Messenger RNA (mRNA) vaccines have transitioned from a research concept of decades to a validated therapeutic platform, accelerated by the rapid development of highly effective vaccines during the COVID-19 pandemic. The hallmark of these vectors is the delivery of genetic instructions, rather than a preformed antigen. The delivered transcript is translated by host cells and the resultant protein is presented to the immune system, thus engaging both the innate and adaptive arms in a manner that closely mimics natural infection . This review summarizes the immunological mechanisms that shape the immune response to mRNA vaccines.
We first describe the molecular architecture of the transcript—the 5′ cap, untranslated regions, open reading frame, and poly(A) tail—and the nucleoside modifications and lipid nanoparticle (LNP) delivery systems that govern its behaviour in vivo. We then examine innate immune sensing by endosomal and cytosolic pattern recognition receptors (TLR3/7/8, RIG-I, MDA5, PKR and the OAS/RNase L system), the pivotal type I interferon response, and the intrinsic adjuvant activity of the LNP carrier. We describe how these signals license dendritic cell maturation and antigen presentation, bridging to the adaptive response: germinal centre formation, T follicular helper and B-cell driven antibody affinity maturation, and CD4⁺ and CD8⁺ T-cell programming, culminating in durable immunological memory. Finally, we consider the balance between immunogenicity and reactogenicity, survey applications in infectious disease and personalised cancer immunotherapy, and outline the principal challenges and future directions of the field, including self-amplifying RNA and tolerogenic mRNA design.
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