Volume 91, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Vaccinations against the encephalitic alphaviruses (western, eastern, and Venezuelan equine encephalitis virus) are of significant interest to biological defense, public health, and agricultural communities alike. Although vaccines licensed for veterinary applications are used in the Western Hemisphere and attenuated or inactivated viruses have been used under Investigational New Drug status to protect at-risk personnel, there are currently no licensed vaccines for use in humans. Here, we will discuss the need for a trivalent vaccine that can protect humans against all three viruses, recent progress to such a vaccine, and a strategy to continue development to Food and Drug Administration licensure.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Paessler S, Weaver SC, , 2009. Vaccines for Venezuelan equine encephalitis. Vaccine 27 (Suppl 4): D80D85.[Crossref] [Google Scholar]
  2. Jose J, Snyder JE, Kuhn RJ, , 2009. A structural and functional perspective of alphavirus replication and assembly. Future Microbiol 4: 837856.[Crossref] [Google Scholar]
  3. Zacks MA, Paessler S, , 2010. Encephalitic alphaviruses. Vet Microbiol 140: 281.[Crossref] [Google Scholar]
  4. Calisher CH, , 1994. Medically important arboviruses of the United States and Canada. Clin Microbiol Rev 7: 89116.[Crossref] [Google Scholar]
  5. Mitchell CJ, Monath TP, Sabattini MS, Daffner JF, Cropp CB, Calisher CH, Darsie RF, Jakob WL, , 1987. Arbovirus isolates from mosquitoes collected during and after the 1982–1983 epizootic of western equine encephalitis in Argentina. Am J Trop Med Hyg 36: 107113. [Google Scholar]
  6. Hahn CS, Lustig S, Strauss EG, Strauss JH, , 1988. Western equine encephalitis virus is a recombinant virus. Proc Natl Acad Sci USA 85: 59976001.[Crossref] [Google Scholar]
  7. Calisher CH, Karabatsos N, Lazuick JS, Monath TP, Wolff KL, , 1988. Reevaluation of the western equine encephalitis antigenic complex of alphaviruses (family Togaviridae) as determined by neutralization tests. Am J Trop Med Hyg 38: 447452. [Google Scholar]
  8. Weaver SC, Kang W, Shirako Y, Rumenapf T, Strauss EG, Strauss JH, , 1997. Recombinational history and molecular evolution of western equine encephalomyelitis complex alphaviruses. J Virol 71: 613623. [Google Scholar]
  9. Bianchi TI, Aviles G, Monath TP, Sabattini MS, , 1993. Western equine encephalomyelitis: virulence markers and their epidemiological significance. Am J Trop Med Hyg 49: 322328. [Google Scholar]
  10. Bianchi TI, Aviles G, Sabattini MS, , 1997. Biological characteristics of an enzootic subtype of western equine encephalomyelitis virus from Argentina. Acta Virol 41: 1320. [Google Scholar]
  11. Nagata LP, Hu WG, Parker M, Chau D, Rayner GA, Schmaltz FL, Wong JP, , 2006. Infectivity variation and genetic diversity among strains of western equine encephalitis virus. J Gen Virol 87: 23532361.[Crossref] [Google Scholar]
  12. Brault AC, Powers AM, Chavez CL, Lopez RN, Cachon MF, Gutierrez LF, Kang W, Tesh RB, Shope RE, Weaver SC, , 1999. Genetic and antigenic diversity among eastern equine encephalitis viruses from North, Central and South America. Am J Trop Med Hyg 61: 579586. [Google Scholar]
  13. Arrigo NC, Adams AP, Weaver SC, , 2010. Evolutionary patterns of eastern equine encephalitis virus in North versus South America suggest ecological differences and taxonomic revision. J Virol 84: 10141025.[Crossref] [Google Scholar]
  14. Carrera JP, Forrester N, Wang E, Vittor AY, Haddow AD, Lopez-Verges S, Abadia I, Castano E, Sosa N, Baez C, Estripeaut D, Diaz Y, Beltran D, Cisneros J, Cedeno HG, Travassos da Rosa AP, Hernandez H, Martinez-Torres AO, Tesh RB, Weaver SC, , 2013. Eastern equine encephalitis in Latin America. N Engl J Med 369: 732744.[Crossref] [Google Scholar]
  15. Brault AC, Powers AM, Holmes EC, Woelk CH, Weaver SC, , 2002. Positively charged amino acid substitutions in the e2 envelope glycoprotein are associated with the emergence of Venezuelan equine encephalitis virus. J Virol 76: 17181730.[Crossref] [Google Scholar]
  16. Weaver SC, Winegar R, Manger ID, Forrester NL, , 2012. Alphaviruses: population genetics and determinants of emergence. Antiviral Res 94: 242257.[Crossref] [Google Scholar]
