BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design

Abstract

The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as "trained immunity." Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a "trained" state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.

Keywords: BCG; heterologous protection; innate immunity; trained immunity; vaccine.

Figure 1

The immune response elicited after BCG vaccination in the newborn. (A) Recognition of the BCG at the inoculation site by neutrophils, macrophages, and DCs. (B) Activated skin DCs migrate to the draining lymph nodes to activate adaptive immune cells (C) Activation of Mycobacteria-specific CD4⁺ and CD8⁺ T cells with a T_H1 profile, secreting elevated amounts of IFN-γ and granzymes (D) Activation of B cells leads to the generation of memory and plasma cells and the production of antigen-specific antibodies in response to the presence of antigens of BCG. After their activation, memory T and B cells reside in lymph nodes.

Figure 2

BCG applications in immunotherapy. Clinical applications of BCG in autoimmunity (left boxes) and cancer (right boxes). HbA1c, glycosylated hemoglobin; CNS, central nervous system; NK, natural killer cells; Mϕ, macrophages; NMI, non-muscle invasive.

Figure 3

BCG vaccination induces an innate immune training. BCG vaccination activates the innate immune system and induces changes in the pattern of histone modifications of specific genes in innate immune cells. This chromatin rearrangement induces a “trained” state in the cell, enhancing the effectiveness of the innate immune response when exposed to a non-specific pathogen, inducing the secretion of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. The pink line represents a trained immune response, the purple line represents a naïve innate immune response.