DNA Vaccines Approach: From Concepts to Applications


DNA vaccines are the third generation vaccines based on purified plasmid preparations containing transgenes that encode antigenic/therapeutic proteins or peptides capable of triggering an immune response against a wide range of diseases. This vaccine platform presents several attributes that confer distinct advantages over other vaccine technologies in terms of safety, ease of fabrication and stability. Many aspects, such as antigen expression and especially vector design, are under study because of their great influence on immunogenicity and efficacy of DNA vaccines. In this regard, with the attempt of improving the efficiency of DNA vaccines, co-expression of stimulatory sequences and diverse vector delivery systems are being optimized. With this in mind, this review aims to giving a conceptual approach of DNA vaccines, explaining their mechanisms of action and listing the already licensed veterinary DNA vaccines presented in the market.

Share and Cite:

Pereira, V. , Zurita-Turk, M. , Saraiva, T. , De Castro, C. , Souza, B. , Mancha Agresti, P. , Lima, F. , Pfeiffer, V. , Azevedo, M. , Rocha, C. , Pontes, D. , Azevedo, V. and Miyoshi, A. (2014) DNA Vaccines Approach: From Concepts to Applications. World Journal of Vaccines, 4, 50-71. doi: 10.4236/wjv.2014.42008.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] WHO (2008) The Global Burden of Disease: 2004 Update.
[2] Kariuki, S. and Hart, C.A. (2001) Global Aspects of Antimicrobial-Resistant Enteric Bacteria. Current Opinion in Infectious Diseases, 14, 579-586.
[3] Threlfall, E.J. (2002) Antimicrobial Drug Resistance in Salmonella: Problems and Perspectives in Food- and Water-Borne Infections. FEMS Microbiology Reviews, 26, 141-148.
[4] van Ginkel, F.W., Nguyen, H.H. and McGhee, J.R. (2000) Vaccines for Mucosal Immunity to Combat Emerging Infectious Diseases. Emerging Infectious Diseases, 6, 123-132.
[5] Mielcarek, N., Alonso, S. and Locht, C. (2001) Nasal Vaccination Using Live Bacterial Vectors. Advanced Drug Delivery Reviews, 51, 55-69.
[6] Gurunathan, S., Wu, C.Y., Freidag, B.L. and Seder, R.A. (2000) DNA Vaccines: A Key for Inducing Long-Term Cellular Immunity. Current Opinion in Immunology, 12, 442-447.
[7] Levine, M.M. and Sztein, M.B. (2004) Vaccine Development Strategies for Improving Immunization: The Role of Modern Immunology. Nature Immunology, 5, 460-464.
[8] Stasney, J., Cantarow, A. and Paschkis, K.E. (1950) Production of Neoplasms by Injection of Fractions of Mammalian Neoplasms. Cancer Research, 10, 775-782.
[9] Will, H., Cattaneo, R., Koch, H.G., Darai, G., Schaller, H., Schellekens, H., van Eerd, P.M. and Deinhardt, F. (1982) Cloned HBV DNA Causes Hepatitis in Chimpanzees. Nature, 299, 740-742.
[10] Dubensky, T.W., Campbell, B.A. and Villarreal, L.P. (1984) Direct Transfection of Viral and Plasmid DNA into the Liver or Spleen of Mice. Proceedings of the National Academy of Sciences of the United States of America, 81, 7529-7533.
[11] Wolff, J.A., Malone, R.W., Williams, P., Chong, W., Acsadi, G., Jani, A. and Felgner, P.L. (1990) Direct Gene Transfer into Mouse Muscle in Vivo. Science, 247, 1465-1468.
[12] Tang, D.C., DeVit, M. and Johnston, S.A. (1992) Genetic Immunization Is a Simple Method for Eliciting an Immune Response. Nature, 356, 152-154.
[13] Fynan, E.F., Webster, R.G., Fuller, D.H., Haynes, J.R., Santoro, J.C., Robinson, H.L. (1993) DNA Vaccines: Protective Immunizations by Parenteral, Mucosal and Gene-Gun Inoculations. Proceedings of the National Academy of Sciences of the United States of America, 90, 11478-11482.
[14] Ulmer, J.B., Donnelly, J.J., Parker, S.E., Rhodes, G.H., Felgner, P.L., Dwarki, V.J., Gromkowski, S.H., Deck, R.R., DeWitt, C.M. and Friedman, A. (1993) Heterologous Protection against Influenza by Injection of DNA Encoding a Viral Protein. Science, 259, 1745-1749.
[15] Reyes-Sandoval, A. and Ertl, H.C. (2001) DNA Vaccines. Current Molecular Medicine, 1, 217-243.
[16] Davidson, A.H., Traub-Dargatz, J.L., Rodeheaver, R.M., Ostlund, E.N., Pedersen, D.D., Moorhead, R.G., Stricklin, J.B., Dewell, R.D., Roach, S.D., Long, R.E., Albers, S.J., Callan, R.J. and Salman, M.D. (2005) Immunologic Responses to West Nile Virus in Vaccinated and Clinically Affected Horses. Journal of the American Veterinary Medical Association, 226, 240-245.
[17] Garver, K.A., LaPatra, S.E. and Kurath, G. (2005) Efficacy of an Infectious Hematopoietic Necrosis (IHN) Virus DNA Vaccine in Chinook Oncorhynchus tshawytscha and Sockeye O. nerka Salmon. Diseases of Aquatic Organisms, 64, 13-22.
