U19AI166058

Early In Vivo Expressed Antigens and Their Role in Virulence, Immune Response, and Vaccines for Coccidioidomycosis

Overall Section Title: Early In Vivo Expressed Antigens and Their Role in Virulence, Immune Response, and Vaccines for Coccidioidomycosis

Summary

Coccidioidomycosis, also known as Valley Fever (VF), is an important fungal disease caused by two different Coccidioides species that results in regionally important mortality and even greater morbidity. We have assembled a team to define the changes that occur in human and animal immune responses to VF, and to use this knowledge for designing new vaccines and diagnostic tests. This work will capitalize upon our detailed observations of Coccidioides gene expression patterns during the earliest stages of infections. We hypothesize that some Coccidioides early genes are virulence factors and critical for causing disease.

Research Project 1 will test their role through gene knockouts using CRISPR-Cas9 technology and virulence testing in wax worm (Galleria) and mouse VF models. Critical virulence factors will become diagnostic and vaccine targets. In addition to the wax worm and mouse models, we develop a non-human primate (pig-tailed macaques) that will more closely resemble VF in humans.

In humans and vertebrate animal models, the role of T cells cannot be overemphasized and Research Project 2 will use focused deep DNA sequencing to identify classes of T cell receptors (TCR) that develop in response to early expressed Coccidioides genes. We will generate TCR sequences from patients at three clinical locations that span the endemic zones for the pathogen. The TCR repertoire from patients will be used to identify novel diagnostic signatures (e.g., public TCRs) and, also, help identify immune responses to key antigens that can be targeted for vaccine development.

Hence, both TCR and early virulence genes represent excellent candidates for vaccine design that will be explored in Research Project 3 using nucleic acid (NA) based vaccines (RNA and DNA) that can rapidly test a large panel of antigens through the immunization of mice against infection. The DNA vaccine will be based upon delivery on gold nanoparticles and gene gun, while the mRNA employs self-replicating RNA molecules (ReprRNA) and a lipid inorganic nanoparticle (LION). Both are proven technologies that are moving forward into clinical trials for other diseases.

Our goal in the NA vaccine mouse studies is to identify the best antigens and delivery modality for vaccine testing in the NHP model and to define their immune mechanisms of protection. This work is only possible through the integrated efforts of investigators at seven different institutions, including three clinical sites, as no single institution has the requisite breadth of expertise and infrastructure. While we will generate fundamental knowledge about Coccidioides and VF, we will also make translational advances towards preventing and diagnosing the disease.

Northern Arizona 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]

Arizona United States

State-Wide

Coccidioidomycosis Collaborative Research Centers (U19 Clinical Trial Not Allowed) (RFA-AI-20-056)

Amendment Since initial award the total obligations have increased 507% from $1,519,099 to $9,218,182.