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Smallpox

Last edited: 4/14/2026

Overview

Smallpox, caused by the variola virus, is a highly contagious disease eradicated globally in 1979 but remains a potential bioterrorism threat due to its historical pathogenicity and high mortality rate of up to 30% 1.

Diagnosis

  • Clinical presentation includes fever, rash progressing from macules to papules, vesicles, pustules, and eventual scarring 7.
  • Differentiation from chickenpox is crucial; smallpox rash typically progresses synchronously across the body and is more deeply embedded 7.
  • Laboratory confirmation involves PCR testing or electron microscopy of lesion samples 28.

    • Management

  • No specific antiviral treatment exists; management focuses on supportive care including fluid hydration, pain management, and isolation to prevent spread 128.
  • Vaccination with live attenuated vaccinia virus (e.g., Dryvax, LC16-KAKETSUKEN) is the primary preventive measure 610.
  • Monitoring for adverse reactions is critical; these can range from mild (e.g., fever, rash) to severe (e.g., encephalitis, eczema vaccinatum) 51126.

    • Special Populations

  • Pregnancy: Smallpox vaccination is contraindicated due to potential risks to the fetus 10.
  • Pediatrics: Vaccination protocols must consider age-specific risks and immune responses; pediatric data is limited but vaccination is generally avoided unless deemed essential 110.
  • Elderly: Increased risk of adverse reactions; careful risk-benefit assessment is necessary 511.
  • Comorbidities: Individuals with compromised immune systems or skin conditions (e.g., eczema) face heightened risks of severe adverse reactions and require cautious consideration 11026.

    • Key Recommendations

  • Implement active surveillance and reporting systems for adverse events following smallpox vaccination to monitor safety effectively (Evidence: Moderate) 1320.
  • Prioritize vaccination of healthcare workers and first responders due to their critical roles in managing potential outbreaks (Evidence: Expert opinion) 929.
  • Provide comprehensive education and training for healthcare providers on recognizing smallpox symptoms and managing vaccination complications (Evidence: Moderate) 731.
  • Ensure strict adherence to vaccination protocols to minimize the risk of autoinoculation and transmission to susceptible individuals (Evidence: Moderate) 216.
  • Establish clear guidelines for contraindications, including pregnancy and severe immunocompromised states, to prevent unnecessary risks (Evidence: Moderate) 1041.

