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Chemically-guided Elucidation of Liposomal Tucaresol Immunopotentiation in a Hepatitis C Vaccine

Award Number: R21AI137868
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Adjuvants are essential components of vaccines, and function to enhance the immune response to a co-administered antigen. Adjuvants are a primary focus of modern vaccine development due to the fact that despite decades of research only two adjuvants, alum and monophosphoryl lipid A (MPLA), are clinically approved for human use. While these adjuvants are effective in stimulating immune responses for some vaccines, their ability to potentiate immune responses against weakly immunogenic haptens or highly diverse antigens has achieved mixed results. For example, clinical translation of vaccines for hepatitis C virus (HCV) has been stunted by the remarkable diversity of the virus and the virus’ immune evasion mechanisms. To address these shortcomings and those of other vaccines, we have undertaken a program to discover new, broadly-applicable adjuvant platforms. Of late, the Janda Laboratory has investigated 4-((2-formyl-3-hydroxyphenoxy)methyl)benzoic acid (tucaresol) as a synthetically-tractable adjuvant. Recently, we reported the first liposomal formulation of tucaresol, termed L(LT1). We used this adjuvant in vaccines for HCV, herpes simplex virus 2, and methamphetamine, and demonstrated high antibody titers in mouse models. Despite our initial successes, our understanding of how L(LT1) stimulates the immune system remains limited. In this proposal, we will elucidate the mechanism of L(LT1) immunopotentiation. Our approach will include investigating the induction of Th-cell proliferation, cytokine production, and expression of co-stimulatory cell surface markers (Aim 1) and evaluating a series of L(LT1) analogues in rodents for their ability to stimulate an immune response after HCV vaccination (Aim 2). In Aim 2, a previously-constructed SAR series will dissect how tucaresol’s chemical makeup plays a role in immunostimulation. The proposed work will help to achieve our long-term goal of delivering a clinically- relevant adjuvant platform with broad applicability to many vaccines. The work proposed here is innovative and impactful because it marks the first detailed, mechanistic study of immunopotentiation by L(LT1). These pioneering studies will have a lasting impact because they provide a foundation for the future development of L(LT1) analogues as next-generation vaccine adjuvants. This work is directly aligned with the mission of NIAID to support research aimed at improving the treatment and prevention of infectious diseases.


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: 2021 ( Subtotal = $0 )
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	6/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $290,250 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	11/21/2019	NON-COMPETING CONTINUATION	$290,250
														Subtotal = $290,250

Issue Date FY: 2019 ( Subtotal = $241,875 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	11/28/2018	NEW	$241,875
														Subtotal = $241,875

Grand Total All Awards = $532,125

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Chemically-guided Elucidation of Liposomal Tucaresol Immunopotentiation in a Hepatitis C Vaccine

Award Number: R21AI137868

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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