[18] Bergman, P.J., Camps-Palaua, M.A., McKnighta, J.A., Leibmana, N.F., Crafta, D.M., Leunga, C., Liaoa, J., Riviereb, I., Sadelainb, M., Hohenhausa, A.E., Gregorb, P., Houghtonb, A.N., Peralesb, M.A. and Wolchokb, J.D. (2006) Development of a Xenogeneic DNA Vaccine Program for Canine Malignant Melanoma at the Animal Medical Center. Vaccine, 24, 4582-4585.
[19] Khan, A.S., Bodles-Brakhop, A.M., Fiorotto, M.L. and Draghia-Akli, R. (2010) Effects of Maternal Plasmid GHRH Treatment on Offspring Growth. Vaccine, 28, 1905-1910.
[20] Khan, A.S., Draghia-Akli, R., Shypailo, R.J., Ellis, K.I., Mersmann, H. and Fiorotto, M.L. (2010) A Comparison of the Growth Responses Following Intramuscular GHRH Plasmid Administration versus Daily Growth Hormone Injections in Young Pigs. Molecular Therapy, 18, 327-333.
[21] Liu, M.A. (2010) DNA Vaccines: An Historical Perspective and View to the Future. Immunological Reviews, 239, 62-84.
[22] Glenting, J. and Wessels S. (2005) Ensuring Safety of DNA Vaccines. Microbial Cell Factories, 4, 26.
[23] Williams, J.A., Carnes, A.E. and Hodgson, C.P. (2009) Plasmid DNA Vaccine Vector Design: Impact on Efficacy, Safety and Upstream Production. Biotechnology Advances, 27, 353-370.
[24] Kowalczyk, D.W. and Ertl, H.C. (1999) Immune Responses to DNA Vaccines. Cellular and Molecular Life Sciences, 55, 751-770.
[25] Garmory, H.S., Leckenby, M.W., Griffin, K.F., Elvin, S.J., Taylor, R.R., Hartley, M.G., Hanak, J.A., Williamson, E.D. and Cranenburgh, R.M. (2005) Antibiotic-Free Plasmid Stabilization by Operator-Repressor Titration for Vaccine Delivery by Using Live Salmonella enteric Serovar Typhimurium. Infection and Immunity, 73, 11.
[26] Mairhofer, J., Pfaffenzeller, I., Merz, D. and Grabherr, R. (2007) A Novel Antibiotic Free Plasmid Selection System: Advances in Safe and Efficient DNA Therapy. Biotechnology Journal, 3, 83-89.
[27] Becker, P.D., Noerder, M. and Guzmán, C.A. (2008) Genetic Immunization: Bacteria as DNA Vaccine Delivery Vehicle. Human Vaccines, 4, 189-202.
[28] Papadakis, E.D., Nicklin, S.A., Baker, A.H. and White, S.J. (2004) Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy. Current Gene Therapy, 4, 89-113.
[29] Vanniasinkam, T., Reddy, S.T. and Ertl, H.C. (2006) DNA Immunization Using a Non-Viral Promoter. Virology, 344, 412-420.
[30] Shan, S., Jiang, Y., Bu, Z., Ellis, T., Zeng, X., Edwards, J., Tian, G., Li, Y., Ge, J., Chen, H. and Fenwick, S. (2011) Strategies for Improving the Efficacy of a H6 Subtype Avian Influenza DNA Vaccine in Chickens. Journal of Virological Methods, 173, 220-226.
[31] Xu, Z.L., Mizuguchi, H., Ishii-Watabe, A., Uchida, E., Mayumi, T. and Hayakawa, T. (2002) Strength Evaluation of Transcriptional Regulatory Elements for Transgene Expression by Adenovirus Vector. Journal of Controlled Release, 81, 155-163.
[32] Li, S., MacLaughlin, F.C., Fewell, J.G., Gondo, M., Wang, J., Nicol, F., Dean, D.A. and Smith, L.C. (2001) Muscle-Specific Enhancement of Gene Expression by Incorporation of SV40 Enhancer in the Expression Plasmid. Gene Therapy, 8, 494-497.
[33] Shedlock, D.J. and Weiner, D.B. (2000) DNA Vaccination: Antigen Presentation and the Induction of Immunity. Journal of Leukocyte Biology, 68, 793-806.
[34] Capone, S., Zampaglione, I., Vitelli, A., Pezzanera, M., Kierstead, L., Burns, J., Ruggeri, L., Arcuri, M., Cappelletti, M., Meola, A., Ercole, B.B., Tafi, R., Santini, C., Luzzago, A., Fu, T.M., Colloca, S., Ciliberto, G., Cortese, R., Nicosia, A., Fattori, E. and Folgori, A. (2006) Modulation of the Immune Response Induced by Gene Electrotransfer of a Hepatitis C Virus DNA Vaccine in Nonhuman Primates. The Journal of Immunology, 177, 7462-7471.
[35] Fioretti, D., Iurescia, S., Fazio, V.M. and Rinaldi, M. (2010) DNA Vaccines: Developing New Strategies against Cancer. Journal of Biomedicine and Biotechnology, 2010, Article ID: 174378.
[36] Manam, S., Ledwith, B.J., Barnum, A.B., Troilo, P.J., Pauley, C.J., Harper, L.B., Griffiths, T.G., Niu, Z., Denisova, L., Follmer, T.T., Pacchione, S.J., Wang, Z., Beare, C.M., Bagdon, W.J. and Nichols, W.W. (2000) Plasmid DNA Vaccines: Tissue Distribution and Effects of DNA Sequence, Adjuvants and Delivery Method on Integration into Host DNA. Intervirology, 43, 273-281.
