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Alphavirus replicon vaccines

  • Ryan L. Vander Veen (a1) (a2) (a3), D. L. Hank Harris (a1) (a4) (a5) and Kurt I. Kamrud (a1) (a4)
Abstract

The alphavirus replicon technology has been utilized for many years to develop vaccines for both veterinary and human applications. Many developments have been made to the replicon platform recently, resulting in improved safety and efficacy of replicon particle (RP) vaccines. This review provides a broad overview of the replicon technology and safety features of the system and discusses the current literature on RP and replicon-based vaccines.

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*Corresponding author: E-mail: rvanderveen@harrisvaccines.com
References
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Alevizatos, AC, McKinney, RW and Feigin, RD (1967). Live, attenuated Venezuelan equine encephalomyelitis virus vaccine: clinical effects in man. American Journal of Tropical Medicine and Hygiene 16: 762768.
Altman-Hamamdzic, S, Groseclose, C, Ma, JX, Hamamdzic, D, Vrindavanam, NS, Middaugh, LD, Parratto, NP and Sallee, FR (1997). Expression of beta-galactosidase in mouse brain: utilization of a novel nonreplicative Sindbis virus vector as a neuronal gene delivery system. Gene Therapy 4: 815822.
Balasuriya, UBR, Heidner, HW, Davis, NL, Wagner, HM, Hullinger, PJ, Hedges, JF, Williams, JC, Johnston, RE, Wilson, WD, Liu, IK and 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: 16091617.
Balasuriya, UBR, Heidner, HW, Hedges, JF, Williams, JQ, Davis, NL, Johnston, RE and 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. Journal of Virology 74: 1062310630.
Berglund, P, Sjoberg, M, Garoff, H, Atkins, GJ, Sheahan, BJ and Liljestrom, P (1993). Semliki Forest virus expression system: production of conditionally infectious recombinant particles. Biotechnology (NY) 11: 916920.
Berglund, P, Smerdou, C, Flee, MN, Tubulekas, I and Liljestrom, P (1998). Enhancing immune responses using suicidal DNA vaccines. Nature Biotechnology 16: 562565.
Bernstein, DI, Reap, EI, Katen, K, Watson, A, Smith, K, Norberg, P, Olmsted, RA, Hoeper, A, Morris, J, Negri, S, Maughan, MF and Chulay, JD (2010). Randomized, double-blind, phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine 28: 484493.
Bosworth, B, Erdman, MM, Stine, DL, Harris, I, Irwin, C, Jens, M, Loynachan, A, Kamrud, K and Harris, DL (2010). Replicon particle vaccine protects swine against influenza. Comparative Immunology, Microbiology, and Infectious Diseases 33: e99–e103.
Botner, A, Strandbygaard, B, Sorensen, KJ, Have, P, Madsen, KG, Madsen, ES and Alexandersen, S (1997). Appearance of acute PRRS-like symptoms in sow herds after vaccination with a modified live PRRS vaccine. Veterinary Record 141: 497499.
Bredenbeek, PJ, Frolov, I, Rice, CM and Schlesinger, S (1993). Sindbis virus expression vectors: packaging of RNA replicons by using defective helper RNAs. Journal of Virology 67: 64396446.
Burke, DS and Ramsburg, HH (1977). Persistence in humans of antibody to subtypes of Venezuelan equine encephalomyelitis (VEE) virus after immunization with attenuated (TC-83) VEE virus vaccine. Journal of Infectious Diseases 136: 354359.
Carrol, TD, Matzinger, SR, Barro, M, Fritts, L, McChesney, MB, Miller, CJ and Johnston, RE (2011). Alphavirus replicon-based adjuvants enhance the immunogenicity and effectiveness of Fluzone in rhesus macaques. Vaccine 29: 931940.
Ciacci-Zanella, JR, Vincent, AL, Prickett, JR, Zimmerman, SM and Zimmerman, JJ (2010). Detection of anti-influenza A nucleoprotein antibodies in pigs using a commercial influenza epitope-blocking enzyme-linked immunosorbent assay developed for avian species. Journal of Veterinary Diagnostic Investigation 22: 39.
