IL-18 expression results in a recombinant vaccinia virus that is highly attenuated and immunogenic.

Abstract

Interferon-γ (IFN-γ) is an attenuating factor for vaccinia virus (VACV), decreasing its virulence in vivo by more than a million fold. It is also a highly effective adjuvant when administered at the time of immunization with protein antigens. However, recombinant VACV (rVACV) vaccines expressing IFN-γ do not induce enhanced immune responses. It is possible that the IFN-γ expressed by rVACVs induces both an antiviral state and increased immunological clearance, thus resulting in decreased levels of antigen expression due to reduced viral replication and spread. We conjectured that delaying expression of IFN-γ would result in enhanced production of antigens by rVACVs thus resulting in increased immune responses to foreign antigens. Interleukin (IL)-18, also known as IFN-γ inducing factor, is a cytokine that induces T and NK cells to produce IFN-γ. In this study, we demonstrated that an rVACV expressing bioactive murine IL-18 replicated to low but detectable levels in vivo, unlike an rVACV expressing IFN-γ. Moreover, the rVACV expressing IL-18 was significantly attenuated in both immunocompromised and immunocompetent mice. This attenuation was dependent on IFN-γ, as IL-18 expression failed to attenuate VACV in IFN-γ knock-out mice. Cytotoxic T-cell (CTL) and anamnestic antibody responses were slightly increased in animals vaccinated with the rVACV expressing IL-18. Thus, induction of IFN-γ because of IL-18 expression resulted in an rVACV that replicated to low but detectable levels in vivo, yet elicited slightly better CTL and anamnestic humoral immune responses.