Orthopoxviruses: Variola, Vaccinia, Cowpox, and Monkeypox

  • Brett W. Petersen
  • Kevin L. Karem
  • Inger K. Damon


Orthopoxviruses are large, complex DNA viruses within the family Poxviridae. Four orthopoxvirus species are known to cause human disease: variola virus (smallpox), vaccinia virus (smallpox vaccine), cowpox virus, and monkeypox virus. Variola virus is likely the best known member of the orthopoxvirus genus (Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone/Elsevier; 2010). As the causative agent of smallpox, this virus caused untold human suffering and loss of life until its eradication in 1980 following the successful completion of a global eradication campaign (Fenner F. Smallpox and its eradication. Geneva: World Health Organization; 1988). Ordinary smallpox presented with fever and flu-like symptoms after an incubation period of 10–14 days. Rash generally followed within 2–3 days and was characterized by a centrifugal distribution and stepwise progression through macular, papular, vesicular, and pustular stages. Mortality rates were estimated as high as 30 %. Edward Jenner was the first person to recognize the ability of orthopoxviruses to induce cross-reactive antibodies that protect against infection from other orthopoxvirus species and pioneer the use of vaccination to prevent disease. Vaccinia virus is still in use today as a vaccine as well as a subject and tool for biomedical research. Human vaccinia infections generally cause self-limited, localized lesions though severe and life-threatening complications can occur, particularly in high-risk populations such as immunocompromised individuals and those with atopic dermatitis. In addition, vaccinia infections present a risk of inadvertent inoculation from infectious virus present in vaccinial lesions. Most vaccinia infections are related to vaccination. However, both vaccinia virus and cowpox virus cause sporadic zoonotic infections as well. Cowpox virus is classically associated with occupational exposure to cattle though other sources include rats, cats, and zoo and circus elephants. In contrast, vaccinia virus is only known to occur naturally in cattle and buffalo in Brazil and select regions of the Middle East and Southeast Asia. Monkeypox virus is also transmitted zoonotically; one or more species of squirrels or other rodents is believed to be the natural reservoir of monkeypox virus. The incidence of monkeypox appears to be increasing since the cessation of routine smallpox vaccination following eradication. The presentation of monkeypox is similar to that of ordinary smallpox with lymphadenopathy being the distinguishing clinical features of monkeypox. Overall, monkeypox is less severe compared to smallpox with an estimated mortality rate of ~10 %. An outbreak of human monkeypox occurred in the United States in 2003 demonstrating the capacity for spread of the disease outside of the previously observed geographic boundaries. Prevention of human orthopoxvirus infections is largely accomplished through vaccination. Few treatment options are available for orthopoxvirus infections after the onset of symptoms. Vaccinia immune globulin (VIG) has been used successfully in treating certain severe adverse events from smallpox vaccine. Other drugs with antiviral activity against orthopoxviruses are in development, but none are currently licensed for this indication. Orthopoxviruses pose a threat to public health based on their ability to cause zoonotic outbreaks and potential to be used as a biological weapon or agent of bioterrorism. These concerns continue to drive poxvirus research and efforts to develop preparedness and response plans, improved vaccines, antivirals, and other medical countermeasures.


Vaccinia Virus Congo Basin Smallpox Vaccination Smallpox Vaccine Variola Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Fields BN, Knipe DM, Howley PM. Fields virology. 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007.Google Scholar
  2. 2.
    Fenner F. Smallpox and its eradication. Geneva: World Health Organization; 1988.Google Scholar
  3. 3.
    Cyrklaff M, Risco C, Fernandez JJ, et al. Cryo-electron tomography of vaccinia virus. Proc Natl Acad Sci U S A. 2005;102:2772–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone/Elsevier; 2010.Google Scholar
  5. 5.
    Goebel SJ, Johnson GP, Perkus ME, Davis SW, Winslow JP, Paoletti E. The complete DNA sequence of vaccinia virus. Virology. 1990;179:247–66, p. 517–63.PubMedCrossRefGoogle Scholar
  6. 6.
