BCG and SARS-CoV-2-What Have We Learned?

Abstract

Despite controversy over the protective effect of the BCG (Bacille Calmette-Guérin) vaccine in preventing pulmonary tuberculosis (TB) in adults, it has been used worldwide since 1921. Although the first reports in the 1930s had noted a remarkable decrease in child mortality after BCG immunization, this could not be explained solely by a decrease in mortality from TB. These observations gave rise to the suggestion of nonspecific beneficial effects of BCG vaccination, beyond the desired protection against M. tuberculosis. The existence of an innate immunity-training mechanism based on epigenetic changes was demonstrated several years ago. The emergence of the pandemic caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in 2019 revived the debate about whether the BCG vaccine can affect the immune response against the virus or other unrelated pathogens. Due to the mortality of the coronavirus disease (COVID-19), it is important to verify each factor that may have a potential protective value against the severe course of COVID-19, complications, and death. This paper reviews the results of numerous retrospective studies and prospective trials which shed light on the potential of a century-old vaccine to mitigate the pandemic impact of the new virus. It should be noted, however, that although there are numerous studies intending to verify the hypothesis that the BCG vaccine may have a beneficial effect on COVID-19, there is no definitive evidence on the efficacy of the BCG vaccine against SARS-CoV-2.

Keywords: COVID-19; Mycobacterium bovis bacillus Calmette-Guérin (BCG); SARS-CoV-2; immunity; non-specific protection; trained immunity; vaccination.

Figure 1

Possible BCG vaccine cross-reaction with SARS-CoV-2 and its mechanism of action. The effectiveness of the immune response consists in the balanced reactivity of both innate and adaptive immunity and their cooperation. It has been shown that cells of innate immunity (for example, macrophages) undergo a process of immune training underpinned by epigenetic changes. BCG, through the induction of epigenetic reprogramming (manifested, for instance, by the production of pro-inflammatory cytokines at appropriate levels), can provide cross-protection during a subsequent infection caused by an infectious agent other than the primary one. Genes, particularly interferon-related, are also subject to epigenetic control by the SARS-CoV-2 virus, the infection of which may be accompanied by the increased production of pro-inflammatory cytokines leading to a cytokine storm. The interferon pathway is one of the most important signaling pathways in the course of infection. In viral infection, an increase in the levels of ISGs is observed, whose stimulation results in the inhibition of viral replication. The BCG vaccine, in particular, leads to the upregulation of ISG15, which may confirm its contribution to the inhibition of viral infection. However, in the case of SARS-CoV-2, its ability to alleviate some ISG15 anti-viral activities was reported. Among the components of the interferon pathway are IFIT proteins. The antiviral properties of IFIT1 are manifested by the recognition of RNA having 5′ triphosphate and lacking 2′-O methylation, followed by the sequestration of the viral nucleic acid. The elevated IFIT1 levels observed after BCG vaccination may indicate its usefulness in mitigating the SARS-CoV-2 infection. Furthermore, it was reported that M. bovis BCG contains similar T cells epitops asSARS-CoV-2. The consequence of this can be the production of cross-reactive antibodies by antigen-specific B lymphocytes. Hence, it has been suggested that BCG immunization, as well as latent M. tuberculosis infection, may result in an increased effectiveness of the immune system against SARS-CoV-2, not only due to the training of innate immunity but also through the generation of antibodies with cross-reactivity. Abbreviations: CCL3—CC motif chemokine ligand 3 (MIP-1α), CCL3L1—CC motif chemokine ligand 3 like 1, CXCL8/10—CXC motif chemokine ligand 8/10 (IL-8/IP-10), IFIT—interferon-induced proteins with tetratricopeptide repeats, IFN—interferon, IL—interleukin, ISG—interferon-stimulating genes, NOD2—nucleotide-binding oligomerization domain containing 2, TNF-α—tumor necrosis factor alpha. Based on [50,51,52,53,54,55,56].