A Naked DNA Vaccine That Arouses Potent Responses - Article Example

A naked DNA vaccine arouses potent responses Researchers from Taiwan have found that gene gun-introduced naked DNA vaccines increase the potency of the immune response and antitumor activity in mice, according to an article published in a March 2009 issue of Gene Therapy 1. Traditionally, DNA vaccines are coated with gold particles to improve the velocity of shooting, which ensures that the vaccines are delivered straight to host cells. However, it was found that even without the gold particle coating, the vaccine can be delivered effectively and induces the immune responses, and produces antitumor effects. This development removes other concerns associated with the gold coating which burn the entry point in the skin, the non-aseptic preparation of gold-coated particles, and accumulation of gold particles in the body with repeated immunizations. The study improves the application of DNA vaccines, which are now the main line of defence against deadly diseases caused by the human immunodeficiency virus (HIV), hepatitis B virus (HPV), and many different forms of cancer. DNA vaccines are the new kids on the immunization block. Vaccination to produce antibodies against infectious diseases is still the best defence against infection. The first generation vaccines injected killed viruses or weak virus strains to elicit activation of the immune response. The main actors in the immune response are the B cells, which produce specific antibodies to the introduced antigen, and T cells, which target the antigen for destruction. Antigens are proteins or any compound that can elicit the immune system to produce antibodies. Normally, the antigens are not produced by the body and come from a foreign entity. Second generation vaccines make use of a part of the antigen to recognize the intruding disease agents. The early vaccines, except those produced from live weakened viruses, elicit only the antibody response but not the killer T cells that are needed to neutralize viral intruders. The use of weak strains of deadly viruses also raises concerns that these strains could evolve into deadly strains. DNA vaccines are also called third generation vaccines. With these vaccines, the DNA or parts of the DNA of the virus, or cell, which code for a certain protein (the antigen) is inserted in a specially designed plasmid or circular DNA. This plasmid has certain other components, which can direct the production of expression of the protein product, and increase its immunogenic trait. The plasmid is directly injected into the body by several ways, where it is taken up by a host cell. Direct uptake means that the vaccine enters the dendritic cells, which are ‘antigen presenting cells’. Alternatively, some of the vaccines wander off and gain entry into keratinocytes and myocytes (muscle cells. It does not actually matter, because whichever cell the DNA vaccine enters, it will eventually express the protein that it is carrying. These proteins enter the cellular space, and are recognized as foreign and the DC will engulf them immediately. DNA vaccines that gain entry into the DC will also express the antigen, which will be directed to the cell surface and bound to the major histocompatibility complex (MHC), together with the other antigens from the cellular space. The advantage of this process is that the produced protein is folded in its natural state, which favours the formation of specific antibodies. When an antigen is displayed on the MHC, it is targeted for destruction by T cells (see illustration). The first report that DNA vaccines could elicit antibody response was in 19922. The ability to deliver a viral antigen in a plasmid for presentation to the immune system was first reported in 1993. This was a very important discovery because then, it became clear that there is no need for peptides or viral carriers to elicit the immune response3. In the same year, another report came out about the use of the DNA vaccine approach to develop anti-HIV-1 vaccines. It was reported that the results obtained were similar to those where live attenuated viruses were used in immunizations. T cells were activated and antibodies were induced against HIV-14. Excited by the results, researchers embarked on a human clinical trial on the efficacy of HIV-1 DNA vaccine. Unfortunately, and much to the disappointment of many, the clinical data showed a weak immune response, raising questions about the potency produced by the technology5. Not to be discouraged, researchers turned to other means to improve the response to DNA vaccination by augmenting it with adjuvants, chemicals that can improve the immune response by increasing antibody production and T cell activation. The fast-paced advances in the development of DNA vaccines also resulted in different ways of introducing the vaccine into the body. The first studies used the gene gun approach where particles of plasmid are bombarded into the skin. This show of strength results in burns on the skin where the plasmid particles gain entry. Another approach was to inject large volumes of DNA-containing solution by intravenous delivery; this approach led to a rapid and strong response6. The conventional method of injection may also be used. Electroporation, which uses an electrical current to introduce the vaccine into the host cells, produces higher cellular and humoral responses, and could be important in immunizing larger animal models (example: humans). Recently, there was a report that tattooing may be a better way to introduce DNA vaccines, although the cleanliness of the technique appears dubious. Gene guns have an advantage over the other techniques because it only requires a very small amount of DNA to elicit an immune response. In addition, bombardment is a fast and quick method, which allows for the uptake of the DNA vaccine by other cells that can express the antigen, which allows for the steady supply of antigen and continuous activation of immunity. A concern with DNA vaccines is their limited potency as shown in earlier studies. This was observed in low level of protein or antigen production, and the long expression time. The study reported here was showed that even without the gold particle coating, the naked DNA can still be delivered under the skin where host cells with the immune response are more plentiful. Moreover, there were less potentially harmful side effects associated with the delivery of naked DNA. The study was conducted on mice that were challenged with infusions of tumour cells; and the DNA vaccines did their job because the mice remained tumour free for more than a month, which show that the immunizations were successful. Currently, the usefulness in the technique is being tested in clinical trials for cancer, retinitis, cardiovascular disease, HIV, and hepatitis B virus 7. These vaccines are introduced into the body through the skin by injection, electroporation (a process where electrical impulse induces uptake), and by shooting with the use of gene gun. The results in the paper have important implications in the pursuit of more potent and more effective DNA vaccines. DNA vaccines are easy to manufacture and are relatively easy to transport, which makes it ideal for mass immunization against impending disease outbreaks. It is without question that the DNA vaccination technology has a very strong role to play in preventing diseases that are not amenable to the traditional vaccination procedures. The fast-paced advances in the technology have produced many vaccines that are already in Phase III of clinical trials. However, there is still much work to be done in other diseases like cancer and HIV. From the study, it can be gleaned that the use of better gene delivery methods improves the immune response, maybe by virtue of a more direct route to the antigen presenting cells, which can result in earlier and faster protein expression and antigen presentation. This means that in the case of DNA vaccine delivery, speed and impact are of primary importance. References 1. Chen, C-A, et al. Gene Therapy, pp. 1-12. (2009). 2. Tang, D.C, DeVit, M and Johnston, S.A. Nature, 356,152-154 (1992). 3. Ulmer, J. B. et al. Science, 259,1745-1749 (1993). 4. Wang, B. et al. Proc. Natl Acad. Sci. USA, 90, 4156-4160 (1993). 5. MacGregor, R. R. et al. J. Infect. Dis., 178, 92-100 (1998). 6. Bates, M.K et al. BioTechniques, 40, 199-208 (2006). 7. Kutzler, M.A and Weiner, D.B. Nature Rev. Gen., 9, 776-788 (2008). Read More