DNA vaccines combining plasmids carrying the variola virus genes M1R, A30L, and F8L of intracellular virion surface membrane proteins as well as A36R and B7R of the extracellular virus envelope proteins under control of Rous sarcoma virus or cytomegalovirus promoters have been constructed. These DNA vaccines induced production of a high titers of vaccinia virus-neutralizing antibodies in mice similar to those elicited by the live vaccinia virus immunization. Mice vaccinated by created DNA vaccine were completely protected against a lethal (10 LD50) challenge with highly pathogenic ectromelia virus. These results suggest that such vaccine should be efficient in immunization of humans against smallpox. 1. Introduction The historically first method used for human protection against devastating smallpox epidemics was the so-called variolation, that is, an intracutaneous inoculation of healthy persons with infectious material from human smallpox cases. The disease thus induced had a shorter incubation period and a milder course as compared with the disease caused by a common respiratory transmission of this infection. The mortality rate after variolation was 0.5？2% versus 20？30% typical for the smallpox epidemics. The discovery of human vaccination using first cowpox virus (CPXV) and then vaccinia virus (VACV) had led to a considerable decrease in the severe side reactions [1, 2]. Taking into account the postvaccination complications caused by classical live vaccine involving VACV and confirmation of the global smallpox eradication, the World Health Organization recommended in 1980 to stop further vaccination against this infection [1]. Subsequent worldwide cessation of the vaccination against smallpox has created a most dangerous situation when the human population year by year becomes ever more unprotected not only from a potential infection with variola virus (VARV) as a result of a bioterrorism attack or reemergence of the virus in nature, but also from infection with other closely related orthopoxviruses, the natural reservoir of which is small rodents [3–5]. This is demonstrated by more frequent outbreaks of human orthopoxvirus infections caused by monkeypox virus (MPXV), CPXV, and VACV [6–10]. The absence of efficient antivirals makes the vaccine prevention the most important specific tool for control of the orthopoxvirus infections among humans. Use of the classical live VACV vaccine for mass vaccinations is now unacceptable because of a relatively large number of potential complications, especially taking into account the increased number of
References
[1]
F. Fenner, D. A. Henderson, I. Arita, Z. Jezek, and I. D. Ladnyi, Smallpox and Its Eradication, World Health Organization, Geneva, Switzerland, 1988.
[2]
F. Fenner, “Risks and benefits of vaccinia vaccine use in the worldwide smallpox eradication campaign,” Research in Virology, vol. 140, pp. 465–466, 1989.
[3]
S. N. Shchelkunov, S. S. Marennikova, and R. W. Moyer, Orthopoxviruses Pathogenic for Humans, Springer, New York, NY, USA, 2005.
[4]
S. N. Shchelkunov, “How long ago did smallpox virus emerge?” Archives of Virology, vol. 154, no. 12, pp. 1865–1871, 2009.
[5]
S. N. Shchelkunov, “Emergence and reemergence of smallpox: the need in development of a new generation smallpox vaccine,” Vaccine, vol. 29, supplement 4, pp. D49–D53, 2011.
[6]
J. Stephenson, “Monkeypox outbreak a reminder of emerging infections vulnerabilities,” Journal of the American Medical Association, vol. 290, no. 1, pp. 23–24, 2003.
[7]
S. Lewis-Jones, “Zoonotic poxvirus infections in humans,” Current Opinion in Infectious Diseases, vol. 17, no. 2, pp. 81–89, 2004.
[8]
H. Campe, P. Zimmermann, K. Glos et al., “Cowpox virus transmission from pet rats to humans, Germany,” Emerging Infectious Diseases, vol. 15, no. 5, pp. 777–780, 2009.
[9]
L. Ninove, Y. Domart, C. Vervel et al., “Cowpox virus transmission from pet rats to humans, France,” Emerging Infectious Diseases, vol. 15, no. 5, pp. 781–784, 2009.
[10]
A. W. Rimoin, P. M. Mulembakani, S. C. Johnston et al., “Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 37, pp. 16262–16267, 2010.
[11]
R. G. Webster, E. F. Fynan, J. C. Santoro, and H. Robinson, “Protection of ferrets against influenza challenge with a DNA vaccine to the haemagglutinin,” Vaccine, vol. 12, no. 16, pp. 1495–1498, 1994.
[12]
J. W. Hooper, K. I. Kamrud, F. Elgh, D. Custer, and C. S. Schmaljohn, “DNA vaccination with hantavirus M segment elicits neutralizing antibodies and protects against seoul virus infection,” Virology, vol. 255, no. 2, pp. 269–278, 1999.
[13]
J. Riemenschneider, A. Garrison, J. Geisbert et al., “Comparison of individual and combination DNA vaccines for B. anthracis, Ebola virus, Marburg virus and Venezuelan equine encephalitis virus,” Vaccine, vol. 21, no. 25-26, pp. 4071–4080, 2003.
[14]
S. N. Shchelkunov, “Functional organization of variola major and vaccinia virus genomes,” Virus Genes, vol. 10, no. 1, pp. 53–71, 1995.
[15]
J. W. Hooper, D. M. Custer, C. S. Schmaljohn, and A. L. Schmaljohn, “DNA vaccination with vaccinia virus L1R and A33R genes protects mice against a lethal poxvirus challenge,” Virology, vol. 266, no. 2, pp. 329–339, 2000.
[16]
J. W. Hooper, D. M. Custer, and E. Thompson, “Four-gene-combination DNA vaccine protects mice against a lethal vaccinia virus challenge and elicits appropriate antibody responses in nonhuman primates,” Virology, vol. 306, no. 1, pp. 181–195, 2003.
