Are We Prepared in Case of a Possible Smallpox-Like Disease Emergence?

Victoria A Olson, Sergei N Shchelkunov, Victoria A Olson, Sergei N Shchelkunov

Abstract

Smallpox was the first human disease to be eradicated, through a concerted vaccination campaign led by the World Health Organization. Since its eradication, routine vaccination against smallpox has ceased, leaving the world population susceptible to disease caused by orthopoxviruses. In recent decades, reports of human disease from zoonotic orthopoxviruses have increased. Furthermore, multiple reports of newly identified poxviruses capable of causing human disease have occurred. These facts raise concerns regarding both the opportunity for these zoonotic orthopoxviruses to evolve and become a more severe public health issue, as well as the risk of Variola virus (the causative agent of smallpox) to be utilized as a bioterrorist weapon. The eradication of smallpox occurred prior to the development of the majority of modern virological and molecular biological techniques. Therefore, there is a considerable amount that is not understood regarding how this solely human pathogen interacts with its host. This paper briefly recounts the history and current status of diagnostic tools, vaccines, and anti-viral therapeutics for treatment of smallpox disease. The authors discuss the importance of further research to prepare the global community should a smallpox-like virus emerge.

Keywords: Variola virus; antivirals; smallpox; vaccine.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Fenner F., Henderson D.A., Arita I., Jezek Z., Ladnyi I.D. Smallpox and Its Eradication. World Health Organization; Geneva, Switzerland: 1988. p. 1460.
    1. Shchelkunov S.N., Marennikova S.S., Moyer R.W. Orthopoxviruses Pathogenic for Humans. Springer; New York, NY, USA: 2005. p. 425.
    1. Kupferschmidt K. Science. [(accessed on 6 June 2017)]; Available online: .
    1. Shchelkunov S.N. An increasing danger of zoonotic orthopoxvirus infections. PLoS Pathog. 2013;9:e1003756. doi: 10.1371/journal.ppat.1003756.
    1. Essbauer S., Pfeffer M., Meyer H. Zoonotic poxviruses. Vet. Microbiol. 2010;140:229–236. doi: 10.1016/j.vetmic.2009.08.026.
    1. Di Giulio D.B., Eckburg P.B. Human monkeypox: An emerging zoonosis. Lancet Infect. Dis. 2004;4:15–25. doi: 10.1016/S1473-3099(03)00856-9.
    1. McCollum A.M., Damon I.K. Human monkeypox. Clin. Infect. Dis. 2014;58:260–267. doi: 10.1093/cid/cit703.
    1. Rimoin A.W., Mulembakani P.M., Johnston S.C., Lloyd Smith J.O., Kisalu N.K., Kinkela T.L., Blumberg S., Thomassen H.A., Pike B.L., Fair J.N., et al. Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. Proc. Natl. Acad. Sci. USA. 2010;107:16262–16267. doi: 10.1073/pnas.1005769107.
    1. Reynolds M.G., Carroll D.S., Karem K.L. Factors affecting the likelihood of monkeypox’s emergence and spread in the post-smallpox era. Curr. Opin. Virol. 2012;2:335–343. doi: 10.1016/j.coviro.2012.02.004.
    1. Campe H., Zimmermann P., Glos K., Bayer M., Bergemann H., Dreweck C., Graf P., Weber B.K., Meyer H., Büttner M., et al. Cowpox virus transmission from pet rats to humans, Germany. Emerg. Infect. Dis. 2009;15:777–780. doi: 10.3201/eid1505.090159.
    1. Ninove L., Domart Y., Vervel C., Voinot C., Salez N., Raoult D., Meyer H., Capek I., Zandotti C., Charrel R.N. Cowpox virus transmission from pet rats to humans, France. Emerg. Infect. Dis. 2009;15:781–784. doi: 10.3201/eid1505.090235.
    1. Kurth A., Straube M., Kuczka A., Dunsche A.J., Meyer H., Nitsche A. Cowpox virus outbreak in banded mongooses (Mungos mungo) and jaguarundis (Herpailurus yagouaroundi) with a time-delayed infection to humans. PLoS ONE. 2009;4:e6883. doi: 10.1371/journal.pone.0006883.
    1. Favier A.L., Flusin O., Lepreux S., Fleury H., Labreze C., Georges A., Crance J.M., Boralevi F. Necrotic ulcerated lesion in a young boy caused by Cowpox virus infection. Case Rep. Dermatol. 2011;3:186–194. doi: 10.1159/000331426.
    1. Switaj K., Kajfasz P., Kurth A., Nitsche A. Cowpox after a cat scratch—Case report from Poland. Ann. Agric. Environ. Med. 2015;22:456–458. doi: 10.5604/12321966.1167713.
    1. Popova A.Y., Maksyutov R.A., Taranov O.S., Tregubchak T.V., Zaikovskaya A.V., Sergeev A.A., Vlashchenko I.V., Bodnev S.A., Ternovoi V.A., Alexandrova N.S., et al. Cowpox in a human, Russia, 2015. Epidemiol. Infect. 2017;145:755–759. doi: 10.1017/S0950268816002922.
    1. Bhanuprakash V., Venkatesan G., Balamurugan V., Hosamani M., Yogisharadhya R., Gandhale P., Reddy K.V., Damle A.S., Kher H.N., Chandel B.S., et al. Zoonotic infections of buffalopox in India. Zoonoses Public Health. 2010;57:e149–e155. doi: 10.1111/j.1863-2378.2009.01314.x.
    1. Venkatesan G., Balamurugan V., Prabhu M., Yogisharadhya R., Bora D.P., Gandhale P.N., Sankar M.S., Kulkarni A.M., Singh R.K., Bhanuprakash V. Emerging and re-emerging zoonotic buffalopox infection: A severe outbreak in Kolhapur (Maharashtra), India. Vet. Ital. 2010;46:439–448.
    1. Singh R.K., Balamurugan V., Bhanuprakash V., Venkatesan G., Hosamani M. Emergence and reemergence of vaccinia-like viruses: Global scenario and perspectives. Indian J. Virol. 2012;23:1–11. doi: 10.1007/s13337-012-0068-1.