    • References

    1 Yu C, Wu Q, Xin J, Yu Q, Ma Z, Xue M et al.. Designing a smallpox B-cell and T-cell multi-epitope subunit vaccine using a comprehensive immunoinformatics approach. Microbiology spectrum 2024. link 2 Carius BM, Dodge PM, Randles JD. Smallpox Autoinoculation Via Tattoo in a Soldier. Military medicine 2019. link 3 Jenson AB, Ghim SJ, Sundberg JP. An inquiry into the causes and effects of the variolae (or Cow-pox. 1798). Experimental dermatology 2016. link 4 Van Heiningen TW. Theodore Tronchin (1709-1781) and his friend Louis de Jaucourt (1704-1779). Histoire des sciences medicales 2016. link 5 Haselow D. Vaccination-Related Side Effects, Humoral Immunity, and Adverse Events during the Civilian Smallpox Vaccination Campaign, Arkansas, 2003. Public health nursing (Boston, Mass.) 2016. link 6 Nishiyama Y, Fujii T, Kanatani Y, Shinmura Y, Yokote H, Hashizume S. Freeze-dried live attenuated smallpox vaccine prepared in cell culture "LC16-KAKETSUKEN": Post-marketing surveillance study on safety and efficacy compliant with Good Clinical Practice. Vaccine 2015. link 7 Kim M, Terashita D, Borenstein L, Mascola L. Responding to suspected smallpox cases in the Los Angeles County from 2002 to 2006: identifying areas for education. The American journal of emergency medicine 2009. link 8 . Smallpox: dispelling the myths. Bulletin of the World Health Organization 2008. link 9 Chapman LE, Mootrey GT, Neff LJ. Introduction: vaccination against smallpox in the posteradication era. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008. link 10 Clark PT, Levin S. The Smallpox Vaccine Injury Compensation Program. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008. link 11 Wells TS, LeardMann CA, Smith TC, Smith B, Jacobson IG, Reed RJ et al.. Self-reported adverse health events following smallpox vaccination in a large prospective study of US military service members. Human vaccines 2008. link 12 Neff J, Modlin J, Birkhead GS, Poland G, Robertson RM, Sepkowitz K et al.. Monitoring the safety of a smallpox vaccination program in the United States: report of the joint Smallpox Vaccine Safety Working Group of the advisory committee on immunization practices and the Armed Forces Epidemiological Board. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008. link 13 Thomas TN, Reef S, Neff L, Sniadack MM, Mootrey GT. A review of the smallpox vaccine adverse events active surveillance system. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008. link 14 Kroger A, Vellozzi C, Deming M, Casey CG, Wen X, Norton SA. Dermatological lesions near the smallpox vaccination site after scab detachment. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008. link 15 McMahon AW, Zinderman C, Ball R, Gupta G, Braun MM. Comparison of military and civilian reporting rates for smallpox vaccine adverse events. Pharmacoepidemiology and drug safety 2007. link 16 Westphall JS. Smallpox--inappropriate vaccination site. Aviation, space, and environmental medicine 2006. link 17 Dellavalle RP, Heilig LF, Francis SO, Johnson KR, Hester EJ, McNealy KM et al.. What dermatologists do not know about smallpox vaccination: results from a worldwide electronic survey. The Journal of investigative dermatology 2006. link 18 Muralles AA, Ray P, Black S, Shinefield H, Casey CG, Campbell S et al.. Active telephone surveillance to evaluate adverse events among civilian smallpox vaccine recipients. Vaccine 2006. link 19 Olmsted SS, Grabenstein JD, Jain AK, Lurie N. Patient experience with, and use of, an electronic monitoring system to assess vaccination responses. Health expectations : an international journal of public participation in health care and health policy 2006. link 20 Casey C, Vellozzi C, Mootrey GT, Chapman LE, McCauley M, Roper MH et al.. Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports 2006. link 21 Weiner D. Smallpox vaccines: circling the wagons. Expert review of vaccines 2005. link 22 Freed HA, Milzman D, Freed M. Knowledge about the initial presentation of smallpox among emergency physicians in Washington, DC. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine 2005. link 23 Yanturali S, Suner S, Aksay E, Cevik AA, Sonmez Y. To be vaccinated or not? A survey of Turkish emergency physicians regarding smallpox. The Journal of emergency medicine 2005. link 24 Auckland C, Cowlishaw A, Morgan D, Miller E. Reactions to small pox vaccine in naïve and previously-vaccinated individuals. Vaccine 2005. link 25 Olmsted SS, Grabenstein JD, Jain AK, Comerford W, Giambo P, Johnson P et al.. Use of an electronic monitoring system for self-reporting smallpox vaccine reactions. Biosecurity and bioterrorism : biodefense strategy, practice, and science 2005. link 26 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. link 27 Spuls PI, Bos JD, Rudikoff D. Smallpox: what the dermatologist should know. Skinmed 2004. link 28 . Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report 2004. link 29 . Smallpox vaccination for emergency physicians. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine 2003. link 30 Thorne CD, Hirshon JM, Himes CD, McDiarmid MA. Emergency medicine tools to manage smallpox (vaccinia) vaccination complications: clinical practice guideline and policies and procedures. Annals of emergency medicine 2003. link00629-2) 31 Kwon N, Raven MC, Chiang WK, Moran GJ, Jui J, Carter RA et al.. Emergency physicians' perspectives on smallpox vaccination. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine 2003. link 32 . Smallpox vaccine adverse events among civilians--United States, January 24-February 18, 2003. MMWR. Morbidity and mortality weekly report 2003. link 33 . Smallpox vaccine adverse events among civilians--United States, March 4-10, 2003. MMWR. Morbidity and mortality weekly report 2003. link 34 . Smallpox vaccine adverse events among civilians--United States, February 25-March 3, 2003. MMWR. Morbidity and mortality weekly report 2003. link 35 . Smallpox vaccine adverse events among civilians--United States, February 18-24, 2003. MMWR. Morbidity and mortality weekly report 2003. link 36 . Update on adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report 2003. link 37 . Update: Adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report 2003. link 38 . Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report 2003. link 39 . Update: Adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report 2003. link 40 . Smallpox Vaccine Adverse Events Monitoring and Response System for the first stage of the smallpox vaccination program. MMWR. Morbidity and mortality weekly report 2003. link 41 Maurer DM, Harrington B, Lane JM. Smallpox vaccine: contraindications, administration, and adverse reactions. American family physician 2003. link 42 Grabenstein JD, Winkenwerder W. US military smallpox vaccination program experience. JAMA 2003. link 43 Cono J, Casey CG, Bell DM. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports 2003. link 44 Haim M, Gdalevich M, Mimouni D, Ashkenazi I, Shemer J. Adverse reactions to smallpox vaccine: the Israel Defense Force experience, 1991 to 1996. A comparison with previous surveys. Military medicine 2000. link 45 Haslam F. Looking at medical history: vaccination. Scottish medical journal 1990. link 46 Broyles SS, Fesler BS. Vaccinia virus gene encoding a component of the viral early transcription factor. Journal of virology 1990. link 47 Knuutila S, Mäki-Paakkanen J, Kähkönen M, Hokkanen E. An increased frequency of chromosomal changes and SCE's in cultured blood lymphocytes of 12 subjects vaccinated against smallpox. Human genetics 1978. link 48 Edwards K. Danger of sunburn following vaccination. Papua and New Guinea medical journal 1977. link 49 Huq F. Effect of temperature and relative humidity on variola virus in crusts. Bulletin of the World Health Organization 1976. link 50 Topciu V, Luca I, Moldovan E, Stoianovici V, Plavoşin L, Milin D et al.. Transmission of vaccinia virus from vaccinated milkers to cattle. Virologie 1976. link 51 Entwistle CC. Antibody to vaccinia. II. Prevalence in blood donors. Vox sanguinis 1975. link 52 Noble J, Loggins MS. Accuracy of smallpox diagnosis by immunfluorescence with a purified conjugate. Applied microbiology 1970. link