[37] Ledwith, B.J., Manam, S., Troilo, P.J., Barnum, A.B., Pauley, C.J., Griffiths, T.G., Harper, L.B., Beare, C.M., Bagdon, W.J. and Nichols, W.W. (2000) Plasmid DNA Vaccines: Investigation of Integration into Host Cellular DNA Following Intramuscular Injection in Mice. Intervirology, 43, 258-272.
[38] Pal, R., Yu, Q., Wang, S., Kalyanaraman, V.S., Nair, B.C., Hudacik, L., Whitney, S., Keen, T., Hung, C.L., Hocker, L., Kennedy, J.S., Markham, P. and Lu, S. (2006) Definitive Toxicology and Biodistribution Study of a Polyvalent DNA Prime/Protein Boost Human Immunodeficiency Virus Type 1 (HIV-1) Vaccine in Rabbits. Vaccine, 24, 1225-1234.
[39] Sheets, R.L. , Stein, J., Manetz, T.S., Duffy, C., Nason, M., Andrews, C., Kong, W.P., Nabel, G.J. and Gomez, P.L. (2006) Biodistribution of DNA Plasmid Vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile Virus Is Similar, without Integration, Despite Differing Plasmid Backbones or Gene Inserts. Toxicological Sciences, 91, 610-619.
[40] Bagarazzi, M.L., Boyer, J.D., Javadian, M.A., Chattergoon, M., Dang, K., Kim, G., Shah, J., Wang, B. and Weiner, D.B. (1997) Safety and Immunogenicity of Intramuscular and Intravaginal Delivery of HIV-1 DNA Constructs to Infant Chimpanzees. Journal of Medical Primatology, 26, 27-33.
[41] MacGregor, R.R., Boyer, J.D., Ugen, K.E., Lacy, K.E.,Gluckman, S.J., Bagarazzi, M.L., Chattergoon, M.A., Baine, Y., Higgins, T.J., Ciccarelli, R.B., Coney, L.R., Ginsberg, R.S. and Weiner, D.B. (1998) First Human Trial of a DNA-Based Vaccine for Treatment of Human Immunodeficiency Virus Type 1 Infection: Safety and Host Response. The Journal of Infectious Diseases, 178, 92-100.
[42] Le, T.P., Coonan, K.M., Hedstrom, R.C., Charoenvit, Y., Sedegah, M., Epstein, J.E., Kumar, S., Wang, R., Doolan, D. L., Maguire, J.D., Parker, S.E., Hobart, P., Norman, J. and Hoffman, S.L. (2000) Safety, Tolerability and Humoral Immune Responses after Intramuscular Administration of a Malaria DNA Vaccine to Healthy Adult Volunteers. Vaccine, 18, 1893-1901.
[43] Vaughan, E.E. and Dean, D.A. (2006) Intracellular Trafficking of Plasmids during Transfection Is Mediated by Microtubules. Molecular Therapy, 13, 422-428.
[44] Payette, P.J., Weeratna, R.D., McCluskie, M.J. and Davis, H.L. (2001) Immune-Mediated Destruction of Transfected Myocytes Following DNA Vaccination Occurs via Multiple Mechanisms. Gene Therapy, 8, 1395-1400.
[45] You, Z., Huang, X., Hester, J., Toh, H.C. and Chen, S.Y. (2001) Targeting Dendritic Cells to Enhance DNA Vaccine Potency. Cancer Research, 61, 3704-3711.
[46] Doria-Rose, N.A. and Haigwood, N.L. (2003) DNA Vaccine Strategies: Candidates for Immune Modulation and Immunization Regimens. Methods, 31, 207-216.
[47] Cherif, M.S., Shuaibu, M.N., Kurosaki, T., Helegbe, G.K., Kikuchi, M., Yanagi, T., Tsuboi, T., Sasaki, H. and Hirayama, K. (2011) Immunogenicity of Novel Nanoparticle-Coated MSP-1 C-Terminus Malaria DNA Vaccine Using Different Routes of Administration. Vaccine, 29, 9038-9050.
[48] Holmgren, J. and Czerkinsky, C. (2005) Mucosal Immunity and Vaccines. Nature Medicine, 11, S45-S53.
[49] Kanazawa, T., Takashima, Y., Hirayama, S. and Okada, H. (2008) Effects of Menstrual Cycle on Gene Transfection through Mouse Vagina for DNA Vaccine. International Journal of Pharmaceutics, 360, 164-170.
[50] Brave, A., Hallengard, D., Schroder, U., Blomberg, P., Wahren, B. and Hinkula, J. (2008) Intranasal Immunization of Young Mice with a Multigene HIV-1 Vaccine in Combination with the N3 Adjuvant Induces Mucosal and Systemic Immune Responses. Vaccine, 26, 5075-5078.
[51] Chatel, J.M., Pothelune, L., Ah-Leung, S., Corthier, G., Wal, J.M. and Langella, P. (2008) In Vivo Transfer of Plasmid from Food-Grade Transiting Lactococci to Murine Epithelial Cells. Gene Therapy, 15, 1184-1190.
[52] Heystek, H.C., Moulon, C., Woltman, A.M., Garonne, P. and van Kooten, C. (2002) Human Immature Dendritic Cells Efficiently Bind and Take Up Secretory IgA without the Induction of Maturation. The Journal of Immunology, 168, 102-107.
[53] Lavelle, E.C. and O’Hagan, D.T. (2006) Delivery Systems and Adjuvants for Oral Vaccines. Expert Opinion on Drug Delivery, 3, 747-762.
[54] Neutra, M.R. and Kozlowski, P.A. (2006) Mucosal Vaccines: The Promise and the Challenge. Nature Reviews Immunology, 6, 148-158.
