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Developing Vault Nanoparticles as a Delivery Platform for Burkholderia pseudomallei and Burkholderia mallei Antigens

Award Number: R21AI137181
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Burkholderia pseudomallei (Bp) is endemic to tropical regions and causes the often-fatal disease melioidosis in humans and animals, posing a significant threat to native residents, tourists, and deployed U.S. military personnel. In highly-endemic areas of southeast Asia, melioidosis is projected to surpass tuberculosis as the second most common cause of infectious disease mortality after HIV/AIDS. There are currently no effective approaches for providing immunity, and treatment confounded by intrinsic antibiotic resistance. The ability to survive intracellularly and utilize membrane fusion as a means for spreading from cell to cell shelters the bacterium from the humoral immune system. Prior efforts to provide protective immunity against Bp rely on live-attenuated strains or bacterial subunits that are only partially protective. Therefore, an antigen-delivery strategy to elicit both antibody and cellular responses is needed for B. pseudomallei, and the factors that promote survival inside mammalian cells will likely constitute effective antigens. This is supported by current evidence in animal models and recovered melioidosis patients, where cytotoxic T lymphocytes (CTLs) play a central role by recognizing and killing Bp-infected cells, with antibody playing an ancillary role. Our goal is to utilize the endogenous human vault nanoparticle as a novel, safe platform for delivering Burkholderia antigens that can elicit strong cell-mediated and humoral responses against Bp. Vaults efficiently deliver antigens and provide remarkable immune responses without additional adjuvants. Vaults are large, naturally-occurring, cytoplasmic riboprotein particles found in all nucleated mammalian cells. Recent observations suggest that vaults function in immune surveillance, delivering antigens from dying cells to facilitate adaptive immunity. Recombinant vaults efficiently deliver antigens to both the MHC class I and II pathways, and have adjuvant-like effects in APCs, eliciting protective CD4 and CD8 T cell responses, while also generating antibody responses. In contrast, native or "empty" vaults do not activate inflammasome or TLR-dependent inflammatory reactions and are non-immunogenic. We have exploited these properties of vaults to elicit robust immune responses in several systems, including a mouse model of mucosal infection by intracellular Chlamydia, which like Bp, is an intracellular pathogen. We will combine our considerable knowledge of pathogenic mechanisms and practiced production approaches for making recombinant vaults containing Burkholderia antigens (BurkAgs). BurkAgs have been identified based on properties that are hypothesized to correlate with robust immunogenicity and the potential to elicit broad responses against diverse strains of Bp. The ability of recombinant BurkVaults to induce antigen-specific antibody, CD4 and CD8 T cell responses following i.n. or s.c. immunization will be determined in established, quantitative assays. Recombinant vaults that display optimal structural, compositional, and immunogenic profiles will be advanced for studies against lethal challenge with Bp in BALB/c mice.


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: 2023 ( Subtotal = -$1,556 )
2023	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	2/2/2023	NON-COMPETING CONTINUATION	-$1,556
														Subtotal = -$1,556

Issue Date FY: 2022 ( Subtotal = -$9,073 )
2022	2019	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	000	3	3/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$9,073
														Subtotal = -$9,073

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR ROOM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	000	3	9/3/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	4/2/2020	NON-COMPETING CONTINUATION	-$55,112
2020	2019	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR ROOM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	003	3	6/25/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$122,039
2020	2019	NORTHERN ARIZONA UNIVERSITY	601 S KNOLES DR ROOM 220	FLAGSTAFF	AZ	86011	COCONINO	USA	Allergy and Infectious Diseases Research	001	3	4/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$55,112
2020	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	2	6/25/2020	NON-COMPETING CONTINUATION	-$122,039
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $195,000 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	5/3/2019	NON-COMPETING CONTINUATION	$195,000
														Subtotal = $195,000

Issue Date FY: 2018 ( Subtotal = $233,875 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	6/12/2018	NEW	$233,875
														Subtotal = $233,875

Grand Total All Awards = $418,246

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Developing Vault Nanoparticles as a Delivery Platform for Burkholderia pseudomallei and Burkholderia mallei Antigens

Award Number: R21AI137181

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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