Louping ill virus (LIV) infection of mice was used as a model to evaluate the protective efficacy of Semliki Forest virus (SFV)-based vaccines in comparison to a standard DNA vaccine and a commercial chemically inactivated vaccine. The recombinant SFV-based vaccines consisted of suicidal particles and a naked layered DNA/RNA construct. The nucleic acid vaccines expressed the spike precursor prME and the nonstructural protein 1 (NS1) antigens of LIV. Three LIV strains of graded virulence for mice were used for challenge. One of these was a naturally occurring antibody escape variant. All vaccines tested induced humoral immunity but gave varying levels of protection against lethal challenge. Only recombinant SFV particles administered twice gave full protection against neuronal degeneration and encephalitis induced by two of the three challenge strains, and partial protection against the highly virulent strain, whereas the other vaccines tested gave lower levels of partial protection.


Article metrics loading...

Loading full text...

Full text loading...



  1. Albert, M. L., Pearce, S. F. A., Francisco, L. M., Sauter, B., Roy, P., Silverstein, R. L. & Bhardwaj, N. (1998a). Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. Journal of Experimental Medicine 188, 1359-1368.[CrossRef] [Google Scholar]
  2. Albert, M. L., Sauter, B. & Bhardwaj, N. (1998b). Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86-89.[CrossRef] [Google Scholar]
  3. Atkins, G. J. , Sheahan, B. J. & Liljeström, P. (1999). The molecular pathogenesis of Semliki Forest virus: a model virus made useful? Journal of General Virology 80, 2287-2297. [Google Scholar]
  4. Berglund, P., Sjöberg, M., Atkins, G. J., Sheahan, B. J., Garoff, H. & Liljeström, P. (1993). Semliki Forest virus expression system: production of conditionally infectious recombinant particles. Bio/Technology 11, 916-920.[CrossRef] [Google Scholar]
  5. Berglund, P., Quesada-Rolander, M., Putkonen, P., Biberfeld, G., Thorstensson, R. & Liljeström, P. (1997). Outcome of immunization of cynomolgus monkeys with recombinant Semliki Forest virus encoding human immunodeficiency virus type 1 envelope protein and challenged with a high dose of SHIV-4 virus. AIDS Research and Human Retroviruses 13, 1487-1495.[CrossRef] [Google Scholar]
  6. Berglund, P., Fleeton, M., Smerdou, C., Tubulekas, I., Sheahan, B. J., Atkins, G. J. & Liljeström, P. (1998a). Vaccination with recombinant suicidal DNA/RNA. In New Developments and New Applications in Animal Cell Technology. Edited by O. Merten, P. Perrin & B. Griffiths. Dordrecht: Kluwer Academic Publishers.
  7. Berglund, P., Smerdou, C., Fleeton, M. N., Tubulekas, I. & Liljeström, P. (1998b). Enhancing immune responses using suicidal DNA vaccines. Nature Biotechnology 16, 562-565.[CrossRef] [Google Scholar]
  8. Berglund, P., Fleeton, M. N., Smerdou, C. & Liljeström, P. (1999). Immunization with recombinant Semliki Forest virus induces protection against influenza challenge in mice. Vaccine 17, 497-507.[CrossRef] [Google Scholar]
  9. Colombage, G., Hall, R., Pavy, M. & Lobigs, M. (1998). DNA-based and alphavirus-vectored immunization with prM and E proteins elicits long-lived and protective immunity against the flavivirus, Murray Valley encephalitis virus. Virology 250, 151-163.[CrossRef] [Google Scholar]
  10. Davidson, M. M., Williams, H. & Macleod, A. J. (1991). Louping ill in man: a forgotten disease. Journal of Infection 23, 241-249.[CrossRef] [Google Scholar]
  11. Driver, D. A., Townsend, K., Brumm, D., Polo, J. M., Belli, B. A., Catton, D. J., Hsu, D., Mittelstaedt, D., McCormack, J. E., Karavodin, L., Dubensky, T. W., Chang, S. M. W. & Banks, T. A. (1998). DNA immunization against Herpes Simplex virus: enhanced efficacy using a Sindbis virus-based vector. Journal of Virology 72, 950-958. [Google Scholar]
