The BCG vaccine might result in less severe COVID-19 and more rapid recovery, writes World Health Organisation Director General Dr Tedros Ghebreyesus. But it is 'very important' to adhere to WHO's recommendation that the BCG vaccine is used for COVID-19 only in randomised controlled trials.
Ghebreyesus, along with with other authors, writes in correspondence in The Lancet:
In addition to its specific effect against tuberculosis, the BCG vaccine has beneficial nonspecific (off-target) effects on the immune system that protect against a wide range of other infections and are used routinely to treat bladder cancer. This has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against severe coronavirus disease 2019 (COVID-19).
Randomised controlled trials have provided evidence that the BCG vaccine's immunomodulatory properties can protect against respiratory infections. In Guinea-Bissau, a high-mortality setting, BCG-Danish reduced all-cause neonatal mortality by 38%, mainly because there were fewer deaths from pneumonia and sepsis. In South Africa, BCG-Danish reduced respiratory tract infections by 73% in adolescents.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded positive-sense RNA virus, and the BCG vaccine has been shown to reduce the severity of infections by other viruses with that structure in controlled trials. For example, the BCG vaccine reduced yellow fever vaccine viraemia by 71% in volunteers in the Netherlands, and it markedly reduced the severity of mengovirus (encephalomyocarditis virus) infection in two studies in mice.
Many of the mechanisms underlying the beneficial off-target effects of the BCG vaccine are now understood. The BCG vaccine and some other live vaccines induce metabolic and epigenetic changes that enhance the innate immune response to subsequent infections, a process termed trained immunity. The BCG vaccine might therefore reduce viraemia after SARS-COV-2 exposure, with consequent less severe COVID-19 and more rapid recovery.
Randomised controlled trials are underway in the Netherlands and Australia to assess whether BCG-Danish reduces the incidence and severity of COVID-19 in health-care workers, and the effect this has on time away from work. It is possible that BCG-Tokyo would be preferable to BCG-Danish.
Until these trials are complete, there are four main reasons why it is very important to adhere to WHO's recommendation that the BCG vaccine is used for COVID-19 only in randomised controlled trials. First, the BCG vaccine is already in short supply, and indiscriminate use could jeopardise the supply needed to protect children against tuberculosis in high-risk areas. Second, whether BCG will be effective remains unknown: findings from the ecological studies suggesting less COVID-19 in countries with routine BCG immunisation are weak evidence because they are based on population rather than individual data and are prone to confounding. Also, it is unlikely that a BCG vaccine given decades ago in childhood will ameliorate COVID-19 now. One reason for this is that the beneficial off-target effects of the BCG vaccine might be altered by subsequent administration of a different vaccine. Third, if the BCG vaccine is not effective against COVID-19, BCG vaccination could engender a false sense of security. Fourth, careful safety monitoring in randomised trials is needed to guard against the remote possibility that up-regulation of immunity by BCG will exacerbate COVID-19 in a minority of patients with severe disease.
If the BCG vaccine or another inducer of trained immunity provides non-specific protection to bridge the gap before a disease-specific vaccine is developed, this would be an important tool in the response to COVID-19 and future pandemics.
A large-scale global trial designed to test the theory that the widely-used BCG vaccine could help protect against COVID-19 will soon recruit healthcare staff and care home workers in the UK. The University of Exeter is leading the UK arm of the trial, called the BCG vaccination to Reduce the impact of COVID-19 in healthcare workers (BRACE) Trial.
The BRACE trial is coordinated by the Murdoch Children’s Research Institute (MCRI) in Melbourne, Australia. The trial has received more than $10m from the Bill and Melinda Gates Foundation to allow its global expansion. The Peter Sowerby Foundation has contributed funding to support the Exeter trial site.
The UK joins study centres in Australia, the Netherlands, Spain, and Brazil in the largest trial of its kind. Together, the trial will recruit more than 10,000 healthcare staff. Participants will be given either the BCG vaccine (currently given to more than 100 million babies worldwide each year to protect against tuberculosis (TB)) or a placebo injection. In the UK, routine BCG vaccination was stopped in 2005 because of low rates of TB in the general population.
Professor John Campbell, of the University of Exeter Medical School, is the UK lead on the BRACE study. He said: “COVID-19 has killed more than a million people globally, with well over 33m people acquiring the disease, sometimes in its severest forms. BCG has been shown to boost immunity in a generalised way, which may offer some protection against COVID-19. We’re excited to be contributing to the large-scale, international BRACE study where we are seeking to establish whether the BCG vaccine could help protect people who are at risk of COVID-19. If it does, we could save lives by administering or topping up this readily available and cost-effective vaccination.”
Previous studies suggest that the Bacillus Calmette-Guerin (BCG) vaccine could reduce susceptibility to a range of infections caused by viruses including those similar to the novel coronavirus causing COVID-19. Examining the mechanism by which this may work is part of the trial being conducted by BRACE researchers.
The BCG vaccine boosts immunity by “training” the immune system to respond to other subsequent infections with greater intensity.
Researchers hope this improved “innate immunity” will buy crucial time to develop an effective and safe vaccine against COVID-19.
The BRACE trial is initially recruiting care and healthcare workers in the South West of England, who can attend clinics in Exeter. The trial is targeting these professionals because they work in fields with high exposure to COVID-19. The trial is specifically looking at whether the BCG vaccine reduces coronavirus infection or COVID-19 symptom severity.
Campbell added: “People on the COVID-19 front line, including healthcare workers and care home workers, are particularly vulnerable to coronavirus infection. Up until now, care home workers have been overlooked by most research. The BRACE trial provides us with a great opportunity to offer potential help to this important group of individuals who are providing healthcare to some of our most vulnerable citizens in important community settings. I’d really encourage care-home staff to join us, to help us find out if the BCG vaccine might provide a safe, widely available and cost-effective way to reduce the risk of COVID-19.”
In the UK, the trial will be conducted by the Exeter Clinical Trials Unit and supported by the local National Institute for Health Research-funded Clinical Research Facility. Lynne Quinn, operations director of Exeter CTU, said the trial is initially seeking to recruit 1,000 participants who work in care homes and other community healthcare settings. She said: “The first wave of recruitment will take place in and around Exeter, and we have exciting plans to expand to other sites across the UK, so we hope to be expanding our recruitment numbers at a later stage.”
Professor Nigel Curtis, global lead of the BRACE trial at MCRI, said: “We are delighted that the UK is joining this international trial to help determine if we can repurpose an existing safe vaccine to reduce the impact of COVID-19 in healthcare workers, including those working in care homes who are at particular risk.”
Participants will be asked to complete a daily symptom diary via an app, be tested for COVID-19 whenever they have symptoms, complete regular questionnaires and provide blood samples. These samples will allow scientists to understand how blood cells respond differently to exposure to COVID-19 and other viruses, with and without the BCG vaccine.
University of Exeter material
Full BBC News report
The Lancet article
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