Future vaccines against emerging encephalitides

  • Robert E. Johnston
  • N. L. Davis
Part of the Archives of Virology. Supplementa book series (ARCHIVES SUPPL, volume 18)


The vaccine strategies available for control of emerging encephalitides range in a continuum from traditional approaches to those utilizing new technologies. In this report, we explore the use of live attenuated vaccines where the attenuating mutations have been selected in a rational way to improve attenuation without sacrificing effectiveness. A strategy for paired lethal and resuscitating mutations is presented that will greatly reduce the possibility of reversion to virulence. Finally, we describe an example of a vaccine vector system that could be rapidly adapted for use against these virus diseases as they emerge.


Drain Lymph Node Sindbis Virus Baby Hamster Kidney Cell Venezuelan Equine Encephalitis Virus Equine Arteritis Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Aronson JF, Davis NL, Grieder FB, Charles PC, Knott TA, Brown K, Johnston RE (2000) A single-site mutant and revertants arising in vivo define early steps in the pathogenesis of Venezuelan equine encephalitis virus. Virology 270:111–123PubMedCrossRefGoogle Scholar
  2. 2.
    Balasuriya UBR, Heidner HW, Davis NL, Wagner HM, Hullinger PJ, Hedges JF, Williams JC, Johnston RE, Wilson WD, Liu IK, MacLachlan NJ (2002) Alphavirus replicon particles expressing the two major envelope proteins of equine arteritis virus induce high level protection against challenge with virulent virus in vaccinated horses. Vaccine 20:1609–1617PubMedCrossRefGoogle Scholar
  3. 3.
    Balasuriya UBR, Heidner HW, Hedges JF, Williams JC, Davis NL, Johnston RE, MacLachlan NJ (2000) Expression of the two major envelope proteins of equine arteritis virus as a heterodimer is necessary for induction of neutralizing antibodies in mice immunized with recombinant Venezuelan equine encephalitis virus replicon particles. J Virol 74:10623–10630PubMedCrossRefGoogle Scholar
  4. 4.
    Baric RS, Moore DB, Johnston RE (1980) In vitro selection of an attenuated variant of Sindbis virus. ICN-UCLA Symp Mol Cell Biol 18:685–694Google Scholar
  5. 5.
    Baric RS, Trent DW, Johnston RE (1981) A Sindbis virus variant with a cell determined latent period. Virology 110:237–242PubMedCrossRefGoogle Scholar
  6. 6.
    Boehme KW, Williams JC, Johnston RE, Heidner HW (2000) Linkage of an alphavirus host-range restriction to the carbohydrate processing phenotypes of the host cells. J Gen Virol 81:161–170PubMedGoogle Scholar
  7. 7.
    Burkhard MJ, Valenski L, Leavell S, Dean GA, Tompkins WA (2002) Evaluation of FlV protein-expressing VEEV-replicon vaccine vectors in cats. Vaccine 21:258–268PubMedCrossRefGoogle Scholar
  8. 8.
    Caley JJ, Betts MR, Davis NL, Swanstrom R, Frelinger JA, Johnston RE (1999) Venezuelan equine encephalitis virus vectors expressing HIV-l proteins: vector design strategies for improved vaccine efficacy. Vaccine 17:3124–3135PubMedCrossRefGoogle Scholar
  9. 9.
    Caley JJ, Betts MR, Irlbeck DM, Davis NL, Swanstrom R, Frelinger JA, Johnston RE (1997) Humoral, mucosal and cellular immunity in response to a human immunodeficiency virus type 1 immunogen expressed by a Venezuelan equine encephalitis virus vaccine vector. J Virol 71:3031–3038PubMedGoogle Scholar
  10. 10.
    Charles PC, Walters E, Margolis F, Johnston RE (1995) Mechanism ofneuroinvasion of Venezuelan equine encephalitis virus in the mouse. Virology 208:662–671PubMedCrossRefGoogle Scholar
  11. 11.
    Davis NL, Brown K, Johnston RE (1996) A viral vaccine vector that expresses foreign genes in lymph nodes and protects against mucosal challenge. J Virol 70:3781–3787PubMedGoogle Scholar
  12. 12.
    Davis NL, Brown KW, Greenwald GF, Zajac AJ, Zacny VL, Smith JF, Johnston RE (1995) Attenuated mutants of Venezuelan equine encephalitis virus containing lethal mutations in the PE2 cleavage signal combined with a second-site suppressor mutation in E1. Virology 212:102–110PubMedCrossRefGoogle Scholar
  13. 13.
    Davis NL, Caley N, Brown KW, Betts MR, Irlbeck DM, McGrath KM, Connell MJ, Montefiori DC, Frelinger JA, Swanstrom R, Johnson PR, Johnston RE (2000) Vaccination of macaques against pathogenic simian immunodeficiency virus with Venezuelan equine encephalitis virus replicon particles. J Virol 74: 371–378PubMedCrossRefGoogle Scholar
