DNA Vaccine Delivery
What are the alternative methods of DNA vaccine delivery?
DNA vaccines have tremendous potential as preventive or therapeutic agents against various cancers and infectious diseases. One of the obstacles to the successful development of DNA vaccines is the limitations associated with most DNA delivery systems. A successful DNA delivery system must be able to effectively and safely deliver the DNA vaccine into cells of targeted tissue where the DNA can subsequently achieve gene expression of the encoded protein at desired levels and for the desired duration of time. To be commercially compelling, the method must also be readily reproducible and low cost.
One method that has shown a compelling balance of safety, efficiency, and economy in pre-clinical and initial human data is Inovio's electroporation-based DNA delivery solution.
The following table compares the main DNA carrier or delivery alternatives:
What are the challenges to DNA vaccine delivery?
Viral vectors (carriers) have been the most studied approach to intracellular DNA delivery. Leveraging the natural ability of viruses to insert and express a "genetic payload" in human cells, scientists modify a virus to carry beneficial genes such as a DNA vaccine. These viral vectors, containing their payload, are then injected by a syringe/needle in target tissue such as muscle.
There are multiple issues that have plagued DNA vaccine developers using this approach:
- Viral vectors may insert their genes randomly into the target cell's chromosomes, risking disruption of genetic regulatory machinery and/or causing mutations which can lead to cancer.
- There are size constraints on the genetic payload that can be delivered.
- They induce an unwanted immune response against themselves, making the patient resistant to subsequent vaccinations with the same viral vector. While these viral vectors may effectively deliver their payload during the prime or first vaccination, if booster (additional) vaccinations are required, the immune system might attack and remove the viral vector before it can deliver the vaccine it is carrying.
- Viral vectors have raised serious acute safety concerns and have been associated with patient deaths.
- It will be difficult and expensive to develop, manufacture in a controlled manner, and obtain regulatory approval for many of these viral vectors.
Examples highlighting these issues include a patient death in 1999 in a gene therapy trial after receiving an agent delivered using a retrovirus. In 2007, Merck halted an HIV clinical study when a higher number of patients became infected with HIV in the placebo group compared to the group receiving Merck's experimental agent. The agent was delivered using an adenovirus. These circumstances have continued to maintain concerns regarding viral vectors.
Liposome or lipid vectors are also modified to carry a DNA vaccine payload and are injected by needle into selected tissue. They are not highly effective in delivering their payload and are challenging to manufacture in a consistent and cost effective manner.
The gene gun or biolistic gun, which blasts microscopic DNA-vaccine-coated gold particles into the patient's skin, faces the challenge of manufacturing complexities but has shown promise in clinical studies. In 2006, the drug giant Pfizer acquired PowderMed, the lead company developing this method of DNA delivery, for reportedly US$400M.
The challenge of these delivery methods is that the "carrier," i.e. virus, lipid, or gold particle, they use to transport the vaccine creates its own unique challenges with respect to safety, utility, or manufacturability.
A method widely considered by scientists to be a safe method of DNA delivery is the injection of naked DNA or DNA plasmids into muscle. Scientists manufacture small circular pieces of DNA, called plasmids, containing the DNA fragment encoding the desired protein relating to a targeted disease. Plasmids can be designed to code almost any desired protein (antigen). Plasmid-based vaccines can be inexpensively produced in large quantities in bacteria. Unfortunately, despite their early promise, plasmids injected into muscle without any other method to enhance their level of cellular uptake typically do not achieve sufficient gene expression to induce a clinically relevant immune response.
The emergence of a promising alternative: electroporation-based DNA delivery
One alternative method of DNA delivery is attracting attention and endorsements from scientists. Called electroporation, this method uses electrical pulses to create pores in cells of selected tumor, muscle, skin, or mucosal tissue and enhances intracellular delivery of DNA plasmids by 1,000 times or more. This method appears to provide a desirable balance of safety, efficiency, and cost effectiveness.
Inovio Biomedical is a leader in developing human applications of electroporation and possesses significant intellectual property, including patents, relating to the use of electroporation for gene therapies and DNA vaccines.