The FLARE Four
- The BCG vaccine likely has some efficacy in preventing TB infection or decreasing severity of TB disease, especially in children
- The BCG vaccine may boost the innate immune response against a myriad of infections through “trained immunity”
- There are no peer-reviewed studies on BCG vaccine and COVID-19; medRxiv pre-print entries have deep methodological flaws
- Articles deposited on medRxiv, bioRxiv, chemRxiv, and other online “pre-print servers” need to be interpreted with an abundance of caution
This piece is courtesy of Dr. Vlad Vinarsky.
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Many people are saying...that childhood BCG vaccination protects against COVID-19.
This FLARE piece explores the historical context of this theory, the narrow unpublished evidence that supports it, and the broad scientific skepticism about the idea that BCG vaccination protects against COVID-19.
What is the BCG Vaccine?
First, a refresher for non-pulmonologists and non-ID doctors: Recall that TB infection and TB disease are distinct entities. The former, frequently referred to as latent TB infection (LTBI) is typically asymptomatic despite serological evidence of an anti-TB immune response. This response is the basis for the purified protein derivative (PPD) test with which most of us are familiar. TB disease, or active TB, on the other hand, is a multi-organ disease (often with primarily pulmonary manifestations) that can occur primarily with TB infection or develop with reactivation of latent TB.
The Bacille Calmette-Guérin (BCG) vaccine was developed from a live attenuated Mycobacterium bovis strain over 100 years ago to prevent tuberculosis and other mycobacterial infections. It is prepared by freeze-drying lab-adapted strains of M. bovis cultures and represents a live, but highly attenuated, bacterial preparation. Newborn BCG vaccination is recommended by the World Health Organization, and the vaccine is routinely administered in many parts of the world. Some countries have adopted universal BCG vaccination programs (Zwerling et al., 2011).
BCG vaccination programs are not static: some countries have initiated these programs over the last 50 years while many others have abandoned them. Furthermore, some countries only administer vaccines to newborns while others have re-vaccination (booster) programs. Finally, BCG substrains vary in different parts of the world.
Does the BCG Vaccine Protect Against TB?
Though an immune response occurs following BCG administration, its presence does not correlate well with protection against TB (Kagina et al., 2010). Indeed, the BCG vaccine exhibits remarkably variable efficacy against TB infection, ranging from 15% to 30% in various studies (Roy et al., 2014). It has a much higher efficacy (up to 90%) in preventing TB disease, especially in children and especially TB meningitis (Rodrigues et al., 1993). Some of the variability has been attributed to the use of different M. bovis substrains for vaccine development, genetic differences in the population, and prevalence of other diseases such as HIV. The efficacy of BCG vaccination in adults is more variable and generally less effective against TB infection and disease.
Why Might BCG Work Against COVID-19? What is the "Trained Immunity" Hypothesis?
There is growing evidence that innate immunity, like adaptive immunity (B and T lymphocytes), can develop memory-like properties and can mount a more robust response to reinfection after a prior exposure (Netea et al., 2016). Unlike the clonal selection of adaptive immunity, in which there is clonal expansion and transcriptional changes in antigen-specific lymphocytes, trained immunity does not involve clonal expansion or antigen specificity. Rather, trained immunity develops through epigenetic changes in innate immune cell populations. The idea that a prior infection can influence the innate immune response to a new infection is central to the “trained immunity” hypothesis. In fact, this hypothesis partly underlies the use of BCG in the treatment of bladder cancer - where the vaccine is believed to act through direct immunostimulatory effects and possibly trained tumor immunity (Pettenati and Ingersoll, 2018). BCG is also being investigated for the treatment of inflammatory and autoimmune diseases (Kühtreiber et al., 2018).