    1. Megid J., Borges I.A., Abrahao J.S., Trindade G.S., Appolinario C.M., Ribeiro M.G., Allendorf S.D., Antunes J.M., Silva-Fernandes A.T., Kroon E.G. Vaccinia virus zoonotic infection, Sao Paulo State, Brazil. Emerg. Infect. Dis. 2012;18:189–191. doi: 10.3201/eid1801.110692.
    1. De Assis F.L., Vinhote W.M., Barbosa J.D., de Oliveira C.H., de Oliveira C.M., Campos K.F., Silva N.S., Trindade G.S. Reemergence of Vaccinia virus during Zoonotic outbreak, Para State, Brazil. Emerg. Infect. Dis. 2013;19:2017–2020. doi: 10.3201/eid1912.130589.
    1. Abrahao J.S., Campos R.K., Trindade G.S., Guimaraes da Fonseca F., Ferreira P.C., Kroon E.G. Outbreak of severe zoonotic Vaccinia virus infection, Southeastern Brazil. Emerg. Infect. Dis. 2015;21:695–698. doi: 10.3201/eid2104.140351.
    1. Costa G.B., Borges I.A., Alves P.A., Miranda J.B., Luiz A.P., Ferreira P.C., Abrahao J.S., Moreno E.C., Kroon E.G., Trindade G.S. Alternative Routes of Zoonotic Vaccinia virus Transmission, Brazil. Emerg. Infect. Dis. 2015;21:2244–2246. doi: 10.3201/eid2112.141249.
    1. Bera B.C., Shanmugasundaram K., Barua S., Venkatesan G., Virmani N., Riyesh T., Gulati B.R., Bhanuprakash V., Vaid R.K., Kakker N.K., et al. Zoonotic cases of camelpox infection in India. Vet. Microbiol. 2011;152:29–38. doi: 10.1016/j.vetmic.2011.04.010.
    1. Balamurugan V., Venkatesan G., Bhanuprakash V., Singh R.K. Camelpox, an emerging orthopox viral disease. Indian J. Virol. 2013;24:295–305. doi: 10.1007/s13337-013-0145-0.
    1. Cann J.A., Jahrling P.B., Hensley L.E., Wahl-Jensen V. Comparative pathology of smallpox and monkeypox in man and macaques. J. Comp. Pathol. 2013;148:6–21. doi: 10.1016/j.jcpa.2012.06.007.
    1. Czerny C.P., Eis-Hubinger A.M., Mayr A., Schneweis K.E., Pfeiff B. Animal poxviruses transmitted from cat to man: Current event with lethal end. J. Vet. Med. 1991;1338:421–431. doi: 10.1111/j.1439-0450.1991.tb00891.x.
    1. Fassbender P., Zange S., Ibrahim S., Zoeller G., Herbstreit F., Meyer H. Generalized Cowpox virus infection in a patient with HIV, Germany, 2012. Emerg. Infect. Dis. 2016;22:553–555. doi: 10.3201/eid2203.151158.
    1. Khalafalla A.I., Abdelazim F. Human and Dromedary Camel Infection with Camelpox virus in Eastern Sudan. Vector-Borne Zoonotic Dis. 2017;17:281–284. doi: 10.1089/vbz.2016.2070.
    1. Shchelkunov S.N., Resenchuk S.M., Totmenin A.V., Blinov V.M., Marennikova S.S., Sandakhchiev L.S. Comparison of the genetic maps of variola and Vaccinia viruses. FEBS Lett. 1993;327:321–324. doi: 10.1016/0014-5793(93)81013-P.
    1. Massung R.F., Liu L.I., Qi J., Knight J.C., Yuran T.E., Kerlavage A.R., Parsons J.M., Venter J.C., Esposito J.J. Analysis of the complete genome of smallpox variola major virus strain Bangladesh-1975. Virology. 1994;201:215–240. doi: 10.1006/viro.1994.1288.
    1. Shchelkunov S.N. Functional organization of variola major and Vaccinia virus genomes. Virus Genes. 1995;10:53–71. doi: 10.1007/BF01724297.
    1. Shchelkunov S.N., Massung R.F., Esposito J.J. Comparison of the genome DNA sequences of Bangladesh-1975 and India-1967 Variola viruses. Virus Res. 1995;36:107–118. doi: 10.1016/0168-1702(94)00113-Q.
    1. Massung R.F., Loparev V.N., Knight J.C., Totmenin A.V., Chizhikov V.E., Parsons J.M., Safronov P.F., Gutorov V.V., Shchelkunov S.N., Esposito J.J. Terminal region sequence variations in Variola virus DNA. Virology. 1996;221:291–300. doi: 10.1006/viro.1996.0378.
    1. Shchelkunov S.N., Totmenin A.V., Loparev V.N., Safronov P.F., Gutorov V.V., Chizhikov V.E., Knight J.C., Parsons J.M., Massung R.F., Esposito J.J. Alastrim smallpox variola minor virus genome DNA sequences. Virology. 2000;266:361–386. doi: 10.1006/viro.1999.0086.
    1. Esposito J.J., Sammons S.A., Frace A.M., Osborne J.D., Olsen-Rasmussen M., Zhang M., Govil D., Damon I.K., Kline R., Laker M., et al. Genome sequence diversity and clues to the evolution of variola (smallpox) virus. Science. 2006;313:807–812. doi: 10.1126/science.1125134.
    1. Shchelkunov S.N., Totmenin A.V., Babkin I.V., Safronov P.F., Ryazankina O.I., Petrov N.A., Gutorov V.V., Uvarova E.A., Mikheev M.V., Sisler J.R., et al. Human monkeypox and smallpox viruses: Genomic comparison. FEBS Lett. 2001;509:66–70. doi: 10.1016/S0014-5793(01)03144-1.
    1. Shchelkunov S.N., Totmenin A.V., Safronov P.F., Mikheev M.V., Gutorov V.V., Ryazankina O.I., Petrov N.A., Babkin I.V., Uvarova E.A., Sandakhchiev L.S., et al. Analysis of the Monkeypox virus genome. Virology. 2002;297:172–194. doi: 10.1006/viro.2002.1446.
    1. Likos A.M., Sammons S.A., Olson V.A., Frace A.M., Li Y., Olsen-Rasmussen M., Davidson W., Galloway R., Khristova M.L., Reynolds M.G., et al. A tale of two clades: Monkeypox viruses. J. Gen. Virol. 2005;86:2661–2672. doi: 10.1099/vir.0.81215-0.
