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Nanoparticle Technology for Minimally-invasive Delivery of DNA Vaccines


OBJECTIVE: Develop an innovative, minimally-invasive and efficient DNA vaccination delivery platform using nanotechnology DESCRIPTION: Endemic, emerging and genetically engineered pathogens pose great risk to deployed military personnel. Although vaccination is the single best means for preventing infectious diseases, conventional vaccine development methods, which require attenuation or inactivation of dangerous pathogens, are not amenable to the rapid development of novel vaccines or for production of multiagent vaccines. In contrast, DNA vaccines can be rapidly engineered, readily combined and present minimal safety risks. Despite these attributes, DNA vaccines face a number of challenges before they can realize their full potential. A key obstacle for mass vaccination with DNA is the absence of an effective and tolerable delivery method. Delivery has remained problematic because it is essential that the DNA enter host cells in order for it to generate immunogenic proteins. The most commonly used method of delivery, needle injection into muscles, results in poor immune responses because the DNA is deposited into intracellular spaces and is not efficiently taken up by the host cells. Other methods, which more effectively deliver the DNA to cells are still inadequate or are too invasive for general use. For example, gene gun delivery requires the DNA vaccines to be coated onto microscopic gold beads that are dispensed into skin cells by gas propulsion. Although this method results in deposition of the DNA directly into cells, only a very small quantity of DNA can be delivered at one time; thus, this method is not well-suited for delivering multiple DNA vaccines. Another method, intramuscular electroporation, involves injecting the DNA then quickly applying short electrical pulses to the delivery site. The electrical charge causes temporary pores to form in cellular membranes and facilitates uptake of the DNA vaccines. Electroporation has been found to greatly improve immune responses to DNA vaccines as compared to injection alone, and it allows for delivery of larger quantities of DNA in a single dose; however, intramuscular electroporation is more invasive and painful than is desirable for routine vaccination. In order to advance DNA vaccine technology, a novel and innovative delivery approach that is more tolerable, yet still effective is needed. Recent advances in nanotechnology provide one promising path toward efficient intracellular delivery of DNA vaccines. Several methods have been reported in the last few years for manufacturing stable nanoparticles that can incorporate biomaterials such as proteins or DNA. Because of their extremely small size and chemical composition, these particles are able to readily penetrate cells to deliver DNA to the cytoplasm or nucleus of cells. Further research and development is required to identify and manufacture safe, reproducible and stable nanoparticle-DNA vaccines that can be delivered in a minimally invasive manner to animal models, and ultimately to humans. The optimal vaccine platform would consist of nanoparticles containing sufficient DNA to elicit a desired immune response after minimally-invasive delivery. Further, the nanoparticle components should be acceptable for use in humans. A marginally successful outcome would provide nanoparticles containing DNA that are able to elicit superior immune responses as compared to those achieved with standard DNA vaccines delivered in solution by intramuscular injection. PHASE I: This Phase will demonstrate the feasibility of generating nanoparticles containing functional DNA vaccines using components suitable for human use. PHASE II: In this Phase, the nanoparticle vaccine platform developed in Phase 1 will be validated with DNA vaccines of interest to the military in an appropriate animal model. Immune responses to the vaccine of interest will be characterized. This phase will involve further refinement of the nanoparticle manufacturing technology, such that the nanoparticles can be demonstrated to be stable and consistent, and to be capable of delivering two or more DNA vaccines to skin using a minimally-invasive method. PHASE III DUAL USE APPLICATIONS: The resultant vaccine technology would be of value to both military and civilian populations for preventing infectious diseases. The technology would provide a means to administer several vaccines in a single dose, with low or no pain; thus, increasing tolerability and decreasing vaccination burden. Examples of vaccines that would be of dual use for civilian and military populations include: trivalent vaccines for Venezuelan, eastern and western equine encephalitis; bivalent vaccines for hemorrhagic fever with renal syndrome; quadravalent vaccines for Dengue hemorrhagic fever; and multigene vaccines for malaria. The technology would also provide both civilian and military populations with a path toward rapid response to unknown, emerging, or genetically engineered pathogens. Spin-off technologies would include further improvement in equipment and biologics required for manufacturing the DNA and nanoparticles. Transition to use in the military and to civilian populations would most likely involve acquisition of the technology by a large Pharmaceutical Company interested in producing commercially viable vaccines for civilian and military use. REFERENCES: 1. Caputo, A., Sparnacci, K., Ensoli, B., and Tondelli, L. (2008). Functional polymeric nano/microparticles for surface adsorption and delivery of protein and DNA vaccines. Curr Drug Deliv 5(4), 230-42. 2. Khatri, K., Goyal, A. K., and Vyas, S. P. (2008). Potential of nanocarriers in genetic immunization. Recent Pat Drug Deliv Formul 2(1), 68-82. 3. Masotti, A., and Ortaggi, G. (2009). Chitosan micro- and nanospheres: fabrication and applications for drug and DNA delivery. Mini Rev Med Chem 9(4), 463-9. 4. Scheerlinck, J. P., and Greenwood, D. L. (2008). Virus-sized vaccine delivery systems. Drug Discov Today 13(19-20), 882-7.
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