Please note this information is specifically directed to, and only to be used by, medical professionals seeking additional information on the BRACE trial. In order to be fully understood, this section may require you to have medical or biomedical research training.
Current Australian BCG vaccination recommendations
Bacille Calmette-Guérin (BCG) vaccination in Australia is limited to selected high-risk groups and is not routinely recommended for most health care workers (HCW).  BCG vaccination is recommended for Aboriginal and Torres Strait Islander neonates in communities with a high incidence of TB; neonates and children 5 years of age and under who will be travelling or living in areas with a high prevalence of TB for extended periods; and neonates born to parents with leprosy. It is recommended that all individuals have a tuberculin skin test (TST) prior to BCG vaccination, except infants less than 6 months of age with no history of tuberculosis (TB) contact, and that BCG should not be given to an individual with a tuberculin reading of 5mm or more. Additionally, BCG revaccination is not recommended, regardless of TST reaction size.
BCG is contraindicated in immunocompromised individuals due to the risk of disseminated BCG infection.  This includes individuals immunocompromised by HIV infection, primary immunodeficiencies, corticosteroids or other immunosuppressive agents, and malignancies involving bone marrow or lymphoid systems. BCG is also contraindicated in individuals with any serious illness and those with generalised septic skin diseases and active skin conditions such as eczema, dermatitis and psoriasis near the site of vaccination.  While BCG has not been shown to cause foetal damage the use of live vaccines is contraindicated in pregnancy. 
Global BCG vaccination recommendations and practices
The current World Health Organization (WHO) position is that BCG revaccination is not recommended for any person, as there is no evidence to support the role of BCG revaccination in protection against tuberculosis.  A number of countries have previously included BCG revaccination as part of their national immunisation policies. In 1999, 30 countries in Europe and an additional 18 countries in the Middle East, South East Asia and the Western Pacific region reported using BCG revaccination. In several countries the national policy included BCG in infancy and again at school entry or leaving. At least seven countries revaccinate adults over 18 years of age.  In some countries, particularly in Eastern Europe, revaccination with BCG up to five times has been recommended. Some countries, such as Poland, recommended universal revaccination while others restrict revaccination to individuals without a BCG scar or those with a ‘negative’ TST. Criteria for TST negativity differs between countries. [4, 6] In countries where BCG revaccination has been part of national immunisation practice, passive surveillance has not reported any cases of disseminated BCG in immunocompetent individuals.
TST and interferon gamma release assay (IGRA) screening aims to identify individuals with latent tuberculosis infection (LTBI).  The diameter of induration following TST gives an indication of the likelihood of LTBI, however, positive results can also arise from previous BCG vaccination and exposure to environmental mycobacteria. This is in contrast to IGRA which are unaffected by previous BCG vaccination. A positive IGRA indicates either current or past infection with TB.  Screening of individuals using TST prior to BCG vaccination is recommended in Australia and other countries on the grounds that it may prevent complications due to pre-existing immunity from previous exposure to mycobacterial antigens  A comprehensive review of complications following more than 1.5 billion BCG doses in children and adults did not find that TST predicted serious complications from BCG vaccination. The most serious reactions recorded were disseminated BCG (3 per million) and death (0.02 per million) due to primary immunodeficiency that would not be detected by TST. The development of subcutaneous abscesses and regional lymphadenopathy were not predicted by prior TST, although the rate of necrotic skin reactions was higher in those who had previously received BCG vaccination. 
Trials of BCG revaccination
Three large randomised controlled trials of BCG revaccination in children and adults in Malawi (n=54865), children in Guinea Bissau (n=2871) and adolescents in South Africa (n=990) did not show increased rates of serious adverse events among BCG revaccinated participants. [10-12] Participants in the Malawi study did not undergo any pre-randomisation screening with TST or IGRA.  This study found a lower rate of leprosy amongst revaccinated participants but no difference in the rates of tuberculosis or death between the groups. Of the children in the Guinea Bissau study, those with a measurable TST (1-14 mm) had increased rates of large local reaction compared to controls (3/6 compared with 18/388). Two months after revaccination, all had healed vaccination scars with no axillary node enlargement, fever or suppurative lymphadenitis. Participants in the South African study all had a negative IGRA at enrolment.  Among BCG-revaccinated adolescents, 93% reported mild local injection site reactions including swelling, induration, discharge, erythema, scab and ulceration. This was compared to 25% in the placebo group. The rates of moderate injection site reactions were similar between the BCG (5%) and placebo (6%) groups. There was one severe and seven serious adverse events in each of the BCG and control groups. The serious adverse events reported in the BCG group were not attributed to BCG revaccination and included gastroenteritis, chest injury, thermal burn, intentional self-injury, suicide attempt and small intestinal obstruction. The rate of upper respiratory tract infections was also lower in the BCG revaccinated group compared to placebo (2.1% compared to 7.9%, p<0.001).
