Vaccinia virus has been used as a live vaccine in the smallpox eradication program, and more recently as a vaccine against cancer (49). It has not been widely accepted as a potential tumor-directed gene therapy vector, however, due to concerns regarding the safety of a systemically administered replicating virus. Although it is generally considered to be a relatively safe vector for vaccinations, a defined risk exists for generalized vaccinia, vaccinia-associated encephalitis, vaccinia ne-crosom, and eczema vaccinatum have been described in infants and the immunosuppressed population, specifically those with deficits in cellular immunity (50-55).
Vaccinia-associated encephalitis is a recognized complication of smallpox vaccination that can lead to death, and vaccinia can be recovered from the central nervous system (54). Classically, vaccinia infection in immunosuppressed patients leads to a progressive necrotic ulcer known as vaccinia necro-sum. This ulcer can progress to destroy significant amounts of tissue, leaving exposed bone, requiring tissue grafts or amputation (56) (Fig. 3). Often this dramatic local infection does not lead to systemic viral spread. Patients with eczema, however, can get vaccinia infection of eczematous skin throughout the body (eczema vaccinatum). A large viral load such as this leads to fever and malaise and can lead to death from a ''septic syndrome.'' The exact cause of vaccinia pathogenicity and lethality in animal models is difficult to determine. Mice moribund from wild-type vaccinia infection have demonstrated high levels of circulating inflammatory cytokines, and it is
suspected that the systemic inflammatory response syndrome plays a significant role in viral pathogenicity as opposed to specific organ dysfunction (Naiak et al., unpublished data, 1999).
The biodistribution of systemic injection of wild-type and TK-deleted vaccinia virus has been studied extensively in many animal models, including mice, rats, rabbits, and primates (10,57,58). The highest titers of recoverable virus are always from the ovary. Many fold less virus is recoverable from the liver, spleen, lung, and brain. Cutaneous pox lesions, which have high titers of vaccinia, can form. Mutations (e.g., TK deletion), which attenuate the virus by making it less efficient for replication in nondividing cells, are less recoverable from normal organs after systemic injection (59).
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