    1. Shchelkunov S.N., Safronov P.F., Totmenin A.V., Petrov N.A., Ryazankina O.I., Gutorov V.V., Kotwal G.J. The genomic sequence analysis of the left and right species-specific terminal region of a Cowpox virus strain reveals unique sequences and a cluster of intact ORFs for immunomodulatory and host range proteins. Virology. 1998;243:432–460. doi: 10.1006/viro.1998.9039.
    1. Carroll D.S., Emerson G.L., Li Y., Sammons S., Olson V., Frace M., Nakazawa Y., Czerny C.P., Tryland M., Kolodziejek J., et al. Chasing Jenner’s vaccine: Revisiting Cowpox virus classification. PLoS ONE. 2011;6:e23086. doi: 10.1371/journal.pone.0023086.
    1. Dabrowski P.W., Radonic A., Kurth A., Nitsche A. Genome-wide comparison of Cowpox viruses reveals a new clade related to Variola virus. PLoS ONE. 2013;8:e79953. doi: 10.1371/journal.pone.0079953.
    1. Goebel S.J., Johnson G.P., Perkus M.E., Davis S.W., Winslow J.P., Paoletti E. The complete DNA sequence of Vaccinia virus. Virology. 1990;179:247–266. doi: 10.1016/0042-6822(90)90294-2.
    1. Antoine G., Scheiflinger F., Dorner F., Falkner F.G. The complete genomic sequence of the modified vaccinia Ankara strain: Comparison with other orthopoxviruses. Virology. 1998;244:365–396. doi: 10.1006/viro.1998.9123.
    1. Gubser C., Smith G.L. The sequence of Camelpox virus shows it is most closely related to Variola virus, the cause of smallpox. J. Gen. Virol. 2002;83:855–872. doi: 10.1099/0022-1317-83-4-855.
    1. Afonso C.L., Tulman E.R., Lu Z., Zsak L., Sandybaev N.T., Kerembekova U.Z., Zaitsev V.L., Kutish G.F., Rock D.L. The genome of Camelpox virus. Virology. 2002;295:1–9. doi: 10.1006/viro.2001.1343.
    1. Uvarova E.A., Shchelkunov S.N. Species-specific differences in the structure of orthopoxvirus complement-binding protein. Virus Res. 2001;81:39–45. doi: 10.1016/S0168-1702(01)00332-X.
    1. Shchelkunov S., Totmenin A., Kolosova I. Species-specific differences in organization of orthopoxvirus Kelch-like proteins. Virus Genes. 2002;24:157–162. doi: 10.1023/A:1014524717271.
    1. Shchelkunov S.N. Interaction of orthopoxviruses with the cellular ubiquitin-ligase system. Virus Genes. 2010;41:309–318. doi: 10.1007/s11262-010-0519-y.
    1. Shchelkunov S.N. Orthopoxvirus genes that mediate disease virulence and host tropism. Adv. Virol. 2012;2012:524743. doi: 10.1155/2012/524743.
    1. Hendrickson R.C., Wang C., Hatcher E.L., Lefkowitz E.J. Orthopoxvirus genome evolution: The role of gene loss. Viruses. 2010;2:1933–1967. doi: 10.3390/v2091933.
    1. Coulson D., Upton C. Characterization of indels in poxvirus genomes. Virus Genes. 2011;42:171–177.
    1. Shchelkunov S.N. Emergence and reemergence of smallpox: The need in development of a new generation smallpox vaccine. Vaccine. 2011;29:D49–D53. doi: 10.1016/j.vaccine.2011.05.037.
    1. Babkina I.N., Babkin I.V., Li Y., Ropp S., Kline R., Damon I., Esposito J., Sandakhchiev L.S., Shchelkunov S.N. Phylogenetic comparison of the genomes of different strains of Variola virus. Dokl. Biochem. Biophys. 2004;398:818–822. doi: 10.1023/B:DOBI.0000046648.51758.9f.
    1. Babkin I.V., Shchelkunov S.N. The time scale in poxvirus evolution. Mol. Biol. 2006;40:16–19. doi: 10.1134/S0026893306010031.
    1. Li Y., Carroll D.S., Gardner S.N., Walsh M.C., Vitalis E.A., Damon I.K. On the origin of smallpox: Correlating variola phylogenics with historical smallpox records. Proc. Natl. Acad. Sci. USA. 2007;104:15787–15792. doi: 10.1073/pnas.0609268104.
    1. Babkin I.V., Shchelkunov S.N. Molecular evolution of poxviruses. Russ. J. Genet. 2008;44:895–908. doi: 10.1134/S1022795408080036.
    1. Shchelkunov S.N. How long ago did smallpox virus emerge? Arch. Virol. 2009;154:1865–1871. doi: 10.1007/s00705-009-0536-0.
    1. Duggan A.T., Perdomo M.F., Piombino-Mascali D., Marciniak S., Poinar D., Emery M.V., Buchmann J.P., Duchene S., Jankauskas R., Humphreys M., et al. 17th Century Variola virus Reveals the Recent History of Smallpox. Curr. Biol. 2016;26:3407–3412. doi: 10.1016/j.cub.2016.10.061.
    1. WHO. [(accessed on 19 July 2017)]; Available online:
    1. CDC. [(accessed on 19 July 2017)]; Available online: .
    1. Bej A.K., Mahbubani M.H., Dicesare J.L., Atlas R.M. Polymerase chain reaction-gene probe detection of microorganisms by using filter-concentrated samples. Appl. Environ. Microbiol. 1991;57:3529–3534.
    1. Arens M. Methods for subtyping and molecular comparison of human viral genomes. Clin. Microbiol. Rev. 1999;12:612–626.
    1. Ropp S.L., Jin Q.I., Knight J.C., Massung R.F., Esposito J.J. Polymerase chain reaction strategy for identification and differentiation of smallpox and other ortopoxviruses. J. Clin. Microbiol. 1995;33:2069–2076.
    1. Meyer H., Ropp S.L., Esposito J.J. Gene for A-type inclusion body protein is useful for a polymerase chain reaction assay to differentiate orthopoxviruses. J. Virol. Methods. 1997;64:217–221. doi: 10.1016/S0166-0934(96)02155-6.
    1. Loparev V.N., Massung R.F., Esposito J.J., Meyer H. Detection and differentiation of Old World orthopoxviruses: Restriction fragment length polymorphism of the crmB gene region. J. Clin. Microbiol. 2001;39:94–100. doi: 10.1128/JCM.39.1.94-100.2001.
