English: Hypothesised link between the innate immune response induced by vaccination and reactogenicity. Upon vaccination, inflammation is triggered by innate immune activation of pattern-recognition receptors (PRR) including Toll-like receptors (TLRs) that recognize and bind antigens (green circle in skeletal muscle) and potential immune enhancers (purple circle in skeletal muscle) present in the vaccine formulation. Resident immune cells, mast cells, monocytes and macrophages are activated within minutes of injection and release soluble factors (proinflammatory cytokines, chemokines, effectors of the complement cascade) and vasodilators, that allow cell recruitment from blood but also lead to the development of redness and swelling symptoms. These newly recruited immune cells, mainly composed of blood-born neutrophils, monocytes and T lymphocytes, also contribute to pain sensation by releasing soluble factors, such as cytokines, prostaglandins or ATP, that can directly interact with local sensory receptors called nociceptors and cause pain through the fast neural route if the threshold is reached. Once produced, cytokines act both locally in autocrine and paracrine manners, and may act systemically at distant organs, leading to the production of C-reactive protein and other acute phase proteins by the liver. Several immune-to-brain signaling pathways may propagate an inflammatory response to the central nervous system after peripheral activation of the innate immune system (slow humoral route), leading to the development of fever and sickness behaviours