title: Immune modulating effect by a phosphoprotein-deleted rabies virus vaccine vector expressing two copies of the rabies virus glycoprotein gene.
abstract: 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-DeltaP), or a recombinant P-deleted virus that expresses two copies of the RV glycoprotein (G) gene (SPBN-DeltaP-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-DeltaP exhibited a mixed IgG1/IgG2a antibody response, which is consistent with the isotype profiles from the replication-competent parental viruses. Survivorship in mice after pathogenic RV challenge indicates a 10-fold higher efficiency of live SPBN-DeltaP compared to UV-inactivated SPBN-DeltaP. In addition, SPBN-DeltaP-RVG induced a more rapid and robust IgG2a response that protected mice more effectively than SPBN-DeltaP. Of note, 10(3)ffu of SPBN-DeltaP-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-DeltaP-RVG enhances the immune response to other RV antigens as well. In addition, Rag2 mice inoculated intramuscularly with 10(5)ffu/mouse of SPBN-DeltaP 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-DeltaP-RVG indicate that this vector holds great promise as either a therapeutic or preventative vaccine against RV or other infectious diseases.
authors.affiliation: Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cenna
authors.forename: Gene S
authors.initials: GS
authors.lastname: Tan
authors.forename: Amy B
authors.initials: AB
authors.lastname: Papaneri
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dietzschold
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Schnell
authors.forename: James P
authors.initials: JP
authors.lastname: McGettigan
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D006224:Cricetinae; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D005822:Genetic Vectors; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000235:genetics; D011818:Rabies / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D011819:Rabies Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D011820:Rabies virus / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology / Q000517:prevention & control* / Q000821:virology
chemical_list: D000914:Antibodies, Viral; D010750:Phosphoproteins; D011819:Rabies Vaccines; D014759:Viral Envelope Proteins