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Vaccinia virus as the smallpox vaccine

Stuart N Isaacs, MD
Harvey M Friedman, MD
Section Editors
Martin S Hirsch, MD
Sheldon L Kaplan, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Vaccinia virus is the live poxvirus that was used as the smallpox vaccine. The development of this vaccine was an important step in the successful eradication of smallpox, an infection characterized by fever, rash and constitutional symptoms, with a high rate of morbidity and mortality.

This topic will address the virology of vaccinia virus, available vaccines, vaccination procedures, contraindications, and adverse events. Vaccinia virus in the research setting is discussed elsewhere. (See "Vaccinia virus in the research setting".)


Attempts at control of smallpox began after it was noted that accidental exposure to smallpox by a scratch on the skin reduced the severity of infection. This led to the practice of "variolation," which involved intentional administration of pustular fluids from smallpox scabs to uninfected persons. The practice of variolation began in China and India in the tenth century; deaths were reported as a complication of this procedure.

In 1796, Edward Jenner showed that inoculation with cowpox virus protected against smallpox and carried less risk of illness than variolation. Subsequently, vaccinia virus became the basis for the smallpox vaccine. The origins of vaccinia virus are uncertain. Successful vaccination was highly protective for development of any disease for five years and could protect from death or severe smallpox for up to 20 years. Periodic revaccination was necessary for optimal protection.

In 1959, the World Health Assembly adopted a program aimed at global eradication of smallpox. The development of stable, freeze-dried vaccine meant that vaccination programs could reach less-developed tropical countries. By 1967, efforts towards eradication were intensified.

