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Early in vivo Expressed Antigens and their Role in Virulence, Immune Response, and Vaccines for Coccidioidomycosis

Award Number: U19AI166058
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 (repRNA) 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR RM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	000	2	12/28/2023	NON-COMPETING CONTINUATION	$0
2024	2023	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR RM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	001	2	3/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $2,932,908 )
2023	2023	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	000	2	8/4/2023	NON-COMPETING CONTINUATION	$1,542,693
2023	2023	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	001	2	8/31/2023	SUPPLEMENT FOR EXPANSION	$1,390,215
														Subtotal = $2,932,908

Issue Date FY: 2022 ( Subtotal = $1,519,099 )
2022	2022	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR ROOM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	000	1	8/24/2022	NEW	$1,519,099
2022	2022	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR ROOM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	001	1	8/30/2022	NEW	$0
														Subtotal = $1,519,099

Grand Total All Awards = $4,452,007

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Early in vivo Expressed Antigens and their Role in Virulence, Immune Response, and Vaccines for Coccidioidomycosis

Award Number: U19AI166058

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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