[55] Wells, J. (2011) Mucosal Vaccination and Therapy with Genetically Modified Lactic Acid Bacteria. Annual Review of Food Science and Technology, 2, 423-445.
[56] Brandtzaeg, P., Kiyono, H., Pabst, R. and Russell, M.W. (2008) Terminology: Nomenclature of Mucosa-Associated Lymphoid Tissue. Mucosal Immunology, 1, 31-37.
[57] Kaiserlian, D. and Etchart, N. (1999) Entry Sites for Oral Vaccines and Drugs: A Role for M Cells, Enterocytes and Dendritic Cells? Seminars in Immunology, 11, 217-224.
[58] Shalaby, W.S. (1995) Development of Oral Vaccines to Stimulate Mucosal and Systemic Immunity: Barriers and Novel Strategies. Clinical Immunology and Immunopathology, 74, 127-134.
[59] Brandtzaeg, P., Farstad, I.N., Haraldsen, G. and Jahnsen, F.L. (1998) Cellular and Molecular Mechanisms for Induction of Mucosal Immunity. Developments in Biological Standardization, 92, 93-108.
[60] Chadwick, S., Kriegel, C. and Amiji, M. (2009) Delivery Strategies to Enhance Mucosal Vaccination. Expert Opinion on Biological Therapy, 9, 427-440.
[61] Calarota, S.A. and Weiner, D.B. (2004) Enhancement of Human Immunodeficiency Virus Type 1-DNA Vaccine Potency through Incorporation of T-Helper 1 Molecular Adjuvants. Immunological Reviews, 199, 84-99.
[62] Kim, M.S. and Sin, J.I. (2005) Both Antigen Optimization and Lysosomal Targeting Are Required for Enhanced Anti-Tumour Protective Immunity in a Human Papillomavirus E7-Expressing Animal Tumour Model. Immunology, 116, 255-266.
[63] Li, K.B., Zhang, X.G., Ma, J., Jia, X.J., Wang, M., Dong, J., Zhang, X.M., Xu, H. and Shu, Y.L. (2008) Codon Optimization of the H5N1 Influenza Virus HA Gene Gets High Expression in Mammalian Cells. Chinese Journal of Virology, 24, 101-105.
[64] Uchijima, M., Yoshida, A., Nagata, T. and Koide, Y. (1998) Class I-Restricted T Cell Responses against Vaccine Is Required for the Effective MHC Optimization of Codon Usage of Plasmid DNA an Intracellular Bacterium. The Journal of Immunology, 161, 5594-5599.
[65] Pulsawat, P., Piboonpocanun, S., Sirivichayakul, S., Buranapraditkun, S., Jacquet, A., Shimada, M., Okuda, K. and Ruxrungtham, K.J. (2010) Production and Immunogenicity of Hypoallergenic Codon-Optimized DNA Vaccine encoding Mature Der p 1 Allergen. Journal of Investigational Allergology and Clinical Immunology, 20, 582-590.
[66] Besse, F. and Ephrussi, A. (2008) Translational Control of Localized mRNAs: Restricting Protein Synthesis in Space and Time. Nature Reviews Molecular Cell Biology, 9, 971-980.
[67] Kumagai, Y., Takeuchi, O. and Akira, S. (2008) TLR9 as a Key Receptor for the Recognition of DNA. Advanced Drug Delivery Reviews, 60, 795-804.
[68] Angel, J.B., Cooper, C.L., Clinch, J., Young, C.D., Chenier, A., Parato, K.G., Lautru, M., Davis, H. and Cameron, D.W. (2008) CpG Increases Vaccine Antigen-Specific Cell-Mediated Immunity When Administered with Hepatitis B vaccine In HIV Infection. Journal of Immune Based Therapies and Vaccines, 6, 4.
[69] Xu, Z.L., Mizuguchi, H., Ishii-Watabe, A., Uchida, E., Mayumi, T. and Hayakawa, T. (2001) Optimization of Transcriptional Regulatory Elements for Constructing Plasmid Vectors. Gene, 272, 149-156.
[70] Chong, S.Y., Egan, M.A., Kutzler, M.A., Megati, S., Masood, A., Roopchard, V., Garcia-Hand, D., Montefiori, D.C., Quiroz, J., Rosati, M., Schadeck, E.B., Boyer, J.D., Pavlakis, G.N., Weiner, D.B., Sidhu, M., Eldridge, J.H. and Israel, Z.R. (2007) Comparative Ability of Plasmid IL-12 and IL-15 to Enhance Cellular and Humoral Immune Responses Elicited by a SIVgag Plasmid DNA Vaccine and Alter Disease Progression Following SHIV(89.6P) Challenge in Rhesus Macaques. Vaccine, 25, 4967-4982.
[71] Wang, Q.M., Sun, S.H., Hu, Z.L., Yin, M., Xiao, C.J. and Zhang, J.C. (2004) Improved Immunogenicity of a Tuberculosis DNA Vaccine Encoding ESAT6 by DNA Priming and Protein Boosting. Vaccine, 22, 3622-3627.
[72] Reyes-Sandoval, A. and Ertl, H.C. (2001) DNA Vaccines. Current Molecular Medicine, 1, 217-243.
[73] Dale, C.J., Thomson, S., De Rose, R., Ranasinghe, C., Medveczky, C.J., Pamungkas, J., Boyle, D.B., Ramshaw, I.A. and Kent, S.J. (2006) Prime-Boost Strategies in DNA Vaccines. Methods in Molecular Medicine, 127, 171-197.
