Fiction and Facts about BCG Imparting Trained Immunity against COVID-19

Abstract

The Bacille Calmette-Guérin or BCG vaccine, the only vaccine available against Mycobacterium tuberculosis can induce a marked Th1 polarization of T-cells, characterized by the antigen-specific secretion of IFN-γ and enhanced antiviral response. A number of studies have supported the concept of protection by non-specific boosting of immunity by BCG and other microbes. BCG is a well-known example of a trained immunity inducer since it imparts 'non-specific heterologous' immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the recent pandemic. SARS-CoV-2 continues to inflict an unabated surge in morbidity and mortality around the world. There is an urgent need to devise and develop alternate strategies to bolster host immunity against the coronavirus disease of 2019 (COVID-19) and its continuously emerging variants. Several vaccines have been developed recently against COVID-19, but the data on their protective efficacy remains doubtful. Therefore, urgent strategies are required to enhance system immunity to adequately defend against newly emerging infections. The concept of trained immunity may play a cardinal role in protection against COVID-19. The ability of trained immunity-based vaccines is to promote heterologous immune responses beyond their specific antigens, which may notably help in defending against an emergency situation such as COVID-19 when the protective ability of vaccines is suspicious. A growing body of evidence points towards the beneficial non-specific boosting of immune responses by BCG or other microbes, which may protect against COVID-19. Clinical trials are underway to consider the efficacy of BCG vaccination against SARS-CoV-2 on healthcare workers and the elderly population. In this review, we will discuss the role of BCG in eliciting trained immunity and the possible limitations and challenges in controlling COVID-19 and future pandemics.

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

Figure 1

The components of innate immunity and trained immunity. (a) Schematic representation of different components of innate immunity. The innate immune system is divided into various subsets to generate the first line of defense against the array of invading pathogens. (b) Different cells of trained immunity are responsible for definitive functions.

Figure 2

The signaling pathways that operate in trained immunity. The exposure of innate immune cells to various stimuli initiates the trained immunity pathways. Interaction or exposure with microorganisms (BCG, C. albicans, S. cerevisiae), endogenous/soluble stimuli (GM-CSF, IFN-γ, β-glucan, oxLDL, IGF1, lipoproteins), or PAMPs with surface/cytosolic receptors leads to metabolic shifts and epigenetic modifications in these innate immune cells. This initiates a series of signaling cascades and increases the secretion of pro-inflammatory cytokines. Intermediates of these signaling pathways (Akt-mTOR-HIF-1α, JAK/STAT, RAS, NF-κB) regulate the genetic machinery through acetylation and methylation processes. Activation of glycolysis and deposition of fumarate (TCA cycle) and mevalonate (cholesterol synthesis) play important roles in the induction of trained immunity. TLR (Toll-like receptor), NOD (nucleotide-binding oligomerization domain), oxLDL (oxidized low density lipoprotein), IGF1 (insulin-like growth factor1), IGF1R (insulin-like growth factor1 receptor), mTOR (mammalian target of rapamycin), JAK (Janus kinase), STAT (signal transducer and activator of transcription), GM-CSF (granulocyte monocyte-colony stimulating factor), IL (interleukin), TNF-α (tumor necrosis factor-α), HIF-1α (hypoxia inducing factor-1α), G6P (glucose 6-phosphate), F1,6-BP (fructose 1, 6 bisphosphate), TCA (tricarboxylic acid).

Figure 3

Mechanism of trained immunity-based vaccines. TibVs can induce both non-specific and specific immunological memory against heterologous pathogens. Non-specific immune memory is generated by trained immunity through epigenetic modifications in IICs in response to pathogen-associated molecular patterns (PAMPs). On the contrary, specific adaptive immune response/memory is produced against nominal antigens carried by TibVs through antigen presentation by APCs (antigen-presenting cells) as well as by the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, secreted by the trained IICs.

Figure 4

Triggering trained immunity to enhance the immune response. Innate memory can be created by training IICs with vaccines or immunomodulators. The trained cells revert faster during reinfection with the same or unrelated pathogens. In an untrained innate immune cell, low infection is easily cleared off through the secretion of pro-inflammatory cytokines and other soluble mediators. In the case of microbial ligands and BCG-trained cells, reprogramming of epigenetic and metabolic machinery takes place, leading to an enhanced innate immune response. The chromatin structure opens up, leading to the binding of the transcription factors and enhancers, ultimately increasing the cell’s responsiveness to various pathogens.