    Massung RF, Liu LI, Qi J, et al. Analysis of the complete genome of smallpox variola major virus strain Bangladesh-1975. Virology. 1994;201:215–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Upton C, Slack S, Hunter AL, Ehlers A, Roper RL. Poxvirus orthologous clusters: toward defining the minimum essential poxvirus genome. J Virol. 2003;77:7590–600.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Shchelkunov SN, Totmenin AV, Babkin IV, et al. Human monkeypox and smallpox viruses: genomic comparison. FEBS Lett. 2001;509:66–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Moss B. Poxvirus cell entry: how many proteins does it take? Viruses. 2012;4:688–707.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Moss B. Poxvirus entry and membrane fusion. Virology. 2006;344:48–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Downie AW, McCarthy K. The antibody response in man following infection with viruses of the pox group. III. Antibody response in smallpox. J Hyg. 1958;56:479–87.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    McCarthy K, Downie AW, Bradley WH. The antibody response in man following infection with viruses of the pox group. II. Antibody response following vaccination. J Hyg. 1958;56:466–78.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 2002;346:1300–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Fenner F. Studies in mousepox, infectious ectromelia of mice; quantitative investigations on the spread of virus through the host in actively and passively immunized animals. Aust J Exp Biol Med Sci. 1949;27:1–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Sarkar JK, Mitra AC, Mukherjee MK. The minimum protective level of antibodies in smallpox. Bull World Health Organ. 1975;52:307–11.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Mack TM, Noble Jr J, Thomas DB. A prospective study of serum antibody and protection against smallpox. Am J Trop Med Hyg. 1972;21:214–8.PubMedGoogle Scholar
  17. 17.
    McClain DJ, Harrison S, Yeager CL, et al. Immunologic responses to vaccinia vaccines administered by different parenteral routes. J Infect Dis. 1997;175:756–63.PubMedCrossRefGoogle Scholar
  18. 18.
    Ennis FA, Cruz J, Demkowicz Jr WE, Rothman AL, McClain DJ. Primary induction of human CD8+ cytotoxic T lymphocytes and interferon-gamma-producing T cells after smallpox vaccination. J Infect Dis. 2002;185:1657–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Seet BT, Johnston JB, Brunetti CR, et al. Poxviruses and immune evasion. Annu Rev Immunol. 2003;21:377–423.PubMedCrossRefGoogle Scholar
  20. 20.
    Smith GL, Symons JA, Khanna A, Vanderplasschen A, Alcami A. Vaccinia virus immune evasion. Immunol Rev. 1997;159:137–54.PubMedCrossRefGoogle Scholar
  21. 21.
    Symons JA, Tscharke DC, Price N, Smith GL. A study of the vaccinia virus interferon-gamma receptor and its contribution to virus virulence. J Gen Virol. 2002;83:1953–64.PubMedGoogle Scholar
  22. 22.
    Puehler F, Weining KC, Symons JA, Smith GL, Staeheli P. Vaccinia virus-encoded cytokine receptor binds and neutralizes chicken interferon-gamma. Virology. 1998;248:231–40.PubMedCrossRefGoogle Scholar
  23. 23.
    Cunnion KM. Tumor necrosis factor receptors encoded by poxviruses. Mol Genet Metab. 1999;67:278–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Loparev VN, Parsons JM, Knight JC, et al. A third distinct tumor necrosis factor receptor of orthopoxviruses. Proc Natl Acad Sci U S A. 1998;95:3786–91.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Calderara S, Xiang Y, Moss B. Orthopoxvirus IL-18 binding proteins: affinities and antagonist activities. Virology. 2001;279:22–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Howard J, Justus DE, Totmenin AV, Shchelkunov S, Kotwal GJ. Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat. J Leukoc Biol. 1998;64:68–71.PubMedGoogle Scholar
  27. 27.
    Mahalingam S, Karupiah G. Modulation of chemokines by poxvirus infections. Curr Opin Immunol. 2000;12:409–12.PubMedCrossRefGoogle Scholar
  28. 28.
    Rubins KH, Hensley LE, Jahrling PB, et al. The host response to smallpox: analysis of the gene expression program in peripheral blood cells in a nonhuman primate model. Proc Natl Acad Sci U S A. 2004;101:15190–5.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Rubins KH, Hensley LE, Relman DA, Brown PO. Stunned silence: gene expression programs in human cells infected with monkeypox or vaccinia virus. PLoS One. 2011;6:e15615.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    World Health Organization fact sheet on smallpox, 2001. Accessed 15 May 2012, at
  31. 31.
    Alibek K. Smallpox: a disease and a weapon. Int J Infect Dis. 2004;8 Suppl 2:S3–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Arvin AM, Patel D, Institute of Medicine (U.S.), Committee on the Assessment of Future Scientific Needs for Live Variola Virus. Live variola virus: considerations for continuing research. Washington, D.C.: National Academies Press; 2009.Google Scholar
  33. 33.
