Military Dermatology

Smallpox Vaccine Complications: The Dermatologist’s Role in Diagnosis and Management

In partnership with the Association of Military Dermatologists

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In 2002, the United States implemented a new program for smallpox vaccinations among military personnel using a live vaccinia virus product. Approximately 2.4 million US military service members and health care workers have since been inoculated, with considerable numbers experiencing adverse reactions. Military dermatologists are at the forefront of describing and treating these reactions, from relatively benign generalized vaccinia (GV) and erythema multiforme (EM) to more severe progressive vaccinia (PV) and eczema vaccinatum (EV). A wide range of providers, including civilian dermatologists and primary care providers, also may see such reactions and must be aware of the spectrum of vaccine reactions. Given current world instability (eg, threats of nuclear war, rise of authoritarian regimes) and concerns for bioterrorism attacks, the smallpox vaccine program likely will continue indefinitely. As the brisk military deployment tempo continues, a larger population of new vaccinees will yield more cutaneous reactions and diagnostic challenges.

Practice Points

  • Dermatologists should be aware that smallpox vaccinations are being administered to patients and may present with a myriad of cutaneous complications.
  • Progressive vaccinia should be suspected if a smallpox inoculation has not healed after 14 days and, most specifically, if there is no inflammation surrounding the site.
  • Generalized vaccinia generally is a benign condition seen in otherwise healthy patients and usually requires no treatment.
  • Atopic patients should be educated to avoid receiving routine smallpox vaccinations if they would be considered at risk for requiring the inoculation.



The practice of variolation, or inoculation of the smallpox virus from a pustule into a healthy person, was described as early as 1500 bc . Starting in 1796, Edward Jenner improved the process by using cowpox for the inoculation; however, over time the cowpox vaccines became contaminated with other viruses, namely vaccinia, which was thought to be derived from the horsepox virus. 1 In 1959, the World Health Organization implemented an eradication program using vaccinia. Vaccination for naturally occurring smallpox in the United States ended in 1972, and the World Health Organization declared smallpox eradicated by 1980; however, prompted by bioterrorism concerns, the United States implemented a new program of smallpox vaccination for military personnel in 2002. 2 By 2003, civilian health care workers and first responders were volunteering for the vaccination as part of a national security preparedness initiative. 3 Since reinitiation of the smallpox vaccination program, 2.4 million US military service members and health care workers have received the live-virus vaccinia vaccine. 4 The resumption of vaccinations after 3 decades introduced a large, immunologically naïve population to the vaccinia virus in the setting of limited awareness of the vaccine’s complications. Military dermatologists were and continue to be at the forefront of reporting and treating these reactions.


Vaccinia is an orthopoxvirus, distinct from the smallpox virus variola, with cross-protective immunity after infection. The smallpox vaccine that is available today is a second-generation vaccinia virus derived from plaque purification cloning from the first-generation version originally licensed in 1932, which was central to eradication.5 Today’s vaccine is administered using a bifurcated needle to puncture the epidermis 15 times. Ideally, a papule forms at the inoculation site 3 to 5 days later, progresses to a vesicle and then a pustule, and finally crusts and reaches maximum size by day 10. The crust separates from the skin at 14 to 21 days, at which time the virus can no longer be isolated from the wound. United States Department of Defense surveillance of the first 450,000 vaccinated personnel noted 1% of recipients developed cutaneous eruptions beyond the vaccination site, 5% developed a localized rash, and 1% experienced a generalized eruption.2 Adverse reactions included generalized vaccinia, erythema multiforme (EM), autoinoculation (including ocular vaccinia), and contact vaccinia. There were no cases of eczema vaccinatum (EV) or progressive vaccinia (PV) reported, and no deaths were attributed to these initial vaccines.2

Immunologic Response

Vaccinia replicates in keratinocytes, spreading from cell to cell, resulting in necrosis and vesicle formation. Components of both cellular and humoral immune responses are in place by 10 days after immunization. Deficiencies in these responses result in vaccine complications secondary to vaccine escape and replication beyond the inoculation site.6 A helper T cell TH2-predominant cytokine response in atopic individuals is the likely pathogenesis required for the rapid viral spread for EV.7 Similarly, patients with cell-mediated immunity deficiencies cannot sufficiently produce enough cytotoxic T cells to eliminate an established infection, which can result in PV. Despite the effectiveness of intravenous vaccinia immunoglobulins (VIGIVs) when administered to patients with certain vaccine complications, observations that children with severe X-linked agammaglobulinemia (Bruton disease) have normal responses to vaccination suggest that antibody production is least important in viral control.8 Simian models also suggest that B-cell depletion has no impact on lesion dissemination, as lesion size is inversely correlated with T-cell count.9

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