Terry M. Bella
DNA vaccines hold promise as the most viable vaccine delivery method in the near future. There are specific health concerns with today’s methods and DNA vaccine technology, when fully realized, will naturally circumvent those concerns. Furthermore there are limitations to today’s vaccines concerning ease of production, transport, and storage.
Recall that non-live, killed or inactivated, vaccines are typically not providing life-long immunity. They work, but do not effectively activate cellular immunity. Live attenuated vaccines provide longer protection but their immunogenicity is linked to their level of attenuation. That means that the less attenuated, the better they work, which has inherent risk. Furthermore, with live attenuated vaccines there is the threat that mutations occur and new subtypes and variants arise. Generating copies of the pathogen, whether it is bacterial, fungal, or viral provides the opportunity for mutation and the incidence of new variants. These new variants may not respond to attenuation the same manner as their predecessor, thus the risk of inoculating people with pathogen that is not attenuated to the degree that was assumed.
Current vaccine technology is also severely limited by issues with temperature stability, impacting storage and transport. Maintaining vaccines at temperature during all times of transport and storage is difficult and consequently increases costs. Antigens are proteins and any given protein will have a temperature range in which it is stable and will maintain its structure. Exceeding the temperature thresholds for a protein will cause it to denature as the bonds that ensure its conformation of structure are compromised. Since antigen recognition is based on shape conformation by a receptor or antibody it is imperative that the shape of the antigen is not jeopardized and altered. This adds many levels of complexity to the distribution and storage of vaccines in the US and other first world countries and is a significant barrier in third world countries. Students may wonder why diseases that we have vaccines for are still prevalent in the world and the matter is sometimes as straightforward as transport and storage. Ultimately, one must question the usefulness of a vaccine if it cannot be delivered to the patient.
DNA vaccines are using the nucleic acid code for the antigen. The code is taken from the pathogens DNA or RNA. This section of nucleic acid is then packaged within a plasmid and adjuvants to be delivered to cells to generate immunity. A plasmid is a circular piece of DNA derived from bacteria. The plasmid enters the nucleus of the target cell and is transcribed and then translated into proteins, the antigens. Nucleic acid has much higher temperature stability than proteins, thus transport and storage barriers are not an issue. The fact that only the instructions for the antigen are even introduced to the patient eliminates any concern of virulence and is inherently extremely safe for the patient.
With DNA vaccines the actual antigen is not being used for inoculation, just the code. The fact that the recipients cells are translating and expressing the antigen themselves helps to increase the immunogenicity of the vaccine because the threat of antigen structure being compromised by any of the conventional vaccine processes has been diminished. Quite simply, the antigen is not even produced until it is within the patient therefore it is not subject to degradation or denaturation before performing its intended function.
DNA vaccines are delivered to somatic cells as well as APC’s and there is evidence they result in long-term immunity by effectively activating B-cells which results in memory B-cells and antibodies. The vaccine must enter the patients cells and make it into the nucleus where it can be transcribed into RNA, processed, and then translated. Adjuvants, like eurkaryotic promotors and enhancers are used to elevate the expression. The delivery methods do vary from the typical vaccine because needle delivery has not proven effective. The delivery methods for DNA vaccines aim to get the product into the cells because the whole process relies on the production and presentation of the antigen.
The inoculation methods are quite advanced. One method utilizes high pressure steam to deliver the plasmid vaccine on microscopic heavy metal particles. Other methods are using pathogen like nanoparticles that can be recognized by a phagocyte and engulfed. Still another method is to use electrical pulses to disturb intramuscular tissue to encourage uptake of the vaccine. Lastly, methods are using liposomes to package the plasmid. Overall, the difficulty in the development of DNA vaccines has been with the delivering the package to the nucleus of the cells.
The DNA vaccine does show promise when it is effectively delivered to the nucleus of the patients cells. Somatic cells are presenting the antigen with a class 1 MHC pathway, that which is recognized by T-cells, confirming cell-mediated immunity. Plasmids are also found to enter APC’s, making them transfected, and initiating immune pathways at both the cellular and humoral level. Furthermore, transfected somatic cells are phagocytosed and the antigen is presented to T-cells.
DNA vaccines also show promise in clinical studies for the treatment of cancers. This is based on the premise that a cancerous cell will display a surface level protein unique to the cancerous cell and not utilized by other cells. The immune system can be alerted to this antigen through DNA vaccination, mobilizing the body’s immune system against the cancer. This is significantly more promising as a treatment as opposed to chemotherapy and transplant which both have some extreme side-effects and risks. Furthermore, research is underway for immunization against cancers such as HIV and HPV.