    Institute of Medicine (U.S.), Committee on the Assessment of Future Scientific Needs for Live Variola Virus. Assessment of future scientific needs for live variola virus. Washington, D.C.: National Academy Press; 1999.Google Scholar
  34. 34.
    Dixon CW. Smallpox. London: Churchill; 1962.Google Scholar
  35. 35.
    Ricketts TF. The diagnosis of smallpox. London: Cassell; 1908.Google Scholar
  36. 36.
    Rao AR. Smallpox. 1st ed. Bombay: Kothari Book Depot; 1972.Google Scholar
  37. 37.
    Dixon CW. Smallpox in Tripolitania, 1946; an epidemiological and clinical study of 500 cases, including trials of penicillin treatment. J Hyg. 1948;46:351–77.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Marsden JP. A critical review of the clinical features of 13,686 cases of smallpox (variola minor)/by J. Pickford Marsden. London: London County Council; 1936.Google Scholar
  39. 39.
    Mack TM, Thomas DB, Khan MM. Variola major in West Pakistan. J Infect Dis. 1970;122:479–88.PubMedCrossRefGoogle Scholar
  40. 40.
    Foege WH, Millar JD, Henderson DA. Smallpox eradication in West and Central Africa. Bull World Health Organ. 1975;52:209–22.PubMedPubMedCentralGoogle Scholar
  41. 41.
    CDC. Summary of notifiable diseases–United States, 2010. MMWR Morb Mortal Wkly Rep. 2012;59:1–111.Google Scholar
  42. 42.
    Smallpox: diagnosis/evaluation. Accessed 15 May 2012, at
  43. 43.
    Nulens E, Voss A. Laboratory diagnosis and biosafety issues of biological warfare agents. Clin Microbiol Infect. 2002;8:455–66.PubMedCrossRefGoogle Scholar
  44. 44.
    Heatherley SS. The Laboratory Response Network for bioterrorism. Clin Lab Sci. 2002;15:177–9.PubMedGoogle Scholar
  45. 45.
    Li Y, Carroll DS, Gardner SN, Walsh MC, Vitalis EA, Damon IK. On the origin of smallpox: correlating variola phylogenics with historical smallpox records. Proc Natl Acad Sci U S A. 2007;104:15787–92.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Esposito JJ, Sammons SA, Frace AM, et al. Genome sequence diversity and clues to the evolution of variola (smallpox) virus. Science. 2006;313:807–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Hopkins DR. The greatest killer: smallpox in history, with a new introduction. Chicago: University of Chicago Press; 2002.Google Scholar
  48. 48.
    Basu RN, Jezek Z, Ward NA, World Health Organization, Regional Office for South-East Asia. The eradication of smallpox from India. New Delhi: World Health Organization/South-East Asia Regional Office; 1979.Google Scholar
  49. 49.
    Nishiura H. Smallpox during pregnancy and maternal outcomes. Emerg Infect Dis. 2006;12:1119–21.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Rao AR, Prahlad I, Swaminathan M, Lakshmi A. Pregnancy and smallpox. J Indian Med Assoc. 1963;40:353–63.PubMedGoogle Scholar
  51. 51.
    Lane JM. Remaining questions about clinical variola major. Emerg Infect Dis. 2011;17:676–80.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Riedel S. Smallpox and biological warfare: a disease revisited. Proc (Bayl Univ Med Cent). 2005;18:13–20.Google Scholar
  53. 53.
    Joarder AK, Tarantola D, Tulloch J. The eradication of smallpox from Bangladesh. New Delhi: World Health Organization/South-East Asia Regional Office; 1980.Google Scholar
  54. 54.
    Harper GJ. Airborne micro-organisms: survival tests with four viruses. J Hyg. 1961;59:479–86.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Wehrle PF, Posch J, Richter KH, Henderson DA. An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bull World Health Organ. 1970;43:669–79.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Downie AW, St Vincent L, Meiklejohn G, et al. Studies on the virus content of mouth washings in the acute phase of smallpox. Bull World Health Organ. 1961;25:49–53.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Mack TM, Thomas DB, Muzaffar Khan M. Epidemiology of smallpox in West Pakistan. II. Determinants of intravillage spread other than acquired immunity. Am J Epidemiol. 1972;95:169–77.PubMedGoogle Scholar
  58. 58.
    Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 1999;281:2127–37.PubMedCrossRefGoogle Scholar
  59. 59.
    Mack T. A different view of smallpox and vaccination. N Engl J Med. 2003;348:460–3.PubMedCrossRefGoogle Scholar
  60. 60.
    Sarkar JK, Mitra AC, Mukherjee MK, De SK. Virus excretion in smallpox. 2. Excretion in the throats of household contacts. Bull World Health Organ. 1973;48:523–7.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Martin DB. The cause of death in smallpox: an examination of the pathology record. Mil Med. 2002;167:546–51.PubMedGoogle Scholar
  62. 62.
    WHO Expert Committee on Smallpox Eradication. Second report. World Health Organ Tech Rep Ser. 1972;493:1–64.Google Scholar
  63. 63.
    Hammarlund E, Lewis MW, Carter SV, et al. Multiple diagnostic techniques identify previously vaccinated individuals with protective immunity against monkeypox. Nat Med. 2005;11:1005–11.PubMedGoogle Scholar
  64. 64.
    Taub DD, Ershler WB, Janowski M, et al. Immunity from smallpox vaccine persists for decades: a longitudinal study. Am J Med. 2008;121:1058–64.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Massoudi MS, Barker L, Schwartz B. Effectiveness of postexposure vaccination for the prevention of smallpox: results of a delphi analysis. J Infect Dis. 2003;188:973–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Rao AR, Jacob ES, Kamalakshi S, Appaswamy S, Bradbury. Epidemiological studies in smallpox. A study of intrafamilial transmission in a series of 254 infected families. Indian J Med Res. 1968;56:1826–54.PubMedGoogle Scholar
  67. 67.
    Heiner GG, Fatima N, McCrumb Jr FR. A study of intrafamilial transmission of smallpox. Am J Epidemiol. 1971;94:316–26.PubMedGoogle Scholar
  68. 68.
    Sommer A. The 1972 smallpox outbreak in Khulna Municipality, Bangladesh. II. Effectiveness of surveillance and containment in urban epidemic control. Am J Epidemiol. 1974;99:303–13.PubMedGoogle Scholar
  69. 69.
    Carroll DS, Emerson GL, Li Y, et al. Chasing Jenner’s vaccine: revisiting cowpox virus classification. PLoS One. 2011;6:e23086.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. N Engl J Med. 1969;281:1201–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis. 1970;122:303–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Grabenstein JD, Winkenwerder Jr W. US military smallpox vaccination program experience. JAMA. 2003;289:3278–82.PubMedCrossRefGoogle Scholar
  73. 73.
    Casey CG, Iskander JK, Roper MH, et al. Adverse events associated with smallpox vaccination in the United States, January-October 2003. JAMA. 2005;294:2734–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Poland GA, Grabenstein JD, Neff JM. The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program. Vaccine. 2005;23:2078–81.PubMedCrossRefGoogle Scholar
  75. 75.
    Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA. 2003;289:3283–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Baxby D, Bennett M, Getty B. Human cowpox 1969–93: a review based on 54 cases. Br J Dermatol. 1994;131:598–607.PubMedCrossRefGoogle Scholar
  77. 77.
    McCollum AM, Austin C, Nawrocki J, et al. Investigation of the first laboratory-acquired human cowpox virus infection in the United States. J Infect Dis. 2012;206:63–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Savaser DJ, Tolia VM, Witucki PJ. Cowpox: what do a dairymaid and a lab technician have in common? J Emerg Med. 2012;44:189–90.PubMedCrossRefGoogle Scholar
  79. 79.
    Pelkonen PM, Tarvainen K, Hynninen A, et al. Cowpox with severe generalized eruption, Finland. Emerg Infect Dis. 2003;9:1458–61.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Blackford S, Roberts DL, Thomas PD. Cowpox infection causing a generalized eruption in a patient with atopic dermatitis. Br J Dermatol. 1993;129:628–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Eis-Hubinger AM, Gerritzen A, Schneweis KE, et al. Fatal cowpox-like virus infection transmitted by cat. Lancet. 1990;336:880.PubMedCrossRefGoogle Scholar
  82. 82.
    Glatz M, Richter S, Ginter-Hanselmayer G, Aberer W, Mullegger RR. Human cowpox in a veterinary student. Lancet Infect Dis. 2010;10:288.PubMedCrossRefGoogle Scholar
  83. 83.