One prediction of the trained immunity hypothesis is that a vaccine against one pathogen may confer protection against unrelated pathogens in an antigen-independent manner. Indeed, the BCG vaccine can confer resistance to systemic candidiasis in mice (van’t Wout et al., 1992) in a macrophage-dependent but lymphocyte-independent manner. There is also emerging evidence for possible non-specific benefit of live vaccines (including BCG) in humans. This evidence includes randomized controlled trials in low birth weight infants, where the BCG vaccine reduced respiratory infections, sepsis, and infant all-cause mortality (Aaby et al., 2011; Biering-Sørensen et al., 2018). However, the role of the BCG vaccine in preventing non-mycobacterial infections is far from established. For example, an RCT in Denmark (Stensballe et al., 2019) of BCG vaccination at birth showed no effect on rates of hospitalization for infection. Furthermore, the evidence from mouse models and human data suggests that innate training does not persist beyond several years or even several months.
So What About COVID-19 and BCG?
Repurposing the BCG vaccine to “battle” COVID-19 has rapidly become a popular idea. Much of the excitement behind the BCG and COVID-19 association stems from a single study that has not been peer-reviewed (Miller et al., 2020). This pre-print, deposited online in its latest form on 3/24/2020, examines national BCG vaccination rates (from BCG World Atlas) and COVID-19 morbidity and mortality in individual countries from a Google COVID-19 tracker dated March 19, 2020. An inverse correlation was noted between the duration of universal BCG vaccination program and COVID-19 mortality. In addition, the authors highlight the large number of COVID-19 cases in countries that never implemented universal vaccination (US, Netherlands, Italy, Lebanon). However, the use of such analyses to mechanistically link BCG to SARS-CoV-2 sequelae is hampered by major methodological concerns:
- The initial COVID-19 pandemic is still developing and remains at different stages in different countries.
- Case numbers and case fatality ratios are deeply biased by differences in testing across countries.
- BCG vaccination data is poorly sourced and may not reflect the actual vaccination rates in a given country.
- Mortality data is poorly sourced.
- There was no attempt to correct for GDP, tourism, duration of infection and other obvious confounders.
- In the countries without BCG revaccination programs, it is unclear how a vaccine could possibly protect against a new infection when BCG vaccine protection against TB typically wanes within 10-20 years.
Several other reports linking BCG and COVID-19 have appeared in non-peer reviewed formats on the internet over the last several weeks. In a non-peer-reviewed pre-print article, Dayal and Gupta (Dayal and Gupta, 2020) examined case fatality rates in countries with BCG revaccination. However, rather than considering some measure of death or disease burden as a function of vaccination rates, the authors literally compare 12 countries with a BCG revaccination programs to another 12 countries with a high COVID-19 burden, and conclude that countries with BCG vaccination have lower incidence of COVID-19 and its associated morbidity and mortality. For unnamed reasons, the other 180 countries of the world were excluded from this analysis. This analysis lacks any scientific merit.
In what likely represents the most serious attempt at interpreting the same flawed data on BCG vaccination and preliminary COVID-19 outcomes, Shet et al. (Shet et al., 2020) considered BCG use and COVID-19 mortality, adjusting for GDP and the age of the population. This is also the only study so far that has attempted to correct for the timing for the entry of the virus into the country (by starting with the 100th reported case in each country), although still without acknowledging that the total disease burden cannot be known before the end of this wave of the pandemic. The study also remains deeply flawed due to testing issues and expected rise of cases as countries progress along the epidemiological trajectory. Furthermore, like other articles on this topic, it has not yet been scrutinized under peer-review.
Overall, all existing attempts to link BCG vaccination and COVID-19 incidence or case fatality rate ignore perhaps most the glaring problem with nationwide analysis: dramatic regional (states in the US, regions in China) differences in COVID-19 burden within the same county with the same BCG vaccination program.
A Note of Caution...
