DNA vaccines: a work in progress

You are all familiar with the idea behind vaccines: an attenuated form of the pathogen stimulates the immune system to produce T-cells and antibodies specific to that particular antigen. These immune responses then become part of our T- and B-memory cells, cells that have previously encountered a certain antigen and have already specialized to recognize it. The challenge behind a vaccine is to use a form of antigen that's weak enough so not to cause the actual disease, but strong enough so to prompt the appropriate immune response. An efficient immune response has to be broad (it has to recognize all possible strains of the antigen) and strong (enough T-cells and antibodies have to be produced in order to clear the infection).

First generation vaccines use the whole organism as an antigen. Unfortunately, weakened forms may still induce full infection in immunocompromised people. Second generation vaccines use portions of the organism. For example, in HIV, one protein that's been used a lot in vaccine trials is env, the envelope protein: this is the outer shell of the virus, and the part most visible to the immune system. The so called "DNA vaccines" are the third generation vaccines. The idea is to inject a circular molecule of DNA (plasmid) that encodes for the specific antigen proteins. DNA is rapidly absorbed by cells and, once inside, it can use the cell machinery to assemble the proteins it encodes for. Just like in a viral infection, these proteins are then displayed on the cell's surface and presented for recognition by the immune system. The advantage of a DNA vaccine is obvious: there is no risk that the DNA itself will trigger the actual disease. Furthermore, studies have so far shown that no anti-DNA antibodies are produced.

Some DNA vaccines are already in use in veterinary medicine. In humans, though safe and well tolerated, they seem to have lower immunogenicity than other vaccines, and hence their potential hasn't been fully exploited yet. While the reason for this is still unknown, several studies have attempted to use other genes and proteins in combination with the vaccine to improve immunogenicity, in particular, genes and proteins that are involved in immune recognition pathways and cell-signaling pathways.

"Advancements in antigen design, improved formulations, inclusion of molecular adjuvants, and physical methods of delivery have greatly enhanced the immunogenicity of DNA vaccines [1]."

In [1] Ferraro et al. review the current studies in this field specifically for vaccines targeting influenza, human papilloma virus (HPV), and HIV. In the case of influenza, the appeal of a DNA vaccine is that it would considerably shorten the preparation time. In terms of immune responses, DNA vaccines have not been able to trigger good antibody responses, but, on the other hand, tend to perform well in triggering cellular responses (recruiting natural killer cells, T-cells, and phagocytes). In HIV in particular, both antibodies and T-cell responses are needed, both broad enough to cover the variability of the virus. Therefore, it is feasible and promising to combine a DNA vaccine with a protein one.

"Combining a DNA prime and viral boost creates a synergistic enhancement in the magnitude of antigen-specific CD81 T-cell responses. A phase I trial that combined a multi-clade DNA vaccine prime with an Ad5 boost demonstrated that this strategy was capable of eliciting humoral responses in addition to cellular responses."

[1] Ferraro, B., Morrow, M., Hutnick, N., Shin, T., Lucke, C., & Weiner, D. (2011). Clinical Applications of DNA Vaccines: Current Progress Clinical Infectious Diseases, 53 (3), 296-302 DOI: 10.1093/cid/cir334