    Hemmer CJ, Littmann M, Lobermann M, Meyer H, Petschaelis A, Reisinger EC. Human cowpox virus infection acquired from a circus elephant in Germany. Int J Infect Dis. 2010;14 Suppl 3:e338–40.PubMedCrossRefGoogle Scholar
  84. 84.
    Kurth A, Wibbelt G, Gerber HP, Petschaelis A, Pauli G, Nitsche A. Rat-to-elephant-to-human transmission of cowpox virus. Emerg Infect Dis. 2008;14:670–1.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Kurth A, Straube M, Kuczka A, Dunsche AJ, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    CDC. Progressive vaccinia in a military smallpox vaccinee – United States, 2009. MMWR Morb Mortal Wkly Rep. 2009;58:532–6.Google Scholar
  87. 87.
    CDC. Household transmission of vaccinia virus from contact with a military smallpox vaccinee–Illinois and Indiana, 2007. MMWR Morb Mortal Wkly Rep. 2007;56:478–81.Google Scholar
  88. 88.
    Rotz LD, Dotson DA, Damon IK, Becher JA, Advisory Committee on Immunization Practices. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Recomm Rep. 2001;50:1–25, quiz CE1–7.PubMedGoogle Scholar
  89. 89.
    MacNeil A, Reynolds MG, Damon IK. Risks associated with vaccinia virus in the laboratory. Virology. 2009;385:1–4.PubMedCrossRefGoogle Scholar
  90. 90.
    CDC. Human vaccinia infection after contact with a raccoon rabies vaccine bait – Pennsylvania, 2009. MMWR Morb Mortal Wkly Rep. 2009;58:1204–7.Google Scholar
  91. 91.
    Rupprecht CE, Blass L, Smith K, et al. Human infection due to recombinant vaccinia-rabies glycoprotein virus. N Engl J Med. 2001;345:582–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Roess AA, Rea N, Lederman E, et al. National surveillance for human and pet contact with oral rabies vaccine baits, 2001–2009. J Am Vet Med Assoc. 2012;240:163–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Medaglia ML, Pessoa LC, Sales ER, Freitas TR, Damaso CR. Spread of cantagalo virus to northern Brazil. Emerg Infect Dis. 2009;15:1142–3.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Damaso CR, Esposito JJ, Condit RC, Moussatche N. An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine. Virology. 2000;277:439–49.PubMedCrossRefGoogle Scholar
  95. 95.
    Trindade GS, Emerson GL, Carroll DS, Kroon EG, Damon IK. Brazilian vaccinia viruses and their origins. Emerg Infect Dis. 2007;13:965–72.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Schatzmayr HG, Costa RV, Goncalves MC, D’Andrea PS, Barth OM. Human and animal infections by vaccinia-like viruses in the state of Rio de Janeiro: a novel expanding zoonosis. Vaccine. 2011;29 Suppl 4:D65–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Damle AS, Gaikwad AA, Patwardhan NS, Duthade MM, Sheikh NS, Deshmukh DG. Outbreak of human buffalopox infection. J Glob Infect Dis. 2011;3:187–8.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Singh RK, Hosamani M, Balamurugan V, Bhanuprakash V, Rasool TJ, Yadav MP. Buffalopox: an emerging and re-emerging zoonosis. Anim Health Res Rev. 2007;8:105–14, conference of research workers in animal diseases.PubMedCrossRefGoogle Scholar
  99. 99.
    Bray M, Wright ME. Progressive vaccinia. Clin Infect Dis. 2003;36:766–74.PubMedCrossRefGoogle Scholar
  100. 100.
    Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics. 1975;55:342–7.PubMedGoogle Scholar
  101. 101.
    Jen M, Chang MW. Eczema herpeticum and eczema vaccinatum in children. Pediatr Ann. 2010;39:658–64.PubMedCrossRefGoogle Scholar
  102. 102.
    Schwartz B, Lebwohl M. Complications of the smallpox vaccine. Int J Dermatol. 2005;44:289–92.PubMedCrossRefGoogle Scholar
  103. 103.
    Rachelefsky GS, Opelz G, Mickey MR, et al. Defective T cell function in atopic dermatitis. J Allergy Clin Immunol. 1976;57:569–76.PubMedCrossRefGoogle Scholar
  104. 104.
    Copeman PW, Wallace HJ. Eczema vaccinatum. Br Med J. 1964;2:906–8.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, Lane JM. Neurologic adverse events associated with smallpox vaccination in the United States, 2002–2004. JAMA. 2005;294:2744–50.PubMedCrossRefGoogle Scholar
  106. 106.
