Vaccinia virus (a live but relatively weak relative of smallpox and cowpox) is used to vaccinate people against the development of smallpox (variola) resulting from an infection with the viral genus Orthopoxvirus. Although, smallpox was thought to be eradicated worldwide during the 1970's, some smallpox cultures have been retained in the laboratories of several countries and may pose a potential threat if used as a biological weapon. This has recently led to programs where mass-inoculations with vaccinia have been initiated throughout the U.S.

Vaccination against smallpox using vaccinia can result in complications. Reactions are rarely serious or life threatening, but one of the most common serious complications occur in and around the eye. This occurs when a person transfers vaccinia viruses by touch from their primary inoculation site to their own eyes (auto-inoculation). Accidental exposure can also occur in the laboratory or by contact with a vaccinated person. Ocular involvement may be confined to the lids or conjunctiva but may easily be transferred to the cornea. Keratitis can result in scarring that could have a severe and permanent impact on vision. Even when the cornea is not affected, extensive lesions on the lid or other ocular tissues can lead to additional sight-threatening complications.

Recently, the US Food and Drug Administration licenced Vaccinia Immune Globulin Intravenous (Human) (VIGIV, formerly known as NP-016). It is indicated for the "treatment and/or modification of the following conditions, which are complications resulting from smallpox vaccination: (a) Eczema vaccinatum; (b) Progressive vaccinia; (c) Severe generalized vaccinia; (d) Vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions; and (e) Aberrant infections induced by vaccinia virus that includes its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard." The precautionary statement regarding isolated vaccinia keratitis appears though it is uncertain whether VIGIV use will decrease or increase corneal scarring in humans. The implication of increased scarringis based on some evidence in animal models indicating that more extensive corneal clouding can occur following VIG therapy. To investigate if this implication has clinical significance, two hundred study participants with corneal involvement following vaccinia vaccination or other exposure will be randomized to receive either placebo or VIGIV. All enrolled participants will be provided standard-of-care antiviral treatments for ocular complications. One-year proportions of corneal scarring will be compared between the two groups. Further knowledge about the biologic mechanisms of complications associated with vaccinia vaccination and rapid diagnostic test may lead to more effective forms of therapy.