    1. Shchelkunov S.N., Gavrilova E.V., Babkin I.V. Multiplex PCR detection and species differentiation of orthopoxviruses pathogenic to humans. Mol. Cell. Probes. 2005;19:1–8. doi: 10.1016/j.mcp.2004.07.004.
    1. Espy M.J., Cockerill F.R., Meyer F.R., Bowen M.D., Poland G.A., Hadfield T.L., Smith T.F. Detection of smallpox virus DNA by LightCycler PCR. J. Clin. Microbiol. 2002;40:1985–1988. doi: 10.1128/JCM.40.6.1985-1988.2002.
    1. Ibrahim M.S., Kulesh D.A., Saleh S.S., Damon I.K., Esposito J.J., Schmaljohn A.L., Jahrling P.B. Real-time PCR assay to detect smallpox virus. J. Clin. Microbiol. 2003;41:3835–3839. doi: 10.1128/JCM.41.8.3835-3839.2003.
    1. Olson V.A., Laue T., Laker M.T., Babkin I.V., Drosten C., Shchelkunov S.N., Niedrig M., Damon I.K., Meyer H. Real-time PCR system for detection of orthopoxviruses and simultaneous identification of smallpox virus. J. Clin. Microbiol. 2004;42:1940–1946. doi: 10.1128/JCM.42.5.1940-1946.2004.
    1. Kulesh D.A., Baker R.O., Loveless B.M., Norwood D., Zwiers S.H., Mucker E., Hartmann C., Herrera R., Miller D., Christensen D., et al. Smallpox and pan-orthopox virus detection by real-time 3′-minor groove binder TaqMan assays on the roche LightCycler and the Cepheid smart Cycler platforms. J. Clin. Microbiol. 2004;42:601–609. doi: 10.1128/JCM.42.2.601-609.2004.
    1. Nitsche A., Ellerbrok H., Pauli G. Detection of orthopoxvirus DNA by real-time PCR and identification of Variola virus DNA by melting analysis. J. Clin. Microbiol. 2004;42:1207–1213. doi: 10.1128/JCM.42.3.1207-1213.2004.
    1. Panning M., Asper M., Kramme S., Schmitz H., Drosten C. Rapid detection and differentiation of human pathogenic orthopox viruses by a fluorescence resonance energy transfer real-time pcr assay. Clin. Chem. 2004;50:702–708. doi: 10.1373/clinchem.2003.026781.
    1. Carletti F., Di Caro A., Calcaterra S., Grolla A., Czub M., Ippolito G., Capobianchi M.R., Horejsh D. Rapid, differential diagnosis of orthopox- and herpesviruses based upon real-time pcr product melting temperature and restriction enzyme analysis of amplicons. J. Virol. Methods. 2005;129:97–100. doi: 10.1016/j.jviromet.2005.05.020.
    1. Nitsche A., Steger B., Ellerbrok H., Pauli G. Detection of Vaccinia virus DNA on the lightcycler by fluorescence melting curve analysis. J. Virol. Methods. 2005;126:187–195. doi: 10.1016/j.jviromet.2005.02.007.
    1. Fedele C.G., Negredo A., Molero F., Sanchez-Seco M.P., Tenorio A. Use of internally controlled real-time genome amplification for detection of Variola virus and other orthopoxviruses infecting humans. J. Clin. Microbiol. 2006;44:4464–4470. doi: 10.1128/JCM.00276-06.
    1. Li Y., Olson V.A., Laue T., Laker M.T., Damon I.K. Detection of Monkeypox virus with real-time PCR assays. J. Clin. Virol. 2006;36:194–203. doi: 10.1016/j.jcv.2006.03.012.
    1. Aitichou M., Javorschi S., Ibrahim M.S. Two-color multiplex assay for the identification of orthopox viruses with real-time lux-PCR. Mol. Cell. Probes. 2005;19:323–328. doi: 10.1016/j.mcp.2005.05.003.
    1. Scaramozzino N., Ferrier-Rembert A., Favier A.L., Rothlisberger C., Richard S., Crance J.M., Meyer H., Garin D. Real-time PCR to identify Variola virus or other human pathogenic orthopox viruses. Clin. Chem. 2007;53:606–613. doi: 10.1373/clinchem.2006.068635.
    1. Putkuri N., Piiparinen H., Vaheri A., Vapalahti O. Detection of human orthopoxvirus infections and differentiation of smallpox virus with real-time PCR. J. Med. Virol. 2009;81:146–152. doi: 10.1002/jmv.21385.
    1. Loveless B.M., Mucker E.M., Hartmann C., Craw P.D., Huggins J., Kulesh D.A. Differentiation of Variola major and Variola minor variants by MGB-Eclipse probe melt curves and genotyping analysis. Mol. Cell. Probes. 2009;23:166–170. doi: 10.1016/j.mcp.2009.03.002.
    1. Li Y., Zhao H., Wilkins K., Hughes C., Damon I.K. Real-time pcr assays for the specific detection of Monkeypox virus west african and congo basin strain DNA. J. Virol. Methods. 2010;169:223–227. doi: 10.1016/j.jviromet.2010.07.012.
    1. Schroeder K., Nitsche A. Multicolour, multiplex real-time pcr assay for the detection of human-pathogenic poxviruses. Mol. Cell. Probes. 2010;24:110–113. doi: 10.1016/j.mcp.2009.10.008.
    1. Kondas A.V., Olson V.A., Li Y., Abel J., Laker M., Rose L., Wilkins K., Turner J., Kline R., Damon I.K. Variola virus-specific diagnostic assays: Characterization, sensitivity, and specificity. J. Clin. Microbiol. 2015;53:1406–1410. doi: 10.1128/JCM.03613-14.
    1. Maksyutov R.A., Gavrilova E.V., Meyer H., Shchelkunov S.N. Real-time PCR assay for specific detection of Cowpox virus. J. Virol. Methods. 2015;211:8–11. doi: 10.1016/j.jviromet.2014.10.004.
    1. Maksyutov R.A., Gavrilova E.V., Shchelkunov S.N. Species-specific differentiation of variola, monkeypox, and varicella-zoster viruses by multiplex real-time PCR assay. J. Virol. Methods. 2016;236:215–220. doi: 10.1016/j.jviromet.2016.07.024.
