Analysis of a novel Crimean-Congo hemorrhagic fever vaccine and its mechanism of protection in rodent models

Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe disease in humans, with fatality rates reaching 40%. CCHFV is endemic to parts of Africa, Asia, the Middle East, and Europe, specifically to regions where the tick vector, species of the Hyalomma genus, is present. Classified as an NIH/NIAID Category A and WHO high- priority pathogen, CCHFV poses the highest possible risk to national security and public health. CCHFV is a negative-sense single-stranded RNA virus in the order Bunyavirales. CCHFV is an Emerging Infectious Disease, posing a high risk of a widespread outbreak. An inactivated whole virus vaccine was the only CCHFV vaccine to be tested in humans and was ineffective. We propose the use of inactivated rabies virus (RABV)- and vesicular stomatitis virus (VSV)-based CCHFV vaccines, as inactivated rhabdoviral vectors have not yet been explored. Inactivated rhabdoviral-based vaccines are safe and effective at inducing immunity and protection against multiple hemorrhagic fever viruses, and a VSV-based surrogate challenge virus is an effective tool in another hemorrhagic fever model. The goal of this project is two-fold: first, to compare RABV- and VSV-based CCHFV/RABV bivalent vaccines in terms of their production, immunogenicity; second, to establish a non-BSL-4 VSV-based surrogate mouse challenge system for CCHFV to determine mechanism of protection. We hypothesize that inactivated rhabdoviral-based CCHFV vaccines will protect against the CCHFV challenge through non-neutralizing antibodies directed against GP38. Toward this hypothesis, we propose three Aims: Aim 1: Characterization of Rhabdoviral-based CCHFV vaccine constructs. This aim does characterize and test the immunogenicity of RABV- and VSV-based CCHFV vaccines and compare them to the Bulgaria human vaccine and an mRNA-based vaccine provided by collaborators. Aim 2: Determine rhabdoviral-based CCHFV vaccine mechanism of protection by establishing a surrogate challenge virus model. This aim aims to develop a non-BSL-4-requiring surrogate challenge model for CCHFV and compare it to the established BSL-4 WT CCHFV model in vaccine efficacy studies. Aim 3: Evaluate the protective efficacy of rhabdoviral-based vaccine candidates in a wildtype CCHFV lethal challenge model using needle and tick challenge. The goal of this aim is to determine the efficacy of our rhabdoviral-based vaccines and control vaccines against WT CCHFV challenge in two different lethal challenge model.