Q&A: Trials Testing BCG Vaccine Against COVID-19

By Lisa Rapaport

April 08, 2020

(Reuters Health) - Clinical trials getting underway in Australia and Europe are testing the effectiveness of BCG vaccination for reducing the prevalence and severity of COVID-19 symptoms in high-risk populations such as health care workers (HCW) and the elderly. Brief descriptions of the studies are below, followed by a condensed Q&A from interviews with researchers who are runnning trials now or who have previously examined the effect of the BCG vaccine on infections other than TB.

The trials include:

- REDUCING HEALTH CARE WORKERS ABSENTEEISM IN COVID-19 PANDEMIC THROUGH BCG VACCINE (BCG-CORONA) (https://clinicaltrials.gov/ct2/show/NCT04328441) Placebo-controlled multi-center RCT in HCW with direct patient contacts where COVID-19 patients are treated. Primary endpoint: number of days of (unplanned) absenteeism for any reason. Secondary endpoints include: number of days of (unplanned) absenteeism because of documented COVID-19 infection, and cumulative incidence of hospital admission, ICU admission, and death. Separately, these researchers plan to start a trial of BCG vaccination in the elderly.

- BCG VACCINATION TO PROTECT HEALTHCARE WORKERS AGAINST COVID-19 (BRACE) (https://clinicaltrials.gov/ct2/show/NCT04327206) Phase III open label RCT. Primary endpoints: number of participants with COVID-19 disease defined as fever plus at least one sign or symptom of respiratory disease and positive SARS-Cov-2 test (PCR or serology); severe COVID-19 defined by hospitalization or death. Secondary endpoints include asymptomatic SARS-Cov-2 infection, work absenteeism, febrile respiratory illness, mechanical ventilation.

- PHASE III STUDIES OF BCG-BASED VACCINE CANDIDATE VPM1002 Max Planck Institute for Infection Biology in Germany plans two phase 3 studies to investigate whether the vaccine candidate VPM1002, a BCG-based vaccine originally developed against tuberculosis, is also effective against SARS-CoV-2. Researchers expect to start both trials - one in health care workers and one in the elderly - within the next few weeks, once they receive regulatory approval.

Q: WHAT EVIDENCE SUGGESTS THE BCG VACCINE MIGHT WORK AGAINST COVID-19?

A: Dr. Mihai Netea, Radboud University Medical Center (BCG-CORONA trial): Epidemiological studies have shown BCG reduces overall mortality in children in countries with high infectious pressure. This 30-50% reduction in mortality is due to reduction in respiratory tract infections and neonatal sepsis. Two clinical trials in adults have shown similar effects of 70% reduction in respiratory tract infections: one in adolescents in South Africa, and one small study in elderly population from Indonesia.

A: Dr. Thijs ten Doesschate, UMC Utrecht (BCG-CORONA): Many epidemiological studies have shown that BCG can induce a powerful protection against infectious diseases other than tuberculosis: the so-called nonspecific effects. In addition, there is clinical and experimental evidence that BCG protects against viral infections. BCG vaccination protects against respiratory syncytial virus, human papillomavirus and herpes simplex virus. After BCG vaccination, there is a lower "viral load" of the influenza A virus, leading to less inflammation and lung damage. BCG vaccination leads to fewer virus particles in the blood and a stronger immune response against viruses compared to placebo in healthy volunteers who received a yellow fever vaccine.

A: Dr. Stefan H.E. Kaufmann, Max Planck Institute for Infection Biology (co-inventor of VPM1002): Mechanistically it has been well established over the last decades that BCG activates phagocytes. These activated phagocytes are better equipped to defend against microbial infections (bacteria and viruses).

A: Dr. Christine Stabell Benn, Professor in Global Health at University of Southern Denmark and Odense University Hospital: Two decades ago, our group was assessing the impact of vaccines on overall health at our field station in Guinea-Bissau, West Africa. We discovered that receiving BCG vaccine recommended to be given at birth was associated with almost a halving of mortality - much more than could be explained by its effects against tuberculosis (Kristensen et al, BMJ 2000). Mortality at that time was almost exclusively due to infectious diseases. This led us to propose that BCG had "non-specific effects" and induced protection against other infectious diseases. We also saw that among those who were BCG vaccinated, having a BCG scar (an indicator of a successful vaccine) was associated with strong mortality reductions (Garly et al, Vaccine 2003). We took the observations into randomized clinical trials. We took advantage of the fact that low weight neonates (<2500 g) were recommended to receive BCG delayed - so we randomized such neonates to BCG-at-birth or the usual delayed BCG - and in three trials we could show that BCG reduced neonatal mortality (before the control group received BCG) by more than a third (38%). Tuberculosis does not kill children in the first months of life, and we could show that the reduction in mortality was due to BCG preventing septicemia and pneumonia (Biering-Sørensen et al, Clin Infect Dis 2017).

Q: WHAT SUGGESTS THE BCG VACCINE MIGHT NOT WORK AGAINST COVID-19?

A: Netea: In the setting of low infectious pressure, two recent studies in Denmark and Australia did not show a significant benefit of BCG vaccination in newborn children. There are no data yet on the effect of BCG vaccination on coronaviruses in general or COVID-19 in particular.

A: Benn: We still need to find out which BCG vaccine strains are the most efficient. There are a number of different BCG strains, they are quite different in terms of their capacity to protect against tuberculosis, they contain varying numbers of viable bacteria, and it seems that they are also have different non-specific effects (Curtis et al, Pediatr Infect Dis J 2019; Angelidou et al, Vaccine 2020). For instance, in our trials we used BCG-Denmark, but two Indian trials recently failed to find any effect on neonatal mortality of BCG-Russia (Jayaraman, Pediatr Infect Dis J 2019).

Q: HOW LONG MIGHT IT TAKE FOR TRIALS TO SHOW WHETHER THE BCG VACCINE PROTECTS AGAINST COVID-19?

A: Netea: Trials that have started in several countries will need probably 2-6 months to answer this question, depending on the dynamics of the epidemics in these countries and how strong the effect of BCG vaccination will be.

A: Dr. Nigel Curtis, Murdoch Childrens Research Institute(BRACE trial): We need to continue trials over the time period when healthcare workers are exposed to COVID-19 so that we can compare severity of COVID-19 in the BCG group with control group - so likely many months.

Q: SHOULD HIGH-RISK POPULATIONS GET THE BCG VACCINE NOW, BEFORE TRIALS ARE DONE?

A: Netea: No, it makes no sense to get the vaccine now. This may lead to shortages of the vaccine for the newborn children in developing countries.

A: Curtis: No. BCG is in relatively short supply as only sufficient doses are manufactured for its two current approved uses: protection of infants against tuberculosis in TB-endemic countries and for treatment of some forms of bladder cancer.

A: Benn: No. While we have lots of evidence that BCG has beneficial non-specific effects in children, we know little of its effects in adults or the elderly. While we do not think so, at this stage we cannot exclude that it could turn out to be harmful in adults/elderly.

A: Kaufmann: Studies have shown that booster vaccination is possible and safe. I consider it worth to give either prime (first time administration) or boost (second time administration).

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