    1. Shchelkunov S.N., Shcherbakov D.N., Maksyutov R.A., Gavrilova E.V. Species-specific identification of variola, monkeypox, cowpox, and Vaccinia viruses by multiplex real-time PCR assay. J. Virol. Methods. 2011;175:163–169. doi: 10.1016/j.jviromet.2011.05.002.
    1. Li D., Wilkins K., McCollum A.M., Osadebe L., Kabamba J., Nquete B., Likafi T., Balilo M.P., Lushima R.S., Malekani J., et al. Evaluation of the GeneXpert for human monkeypox diagnosis. Am. J. Trop. Med. Hyg. 2017;96:405–410. doi: 10.4269/ajtmh.16-0567.
    1. Lapa S., Mikheev M., Shchelkunov S., Mikhailovich V., Sobolev A., Blinov V., Babkin I., Guskov A., Sokunova E., Zasedatelev A., et al. Species-level identification of orthopoxviruses with an oligonucleotide microchip. J. Clin. Microbiol. 2002;40:753–757. doi: 10.1128/JCM.40.3.753-757.2002.
    1. Laassri M., Chizhikov V., Mikheev M., Shchelkunov S., Chumakov K. Detection and discrimination of orthopoxviruses using microarrays of immobilized oligonucleotides. J. Virol. Methods. 2003;112:67–78. doi: 10.1016/S0166-0934(03)00193-9.
    1. Ryabinin V.A., Shundrin L.A., Kostina E.B., Laassri M., Chizhikov V., Shchelkunov S.N., Chumakov K., Sinyakov A.N. Microarray assay for detection and discrimination of Orthopoxvirus species. J. Med. Virol. 2006;78:1325–1340. doi: 10.1002/jmv.20698.
    1. Fitzgibbon J.E., Sagripanti J.L. Simultaneous identification of orthopoxviruses and alphaviruses by oligonucleotide macroarray with special emphasis on detection of variola and Venezuelan equine encephalitis viruses. J. Virol. Methods. 2006;131:160–167. doi: 10.1016/j.jviromet.2005.08.007.
    1. Vora N.M., Li Y., Geleishvili M., Emerson G.L., Khmaladze E., Maghlakelidze G., Navdarashvili A., Zakhashvili K., Kokhreidze M., Endeladze M., et al. Human infection with a zoonotic orthopoxvirus in the country of Georgia. N. Engl. J. Med. 2015;372:1223–1230. doi: 10.1056/NEJMoa1407647.
    1. Springer Y.P., Hsu C.H., Werle Z.R., Olson L.E., Cooper M.P., Castrodale L.J., Fowler N., McCollum A.M., Goldsmith C.S., Emerson G.L., et al. Novel Orthopoxvirus infection in an Alaska resident. Clin. Infect. Dis. 2017;64:1737–1741. doi: 10.1093/cid/cix219.
    1. Sanchez-Sampedro L., Perdiguero B., Mejias-Perez E., Garcia-Arriaza J., Di Pilato M., Esteban M. The evolution of poxvirus vaccines. Viruses. 2015;7:1726–1803. doi: 10.3390/v7041726.
    1. Qin L., Upton C., Hazes B., Evans D.H. Genomic analysis of the Vaccinia virus strain variants found in Dryvax vaccine. J. Virol. 2011;85:13049–13060. doi: 10.1128/JVI.05779-11.
    1. Qin L., Liang M., Evans D.H. Genomic analysis of Vaccinia virus strain TianTan provides new insights into the evolution and evolutionary relationships between Orthopoxviruses. Virology. 2013;442:59–66. doi: 10.1016/j.virol.2013.03.025.
    1. Zhang Q., Tian M., Feng Y., Zhao K., Xu J., Liu Y., Shao Y. Genomic sequence and virulence of clonal isolates of Vaccinia virus Tiantan, the Chinese smallpox vaccine strain. PLoS ONE. 2013;8:e60557. doi: 10.1371/journal.pone.0060557.
    1. Damon I.K., Davidson W.B., Hughes C.M., Olson V.A., Smith S.K., Holman R.C., Frey S.E., Newman F., Belshe R.B., Yan L., et al. Evaluation of smallpox vaccines using variola neutralization. J. Gen. Virol. 2009;90:1962–1966. doi: 10.1099/vir.0.010553-0.
    1. Weltzin R., Liu J., Pugachev K.V., Myers G.A., Coughlin B., Blum P.S., Nichols R., Johnson C., Cruz J., Kennedy J.S., et al. Clonal Vaccinia virus grown in cell culture as a new smallpox vaccine. Nat. Med. 2003;9:1125–1130. doi: 10.1038/nm916.
    1. Monath T.P., Caldwell J.R., Mundt W., Fusco J., Johnson C.S., Buller M., Liu J., Gardner B., Downing G., Blum P.S., et al. ACAM2000 clonal Vero cell culture Vaccinia virus (New York City Board of Health strain)—a second-generation smallpox vaccine for biological defense. Int. J. Infect. Dis. 2004;8:31–44. doi: 10.1016/j.ijid.2004.09.002.
    1. Osborne J.D., Da Silva M., Frace A.M., Sammons S.A., Olsen-Rasmussen M., Upton C., Buller R.M., Chen N., Feng Z., Roper R.L., et al. Genomic differences of Vaccinia virus clones from Dryvax smallpox vaccine: The Dryvax-like ACAM2000 and the mouse neurovirulent Clone-3. Vaccine. 2007;25:8807–8832. doi: 10.1016/j.vaccine.2007.10.040.
    1. Poland G.A., Grabenstein J.D., Neff J.M. The US smallpox vaccination program: A review of a large modern era smallpox vaccination implementation program. Vaccine. 2005;23:2078–2081. doi: 10.1016/j.vaccine.2005.01.012.
    1. Frey S.E., Newman F.K., Kennedy J.S., Ennis F., Abate G., Hoft D.F., Monath T.P. Comparison of the safety and immunogenicity of ACAM1000, ACAM2000 and Dryvax in healthy vaccinia-naive adults. Vaccine. 2009;10:1637–1644. doi: 10.1016/j.vaccine.2008.11.079.
    1. Meyer H., Sutter G., Mayr A. Mapping of deletions in the genome of the highly attenuated Vaccinia virus MVA and their influence on virulence. J. Gen. Virol. 1991;72:1031–1038. doi: 10.1099/0022-1317-72-5-1031.