[74] Kent, S., De Rose, R. and Rollman, E. (2007) Drug Evaluation: DNA/MVA Prime-Boost HIV Vaccine. Current Opinion in Investigational Drugs, 8, 159-167.
[75] Patterson, L.J. and Robert-Guroff, M. (2008) Replicating Adenovirus Vector Prime/Protein Boost Strategies for HIV Vaccine Development. Expert Opinion on Biological Therapy, 8, 1347-1363.
[76] Pan, Z., Zhang, X., Geng, S., Cheng, N., Sun, L., Liu, B., Huang, J. and Jiao, X. (2009) Priming with a DNA Vaccine Delivered by Attenuated Salmonella typhimurium and Boosting with a Killed Vaccine Confers Protection of Chickens against Infection with the H9 Subtype of Avian Influenza Virus. Vaccine, 27, 1018-1023.
[77] Fan, X., Gao, Q. and Fu, R. (2007) DNA Vaccine Encoding ESAT-6 Enhances the Protective Efficacy of BCG against Mycobacterium tuberculosis Infection in Mice. Scandinavian Journal of Immunology, 66, 523-528.
[78] Lu, J., Wang, C., Zhou, Z., Ying Zhang, Cao, T., Shi, C., Chen, Z., Chen, L., Cai, C. and Fan, X. (2011) Immunogenicity and Protective Efficacy against Murine Tuberculosis of a Prime-Boost Regimen with BCG and a DNA Vaccine Expressing ESAT-6 and Ag85A Fusion Protein. Clinical and Developmental Immunology, 2011, Article ID: 617892.
[79] Moore, A.C. and Hill, A.V. (2004) Progress in DNA-Based Heterologous Prime-Boost Immunization Strategies for Malaria. Immunological Reviews, 199, 126-143.
[80] Dean, D.A. (1997) Import of Plasmid DNA into the Nucleus Is Sequence Specific. Experimental Cell Research, 230, 293-302.
[81] Dean, D.A., Dean, B.S., Muller, S. and Smith, L.C. (1999) Sequence Requirements for Plasmid Nuclear Import. Experimental Cell Research, 253, 713-722.
[82] Vacik, J., Dean, B.S., Zimmer, W.E. and Dean, D.A. (1999) Cell-Specific Nuclear Import of Plasmid DNA. Gene Therapy, 6, 1006-1014.
[83] Young, J.L., Benoir, J.N. and Dean, D.A. (2003) Effect of a DNA Nuclear Targeting Sequence on Gene Transfer and Expression of Plasmids in the Intact Vasculature. Gene Therapy, 10, 1465-1470.
[84] Young, J.L., Zimmer, W.E. and Dean, D.A. (2008) Smooth Muscle-Specific Gene Delivery in the Vasculature Based on Restriction of DNA Nuclear Import. Experimental Biology and Medicine, 233, 840-848.
[85] Mesika, A., Grigoreva, I., Zohar, M. and Reich, Z. (2001) A Regulated, NFkappaB-Assisted Import of Plasmid DNA into Mammalian cell Nuclei. Molecular Therapy, 3, 653-657.
[86] Langle-Rouault, F., Patzel, V., Benavente, A., Taillez, M., Silvestre, N., Bompard, A., Sczakiel, G., Jacobs, E. and Rittner, K. (1998) Up to 100-Fold Increase of Apparent Gene Expression in the Presence of Epstein-Barr Virus oriP Sequences and EBNA1: Implications of the Nuclear Import of Plasmids. Journal of Virology, 72, 6181-6185.
[87] Vaysse, L., Harbottle, R., Bigger, B., Bergau, A., Tolmachov, O. and Coutelle, C. (2004) Development of a Self-As- sembling Nuclear Targeting Vector System Based on the Tetracycline Repressor Protein. The Journal of Biological Chemistry, 279, 5555-5564.
[88] Pichon, C., Billiet, L. and Midoux, P. (2010) Chemical Vectors for Gene Delivery: Uptake and Intracellular Trafficking. Current Opinion in Biotechnology, 21, 640-645.
[89] Thomas, C.E., Ehrhardt, A. and Kay, M.A. (2003) Progress and Problems with the Use of Viral Vectors for Gene Therapy. Nature Reviews Genetics, 4, 346-358.
[90] Naldini, L., Bl?mer, U., Gage, F.H., Trono, D. and Verma, I.M. (1996) Efficient Transfer, Integration, and Sustained Long-Term Expression of the Transgene in Adult Rat Brains Injected with a Lentiviral Vector. Proceedings of the National Academy of Sciences of the United States of America, 93, 11382-11388.
[91] Verma, I.M. and Weitzman, M.D. (2005) Gene Therapy: Twenty-First Century Medicine. Annual Review of Biochemistry, 74, 711-738.
[92] Casimiro, D.R., Chen, L., Fu, T.M., Evans, R.K., Caulfield, M.J., Davies, M.E., Tang, A., Chen, M., Huang, L., Harris, V., Freed, D.C., Wilson, K.A., Dubey, S., Zhu, D.M., Nawrocki, D., Mach, H., Troutman, R., Isopi, L., Williams, D., Hurni, W., Xu, Z., Smith, J.G., Wang, S., Liu, X., Guan, L., Long, R., Trigona, W., Heidecker, G.J., Perry, H.C., Persaud, N., Toner, T.J., Su, Q., Liang, X., Youil, R., Chastain, M., Bett, A.J., Volkin, D.B., Emini, E.A. and Shiver, J.W. (2003) Comparative Immunogenicity in Rhesus Monkeys of DNA Plasmid, Recombinant Vaccinia Virus, and Replication-Defective Adenovirus Vectors Expressing a Human Immunodeficiency Virus Type 1 Gag Gene. Journal of Virology, 77, 6305-6313.