[17]
P. Sakhatskyy, S. Wang, T. H. W. Chou, and S. Lu, “Immunogenicity and protection efficacy of monovalent and polyvalent poxvirus vaccines that include the D8 antigen,” Virology, vol. 355, no. 2, pp. 164–174, 2006.
[18]
J. W. Hooper, E. Thompson, C. Wilhelmsen et al., “Smallpox DNA vaccine protects nonhuman primates against lethal monkeypox,” Journal of Virology, vol. 78, no. 9, pp. 4433–4443, 2004.
[19]
J. M. Heraud, Y. Edghill-Smith, V. Ayala et al., “Subunit recombinant vaccine protects against monkeypox,” Journal of Immunology, vol. 177, no. 4, pp. 2552–2564, 2006.
[20]
P. Sakhatskyy, S. Wang, C. Zhang, T. H. Chou, M. Kishko, and S. Lu, “Immunogenicity and protection efficacy of subunit-based smallpox vaccines using variola major antigens,” Virology, vol. 371, no. 1, pp. 98–107, 2008.
[21]
S. N. Shchelkunov, S. S. Marennikova, A. V. Totmenin et al., “Creation of a clone library of fragments from the natural variola virus and study of the structural and functional organization of viral genes from a circle of hosts,” Doklady Akademii Nauk SSSR, vol. 321, no. 2, pp. 402–406, 1991.
[22]
S. N. Shchelkunov, S. M. Resenchuk, A. V. Totmenin, V. M. Blinov, S. S. Marennikova, and L. S. Sandakhchiev, “Comparison of the genetic maps of variola and vaccinia viruses,” The FEBS Letters, vol. 327, no. 3, pp. 321–324, 1993.
[23]
R. F. Massung, L. I. Liu, J. Qi et al., “Analysis of the complete genome of smallpox variola major virus strain Bangladesh-1975,” Virology, vol. 201, no. 2, pp. 215–240, 1994.
[24]
S. N. Shchelkunov, A. V. Totmenin, V. N. Loparev et al., “Alastrim smallpox variola minor virus genome DNA sequences,” Virology, vol. 266, no. 2, pp. 361–386, 2000.
[25]
S. N. Shchelkunov, A. V. Totmenin, I. V. Babkin et al., “Human monkeypox and smallpox viruses: genomic comparison,” The FEBS Letters, vol. 509, no. 1, pp. 66–70, 2001.
[26]
A. M. Likos, S. A. Sammons, V. A. Olson et al., “A tale of two clades: monkeypox viruses,” Journal of General Virology, vol. 86, no. 10, pp. 2661–2672, 2005.
[27]
S. N. Shchelkunov, P. F. Safronov, A. V. Totmenin et al., “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, vol. 243, no. 2, pp. 432–460, 1998.
[28]
F. Q. Hu, C. A. Smith, and D. J. Pickup, “Cowpox virus contains two copies of an early gene encoding a soluble secreted form of the type II TNF receptor,” Virology, vol. 204, no. 1, pp. 343–356, 1994.
[29]
S. J. Goebel, G. P. Johnson, M. E. Perkus, S. W. Davis, J. P. Winslow, and E. Paoletti, “The complete DNA sequence of vaccinia virus,” Virology, vol. 179, no. 1, pp. 247–566, 1990.
[30]
G. Antoine, F. Scheiflinger, F. Dorner, and F. G. Falkner, “The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses,” Virology, vol. 244, no. 2, pp. 365–396, 1998.
[31]
B. M. Baroudy and B. Moss, “Sequence homologies of diverse length tandem repetitions near ends of vaccinia virus genome suggest unequal crossing over,” Nucleic Acids Research, vol. 10, no. 18, pp. 5673–5679, 1982.
[32]
K. Mossman, C. Upton, R. M. L. Buller, and G. McFadden, “Species specificity of ectromelia virus and vaccinia virus interferon-γ binding proteins,” Virology, vol. 208, no. 2, pp. 762–769, 1995.
[33]
E. J. Dick Jr., C. L. Kittell, H. Meyer, et al., “Mousepox outbreak in a laboratory mouse colony,” Laboratory Animal Science, vol. 46, no. 6, pp. 602–611, 1996.
[34]
A. Z. Maksyutov and E. S. Zagrebelnaya, “ADEPT: a computer program for prediction of protein antigenic determinants,” Computer Applications in the Biosciences, vol. 9, no. 3, pp. 291–297, 1993.
[35]
R. A. Maksyutov, I. N. Babkina, A. E. Nesterov, and S. N. Shchelkunov, “Creation of a candidate DNA vaccine against human orthopoxvirus infections,” Biotekhnologiya, vol. 4, pp. 23–30, 2006.
[36]
N. A. Doria-Rose and N. L. Haigwood, “DNA vaccine strategies: candidates for immune modulation and immunization regimens,” Methods, vol. 31, no. 3, pp. 207–216, 2003.
[37]
D. J. Pulford, A. Gates, S. H. Bridge, J. H. Robinson, and D. Ulaeto, “Differential efficacy of vaccinia virus envelope proteins administered by DNA immunisation in protection of BALB/c mice from a lethal intranasal poxvirus challenge,” Vaccine, vol. 22, no. 25-26, pp. 3358–3366, 2004.
[38]
E. Raz, D. A. Carson, S. E. Parker, et al., “Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 20, pp. 9519–9523, 1994.
