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Structure based design of dengue subunit vaccines for inducing protective but not disease enhancing antibodies

Award Number: R01AI161025
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Structure based design of dengue subunit vaccines for inducing protective but not disease enhancing antibodies - ABSTRACT Dengue virus (DENV) vaccine development has been challenging because of the presence of 4 serotypes (DENV1-4) and the potential for vaccine enhanced severe disease. The leading live attenuated tetravalent DENV vaccines have been plagued by poorly balanced replication of vaccine components leading to variable efficacy and vaccine primed severe dengue disease in some children. The goal of this proposal is to develop novel recombinant DENV envelope (E) protein and virus like particle (VLP) vaccines that overcome barriers faced by live attenuated tetravalent vaccines. We have discovered that the DENV E protein produced as a secreted protein is a poor vaccine because it is a monomer that does not display major quaternary epitopes targeted by human neutralizing and protective antibodies (Abs). This proposal is based on new discoveries from our group about how structure based, computational approaches can be used to produce highly stable and properly folded DENV E dimers that are efficiently secreted from mammalian cells. We will use mouse models of DENV vaccination and infection to test if artificially stabilized DENV E dimers stimulate Ab responses that are similar to serotype-specific and serotype-cross-protective Ab responses in people exposed to primary and secondary wild type DENV infections. The stabilized E dimers will be further modified to test if large-scale resurfacing of the E dimer can be used to focus the immune response on epitopes recognized by potent neutralizing Abs, while eliminating responses to off target, disease enhancing epitopes. Finally, we will design membrane anchored variants of stabilized E dimers to promote the formation of dengue virus-like particle (VLP) vaccine candidates that better resemble mature infectious virions than VLPs made with current techniques. Our studies, which explore how to design and deliver recombinant E antigens to focus the host antibody response on important quaternary structure neutralizing epitopes, will stimulate new research directions in the field of flavivirus subunit vaccines.


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 = $723,184 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	4	4/30/2025	NON-COMPETING CONTINUATION	$723,184
														Subtotal = $723,184

Issue Date FY: 2024 ( Subtotal = $723,184 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	2/27/2024	NON-COMPETING CONTINUATION	$650,867
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$72,317
														Subtotal = $723,184

Issue Date FY: 2023 ( Subtotal = $723,184 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	3/21/2023	NON-COMPETING CONTINUATION	$723,184
														Subtotal = $723,184

Issue Date FY: 2022 ( Subtotal = $723,184 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	4/21/2022	NEW	$723,184
														Subtotal = $723,184

Grand Total All Awards = $2,892,736

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Structure based design of dengue subunit vaccines for inducing protective but not disease enhancing antibodies

Award Number: R01AI161025

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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