Immune Responses to Bacillus Calmette-Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

Abstract

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the current leading cause of death due to a single infectious organism. Although curable, the broad emergence of multi-, extensive-, extreme-, and total-drug resistant strains of M.tb has hindered eradication efforts of this pathogen. Furthermore, computational models predict a quarter of the world's population is infected with M.tb in a latent state, effectively serving as the largest reservoir for any human pathogen with the ability to cause significant morbidity and mortality. The World Health Organization has prioritized new strategies for improved vaccination programs; however, the lack of understanding of mycobacterial immunity has made it difficult to develop new successful vaccines. Currently, Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine approved for use to prevent TB. BCG is highly efficacious at preventing meningeal and miliary TB, but is at best 60% effective against the development of pulmonary TB in adults and wanes as we age. In this review, we provide a detailed summary on the innate immune response of macrophages, dendritic cells, and neutrophils in response to BCG vaccination. Additionally, we discuss adaptive immune responses generated by BCG vaccination, emphasizing their specific contributions to mycobacterial immunity. The success of future vaccines against TB will directly depend on our understanding of mycobacterial immunity.

Keywords: Mycobacterium tuberculosis; adaptive immunity; bacillus Calmette–Guérin vaccine; innate immunity; tuberculosis.

Figure 1

Innate immune cell responses to bacillus Calmette–Guérin (BCG) vaccination. The initial immune response to BCG occurs at the site of inoculation (usually the dermal layer of the skin) where resident macrophages and dendritic cells (DCs) interact with the bacillus via different receptors expressed on their surface. Macrophages and DCs phagocytose the bacteria initiating the innate immune response through the secretion of immunomodulatory components such as cytokines and chemokines. Bacteria are degraded via intracellular killing mechanisms and their peptides are trafficked to the plasma membrane along with major histocompatibility complex (MHC) class I and II where they are presented to cells of the adaptive immune system. Neutrophils also enter the site of inoculation and participate in the response. Finally, DCs, loaded with bacteria, and expressing antigen on their surface, home to draining lymph nodes. Abbreviations: P–L, phagosome–lysosome; ROS, reactive oxygen species; RNS, reactive nitrogen species; CRs, complement receptors; TLR, toll-like receptors; GPCRs, G-protein-coupled receptors; CLRs, C-type lectin receptors; MR, mannose receptor; MINCLE, macrophage inducible Ca²⁺-dependent lectin; NLRs, NOD-like receptors; FcγRs, Fcγ receptors; SRs, scavenger receptors; DLNs, draining lymph nodes; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin.

Figure 2

Adaptive immune cell responses to bacillus Calmette–Guérin (BCG) vaccination. Upon entering the lymph nodes, dendritic cells stimulate CD4⁺, CD8⁺, CD1⁺-restricted T cells, T_FH, T regulatory cells, and B cells. CD4⁺ and CD8⁺ T cells migrate out of the lymph nodes toward the site of inoculation and provide the necessary stimulation to innate cells. CD4⁺ T cells differentiate into T_h1, T_h17, or T_h2 cells depending on the stimuli present in their microenvironment and aid in the activation of macrophages, whereas CD8⁺ T cells mediate their functions by lysing infected cells or by secreting cytokines. B cells differentiate into antibody producing plasma cells or memory B cells. Throughout the process, memory cells arise from those that responded to the infection and populate peripheral organs, such as the lung. Together, the cells of the adaptive immune systems orchestrate the immune response in an attempt to establish mycobacteria immunity. Abbreviations: EM, environmental mycobacteria.