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ANTIBODY-BASED PROTECTION AGAINST FLAVIVIRUSES

Award Number: U01AI073755
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2007
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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ANTIBODY-BASED PROTECTION AGAINST FLAVIVIRUSES - Project Summary Flaviviruses are enveloped, single-stranded RNA viruses that cause epidemics of debilitating human disease on a global scale. The four serotypes of dengue virus (DENV) cause up to ~100 million infections per year including life-threatening shock syndrome. Zika virus (ZIKV) is linked to microcephaly and congenital malformations. Tick- borne flaviviruses (TBFV) are emergent threats that cause encephalitis, long-term neurological sequelae, and death. No specific therapy is available for any flavivirus. Flaviviruses adopt ensembles of structures in which certain antibody epitopes are exposed or hidden. Elucidating how antibodies recognize different structural ensembles of flavivirus virions can enhance our understanding of their functional properties including neutralizing activity. In this competitive renewal application, our long-standing collaborative team (Diamond, Kuhn, Fremont, Crowe, and Pierson) proposes to continue studying structural mechanisms of antibody recognition and neutralization of flaviviruses. We will define the functional properties of protective antibodies that neutralize DENV and ZIKV in a conformationally-restricted manner. We will use these antibodies to probe the spectrum of structures sampled by flaviviruses and how this influences epitope exposure. We also will perform new campaigns to identify neutralizing antibodies against ZIKV and the distantly-related tick-borne flaviviruses that recognize quaternary epitopes. We will use this information to engineer ZIKV subviral particles (prM-E; SVPs) that optimally enable binding of neutralizing antibodies including those quaternary epitopes spanning dimer rafts. Genetically modified ZIKV SVPs will be tested for improved immunogenicity and protection in mice. Overall, our experiments will provide new insight into the dynamic states of flaviviruses and the nature of accessible neutralizing antibody epitopes. These studies may facilitate the generation of novel sculpted antigens and immunogens with improved capacity to detect and elicit specific protective antibody responses against DENV, ZIKV, and likely other emerging flaviviruses.


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 = $1,134,662 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	18	12/30/2025	NON-COMPETING CONTINUATION	$1,134,662
														Subtotal = $1,134,662

Issue Date FY: 2025 ( Subtotal = $1,111,778 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	17	2/13/2025	NON-COMPETING CONTINUATION	$1,111,778
														Subtotal = $1,111,778

Issue Date FY: 2024 ( Subtotal = $1,106,509 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	16	3/14/2024	COMPETING CONTINUATION	$1,101,100
2024	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	002	16	9/19/2024	COMPETING CONTINUATION	$5,409
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	16	6/11/2024	COMPETING CONTINUATION	$0
														Subtotal = $1,106,509

Grand Total All Awards = $3,352,949

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ANTIBODY-BASED PROTECTION AGAINST FLAVIVIRUSES

Award Number: U01AI073755

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2007

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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