Immune Responses Induced by mRNA Vaccination in Mice, Monkeys and Humans

Abstract

In this concise review, we summarize the concepts behind mRNA vaccination. We discuss the innate and adaptive immune response generated by mRNA vaccines in different animal models and in humans. We give examples of viral infections where mRNA vaccines have shown to induce potent responses and we discuss in more detail the recent SARS-CoV-2 mRNA vaccine trials in humans.

Keywords: SARS-CoV-2; Th1 polarization; antibody response; dendritic cell; mRNA vaccine; protein translation; type I interferon.

Figure 1

Simplified overview of the events that follow uptake of an LNP-formulated mRNA vaccine by a cell. Once the mRNA molecule is released from the LNP into the cytosol, it is sensed by toll-like receptors (TLR), e.g., TLR3 or 7/8 and by retinoic acid-inducible gene (RIG)-I, which promotes secretion of type I interferons (IFNs) to the extracellular matrix that will create a milieu that favors Th1 responses over Th2. mRNA is directly translated by ribosomes into polypeptides which are processed by the proteasome system, leading to peptide presentation onto MHC-I on the cell surface (similarly as during a viral infection), and post-translationally modified to be folded into the protein which, depending on the mRNA design, can either be membrane-anchored or be secreted. Peptide presentation onto MHC-II may occur on APCs after protein uptake of extracellular proteins or of cell debris containing protein. This figure was created using BioRender.com.

Figure 2

Proposed sequence of events leading to the generation of adaptive immune responses upon mRNA vaccination. Local inflammation at the injection site promotes the infiltration of immune cells, including neutrophils, monocytes, myeloid dendritic cells (MDCs) and plasmacytoid dendritic cells (PDCs). Neutrophils can efficiently take up LNPs, but monocytes and MDCs translate mRNA more efficiently. Secretion of type I interferons (IFNs) is stimulated. mRNA/LNP and protein antigen will disseminate and cells will migrate to the vaccine-draining lymph nodes. Antigen presentation to T cells and interactions of antigen and B cells take place at these sites. This leads to the formation of germinal centers, which results in the generation of memory B cells and antibody-producing plasma cells that reside to the bone marrow. The basic illustration was made by Elizabeth Thompson and some elements were created using BioRender.com.