Delivery, delivery, delivery is the major focus of DNA vaccine research, according to David Weiner, Ph.D., University of Pennsylvania professor and also chair of the recent conference on “DNA Vaccines: Building on Clinical Progress and Exploring New Targets.”
In his keynote address, Dr. Weiner reviewed the history of the field, detailing how trials of a DNA HIV vaccine dealt a huge blow to the field when it was observed that plasmids carrying five different HIV proteins failed to induce immunity when injected into patients. In the years since, the technology has advanced dramatically, and therapies currently under evaluation are demonstrating the superb potential of plasmid-based vaccines.
DNA vaccines represent a simple, elegant, and straightforward approach. They do not require the handling of live, unstable, and dangerous pathogens; they can be produced and ramped up rapidly to confront epidemics; and because they are composed of DNA they are stable at room temperature, a claim that cannot be made for many proteins. Since no actual viruses are used in the vaccines there is no possibility of a debilitated form mutating back to an aggressive wild type. Finally, DNA is not perceived by the host to be a foreign material and so no immune response would be expected to be mounted against it.
Dr. Weiner emphasized at the meeting, which was sponsored by the International Society of DNA Vaccines and organized by BioConferences International, that in the intervening years, a coterie of new vaccine methods have been developed including new strategies for getting the plasmids into cells, increasing protein production once they are inside, and modifications of the vaccine proteins that increase their recognition and response by the immune system.
Some of the new heavy hitters include transdermal, needle-free patches; devices that blast the plasmids into the skin with air pressure; and electroporation, in which electrical pulses are used to temporarily open the cell membrane, allowing the plasmids easier access to the interior of cells.
Codon modification can also improve the rates of gene transcription, speeding protein manufacture. In addition, adding a so-called leader sequence can improve the stability of the final protein molecule.
Today, dozens of DNA vaccines are being evaluated. Targets include H1N5 avian flu, HIV, and cancer. Dr. Weiner cautioned that such efforts may appear to be simple and straightforward, yet present years of setbacks and frustrations. “The next two years of clinical testing of new and more complex DNA vaccines will be pivotal for either generating a true clinical success based on immune potency, or for telling us that we still have much further to go.”