BCG-induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next-generation vaccines

Abstract

The tuberculosis (TB) vaccine Bacillus Calmette-Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG-induced protection against Mtb infection from observational and BCG re-vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody-mediated protection, and innate immune mechanisms, with a specific focus on BCG-induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.

Keywords: BCG; epigenetics; innate immunity; phenotypes; tuberculosis; vaccine.

FIGURE 1

BCG vaccination induces trained immunity in monocytes and enhances subsequent responses to unrelated pathogens. (A) Interaction of macrophages with various pathogens induces the release of cytokines and activation of several antimicrobial functions to clear the infection. (B) BCG vaccination induces persistent epigenetic modifications and metabolic reprogramming in innate immune cells (depicted here in monocytes, giving rise to trained macrophages). These changes allow the trained innate immune cells to exhibit enhanced level of cytokine production and antimicrobial functions in response to unrelated pathogens, leading to better protection compared to untrained innate immune cells. Created with BioRender.com

FIGURE 2

Molecular mechanisms of BCG‐induced trained immunity. (A) Muramyl dipeptide (MDP) from BCG interacts with the cytosolic NOD2 receptor. NOD2‐Rip2 signalling mediates epigenetic modifications such as increased H3K4me3 and decreased H3K9me3 at the promoter regions, and increased H3K27ac at the enhancer regions of pro‐inflammatory genes, leading to increased chromatin accessibility and transcriptional activity. (B) In addition, metabolic reprogramming through the activation of the Akt/mTOR signalling pathway results in increased glycolysis and glutaminolysis. (C) Fumarate and metabolites from glutaminolysis accumulate, acting as a link between metabolic and epigenetic changes by inhibiting KD5M demethylases and promoting the deposition of H3K4me3 and H3K27ac. Created with BioRender.com