    Schreuder JT, van Rijssel R, Verlinde JD. Encephalomyelitis following infection with cowpox. Ned Tijdschr Geneeskd. 1950;94:2603–9.PubMedGoogle Scholar
  107. 107.
    Kurata T, Aoyama Y, Kitamura T. Demonstration of vaccinia virus antigen in brains of postvaccinal encephalitis cases. Jpn J Med Sci Biol. 1977;30:137–47.PubMedCrossRefGoogle Scholar
  108. 108.
    Gurvich EB, Vilesova IS. Vaccinia virus in postvaccinal encephalitis. Acta Virol. 1983;27:154–9.PubMedGoogle Scholar
  109. 109.
    Lane JM, Ruben FL, Abrutyn E, Millar JD. Deaths attributable to smallpox vaccination, 1959 to 1966, and 1968. JAMA. 1970;212:441–4.PubMedCrossRefGoogle Scholar
  110. 110.
    Cono J, Casey CG, Bell DM. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep. 2003;52:1–28.PubMedGoogle Scholar
  111. 111.
    Kelly CD, Egan C, Davis SW, et al. Laboratory confirmation of generalized vaccinia following smallpox vaccination. J Clin Microbiol. 2004;42:1373–5.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Miller JR, Cirino NM, Philbin EF. Generalized vaccinia 2 days after smallpox revaccination. Emerg Infect Dis. 2003;9:1649–50.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    CDC. Women with smallpox vaccine exposure during pregnancy reported to the National Smallpox Vaccine in Pregnancy Registry–United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:386–8.Google Scholar
  114. 114.
    Ryan MA, Seward JF, Smallpox Vaccine in Pregnancy Registry Team. Pregnancy, birth, and infant health outcomes from the National Smallpox Vaccine in Pregnancy Registry, 2003–2006. Clin Infect Dis. 2008;46 Suppl 3:S221–6.PubMedCrossRefGoogle Scholar
  115. 115.
    Mora LF, Khan AH, Sperling LS. Cardiac complications after smallpox vaccination. South Med J. 2009;102:615–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Arness MK, Eckart RE, Love SS, et al. Myopericarditis following smallpox vaccination. Am J Epidemiol. 2004;160:642–51.PubMedCrossRefGoogle Scholar
  117. 117.
    Greenberg RN, Kennedy JS. ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008;17:555–64.PubMedCrossRefGoogle Scholar
  118. 118.
    Morgan J, Roper MH, Sperling L, et al. Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January–October 2003. Clin Infect Dis. 2008;46 Suppl 3:S242–50.PubMedCrossRefGoogle Scholar
  119. 119.
    Eckart RE, Love SS, Atwood JE, et al. Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination. J Am Coll Cardiol. 2004;44:201–5.PubMedCrossRefGoogle Scholar
  120. 120.
    Arita I, Gispen R, Kalter SS, et al. Outbreaks of monkeypox and serological surveys in nonhuman primates. Bull World Health Organ. 1972;46:625–31.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Ladnyj ID, Ziegler P, Kima E. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ. 1972;46:593–7.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Marennikova SS, Seluhina EM, Mal’ceva NN, Cimiskjan KL, Macevic GR. Isolation and properties of the causal agent of a new variola-like disease (monkeypox) in man. Bull World Health Organ. 1972;46:599–611.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Damon IK. Status of human monkeypox: clinical disease, epidemiology and research. Vaccine. 2011;29 Suppl 4:D54–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Rimoin AW, Mulembakani PM, Johnston SC, 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 U S A. 2010;107:16262–7.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Jezek Z, Fenner F. Human monkeypox. Basel/New York: Karger; 1988.Google Scholar
  126. 126.
    Breman JG. Monkeypox: an emerging infection for humans? In: Scheld WM, Craig WA, Hughes JM, editors. Emerging infections 4. Washington, D.C.: ASM Press; 2000. p. 45–67.CrossRefGoogle Scholar
  127. 127.
    Jezek Z, Szczeniowski M, Paluku KM, Mutombo M. Human monkeypox: clinical features of 282 patients. J Infect Dis. 1987;156:293–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Hutin YJ, Williams RJ, Malfait P, et al. Outbreak of human monkeypox, Democratic Republic of Congo, 1996 to 1997. Emerg Infect Dis. 2001;7:434–8.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Reynolds MG, Damon IK. Outbreaks of human monkeypox after cessation of smallpox vaccination. Trends Microbiol. 2012;20:80–7.PubMedCrossRefGoogle Scholar
  130. 130.
