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Clinical Infection & Immunity

Editorial

olume 6, Number 2, June 2021, pages 31-33

Bacillus Calmette-Guerin Utilization for Immunotherapy and Prevention of COVID-19

Vaccinations are an essential public health tool for prevention of diseases. Through induction of an immune response against antigens derived from pathogens, they generate mobilizations of immune cells and production of inflammatory mediators and antibodies. Some vaccines are known to have heterologous or non-specific effects, as well as immunotherapeutic benefits beyond their targeted pathogens and diseases. A major example of this is bacillus Calmette-Guerin (BCG), a vaccine used against non-pulmonary forms of tuberculosis (TB), that also possesses non-specific immunotherapeutic effects against other infections and bladder cancer [1].

Initial reports of BCG in the 1970s, used as an immunotherapeutic agent against melanoma and bladder cancer, showed tumor regression and changes in recurrence [1]. BCG is currently Food and Drug Administration (FDA)-approved as a first-line therapy for intermediate and high-risk non-muscle invasive bladder cancer. While the exact pathway distinguishing BCG’s role as an immunotherapeutic agent is not yet well established, it has been observed that BCG can induce a form of innate immune memory via monocytes, natural killer (NK) cells, and other innate immune cells [1, 2]. This involves recognition of pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRRs), such as dectin-2, NOD2, and toll-like receptors (TLRs). These processes lead to a profound activation of the immune system, via epigenetic programming, following secondary exposure of BCG, suggesting that BCG enhances activation and functional specialization of immune cells against tumors [1, 2].

The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a unique multisystem inflammatory disease that can lead to debilitating or life-threatening outcomes in some patients. Recent literature has explored the clinical characteristics and immune responses to SARS-CoV-2, suggesting a dysregulation of the immune response leading to a cytokine storm and lymphopenia in severe COVID-19 patients [3]. COVID-19 patients are found to have decreased total counts for cluster of differentiation (CD)4⁺ T cells, CD8⁺ T cells, NK cells, and B cells, with levels even lower in severe cases than mild cases, as compared to their healthy counterparts [4]. Severe COVID-19 patients also have higher levels of pro-inflammatory cytokines, which appear to correlate with severe outcome [3]. In addition to the increased inflammatory process that leads to acute lung injury in severe COVID-19, it is possible that SARS-CoV-2 infection may also trigger a chronic inflammatory state which could impair antiviral immunity by hijacking the host immune system [5].

SARS-CoV-2 can lead to activation of the inflammasome by affecting type I interferon (IFN)-dependent antiviral responses, skewing cytokine release [3, 6]. It is important to note that type I IFNs, T cells, and signal transducer and activator of transcription 1 (STAT-1) are essential for clearance of SARS-CoV-2. Worse clinical outcomes have been noted in patients with impaired type I IFN activity [3, 6], and life-threatening COVID-19 has been strongly over-represented in patients with inborn mutations of the type I IFN pathway or in the presence of neutralizing autoantibodies to type I IFNs [7, 8]. SARS-CoV-2 inhibits type I IFN responses in infected cells, allowing an unchecked replication, and triggering an exaggerated immune response which leads to major tissue damage [6]. A delayed-type I IFN signaling has been shown to impair antigen-specific T-cell responses and enhance high cytokine secretion by monocytes in lungs, leading to vascular leakage and fatal outcomes in mice infected with SARS-CoV-2 [3, 6].

Though predicted to face the maximum mortality from COVID-19 due to lack of resources and poor healthcare infrastructure, developing countries turned out having fewer reported cases than expected, with mild disease recovery in the majority of cases [9]. Countries with extensive BCG vaccine programs and coverage are found to have reduced morbidity and mortality from COVID-19, suggesting that the lower incidences of COVID-19 in TB-endemic areas could be attributed to the protective role of BCG vaccination [10].

Epidemiological studies have shown a significant association between BCG vaccinations and lower COVID-19 deaths even after controlling for various factors like social conditions and status [11-14]. A comparison of COVID-19 mortality in the USA, which lacks exposure to BCG, versus South American countries with a current universal BCG vaccination program, showed that unvaccinated US states had a significantly higher mortality compared to South American cities, despite higher populations present in the latter ones [12]. One could argue that ethnic differences, which could be linked to particular immunogenetic susceptibilities, could be responsible for the observed contrast. This does not appear to be the case, as shown by a study on healthcare workers in California where a history of BCG vaccination had a lower prevalence of SARS-CoV-2 infection, while no difference was observed with a history of other vaccines [15]. The COVID-19 mortality rate in West German states was found to be 2.9-fold higher than that in East German states, where BCG vaccination was more extensive [12]. A similar association between BCG vaccination and COVID-19 mortality was observed in European countries, where Western European countries were found to have a mean mortality 9.92 times higher than that in Eastern European countries, where universal BCG vaccination programs are generally more extensive [12]. These correlations remained highly significant despite controlling for confounding factors that could affect COVID-19 mortality, such as level of urbanization, population density, age, access to health, income, education, as well as stage and size of the COVID-10 epidemic.

The exact mechanism of the immunotherapeutic effects of BCG against SARS-CoV-2 is still not well understood. The concept of “trained immunity”, where bacteria such as BCG would elevate basal systemic levels of type I pathways and immune cells, is proposed as one of the mechanisms by which BCG would confer protections against unrelated viral infections [16, 17]. Cross-reactivity between BCG-derived peptides and SARS-CoV-2 does exist. Significant sequence homology has been identified in BCG-derived, and SARS-CoV-2 NSP3 or NSP13-derived peptides [18]. In vitro and in silico studies have shown that in patients who received BCG, CD4⁺ and CDB⁺ T cells primed with BCG-derived peptides developed a robust immunogenic reactivity upon re-stimulation with homologous SARS-CoV-2-derived peptides, suggesting its importance in effective viral clearance [18, 19]. Furthermore, using a bioinformatics approach, a significant upregulation in interleukin-17, tumor necrosis factor, NOD-like receptors, and nuclear factor-κB signaling pathways in SARS-CoV-2 infection were found to overlap with pathways downregulated following the BCG vaccination [19]. This inverse relationship may explain the protective role of the BCG against severe COVID-19.

BCG has long been shown to have non-specific effects beyond its target pathogen and has shown immunotherapeutic effects against other infections and cancers. Increasing evidence suggests that BCG vaccinations may be a safe alternative in acquiring partial immunity against SARS-CoV-2 infection in TB-endemic areas. Homology in BCG-derived and SARS-CoV-2-derived peptides, in addition to modulation of various immune pathways, may result in protection against COVID-19 in BCG-vaccinated individuals. Further research is needed to have a more thorough understanding of the role of BCG in COVID-19, by evaluating the benefits of BCG as an adjuvant therapy for COVID-19.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Author Contributions

AK, NS, and JC wrote the manuscript.

Data Availability

Any inquiries regarding supporting data availability of this study should be directed to the corresponding author.

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