    1. Sonnenburg F., Perona P., Darsow U., Ring J., von Krempelhuber A., Vollmar J., Roesch S., Baedeker N., Kollaritsch H., Chaplin P. Safety and immunogenicity of modified vaccinia Ankara as a smallpox vaccine in people with atopic dermatitis. Vaccine. 2014;32:5696–5702. doi: 10.1016/j.vaccine.2014.08.022.
    1. Overton E.T., Stapleton J., Frank I., Hassler S., Goepfert P.A., Barker D., Wagner E., von Krempelhuber A., Virgin G., Meyer T.P., et al. Safety and immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic smallpox vaccine in vaccinia-naive and experienced human immunodeficiency virus-infected individuals: An Open-label, controlled clinical phase II trial. Open Forum Infect. Dis. 2015;2:ofv040. doi: 10.1093/ofid/ofv040.
    1. Zitzmann-Roth E.M., von Sonnenburg F., de la Motte S., Arndtz-Wiedemann N., von Krempelhuber A., Uebler N., Vollmar J., Virgin G., Chaplin P. Cardiac safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population. PLoS ONE. 2015;10:e0122653. doi: 10.1371/journal.pone.0122653.
    1. Greenberg R.N., Hay C.M., Stapleton J.T., Marbury T.C., Wagner E., Kreitmeir E., Roesch S., von Krempelhuber A., Young P., Nichols R., et al. A Randomized, double-blind, placebo-controlled phase II trial investigating the safety and immunogenicity of Modified Vaccinia Ankara smallpox vaccine (MVA-BN®) in 56–80-year-old subjects. PLoS ONE. 2016;11:e0157335. doi: 10.1371/journal.pone.0157335.
    1. Earl P.L., Americo J.L., Wyatt L.S., Eller L.A., Whitbeck J.C., Cohen G.H., Eisenberg R.J., Hartmann C.J., Jackson D.L., Kulesh D.A., et al. Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature. 2004;428:182–185. doi: 10.1038/nature02331.
    1. Jones D.I., McGee C.E., Sample C.J., Sempowski G.D., Pickup D.J., Staats H.F. Modified vaccinia Ankara virus vaccination provides long-term protection against nasal Rabbitpox virus challenge. Clin. Vaccine Immunol. 2016;23:648–651. doi: 10.1128/CVI.00216-16.
    1. Volz A., Sutter G. Modified Vaccinia virus Ankara: History, value in basic research, and current perspectives for vaccine development. Adv. Virus Res. 2017;97:187–243.
    1. Kidokoro M., Tashiro M., Shida H. Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8. Proc. Natl. Acad. Sci. USA. 2005;102:4152–4157. doi: 10.1073/pnas.0406671102.
    1. Eto A., Saito T., Yokote H., Kurane I., Kanatani Y. Recent advances in the study of live attenuated cell-cultured smallpox vaccine LC16m8. Vaccine. 2015;33:6106–6111. doi: 10.1016/j.vaccine.2015.07.111.
    1. Yokote H., Shinmura Y., Kanehara T., Maruno S., Kuranaga M., Matsui H., Hashizume S. Vaccinia virus strain LC16m8 defective in the B5R gene keeps strong protection comparable to its parental strain Lister in immunodeficient mice. Vaccine. 2015;33:6112–6119. doi: 10.1016/j.vaccine.2015.07.076.
    1. Empig C., Kenner J.R., Perret-Gentil M., Youree B.E., Bell E., Chen A., Gurwith M., Higgins K., Lock M., Rice A.D., et al. Highly attenuated smallpox vaccine protects rabbits and mice against pathogenic orthopoxvirus challenge. Vaccine. 2006;24:3686–3694. doi: 10.1016/j.vaccine.2005.03.029.
    1. Iizuka I., Ami Y., Suzaki Y., Nagata N., Fukushi S., Ogata M., Morikawa S., Hasegawa H., Mizuguchi M., Kurane I., et al. A single vaccination of nonhuman primates with highly attenuated smallpox vaccine, LC16m8, provides long-term protection against monkeypox. Jpn. J. Infect. Dis. 2017;70:408–415. doi: 10.7883/yoken.JJID.2016.417.
    1. Tartaglia J., Perkus M.E., Taylor J., Norton E.K., Audonnet J.C., Cox W.I., Davis S.W., van der Hoeven J., Meignier B., Riviere M., et al. NYVAC: A highly attenuated strain of Vaccinia virus. Virology. 1992;188:217–232. doi: 10.1016/0042-6822(92)90752-B.
    1. Midgley C.M., Putz M.M., Weber J.N., Smith G.L. Vaccinia virus strain NYVAC induces substantially lower and qualitatively different human antibody responses compared with strains Lister and Dryvax. J. Gen. Virol. 2008;89:2992–2997. doi: 10.1099/vir.0.2008/004440-0.
    1. Yakubitskiy S.N., Kolosova I.V., Maksyutov R.A., Shchelkunov S.N. Attenuation of Vaccinia virus. Acta Naturae. 2015;7:113–121.
    1. Yakubitskyi S.N., Kolosova I.V., Maksyutov R.A., Shchelkunov S.N. Highly immunogenic variant of attenuated Vaccinia virus. Dokl. Biochem. Biophys. 2016;466:35–38. doi: 10.1134/S1607672916010105.
    1. Stittelaar K.J., Neyts J., Naesens L., van Amerongen G., van Lavieren R.F., Holy A., De Clercq E., Niesters H.G., Fries E., Maas C., et al. Antiviral treatment is more effective than smallpox vaccination upon lethal Monkeypox virus infection. Nature. 2006;439:745–748. doi: 10.1038/nature04295.
    1. Smee D.F. Progress in the discovery of compounds inhibiting orthopoxviruses in animal models. Antivir. Chem. Chemother. 2008;19:115–124. doi: 10.1177/095632020801900302.
    1. Reeves P.M., Smith S.K., Olson V.A., Thorne S.H., Bornmann W., Damon I.K., Kalman D. Variola and monkeypox utilize conserved mechanisms of virion motility and release that depend on Abl- and Src-family tyrosine kinases. J. Virol. 2011;85:21–31. doi: 10.1128/JVI.01814-10.
