BCG Vaccination to Protect Healthcare Workers Against COVID-19

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.

Eligibility Criteria:
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