[93] Catanzaro, A.T., Koup, R.A., Roederer, M., Bailer, R.T., Enama, M.E., Moodie, Z., Gu, L., Martin, J.E., Novik, L., Chakrabarti, B.K., Butman, B.T., Gall, J.G., King, C.R., Andrews, C.A., Sheets, R., Gomez, P.L., Mascola, J.R., Nabel, G.J. and Graham, B.S. (2006) Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV-1 Candidate Vaccine Delivered by a Replication-Defective Recombinant Adenovirus Vector. The Journal of Infectious Diseases, 194, 1638-1649.
[94] Lee, H.J., Park, N., Cho, H.J., Yoon, J.K., Van, N.D., Oh, Y.K. and Kim, Y.B. (2009) Development of a Novel Viral DNA Vaccine against Human Papillomavirus: AcHERV-HP16L1. Vaccine, 28, 1613-1619.
[95] Van DrunenLittel-van den Hurk, S., Gerdts, V., Loehr, B.I., Pontarollo, R., Rankin, R., Uwiera, R. and Babiuk, L.A. (2000) Recent Advances in the Use of DNA Vaccines for the Treatment of Diseases of Farmed Animals. Advanced Drug Delivery Reviews, 43, 13-28.
[96] Babuik, L.A., Pontarollo, R., Babiuk, S., Loehr, B. and Van Drunen Little-van den Hurk, S. (2003) Induction of Immune Responses by DNA Vaccines in Large Animals. Vaccine, 21, 649-658.
[97] Palumbo, R.N., Zhong, X., Panus, D., Han, W., Ji, W. and Wang, C. (2012) Transgene Expression and Local Tissue Distribution of Naked and Polymer-Condensed Plasmid DNA after Intradermal Administration in Mice. Journal of Controlled Release, 159, 232-239.
[98] Lodmell, D.L., Ray, N.B. and Ewalt, L.C. (1998) Gene Gun Particle Mediated Vaccination with Plasmid DNA Confers Protective Immunity against Rabies Virus Infection. Vaccine, 16, 115-118.
[99] Yoshida, A., Nagata, T., Uchijima, M., Higashi, T. and Koide, Y. (2000) Advantage of Gene Gun-Mediated over Intramuscular Inoculation of Plasmid DNA Vaccine in Reproducible Induction of Specific Immune Responses. Vaccine, 18, 1725-1729.
[100] Fuller, D.H., Loudon, P. and Schmaljohn, C. (2006) Preclinical and Clinical Progress of Particle-Mediated DNA Vaccines for Infectious Diseases. Methods, 40, 86-97.
[101] Tacket, C.O., Roy, M.J., Widera, G., Swain, W.F., Broome, S. and Edelman, R. (1999) Phase 1 Safety and Immune Response Studies of a DNA Vaccine Encoding Hepatitis B Surface Antigen Delivered by a Gene Delivery Device. Vaccine, 17, 2826-2829.
[102] Dileo, J., Miller, J.R., Chesnoy, S. and Huang, L. (2003) Gene Transfer to Subdermal Tissues via a New Gene Gun Design. Human Gene Therapy, 14, 79-87.
[103] Trimble. C., Lin, C.T., Hung, C.F., Pai, S., Juang, J., He, L., Gillison, M., Pardoll, D., Wu, L. and Wu, T.C. (2003) Comparison of the CD8+ T Cell Responses and Antitumor Effects Generated by DNA Vaccine Administered through Gene Gun, Biojector, and Syringe. Vaccine, 21, 4036-4042.
[104] Parham, J., Iannone, M., Overton, L. and Hutchins, J. (1998) Optimization of Transient Gene Expression in Mammalian Cells and Potential for Scale-Up Using Flow Lectroporation. Cytotechnology, 28, 147-155.
[105] Kima, J., Choa, K., Shin, Y., Jung, N., Chunga, C. and Changa, J. (2007) A Multi-Channel Electroporation Microchip for Gene Transfection in Mammalian Cells. Biosensors and Bioelectronics, 22, 3273-3277.
[106] Canatella, P.J., Karr, J.F., Petros, J.A. and Prausnitz, M.R. (2001) Quantitative Study of Electroporation Mediated Molecular Uptake and Cell Viability. Biophysical Journal, 80, 755-764.
[107] Gursel, I., Gursel, M., Ishii, K.J. and Klinman, D.M. (2001) Sterically Stabilized Cationic Liposomes Improve the Uptake and Immunostimulatory Activity of CpG Oligonucleotides. The Journal of Immunology, 167, 3324e8.
[108] Godbey, W.T., Wu, K.K. and Mikos, A.G. (1999) Tracking the Intracellular Path of Poly(Ethylenimine)/DNA Complexes for Gene Delivery. Proceedings of the National Academy of Sciences of the United States of America, 96, 5177-5181.
[109] Vuorimaa, E., Urtti, A., Seppanen, R., Lemmetyinen, H. and Yliperttula, M. (2008) Time-Resolved Fluorescence Spectroscopy Reveals Functional Differences of Cationic Polymer DNA Complexes. Journal of the American Chemical Society, 130, 11695-11700.
[110] Kircheis, R., Wightman, L. and Wagner, E. (2001) Design and Gene Delivery Activity of Modified Polyethylenimines. Advanced Drug Delivery Reviews, 53, 341-358.
