microbeПроблемы особо опасных инфекцийProblems of Particularly Dangerous Infections0370-10692658-719XRussian Research Anti-Plague Institute “Microbe”10.21055/0370-1069-2014-3-86-91microbe-171Research ArticleИММУНОЛОГИЯIMMUNOLOGYПерспективы разработки и применения вакцин на основе РНК-репликона вируса венесуэльского энцефаломиелита лошадей против особо опасных вирусных инфекцийFuture Developments and Applications of the Vaccines against Dangerous Viral Infections, RNA-Replicon-Based, Obtained from the Venezuelan Equine Encephalomyelitis VirusПетровА. А.PetrovA. A.noemail@neicon.ruЛебедевВ. Н.LebedevV. N.noemail@neicon.ruПлехановаТ. М.PlekhanovaT. M.noemail@neicon.ruСтовбаЛ. Ф.StobvaL. F.noemail@neicon.ruСидороваО. Н.SidorovaO. N.noemail@neicon.ruМельниковаЕ. В.Mel’NikovaE. V.noemail@neicon.ruБорисевичС. В.BorisevichS. V.noemail@neicon.ru48 Центральный научно-исследовательский институт» Министерства обороныРоссияThe 48th Central Research Institute of the Ministry of DefenseRussian Federation201420092014038691Copyright © Петров А.А., Лебедев В.Н., Плеханова Т.М., Стовба Л.Ф., Сидорова О.Н., Мельникова Е.В., Борисевич С.В., 20142014Петров А.А., Лебедев В.Н., Плеханова Т.М., Стовба Л.Ф., Сидорова О.Н., Мельникова Е.В., Борисевич С.В.Petrov A.A., Lebedev V.N., Plekhanova T.M., Stobva L.F., Sidorova O.N., Mel’Nikova E.V., Borisevich S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.microbe.ru/jour/article/view/171

Представители семейства Filoviridae (вирусы Марбург, Эбола) и Arenaviridae (вирусы Ласса, Луйо, Мачупо, Хунин, Гуанарито, Сэбиа) являются этиологическими агентами особо опасных вирусных геморрагических лихорадок. Данные возбудители представляют потенциальную угрозу для здравоохранения вследствие возможности их случайного завоза в неэндемичные регионы, поэтому актуальным является вопрос о создании специфических медицинских средств защиты в отношении вызываемых ими заболеваний. По мнению ведущих специалистов, вакцинация групп риска является наиболее эффективным и экономичным способом защиты от развития эпидемии. В обзоре рассмотрено новое перспективное направление разработки защитных препаратов в отношении особо опасных вирусных инфекций - создание вакцин на основе репликонов альфавирусов. Разработка рекомбинантных репликонов не требует культивирования патогенных микроорганизмов. Особенностью РНК-репликонов является их неспособность продуцировать инфекционное потомство, что имеет особое значение при создании вакцин в отношении особо опасных вирусных геморрагических лихорадок. Преимущества альфавирусных репликонов перед другими РНК-репликонами при разработке вакцин заключаются в высоком уровне экспрессии гетерологичных генов и резистентности к анти-векторному иммунитету. РНК-репликоны альфавирусов сочетают безопасность инактивированных и иммуногенность живых аттенуированных вакцин. Репликоны на основе альфавирусов пригодны для экспрессной разработки вакцин с целью специфической профилактики вирусных инфекционных заболеваний.

The members of the Filoviridae (Marburg and Ebola viruses) and Arenaviridae (Lassa, Lujo, Machupo, Junin, Guanarito, Sabia viruses) families are the etiological agents of particularly dangerous viral hemorrhagic fevers. These agents pose a potential threat to public health care in view of the possibility of their unintended import into the non-endemic regions, and thus construction of specific medical protectors as regards induced by them diseases is a pressing issue. According to leading experts, vaccination of the cohorts that fall in the risk groups is the most effective and least expensive method to prevent the development of epidemics. The review contains information on a new prospective line of protective preparations development as regards particularly dangerous viral infections - construction of alphavirus-replicon-based vaccine. Elaboration of recombinant replicons does not require cultivation of pathogenic microorganisms. RNA-replicons are distinguished by their incapacity to produce infective progeny, which is of a great importance for the development of vaccines against particularly dangerous viral hemorrhagic fevers. Advantages of alphaviral replicons over other RNA-replicons are as follows: high levels of heterologous gene expression and resistance to anti-vector immunity. RNA-replicons of alphaviruses combine the safety of inactivated, and immunogenicity of live attenuated vaccines. Alphaviruses-based replicons are suitable for express vaccine development with the purpose of specific prophylaxis of viral infectious diseases.

