Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations

Abstract

Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with in vitro models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.

Keywords: BCG; epidemiology; epigenetics; non-specific effects; trained immunity; vaccines.

Figure 1

Summary of the potential mechanisms of vaccine NSEs. (A) The top half illustrates adaptive mechanisms. Cross-reactive TCRs and antibodies. Lymphocyte antigen receptors recognize similar epitopes from different antigens. Bystander effect. Bystander activation of pre-existing effector or memory cells occurs via changes in the cytokine environment. Classical cell-mediated immunity. Adaptive immune cells potentiate the non-specific activity of innate cells in classical cell-mediated immunity. (B) The bottom half illustrates pathways of trained immunity. Primary stimulus of BCG. PRR signaling leads to TF activation, which then recruits chromatin modifiers to genes of interest. This stimulus also activate the autophagy and NOD2 signaling pathway. Upregulation of the Akt/mTOR pathway alters metabolite levels that regulate chromatin-modifying enzymes. Heterologous secondary stimulus. Epigenetic changes within innate cells after training act as de novo enhancers to boost the immune response against a secondary challenge.

Figure 2

Approaches to investigate BCG NSEs. After designing a model to study trained innate immunity in vitro, -omics studies help to identify the global cellular pathways involved. The variations in gene expression are assessed both at the transcriptomic level and at the epigenetic level and then confirmed at the protein level. The modifications of cell metabolism and effector functions are also various angles by which to grant NSEs biological plausibility. The last step consists in narrowing down these modifications in order to find protective biomarkers which can be applied in vivo in clinical settings.