In multiple studies comparing the effect of coronavirus disease 2019 (COVID-19) worldwide, findings thus far suggest lower rates of infection and mortality in countries with universal neonatal Bacille Calmette-Guérin (BCG) tuberculosis vaccination policies compared with countries without this practice.1 In research published in July 2020, every 10% increase in the BCG index (which reflects the extent of a country’s BCG vaccination) was associated with a 10.4% reduction in mortality from COVID-19, and higher mortality rates were observed in countries with later vs early initiation of universal BCG vaccination.2
Additionally, epidemiologic studies conducted prior to the emergence of COVID-19 “showed that BCG vaccination seems to have a beneficial effect not only in preventing tuberculosis but also in all-cause mortality,” according to Bali Pulendran, PhD, the Violetta L. Horton Professor and professor of microbiology and immunology in the department of virology at Stanford University in California.3
Some findings also support a broad protective effect of the BCG vaccine against viral pathogens including respiratory infections.4 It is believed that BCG may stimulate “trained immunity,” which has been a focus of interest for roughly the past 10 years since scientists “realized that the innate immune system does have some memory of infection,” Dr Pulendran explained.4 “It may be much shorter than that of the adaptive immune system, but it’s much broader.”
Taken together, such observations have further piqued researchers’ interest in the effect of BCG vaccination in relation to COVID-19 infection. The hope is that, through the broad protection conferred by trained immunity, the vaccine may at least limit the severity of infection.2
However, other research has produced conflicting results, including a study published in August 2020 in Clinical Infectious Diseases that analyzed the effects of BCG vaccination on COVID-19-related outcomes in individuals born in Sweden before and after April 1975 (n=1,026,304 and n=1,018,544, respectively). At that time point, the national practice of vaccinating all newborns was discontinued, thereby “allowing us to estimate the BCG’s effect without the biases associated with cross-country comparisons,” wrote the authors.5
Using regression discontinuity, they “were able to show that those cohorts do not have different numbers of COVID-19 cases and hospitalizations per capita, with a high precision that would hardly be possible to reach with a [randomized controlled trial] design.” These findings indicate that BCG vaccination at birth does not protect against COVID-19 in middle age.
Further research is needed to elucidate the effect of BCG vaccination on COVID-19 infection in various populations. “It’s an attractive hypothesis that should be tested rigorously in well-controlled clinical trials with sufficiently large numbers of [participants] that would allow one to draw rigorous and sound conclusions,” said Dr Pulendran.
Currently, at least 12 randomized controlled trials are exploring the potential benefit of BCG vaccination for this purpose. For example, 2 trials are investigating whether receiving the vaccine (in adulthood) can protect against COVID-19 incidence and severity in healthcare workers and reduce workplace absenteeism in this population, while another trial is focused on the effect of the vaccine on the incidence of COVID-19-related hospital admissions in elderly adults.3,6
In related work, Dr Pulendran and colleagues have been exploring the use of systems vaccinology to predict immune responses to vaccinations, as well as the use of adjuvants to enhance the immune response to vaccines.7,8
To learn more about findings regarding the potential role of BCG in protecting against COVID-19 infection, we spoke with Pramod Kumar Gupta, PhD, a researcher in the Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre at the Bhabha Atomic Research Centre in Mumbai, India. Dr Gupta published a paper on the topic in October 2020 in Cellular Immunology.9
What do the data suggest thus far about the protective effects of BCG vaccination against COVID-19?
BCG is a century-old vaccine with an excellent safety profile in all age groups including infants, adults, and the elderly. To date, several clinical studies have shown that BCG reduces overall infant mortality in through protection from nonmycobacterial diseases. Further, BCG offers protection against nonspecific respiratory infections in adults and the elderly population as well.
Recently, many groups have reported that COVID-19-related mortality in countries with universal BCG vaccination programs are lower than in countries without such programs. However, BCG vaccination is not the only reason for the protective effects of BCG — other variables such as average age of the population, ethnicity, health infrastructure, testing facilities, and proper death monitoring systems are also involved.
What are the possible mechanisms underlying these effects?
The main underlying mechanism of BCG-mediated heterologous protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or any other pathogen is the induction of trained immunity.9 Trained immunity is defined as memory response in innate immune cells, and it is regulated by epigenetic modification and metabolic reprogramming in innate immune cells.9
What additional research is needed to further investigate BCG as a potential vaccine against COVID-19?
All of the studies reporting the protective effects of BCG vaccination are ecologic in nature and prone to confounding bias. The real potential of BCG against COVID-19 can only be realized after well-planned clinical trials. More than 12 clinical trials are underway, and results are expected soon.
I would like to add that “recombinant BCG expressing SARS-CoV-2 antigens” may have potential protective effects against COVID-19, and the necessary approvals may be accelerated due to the inherent safety profile of BCG.
Is there any notable research on other existing vaccines being explored for this purpose?
Aside from BCG, other live vaccines which have shown heterologous protective effects are MMR [measles-mumps-rubella] and oral polio vaccine.4 Both of these are being investigated in clinical trials to explore their efficacy against COVID-19.
1. Pereira M, Paixão E, Trajman A, et al. The need for fast-track, high-quality and low-cost studies about the role of the BCG vaccine in the fight against COVID-19. Respir Res. 2020;21(1):178.
2. Escobar LE, Molina-Cruz A, Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). Proc Natl Acad Sci U S A. 2020;117(30):17720-17726.
3. Curtis N, Sparrow A, Ghebreyesus TA, Netea MG. Considering BCG vaccination to reduce the impact of COVID-19. Lancet. 2020;395(10236):1545-1546.
4. Netea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J, et al. Trained immunity: a tool for reducing susceptibility to and the severity of SARS-CoV-2 infection. Cell. 2020;181(5):969-977.
5. de Chaisemartin C, de Chaisemartin L. BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden Clin Infect Dis. Published online August 23, 2020. doi:10.1093/cid/ciaa1223
6. ten Doesschate T, Moorlag SJCFM, van der Vaart TW, et al; on behalf of the BCG-CORONA study team. Two randomized controlled trials of Bacillus Calmette-Guérin vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: a structured summary of the study protocols for two randomised controlled trials. Trials. 2020;21(1):481. doi:10.1186/s13063-020-04389-w
7. Cortese M, Sherman AC, Rouphael NG, Pulendran B. Systems biological analysis of immune response to influenza vaccination. Cold Spring Harb Perspect Med. Published online March 9, 2020. doi:10.1101/cshperspect.a038596
8. Ellebedy AH, Nachbagauer R, Jackson KJL, et al. Adjuvanted H5N1 influenza vaccine enhances both cross-reactive memory B cell and strain-specific naive B cell responses in humans. Proc Natl Acad Sci U S A. 2020;117(30):17957-17964.
9. Gupta PK. New disease old vaccine: Is recombinant BCG vaccine an answer for COVID-19? Cell Immunol. 2020;356:104187. doi:10.1016/j.cellimm.2020.104187