Vaccine Design pp 313-328 | Cite as

Alphavirus-Based Vaccines

  • Kenneth LundstromEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1404)


Alphavirus vectors based on Semliki Forest virus, Sindbis virus, and Venezuelan equine encephalitis virus have been widely applied for vaccine development. Naked RNA replicons, recombinant viral particles, and layered DNA vectors have been subjected to immunization in preclinical animal models with antigens for viral targets and tumor antigens. Moreover, a limited number of clinical trials have been conducted in humans. Vaccination with alphavirus vectors has demonstrated efficient immune responses and has showed protection against challenges with lethal doses of virus and tumor cells, respectively. Moreover, vaccines have been developed against alphaviruses causing epidemics such as Chikungunya virus.


Alphaviruses Immunization Viral vaccines Cancer vaccines Protection 


  1. 1.
    Delrue I, Verzele D, Madder A, Nauwynck HJ (2012) Inactivated virus vaccines: from chemistry to prophylaxis: merits, risks and challenges. Expert Rev Vaccines 11:695–719CrossRefPubMedGoogle Scholar
  2. 2.
    Deng MP, Hu ZH, Wang HL, Deng F (2012) Developments of subunit and VLP vaccines against influenza A virus. Virol Sin 27:145–153CrossRefPubMedGoogle Scholar
  3. 3.
    Liljestrom P, Garoff H (1991) A new generation of animal cell expression vectors based on the Semliki Forest virus replicon. Biotechnology (N Y) 9:1356–1361CrossRefGoogle Scholar
  4. 4.
    Xiong C, Levis R, Shen P, Schlesinger S, Rice CM, Huang HV (1989) Sindbis virus: an efficient, broad host range vector for gene expression in animal cells. Science 243:1188–1191CrossRefPubMedGoogle Scholar
  5. 5.
    Davies NL, Brown KW, Johnston RE (1989) In vitro synthesis of infectious Venezuelan equine encephalitis virus RNA from a cDNA clone: analysis of a viable deletion mutant. Virology 171:189–204CrossRefGoogle Scholar
  6. 6.
    Lundstrom K (2003) Alphavirus vectors for vaccine production and gene therapy. Expert Rev Vaccines 2:447–459CrossRefPubMedGoogle Scholar
  7. 7.
    Lundstrom K (2014) Alphavirus-based vaccines. Viruses 6:2392–2415CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Brand D, Lemiale F, Turbica I, Buzelay L, Brunet S, Barin F (2000) Comparative analysis of humoral immune responses to HIV type 1 envelope glycoproteins in mice immunized with a DNA vaccine, recombinant Semliki Forest virus RNA, or recombinant Semliki Forest virus particles. AIDS Res Hum Retroviruses 14:1369–1377CrossRefGoogle Scholar
  9. 9.
    Kirman JR, Turon T, Su H, Li A, Kraus C, Polo JM et al (2003) Enhanced immunogenicity to Mycobacterium tuberculosis by vaccination with an alphavirus plasmid replicon expressing antigen 85A. Infect Immun 71:575–579CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Giraud A, Ataman-Onal Y, Battail N, Piga N, Brand D, Mandrand B et al (1999) Generation of monoclonal antibodies to native human immunodeficiency virus type 1 envelope glycoprotein by immunization of mice with naked RNA. J Virol Methods 79:75–84CrossRefPubMedGoogle Scholar
  11. 11.
    Caley IJ, Betts MR, Irlbeck DM, Davis NL, Swanstrom R, Frelinger JA et al (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 71:3031–3038PubMedPubMedCentralGoogle Scholar
  12. 12.
    Pushko P, Bray M, Ludwig GV, Parker M, Schmaljohn A, Sanchez A et al (2000) Recombinant RNA replicons derived from attenuated Venezuelan equine encephalitis virus protect guinea pigs and mice from Ebola hemorrhagic fever virus. Vaccine 19:142–153CrossRefPubMedGoogle Scholar
  13. 13.
    Yang SG, Wo JE, Li MW, Mi FF, Yu CB, Lv GL et al (2009) Construction and cellular immune response induction of HA-based alphavirus replicon vaccines against human-avian influenza (H5N1). Vaccine 27:7451–7458CrossRefPubMedGoogle Scholar
  14. 14.
