The concern about bioterrorism with
smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer
vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified
vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth
vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified
vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal
infection in unimmunized animals. These properties, shared with the existing
smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer
vaccines against
smallpox or against complications from vaccinia virus.