Abstract
We describe a DNA vaccine strategy that allows antigens to be produced in vivo in the context of an alphaviral replicon. Mice immunized with such vectors developed humoral and cellular immune responses at higher levels than mice that received a conventional DNA vaccine vector. Immunized animals acquired protective immunity to lethal influenza challenge. Compared with traditional DNA vaccine strategies in which vectors are persistent and the expression constitutive, the expression mediated by the alphaviral vector was transient and lytic. As a result, biosafety risks such as chromosomal integration, and the induction of immunological tolerance, could be circumvented.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Donnelly, J.J., Ulmer, J.B., Shiver, J.W., and 1997 DNA vaccines. Annu. Rev. Immunol. 15: 17–648.
Robinson, H.L., Lu, S., Feltquate, D.M., Torres, C.T., Richmond, J., Boyle, C.M. et al. 1996. DNA vaccines. AIDS Res. Hum. Retroviruses 12: 455–457.
Tang, D.C., De Vrt, M. and Johnston, S.A. 1992. Genetic immunization is a simple method for eliciting an immune response. Nature 356: 152–154.
Davis, H.L., Michel, M.L. and Whalen, R.G. 1993. DNA-based immunization induces continuous secretion of hepatitis B surface antigen and high levels of circulating antibody. Hum. Mol. Genet. 2: 1847–1851.
Zarozinski, C.C., Fynan, E.F., Selin, L.K., Robinson, H.L. and Welsh, R.M. 1995. Protective CTL-dependent immunity and enhanced immunopathology in mice immunized by particle bombardment with DNA encoding an internal virion protein. J. Immunol. 154: 4010–4017.
Fu, T.-M., Friedman, A., Ulmer, J.B., Liu, M.A., and Donnelly, J.J 1997. Protective cellular immunity: cytotoxic T-lymphocyte responses against dominant and recessive epitopes of Influenza virus nucleoproteins induced by DNA immunization. J. Virol. 71: 2715–2721.
Ulmer, J.B.J.J., Parker, S.E., Rhodes, G.H., Feigner, P.L., Dwarki, V.J. et al. 1993. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259: 1745–1749.
Xiang, Z.Q., Spitalnik, S., Tran, M., Wunner, W.H., Cheng, J. and Ertl, H.C.J. 1994. Vaccination with a plasmid vector carrying the rabies virus glycoprotein gene induces protective immunity against rabies virus. Virology 199: 132–140.
Robinson, H.L., Hunt, L A., and Webster, R.G. 1993. Protection against a lethal influenza challenge by immunization with a haemagglutinin-expressing plasmid DNA. Vaccine 11: 957–960.
Letvin, N.L., Monteflori, D.C., Yasutomi, Y., Perry, H.C., Davies, M.E., Lekutis, C. et al. 1997. Potent, protective anti-HIV immune responses generated by bimodal HIV envelope DNA plus protein vaccination. Proc. Natl. Acad. Sci. USA 94: 9378–9383.
Wolff, J.A., Malone, R.W., Williams, P., Chong, W., Acsadi, G., Jani, A. et al. 1990. Direct gene transfer into mouse muscle in vivo. Science 247: 1465–1468.
Wolff, J.A., Ludtke, J.J., Acsadi, G., Williams, P. and Jani, A. 1992. Long-term persistence of plasmid DNA and foreign gene expression in mouse muscle. Hum. Mol. Genet. 1: 363–369.
Alferink, J., Schittek, B., Schonrich, G., Hammerling, G.J. and Arnold, B. 1995. Long life span of tolerant T cells and the role of antigen in maintenance of peripheral tolerance. Int. Immunol. 7: 331–336.
Ferber, I., Schonrich, G., Schenkel, J., Mellor, A.L., Hammerling, G.J. and Arnold, B. 1994. Levels of peripheral T cell tolerance induced by different doses of tolerogen. Science 263: 674–676.
Nichols, W.W., Ledwith, B.J., Manam, S.V. and Troilo, P.J. 1995. Potential DNA vaccine integration into host cell genome. Ann. NY Acad. Sci. 772: 30–39.
Mor, G., Yamschchikov, G., Sedagh, M., Takeno, M., Wang, R., Houghten, R.A. et al. 1996. Induction of neonatal tolerance by plasmid DNA vaccination of mice. J. Clin. Invest. 98: 2700–2705.
Zhou, X., Berglund, P., Zhao, H., Liljestrom, P. and Jondal, M. 1995. Generation of cytotoxic and humoral immune responses using non-replicative recombinant Semliki Forest virus. Proc. Natl. Acad. Sci. USA 92: 3009–3013.
Zhou, X., Berglund, P., Rhodes, G., Parker, S.E., Jondal, M. and Liljestrom, P. 1994. Self-replicating Semliki Forest virus RNA as recombinant vaccine. Vaccine 12: 1510–1514.
Tubulekas, I., Berglund, P., Fleeton, M. and Liljestrom, P. 1997. Alphavirus expression vectors and their use as recombinant vaccines—a minireview. Gene 190: 191–195.
Dubensky, T.W., Jr., Driver, D.A., Polo, J.M., Belli, B.A., Latham, E.M., Ibanez, C.E. et al. 1996. Sindbis virus DNA-based expression vectors: utility for in vitro and in vivo gene transfer. J. Wol. 70: 508–519.
Herweijer, H., Latendresse, J.S., Williams, P., Zhang, G., Danko, I., Schlesinger, S. et al. 1995. A plasmid-based self-amplifying Sindbis virus vector. Hum. Gene Ther. 6: 1161–1167.
Frolov, I. and Schlesinger, S. 1994. Comparison of the effects of Sindbis virus and Sindbis virus replicons on host cell protein synthesis and cytopathogeneticity in BHK cells. J. Virol. 68: 1721–1727.