There may also be a cautionary tale in these attempts to link BCG and COVID-19. BCG and COVID-19 association reports have relied exclusively on online “pre-print servers” of unpublished manuscripts, such as medRxiv. The preliminary and deeply flawed nature of these studies has not prevented them from being described in the mainstream media, including CNN and Bloomberg News, as “scientific studies” and “published” reports, albeit with caveats that they lack peer review. The danger, of course, stems from these inconclusive studies influencing a national or individual response to COVID-19. A nation may conclude that its population is relatively immune to SARS-CoV-2 because of a national BCG vaccination program, while an immigrant group in the United States may assume its members are immune to COVID-19 because they received a BCG vaccine before Coming to America.
The Bottom Line
There is some evidence that BCG vaccine derived from a live attenuated strain of M. bovis, can generate an innate immune memory that may not only protect against TB and other mycobacteria, but also against fungal, perhaps bacterial pathogens, and maybe even viral pathogens. In fact, there are clinical trials in Australia and the Netherlands testing whether the BCG vaccine can protect healthcare workers against COVID-19. However, it is much too early in this COVID-19 pandemic to understand whether national BCG vaccination programs have any impact on morbidity and mortality from COVID-19.
- Aaby, P., Roth, A., Ravn, H., Napirna, B.M., Rodrigues, A., Lisse, I.M., Stensballe, L., Diness, B.R., Lausch, K.R., Lund, N., et al. (2011). Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 204, 245–252.
- Biering-Sørensen, S., Jensen, K.J., Monterio, I., Ravn, H., Aaby, P., and Benn, C.S. (2018). Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials. J. Infect. Dis. 217, 759–766.
- Dayal, D., and Gupta, S. (2020). Connecting BCG Vaccination and COVID-19: Additional Data (medRxiv).
- Kagina, B.M.N., Abel, B., Scriba, T.J., Hughes, E.J., Keyser, A., Soares, A., Gamieldien, H., Sidibana, M., Hatherill, M., Gelderbloem, S., et al. (2010). Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guérin vaccination of newborns. Am. J. Respir. Crit. Care Med. 182, 1073–1079.
- Kühtreiber, W.M., Tran, L., Kim, T., Dybala, M., Nguyen, B., Plager, S., Huang, D., Janes, S., Defusco, A., Baum, D., et al. (2018). Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations. NPJ Vaccines 3, 23.
- Miller, A., Reandelar, M.J., Fasciglione, K., Roumenova, V., Li, Y., and Otazu, G.H. (2020). Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study (medRxiv).
- Netea, M.G., Joosten, L.A.B., Latz, E., Mills, K.H.G., Natoli, G., Stunnenberg, H.G., O’Neill, L.A.J., and Xavier, R.J. (2016). Trained immunity: A program of innate immune memory in health and disease. Science 352, aaf1098.
- Pettenati, C., and Ingersoll, M.A. (2018). Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 15, 615–625.
- Rodrigues, L.C., Diwan, V.K., and Wheeler, J.G. (1993). Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int. J. Epidemiol. 22, 1154–1158.
- Roy, A., Eisenhut, M., Harris, R.J., Rodrigues, L.C., Sridhar, S., Habermann, S., Snell, L., Mangtani, P., Adetifa, I., Lalvani, A., et al. (2014). Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 349, g4643.
- Shet, A., Ray, D., Malavige, N., Santosham, M., and Bar-Zeev, N. (2020). Differential COVID-19-attributable mortality and BCG vaccine use in countries (medRxiv).
- Stensballe, L.G., Ravn, H., Birk, N.M., Kjærgaard, J., Nissen, T.N., Pihl, G.T., Thøstesen, L.M., Greisen, G., Jeppesen, D.L., Kofoed, P.-E., et al. (2019). BCG Vaccination at Birth and Rate of Hospitalization for Infection Until 15 Months of Age in Danish Children: A Randomized Clinical Multicenter Trial. J Pediatric Infect Dis Soc 8, 213–220.
- van ’t Wout, J.W., Poell, R., and van Furth, R. (1992). The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol. 36, 713–719.
- Zwerling, A., Behr, M.A., Verma, A., Brewer, T.F., Menzies, D., and Pai, M. (2011). The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 8, e1001012.
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