    1. Olson V.A., Smith S.K., Foster S., Li Y., Lanier E.R., Gates I., Trost L.C., Damon I.K. In vitro efficacy of brincidofovir against Variola virus. Antimicrob. Agents Chemother. 2014;58:5570–5571. doi: 10.1128/AAC.02814-14.
    1. Zaitseva M., McCullough K.T., Cruz S., Thomas A., Diaz C.G., Keilholz L., Grossi I.M., Trost L.C., Golding H. Postchallenge administration of brincidofovir protects healthy and immune-deficient mice reconstituted with limited numbers of T cells from lethal challenge with IHD-J-Luc Vaccinia virus. J. Virol. 2015;89:3295–3307. doi: 10.1128/JVI.03340-14.
    1. Arndt W., Mitnik C., Denzler K.L., White S., Waters R., Jacobs B.L., Rochon Y., Olson V.A., Damon I.K., Langland J.O. In vitro characterization of a nineteenth-century therapy for smallpox. PLoS ONE. 2012;7:e32610. doi: 10.1371/journal.pone.0032610.
    1. Dower K., Filone C.M., Hodges E.N., Bjornson Z.B., Rubins K.H., Brown L.E., Schaus S., Hensley L.E., Connor J.H. Identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library. J. Virol. 2012;86:2632–2640. doi: 10.1128/JVI.05416-11.
    1. Smith S.K., Olson V.A., Karem K.L., Jordan R., Hruby D.E., Damon I.K. In vitro efficacy of ST246 against smallpox and monkeypox. Antimicrob. Agents Chemother. 2009;53:1007–1012. doi: 10.1128/AAC.01044-08.
    1. Mucker E.M., Goff A.J., Shamblin J.D., Grosenbach D.W., Damon I.K., Mehal J.M., Holman R.C., Carroll D.S., Gallardo N., Olson V.A., et al. Efficacy of tecovirimat (ST-246) in nonhuman primates infected with Variola virus (Smallpox) Antimicrob. Agents Chemother. 2013;57:6246–6253. doi: 10.1128/AAC.00977-13.
    1. Jordan R., Leeds J.M., Tyavanagimatt S., Hruby D.E. Development of ST-246 for treatment of poxvirus infections. Viruses. 2010;2:2409–2435. doi: 10.3390/v2112409.
    1. Sbrana E., Jordan R., Hruby D.E., Mateo R.I., Xiao S.Y., Siirin M., Newman P.C., Da Rosa A.P., Tesh R.B. Efficacy of the anti-poxvirus compound ST-246 for treatment of severe orthopoxvirus infection. Am. J. Trop. Med. Hyg. 2007;76:768–773.
    1. Smith S.K., Self J., Weiss S., Carroll D., Braden Z., Regnery R.L., Davidson W., Jordan R., Hruby D.E., Damon I.K. Effective antiviral treatment of systemic orthopoxvirus disease: ST-246 treatment of prairie dogs infected with Monkeypox virus. J. Virol. 2011;85:9176–9187. doi: 10.1128/JVI.02173-10.
    1. Mazurkov O.Y., Kabanov A.S., Shishkina L.N., Sergeev A.A., Skarnovich M.O., Bormotov N.I., Skarnovich M.A., Ovchinnikova A.S., Titova K.A., Galahova D.O., et al. New effective chemically synthesized anti-smallpox compound NIOCH-14. J. Gen. Virol. 2016;97:1229–1239. doi: 10.1099/jgv.0.000422.
    1. Huggins J., Goff A., Hensley L., Mucker E., Shamblin J., Wlazlowski C., Johnson W., Chapman J., Larsen T., Twenhafel N., et al. Nonhuman primates are protected from smallpox virus or Monkeypox virus challenges by the antiviral drug ST-246. Antimicrob. Agents Chemother. 2009;53:2620–2625. doi: 10.1128/AAC.00021-09.
    1. Chinsangaram J., Honeychurch K.M., Tyavanagimatt S.R., Leeds J.M., Bolken T.C., Jones K.F., Jordan R., Marbury T., Ruckle J., Mee-Lee D., et al. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers. Antimicrob. Agents Chemother. 2012;56:4900–4905. doi: 10.1128/AAC.00904-12.
    1. Vora S., Damon I., Fulginiti V., Weber S.G., Kahana M., Stein S.L., Gerber S.I., Garcia-Houchins S., Lederman E., Hruby D., et al. Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin. Infect. Dis. 2008;46:1555–1561. doi: 10.1086/587668.
    1. Lederman E.R., Davidson W., Groff H.L., Smith S.K., Warkentien T., Li Y., Wilkins K.A., Karem K.L., Akondy R.S., Ahmed R., et al. Progressive vaccinia: Case description and laboratory-guided therapy with vaccinia immune globulin, ST-246, and CMX001. J. Infect. Dis. 2012;206:1372–1385. doi: 10.1093/infdis/jis510.
    1. Wold W.S., Toth K. New drug on the horizon for treating adenovirus. Expert Opin. Pharmacother. 2015;16:2095–2099. doi: 10.1517/14656566.2015.1083975.
    1. Parker S., Chen N.G., Foster S., Hartzler H., Hembrador E., Hruby D., Jordan R., Lanier R., Painter G., Painter W., et al. Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox—An animal model of smallpox. Antivir. Res. 2012;94:44–53. doi: 10.1016/j.antiviral.2012.02.005.
    1. Trost L.C., Rose M.L., Khouri J., Keilholz L., Long J., Godin S.J., Foster S.A. The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal Rabbitpox virus infection: A model of smallpox disease. Antivir. Res. 2015;117:115–121. doi: 10.1016/j.antiviral.2015.02.007.
    1. Florescu D.F., Keck M.A. Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses. Expert Rev. Anti-Infect. Ther. 2014;12:1171–1178. doi: 10.1586/14787210.2014.948847.
    1. Chittick G., Morrison M., Brundage T., Nichols W.G. Short-term clinical safety profile of brincidofovir: A favorable benefit-risk proposition in the treatment of smallpox. Antivir. Res. 2017;143:269–277. doi: 10.1016/j.antiviral.2017.01.009.
    1. Yang G., Pevear D.C., Davies M.H., Collett M.S., Bailey T., Rippen S., Barone L., Burns C., Rhodes G., Tohan S., et al. An orally bioavailable anti-poxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J. Virol. 2005;79:13139–13149. doi: 10.1128/JVI.79.20.13139-13149.2005.
