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.