The relationship between the immunogenicity and reactogenicity of vaccines: A narrative review

The relationship between vaccine reactogenicity and immunogenicity remains an underexplored but increasingly critical area of vaccinology. This narrative review synthesizes evidence examining this relationship across a diverse array of vaccine platforms and pathogens. The available data suggest a modest but consistent positive association between systemic reactogenicity and humoral immunogenicity, particularly for mRNA-based SARS-CoV-2 vaccines. Associations with innate and adaptive cellular immunity are less well studied. Local reactions are less consistently predictive of immune response than systemic ones. Reactogenicity appears more pronounced in younger adults, females, and those with certain HLA alleles-factors also associated with stronger immune responses. Whether the priming or booster dose of a vaccine series drives greater reactogenicity and immunogenicity appears to depend upon whether the vaccine is live-attenuated or not. However, substantial heterogeneity exists in study design, population, outcome measurement, and statistical analysis. This review emphasizes the need for harmonized tools to quantify vaccine reactogenicity and for study designs that account for pre-vaccination immune status to distinguish true associations from confounding factors and better clarify the relationship between post-vaccine symptoms and immunologic outcomes. Understanding the mechanistic links between innate immune activation, tolerability, and adaptive immune responses could inform vaccine development, clinical trial endpoints, and public communication strategies. As vaccine technologies evolve and tolerability becomes a differentiating factor, further research is needed to unravel the biological basis of vaccine-associated symptoms and their role in predicting protection.