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Developing A Tissue-Targeted Ocular HSV Therapeutic Vaccine

Award Number: R01EY019896
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2010
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Developing A Tissue-Targeted Ocular HSV Therapeutic Vaccine - SUMMARY/ABSTRACT Herpes simplex type virus-1 (HSV-1) infects over 3.72 billion people worldwide, including 200 million individuals in the United States. Following primary infection of the cornea, HSV-1 establishes latency in sensory neurons of the trigeminal ganglia (TG). Reactivation of HSV-1 from latently infected TG leads to shedding of the virus in tears causing recurrent ocular herpetic disease, a major cause of infectious blindness in the Western world. Currenly, an FDA-approved herpes simplex vaccine is unavailable. Our long-term goal is to develop an immunotherapeutic ocular herpes vaccine. While a role for CD8+ T cells (but not CD4+ T cells) in reducing HSV- 1 reactivations from latently infected TG is gaining wider acceptance, the small numbers of functional tissue- resident memory CD8+ TRM cells that are present in latently infected TG are not enough to prevent virus reactivation. We have made several significant findings, during the last funding period: (1) HSV-specific CD8+ T cells from “naturally protected” HLA-A*0201-positive asymptomatic individuals (who never develop recurrent ocular herpetic disease despite being infected) mainly targeted five HSV-1 epitopes; (2) Phenotypic and transcriptomicprofiling indicates that frequent HSV-specific CD8+ TRM cells, which expressed high levels of tissue-homing and tissue-residency receptors (i.e. CXCR3, IL-2R/IL-15R, CD69, and CD103), found in the TG of HSV-1 infected HLA-A*0201 transgenic rabbits (HLA Tg rabbits) are associated with decreased virus shedding; (3) Topical ocular delivery to latently infected HLA Tg rabbits of prototype neurotropic adeno- associated virus (AAV8) constructs, which express either the T cell attracting CXCL11 chemokine (CXCR3 ligand) or IL-2/IL-15 cytokines (IL-2Rb/IL-15Rb ligands), increased the frequency of TG-resident CD8+ TRM cells specific to the five immunodominant epitopes; (4) Increased numbers of exhausted TG-resident CD8+ TRM cells were associated with increased virus shedding in HLA Tg rabbits; and (5) Ex vivo blockade of T cells exhaustion pathways PD-1, LAG-3 and TIGIT, ex vivo, in rabbit TG explants significantly reduced virus reactivation. Building on the above published and preliminary results, the central hypothesis of this revised competitive renewal proposal is that a TG-targeted vaccine that boosts the number, function and longevity of anti-viral TG-resident CD8+TRM cells will reduce virus reactivation and shedding. Specific Aims: Aim 1: Test the hypothesis that a tissue-targeted Prime/Pull/Keep therapeutic vaccine (designated as PPK vaccine) that incorporates the five immunodominant HSV-1 CD8+ TRM cell epitopes (prime), CXCL11 (pull) and IL-2/IL-15 (keep) will boost the number and longevity of TG-resident CD8+ TRM cells and significantly decrease HSV-1 reactivation in latently infected HLA Tg rabbits. Aim 2: Test the hypothesis that tissue-targeted PPK vaccine combined with blockade of PD-1, LAG-3 and/or TIGIT immune checkpoints will increase the number of functional CD8+ TRM cells in the TG and produce even more robust protection in latently infected HLA Tg rabbits. This translational research is expected to pave the way towards developing a PPK vaccine to protect against recurrent ocular herpes in man.


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: 2025 ( Subtotal = $409,999 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	13	3/24/2025	NON-COMPETING CONTINUATION	$409,999
														Subtotal = $409,999

Issue Date FY: 2024 ( Subtotal = $409,999 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	12	4/30/2024	NON-COMPETING CONTINUATION	$409,999
														Subtotal = $409,999

Issue Date FY: 2023 ( Subtotal = $409,999 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	11	4/3/2023	NON-COMPETING CONTINUATION	$409,999
														Subtotal = $409,999

Issue Date FY: 2022 ( Subtotal = $409,999 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	10	4/1/2022	COMPETING CONTINUATION	$409,999
2022	2019	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	9	1/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $409,999

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	9	8/6/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $463,500 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	9	3/28/2019	NON-COMPETING CONTINUATION	$463,500
														Subtotal = $463,500

Issue Date FY: 2018 ( Subtotal = $463,500 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	8	4/9/2018	NON-COMPETING CONTINUATION	$463,500
														Subtotal = $463,500

Issue Date FY: 2017 ( Subtotal = $463,500 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	7	3/20/2017	NON-COMPETING CONTINUATION	$417,148
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	7	7/10/2017	NON-COMPETING CONTINUATION	$46,352
														Subtotal = $463,500

Issue Date FY: 2016 ( Subtotal = $463,500 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	6	3/17/2016	COMPETING CONTINUATION	$463,500
2016	2014	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	926971050	ORANGE	USA	Vision Research	000	5	3/14/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $463,500

Issue Date FY: 2014 ( Subtotal = $359,856 )
2014	2014	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	5	7/21/2014	NON-COMPETING CONTINUATION	$359,856
														Subtotal = $359,856

Issue Date FY: 2013 ( Subtotal = $348,840 )
2013	2013	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	4	7/31/2013	NON-COMPETING CONTINUATION	$348,840
														Subtotal = $348,840

Issue Date FY: 2012 ( Subtotal = $367,200 )
2012	2012	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	3	8/6/2012	NON-COMPETING CONTINUATION	$367,200
														Subtotal = $367,200

Issue Date FY: 2011 ( Subtotal = $367,200 )
2011	2011	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	2	9/1/2011	NON-COMPETING CONTINUATION	$367,200
														Subtotal = $367,200

Issue Date FY: 2010 ( Subtotal = $191,250 )
2010	2010	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	1	8/13/2010	NEW	$191,250
														Subtotal = $191,250

Grand Total All Awards = $5,128,342

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Developing A Tissue-Targeted Ocular HSV Therapeutic Vaccine

Award Number: R01EY019896

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2010

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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