    Herbert AS, Kuehne AI, Barth JF, Ortiz RA, Nichols DK, Zak SE et al (2013) Venezuelan equine encephalitis virus replicon particle vaccine protects nonhuman primates from intramuscular and aerosol challenge with Ebolavirus. J Virol 87:4952–4964CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Moran TP, Burgents JE, Long B, Ferrer I, Jaffee EM, Tisch RM et al (2007) Alphaviral vector-transduced dendritic cells are successful therapeutic vaccines against neu-overexpressing tumors in wild-type mice. Vaccine 25:6604–6612CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lachman LB, Rao XM, Kremer RH, Ozpolat B, Kiriakova G, Price JE (2001) DNA vaccination against neu reduces breast cancer incidence and metastasis in mice. Cancer Gene Ther 8:259–268CrossRefPubMedGoogle Scholar
  17. 17.
    Ying H, Zaks TZ, Wang RF, Irvine KR, Kammula US, Marincola FM et al (1999) Cancer therapy using a self-replicating RNA vaccine. Nat Med 5:823–827CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hart MK, Caswell-Stephan K, Bakken R, Tammariello R, Pratt W, Davis N et al (2000) Improved mucosal protection against Venezuelan equine encephalitis virus is induced by the molecularly defined, live-attenuated V3526 vaccine candidate. Vaccine 18:3067–3075CrossRefPubMedGoogle Scholar
  19. 19.
    Mallilankaraman K, Shedlock DJ, Bao H, Kawalekar OU et al (2011) A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates. PLoS Negl Trop Dis 5, e928CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Edelman R, Tacket CO, Wasserman SS, Bodison SA, Perry JG, Mangiafico JA (2000) Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218. Am J Trop Med Hyg 62:681–685PubMedGoogle Scholar
  21. 21.
    Bernstein DI, Reap EA, Katen K, Watson A, Smith K, Norberg P et al (2009) Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine 28:484–493CrossRefPubMedGoogle Scholar
  22. 22.
    Morse MA, Hobeika AC, Osada T, Berglund P, Hubby B, Negri S et al (2010) An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer. J Clin Invest 120:3234–3241CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Slovin SF, Kehoe M, Durso R, Fernandez C, Olson W, Gao JP et al (2013) A phase I dose escalation trial of vaccine replicon particles (VRP) expressing prostate-specific membrane antigen (PSMA) in subjects with prostate cancer. Vaccine 31:943–949CrossRefPubMedGoogle Scholar
  24. 24.
    Sjöberg EM, Suomalainen M, Garoff H (1994) A significantly improved Semliki Forest virus expression system based on translation enhancer segments from the viral capsid gene. Biotechnology 12:1127–1131CrossRefPubMedGoogle Scholar
  25. 25.
    Lundstrom K, Abenavoli A, Malgaroli A, Ehrengruber MU (2003) Novel Semliki Forest virus vectors with reduced toxicity and temperature-sensitivity for long-term enhancement of transgene expression. Mol Ther 7:202–209CrossRefPubMedGoogle Scholar
  26. 26.
    Berglund P, Sjöberg M, Garoff H, Atkins GJ, Sheahan BJ, Liljestrom P (1993) Semliki forest virus expression system: production of conditionally infectious recombinant particles. Biotechnology 11:916–920CrossRefPubMedGoogle Scholar
  27. 27.
    Irvine KR, Rao JB, Rosenberg SA, Restifo NP (1996) Cytokine enhancement of DNA immunization leads to effective treatment of established pulmonary metastases. J Immunol 156:238–245PubMedPubMedCentralGoogle Scholar
  28. 28.
    Avogadri F, Merghoub T, Maughan MF, Hirschhorn-Cymerman D et al (2010) Alphavirus replicon particles expressing TRP-2 provide potent therapeutic effect on melanoma through activation of humoral and cellular immunity. PLoS One 5, e12670CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Reitner WW, Hwang NL, de Veer MJ, Zhou A, Silverman RH, Williams BRG et al (2003) Alphavirus-based DNA vaccine breaks immunological tolerance by activating innate antiviral pathways. Nat Med 5:33–39Google Scholar
  30. 30.
    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 250:151–163CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.PanTherapeuticsLutrySwitzerland

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