Role of Genes That Modulate Host Immune Responses in the Immunogenicity and Pathogenicity of Vaccinia Virus

Abstract

Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.

Removal of Vaccinia Virus Genes That Block Interferon Type I and II Pathways Improves Adaptive and Memory Responses of the HIV/AIDS Vaccine Candidate NYVAC-C in Mice

“…Previous data concerning VACV vIFN-␣/␤R or vIFN-␥R functions on vector immunogenicity after their blockade have not revealed any positive results (12,22,54). In those studies, the authors used different replication-competent VACV strains, such as WR (54), Lister (12), and Wyeth (22), which still retain the rest of the genes involved in VACV evasion of IFN signaling pathways.…”

“…In those studies, the authors used different replication-competent VACV strains, such as WR (54), Lister (12), and Wyeth (22), which still retain the rest of the genes involved in VACV evasion of IFN signaling pathways. It is known that in addition to B8R and B19R, the products of the genes E3L, K3L, H1L, C7L and more recently C6L act within infected cells, blocking the IFN signaling cascade or IFN-induced antiviral state (16,37,52).…”

Deletion of Major Nonessential Genomic Regions in the Vaccinia Virus Lister Strain Enhances Attenuation without Altering Vaccine Efficacy in Mice

“…On the other hand, deletion of the E3L gene, encoding a double-stranded RNA (dsRNA) binding protein, resulted in striking attenuation in a mouse model of severe combined immunodeficiency and considerable vaccine potency by scarification of immunocompetent mice despite the fact that the deletion mutant appeared inefficient at inducing VACV-neutralizing antibodies (31). Deletion of several genes encoding immunomodulatory functions from the Wyeth strain resulted in only moderate attenuation in an intracranial weanling mouse model, and most of the mutants maintained immunogenicity although no vaccine protection studies were performed (30). Deletion of the genes encoding serpin 1 (B22R; equivalent to ORF 008 in the Lister strain) and serpin 2 (B13R in VACV Cop) from the VACV WR strain led to significant attenuation, characterized by a delay in death after infection of nude mice and lack of pathogenicity in immunocompetent mice after intraperitoneal inoculation (38).…”

Transcriptional Interactions During Smallpox Infection and Identification of Early Infection Biomarkers

“…First, since smallpox can manipulate immune response mechanisms (26,27), it is plausible that the host activates alternative viral defense responses including the EIB reported here. Second, it is possible that smallpox proteins regulate the expression of the EIBs and use these protein products to complete a specific biological process.…”