R01AI167295

Analysis of a novel Crimean-Congo Hemorrhagic Fever (CCHF) vaccine and its mechanism of protection in rodent models.

CCHFV causes severe disease in humans, with fatality rates reaching 40%. It 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. It 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 models.

Thomas Jefferson University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Philadelphia, Pennsylvania 191071820 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 303% from $779,687 to $3,145,040.