Recruitment ended in March 2021 for this multi-centre randomised controlled clinical trial of the BCG vaccine against COVID-19.

Half of the healthcare workers received the BCG vaccine to test whether it can protect those exposed to SARS-CoV-2 from developing severe symptoms by boosting their frontline immunity. The below information was provided at recruitment:

What to expect following the BCG vaccination

• The BCG vaccination is given just under the skin (into the ‘intradermal’ layer) of the left upper arm 
• The usual expected reaction to BCG vaccination is redness and/or a small ‘papule’ (a pimple or lump) at the injection site that appears weeks to months after vaccination 
• A few weeks later, the papule usually softens and breaks down to a small ulcer (an open sore - usually less than 15 mm in diameter) 
• The ulcer may last from weeks to months 
• Once the ulcer has healed, this usually (but not always) leaves a small flat scar
  
  

Caring for the injection site 

• Keep the area clean and dry 
• Normal bathing is acceptable—pat dry after washing 
• A temporary dry dressing with gauze may be used if the area oozes 
• A sterile alcohol swab may clean the area if required 
• Do not apply ointment, antiseptic creams, sticking plaster or band aids 
• Do not squeeze any pus out of the papule or ulcer that develops
  
  

Rare complications following BCG vaccine

• A large abscess (collection of pus) at the injection site 
• Infection of the glands in the left armpit (‘axillary lymph nodes’) causing tenderness and swelling under the arm ‘Keloid’ scarring (very noticeable scarring on the skin) 
• Severe immediate allergic reaction (very rare), please stay on the hospital grounds for the next 20 minutes
  
  

When to seek medical advice 

• If you notice any severe or rare reactions, such as a large persistent discharging abscess at the injection site
• If you notice swelling or tenderness of the glands (‘lymph nodes’) in the left armpit
  
  

How to take the best picture of your vaccination site

• Attach a standard-sized object to your upper arm such as a coin or beer bottle cap using rolled up sticky tape or Blu Tack, next to the vaccination site
• You can also place a ruler or a measuring tape next to the vaccination site
• Hold your phone approximately 15 cm away from the area being photographed
• Ensure the entire injection site and coin are in the photo and in focus
  
  

Who to contact for advice

Contact us or your General Practitioner.

For medical professionals, seeking additional information on the BRACE trial.

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 Bacille Calmette-Guérin (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. BCG revaccination is not recommended, regardless of TST reaction size.

BCG is contraindicated in immunocompromised individuals because of 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. Several 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. 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.

Pre-vaccination screening

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. 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 the 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 an 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). Cohort studies done in countries where BCG revaccination was routinely performed also showed no additional protection against tuberculosis. 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 a 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.

For medical professionals, seeking additional information on the BRACE trial.

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.

BCG vaccination in pregnancy and lactation

BCG vaccination is not recommended for use in pregnancy because of a lack of safety data and theoretical concerns associated with a live vaccine. However, no evidence of adverse effects to the developing foetus has been observed.

BCG vaccination is not contraindicated in lactating women, although there is limited data on safety and immunogenicity of the vaccine in this group. 

• Although no harmful effects of the BCG vaccine on the foetus have been observed, BCG vaccination should not be given during pregnancy due to theoretical concerns associated with a live vaccine [2]
• BCG vaccination is not contraindicated in lactating women, although there is limited data on safety and immunogenicity of the vaccine in this group [1]. 
• In the 1990s, a number of European countries gave repeat BCG vaccinations in adolescence or early adulthood, including Luxembourg (18-25 years), Portugal (18-20 years), Albania (18 years), Greece (21 years), Hungary (16-17 years), Poland (18 years), Slovakia (16 years), Yugoslavia (15 years), Azerbaijan (25 years), Lithuania (17 years) and Russia (21-22 years) [4].
• Bulgaria is the only European country that routinely gives BCG vaccine in adolescence, with a catch-up dose given at 17 years if previous doses were missed [5]. Patients are screened for latent TB infection (LTBI) with a tuberculin skin test (TST) prior to the catch-up doses. 

This review was done in accordance with the ‘preferred reporting items for systematic reviews and meta-analyses’ (PRISMA) statement. A systematic search of MEDLINE was done in March 2020 using the OVID interface using the following search terms: (exp BCG vaccine OR exp tuberculosis vaccines) AND (exp pregnancy OR exp breast feeding OR exp pregnant women OR exp pregnancy complications/ OR exp prenatal care/ OR exp pregnancy complications, infectious). Reference lists of identified relevant publications were also hand-searched. 

Studies were included if they:

1. Assessed the safety of BCG vaccination antenatally or during lactation, or
2. Described case reports of BCG vaccination during pregnancy or lactation. The search identified 253 studies, none of which fulfilled the inclusion criteria. 

Victoria

Professor Nigel Curtis
Tony Korman
Niki Tan

New South Wales

Nicholas Wood
Mark Douglas
Brendan McMullan
Jeffrey Post
Anthony Byrne
Craig Munns

South Australia

David Lynn
Simone Barry
Helen Marshall

Western Australia

Peter Richmond
Laurens Manning
Michaela Lucas

Brazil

Julio Croda
Margareth Dalcolmo
Marcus Lacerda
Bruno Jardim

The Netherlands

Marc Bonten
Cristina Prat Aymerich
Jan Kluytmans
Wouter van den Bijllaardt
Jet Gisolf
Wim Boersma
Jaap ten Oever

Spain

Jesús Rodríguez Baño
Antoni Rosell
Tomás Perez Porcuna
Josune Goikoetxea
Maria Carmen Fariñ Álvarez

United Kingdom

John Campbell
Adilia Warris
Daniel Webber-Rookes
Alex Harding
James Moore
Michael Gibbons
Tamsin Venton