Dea, S, Gagnon, CA, Mardassi, H, Pirzadeh, B and Rogan, D (2000). Current knowledge on the structural proteins of porcine reproductive and respiratory syndrome (PRRS) virus: comparison of the North American and European isolates. Archives of Virology 145: 659688.
Defang, GN, Khetawat, D, Broder, CC and Quinnan, GV Jr (2011). Induction of neutralizing antibodies to Hendra and Nipah glycoproteins using a Venezuelan equine encephalitis virus in vivo expression system. Vaccine 29: 212220.
Dubensky, TW Jr, Driver, DA, Polo, JM, Belli, BA, Latham, EM, Ibanez, CE, Chada, S, Brumm, D, Banks, TA, Mento, SJ, Jolly, DJ and Chang, SM (1996). Sindbis virus DNA-based expression vectors: utility for in vitro and in vivo gene transfer. Journal of Virology 70: 508519.
Erdman, MM, Kamrud, KI, Harris, DL and Smith, J (2010). Alphavirus eplicon particle vaccines developed for use in humans induce high levels of antibodies to influenza virus hemagglutinin in swine: proof of concept. Vaccine 28: 594596.
Frolov, I, Frolova, E and Schlesinger, S (1997). Sindbis virus replicons and Sindbis virus: assembly of chimeras and of particles deficient in virus RNA. Journal of Virology 71: 28192829.
Gardner, JP, Frolov, I, Perri, S, Ji, Y, MacKichan, ML, Zur, Megede J, Chen, M, Belli, BA, Driver, DA, Sherrill, S, Greer, CD, Olten, GR, Barnett, SW, Liu, MA, Dubensky, TW and Polo, JM (2000). Infection of human dendritic cells by a Sindbis viral replicon vector is determined by a single amino acid substitution in the E2 glycoprotein. Journal of Virology 74: 1184911857.
Geigenmuller-Gnirke, U, Weiss, B, Wright, R and Schlesinger, S (1991). Complementation between Sindbis viral RNAs produces infectious particles with a bipartite genome. Proceedings of the National Academy of Sciences of the United States of America 88: 32533257.
Griffin, DE (2007). Alphaviruses. In: Knipe, DM and Howley, PM (eds) Fields Virology, 5th ednLippincott Williams & Wilkins, pp. 10231067.
Hariharan, MJ, Driver, DA, Townsend, K, Brumm, D, Polo, JM, Belle, BA, Catton, DJ, Hsu, D, Mittelstaedt, D, McCormack, JE, Karavodin, L, Dubensky, DW Jr, Chang, SM and Banks, TA (1998). DNA immunization against herpes simplex virus: enhanced efficacy using a Sindbis virus-based vector. Journal of Virology 72: 950958.
Hooper, JW, Ferro, AM, Golden, JW, Sivera, P, Dudek, JM, Alterson, KD, Custer, M, Rivers, B, Morris, J, Owens, G, Smith, JF and Kamrud, KI (2009). Molecular smallpox vaccine delivered by alphavirus replicons elicits protective immunity in mice and non-human primates. Vaccine 28: 494511.
Hubby, B, Talarico, T, Maughan, M, Reap, EA, Berglund, P, Kamrud, KI, Copp, L, Lewis, W, Cecil, C, Norberg, P, Wagner, J, Watson, A, Negri, S, Burnett, BK, Graham, A, Smith, JF and Chulay, JD (2007). Development and preclinical evaluation of an alphavirus replicon vaccine for influenza. Vaccine 25: 81808189.
Jiang, W, Jiang, P, Li, Y, Tang, J, Wang, X and Ma, S (2006a). Recombinant adenovirus expressing GP5 and M fusion proteins of porcine reproductive and respiratory syndrome virus induce both humoral and cell-mediated responses in mice. Veterinary Immunology and Immunopathology 113: 169180.
Jiang, Y, Fang, L, Xiao, S, Zhang, H, Pan, Y, Luo, R, Li, B and Chen, H (2006b). Immunogenicity and protective efficacy of recombinant pseudorabies virus expressing the two major membrane-associated proteins of porcine reproductive and respiratory syndrome virus. Vaccine 25: 547560.
Jiang, Y, Xiao, S, Fang, L, Yu, X, Song, Y, Niu, C and Chen, H (2006c). DNA vaccines co-expressing GP5 and M proteins of porcine reproductive and respiratory syndrome virus (PRRSV) display enhanced immunogenicity. Vaccine 24: 28692879.