Further studies looking at BCG revaccination in individuals with positive TST or IGRA do not show increased risk of significant adverse effects. A case-control study of 200 healthy nursing students in India included 28 participants with a positive IGRA who received BCG revaccination.  There were no serious side effects reported and no participants developed active tuberculosis during the follow-up study period. A randomised controlled trial of BCG revaccination in healthy adults with a positive TST (>15 mm) with or without isoniazid pre-treatment (n=82) showed no difference in the rate of reactions between groups with only local injection site reactions (35-76%) and mild systemic adverse effects (19%) including headache, fever and nausea.  Among the 76% of participants who developed ulceration, the median ulcer size was 5 mm (IQR 4.0-6.0). Maximum ulcer diameter did not correlate with IGRA result prior to BCG vaccination in either group. There were no reports of regional lymphadenitis or serious morbidity.
Enhanced routine passive surveillance of BCG revaccinated school children in the BCG-REVAC trial in Brazil is available for 71718 individuals.  There were only 33 reported adverse events of which 60% were local cutaneous reactions and 28% axillary lymphadenopathy without suppuration. There were no deaths, permanent injuries or disseminated infections reported. In a case series of 13 children who experienced adverse events following BCG revaccination in Brazil, all developed local ulceration or abscess formation with complete recovery following antimycobacterial therapy.  There were no cases of suppurative lymphadenitis or disseminated BCG.
Two large randomised controlled trials showed BCG revaccination did not confer any additional protection against tuberculosis, however, it may provide some additional protection against leprosy (cause by Mycobacterium leprae). [11, 15] Cohort studies done in countries where BCG revaccination was routinely performed also showed no additional protection against tuberculosis. [17, 18] The data presented above supports the WHO position that while BCG revaccination is not recommended due to a lack of evidence of efficacy against tuberculosis, ‘the risk of administering BCG vaccine to persons with positive tuberculin reactions due to either prior BCG vaccination or to natural infection is minimal’.
One aim of the BRACE trial is to document the safety of BCG vaccination (and revaccination) in HCW in Australia. The decision not to perform pre-vaccination TST screening in the study is pragmatic to reduce barriers to participation for already busy and stretched healthcare workers during the current COVID-19 outbreak. While it does not align with current Australian vaccination guidelines it has been carefully considered upon systematic review of the literature presented above. Adverse events will be actively monitored during the trial and medical review available for any participants who have concerns about their BCG vaccination site or scar.
- The BCG vaccine: information and recommendations for use in Australia, in Communicable Diseases Intelligence. Australian Government Department of Health.
- Australian Immunisation Handbook. Tuberculosis. 2018: Australian Government Department of Health.
- WHO News and activities. Bulletin of the World Health Organization, 1995. 73(6): p. 805-817.
- Paul Fine, I.C., Julie Milstien, C. John Clements, Issues relating to the use of BCG in immunization programmes: a discussion document. 1999, Department of Vaccines and Biologicals, World Health Organization: Geneva.
- Trnka, L., et al., Survey of BCG vaccination policy in Europe: 1994-96. Bull World Health Organ, 1998. 76(1): p. 85-91.
- Immunisation schedules in the WHO European Region, in WHO Wkly Epidem Rec. 1995, World Health Organization. p. 221-227.
- Coulter, C., Tuberculosis testing. Australian Family Physician, 2012. 41(7): p. 489-492.
- Bothamley, G.H., et al., Tuberculin testing before BCG vaccination. BMJ, 2003. 327(7409): p. 243-4.
- Lotte, A., et al., BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res, 1984. 21: p. 107-93.
- Nemes, E., et al., Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med, 2018. 379(2): p. 138-149.
- Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Karonga Prevention Trial Group. Lancet, 1996. 348(9019): p. 17-24.
- Roth, A.E., et al., Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ, 2010. 340: p. c671.
- Rakshit, S., et al., BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA- Indian adults. JCI Insight, 2019. 4(24).
- Hatherill, M., et al., Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine, 2014. 32(31): p. 3982-8.
- Rodrigues, L.C., et al., Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet, 2005. 366(9493): p. 1290-5.
- Cunha, A.J., et al., Adverse effects of BCG revaccination: a report on 13 cases from Rio de Janeiro, Brazil. Int J Tuberc Lung Dis, 2002. 6(12): p. 1110-3.
- Tala-Heikkila, M.M., J.E. Tuominen, and E.O. Tala, Bacillus Calmette-Guerin revaccination questionable with low tuberculosis incidence. Am J Respir Crit Care Med, 1998. 157(4 Pt 1): p. 1324-7.
- Leung, C.C., et al., Efficacy of the BCG revaccination programme in a cohort given BCG vaccination at birth in Hong Kong. Int J Tuberc Lung Dis, 2001. 5(8): p. 717-23.
- Bulletin of the World Health Organization 1995. World Health Organization. p. 805-810.