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Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine

Award Number: U01AI141997
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The four serotypes of dengue virus pose a significant and increasing disease risk to endemic areas (40% of the world) and (via mosquito vector spread or travel) to areas not yet endemic. Tetravalent dengue vaccines are critical to prevent dengue illness. They must generate concurrent and durable protection against all serotypes without increasing risk of severe disease via imbalanced immunity leading to antibody-dependent enhancement of infection. Given concerns with imbalanced dengue vaccine candidates, it is critical to define components and mechanisms of durable four-serotype protection following vaccination, particularly in people (especially children) who have not established protective immunity via sequential natural exposures. This proposal builds on the work of long-standing collaborative investigators involved in developing the NIH live-attenuated tetravalent dengue vaccine TetraVax (TV) in studies in the U.S. and in dengue-endemic Bangladesh. TV protected dengue-naïve individuals from experimental infection six months later with dengue virus serotype 2 challenge and induced robust dengue serotype-specific B cell and CD4+ and CD8+ T cell responses. Key questions include: the durability of protective responses, whether similar protective mechanisms are at play in individuals in dengue- endemic areas and in individuals previously exposed to dengue prior to vaccination. In Aim 1 we will evaluate the development of serotype-specific B cells producing antibodies with neutralizing and Fc effector functions as well as virus-specific CD4+ and CD8+ T cell responses throughout a 6–12-year period after TV vaccination and assess whether these responses correlate with protection from subsequent DENV2 challenge. In Aim 2 we will demonstrate the importance, persistence, and function of serotype-specific neutralizing vs. enhancing antibodies following TV of dengue-naïve adults. In Aim 3 we will investigate whether TV vaccination contributes to protection in dengue-exposed individuals via potent cross-reactive neutralizing antibodies. Overall, these insights into immune mechanisms of durable protection will help answer persistent questions about dengue vaccine risk and efficacy. Leveraged with highly controlled clinical studies these data should be broadly generalizable to the understanding of safe and durable immunity following any tetravalent dengue vaccine.


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 = $635,890 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	6	12/6/2023	COMPETING CONTINUATION	$635,890
														Subtotal = $635,890

Issue Date FY: 2023 ( Subtotal = $608,440 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	5	1/25/2023	NON-COMPETING CONTINUATION	$608,440
														Subtotal = $608,440

Issue Date FY: 2022 ( Subtotal = $608,997 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	4	2/10/2022	NON-COMPETING CONTINUATION	$608,997
														Subtotal = $608,997

Issue Date FY: 2021 ( Subtotal = $611,648 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	3	1/26/2021	NON-COMPETING CONTINUATION	$611,648
2021	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	2	11/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $611,648

Issue Date FY: 2020 ( Subtotal = $615,445 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	2	1/27/2020	NON-COMPETING CONTINUATION	$615,445
														Subtotal = $615,445

Issue Date FY: 2019 ( Subtotal = $640,554 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	1	5/10/2019	NEW	$0
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	1	1/29/2019	NEW	$640,554
														Subtotal = $640,554

Grand Total All Awards = $3,720,974

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Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine

Award Number: U01AI141997

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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