    Mukinda VB, Mwema G, Kilundu M, Heymann DL, Khan AS, Esposito JJ. Re-emergence of human monkeypox in Zaire in 1996. Monkeypox Epidemiologic Working Group. Lancet. 1997;349:1449–50.PubMedCrossRefGoogle Scholar
  131. 131.
    Huhn GD, Bauer AM, Yorita K, et al. Clinical characteristics of human monkeypox, and risk factors for severe disease. Clin Infect Dis. 2005;41:1742–51.PubMedCrossRefGoogle Scholar
  132. 132.
    Reed KD, Melski JW, Graham MB, et al. The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med. 2004;350:342–50.PubMedCrossRefGoogle Scholar
  133. 133.
    Likos AM, Sammons SA, Olson VA, et al. A tale of two clades: monkeypox viruses. J Gen Virol. 2005;86:2661–72.PubMedCrossRefGoogle Scholar
  134. 134.
    Chen N, Li G, Liszewski MK, et al. Virulence differences between monkeypox virus isolates from West Africa and the Congo basin. Virology. 2005;340:46–63.PubMedCrossRefGoogle Scholar
  135. 135.
    Esposito JJ, Knight JC. Orthopoxvirus DNA: a comparison of restriction profiles and maps. Virology. 1985;143:230–51.PubMedCrossRefGoogle Scholar
  136. 136.
    Hutson CL, Carroll DS, Self J, et al. Dosage comparison of Congo Basin and West African strains of monkeypox virus using a prairie dog animal model of systemic orthopoxvirus disease. Virology. 2010;402:72–82.PubMedCrossRefGoogle Scholar
  137. 137.
    Hutson CL, Abel JA, Carroll DS, et al. Comparison of West African and Congo Basin monkeypox viruses in BALB/c and C57BL/6 mice. PLoS One. 2010;5:e8912.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Hutson CL, Olson VA, Carroll DS, et al. A prairie dog animal model of systemic orthopoxvirus disease using West African and Congo Basin strains of monkeypox virus. J Gen Virol. 2009;90:323–33.PubMedCrossRefGoogle Scholar
  139. 139.
    Breman JG, Kalisa R, Steniowski MV, Zanotto E, Gromyko AI, Arita I. Human monkeypox, 1970–79. Bull World Health Organ. 1980;58:165–82.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Khodakevich L, Jezek Z, Kinzanzka K. Isolation of monkeypox virus from wild squirrel infected in nature. Lancet. 1986;1:98–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Khodakevich L, Szczeniowski M, Manbu ma D, et al. The role of squirrels in sustaining monkeypox virus transmission. Trop Geogr Med. 1987;39:115–22.PubMedGoogle Scholar
  142. 142.
    Khodakevich L, Szczeniowski M, Nambu ma D, et al. Monkeypox virus in relation to the ecological features surrounding human settlements in Bumba zone, Zaire. Trop Geogr Med. 1987;39:56–63.PubMedGoogle Scholar
  143. 143.
    Reynolds MG, Davidson WB, Curns AT, et al. Spectrum of infection and risk factors for human monkeypox, United States, 2003. Emerg Infect Dis. 2007;13:1332–9.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Jamieson DJ, Cono J, Richards CL, Treadwell TA. The role of the obstetrician-gynecologist in emerging infectious diseases: monkeypox and pregnancy. Obstet Gynecol. 2004;103:754–6.PubMedCrossRefGoogle Scholar
  145. 145.
    Fine PE, Jezek Z, Grab B, Dixon H. The transmission potential of monkeypox virus in human populations. Int J Epidemiol. 1988;17:643–50.PubMedCrossRefGoogle Scholar
  146. 146.
    Learned LA, Reynolds MG, Wassa DW, et al. Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003. Am J Trop Med Hyg. 2005;73:428–34.PubMedGoogle Scholar
  147. 147.
    Foster SO, Brink EW, Hutchins DL, et al. Human monkeypox. Bull World Health Organ. 1972;46:569–76.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Reynolds MG, Yorita KL, Kuehnert MJ, et al. Clinical manifestations of human monkeypox influenced by route of infection. J Infect Dis. 2006;194:773–80.PubMedCrossRefGoogle Scholar
  149. 149.
