Heterologous effects of infant BCG vaccination: potential mechanisms of immunity

Abstract

The current antituberculosis vaccine, BCG, was derived in the 1920s, yet the mechanisms of BCG-induced protective immunity and the variability of protective efficacy among populations are still not fully understood. BCG challenges the concept of vaccine specificity, as there is evidence that BCG may protect immunized infants from pathogens other than Mycobacterium tuberculosis - resulting in heterologous or nonspecific protection. This review summarizes the up-to-date evidence for this phenomenon, potential immunological mechanisms and implications for improved childhood vaccine design. BCG induces functional changes in infant innate and adaptive immune compartments, encouraging their collaboration in the first year of life. Understanding biological mechanisms beyond heterologous BCG effects is crucial to improve infant protection from infectious diseases.

Keywords: BCG; NK cells; T cells; childhood immunization; heterologous vaccine effects; humoral responses; infant immunity; innate memory; monocytes; trained immunity.

Figure 1.. BCG training-induced phenotype changes in monocytes and NK cells.

BCG training of human monocytes in vitro or by vaccination increases their surface marker expression and cytokine production in response to heterologous antigen stimulation [36,40]. In monocytes, these changes are regulated by metabolic shift from oxidative phosphorylation to glycolysis and histone modifications [41], with increased frequency of permissive H3K4me3 and reduced presence of inhibitory H3K9me3 at the promoters of cytokine, receptor and metabolic pathway component encoding genes [36,37,41–43]. The left side of the diagram depicts model innate immune cells prior to the BCG training and the right side – post-training. Enhanced cytokine production post-training is indicated by arrows. Heterologous microorganism – secondary, nonmycobacterial infectious agent. + BCG – in vitro or in vivo cell training with BCG. TLR4: Toll-like receptor 4; H3K4me3: Trimethylation of lysine at position 4 on histone 3; H3K9me3: Trimethylation of lysine at position 9 on histone 3.

Figure 2.. A model of cell populations mediating BCG-vaccinated infant heterologous responses.

The diagram shows the innate and adaptive immune cells implicated in nonspecific infant protection and the likely timings for their involvement with respect to BCG vaccination and infant age. At of or immediately after BCG-vaccination, monocytes and NK cells of young infants are ‘untrained’, by low surface receptor expression or cytokine production. Once these cells become ‘trained’ by BCG, they increase surface receptor expression and inflammatory cytokine production and may cope with childhood infections more readily [30,36,40]. This effect diminishes over time, subsiding by 1 year postvaccination [38]. BCG, however, induces mycobacteria-specific Th1 or CTL responses [30,40]. BCG-supported heterologous T-cell responses may enhance trained innate immune responses from several weeks postimmunization and provide heterologous protection from childhood infections once trained innate immunity fades. The impact of BCG on heterologous B-cell responses is not yet clear, the current evidence being contradictive. CTL: Cytotoxic T-cell; Mo: Monocyte; Th1: T-helper cell 1; Th17: T-helper cell 17. The role of other cells in trained immunity or heterologous adaptive responses is not well characterized yet and is therefore not presented.