How do they work?

DNA vaccines elicit protective immunity against an infectious agent, or pathogen, primarily by activating two branches of the immune system: the humoral arm (antibody specific response) attacking pathogens outside of cells, and the cellular arm eliminating cells that are colonized by an invader (non-specific response).

Immunity is achieved when such activity produces longlasting “memory” cells—the sentries that stand ready to stop the pathogen from causing disease. A simplified description of how the vaccines induce immunity begins at the far left of the diagram, with entry of a DNA vaccine into a targeted cell, such as muscle, and the cell’s subsequent production of antigens normally found on the pathogen of interest. ^[9]

In the humoral response (top unboxed sequence), white blood cells called B cells bind to released copies of antigenic proteins and then multiply. Many of the progeny secrete antibody molecules that during an infection would glom onto the pathogen and mark it for destruction. Other offspring become the memory cells that will quell the pathogen if it circulates outside cells.

Meanwhile display of antigenic protein fragments, or peptides, on inoculated cells (within grooves on MHC class I molecules) can trigger a cellular response (bottom unboxed sequence). Binding to the antigenic complexes induces white blood cells known as cytotoxic (killer) T cells to multiply and kill the bound cells and others displaying those same peptides in the same way. Some activated cells will also become memory cells, ready to eliminate cells invaded by the pathogen in the future. In actuality, several preliminary steps must occur before such responses can arise. To set the stage for B cell activation (top box), “professional” antigen-presenting cells (APCs) must ingest antigen molecules, chop them and display the resulting peptides on MHC class II molecules. Helper T cells, in turn, must recognize both the peptide complexes and “co-stimulatory” molecules found only on the professional antigen presenters. If those steps occur, the helper cells may secrete signalling molecules known as Th2 cytokines, which help to activate B cells bound to antigens. Priming of cytotoxic T cell responses involves APCs as well (bottom box).

Before the cytotoxic cells can respond to antigens on inoculated cells, APCs have to take up vaccine plasmids, synthesize the encoded antigens, and exhibit fragments of the antigens on MHC class I molecules along with co-stimulatory molecules. Then the killer T cells must recognize those signals and also be hit by cytokines (this time of the Th1 type) from helper T cells. In steps not shown, DNA vaccines also yield memory helper T cells needed to support the defensive activities of other memory cells.