  12. Fleeton, M. N., Sheahan, B. J., Gould, E. A., Atkins, G. J. & Liljeström, P. (1999). Recombinant Semliki Forest virus particles encoding the prME or NS1 proteins of louping ill virus protect mice from lethal challenge. Journal of General Virology 80, 1189-1198. [Google Scholar]
  13. Gao, G. F., Hussain, M. H., Reid, H. W. & Gould, E. A. (1994). Identification of naturally occurring monoclonal antibody escape variants of louping ill virus.Journal of General Virology 75, 609-614.[CrossRef] [Google Scholar]
  14. Glasgow, G. M., McGee, M. M., Mooney, D. A., Sheahan, B. J. & Atkins, G. J. (1997). Death mechanisms in cultured cells infected by Semliki Forest virus. Journal of General Virology 78, 1559-1563. [Google Scholar]
  15. Glasgow, G. M., McGee, M. M., Tarbatt, C. J., Mooney, D. A., Sheahan, B. J. & Atkins, G. J. (1998). The Semliki Forest virus vector induces p53-independent apoptosis. Journal of General Virology 79, 2405-2410. [Google Scholar]
  16. Heinz, F. X., Allison, S. L., Stiasny, K., Schalich, J., Holzman, H., Mandl, C. W. & Künz, C. (1995). Recombinant and virion-derived soluble and particulate immunogens for vaccination against tick-borne encephalitis. Vaccine 13, 1636-1642.[CrossRef] [Google Scholar]
  17. Jacobs, S. C., Stephenson, J. R. & Wilkinson, G. W. G. (1992). High level expression of the tick-borne encephalitis virus NS1 protein by using an adenovirus-based vector: protection elicited in a murine model. Journal of Virology 66, 2086-2095. [Google Scholar]
  18. Kohno, A., Emi, N., Kasai, M., Tanimoto, M & Saito, H. (1998). Semliki Forest virus-based DNA expression vector – transient protein production followed by cell death. Gene Therapy 5, 415-418.[CrossRef] [Google Scholar]
  19. Konishi, E., Pincus, S., Paoletti, E., Shope, R. E., Burrage, T. & Mason, P. W. (1992). Mice immunized with a subviral particle containing the Japanese encephalitis virus prM/M and E proteins are protected from lethal JEV infection. Virology 188, 714-720.[CrossRef] [Google Scholar]
  20. Konishi, E., Yamaoka, M., Khin-Sane-Win, Kurane, I., Takada, K. & Mason, P. W. (1999). The anamnestic neutralising antibody response is critical for protection of mice from challenge following vaccination with a plasmid encoding the Japanese encephalitis virus premembrane and envelope genes. Journal of Virology 73, 5527-5534. [Google Scholar]
  21. Koprowski, H. & Weiner, D. B. (1998). DNA vaccination/genetic vaccination. Current Topics in Microbiology and Immunology 226, 5-13. [Google Scholar]
  22. Liljeström, P. & Garoff, H. (1991). A new generation of animal cell expression vectors based on the Semliki Forest virus replicon. Bio/Technology 9, 1356-1361.[CrossRef] [Google Scholar]
  23. Lin, Y. L., Chen, L. K., Liao, C. L., Yeh, C. T., Ma, S. H., Chen, J. L., Huang, Y. L., Chen, S. S. & Chiang, H. Y. (1998). DNA immunization with Japanese encephalitis virus nonstructural protein NS1 elicits protective immunity in mice.Journal of Virology 72, 191-200. [Google Scholar]
  24. McGuire, K., Holmes, E. C., Gao, G. F., Reid, H. W. & Gould, E. A. (1998). Tracing the origins of louping ill virus by molecular phylogenetic analysis. Journal of General Virology 79, 981-988. [Google Scholar]
  25. Monath, T. P. & Heinz, F. X. (1996). Flaviviruses. In Fields Virology, pp. 961-1034. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. Philadelphia: Lippincott–Raven.
