Ecological studies have suggested fewer COVID-19 morbidities and mortalities in Bacillus Calmette–Guérin (BCG)-vaccinated countries than BCG-non-vaccinated countries. However, these studies obtained data during the early phase of the pandemic and did not adjust for potential confounders, including PCR-test numbers per population (PCR-tests).1
In the absence of specific therapy, researchers have been exploring potential preventive and therapeutic options. There was a huge buzz about the protective effect of Bacille Calmette-Guérin (BCG) vaccine in COVID-19. Based on epidemiological correlations, many unpublished preprints hypothesized that the BCG vaccine may offer protection against COVID-19. It gained so much popularity that within 20 days three randomized controlled trials (RCTs) got registered, and many more are in the pipeline.2 However, to make an informed decision, it is critical to understand the mechanism of action of BCG, and appraise the robustness of the evidence.
The basis of the possible use of the BCG vaccine against COVID-19 lies in its non-specific effects (NSEs) over the immune system.3 The NSEs of BCG are mainly mediated by potentiating innate immune response through epigenetic mechanisms, which act as de novo enhancers to boost the immune response against a secondary challenge.3-5 This enhancing response is popularly known as ‘trained immunity’ and is very characteristic of BCG. This trained immunity also offers protection against a variety of pathogens (Salmonella, Shigella, malaria, respiratory viruses, etc.) other than Mycobacterium tuberculosis, and forms the basis of its use in bladder cancer, melanoma etc.
However, in terms of COVID-19 context, the relationship between BCG and COVID-19 is being proven by looking at correlation/ association among two data set (BCG vaccine coverage and COVID-19), without acknowledging the variables like the difference in testing strategies, reporting bias, demographics, nation’s ability to respond to the pandemic, prevalence of co-morbidities, and different stages of the pandemic across various countries might have a significant impact on these associations/correlations and must be interpreted carefully. Therefore, at this stage, this association should be considered as a hypothesis only and should be tested through appropriately designed studies. Though the epidemiological association between BCG and COVID-19 is striking, it does not prove causal relationship unless tested in well-designed clinical trials.
Also, it should be noted that the NSEs of the BCG vaccine have not been well-studied in human beings and their clinical relevance is unknown.2,3
A December 2020 study6 also states that besides unproven efficacy of the BCG vaccine, believing such reports and going for revaccination with BCG can put at serious risk patients with primary or secondary immunodeficiency. The report further states that even if the BCG vaccine is effective in preventing COVID-19 deaths or reducing its severity, the effect of this vaccine and its relevance is yet to be proven. Furthermore, It is very difficult to compare the epidemiologic data about COVID-19 in different countries. There are countless factors, mainly social and related to the healthcare system, which can be more decisive than the hypothesis of trained immunity induced by BCG. Until now, we can say that BCG’s protective role is, at least, insufficient, given many other factors that corroborate SARS-CoV-2 infection and/or its severity.
Therefore, in the absence of evidence, the BCG vaccination for the prevention of COVID-19 cannot be recommended. Despite the fact that greater BCG vaccine coverage may reduce the risk of deaths due to COVID-19, this needs to be further studied by observational studies and confirmed by randomized clinical trials.
Source:
1 Urashima M, Otani K, Hasegawa Y and Akutsu T. BCG Vaccination and Mortality of COVID-19 across 173 Countries: An Ecological Study. Int J Environ Res Public Health. 2020;17(15):5589.
2 World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19. Available from: https:/ /www.who.int/news-room/commentaries/detail/ bacillecalmette-guérin-(bcg)-vaccination-and-covid-19.
3 SAGE Working Group on BCG Vaccines and WHO Secretariat. Report on BCG vaccine use for protection against mycobacterial infections including tuberculosis, leprosy, and other nontuberculous mycobacteria (NTM) infections. World Health Organization; 2017. Available from: https://www.who.int/immunization/sage/ meetings/ 2017/october/1_BCG_report_revised_version_online.pdf. Accessed April 14, 2020.
4 Moorlag SJCFM, Arts RJW, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019;25:1473-8.
5 Arts RJW, Moorlag SJCFM, Novakovic B, et al. BCG vaccination protects againstexperimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe. 2018;23:89-100.e5.
6 Sarinho E, Goudouris E, Solé D. BCG vaccine: Worrying proposal for COVID-19. Vaccine. 2020;S0264-410X(20)31593-0. doi: 10.1016/j.vaccine.2020.12.026.