вирус венесуэльского энцефаломиелита лошадейРНК-репликональфавирусыфиловирусыаренавирусывакцинaвекторVenezuelan equine encephalomyelitis virusRNA-repliconalphavirusesfilovirusesarenavirusesvaccinevectorReferencesAlbarino C.G., Bird B.H., Chakrabarti A.K., Dodd K.A., Erickson B.R., Nichol S.T. Efficient rescue of recombinant Lassa virus reveals the Influence of S segment noncoding regions on virus replication and virulence. J. Virol. 2011; 85(8):4020-4.Albarino C.G., Bird B.H., Chakrabarti A.K., Dodd K.A., Erickson B.R., Nichol S.T. Efficient rescue of recombinant Lassa virus reveals the Influence of S segment noncoding regions on virus replication and virulence. J. Virol. 2011; 85(8):4020–4.Balasuriya U.B.R., Heidner H.W., Davis N.L., Johnston R.E., Wagner H.M., Hullinger P.J., Hedges J.F., Williams J.C., Johnston R.E., David Wilson W., Liu I.K., James MacLachlan N. 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. 2002; 20:1609-17.Balasuriya U.B.R., Heidner H.W., Davis N.L., Johnston R.E., Wagner H.M., Hullinger P.J., Hedges J.F., Williams J.C., Johnston R.E., David Wilson W., Liu I.K., James MacLachlan N. 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. 2002; 20:1609–17.Bausch D.G., Geisbert T.W. Development of vaccines for Marburg hemorrhagic fever. Expert Rev. Vaccines. 2007; 6:57-74.Bausch D.G., Geisbert T.W. Development of vaccines for Marburg hemorrhagic fever. Expert Rev. Vaccines. 2007; 6:57–74.Branco L.M., Grove J.N., Geske F.J., Boisen M.L., Muncy I.J., Magliato S.A., Magliato S.A., Henderson L.A., Schoepp R.J., Cashman K.A., Hensley L.E., Garry R.F. Lassa virus-like particles displaying all major immunological determinants as a vaccine candidate for Lassa hemorrhagic fever. Virol. J. 2010; 7:279.Branco L.M., Grove J.N., Geske F.J., Boisen M.L., Muncy I.J., Magliato S.A., Magliato S.A., Henderson L.A., Schoepp R.J., Cashman K.A., Hensley L.E., Garry R.F. Lassa virus-like particles displaying all major immunological determinants as a vaccine candidate for Lassa hemorrhagic fever. Virol. J. 2010; 7:279.Bredenbeek P.J., Molenkamp R., Spaan W.J.M., Deubel V., Marianneau P., Salvato M.S., Moshkoff D., Zapata J., Tikhonov I., Patterson J., Carrion R., Ticer A., Brasky K., Lukashevich I.S. A recombinant yellow fever 17D vaccine expressing Lassa virus glycoproteins. Virology. 2006; 345(2):299-4.Bredenbeek P.J., Molenkamp R., Spaan W.J.M., Deubel V., Marianneau P., Salvato M.S., Moshkoff D., Zapata J., Tikhonov I., Patterson J., Carrion R., Ticer A., Brasky K., Lukashevich I.S. A recombinant yellow fever 17D vaccine expressing Lassa virus glycoproteins. Virology. 2006; 345(2):299–4.Davis N.L., West A., Reap E., MacDonald G., Collier M., Dryga S., Maughan M., Connell M., Walker C., McGrath K., Cecil C., Ping L.-H., Frelinger J., Olmsted R., Keith P., Swanstrom R., Williamson C., Johnson P., Montefiori D., Johnston R.E. Alphavirus replicon particles as candidate HIV vaccines. IUBMB Life. 2002; 53:209-11.Davis N.L., West A., Reap E., MacDonald G., Collier M., Dryga S., Maughan M., Connell M., Walker C., McGrath K., Cecil C., Ping L.-H., Frelinger J., Olmsted R., Keith P., Swanstrom R., Williamson C., Johnson P., Montefiori D., Johnston R.E. Alphavirus replicon particles as candidate HIV vaccines. IUBMB Life. 2002; 53:209–11.Dupuy L.C., Schmaljohn C.S. DNA vaccines for biodefence. Expert Rev. Vaccines. 2009; 8:1739-54.Dupuy L.C., Schmaljohn C.S. DNA vaccines for biodefence. Expert Rev. Vaccines. 