Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Abstract

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and "innate memory-based vaccines" will be examined.

Keywords: Bacillus Calmette-Guérin (BCG); innate immune memory; mucosal immunity; vaccine.

Figure 1

Mechanisms of in vitro Bacillus Calmette-Guérin (BCG) training. Naive monocytes are stimulated with BCG, then rested for several days. Phagosomal digestion of BCG causes the release of muramyl dipeptide (MDP), as well as a metabolic shift towards glycolysis through the Protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. MDP binds nucleotide-binding oligomerization domain-containing protein 2 (NOD2) to induce epigenetic histone alterations, which are interconnected with the metabolic changes. Epigenetic modifications result in increased access to the promoter regions of genes related to inflammatory pathways, such as cytokine and pattern recognition receptors (PRRs). Trained monocytes express higher levels of PRRs and produce increased levels of cytokines following stimulation with heterologous pathogens or pathogen-associated molecular patterns (PAMPs).

Figure 2

Intradermal BCG vaccination and establishment of trained immunity in vivo. Lyophilized BCG bacilli reconstituted in saline is administered by intradermal injection. Neutrophils, monocytes, and lymphocytes are the predominant cells that infiltrate the vaccination site, where live BCG can persist for up to four weeks. A yet uncharacterized signal (potentially MDP) causes a change in the hematopoietic stem cells of the patient’s bone marrow, which induces a transcriptional shift resulting in increased myelopoiesis. As early as two weeks following inoculation, monocytes have a trained immunity phenotype with sustained epigenetic changes that last up to a year.

Figure 3

Proposed mechanism of action for hypothetical mucosal trained immunity-based vaccine (TIbV). TIbV vaccination at mucosal surfaces could induce trained immunity to tissue-resident and peripheral innate cells and epithelial cells, while producing a complementary adaptive response. Vaccination at one mucosal site does demonstrate effects at distal mucosal sites.