Laboratory Studies
- The diagnosis of vaccinia virus complications is usually straightforward and depends on obtaining the history of recent vaccinia virus exposure by vaccination or contact with a vaccinated individual. A careful workup for immune deficiency should be considered in patients who do not promptly improve.
- The diagnosis of CNS complications is more difficult because the signs and symptoms are nonspecific. Although rare, postvaccinial encephalitis should be considered in any patient with neurologic symptoms developing 1-2 weeks after exposure to live vaccinia virus. Vaccinia virus has not been isolated from cerebrospinal fluid (CSF) of patients with encephalitis, and CSF analysis usually produces normal results, except for increased pressure; however, CSF analysis may be indicated to exclude other causes of encephalitis.
Imaging Studies
- Imaging studies are not useful in the diagnosis of vaccinia infection or a postvaccinial complication, although imaging modalities may be helpful to exclude other causes of disease (eg, MRI of the brain in cases of suspected encephalitis).
Other Tests
- Patients who present with skin manifestations usually have live viral particles replicating in the dermal lesions. The presence of vaccinia virus can be confirmed by obtaining a biopsy of the skin lesion and examination through microscopy, plaque titer assay, Western blot, and polymerase chain reaction (PCR) analysis.
Histologic Findings
Light microscopy may reveal characteristic inclusions (ie, Guarnieri bodies) in the cytoplasm of infected cells. This is distinct from the appearance of cells infected by viruses such as herpes simplex virus, which typically demonstrate intranuclear inclusion bodies.
Couch RB, Winokur P, Edwards KM, Black S, Atmar RL, Stapleton JT, et al. Reducing the dose of smallpox vaccine reduces vaccine-associated morbidity without reducing vaccination success rates or immune responses. J Infect Dis. Mar 15 2007;195(6):826-32. [Medline].
Rimmelzwaan GF, Sutter G. Candidate influenza vaccines based on recombinant modified vaccinia virus Ankara. Expert Rev Vaccines. Apr 2009;8(4):447-54. [Medline].
Tykodi SS, Thompson JA. Development of modified vaccinia Ankara-5T4 as specific immunotherapy for advanced human cancer. Expert Opin Biol Ther. Dec 2008;8(12):1947-53. [Medline].
Perera LP, Waldmann TA, Mosca JD, Baldwin N, Berzofsky JA, Oh SK. Development of smallpox vaccine candidates with integrated interleukin-15 that demonstrate superior immunogenicity, efficacy, and safety in mice. J Virol. Aug 2007;81(16):8774-83. [Medline].
Wertheimer ER, Olive DS, Brundage JF, Clark LL. Contact transmission of vaccinia virus from smallpox vaccinees in the United States, 2003-2011. Vaccine. Dec 19 2011;[Medline].
Redfield RR, Wright DC, James WD. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med. Mar 12 1987;316(11):673-6. [Medline].
Artenstein AW. New generation smallpox vaccines: a review of preclinical and clinical data. Rev Med Virol. Jul-Aug 2008;18(4):217-31. [Medline].
Baxby D. Indications for smallpox vaccination: policies still differ. Vaccine. 1993;11(4):395-6. [Medline].
Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. Apr 25 2002;346(17):1300-8. [Medline].
Buller RM, Palumbo GJ. Poxvirus pathogenesis. Microbiol Rev. Mar 1991;55(1):80-122. [Medline].
Carroll MW, Moss B. Poxviruses as expression vectors. Curr Opin Biotechnol. Oct 1997;8(5):573-7. [Medline].
[Guideline] Casey C, Vellozzi C, Mootrey GT, Chapman LE, McCauley M, Roper MH. Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. MMWR Recomm Rep. Feb 3 2006;55(RR-1):1-16. [Medline].
Casey CG, Iskander JK, Roper MH, Mast EE, Wen XJ, Török TJ. Adverse events associated with smallpox vaccination in the United States, January-October 2003. JAMA. Dec 7 2005;294(21):2734-43. [Medline].
Clark J, Diven D. Poxviruses. In: Tyring S, Moore A, Lupi O, eds. Mucocutaneous Manifestations of Viral Diseases. 2nd ed. New York, NY: Informa HealthCare; In press.
Damon I. Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 6th ed. Orlando, FL: Churchill Livingstone; 2005:1742-55.
Egan C, Kelly CD, Rush-Wilson K, Davis SW, Samsonoff WA, Pfeiffer H. Laboratory-confirmed transmission of vaccinia virus infection through sexual contact with a military vaccinee. J Clin Microbiol. Nov 2004;42(11):5409-11. [Medline].
Franz DR, Jahrling PB, Friedlander AM, McClain DJ, Hoover DL, Bryne WR, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA. Aug 6 1997;278(5):399-411. [Medline].
Friedman HM. Smallpox, Vaccinia, and Other Poxviruses. In: Isselbacher, et al, eds. Harrison's Principles of Internal Medicine. 13th ed. New York, NY: McGraw-Hill; 1994:798-9.
Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA. Jun 25 2003;289(24):3278-82. [Medline].
Haga IR, Bowie AG. Evasion of innate immunity by vaccinia virus. Parasitology. 2005;130 Suppl:S11-25. [Medline].
Harrop R, Ryan MG, Golding H, Redchenko I, Carroll MW. Monitoring of human immunological responses to vaccinia virus. Methods Mol Biol. 2004;269:243-66. [Medline].
Hopkins RJ, Lane JM. Clinical efficacy of intramuscular vaccinia immune globulin: a literature review. Clin Infect Dis. Sep 15 2004;39(6):819-26. [Medline].
Lane HC, Fauci AS. Microbial bioterrorism. In: Kasper, et al, eds. Harrison's Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005.
Lane JM, Millar JD. Risks of smallpox vaccination complications in the United States. Am J Epidemiol. Apr 1971;93(4):238-40. [Medline].
Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. N Engl J Med. Nov 27 1969;281(22):1201-8. [Medline].
Lewis FS, Norton SA, Bradshaw RD, Lapa J, Grabenstein JD. Analysis of cases reported as generalized vaccinia during the US military smallpox vaccination program, December 2002 to December 2004. J Am Acad Dermatol. Jul 2006;55(1):23-31. [Medline].
Moss B. Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety. Proc Natl Acad Sci U S A. Oct 15 1996;93(21):11341-8. [Medline].
Moss B. Poxvirus entry and membrane fusion. Virology. Jan 5 2006;344(1):48-54. [Medline].
Moss B. Vaccinia virus: a tool for research and vaccine development. Science. Jun 21 1991;252(5013):1662-7. [Medline].
Neff JM. Vaccinia Virus (Cowpox). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000:1553-5.
Notice to Readers: Newly Licensed Smallpox Vaccine to Replace Old Smallpox Vaccine. MMWR Morb Mortal Wkly. 2008;57:207-208.
Ojeda S, Domi A, Moss B. Vaccinia virus G9 protein is an essential component of the poxvirus entry-fusion complex. J Virol. Oct 2006;80(19):9822-30. [Medline].
Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. Oct 15 1996;93(21):11349-53. [Medline].
Rotz LD, Dotson DA, Damon IK, Becher JA. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Recomm Rep. Jun 22 2001;50:1-25; quiz CE1-7. [Medline].
Savona MR, Dela Cruz WP, Jones MS, Thornton JA, Xia D, Hadfield TL, et al. Detection of vaccinia DNA in the blood following smallpox vaccination. JAMA. Apr 26 2006;295(16):1898-900. [Medline].
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. Dec 7 2005;294(21):2744-50. [Medline].
Sepkowitz KA. How contagious is vaccinia?. N Engl J Med. Jan 30 2003;348(5):439-46. [Medline].
Stanley SL Jr, Frey SE, Taillon-Miller P, Guo J, Miller RD, Koboldt DC, et al. The immunogenetics of smallpox vaccination. J Infect Dis. Jul 15 2007;196(2):212-9. [Medline].
Stark JH, Frey SE, Blum PS, Monath TP. Lack of transmission of vaccinia virus. Emerg Infect Dis. Apr 2006;12(4):698-700. [Medline].
Townsley AC, Moss B. Two distinct low-pH steps promote entry of vaccinia virus. J Virol. Aug 2007;81(16):8613-20. [Medline].
| Complication | Number of cases from 450,293 vaccinations administered between 12/13/2002 and 5/28/2003 | Department of Defense rate per million vaccinees (95% confidence interval) | Historical number of cases from 1950s and 1960s |
| Death | 0 | 0 (0-3.7) | Age 1 y at first vaccination - 5 per 1 million primary vaccinees |
| Age 1-4 y at first vaccination - 0.5 per 1 million primary vaccinees | |||
| Age 5-19 y at first vaccination - 0.5 per 1 million primary vaccinees | |||
| Age ≥ 20 y at first vaccination - No data | |||
| Encephalitis | 1 | 2.2 (0.6-7.2) | 3 per 1 million primary vaccinees |
| Vaccinia necrosum/progressive vaccinia | 0 | 0 (0-3.7) | Approximately 1 patient per million during primary or revaccination |
| Usually fatal over a period of several months | |||
| Eczema vaccinatum | 0 | 0 (0-3.7) | 1 per 100,000 primary vaccinees |
| 1 per 1 million revaccinees | |||
| Generalized vaccinia | 36 | 80 (63-100) | Occasional occurrence in immunocompetent individuals |
| 3 per 100,000 primary vaccinees | |||
| 1 per 1 million revaccinees | |||
| Accidental vaccinia | 48 | 107 (88-129) | 3 per 100,000 to 1 million vaccinees |
| Erythematous rash | 36 | 80 (63-100) | Approximately 1 per 100,000 primary vaccinees* |
| Acute myopericarditis | 37 | 82 (65-102) | 100 per 1 million vaccinees |
| *Incidence was slightly higher when vaccination occurred before age 1 year. | |||

