Immune modulating effect by a phosphoprotein-deleted rabies virus vaccine vector expressing two copies of the rabies virus glycoprotein gene

The type of immune response induced by a vaccine is a critical factor that determines its effectiveness in preventing infection or disease. Inactivated and live rabies virus (RV) vaccine strains elicit an IgG1-biased and IgG1/IgG2a-balanced antibody response, respectively. However, IgG2a antibodies are potent inducers of anti-viral effector functions, and therefore, a viral vaccine vector that can elicit an IgG2a-biased antibody response may be more effective against RV infection. Here we describe the humoral immune response of a live replication-deficient phosphoprotein (P)-deleted RV vector(SPBN-Delta P), or a recombinant P-deleted virus that expresses two copies of the RV glycoprotein (G) gene (SPBN-Delta P-RVG), and compare it to a UV-inactivated RV. Mice inoculated with UV-inactivated RV induced predominantly an IgG1-specific antibody response, while live recombinant SPBN-Delta P exhibited a mixed IgG1/IgG2a antibody response. which is consistent with the isotype profiles from the replication-competent parental viruses. Survivors hip in mice after pathogenic RV challenge indicates a 10-fold higher efficiency of live SPBN-Delta P compared to UV-inactivated SPBN-Delta P. In addition, SPBN-Delta P-RVG induced a more rapid and robust IgG2a response that protected mice more effectively than SPBN-Delta P. Of note, 10(3) ffu of SPBN-Delta P-RVG-induced anti-RV antibodies that were 100% protective in mice against pathogenic RV challenge. The increased immune response was directed not only against RV G but also against the ribonucleoprotein (RNP), indicating that the expression of two RV G genes from SPBN-Delta P-RVG enhances the immune response to other RV antigens as well. In addition, Rag2 mice inoculated intramuscularly with 10(5) ffu/mouse of SPBN-Delta P showed no clinical signs of rabies, and no viral RNA was detected in the spinal cord or brain of inoculated mice. Therefore, the safety of the P-deleted vectors along with the onset and magnitude of the IgG2a-induced immune response by SPBN-Delta P-RVG indicate that this vector holds great promise as either a therapeutic or preventative vaccine against RV or other infectious diseases. (c) 2008 Elsevier Ltd. All rights reserved.