  26. Mossman, S., Bex, F., Berglund, P., Arthos, J., O’Neill, S. P., Riley, D., Maul, D. H., Bruck, C., Momin, P., Burny, A., Fultz, P. N., Mullins, J. I., Liljeström, P. & Hoover, E. A. (1996). Protection against lethal SIVsmmPBj14 disease by a recombinant Semliki Forest virus gp160 vaccine and by gp120 subunit vaccine. Journal of Virology 70, 1953-1960. [Google Scholar]
  27. Pugachev, K. V., Mason, P. W., Shope, R. E. & Frey, T. K. (1995). Double-subgenomic Sindbis virus recombinants expressing immunogenic proteins of Japanese encephalitis virus induce significant protection in mice against lethal JEV infection. Virology 212, 587-594.[CrossRef] [Google Scholar]
  28. Salminen, A., Wahlberg, J. M., Lobigs, M., Liljeström, P. & Garoff, H. (1992). Membrane fusion process of Semliki Forest virus. II. Cleavage-dependent reorganisation of the spike protein complex controls virus entry. Journal of Cell Biology 116, 349-357.[CrossRef] [Google Scholar]
  29. Schlesinger, J. J., Brandriss, M. W., Cropp, C. P. & Monath, T. P. (1986). Protection against yellow fever in monkeys by immunization with yellow fever nonstructural protein NS1. Journal of Virology 60, 1153-1155. [Google Scholar]
  30. Schmaljohn, C., Vanderzanden, L., Bray, M., Custer, D., Meyer, B., Li, D., Rossi, C., Fuller, D., Fuller, J., Haynes, J. & Huggins, J. (1997). Naked DNA vaccines expressing the prM and E genes of Russian spring summer encephalitis virus and Central European encephalitis virus protect mice from homologous and heterologous challenge. Journal of Virology 71, 9563-9569. [Google Scholar]
  31. Sheahan, B. J., Ibrahim, M. A. & Atkins, G. J. (1996). Demyelination of olfactory pathways in mice following intranasal infection with the avirulent A7 strain of Semliki Forest virus. European Journal of Veterinary Pathology 2, 117-125. [Google Scholar]
  32. Shiu, S. Y. W., Reid, H. W. & Gould, E. A. (1992). Louping ill virus envelope protein expressed by recombinant baculovirus and vaccinia virus fails to stimulate protective immunity. Virus Research 26, 213-229.[CrossRef] [Google Scholar]
  33. Smerdou, C. & Liljeström, P. (1999a). Non-viral amplification systems for gene transfer: vectors based on alphaviruses. Current Opinion in Molecular Therapy (in press).
  34. Smerdou, C. & Liljeström, P. (1999b). Two-helper RNA system for production of recombinant Semliki Forest virus particles. Journal of Virology 73, 1092-1098. [Google Scholar]
  35. Timofeev, A. V., Ozherelkov, S. V., Pronin, A. V., Deeva, A. V., Karganova, G. G., Elbert, L. B. & Stephenson, J. R. (1998). Immunological basis for protection in a murine model of tick-borne encephalitis by a recombinant adenovirus carrying the gene encoding the NS1 non-structural protein. Journal of General Virology 79, 689-695. [Google Scholar]
  36. Tubulekas, I., Berglund, P., Fleeton, M. & Liljeström, P. (1997). Alphavirus expression vectors and their use as recombinant vaccines – a minireview. Gene 190, 191-195.[CrossRef] [Google Scholar]
  37. Vene, S., Haglund, M., Vapalahti, O. & Lundkvist, A. (1998). A rapid fluorescent focus inhibition test for detection of neutralizing antibodies to tick-borne encephalitis virus. Journal of Virological Methods 73, 71-75.[CrossRef] [Google Scholar]
  38. Zhou, X. P., Berglund, G., Rhodes, G., Parker, S. E., Jondal, M. & Liljeström, P. (1994). Self-replicating Semliki Forest virus RNA as recombinant vaccine. Vaccine 12, 1510-1514.[CrossRef] [Google Scholar]
  39. Zhou, X. P., Berglund, G., Zhao, H., Liljeström, P. & Jondal, M. (1995). Generation of cytotoxic and humoral immune responses by nonreplicative recombinant Semliki Forest virus. Proceedings of the National Academy of Sciences, USA 92, 3009-3013.[CrossRef] [Google Scholar]

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error