Johnston, LJ, Halliday, GM and King, NJ (2000). Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus. Journal of Investigative Dermatology 114: 560568.
Jose, J, Snyder, JE and Kuhn, RJ (2009). A structural and functional perspective of alphavirus replication and assembly. Future Microbiology 4: 837856.
Kamrud, KI, Alterson, K, Custer, M, Dudek, J, Goodman, C, Owens, G and Smith, JF (2010a). Development and characterization of promotorless helper RNAs for the production of alphavirus replicon particles. Journal of General Virology 91: 17231727.
Kamrud, KI, Alterson, KD, Andrews, C, Copp, LO, Lewis, WC, Hubby, B, Patel, D, Rayner, JO, Talarico, T and Smith, JF (2008). Analysis of Venezuelan equine encephalitis replicon particles packaged in different coats. PLoS ONE 3: 18.
Kamrud, KI, Coffield, VM, Owens, G, Goodman, C, Alterson, K, Custer, M, Lewis, W, Timberlake, S, Wansley, EK and Berglund, P (2010b). In vitro and in vivo characterization of microRNA-targeted alphavirus replicon and helper RNAs. Journal of Virology 84: 77137725.
Kamrud, KI, Custer, M, Dudek, JM, Owens, G, Alterson, KD, Lee, JS, Groebner, JL and Smith, JF (2007). Alphavirus replicon approach to promoterless analysis of IRES elements. Virology 360: 376387.
Kinney, RM, Chang, GJ, Tsuchiya, KR, Sneider, JM, Roehrig, JT, Woodward, TM and Trent, DW (1993). Attenuation of Venezuelan equine encephalitis virus strain TC-83 is encoded by the 5 ′-noncoding region and the E2 envelope glycoprotein. Journal of Virology 67: 12691277.
Kinney, RM, Johnson, BJB, Welch, JB, Tsuchiya, KR and Trent, DW (1988). The full-length nucleotide sequences of the virulent Trinidad donkey strain of Venezuelan equine encephalitis virus and its attenuated vaccine derivative, strain TC-83. Virology 170: 1930.
Kohno, A, Emi, N, Kasai, M, Tanimoto, M and Saito, H (1998). Semliki Forest virus-based DNA expression vector: transient protein production followed by cell death. Gene Therapy 5: 415418.
Kowalski, J, Adkins, K, Gangolli, S, Ren, J, Arendt, H, DeStefano, J, Obregon, J, Tummolo, D, Natuk, R, Brown, T, Parks, C, Udem, S and Long, D (2007). Evaluation of neurovirulence and biodistribution of Venezuelan equine encephalitis replicon particles expressing herpes simplex virus type 2 glycoprotein D. Vaccine 25: 22962305.
Lee, JS, Groebner, JL, Hadjipanayis, AG, Negley, DL, Schmaljohn, AL, Welkos, SL, Smith, LA and Smith, JF (2006). Multiagent vaccines vectored by Venezuelan equine encephalitis virus replicon elicits immune responses to Marburg virus and protection against anthrax and botulinum neurotoxin in mice. Vaccine 24: 68866892.
Lee, JS, Hadjipanayis, AG and Welkos, SL (2003). Venezuelan equine encephalitis virus-vectored vaccines protect mice against anthrax spore challenge. Infection and Immunity 71: 14911496.
Levinson, R, Strauss, JH and Strauss, EG (1990). Determination of the complete nucleotide sequence of the genomic RNA of the O'nyong-nyong virus and its use in the construction of phylogenetic trees. Virology 175: 110123.
Li, N, Zhao, JJ, Zhao, HP, Sun, Y, Zhu, QH, Tong, GZ and Qiu, HJ (2007). Protection of pigs from lethal challenge by a DNA vaccine based on an alphavirus replicon expressing the E2 glycoprotein of classical swine fever virus. Journal of Virological Methods 144: 7378.
Liljestrom, P and Garoff, H (1991). A new generation of animal cell expression vectors based on the Semliki Forest virus replicon. Biotechnology (NY) 9: 13561361.
