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Hepacivirus control by vaccine-elicited T cells.

Award Number: F30AI143060
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/17/2018
PERIOD OF PERFORMANCE END DATE: 12/16/2022

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Hepacivirus control by vaccine-elicited T cells. - PROJECT ABSTRACT/SUMMARY The hepatitis C virus (HCV) is a human hepatotropic hepacivirus known for causing persistent infections that often progress to fatal liver diseases. Although new antivirals cure >97% of infections, the vast majority of infected patients are either undiagnosed or unable to receive therapy due to substantial socioeconomic barriers. To achieve global eradication, a vaccine to prevent HCV persistence will be needed. Although the immune factors that dictate whether an infection will be controlled are poorly defined, T cells are considered key immunological determinants. Indeed, silencing of virus-specific CD8+ T cells is a classic feature of infections that persist. Furthermore, the only vaccine to advance to phase II clinical testing in humans is based on a T cell immunization strategy that showed signs of efficacy in the chimpanzee model. Despite this promising momentum, it is not fully clear why this approach succeeded in chimps and whether similar results can be expected in humans. Indeed, mechanisms of vaccine-induced immunity are incompletely known and deciphering these in humans will be challenging and slow. Furthermore, due to the elimination of chimps from research, there are no suitable animal models available to further evaluate vaccine-mediated protection against HCV persistence. Recently, we developed a surrogate model for HCV using a homologous hepacivirus found in feral rats. Several aspects of this model are significant. First, infection in lab rats is strictly hepatotropic and highly persistent despite the activation of host adaptive immunity. Second, immune responses can be readily analyzed in the infected liver, which is poorly accessible in humans. Finally, use of a rodent host permits the expedited testing and mechanistic deconstruction of promising vaccination concepts, which was not easily afforded by chimps. Our long-term goal in this proposal is to identify correlates of vaccine-induced immunity to chronic hepacivirus infection and to translate this knowledge into rational HCV vaccine designs. As the impetus for our studies, we show in our preliminary data that persistent infection in rats can be prevented using an adenovirus-vectored vaccine encoding non-structural proteins, which primes cellular immunity in the absence of neutralizing antibodies. How this approach leads to control of an otherwise highly persistent infection is unclear. Our central hypothesis is that CD8+ T cell function is essential for hepacivirus clearance, and pre-exposure priming of CD4+ T cell help via vaccine protects virus-specific CD8+ T cells from failure during infection, resulting in effective antiviral control. Two specific aims are proposed. Aim 1 will provide a detailed comparison of cellular immunity between vaccinated and unvaccinated animals after virus challenge; functional responses will be comprehensively analyzed and minimal T cell epitopes will be mapped. Aim 2 will test the requirement for CD4+ and CD8+ T cells in vaccine-induced protection; cell depletion and active/passive vaccination experiments will be performed. Our overall results from this proposal will have major implications for HCV vaccine and immunotherapy development in humans, where experiments of this type are not possible.


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 = -$50,587 )
2024	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	10/31/2023	NON-COMPETING CONTINUATION	-$50,587
														Subtotal = -$50,587

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	11/15/2021	NON-COMPETING CONTINUATION	$51,036
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	4	5/26/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	3	12/31/2020	NON-COMPETING CONTINUATION	$50,520
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	3	2/18/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $33,717 )
2020	2020	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	2	2/21/2020	NON-COMPETING CONTINUATION	$504
2020	2020	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	2	12/5/2019	NON-COMPETING CONTINUATION	$33,213
														Subtotal = $33,717

Issue Date FY: 2019 ( Subtotal = $33,213 )
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	12/17/2018	NEW	$33,213
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	1	12/17/2018	NEW	$0
														Subtotal = $33,213

Grand Total All Awards = $119,131

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Hepacivirus control by vaccine-elicited T cells.

Award Number: F30AI143060

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/17/2018

PERIOD OF PERFORMANCE END DATE: 12/16/2022

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