  14. 14.
    Davis NL, Fuller FJ, Dougherty WG, Olmsted RA, Johnston RE (1986) A single nucleotide change in the E2 glycoprotein gene of Sindbis virus affects penetration rate in cell culture and virulence in neonatal mice. Proc Natl Acad Sci USA 83:6771–6775PubMedCrossRefGoogle Scholar
  15. 15.
    Davis NL, Grieder FB, Smith JF, Greenwald GF, Valenski ML, Sellon DC, Charles PC, Johnston RE (1994) A molecular genetic approach to the study of Venezuelan equine encephalitis virus pathogenesis. Arch Virol Suppl 9:99–1091PubMedGoogle Scholar
  16. 16.
    Davis NL, Powell N, Greenwald GF, Willis LV, Johnson BJB, Smith JF, Johnston RE (1991) Attenuating mutations in the E2 glycoprotein gene of Venezuelan equine encephalitis virus: Construction of single and multiple mutants in a full-length cDNA clone. Virology 183:20–31PubMedCrossRefGoogle Scholar
  17. 17.
    Davis NL, West A, Reap E, MacDonald G, Collier M, Dryga S, Maughan M, Connell M, Walker C, McGrathw K, Cecil C, Ping L-H, Frelinger J, Olmsted R, Keith P, Swanstrom R, Williamson C, Johnson P, Montefiori D, Johnston RE (2002) Alphavirus replicon particles as candidate HIV vaccines. IUBMB Life 53:209–211PubMedCrossRefGoogle Scholar
  18. 18.
    Davis NL, Willis LV, Smith JF, Johnston RE (1989) In vitro synthesis of infectious Venezuelan equine encephalitis virus RNA from a cDNA clone: Analysis of a viable deletion mutant. Virology 171:189–204PubMedCrossRefGoogle Scholar
  19. 19.
    Dong M, Zhang PF, Grieder F, Lee J, Krishnamurthy G, VanCott T, Broder C, Polonis VR, Yu XF, Shao Y, Faix D, Valente P, Quinnan GV Jr (2003) Induction of primary virus-cross-reactive human immunodeficiency virus type I-neutralizing antibodies in small animals by using an alphavirus-derived in vivo expression system. J Virol 77: 3119–3130PubMedCrossRefGoogle Scholar
  20. 20.
    Eiben GL, Velders MP, Schreiber H, Cassetti MC, Pullen JK, Smith LR, Kast WM (2002) Establishment of an HLA-A *0201 human papillomavirus type 16 tumor model to determine the efficacy of vaccination strategies in HLA-A *0201 transgenic mice. Cancer Res 62: 5792–5799PubMedGoogle Scholar
  21. 21.
    Gipson CL, Davis NL, Johnston RE, deSilva AM (2003) Evaluation of Venezuelan equine encephalitis (VEEV) replicon-based outer surface protein A (OspA) vaccines in a tick challenge mouse model of Lyme disease. Vaccine 21:3875–3884PubMedCrossRefGoogle Scholar
  22. 22.
    Grieder FB, Davis NL, Aronson JF, Charles PC, Sellon DC, Suzuki K, Johnston RE (1995) Specific restrictions in the progression of Venezuelan equine encephalitis virus induced disease resulting from single amino acid changes in the glycoproteins. Virology 206:994–1006PubMedCrossRefGoogle Scholar
  23. 23.
    Harrington PR, Yount B, Johnston RE, Davis NL, Moe C, Baric RS (2002) Systemic, mucosal and heterotypic immune induction in mice inoculated with Venezuelan equine encephalitis replicons expressing Norwalk virus-like particles. J Virol 76: 730–742PubMedCrossRefGoogle Scholar
  24. 24.
    Heidner HW, Johnston RE (1994) The amino-terminal residue of Sindbis virus glycoprotein E2 influences virus maturation, specific infectivity for BHK cells, and virulence in mice. J Virol 68:8064–8070PubMedGoogle Scholar
  25. 25.
    Heidner HW, Knott TA, Johnston RE (1996) Differential processing of Sindbis virus glycoprotein PE2 in cultured vertebrate and arthropod cells. J Virol 70: 2069–2073PubMedGoogle Scholar
  26. 26.
    Heidner HW, McKnight KL, Davis NL, Johnston RE (1994) Lethality of PE2 incorporation into Sindbis virus can be suppressed by second-site mutations in E3 and E2. J Virol 68:2683–2692PubMedGoogle Scholar
  27. 27.
    Hevey M, Negley D, Pushko P, Smith J, Schmaljohn A (1998) Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates. Virology 251:28–37PubMedCrossRefGoogle Scholar
  28. 28.
    Hevey M, Negley D, VanderZanden L, Tammariello RF, Geisbert J, Schmaljohn C, Smith JF, Jahrling PB, Schmaljohn AL (2001) Marburg virus vaccines: comparing classical and new approaches. Vaccine 20: 586–593PubMedCrossRefGoogle Scholar
  29. 29.
    Johnston RE, Smith JF (1988) Selection for accelerated penetration in cell culture coselects for attenuated mutants of Venezuelan equine encephalitis virus. Virology 162: 437–443PubMedCrossRefGoogle Scholar