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Literature review current through: Nov 2017. | This topic last updated: Jun 26, 2017.
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  1. Moss B. Poxviridae: The viruses and their replication. In: Fields Virology, Fields BN, Knipe DM, Howley PM (Eds), Lippincott-Raven Press, Philadelphia 1996. p.2637.
  2. Moss B. Vaccinia virus: a tool for research and vaccine development. Science 1991; 252:1662.
  3. Brochier B, Aubert MF, Pastoret PP, et al. Field use of a vaccinia-rabies recombinant vaccine for the control of sylvatic rabies in Europe and North America. Rev Sci Tech 1996; 15:947.
  4. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A 1996; 93:11349.
  5. Peplinski GR, Tsung K, Norton JA. Vaccinia virus for human gene therapy. Surg Oncol Clin N Am 1998; 7:575.
  6. Rotz LD, Dotson DA, Damon IK, et al. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Recomm Rep 2001; 50:1.
  7. Fauci AS. Smallpox vaccination policy--the need for dialogue. N Engl J Med 2002; 346:1319.
  8. Bicknell WJ. The case for voluntary smallpox vaccination. N Engl J Med 2002; 346:1323.
  9. Rupprecht CE, Blass L, Smith K, et al. Human infection due to recombinant vaccinia-rabies glycoprotein virus. N Engl J Med 2001; 345:582.
  10. Centers for Disease Control and Prevention (CDC). Human vaccinia infection after contact with a raccoon rabies vaccine bait - Pennsylvania, 2009. MMWR Morb Mortal Wkly Rep 2009; 58:1204.
  11. Centers for Disease Control and Prevention (CDC). Supplemental recommendations on adverse events following smallpox vaccine in the pre-event vaccination program: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2003; 52:282.
  12. Petersen BW, Damon IK, Pertowski CA, et al. Clinical guidance for smallpox vaccine use in a postevent vaccination program. MMWR Recomm Rep 2015; 64:1.
  13. Notice to Readers: Newly Licensed Smallpox Vaccine to Replace Old Smallpox Vaccine. MMWR Morb Mortal Wkly Rep 2008; 57:207.
  14. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm094065.htm (Accessed on November 18, 2011).
  15. Weltzin R, Liu J, Pugachev KV, et al. Clonal vaccinia virus grown in cell culture as a new smallpox vaccine. Nat Med 2003; 9:1125.
  16. Kennedy JS, Greenberg RN. IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine. Expert Rev Vaccines 2009; 8:13.
  17. von Krempelhuber A, Vollmar J, Pokorny R, et al. A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE. Vaccine 2010; 28:1209.
  18. Greenberg RN, Hay CM, Stapleton JT, 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.
  19. Greenberg RN, Overton ET, Haas DW, et al. Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects. J Infect Dis 2013; 207:749.
  20. Greenberg RN, Hurley MY, Dinh DV, et al. A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis. PLoS One 2015; 10:e0138348.
  21. Cooney EL, Collier AC, Greenberg PD, et al. Safety of and immunological response to a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein. Lancet 1991; 337:567.
  22. Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med 2003; 9:1131.
  23. Breman JG, Henderson DA. Poxvirus dilemmas--monkeypox, smallpox, and biologic terrorism. N Engl J Med 1998; 339:556.
  24. Centers for Disease Control and Prevention (CDC). Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR Morb Mortal Wkly Rep 2004; 53:106.
  25. Redfield RR, Wright DC, James WD, et al. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987; 316:673.
  26. Centers for Disease Control and Prevention (CDC). Human monkeypox -- Kasai Oriental, Democratic Republic of Congo, February 1996-October 1997. MMWR Morb Mortal Wkly Rep 1997; 46:1168.
  27. Cohen J. Is an old virus up to new tricks? Science 1997; 277:312.
  28. Hooper C. Poxvirus dilemmas. N Engl J Med 1998; 339:2027.
  29. 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.
  30. Centers for Disease Control and Prevention (CDC). Update: multistate outbreak of monkeypox--Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:642.
  31. KEMPE CH. Studies smallpox and complications of smallpox vaccination. Pediatrics 1960; 26:176.
  32. Lane JM, Ruben FL, Abrutyn E, Millar JD. Deaths attributable to smallpox vaccination, 1959 to 1966, and 1968. JAMA 1970; 212:441.
  33. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. N Engl J Med 1969; 281:1201.
  34. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis 1970; 122:303.
  35. 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.
  36. Frey SE, Newman FK, Yan L, et al. Response to smallpox vaccine in persons immunized in the distant past. JAMA 2003; 289:3295.
  37. Vellozzi C, Lane JM, Averhoff F, et al. Generalized vaccinia, progressive vaccinia, and eczema vaccinatum are rare following smallpox (vaccinia) vaccination: United States surveillance, 2003. Clin Infect Dis 2005; 41:689.
  38. Suarez VR, Hankins GD. Smallpox and pregnancy: from eradicated disease to bioterrorist threat. Obstet Gynecol 2002; 100:87.
  39. Badell ML, Meaney-Delman D, Tuuli MG, et al. Risks Associated With Smallpox Vaccination in Pregnancy: A Systematic Review and Meta-analysis. Obstet Gynecol 2015; 125:1439.
  40. Kamboj M, Sepkowitz KA. Risk of transmission associated with live attenuated vaccines given to healthy persons caring for or residing with an immunocompromised patient. Infect Control Hosp Epidemiol 2007; 28:702.
  41. Centers for Disease Control and Prevention (CDC). Update: cardiac and other adverse events following civilian smallpox vaccination--United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:639.
