Development of Rhabdoviral-Based Crimean-Congo Hemorrhagic Fever Virus Vaccines
Abstract
Crimean-Congo Hemorrhagic Fever virus (CCHFV) is an emerging, tickborne, zoonotic virus with an expansive global distribution. CCHFV is a biosafety level 4 (BSL-4) pathogen and classified as an NIH/NIAID Category A and WHO high-priority pathogen, thus of great risk to public health. There are currently no globally licensed therapeutics or vaccines available. The goal of this thesis was to use rhabdoviral vectors to develop CCHFV vaccines. Rabies virus (RABV) and vesicular stomatitis virus (VSV) were chosen as vaccine vectors given their safety record, easily manipulated genomes and ability to incorporate foreign glycoproteins. The CCHFV-GP38 protein was shown to be indispensable for virus replication and an anti-GP38 monoclonal antibody protected mice against wildtype (WT) CCHFV challenge. Thus, GP38 was hypothesized to be a protective antigen. RABV- and VSV-based CCHFV vaccines with or without GP38, either alone or with the other CCHFV glycoproteins were developed to test this hypothesis. The vaccine viruses were characterized to look for incorporation of the desired glycoproteins and then inactivated, administered to mice, and shown to elicit a humoral response through enzyme-linked immunosorbent assay. A VSV with its native glycoprotein replaced by the CCHFV glycoprotein gene (M) (VSV-ΔG-coM) was used as a non-BSL-4 surrogate challenge model for CCHFV. Interferon α/β receptor 1 knockout mice immunized with a GP38 only vaccine were protected against VSV-ΔG-coM challenge compared to controls, demonstrating vaccine efficacy and utility of the surrogate challenge model. Additionally, rhabdoviral-based CCHFV vaccines were tested in a WT CCHFV challenge model, in which only mice immunized with vaccines containing GP38 were protected. Thus, GP38 is required and sufficient for protection against CCHFV. Strikingly, the GP38 only vaccine did not induce CCHFV neutralizing antibodies or significant GP38-specific T cell responses, indicating that the mechanism of protection is likely mediated by non-neutralizing antibody functions. The results presented here advance the effort to design a successful CCHFV vaccine by defining a protective target antigen.
Subject Area
Virology|Immunology|Pathology
Recommended Citation
Scher, Gabrielle, "Development of Rhabdoviral-Based Crimean-Congo Hemorrhagic Fever Virus Vaccines" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30487486.
https://jdc.jefferson.edu/dissertations/AAI30487486