2009; 8:1739–54.Falzarano D., Geisbert T.W., Feldmann H. Progress in filovirus vaccine development: evaluating the potential for clinical use. Expert Rev. Vaccines. 2011; 10:63-77.Falzarano D., Geisbert T.W., Feldmann H. Progress in filovirus vaccine development: evaluating the potential for clinical use. Expert Rev. Vaccines. 2011; 10:63–77.Feldman H., Klenk H.D., Sanchez A. Molecular biology and evolution of filoviruses. Arch. Virol. 1993; 7:81-100.Feldman H., Klenk H.D., Sanchez A. Molecular biology and evolution of filoviruses. Arch. Virol. 1993; 7:81–100.Fluet M.E., Whitemore A.C., Moshkoff D.A., Fu K., Tang Y., Collier M.L., West A., Moore D.T., Swanstrom R., Johnston R.E., Davis N.L. Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine. Virology. 2008; 370(1):22-32.Fluet M.E., Whitemore A.C., Moshkoff D.A., Fu K., Tang Y., Collier M.L., West A., Moore D.T., Swanstrom R., Johnston R.E., Davis N.L. Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine. Virology. 2008; 370(1):22–32.Grant-Klein R.J., Altamura L.A., Schmaljohn C.S. Progress in recombinant DNA-derived vaccines for Lassa virus and filoviruses. Virus Research. 2011; 162(1-2):148-61.Grant-Klein R.J., Altamura L.A., Schmaljohn C.S. Progress in recombinant DNA-derived vaccines for Lassa virus and filoviruses. Virus Research. 2011; 162(1–2):148–61.Hevey M., Negley D., Pushko P., Smith J., Schmaljohn A. Marburg virus vaccines based upon alphavirus replicons protects guinea pigs and nonhuman primates. Virology. 1998; 251(1):28-37.Hevey M., Negley D., Pushko P., Smith J., Schmaljohn A. Marburg virus vaccines based upon alphavirus replicons protects guinea pigs and nonhuman primates. Virology. 1998; 251(1):28–37.Hevey M.C., Negley D.L., Pushko P., Smith J.F., Schmaljohn A.L. Marburg Virus Vaccine. US Patent 6,517,842 B1, 2003.Hevey M.C., Negley D.L., Pushko P., Smith J.F., Schmaljohn A.L. Marburg Virus Vaccine. US Patent 6,517,842 B1, 2003.Lee J.S., Groebner J.L., Hadjipanayis A.G., Negley D.L., Schmaljohn A.L., Welkos S.L., Smith L.A., Smith J.F. 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. 2006; 24:6886-92.Lee J.S., Groebner J.L., Hadjipanayis A.G., Negley D.L., Schmaljohn A.L., Welkos S.L., Smith L.A., Smith J.F. 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. 2006; 24:6886–92.Lesley C.D., Schmaljohn C.S. DNA vaccines for biodefense. Expert Rev. Vaccines. 2009; 8(12):1739-54.Lesley C.D., Schmaljohn C.S. DNA vaccines for biodefense. Expert Rev. Vaccines. 2009; 8(12):1739–54.Ljungberg K., Whitmore A.C., Fluet M.E., Moran T.P., Shabman R.S., Collier M.L., Kraus A.A., Thompson J.M., Montefiori D.C., Beard C., Johnston R.E. Increased immunogenicity of a DNA-launched Venezuelan equine encephalitis virus-based replicon DNA vaccine. J. Virol. 2007; 81:13412-23.Ljungberg K., Whitmore A.C., Fluet M.E., Moran T.P., Shabman R.S., Collier M.L., Kraus A.A., Thompson J.M., Montefiori D.C., Beard C., Johnston R.E. Increased immunogenicity of a DNA-launched Venezuelan equine encephalitis virus-based replicon DNA vaccine. J. Virol. 2007; 81:13412–23.Lundstrom K. Alphavirus vectors for vaccine production and gene therapy. Expert Rev. Vaccines. 2003; 2:447-59.Lundstrom K. Alphavirus vectors for vaccine production and gene therapy. Expert Rev. Vaccines. 