Progressive vaccinia is the most severe complication of vaccinia (smallpox) vaccination. It is almost always life-threatening. Progressive vaccinia occurs because of an immune defect in the vaccinated individual or in a susceptible contact of a vaccinee. Nearly all instances have been in those with a defined cell-mediated immune (CMI) defect (T-cell deficiency). In patients with CMI deficiency but intact antibody (B-cell) function, progressive vaccinia occurs but is a less extensive disease, often limited to progression in the skin without viremic spread.

Virus gains entry into the blood at an early stage in patients with close to totally deficient immune systems and implants in distant skin sites and in multiple organs. Secondary skin lesions follow the same pattern as the vaccination site lesion, each expanding in situ. Local and systemic bacterial infection as well as parasitic (P. carinii and fungi) infections can ensue with progressive disease.

Untreated or unsuccessfully treated patients succumb in what appears to be toxic or septic shock. Death occurs in nearly all individuals with profound CMI defects. In the past, individuals survived when their immune function improved coincident with the withdrawal of immunosuppressive therapy or spontaneous improvement in their underlying disease. Aggressive administration of vaccinia immune globulin (VIG) then resulted in cures. Patients with milder degrees of depression of CMI responded to aggressive VIG therapy.