Phase III, two-group multicentre, randomised controlled trial in up to 10 078 healthcare workers to determine if BCG vaccination reduces the incidence and severity of COVID-19 during the 2020 pandemic.

Healthcare workers are at the frontline of the coronavirus disease (COVID-19) pandemic. They will be randomised to receive a single dose of BCG vaccine or 0.9% NaCl placebo. Participants will be followed-up for 12 months with notification from a Smartphone application or phone calls (up to daily when ill) and surveys to identify and detail COVID-19 infection. Additional information on severe disease will be obtained from hospital medical records and/or government databases. Blood samples will be collected prior to randomisation and at 3, 6, 9 and 12 months to determine exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Where required, swab/blood samples will be taken at illness episodes to assess SARS-CoV-2 infection.

The trial includes a pre-planned meta-analysis with data from 2834 participants recruited in the Stage 1 of this study, where participants were randomised to receive BCG or no BCG vaccine at the time of receiving influenza vaccination.

Inclusion Criteria:

• Over 18 years of age

• Healthcare worker

  • This is defined as anyone who works in a healthcare setting or has face to face contact with patients.

• Provide a signed and dated informed consent form

• Australian sites only: If annual influenza vaccination is available, receiving the flu vaccine is an eligibility requirement. The flu vaccine will be required a minimum of 3 days in advance of randomisation in the BRACE trial.

• Pre-randomisation blood collected

Exclusion Criteria:

• Has any BCG vaccine contraindication

  • Fever or generalised skin infection (where feasible, randomisation can be delayed until cleared)

  • Weakened resistance toward infections due to a disease in/of the immune system

  • Receiving medical treatment that affects the immune response or other immunosuppressive therapy in the last year.

    • These therapies include systemic corticosteroids (≥20 mg for ≥2 weeks), non-biological immunosuppressant (also known as 'DMARDS'), biological agents (such as monoclonal antibodies against tumour necrosis factor (TNF)-alpha).

  • People with congenital cellular immunodeficiencies, including specific deficiencies of the interferon-gamma pathway

  • People with malignancies involving bone marrow or lymphoid systems

  • People with any serious underlying illness (such as malignancy)

    • NB: People with cardiovascular disease, hypertension, diabetes, and/or chronic respiratory disease are eligible if not immunocompromised, and if they meet other eligibility criteria

  • Known or suspected HIV infection,even if they are asymptomatic or have normal immune function.

  • This is because of the risk of disseminated BCG infection

  • People with active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination

  • A different adjacent site on the upper arm can be chosen if necessary

  • Pregnant

    • Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women who think they could be pregnant or are planning to become pregnant within the next month.
    • UK specific: Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women of childbearing potential (WOCBP) who think they could be pregnant.
    • Spain specific: If the patient is female, and of childbearing potential, she must have a negative pregnancy test at the time of inclusion and practice a reliable method of birth control for 30 days after receiving the BCG vaccination.

  • Another live vaccine administered in the month prior to randomisation

  • Require another live vaccine to be administered within the month following BCG randomisation

    • If the other live vaccine can be given on the same day, this exclusion criteria does not apply

  • Known anaphylactic reaction to any of the ingredients present in the BCG vaccine

  • Previous active TB disease

  • Currently receiving long term (more than 1 month) treatment with isoniazid, rifampicin or quinolone as these antibiotics have activity against Mycobacterium bovis

• Previous adverse reaction to BCG vaccine (significant local reaction (abscess) or suppurative lymphadenitis)

• BCG vaccine given within the last year

• Have previously had a SARS-CoV-2 positive test result (positive PCR on a respiratory sample or a positive SARS-CoV-2 diagnostic antigen test approved by the local jurisdiction's public health policy)

• Already part of this trial, recruited at a different site/hospital.

• Participation in another COVID-19 prevention trial

• Have previously received a COVID-19-specific vaccine

Under the terms of the funding agreement with the Bill and Melinda Gates foundation, the BRACE trial has a data sharing agreement in place.

An anonymised Individual Participant Data (IPD) dataset and a data dictionary will be provided to Vivli (https://vivli.org/) under the terms of the agreements with the Bill and Melinda Gates foundation grant and Vivli.

After database lock, the following may be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions, under a collaborator agreement, for accessing:

• Individual participant data that underlie the results reported in our articles after deidentification (text, tables, figures and appendices)
• Study protocol, Statistical Analysis Plan, PICF

After database lock, a 12-month embargo period will be in place, to allow adequate time for analyses and publication outputs. Data transfer to Vivli should occur during the embargo period.

Researchers from a recognised research institution can approach MCRI for access of data.

The researcher will need to provide evidence that the proposed use of the data has been ethically reviewed and approved by an Institutional Review Board (IRB)/ Human Research Ethics Committee(HREC), and accept MCRI's conditions, under a collaborator agreement.

The control group will receive a placebo of 0.9% sodium chloride (NaCl). Members of the research team doing the follow-up of participants and analysis will be blinded to the group allocation (by the removal of this variable and all other variables related to BCG from the dataset) until the formal detailed statistical analysis plan is confirmed and signed by all investigators and all data cleaning/preparation is complete.