Fig. 3.

The mode of action of mRNA vaccines. (a –at the injection site) Upon endocytosis by muscle-resident cells, mRNA LNPs trigger a transient inflammatory response recruiting neutrophils, monocytes and DCs to the injection site. Local and recruited APC subsets transiently express the S protein mRNA and undergo maturation in response to innate immune sensing of the mRNA. The migration of targeted/activated APCs and direct lymphatic transport of mRNA LNPs and cell debris containing S proteins, brings the S antigen to B cells and T cells in draining lymph nodes. (b – at the cellular level) To avoid lysosomal degradation, mRNA must escape the endosomes and binds to ribosomes, known as a complex and rate-limiting process, which is facilitated by the ionizable LNP carrier. After translation and transport of S proteins through the endoplasmatic reticulum and Golgi apparatus, S proteins are exposed as prefusion-stabilized trimer constructs at the cell surface. This membrane-bound S antigen can efficiently be recognized and internalized by B cells, which leads to a series of events activating B cells responses towards neutralizing antibody generation against the S protein. Moreover, the expressed S antigens can gain access to the MHC class I antigen presentation pathway to prime CD8⁺ T cells that can eliminate infected cells, while recycling mechanisms allow the presentation of antigenic epitopes in MHC-II complexes to CD4⁺ helper T cells, especially needed to promote the antibody production by providing B cell help. Abbreviations: APC; Antigen presenting cell, RBD; Receptor binding domain, MHC; major histocompatibility complex.