Vaccination triggers large metabolic and epigenetic rewiring in the adaptive and innate immune system. In the resting state, immune cells do not present high energetic and metabolic requirements, relying mostly on efficient processes, such as fatty acid oxidation (FAO) or oxidative phosphorylation (OXPHOS). The chromatin of cells prior to vaccination is in a closed conformation, in line with low transcriptional activity. After vaccination and subsequent activation of primary and long-term responses to vaccination, immune cells greatly increase their biosynthetic demands and use different metabolic routes and nutrients to fulfill their increased energetic and nutritional requirements. Their chromatin unfolds, allowing the transcription of inflammatory factors. The specific memory T and B cells that stay in circulation and in tissues do not go back to baseline, but they keep an increased metabolic activity and chromatin remains in the open conformation to allow their increased responsiveness when they encounter a subsequent pathogenic stimulus.