    1. Kornbluth R.S., Smee D.F., Sidwell R.W., Snarsky V., Evans D.H., Hostetler K.Y. Mutations in the E9L polymerase gene of cidofovir-resistant Vaccinia virus strain WR are associated with the drug resistance phenotype. Antimicrob. Agents Chemother. 2006;50:4038–4043. doi: 10.1128/AAC.00380-06.
    1. Kempe C.H., Berge T.O., England B. Hyperimmune vaccinial gamma globulin: Source, evaluation, and use in prophylaxis and therapy. Pediatrics. 1956;18:177–187.
    1. Kempe C.H., Bowles C., Meiklejohn G., Berge T.O., St. Vincent L., Sundara Babu B.V., Govindarajan S., Ratnakannan N.R., Downie A.W., Murthy V.R. The use of vaccinia hyperimmune gamma-globulin in the prophylaxis of smallpox. Bull. World Health Organ. 1961;25:41–48.
    1. Marennikova S.S. The use of hyperimmune antivaccinia gamma-globulin for the prevention and treatment of smallpox. Bull. World Health Organ. 1962;27:325–330.
    1. Gilchuk I., Gilchuk P., Sapparapu G., Lampley R., Singh V., Kose N., Blum D.L., Hughes L.J., Satheshkumar P.S., Townsend M.B., et al. Cross-neutralizing and protective human antibody specificities to poxvirus infections. Cell. 2016;167:684–694. doi: 10.1016/j.cell.2016.09.049.
    1. Chapman J.L., Nichols D.K., Martinez M.J., Raymond J.W. Animal models of orthopoxvirus infection. Vet. Pathol. 2010;47:852–870. doi: 10.1177/0300985810378649.
    1. Hutson C.L., Damon I.K. Monkeypox virus infections in small animal models for evaluation of anti-poxivurs agents. Viruses. 2010;2:2763–2776. doi: 10.3390/v2122763.
    1. Americal J.L., Moss B., Earl P.L. Identification of wild-derived inbred mouse strains highly susceptible to Monkeypox virus infection for use as small animal models. J. Virol. 2010;84:8172–8180. doi: 10.1128/JVI.00621-10.
    1. Titova K.A., Sergeev A.A., Kabanov A.S., Bulychev L.E., Sergeev A.A., Gorbatovskaya D.O., Zamedyanskaya A.S., Shishkina L.N., Taranov O.S., Omigov V.V., et al. SCID mice as an animal model to evaluate the efficacy of antismallpox drugs. Russ. J. Genet. Appl. Res. 2016;6:477–484. doi: 10.1134/S2079059716040213.
    1. Hutson C.L., Self J., Weiss S., Carroll D.S., Hughes C.M., Braden Z.H., Olson V.A., Smith S.K., Karem K.L., Damon I.K., et al. Dosage comparison of Congo Basin and West African strains of Monkeypox virus using a prairie dog animal model of systemic orthopox disease. Virology. 2010;402:72–82. doi: 10.1016/j.virol.2010.03.012.
    1. Hutson C.L., Gallardo-Romero N.F., Carroll D.S., Clemmons C., Salzer J.S., Nagy T., Hughes C.M., Olson V.A., Karem K.L., Damon I.K. Transmissibility of the Monkeypox virus clades via respiratory transmission: Investigation using the prairie dog-Monkeypox virus challenge system. PLoS ONE. 2013;8:e55488. doi: 10.1371/journal.pone.0055488.
    1. Hutson C.L., Carroll D.S., Gallardo-Romero N., Drew C., Zaki S.R., Nagy T., Hughes C., Olson V.A., Sanders J., Patel N., et al. Comparison of Monkeypox virus clade kinetics and pathology within the prairie dog animal model using a serial sacrifice study design. Biomed Res. Int. 2015;2015:965710. doi: 10.1155/2015/965710.
    1. Sergeev A.A., Kabanov A.S., Bulychev L.E., Sergeev A.A., Pyankov O.V., Bodnev S.A., Galahova D.O., Zamedyanskaya A.S., Titova K.A., Glotova T.I., et al. Using the ground squirrel (Marmota bobak) as an animal model to assess monkeypox drug efficacy. Transbound. Emerg. Dis. 2017;64:226–236. doi: 10.1111/tbed.12364.
    1. Carroll D.S., Olson V.A., Smith S.K., Braden Z.H., Patel N., Abel J., Li Y., Damon I.K., Karem K.L. Orthopoxvirus variola infection of Cynomys. ludovicianus (North American black tailed prairie dog) Virology. 2013;443:358–362. doi: 10.1016/j.virol.2013.05.029.
    1. Kim K.C., Choi B.S., Kim K.C., Park K.H., Lee H.J., Cho Y.K., Kim S.I., Kim S.S., Oh Y.K., Kim Y.B. A simple mouse model for the study of human immunodeficiency virus. AIDS Res. Hum. Retroviruses. 2016;32:194–202. doi: 10.1089/aid.2015.0211.
    1. Jaiswal S., Smith K., Ramirez A., Woda M., Pazoles P., Shultz L.D., Greiner D.L., Brehm M.A., Mathew A. Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice. Exp. Biol. Med. 2015;240:67–78. doi: 10.1177/1535370214546273.
    1. Shultz L.D., Saito Y., Najima Y., Tanaka S., Ochi T., Tomizawa M., Doi T., Sone A., Suzuki N., Fujiwara H., et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc. Natl. Acad. Sci. USA. 2010;107:13022–13027. doi: 10.1073/pnas.1000475107.
    1. Bird B.H., Spengler J.R., Chakrabarti A.K., Khristova M.L., Sealy T.K., Coleman-McCray J.D., Martin B.E., Dodd K.A., Goldsmith C.S., Sanders J., et al. Humanized Mouse Model of Ebola Virus Disease Mimics the Immune Responses in Human Disease. J. Infect. Dis. 2016;213:703–711. doi: 10.1093/infdis/jiv538.
    1. Alcami A., Damon L., Evans D., Huggins J.W., Hughes C., Jahrling P.B., McFadden G., Meyer H., Moss B., Shchelkunov S., et al. Scientific Review of Variola. Virus Research, 1999–2010. World Health Organization; Geneva, Switzerland: 2010. p. 128.

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