  17. Centers for Disease Control and Prevention, 2005. Fact Sheet Western Equine Encephalitis. Available at: http://www.cdc.gov/ncidod/dvbid/arbor/weefact.htm. Accessed March 6, 2014. [Google Scholar]
  18. Steele K, Reed DS, Glass PJ, Hart MK, Ludwig GV, Pratt WD, Parker MD, Smith JF, Dembek ZF, , 2007. Alphavirus encephalitides. , ed. Medical Aspects of Biological Warfare. Fort Sam Houston, TX: Office of the Surgeon General, Department of the Army and US Army Medical Department Center and School, 241270. [Google Scholar]
  19. Rivas F, Diaz LA, Cardenas VM, Daza E, Bruzon L, Alcala A, De la Hoz O, Caceres FM, Aristizabal G, Martinez JW, Revelo D, De la Hoz F, Boshell J, Camacho T, Calderon L, Olano A, Villareal LI, Roselli D, Alvarez G, Ludwig G, Tsai T, , 1997. Epidemic Venezuelan Equine Encephalits in La Guajira, Colombia, 1995. J Infect Dis 175: 828832.[Crossref] [Google Scholar]
  20. Sewell D, , 1995. Laboratory-associated infections and biosafety. Clin Microbiol Rev 8: 389405. [Google Scholar]
  21. Croddy EC, Hart C, Perez-Armendariz J, , 2002. Chemical and Biological Warfare. Berlin, Germany: Springer, 3031.[Crossref] [Google Scholar]
  22. Walton TE, Alvarez O, Buckwalter RM, Johnson KM, , 1973. Experimental infection of horses with enzootic and epizootic strains of Venezuelan equine encephalomyelitis virus. J Infect Dis 128: 271282.[Crossref] [Google Scholar]
  23. Walton TE, Alvarez O, Buckwalter RM, Johnson KM, , 1972. Experimental infection of horses with an attenuated Venezuelan equine encephalomyelitis vaccine (strain TC-83). Infect Immun 5: 750756. [Google Scholar]
  24. 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: 102110.[Crossref] [Google Scholar]
  25. Spertzel RO, Kahn DE, , 1971. Safety and efficacy of an attenuated Venezuelan equine encephalomyelitis vaccine for use in Equidae. J Am Vet Med Assoc 159: 731738. [Google Scholar]
  26. Fine DL, Roberts BA, Teehee ML, Terpening SJ, Kelly CLH, Raetz JL, Baker DH, Powers AM, Bowen RA, , 2007. Venezuelan equine encephalitis virus vaccine candidate (V3526) safety, immunogenicity and efficacy in horses. Vaccine 25: 18681876.[Crossref] [Google Scholar]
  27. Martin SS, Bakken RR, Lind CM, Garcia P, Jenkins E, Glass PJ, Parker MD, Hart MK, Fine DL, , 2010. Comparison of the immunological responses and efficacy of gamma irradiated V3526 vaccine formulations against subcutaneous and aerosol challenge with venezuelan equine encephalitis virus subtype IAB. Vaccine 28: 1031.[Crossref] [Google Scholar]
  28. American Association of Equine Practitioners, 2014. Core Vaccination Guidelines, Eastern/Western Encephalomyelitis. Available at: http://www.aaep.org/-i-165.htm. Accessed March 6, 2014. [Google Scholar]
  29. Pittman PR, Liu C, Cannon TL, Mangiafico JA, Gibbs PH, , 2009. Immune interference after sequential alphavirus vaccine vaccinations. Vaccine 27: 48794882.[Crossref] [Google Scholar]
  30. Pittman PR, Makuch RS, Mangiafico JA, Cannon TL, Gibbs PH, Peters CJ, , 1996. Long-term duration of detectable neutralizing antibodies after administration of live-attenuated VEE vaccine and following booster vaccination with inactivated VEE vaccine. Vaccine 14: 337343.[Crossref] [Google Scholar]
  31. Reisler RB, Gibbs PH, Danner DK, Boudreau EF, , 2012. Immune interference in the setting of same-day administration of two similar inactivated alphavirus vaccines: eastern equine and western equine encephalitis. Vaccine 30: 72717277.[Crossref] [Google Scholar]
  32. Paessler S, Weaver SC, , 2009. Vaccines for Venezuelan equine encephalitis. Vaccine 27: D80D85.[Crossref] [Google Scholar]
  33. Guerbois M, Volkova E, Forrester NL, Rossi SL, Frolov I, Weaver SC, , 2013. IRES-driven expression of the capsid protein of the Venezuelan equine encephalitis virus TC-83 vaccine strain increases its attenuation and safety. PLoS Negl Trop Dis 7: e2197.[Crossref] [Google Scholar]
  34. Dupuy LC, Richards MJ, Ellefsen B, Chau L, Luxembourg A, Hannaman D, Livingston BD, Schmaljohn CS, , 2011. A DNA vaccine for Venezuelan equine encephalitis virus delivered by intramuscular electroporation elicits high levels of neutralizing antibodies in multiple animal models and provides protective immunity to mice and nonhuman primates. Clin Vaccine Immunol 18: 707716.[Crossref] [Google Scholar]
