undertook a TB prevention trial in South Africa. South Africa has a higher incidence of TB than most other countries, at 468 per 100,000 people in 2022. There, the prevalence of TB infection rises rapidly during the adolescent years; approximately 10% of adolescents develop newly positive interferon gamma release assay (IGRA) TB tests each year.
Bacille Calmette-Guérin (BCG) vaccine is routinely given to newborns to prevent TB in much of the world. A 2018 report suggested that BCG administration to IGRA-negative HIV-negative adolescents (12-17 years of age, 622 subjects split between placebo and BCG groups) who had received neonatal BCG did not prevent conversion to IGRA-positivity but did reduce the risk that those who converted to a positive IGRA would go on to have sustained IGRA-positivity three and six months later.1 Seeking to confirm or refute these findings, the authors tested the effectiveness of adolescent revaccination with BCG in preventing IGRA-conversion and subsequent sustained IGRA-positivity in a randomized, placebo-controlled therapeutic trial in 1,836 adolescents 10 to 18 years of age.
On or after day 71 following vaccine/placebo administration, statistically similar 16% of BCG recipients and 15% of placebo recipients had positive IGRA tests. Similarly, there was no statistically significant difference in the risk of sustained IGRA-positivity during follow-up (two to five years).
There were some differences in study populations between this negative study and the previous study that suggested there was a favorable effect of revaccination. Although the locations of the populations were very similar, this current study included subjects in a somewhat broader region of South Africa. The current study also included some slightly younger and slightly older adolescents. The authors did not think that either of these differences would account for the inconsistent results between the two studies. Rather, the current study was larger and better powered to identify true differences between treatment and placebo groups. The authors also noted that a similar recent study in approximately 2,000 adult healthcare workers in Brazil showed no helpful preventive response to revaccination with BCG.2
Thus, this new study conclusively shows that adolescents in an area with a high risk of TB infection are protected neither from Mycobacterium tuberculosis infection nor from persistent IGRA-positivity following a new TB infection. Revaccination of adolescents who previously received a neonatal dose of BCG does not appear to be a helpful strategy to prevent TB infection.
Commentary
BCG vaccine was originally designed to prevent cows from getting Mycobacterium bovis disease, and the vaccine was first given to a human newborn in 1921.3 During the first 100 years of BCG use in humans, the vaccine is credited with saving millions of lives and likely has been given to more people than has any other vaccine.3 In fact, nearly 90% of newborns on this planet receive BCG each year.3 BCG is approximately 70% effective in preventing miliary and meningeal TB in children, but it is less effective in adults and has no to limited and highly variable effect on actually preventing pulmonary tuberculosis.3
BCG is the only licensed vaccine for prevention of tuberculosis. However, many vaccine candidates are in development, and a dozen are undergoing clinical trials.4
Schmidt et al have now provided helpful “negative” data showing that there is no compelling reason to further pursue revaccination of adolescents with a second BCG dose. The World Health Organization, realizing that even a small and variable benefit would make BCG administration reasonable in resource-limited areas, continues to recommend BCG use for newborns while recognizing that BCG is just one of many parts of a comprehensive TB prevention program.5 In the United States, BCG is sometimes instilled in the bladder to treat noninvasive bladder cancer, but it is not routinely used as a TB vaccine since the minimal benefit against primary pulmonary TB seems less than the costs of vaccinating low-risk newborns and since use of BCG reduces the reliability of TB skin testing.6
Philip R. Fischer, MD, DTM&H, is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
References
1. Nemes E, Geldenhuys H, Rozot V, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med. 2018;379(2):138-149.
2. Dos Santos PCP, Messina NL, de Oliveira RD, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in adult Brazilian health-care workers: A nested clinical trial. Lancet Infect Dis. 2024;24(6):594-601.
3. Lange C, Aaby P, Behr MA, et al. 100 years of Mycobacterium bovis bacille Calmette-Guérin. Lancet Infect Dis. 2022;22(1):e2-e12.
4. Sachdeva KS, Chadha VK. TB-vaccines: Current status & challenges. Indian J Med Res. 2024;160(3&4):338-345.
5. World Health Organization. BCG vaccines: WHO position paper — February 2018. Wkly Epidemiol Rec. 2018;93(8):73-96.
6. Centers for Disease Control and Prevention. Bacille Calmette-Guérin (BCG) vaccine for tuberculosis. Jan. 31, 2025. www.cdc.gov/tb/hcp/vaccines/index.html
Despite a previous study raising the hope that giving Bacille Calmette-Guérin (BCG) vaccine to adolescents who previously had received BCG as newborns would better prevent sustained tuberculosis (TB) infections, a new study conclusively demonstrates that revaccination with BCG during adolescence has no statistically significant effect on the incidence of subsequent TB infection or sustained positivity of interferon gamma receptor assay tests.
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