    Original source

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      Designing a smallpox B-cell and T-cell multi-epitope subunit vaccine using a comprehensive immunoinformatics approach. — Yu C, Wu Q, Xin J, Yu Q, Ma Z, Xue M et al. Microbiology spectrum (2024)
    2. [2]
      Smallpox Autoinoculation Via Tattoo in a Soldier. — Carius BM, Dodge PM, Randles JD Military medicine (2019)
    3. [3]
      An inquiry into the causes and effects of the variolae (or Cow-pox. 1798). — Jenson AB, Ghim SJ, Sundberg JP Experimental dermatology (2016)
    4. [4]
      Theodore Tronchin (1709-1781) and his friend Louis de Jaucourt (1704-1779). — Van Heiningen TW Histoire des sciences medicales (2016)
    5. [5]
      Vaccination-Related Side Effects, Humoral Immunity, and Adverse Events during the Civilian Smallpox Vaccination Campaign, Arkansas, 2003. — Haselow D Public health nursing (Boston, Mass.) (2016)
    6. [6]
      Freeze-dried live attenuated smallpox vaccine prepared in cell culture "LC16-KAKETSUKEN": Post-marketing surveillance study on safety and efficacy compliant with Good Clinical Practice. — Nishiyama Y, Fujii T, Kanatani Y, Shinmura Y, Yokote H, Hashizume S Vaccine (2015)
    7. [7]
      Responding to suspected smallpox cases in the Los Angeles County from 2002 to 2006: identifying areas for education. — Kim M, Terashita D, Borenstein L, Mascola L The American journal of emergency medicine (2009)
    8. [8]
      Smallpox: dispelling the myths. Bulletin of the World Health Organization (2008)
    9. [9]
      Introduction: vaccination against smallpox in the posteradication era. — Chapman LE, Mootrey GT, Neff LJ Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2008)
    10. [10]
      The Smallpox Vaccine Injury Compensation Program. — Clark PT, Levin S Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2008)
    11. [11]
      Self-reported adverse health events following smallpox vaccination in a large prospective study of US military service members. — Wells TS, LeardMann CA, Smith TC, Smith B, Jacobson IG, Reed RJ et al. Human vaccines (2008)
    12. [12]
      Monitoring the safety of a smallpox vaccination program in the United States: report of the joint Smallpox Vaccine Safety Working Group of the advisory committee on immunization practices and the Armed Forces Epidemiological Board. — Neff J, Modlin J, Birkhead GS, Poland G, Robertson RM, Sepkowitz K et al. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2008)
    13. [13]
      A review of the smallpox vaccine adverse events active surveillance system. — Thomas TN, Reef S, Neff L, Sniadack MM, Mootrey GT Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2008)
    14. [14]
      Dermatological lesions near the smallpox vaccination site after scab detachment. — Kroger A, Vellozzi C, Deming M, Casey CG, Wen X, Norton SA Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2008)
    15. [15]
      Comparison of military and civilian reporting rates for smallpox vaccine adverse events. — McMahon AW, Zinderman C, Ball R, Gupta G, Braun MM Pharmacoepidemiology and drug safety (2007)
    16. [16]
      Smallpox--inappropriate vaccination site. — Westphall JS Aviation, space, and environmental medicine (2006)
    17. [17]
      What dermatologists do not know about smallpox vaccination: results from a worldwide electronic survey. — Dellavalle RP, Heilig LF, Francis SO, Johnson KR, Hester EJ, McNealy KM et al. The Journal of investigative dermatology (2006)
    18. [18]
      Active telephone surveillance to evaluate adverse events among civilian smallpox vaccine recipients. — Muralles AA, Ray P, Black S, Shinefield H, Casey CG, Campbell S et al. Vaccine (2006)
    19. [19]
      Patient experience with, and use of, an electronic monitoring system to assess vaccination responses. — Olmsted SS, Grabenstein JD, Jain AK, Lurie N Health expectations : an international journal of public participation in health care and health policy (2006)
    20. [20]
      Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. — Casey C, Vellozzi C, Mootrey GT, Chapman LE, McCauley M, Roper MH et al. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports (2006)
    21. [21]
      Smallpox vaccines: circling the wagons. — Weiner D Expert review of vaccines (2005)
    22. [22]
      Knowledge about the initial presentation of smallpox among emergency physicians in Washington, DC. — Freed HA, Milzman D, Freed M Academic emergency medicine : official journal of the Society for Academic Emergency Medicine (2005)
    23. [23]