2003; 2:447–59.Nabel C., Yang Z., Sulliva N., Sanches A. Development of a preventive vaccine for filovirus infection in primates. US Patent 8,124,592 B2, 2012.Nabel C., Yang Z., Sulliva N., Sanches A. Development of a preventive vaccine for filovirus infection in primates. US Patent 8,124,592 B2, 2012.Papaneri A.B., Schnell M.J., Wirblich C., Cooper K., Jahrling P.B., Blaney J.E. Further characterization of the immune response in mice to inactivated and live rabies vaccines expressing Ebola virus glycoprotein. Vaccine. 2012; 30(43):6136-41.Papaneri A.B., Schnell M.J., Wirblich C., Cooper K., Jahrling P.B., Blaney J.E. Further characterization of the immune response in mice to inactivated and live rabies vaccines expressing Ebola virus glycoprotein. Vaccine. 2012; 30(43):6136–41.Peters C.J., Sanchez A., Rollin P.E., Ksiazek T.G., Murphy F.A. Filoviridae: Marburg and Ebola viruses. In: Fields B.N., Knipe D.M., Howley P.M., Chanock P.M., Memick J.L., Monath T.P., Roizman R., Straus S.E., editors. Virology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1996. P. 1161-76.Peters C.J., Sanchez A., Rollin P.E., Ksiazek T.G., Murphy F.A. Filoviridae: Marburg and Ebola viruses. In: Fields B.N., Knipe D.M., Howley P.M., Chanock P.M., Memick J.L., Monath T.P., Roizman R., Straus S.E., editors. Virology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1996. P. 1161–76.Peters C.J., Buchmeier M., Rollin P.E., Ksiazek Т.О. Arenaviridae. In: Fields B.N., Knipe D.M., Howley P.M. Chanock P.M., Memick J.L., Monath T.P., Roizman R., Straus S.E. editors. Virology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1996. P. 1521-51.Peters C.J., Buchmeier M., Rollin P.E., Ksiazek Т.О. Arenaviridae. In: Fields B.N., Knipe D.M., Howley P.M. Chanock P.M., Memick J.L., Monath T.P., Roizman R., Straus S.E. editors. Virology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1996. P. 1521–51.Pushko P., Geisbert J., Parker M., Jahrling P., Smith J. Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses. J. Virol. 2001; 75:11677-85.Pushko P., Geisbert J., Parker M., Jahrling P., Smith J. Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses. J. Virol. 2001; 75:11677–85.Radoshitzky S.R., Kuhn J.H., de Kok-Mercado F., Jahrling P.B., Bavari S. Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses. Exp. Opin. Drug Discov. 2012; 7(7):613-32.Radoshitzky S.R., Kuhn J.H., de Kok-Mercado F., Jahrling P.B., Bavari S. Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses. Exp. Opin. Drug Discov. 2012; 7(7):613–32.Rayner J.O., Dryga S.A., Kamrud K.I. Alphavirus vectors and vaccination. Rev. Med. Virol. 2002; 12(5):279-96.Rayner J.O., Dryga S.A., Kamrud K.I. Alphavirus vectors and vaccination. Rev. Med. Virol. 2002; 12(5):279–96.Richardson J.S., Yao M.K., Tran K.N., Croyle M.A., Strong J.E., Feldmann H., Kobinger G.P. Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine. PLoS One. 2009; 4(4):e5308. doi: 10.1371/journal.pone.0005308.Richardson J.S., Yao M.K., Tran K.N., Croyle M.A., Strong J.E., Feldmann H., Kobinger G.P. Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine. PLoS One. 2009; 4(4):e5308. doi: 10.1371/journal.pone.0005308.Smith J.F., Kamrud K.I., Rayner J.O. Alphavirus replicons and helper constructs. US Patent 7,442,381 B2, 2008.Smith J.F., Kamrud K.I., Rayner J.O. Alphavirus replicons and helper constructs. US Patent 7,442,381 B2, 2008.Seregin A.V., Yun N.E., Poussard A.L., Peng B.H., Smith J.K., Smith J.N., Salazar M., Paessler S. TC83 replicon vectored vaccine provides protection against Junin virus in guinea pigs. Vaccine. 