  30. 30.
    Kofler RM, Heinz FX, Mandl CW (2002) Capsid protein C of tick-borne encephalitis virus tolerates large internal deletions and is a favorable target for attenuation of virulence. J Virol 76: 3534–3543PubMedCrossRefGoogle Scholar
  31. 31.
    Kofler RM, Leitner A, O’Riordain G, Heinz FX, Mandl CW (2003) Spontaneous mutations restore the viability of tick-borne encephalitis virus mutants with large deletions in protein C. J Virol 77: 443–451PubMedCrossRefGoogle Scholar
  32. 32.
    Lee JS, Dyas BK, Nystrom SS, Lind CM, Smith JF, Ulrich RG (2002) Immune protection against staphylococcal enterotoxin-induced toxic shock by vaccination with a Venezuelan equine encephalitis virus replicon. J Infect Dis 185: 1192–1196PubMedCrossRefGoogle Scholar
  33. 33.
    Lee JS, Hadjipanayis AG, Welkos SL (2003) Venezuelan equine encephalitis virusvectored vaccines protect mice against anthrax spore challenge. Infect Immun 71:1491–1496PubMedCrossRefGoogle Scholar
  34. 34.
    Lee JS, Pushko P, Parker MD, Dertzbaugh MT, Smith LA, Smith JF (2001) Candidate vaccine against botulinum neurotoxin serotype A derived from a Venezuelan equine encephalitis virus vector system. Infect Immun 69:5709–5715PubMedCrossRefGoogle Scholar
  35. 35.
    MacDonald GH, Johnston RE (2000) The role of dendritic cell targeting in Venezuelan equine encephalitis virus pathogenesis. J Virol 74:914–922PubMedCrossRefGoogle Scholar
  36. 36.
    Olmsted RA, Baric RS, Sawyer BA, Johnston RE (1984) Sindbis virus mutants selected for rapid growth in cell culture display attenuated virulence in animals. Science 225:424–427PubMedCrossRefGoogle Scholar
  37. 37.
    Paredes AM, Heidner H, Thuman-Commike P, Prasad BVV, Johnston RE, Chiu W (1998) Structural localization of the E3 glycoprotein in attenuated Sindbis virus mutants. J Virol 72: 1534–1541PubMedGoogle Scholar
  38. 38.
    Pratt WD, Davis NL, Johnston RE, Smith JF (2003) Genetically engineered live attenuated vaccines for Venezuelan equine encephalitis: testing in animal models. Vaccine 21:3854–3862PubMedCrossRefGoogle Scholar
  39. 39.
    Pushko P, Bray M, Ludwig GV, Parker M, Schmaljohn A, Sanchez A, Jahrling PB, Smith JF (2000) Recombinant RNA replicons derived from attenuated Venezuelan equine encephalitis virus protect guinea pigs and mice from Ebola hemorrhagic fever virus. Vaccine 19:142–153PubMedCrossRefGoogle Scholar
  40. 40.
    Pushko P, Parker M, Ludwig GV, Davis NL, Johnston RE, Smith JF (1997) Repliconhelper systems from attenuated Venezuelan equine encephalitis virus: expression of heterologous genes in vitro and immunization against heterologous pathogens in vivo. Virology 239:389–401PubMedCrossRefGoogle Scholar
  41. 41.
    Russell DL, Dalrymple JM, Johnston RE (1989) Sindbis virus mutations which coordinately affect glycoprotein processing, penetration and virulence in mice. J Virol 63:1619–1629PubMedGoogle Scholar
  42. 42.
    Schultz-Cherry S, Dybing JK, Davis NL, Williamson C, Suarez D, Johnston R, Perdue ML (2000) Influenza virus (NHKlI56/97) hemagglutinin expressed by an alphavirus replicon system protects chickens against lethal infection with Hong Kong-origin H5Nl viruses. Virology 278:55–59PubMedCrossRefGoogle Scholar
  43. 43.
    Thomas CE, Van Dam CN, Zhu W, Davis NL, Johnston RE, Sparling PF (2004) Vaccination of mice with gonococcal antigens expressed from Venezuelan equine encephalitis viral replicon particles. Inf Immun (submitted)Google Scholar
  44. 44.
    Velders MP, McElhiney S, Cassetti MC, Eiben GL, Higgins T, Kovacs GR, Elmishad AG, Kast WM, Smith LR (2001) Eradication of established tumors by vaccination with Venezuelan equine encephalitis virus replicon particles delivering human papillomavirus 16 E7 RNA. Cancer Res 61: 7861–7867PubMedGoogle Scholar
  45. 45.
    Williamson C, Johnston RE, Williamson AL (2002) HIV-l vaccine candidates for South Africa. South African J HIV Med (March): 10–14Google Scholar

Copyright information

© Springer-Verlag Wien 2004

Authors and Affiliations

  • Robert E. Johnston
    • 1
  • N. L. Davis
    • 1
  1. 1.Carolina Vaccine InstituteUniversity of North CarolinaChapel HillNorth CarolinaUSA

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