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Identification of attenuating mutations in the envelope protein for the rational design of a candidate West Nile live-attenuated vaccine.

Award Number: R01AI198488
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: 06/03/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Identification of attenuating mutations in the envelope protein for the rational design of a candidate West Nile live-attenuated vaccine. - Project Summary. The Orthoflavivirus genus in the family Flaviviridae contains several pathogenic arthropod- borne viruses, including West Nile virus (WNV) a mosquito-borne orthoflavivirus in the Japanese encephalitis (JE) sero-/genetic complex. The United States has reported >27,000 cases of WN neuroinvasive disease and >2,900 deaths since the introduction of WNV in 1999, making WN vaccine development a public health priority. Live-attenuated vaccines (LAVs) have successfully controlled mosquito-borne orthoflaviviruses, yellow fever and JE virus. Thus, development of a WN LAV is realistic. The development of an attenuation strategy built on multigenic mutations will support the rational design of a candidate WN LAV. To date, attenuating mutations have been identified in 3 virally encoded nonstructural (NS) proteins, but few attenuating mutations have been identified in the structural proteins, including the envelope (E) protein. Because the E protein not only mediates the binding and membrane fusion with the cell but is the primary target of neutralizing antibodies, a correlate of protection for WNV, mutations in the E protein of a candidate WN LAV must not compromise immunogenicity. This project aims to identify attenuating mutations in the E protein to be incorporated into the rational design of a candidate WN LAV alongside those in the NS proteins. The E protein is a class II fusion protein that forms a fusogenic trimer to mediate the membrane fusion process, which is the fundamental viral entry mechanism and is crucial for WNV neurotropism in vertebrate hosts and transmission by mosquitoes. The formation of the E protein trimer requires the rearrangement of its 3 domains (EDI, EDII, and EDIII). The 4 motifs between the EDI and EDII exert a hinge effect for the EDI-EDII interdomain movement to initiate the formation of the E protein trimer, hence the name EDI-EDII hinge region. Site-directed mutagenesis of the EDI-EDII hinge region in WNV strain NY99 rescued from an infectious clone (WNV-NY99ic) demonstrated that the E-A54 and E-Y201 residues each control the formation of the E protein trimer. WNV-NY99ic retained 13 alternative amino acid (aa) substitutions of the respective residues. The E-A54I and E-Y201P mutations each fully attenuated the neuroinvasive phenotype of WNV-NY99ic in outbred Swiss mice, while retaining induction of serum neutralizing antibodies. Built on the attenuated phenotype and immunogenicity of the E-A54I and E-Y201P mutants, the central hypothesis is that impairment of the membrane fusion process by mutations of either the E-A54 residue or the E-Y201 residue will attenuate murine neurotropism and mosquito transmission of WNV- NY99ic without compromising antibody-mediated neutralization. This project will select the lead mutation of the respective residues based on 1) attenuation of the mouse neuroinvasive phenotype and neurovirulence, 2) impairment of transmission by Culex species mosquitoes that are WN vectors, and 3) immunogenicity that elicits serum neutralizing antibody responses conferring passive protection to identify the E protein mutation(s) suited for the rational design of a candidate WN LAV.


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 = $420,921 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Allergy and Infectious Diseases Research	000	1	6/3/2026	NEW	$420,921
														Subtotal = $420,921

Grand Total All Awards = $420,921

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Identification of attenuating mutations in the envelope protein for the rational design of a candidate West Nile live-attenuated vaccine.

Award Number: R01AI198488

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: 06/03/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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