2010; 28:4713-8.Seregin A.V., Yun N.E., Poussard A.L., Peng B.H., Smith J.K., Smith J.N., Salazar M., Paessler S. TC83 replicon vectored vaccine provides protection against Junin virus in guinea pigs. Vaccine. 2010; 28:4713–8.Swenson D.L., Wang D., Luo M., Warfield K.L., Woraratanadharm J., Holman D.H., Dong J.Y., Pratt W.D. Vaccine to confer to nonhuman primates complete protection against multistrain Ebola and Marburg virus infections. Clin. Vaccine Immunol. 2008; 15(3):460-7.Swenson D.L., Wang D., Luo M., Warfield K.L., Woraratanadharm J., Holman D.H., Dong J.Y., Pratt W.D. Vaccine to confer to nonhuman primates complete protection against multistrain Ebola and Marburg virus infections. Clin. Vaccine Immunol. 2008; 15(3):460–7.Swenson D.L., Warfield K.L., Larsen T., Alves D.A., Coberley S.S., Bavari S. Monovalent virus-like particle vaccine protect guinea pigs and nonhuman primates against infection with multiple Marburg virus. Exp. Rev. Vaccines. 2008; 7:417-29.Swenson D.L., Warfield K.L., Larsen T., Alves D.A., Coberley S.S., Bavari S. Monovalent virus-like particle vaccine protect guinea pigs and nonhuman primates against infection with multiple Marburg virus. Exp. Rev. Vaccines. 2008; 7:417–29.Thompson J.M., Whitmore A.C., Konopka J.L., Collier M.L., Richmond E.M., Davis N.L., Staats H.F., Johnston R.E. Mucosal and systemic adjuvant activity of alphavirus replicon particles. Proc. Natl. Acad. Sci. USA. 2006; 103(10):3722-7.Thompson J.M., Whitmore A.C., Konopka J.L., Collier M.L., Richmond E.M., Davis N.L., Staats H.F., Johnston R.E. Mucosal and systemic adjuvant activity of alphavirus replicon particles. Proc. Natl. Acad. Sci. USA. 2006; 103(10):3722–7.Vander Veen R.L., Harris D.L., Kamrud K.I. Alphavirus replicon vaccines. Anim. Health Res. Rev. 2012; 13:1-9.Vander Veen R.L., Harris D.L., Kamrud K.I. Alphavirus replicon vaccines. Anim. Health Res. Rev. 2012; 13:1–9.Vander Veen R.L., Loynachan A.T. Mogler M.A., Russell B.J., Harris D.L., Kamrud K.I. Safety, immunogenicity, and efficacy of an alphavirus replicon-based swine influenza virus hemagglutinin vaccine. Vaccine. 2012; 30:1944-50.Vander Veen R.L., Loynachan A.T. Mogler M.A., Russell B.J., Harris D.L., Kamrud K.I. Safety, immunogenicity, and efficacy of an alphavirus replicon-based swine influenza virus hemagglutinin vaccine. Vaccine. 2012; 30:1944–50.Wang D., Raja N.U., Trubey C.M., Juompan L.Y., Luo M., Woraratanadharm J., Deitz S.B., Yu H., Swain B.M., Moore K.M., Pratt W.D., Hart M.K., Dong J.Y. Development of a cAdVax-based bivalent Ebola virus vaccine that induces immune responses against both the Sudan and Zaire species of Ebola virus. J. Virol. 2006; 80:2738-46.Wang D., Raja N.U., Trubey C.M., Juompan L.Y., Luo M., Woraratanadharm J., Deitz S.B., Yu H., Swain B.M., Moore K.M., Pratt W.D., Hart M.K., Dong J.Y. Development of a cAdVax-based bivalent Ebola virus vaccine that induces immune responses against both the Sudan and Zaire species of Ebola virus. J. Virol. 2006; 80:2738–46.Warfield K.L., Aman M.J. Advances in virus-like particle vaccines for filoviruses. J. Infect. Dis. 2011; 204(Suppl. 3):S1053-9.Warfield K.L., Aman M.J. Advances in virus-like particle vaccines for filoviruses. J. Infect. Dis. 2011; 204(Suppl. 3):S1053–9.Zimmer G. RNA replicons - a new approach for influenza virus immunoprophylaxis. Viruses. 2010; 2:413-34.Zimmer G. RNA replicons – a new approach for influenza virus immunoprophylaxis. Viruses. 2010; 2:413–34.

The authors declare that there are no conflicts of interest present.