Could BCG Vaccination Induce Protective Trained Immunity for SARS-CoV-2?

Abstract

Trained immunity is a type of non-specific memory-like immune response induced by some pathogens and vaccines, such as BCG, which can confer antigen-independent protection against a wide variety of pathogens. The BCG vaccine has been extensively used to protect against tuberculosis for almost a 100 years. Interestingly, this vaccine reduces children's mortality caused by infections unrelated to Mycobacterium tuberculosis infection, a phenomenon thought to be due to the induction of trained immunity. The SARS-CoV-2 pandemic has infected, as of April 22, 2020, 2,623,231 people globally, causing a major public health problem worldwide. Currently, no vaccine or treatment is available to control this pandemic. We analyzed the number of positive cases and deaths in different countries and correlated them with the inclusion of BCG vaccination at birth in their national vaccination programs. Interestingly, those countries where BCG vaccination is given at birth have shown a lower contagion rate and fewer COVID-19-related deaths, suggesting that this vaccine may induce trained immunity that could confer some protection for SARS-CoV-2.

Keywords: BCG; COVID-19; SARS-CoV-2; innate immunity; trained immunity; vaccine.

Figure 1

Schematic representation of trained immunity elicits by BCG immunization. (a) The BCG vaccine develops a specific adaptive and protective immune response against M. tuberculosis. It also promotes a non-specific immune memory called Trained immunity. The BCG vaccine contributes in many countries to reducing the infection rate of children against other unrelated pathogens such as malaria, respiratory infections, and leprosy. (b) BCG vaccination in adults leads to a trained phenotype in circulating monocytes (MO) that quickly respond, secreting IL-1β, TNF-α, and IL-6 after stimulation with unrelated pathogens such as S. aureus and C. albicans. This response is explained by epigenetic modifications in regulatory elements of tnfa, il6, and il1b genes. (c) In healthy human volunteers, the vaccination enhanced the capacity of NK cells to secrete proinflammatory cytokines and type I interferons after stimulation with M. tuberculosis, S. aureus, C. albicans, and Yellow fever virus (YFV).

Figure 2

Protective role of BCG in SARS-CoV-2 infection. (A) Confirmed cases of COVID-19 since the day they exceeded 2 cases per million up to date. Country curves with a black line and yellow background correspond to those without BCG vaccination program. Country curves with a pink background correspond to those where BCG vaccination is administered at birth. (B) Confirmed cases of COVID-19 per million inhabitants, (C) deaths per million inhabitants, and (D) mortality rates in countries with or without BCG vaccination schedule. Statistical Method: Each group represents the mean ± SD (error bars) of the responses in populations vaccinated (22 countries) and unvaccinated (16 countries) with BCG. Data were compared by t-test with a confidence interval of 95% to discriminate statistically significant differences between groups (**), we determine that variances are equals, contrasted by F test (P < 0.05). To see updated data, please follow the following link http://www.imii.cl/en/confirmed-covid-19-cases-per-million-inhabitants/ (Source: Center for Systems Science and Engineering, CSSE, Johns Hopkins University, Accessed on April 22, 2020; World Health Organization, WHO).