Glasgow, G.M., McGee, M.M., Sheahan, B.J. and Atkins, G.J. 1997. Death mechanisms in cultured cells infected by Semliki Forest virus. J. Gen. Wol. 78: 1559–1563.
Davis, N.L., Brown, K.W. and Johnston, R.E. 1996. A viral vaccine vector that expresses foreign genes in lymph nodes and protects against mucosal challenge. J. Virol. 70: 3781–3787.
Pushko, P., Parker, M., Ludwig, G.V., Davis, N.L., Johnstone, R.E. and Smith, J.F. 1997. Replicon-helper systems from attenuated Venezuelan equine encephalitis virus-expression of heterologous genes in vitro and immunization against heterologous pathogens in vivo. Virology 239: 389–401.
Liljestrom, P. and Garoff, H. 1991. A new generation of animal cell expression vectors based on the Semliki Forest virus replicon. Bio/Technology 9: 1356–1361.
Sjoberg, M.E., Suomalainen, M. and Garoff, H. 1994. A significantly improved Semliki Forest virus expression system based on translational enhancer segments from the viral capsid gene. Bio/Technology 12: 1127–1131.
Levine, B., Huang, Q., Isaacs, J.T., Reed, J.C., Griffin, D.E. and Hardwick, J.M. 1993. Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature 361: 739–742.
Zhang, J., Asselin-Paturel, C., Bex, F., Bemhard, J., Chehimi, J., Willems, F. et al. 1997. Cloning of IL-12 p40 and p35 DNA into the Semliki Forest virus vector: expression of IL-12 in human tumor cells. Gene Ther. 4: 367–374.
Raz, E., Carson, D.A., Parker, S.E., Parr, T.B., Abai, A.M., Aichinger, G. et al. 1994. Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. Proc. Natl. Acad. Sci. USA 91: 9519–9523.
Manthorpe, M., Cornefert-Jensen, F., Hartikka, J., Feigner, J., Rundell, A., Margalith, M. et al. 1993. Gene therapy by intramuscular injection of plasmid DNA: studies on firefly luciferase gene expression in mice. Hum. Gene Ther. 4: 419–431.
Hariharan, M.J., Driver, D.A., Townsend, K., Brumm, D., Polo, J.M., Belli, B.A. et al. 1998. DNA immunization against Herpes Simplex virus: Enhanced efficacy using a Sindbis virus-based vector. J. Virol. 72: 950–958.
Brandt, E.R., Linnane, A.W. and Devenish, R.J. 1994. Expression of IFN A genes in subpopulations of peripheral blood cells. Br. J. Haematol. 86: 717–725.
Kaluza, G., Lell, G., Reinacher, M., Stitz, L., and Willems, W.R 1987. Neurogenic spread of Semliki Forest virus in mice. Arch. Virol. 93: 97–110.
Gates, M.C., Sheahan, B.J. and Atkins, G.J. 1984. The pathogenicity of the M9 mutant of Semliki Forest virus in immune-compromised mice. J. Gen. Virol. 65: 73–80.
Donnelly, S.M., Sheahan, B.J. and Atkins, G.J. 1997. Long-term effects of Semliki Forest virus infection in the mouse central nervous system. Neuropathol. Appl. Neurobiol. 23: 235–241.
Krieg, A.M., Yi, A.-K., Schorr, J., and Davis, H.L., 1998. The role of CpG dinucleotides in DNA vaccines. Trends Microbiol. 6: 23–26.
Donnelly, J.J., Ulmer, J.B. and Liu, M.A., 1997. DNA vaccines. Life Sci. 60: 163–172.
Berglund, P., Sjöberg, M., Atkins, G.J., Sheahan, B.J., Garoff, H. and Liljestrom, P. 1993. Semliki Forest virus expression system: production of conditionally infectious recombinant particles. Bio/Technology 11: 916–920.
Liljeström, P. and Garoff, H., 1994. Expression of proteins using Semliki Forest virus vectors, 16.20.11–16.20.16 in Current Protocols in Molecular Biology, Vol. 2. Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Smith, JA, Seidman, J.G. et al. (eds.). Greene Publishing Associates and Wiley Interscience, New York.
Rhodes, G.H., Dwarki, V.J., Abai, A.M., Feigner, J., Feigner, P.L., Gromkovski, S.H. et al. 1993. Injection of expression vectors containing viral genes induces cellular, humoral and protective immunity, 137–141 in Vaccines 93. Ginsberg, H.S., Brown, F, Chanock, R.M., and Lerner, R.A. (eds.). Cold Spring Harbor Press, Cold Spring Harbor, NY
Taswell, C. 1981. Limiting dilution assay for the determination of imunocompetent cell frequencies. J. Immunol. 126: 1614–1619.
Rouml;tzschke, O., Falk, K., Dere, K., Schild, H., Norda, M., Metzger, J. et al. 1990. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 348: 252–254.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Berglund, P., Smerdou, C., Fleeton, M. et al. Enhancing immune responses using suicidal DNA vaccines. Nat Biotechnol 16, 562–565 (1998). https://doi.org/10.1038/nbt0698-562
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nbt0698-562
This article is cited by
An alphavirus-based therapeutic cancer vaccine: from design to clinical trial
Cancer Immunology, Immunotherapy (2019)
Immunization with a suicidal DNA vaccine expressing the E glycoprotein protects ducklings against duck Tembusu virus
Virology Journal (2018)
DNA-launched RNA replicon vaccines induce potent anti-Ebolavirus immune responses that can be further improved by a recombinant MVA boost
Scientific Reports (2018)
Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis
Translational Psychiatry (2017)
Immunologic treatments for precancerous lesions and uterine cervical cancer
Journal of Experimental & Clinical Cancer Research (2014)