Trained Immunity Induced by Vaccines: A Shifting Paradigm for Infant and Adult Immunity

In addition to inducing pathogen-specific adaptive immune responses, vaccines can train the innate immune system, thereby providing broader host protection. This concept of trained immunity (TRIM) is well-established in benchtop laboratory science. This review aims to evaluate the current evidence of vaccine-induced TRIM and translate these findings into a clinical context. Various laboratory methods are used to assess TRIM; however, inconsistent results have been reported across non-BCG vaccine studies. Existing analyses lack exploration of the mechanistic basis of vaccine-induced TRIM, particularly epigenetic reprogramming and metabolic rewiring. Patterns emerge between vaccines: live-attenuated vaccines generally induce TRIM, as evidenced by increased inflammatory cytokine production upon restimulation, whereas non-live vaccines tend to demonstrate reduced trained immunity. Such findings are not consistently observed for mRNA vaccines, which show heterogeneous patterns. The limited variety of studies on non-BCG vaccines impacts the reliability of findings. A more comprehensive understanding of the mechanisms and outputs of TRIM induced by specific vaccines could better inform rational vaccine design. Furthermore, various modifiers can alter vaccine-induced TRIM responses, including sequence and route of administration, sex, and age. Consideration of these modifiers has important clinical implications in optimising vaccine administration for enhanced immune protection.