  35. Sharma A, Gupta P, Glass PJ, Parker MD, Maheshwari RK, , 2011. Safety and protective efficacy of INA-inactivated Venezuelan equine encephalitis virus: implication in vaccine development. Vaccine 29: 953959.[Crossref] [Google Scholar]
  36. Fine DL, Jenkins E, Martin SS, Glass P, Parker MD, Grimm B, , 2010. A multisystem approach for development and evaluation of inactivated vaccines for Venezuelan Equine Encephalitis Virus (VEEV). J Virol Methods 163: 424.[Crossref] [Google Scholar]
  37. 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: 142153.[Crossref] [Google Scholar]
  38. Akahata W, Yang Z, Andersen H, Sun S, Holdaway HA, Kong W, Lewis MG, Higgs S, Rossmann MG, Rao S, Nabel GJ, , 2010. A VLP vaccine for epidemic Chikungunya virus protects non-human primates against infection. Nat Med 16: 334338.[Crossref] [Google Scholar]
  39. Aronson JF, Grieder FB, Davis NL, Charles PC, Knott T, 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: 111123.[Crossref] [Google Scholar]
  40. Pratt WD, Hart MK, Reed DS, Steele KS, Swearengen JR, , 2006. Alphaviruses. , ed. Biodefense: Research Methodology and Animal Models. Boca Raton, FL: Taylor & Francis, 181206. [Google Scholar]
  41. Ryzhikov AB, Ryabchikova EI, Sergeev AN, Tkacheva NV, , 1995. Spread of Venezuelan equine encephalitis virus in mice olfactory tract. Arch Virol 140: 22432254.[Crossref] [Google Scholar]
  42. Vogel P, Kell WM, Frtiz DL, Parker MD, Schoepp RJ, , 2005. Early events in the pathogenesis of eastern equine encephalitis virus in mice. Am J Pathol 166: 159171.[Crossref] [Google Scholar]
  43. Steele KE, Twenhafel NA, , 2010. Review paper: pathology of animal models of alphavirus encephalitis. Vet Pathol 47: 790805.[Crossref] [Google Scholar]
  44. Reed DS, Lackemeyer MG, Garza NL, Norris S, Gamble S, Sullivan LF, Lind CM, Raymond JL, , 2007. Severe encephalitis in cynomolgus macaques exposed to aerosolized eastern equine encephalitis virus. J Infect Dis 196: 441450.[Crossref] [Google Scholar]
  45. Reed DS, Larsen T, Sullivan LJ, Lind CM, Lackemeyer MG, Pratt WD, Parker MD, , 2005. Aerosol exposure to western equine encephalitis virus causes fever and encephalitis in cynomolgus macaques. J Infect Dis 192: 11731182.[Crossref] [Google Scholar]
  46. Coffey LL, Vasilakis N, Brault AC, Powers AM, Tripet F, Weaver SC, , 2008. Arbovirus evolution in vivo is constrained by host alternation. Proc Natl Acad Sci USA 105: 69706975.[Crossref] [Google Scholar]
  47. McCurdy K, Joyce J, Hamliton S, Nevins C, Sosna W, Puricelli K, Rayner JO, , 2011. Differential accumulation of genetic and phenotypic changes in Venezuelan equine encephalitis virus and Japanese encephalitis virus following passage in vitro and in vivo . Virology 415: 2029.[Crossref] [Google Scholar]
  48. Bernard KA, Klimstra WB, Johnston RE, , 2000. Mutations in the E2 glycoprotein of Venezuelan equine encephalitis virus confer heparan sulfate interaction, low morbidity, and rapid clearance from blood of mice. Virology 276: 93103.[Crossref] [Google Scholar]
  49. Carrera JP, Forrester NM, Wang E, Vittor AY, Haddow AD, Lopez-Verges S, Abadia I, Castano E, Sosa N, Baez C, Estripeaut D, Diaz Y, Beltran D, Cisneros J, Cedeno HG, Travassos da Rosa AP, Hernandez H, Martinez-Torres AO, Tesh RB, Weaver SC, , 2013. Eastern equine encephalitis in Latin America. N Engl J Med 369: 732744.[Crossref] [Google Scholar]
  50. Mossel EC, Ledermann JP, Phillips AT, Borland EM, Powers AM, Olson KE, , 2013. Molecular determinants of mouse neurovirulence and mosquito infection for western equine encephalitis virus. PLoS ONE 8: e60427.[Crossref] [Google Scholar]
  51. Gardner SN, Hall BG, , 2013. When whole-genome alignments just won't work: kSNP v2 software for alignment-free SNP discovery and phylogenetics of hundreds of microbial genomes. PLoS ONE 8: e8170. [Google Scholar]
  52. Hall BG, , 2014. SNP-associations and phenotype predictions from hundreds of microbial genomes without genome alignments. PLoS ONE 9: e90490.[Crossref] [Google Scholar]
  53. Burns DL, , 2012. Licensure of vaccines using the Animal Rule. Curr Opin Virol 2: 353356.[Crossref] [Google Scholar]
  54. Plotkin SA, , 2013. Complex correlates of protection after vaccination. Clin Infect Dis 56: 14581465.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 22 Jan 2014
  • Accepted : 02 Apr 2014
  • Published online : 03 Sep 2014

Most Cited This Month

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