[111] Ai, H., Jones, S.A., de Villiers, M.M. and Lvov, Y.M. (2003) Nano-Encapsulation of Furosemide Microcrystals for Controlled Drug Release. Journal of Controlled Release, 86, 59-68.
[112] Garzon, M.R., Berraondo, P., Crettaz, J., Ochoa, L., Vera, M., Lasarte, J.J., Vales, A., Van Rooijen, N., Ruiz, J., Prieto, J., Zulueta, J. and González-Aseguinolaza, G. (2005) Induction of gp120-Specific Protective Immune Responses by Genetic Vaccination with Linear Polyethylenimine-Plasmid Complex. Vaccine, 23, 1384-1392.
[113] Kasturi, S.P., Sachaphibulkij, K. and Roy, K. (2005) Covalent Conjugation of Polyethyleneimine on Biodegradable Microparticles for Delivery of Plasmid DNA Vaccines. Biomaterials, 26, 6375-6385.
[114] Orson, F.M., Kinsey, B.M., Densmore, C.L., Nguyen, T., Wu, Y., Mbawuike, I.N. and Wyde, P.R. (2006) Protection against Influenza Infection by Cytokine-Enhanced Aerosol Genetic Immunization. The Journal of Gene Medicine, 8, 488-497.
[115] de Azevedo, M., Karczewski, J., Lefévre, F., Azevedo, V., Miyoshi, A., Wells, J.M., Langella, P. and Chatel, J.M. (2012) In Vitro and in Vivo Characterization of DNA Delivery Using Recombinant Lactococcus lactis Expressing a Mutated Form of L. monocytogenes Internalin A. BMC Microbiology, 12, 299.
[116] Schaffner, W. (1980) Direct Transfer of Cloned Genes from Bacteria to Mammalian Cells. Proceedings of the National Academy of Sciences of the United States of America, 77, 2163-2167.
[117] Grillot-Courvalin, C., Goussard, S. and Courvalin, P. (1999) Bacteria as Gene Delivery Vectors for Mammalian Cells. Current Opinion in Biotechnology, 10, 477-481.
[118] Schoen, C., Stritzker, J., Goebel, W. and Pilgrim, S. (2004) Bacteria as DNA Vaccine Carriers for Genetic Immunization. International Journal of Medical Microbiology, 294, 319-335.
[119] Hoebe, K., Janssen, E. and Beutler, B. (2004) The Interface between Innate and Adaptive Immunity. Nature Immunology, 5, 971-974.
[120] Pilgrim, S., Stritzker, J., Schoen, C., Kolb-Mäurer, A., Geginat, G., Loessner, M.J., Gentschev, I. and Goebel, W. (2003) Bactofection of Mammalian Cells by Listeria monocytogenes: Improvement and Mechanism of DNA Delivery. Gene Therapy, 10, 2036-2045.
[121] Fennelly, G.J., Khan, S.A., Abadi, M.A., Wild, T.F. and Bloom, B.R. (1999) Mucosal DNA Vaccine Immunization against Measles with a Highly Attenuated Shigella Flexneri Vector. The Journal of Immunology, 162, 1603-1610.
[122] Shata, M.T. and Hone, D.M. (2001) Vaccination with a Shigella DNA Vaccine Vector Induces Antigen-Specific CD8+ T Cells and Antiviral Protective Immunity. Journal of Virology, 75, 9665-9670.
[123] Woo, P.C.Y., Wong, L., Zheng, B. and Yuen, K. (2001) Unique Immunogenicity of Hepatitis B Virus DNA Vaccine Presented by Live-Attenuated Salmonella typhimurium. Vaccine, 19, 2945-2954.
[124] Zheng, B., Woo, P.C.Y., Ng, M., Tsoi, H., Wong, L. and Yuen, K. (2001) A Crucial Role of Macrophages in the Immune Responses to oral DNA Vaccination against Hepatitis B Virus in a Murine Model. Vaccine, 20, 140-147.
[125] Miki, K., Nagata, T., Tanaka, T., Kim, Y.H., Uchijima, M., Ohara, N., Nakamura, S., Okada, M. and Koide, Y. (2004) Induction of Protective Cellular Immunity against Mycobacterium tuberculosis by Recombinant Attenuated Self-Destructing Listeria monocytogenes Strains Harboring Eukaryotic Expression Plasmids for Antigen 85 Complex and MPB/MPT51. Infection and Immunity, 72, 2014-2021.
[126] Dunham, S.P. (2002) The Application of Nucleic Acid Vaccines in Veterinary Medicine. Research in Veterinary Science, 73, 9-16.
[127] Pontes, D.S., de Azevedo, M.S.P., Chatel, J.M., Langella, P., Azevedo, V. and Miyoshi, A. (2011) Lactococcus lactis as a Live Vector: Heterologous Protein Production and DNA Delivery Systems. Protein Expression and Purification, 79, 165-175.
[128] Wells, J.M. and Mercenier, A. (2008) Mucosal Delivery of Therapeutic and Prophylactic Molecules Using Lactic Acid Bacteria. Nature, 1038, 1-14.
[129] Guimarães, V.D., Innocentin, S., Lefèvre, F., Azevedo, V., Wal, J.M., Langella, P. and Chatel, J.M. (2006) Use of Native Lactococci as Vehicles for Delivery of DNA into Mammalian Epithelial Cells. Applied and Environmental Microbiology, 72, 7091-7097.
[130] Gram, G. J., Fomsgaard, A., Thorn, M., Madsen, S.M. and Glenting, J. (2007) Immunological Analysis of a Lactococcus lactis-Based DNA Vaccine Expressing HIV gp120. Genetic Vaccines and Therapy, 5, 3.
