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Principal Investigator: Dennis A Bente
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2023
Award: $788,347
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <(IFN) α><(IFN)-α><(IFN)α><Ab-mediated immunity><Ab-mediated protection><Adoptive Transfer><Africa><Alferon><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody immunity><Antibody protection><Antibody-mediated protection><Asia><Assay><BSL-4 facility><BSL4 facility><Bioassay><Biologic Assays><Biological Assay><Biotinylation><Bulgaria><Bunyavirales><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 outbreak><COVID19 outbreak><Categories><Cellular Assay><Classification><Clinical><Clinical Treatment Moab><Complement Activation><Congo Virus><Congo Virus Infection><Congo hemorrhagic fever virus><Congo-Crimean Hemorrhagic Fever><Crimean Hemorrhagic Fever><Crimean Hemorrhagic Fever Virus><Crimean-Congo Hemorrhagic Fever Virus><Crimean-Congo hemorrhagic fever orthonairovirus><Development and Research><Disease><Disease Outbreaks><Disorder><Dose><ELISA><Emerging Communicable Diseases><Emerging Infectious Diseases><Enzyme-Linked Immunosorbent Assay><Europe><Evaluation><Fatality rate><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Generalized Growth><Genes><Glycoproteins><Goals><Growth><Hand><Human><IFN Alpha><IFN α><IFN-α><IFNAR><IFNAR1><IFNAR1 gene><IFNa><IFNα><Immune response><Immunity><Immunize><Immunological response><Inactivated Vaccines><Inactivated Virus Vaccine><Infection><Interferon Alfa-n3><Interferon alpha><Interferon-α><Ixodida><Killed Vaccines><Knock-out><Knockout><Leukocyte Interferon><Lymphoblast Interferon><Lymphoblastoid Interferon><Membrane><Mice><Mice Mammals><Middle East><Modeling><Modern Man><Monoclonal Antibodies><Murine><Mus><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><National Security><Needles><Outbreaks><Patients><Predisposition><Prevention><Production><Public Health><R & D><R&D><RNA Viruses><RNA vaccine><RNA-based vaccine><Rabies virus><Receptor Protein><Recombinants><Rhabdoviridae><Rhabdoviruses><Risk><Rodent Model><Route><SARS-CoV-2 outbreak><Severe acute respiratory syndrome coronavirus 2 outbreak><Severity of illness><Susceptibility><System><Systematics><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Ticks><Tissue Growth><Transmission><United States National Institutes of Health><VSV><Vaccinated><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral Diseases><Viral Genome><Viral Hemorrhagic Fevers><Viral Vector><Virion><Virus><Virus Diseases><Virus Particle><Wild Type Mouse><antibody-mediated immunity><biosafety level 4 facility><bullet shaped virus group><cell assay><complement pathway regulation><coronavirus disease 2019 outbreak><coronavirus disease-19 outbreak><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><disease severity><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><enzyme linked immunoassay><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><flow cytophotometry><hands><hemorrhagic fever><hemorrhagic fever virus><high risk><host response><immune system response><immunogenicity><immunoresponse><mAbs><mRNA vaccine><mRNA-based vaccine><membrane structure><model of animal><monoclonal Abs><next generation><novel><ontogeny><outbreak of SARS-CoV-2><pathogen><priority pathogen><protective efficacy><rabies virus G protein><rabies virus glycoprotein><rabies virus glycoprotein G><receptor><research and development><thymus derived lymphocyte><tick bite><tool><transmission process><vaccine candidate><vaccine development><vaccine efficacy><vaccine platform><vector><vector tick><viral infection><virus genome><virus infection><virus-induced disease><wildtype mouse>