      To be vaccinated or not? A survey of Turkish emergency physicians regarding smallpox. — Yanturali S, Suner S, Aksay E, Cevik AA, Sonmez Y The Journal of emergency medicine (2005)
    24. [24]
      Reactions to small pox vaccine in naïve and previously-vaccinated individuals. — Auckland C, Cowlishaw A, Morgan D, Miller E Vaccine (2005)
    25. [25]
      Use of an electronic monitoring system for self-reporting smallpox vaccine reactions. — Olmsted SS, Grabenstein JD, Jain AK, Comerford W, Giambo P, Johnson P et al. Biosecurity and bioterrorism : biodefense strategy, practice, and science (2005)
    26. [26]
      Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004. — Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, Lane JM JAMA (2005)
    27. [27]
      Smallpox: what the dermatologist should know. — Spuls PI, Bos JD, Rudikoff D Skinmed (2004)
    28. [28]
      Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report (2004)
    29. [29]
      Smallpox vaccination for emergency physicians. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine (2003)
    30. [30]
      Emergency medicine tools to manage smallpox (vaccinia) vaccination complications: clinical practice guideline and policies and procedures. — Thorne CD, Hirshon JM, Himes CD, McDiarmid MA Annals of emergency medicine (2003)
    31. [31]
      Emergency physicians' perspectives on smallpox vaccination. — Kwon N, Raven MC, Chiang WK, Moran GJ, Jui J, Carter RA et al. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine (2003)
    32. [32]
      Smallpox vaccine adverse events among civilians--United States, January 24-February 18, 2003. MMWR. Morbidity and mortality weekly report (2003)
    33. [33]
      Smallpox vaccine adverse events among civilians--United States, March 4-10, 2003. MMWR. Morbidity and mortality weekly report (2003)
    34. [34]
      Smallpox vaccine adverse events among civilians--United States, February 25-March 3, 2003. MMWR. Morbidity and mortality weekly report (2003)
    35. [35]
      Smallpox vaccine adverse events among civilians--United States, February 18-24, 2003. MMWR. Morbidity and mortality weekly report (2003)
    36. [36]
      Update on adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report (2003)
    37. [37]
      Update: Adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report (2003)
    38. [38]
      Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report (2003)
    39. [39]
      Update: Adverse events following civilian smallpox vaccination--United States, 2003. MMWR. Morbidity and mortality weekly report (2003)
    40. [40]
      Smallpox Vaccine Adverse Events Monitoring and Response System for the first stage of the smallpox vaccination program. MMWR. Morbidity and mortality weekly report (2003)
    41. [41]
      Smallpox vaccine: contraindications, administration, and adverse reactions. — Maurer DM, Harrington B, Lane JM American family physician (2003)
    42. [42]
      US military smallpox vaccination program experience. — Grabenstein JD, Winkenwerder W JAMA (2003)
    43. [43]
      Smallpox vaccination and adverse reactions. Guidance for clinicians. — Cono J, Casey CG, Bell DM MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports (2003)
    44. [44]
      Adverse reactions to smallpox vaccine: the Israel Defense Force experience, 1991 to 1996. A comparison with previous surveys. — Haim M, Gdalevich M, Mimouni D, Ashkenazi I, Shemer J Military medicine (2000)
    45. [45]
      Looking at medical history: vaccination. — Haslam F Scottish medical journal (1990)
    46. [46]
      Vaccinia virus gene encoding a component of the viral early transcription factor. — Broyles SS, Fesler BS Journal of virology (1990)
    47. [47]
      An increased frequency of chromosomal changes and SCE's in cultured blood lymphocytes of 12 subjects vaccinated against smallpox. — Knuutila S, Mäki-Paakkanen J, Kähkönen M, Hokkanen E Human genetics (1978)
    48. [48]
      Danger of sunburn following vaccination. — Edwards K Papua and New Guinea medical journal (1977)
    49. [49]
      Effect of temperature and relative humidity on variola virus in crusts. — Huq F Bulletin of the World Health Organization (1976)
    50. [50]
      Transmission of vaccinia virus from vaccinated milkers to cattle. — Topciu V, Luca I, Moldovan E, Stoianovici V, Plavoşin L, Milin D et al. Virologie (1976)
    51. [51]
      Antibody to vaccinia. II. Prevalence in blood donors. — Entwistle CC Vox sanguinis (1975)
    52. [52]
      Accuracy of smallpox diagnosis by immunfluorescence with a purified conjugate. — Noble J, Loggins MS Applied microbiology (1970)
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