[131] Tao, L., Pavlova, S.I., Ji, X., Jin, L. and Spear, G. (2011) A Novel Plasmid for Delivering Genes into Mammalian Cells with Noninvasive Food and Commensal Lactic Acid Bacteria. Plasmid, 65, 8-14.
[132] Pontes, D., Innocentin, S., Del Carmen, S., Almeida, J.F., Leblanc, J.G., de Moreno de Leblanc, A., Blugeon, S., Cherbuy, C., Lefèvre, F., Azevedo, V., Miyoshi, A., Langella, P. and Chatel, J.M. (2012) Production of Fibronectin Binding Protein A at the Surface of Lactococcus lactis Increases Plasmid Transfer in Vitro and in Vivo. PLoS ONE, 7, e44892.
[133] Gaillard, J.L., Berchem P., Frehel, C., Gouln, E. and Cossart, P. (1991) Entry of Listeria monocytogenes into Cells Is Mediated by Internalin, a Repeat Protein Reminiscent of Surface Antigens from GRAM-Positive Cocci. Cell, 65, 1127-1141.
[134] Mengaud, J., Ohayon, H., Gounon, P., Mège, R.M. and Cossart, P. (1996) E-Cadherin Is the Receptor for Internalin, a Surface Protein Required for Entry of L. monocytogenes into Epithelial Cells. Cell, 84, 923-932.
[135] Guimarães, V.D., Gabriel, J.E., Lefèvre, F., Cabanes, D., Gruss, A., Cossart, P., Azevedo, V. and Langella, P. (2005) Internalin-Expressing Lactococcus lactis Is Able to Invade Small Intestine of Guinea Pigs and Deliver DNA into Mammalian Epithelial Cells. Microbes and Infection, 7, 836-844.
[136] Innocentin, S., Guimarães, V., Miyoshi, A., Azevedo, V., Langella, P., Chatel., J.M. and Lefèvre, F. (2009) Lactococcus lactis Expressing Either Staphylococcus aureus Fibronectin-Binding Protein A or Listeria monocytogenes Internalin A Can Efficiently Internalize and Deliver DNA in Human Epithelial Cells. Applied and Environmental Microbiology, 75, 4870-4878.
[137] Que, Y.A., Francois, P., Haefliger, J.A., Entenza, J.M., Vaudaux, P. and Moreillon, P. (2001) Reassessing the Role of Staphylococcus aureus Clumping Factor and Fibronectin-Binding Protein by Expression in Lactococcus lactis. Infection and Immunity, 69, 6296-6302.
[138] Davis, B.S., Chang, G.J., Cropp, B., Roehrig, J.T., Martin, D.A., Mitchell, C.J., Bowen, R. and Bunning, M.L. (2001) West Nile Virus Recombinant DNA Vaccine Protects Mouse and Horse from Virus Challenge and Expresses in Vitro a Noninfectious Recombinant Antigen That Can Be Used in Enzyme-Linked Immunosorbent Assays. Journal of Virology, 75, 4040-4047.
[139] Davidson, A.H., Traub-Dargatz, J.L., Rodeheaver, R.M., Ostlund, E.N., Pedersen, D.D., Moorhead, R.G., Stricklin, J.B., Dewell, R.D., Roach, S.D., Long, R.E., Albers, S.J., Callan, R.J. and Salman, M.D. (2005) Immunologic Responses to West Nile Virus in Vaccinated and Clinically Affected Horses. Journal of the American Veterinary Medical Association, 226, 240-245.
[140] Bergman, P.J., McKnight, J., Novosad, A., Charney, S., Farrelly, J., Craft, D., Wulderk, M., Jeffers, Y., Sadelain, M., Hohenhaus, A.E., Segal, N., Gregor, P., Engelhorn, M., Riviere, I., Houghton, A.N. and Wolchok, J.D. (2003) Long-Term Survival of Dogs with Advanced Malignant Melanoma after DNA Vaccination with Xenogeneic Human Tyrosinase: A Phase I Trial. Clinical Cancer Research, 9, 1284-1290.
[141] Liao, J.C., Gregor, P., Wolchok, J.D., Orlandi, F., Craft, D., Leung, C., Houghton, A.N. and Bergman, P.J. (2006) Vaccination with Human Tyrosinase DNA Induces Antibody Responses in Dogs with Advanced Melanoma. Cancer Immunity, 6, 8.
[142] Kalams, S.A., Parker, S., Jin, X., Elizaga, M., Metch, B., Wang, M., Hural, J., Lubeck, M., Eldridge, J., Cardinali, M., Blattner, W.A., Sobieszczyk, M., Suriyanon, V., Kalichman, A., Weiner, D.B. and Baden, L.R. (2012) Safety and Immunogenicity of an HIV-1 Gag DNA Vaccine with or without IL-12 and/or IL-15 Plasmid Cytokine Adjuvant in Healthy, HIV-1 Uninfected Adults. PLoS ONE, 7, e29231.
[143] Pereira, V.B., Zurita-Turk, M., Saraiva, T.D.L., Prósperi, C.D.C., Souza, B.M., Mancha-Agreti, P., Lima, F.A., Pfeiffer, V.N., Azevedo, M.S.P., Rocha, C.S., Pontes, D.S., Azevedo, V. and Miyoshi, A. (2013) DNA Vaccines Approach: From Concepts to Applications. Microbial Pathogens and Strategies for Combating Them: Science, Technology and Education. Microbial Book Series, 2013 Edition.
[144] Kutzler, M. and Weiner, D.B. (2008) DNA Vaccines: Ready for Prime Time? Nature, 9, 776-788.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.