Development of safe and efficacious viral vaccines for animals.

We have taken a number of approaches to improve the safety and efficacy of recombinant vaccines for use in humans and animals, including: choice of the strain of vaccinia virus (VACV) used as a vector, insertional inactivation of virulence and immunoregulatory genes of VACV, and expression of cytokine genes that attenuate the vector by more than a million-fold without reduction in immunogenicity. These strategies are illustrated by providing examples of recombinant VACV (rVACV) vaccines we have developed for rinderpest, vesicular stomatitis, simian immunodeficiency virus, and smallpox. We constructed rVACVs expressing interferon-gamma (IFN-gamma) and lacking the immune-modulating genes B8R, B13R, and B22R. IFN-gamma is a cytokine with potent immunoregulatory, antineoplastic, and antiviral properties. These rVACVs replicated to high titers in tissue culture, yet were avirulent in both immunocompromised and immunocompetent mice with no detectable viral replication in these animals. A single immunization elicited potent humoral, T-helper, and cytotoxic T-cell immune responses in mice despite the absence of any detectable virus replication in vivo. IFN-gamma co-expression and the inactivation of one or more VACV immune-modulating genes provide an optimized method for increasing the safety while maintaining the efficacy of rVACV vaccines for use in humans and animals.