Ljungberg, K, Whitmore, AC, Fluet, ME, Moran, TP, Shabman, RS, Collier, ML, Kraus, AA, Thompson, JM, Montefiori, DC, Beard, C and Johnston, RE (2007). Increased immunogenicity of a DNA-launched Venezuelan equine encephalitis virus-based replicon DNA vaccine. Journal of Virology 81: 1341213423.
Lundstrom, K, Grayson, RJ, Richard, PJ and Francois, J (1999). Efficient in vivo expression of a reporter gene in a rat brain after injection of recombinant replication-deficient Semliki Forest virus. Gene Therapy and Molecular Biology 3: 1523.
MacDonald, GH and Johnston, RE (2000). Role of dendritic cell targeting in Venezuelan equine encephalitis virus pathogenesis. Journal of Virology 74: 914922.
Madsen, KG, Hansen, CM, Madsen, ES, Strandbygaard, B, Botner, A and Sorensen, KJ (1998). Sequence analysis of porcine reproductive and respiratory syndrome virus of the American type collected from Danish swine herds. Archives in Virology 143: 16831700.
Meeusen, ENT, Walker, J, Peters, A, Pastoret, PP and Jungersen, G (2007). Current status of veterinary vaccines. Clinical Microbiology Reviews 20: 489510.
Minke, JM, Audonnet, JC and Fischer, L (2004). Equine viral vaccines: the past, present and future. Veterinary Research 35: 425443.
Mogler, M (2009). Replicon particle PRRSV vaccine provides partial protection from challenge. Proceedings of the American Association of Swine Veterinarians 2009: 367368.
Mogler, M, Vander, Veen R, McVicker, J, Russell, B and Harris, DL (2010). Vaccination of pigs with PRRVENT or PRRSV-RP recombinant vaccines reduces viremia following heterologous challenge. Proceedings of the American Association of Swine Veterinarians 2010: 403404.
Morris-Downes, MM, Phenix, KV, Smyth, J, Sheahan, BJ, Lilegvist, S, Mooney, DA, Liljestrom, P, Todd, D and Atkins, GJ (2001). Semliki Forest virus-based vaccines: persistence, distribution and pathological analysis in two animal systems. Vaccine 19: 19781988.
Neumann, EJ, Kleibenstein, J, Johnson, C, Mabry, JW, Bush, EJ, Seitzinger, AH, Green, AL and Zimmerman, JJ (2005). Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. Journal of the American Veterinary Medical Association 227: 385392.
Nishimoto, KP, Laust, AK, Wang, K, Kamrud, KI, Hubby, B, Smith, JF and Nelson, EL (2007). Restricted and selective tropism of a Venezuelan equine encephalitis virus-derived replicon vector for human dendritic cells. Viral Immunology 20: 88–104.
Pittman, PR, Makuch, RS, Mangiafico, JA, Cannon, TL, Gibbs, PH and 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.
Polo, JM, Belli, BA, Driver, DA, Frolov, I, Sherrill, S, Hariharan, MJ, Townsend, K, Perri, S, Mento, SJ, Jolly, DJ, Chang, SMW, Schlesinger, S and Dubensky, TW Jr (1999). Stable alphavirus packaging cell lines for Sindbis virus- and Semliki Forest virus-derived vectors. Proceedings of the National Academy of Sciences of the United States of America 96: 45984603.
Pushko, P, Geisbert, J, Parker, M, Jahrling, P and Smith, J (2001). Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses. Journal of Virology 75: 1167711685.
Pushko, P, Parker, M, Ludwig, GV, Davis, NL, Johnston, RE and Smith, JF (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: 389401.
Rayner, JO, Dryga, SA and Kamrud, KI (2002). Alphavirus vectors and vaccination. Reviews in Medical Virology 12: 279296.
Reap, EA, Dryga, SA, Morris, J, Rivers, B, Norberg, PK, Olmsted, RA and Chulay, JD (2007a). Cellular and humoral immune responses to alphavirus replicon vaccines expressing cytomegalovirus pp65, IE1, and gB proteins. Clinical and Vaccine Immunology 14: 748755.
Reap, EA, Morris, J, Dryga, SA, Maughan, M, Talarico, T, Esch, RE, Negri, S, Burnett, B, Graham, A, Olmsted, RA and Chulay, JD (2007b). Development and preclinical evaluation of an alphavirus replicon particle vaccine for cytomegalovirus. Vaccine 25: 74417449.