    Karem KL, Reynolds M, Hughes C, et al. Monkeypox-induced immunity and failure of childhood smallpox vaccination to provide complete protection. Clin Vaccine Immunol. 2007;14:1318–27.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Kennedy JS, Greenberg RN. IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine. Expert Rev Vaccines. 2009;8:13–24.PubMedCrossRefGoogle Scholar
  151. 151.
    Verardi PH, Titong A, Hagen CJ. A vaccinia virus renaissance: new vaccine and immunotherapeutic uses after smallpox eradication. Hum Vaccin Immunother. 2012;8:961–70.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Smallpox response plan and guidelines (Version 3.0), 2002. Accessed 15 May 2012, at
  153. 153.
    Rimoin AW, Graham BS. Whither monkeypox vaccination. Vaccine. 2011;29 Suppl 4:D60–4.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Sliva K, Schnierle B. From actually toxic to highly specific–novel drugs against poxviruses. Virol J. 2007;4:8.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Baker RO, Bray M, Huggins JW. Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antiviral Res. 2003;57:13–23.PubMedCrossRefGoogle Scholar
  156. 156.
    Magee WC, Hostetler KY, Evans DH. Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate. Antimicrob Agents Chemother. 2005;49:3153–62.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Quenelle DC, Collins DJ, Kern ER. Efficacy of multiple- or single-dose cidofovir against vaccinia and cowpox virus infections in mice. Antimicrob Agents Chemother. 2003;47:3275–80.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Dropulic LK, Cohen JI. Update on new antivirals under development for the treatment of double-stranded DNA virus infections. Clin Pharmacol Ther. 2010;88:610–9.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Painter W, Robertson A, Trost LC, Godkin S, Lampert B, Painter G. First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob Agents Chemother. 2012;56:2726–34.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Yang G, Pevear DC, Davies MH, et al. An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J Virol. 2005;79:13139–49.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Nalca A, Hatkin JM, Garza NL, et al. Evaluation of orally delivered ST-246 as postexposure prophylactic and antiviral therapeutic in an aerosolized rabbitpox rabbit model. Antiviral Res. 2008;79:121–7.PubMedCrossRefGoogle Scholar
  162. 162.
    Huggins J, Goff A, Hensley L, et al. Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246. Antimicrob Agents Chemother. 2009;53:2620–5.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Duraffour S, Andrei G, Snoeck R. Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection. IDrugs. 2010;13:181–91.PubMedGoogle Scholar
  164. 164.
    Lederman ER, Davidson W, Groff HL, et al. Progressive vaccinia: case description and laboratory-guided therapy with vaccinia immune globulin, ST-246, and CMX001. J Infect Dis. 2012;206:1372–85.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Arndt W, Mitnik C, Denzler KL, et al. In vitro characterization of a nineteenth-century therapy for smallpox. PLoS One. 2012;7:e32610.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Quenelle DC, Prichard MN, Keith KA, et al. Synergistic efficacy of the combination of ST-246 with CMX001 against orthopoxviruses. Antimicrob Agents Chemother. 2007;51:4118–24.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Aebersold P. FDA experience with medical countermeasures under the animal rule. Adv Prev Med. 2012;2012:507571.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Gallardo-Romero NF, Velasco-Villa A, Weiss SL, et al. Detection of North American orthopoxviruses by real time-PCR. Virol J. 2011;8:313.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Reynolds MG, Carroll DS, Olson VA, et al. A silent enzootic of an orthopoxvirus in Ghana, West Africa: evidence for multi-species involvement in the absence of widespread human disease. Am J Trop Med Hyg. 2010;82:746–54.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Emerson GL, Li Y, Frace MA, et al. The phylogenetics and ecology of the orthopoxviruses endemic to North America. PLoS One. 2009;4:e7666.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Weinstein RS. Should remaining stockpiles of smallpox virus (variola) be destroyed? Emerg Infect Dis. 2011;17:681–3.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Jackson RJ, Ramsay AJ, Christensen CD, Beaton S, Hall DF, Ramshaw IA. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J Virol. 2001;75:1205–10.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Brett W. Petersen
    • 1
  • Kevin L. Karem
    • 2
  • Inger K. Damon
    • 1
  1. 1.Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and PreventionAtlantaUSA
  2. 2.Laboratory Reference and Research Branch, Division of Sexually Transmitted Disease and PreventionNational Center for HIV/AIDS, Viral Hepatitis, STD and TB PreventionAtlantaUSA

Personalised recommendations