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Rational design and efficacy testing of vaccines against HCV

Award Number: R01AI168048
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Rational design and efficacy testing of vaccines against HCV - Project Summary An estimated 71 million people worldwide are infected with HCV and are at heightened risk for severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. Although effective directly-acting antiviral treatment is available, only an HCV vaccine will help prevent infection, associated pathologies, and effectively reduce global disease burden. Cumulative evidence has shown that both B and T cell immunity contribute to the control of acute HCV infection. A major challenge is the high variability across the genome especially in the envelope E1E2 glycoproteins, the natural target of protective antibodies. An E1E2-based immunogen will need to elicit broadly neutralizing antibodies (bnAbs) to multiple epitopes to overcome the high antigenic diversity of HCV isolates and be of sufficient titers to achieve protective immunity. Our approach is supported by our recent data that a secreted form of E1E2 (sE1E2) maintains its native-like properties and can elicit broader neutralizing antibody responses than the membrane-bound form of E1E2 and secreted E2. Also, we have shown that presentation of sE1E2 as multivalent virus-mimicking polymer assemblies (VMPAs) that include HCV core protein can elicit cellular immune responses to sE1E2 and core antigens with potential immunopotentiating activity for B and T cell responses. Accordingly, our central hypothesis is that rational structure-guided design of E1E2 and co-formulation with conserved HCV T cell antigens as a VMPA vaccine will lead to optimal presentation of conserved bnAb epitopes and elicit long-lasting B and T cell mediated immunity. Towards this end, we propose the following Specific Aims: Aim 1, Rational E1E2 antigen design. We will advance our structure-guided E1E2 design to increase the immunogenicity of bnAb epitopes, and stabilize the native-like sE1E2 complex using synthetic scaffolds. Aim 2, Structural characterization of HCV envelope complexes. We will structurally characterize the E1E2 heterodimer complexed with key bnAbs, and new structures will be used for further E1E2 optimization. Aim 3, Formulation and characterization of virus-mimicking polymer assemblies. We plan to further develop supramolecular assemblies of E1E2 for multimeric presentation of E1E2 and T cell antigens. Aim 4, Immunological evaluation of B and T cell responses in animal models. Immunological assessment of our vaccine candidates will be performed in mice, guinea pigs, and macaques. These studies will include an examination of the specificity of neutralizing antibody responses as well as systemic and tissue resident memory T cells. Aim 5, Vaccine efficacy in challenge model systems. Protection studies will utilize the only two available challenge models. The first, an immunocompetent humanized mouse model to test the protective efficacy of our lead vaccine candidates. The second, a human-mouse liver chimeric model that can be infected with antigenically diverse clinical HCV isolates to demonstrate serum antibodies from vaccinated macaques passively transferred to the chimeric mice will be protective. The overall program will lead to a rationally designed vaccine candidate to induce broadly neutralizing antibodies and long-term memory T cell responses to prevent HCV infection.


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: 2026 ( Subtotal = $1,317,020 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	5	4/29/2026	NON-COMPETING CONTINUATION	$1,317,020
														Subtotal = $1,317,020

Issue Date FY: 2025 ( Subtotal = $1,357,012 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	4	5/8/2025	NON-COMPETING CONTINUATION	$1,357,012
														Subtotal = $1,357,012

Issue Date FY: 2024 ( Subtotal = $1,590,001 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	3	8/20/2024	SUPPLEMENT FOR EXPANSION	$179,958
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	3	4/12/2024	NON-COMPETING CONTINUATION	$1,410,043
														Subtotal = $1,590,001

Issue Date FY: 2023 ( Subtotal = $1,379,680 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	5/2/2023	NON-COMPETING CONTINUATION	$1,379,680
														Subtotal = $1,379,680

Issue Date FY: 2022 ( Subtotal = $1,410,544 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	5/5/2022	NEW	$1,410,544
														Subtotal = $1,410,544

Grand Total All Awards = $7,054,257

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Rational design and efficacy testing of vaccines against HCV

Award Number: R01AI168048

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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