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
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