  42. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002; 346:1265.
  43. Stanley SL Jr, Frey SE, Taillon-Miller P, et al. The immunogenetics of smallpox vaccination. J Infect Dis 2007; 196:212.
  44. Crowe JE Jr. Genetic predisposition for adverse events after vaccination. J Infect Dis 2007; 196:176.
  45. Sejvar JJ, Labutta RJ, Chapman LE, et al. Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004. JAMA 2005; 294:2744.
  46. Kempe CH, Benenson AS. Smallpox immunization in the United States. JAMA 1965; 194:161.
  47. Gurvich EB. The age-dependent risk of postvaccination complications in vaccinees with smallpox vaccine. Vaccine 1992; 10:96.
  48. Hopkins RJ, Lane JM. Clinical efficacy of intramuscular vaccinia immune globulin: a literature review. Clin Infect Dis 2004; 39:819.
  49. NANNING W. Prophylactic effect of antivaccinia gamma-globulin against post-vaccinal encephalitis. Bull World Health Organ 1962; 27:317.
  50. Centers for Disease Control and Prevention (CDC). Progressive vaccinia in a military smallpox vaccinee - United States, 2009. MMWR Morb Mortal Wkly Rep 2009; 58:532.
  51. 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.
  52. Reed JL, Scott DE, Bray M. Eczema vaccinatum. Clin Infect Dis 2012; 54:832.
  54. Centers for Disease Control and Prevention (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.
  55. Vora S, Damon I, Fulginiti V, et al. Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin Infect Dis 2008; 46:1555.
  56. Monath TP, Frey SE. Possible autoimmune reactions following smallpox vaccination: the biologic false positive test for syphilis. Vaccine 2009; 27:1645.
  57. Centers for Disease Control and Prevention (CDC). Update: cardiac-related events during the civilian smallpox vaccination program--United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:492.
  58. Cassimatis DC, Atwood JE, Engler RM, et al. Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol 2004; 43:1503.
  59. Vellozzi C, Averhoff F, Lane JM, et al. Superinfection following smallpox vaccination (Vaccinia), United States: surveillance January 2003 through January 2004. Clin Infect Dis 2004; 39:1660.
  60. Cummings JF, Polhemus ME, Hawkes C, et al. Persistence of vaccinia at the site of smallpox vaccination. Clin Infect Dis 2008; 46:101.
  61. Ellis PP, Winograd LA. Ocular vaccinia: A specific treatment. Arch Ophthalmol 1962; 68:600.
  62. Ruben FL, Lane JM. Ocular vaccinia. An epidemiologic analysis of 348 cases. Arch Ophthalmol 1970; 84:45.
  63. Fulginiti VA, Winograd LA, Jackson M, Ellis P. Therapy of experimental vaccinal keratitis. Effect of idoxuridine and VIG. Arch Ophthalmol 1965; 74:539.
  64. Egan C, Kelly CD, Rush-Wilson K, et al. Laboratory-confirmed transmission of vaccinia virus infection through sexual contact with a military vaccinee. J Clin Microbiol 2004; 42:5409.
  65. Centers for Disease Control and Prevention (CDC). Vulvar vaccinia infection after sexual contact with a military smallpox vaccinee--Alaska, 2006. MMWR Morb Mortal Wkly Rep 2007; 56:417.
  66. Centers for Disease Control and Prevention (CDC). Secondary and tertiary transmission of vaccinia virus after sexual contact with a smallpox vaccinee--San Diego, California, 2012. MMWR Morb Mortal Wkly Rep 2013; 62:145.
  67. Casey C, Vellozzi C, Mootrey GT, et al. Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. MMWR Recomm Rep 2006; 55:1.
  68. "Pharmaceutical Approvals Monthly" F-D-C Reports. Chevy Chase, MD. 2005; 10(3):9.
  69. Sbrana E, Jordan R, Hruby DE, et al. Efficacy of the antipoxvirus compound ST-246 for treatment of severe orthopoxvirus infection. Am J Trop Med Hyg 2007; 76:768.
  70. 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.
  71. Chinsangaram J, Honeychurch KM, Tyavanagimatt SR, 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.
  72. Franz DR, Jahrling PB, Friedlander AM, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997; 278:399.
  73. Smee DF, Bailey KW, Wong MH, et al. Topical cidofovir is more effective than is parenteral therapy for treatment of progressive vaccinia in immunocompromised mice. J Infect Dis 2004; 190:1132.
  74. Kern ER, Hartline C, Harden E, et al. Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob Agents Chemother 2002; 46:991.
  75. Rice AD, Adams MM, Wallace G, et al. Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses 2011; 3:47.
  76. Zaitseva M, McCullough KT, Cruz S, et al. 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.
  77. Brainerd HD, Hanna L, Jawetz E. Methisazone in progressive vaccinia. N Engl J Med 1967; 276:620.
  78. Hermans PE, Cockerill FR 3rd. Antiviral agents. Mayo Clin Proc 1983; 58:217.
  79. Kesson AM, Ferguson JK, Rawlinson WD, Cunningham AL. Progressive vaccinia treated with ribavirin and vaccinia immune globulin. Clin Infect Dis 1997; 25:911.
  80. Grosenbach DW, Jordan R, King DS, et al. Immune responses to the smallpox vaccine given in combination with ST-246, a small-molecule inhibitor of poxvirus dissemination. Vaccine 2008; 26:933.
  81. Parker S, Crump R, Foster S, et al. Co-administration of the broad-spectrum antiviral, brincidofovir (CMX001), with smallpox vaccine does not compromise vaccine protection in mice challenged with ectromelia virus. Antiviral Res 2014; 111:42.
  82. Reif DM, McKinney BA, Motsinger AA, et al. Genetic basis for adverse events after smallpox vaccination. J Infect Dis 2008; 198:16.