Saxena, S, Dahiya, SS, Sonwane, AA, Patel, CL, Saini, M, Rai, A and Gupta, PK (2008). A Sindbis virus replicon-based DNA vaccine encoding the rabies virus glycoprotein elicits immune responses and complete protection in mice from lethal challenge. Vaccine 26: 65926601.
Schultz-Cherry, S, Dybing, JK, Davis, NL, Williamson, C, Suarez, DL, Johnston, R and Perdue, ML (2000). Influenza virus (A/HK/156/97) hemagglutinin expressed by an alphavirus replicon system protects chickens against lethal Infection with Hong Kong-origin H5N1 viruses. Virology 278: 5559.
Smerdou, C and Liljestrom, P (1999). Two-helper RNA system for production of recombinant Semliki Forest virus particles. Journal of Virology 73: 10921098.
Strauss, J and Strauss, E (1994). The alphaviruses: gene expression, replication, and evolution. Microbiological Reviews 58: 491562.
Sun, SQ, Liu, T, Guo, HC, Yin, SH, Shang, YJ, Feng, X, Liu, ZX and Xie, QG (2007). Protective immune responses in guinea pigs and swine induced by a suicidal DNA vaccine of the capsid gene of swine vesicular disease virus. Journal of General Virology 88: 842848.
Sylte, MJ, Hubby, B and Suarez, DL (2007). Influenza neuraminidase antibodies provide partial protection for chickens against high pathogenic avian influenza infection. Vaccine 25: 37693772.
Takkinen, K (1986). Complete nucleotide sequence of the nonstructural protein genes of Semliki Forest virus. Nucleic Acids Research 14: 56675682.
Thorner, AR, Lemckert, AAC, Goudsmit, J, Lynch, DM, Ewald, BA, Denholtz, M, Havenga, MJE and Barouch, DH (2006). Immunogenicity of heterologous recombinant adenovirus prime-boost vaccine regimens is enhanced by circumventing vector cross-reactivity. Journal of Virology 80: 1200912016.
Uttenthal, A, Parida, S, Rasmussen, TB, Paton, DJ, Haas, B and Dundon, WG (2010). Strategies for differentiating infection in vaccinated animals (DIVA) for foot-and-mouth disease, classical swine fever and avian influenza. Expert Reviews of Vaccines 9: 7387.
Vander Veen, RL, Kamrud, KI, Mogler, MA, Loynachan, AT, McVicker, J, Owens, G, Berglund, P, Timberlake, S, Whitney, L, Smith, J and Harris, DL (2009). Rapid development of an efficacious swine vaccine for novel H1N1. PLoS Currents Influenza 1: RRN1123.
Vander Veen, RL, Loynachan, AT, Mogler, MA, Russell, BJ, Harris, DL and Kamrud, KI (2012). Safety, immunogenicity, and efficacy of an alphavirus-based swine influenza virus hemagglutinin vaccine. Vaccine 11: 19441950.
Volkova, E, Gorchakov, R and Frolov, I (2006). The efficient packaging of Venezuelan equine encephalitis virus-specific RNAs into viral particles is determined by nsp1–3 synthesis. Virology 344: 315327.
Weiss, BG and Schlesinger, S (1991). Recombination between Sindbis virus RNAs. Journal of Virology 65: 40174025.
Yu, X, Xiao, S, Fang, L, Jiang, Y and Chen, H (2006). Enhanced immunogenicity to foot-and-mouth disease virus in mice following vaccination with alphaviral replicon-based DNA vaccine expressing the capsid precursor polypeptide (P1). Virus Genes 33: 337344.
Zhao, HP, Li, N, Sun, Y, Wang, Y and Qiu, HJ (2009a). Prime-boost immunization using alphavirus replicon and adenovirus vectored vaccines induces enhanced immune responses against classical swine fever virus in mice. Veterinary Immunology and Immunopathology 15: 158166.
Zhao, HP, Sun, JF, Li, N, Sun, Y, Xia, ZH, Wang, Y, Cheng, D, Qi, F, Jin, ML and Qiu, HJ (2009b). Assessment of the cell-mediated immunity induced by alphavirus replicon-vectored DNA vaccines against classical swine fever in a mouse model. Veterinary Immunology and Immunopathology 129: 5765.
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