The how's and what's of vaccine reactogenicity

Abstract

Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting.

Keywords: Signs and symptoms; Vaccines.

Fig. 1

Summary of expected biological mechanisms underlying the development of reactogenicity symptoms. Vaccine antigens and immune enhancers (as adjuvants) injected into the muscle are recognised by the body as potential pathogens and/or danger signals. This recognition leads to the stimulation of local cells, followed by the recruitment of blood immune cells to the local site and the production of different soluble factors including vasodilators and cytokines, which may trigger the development of signs and symptoms of local inflammation (pain, redness and swelling). The passage of some of those factors in the bloodstream, as well as the production of other systemic factors by immune blood cells or distant organs (e.g. liver), may contribute to the development of general symptoms (fever, myalgia, headache etc) in the vaccinee. CRP C-reactive protein

Fig. 2

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

Fig. 3

Summary of vaccination and host factors that can influence reactogenicity. As a general concept, all the conditions that can influence the immune, the endocrine or the hormonal systems of the host (intrinsic factors), all the conditions that can increase tissue stress (administration factors) and the components that activate innate immunity contained in the vaccines (vaccine factors) could theoretically impact the incidence and severity of local and general symptoms induced after vaccination

Fig. 4

Practical recommendations to decrease side-effects that may occur at the time of injection: adapted from the World Health Organization recommendations. *There are no additional evidence-based, age-specific recommendations available for adolescents beyond the general measures recommended for all age groups