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Principal Investigator: Aravinda M. DeSilva
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $4,782,234
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Arthropod vector-borne flaviviruses threaten the health of people in nearly all countries of the world. Over the
past 30 years, the epidemiology of flaviviruses has been characterized by intense year-round transmission in
some areas, abrupt and permanent expansion of the range of viruses to new regions and continents, and
severe epidemics caused by viral species previously considered to be a minor nuisance. FLARE Center
Project 2 is based on our recent discovery of a structure-based method, broadly applicable to flaviviruses, for
producing highly stable, secreted envelope (E) protein homodimers displaying quaternary structure epitopes
recognized by human antibodies that strongly neutralize flaviviruses. The goal of Project 2 is to build on this
discovery and establish ‘plug and play’ modular protein subunit and mRNA vaccine platforms to counter
currently circulating and future epidemic flaviviruses. The prototype flavivirus selected for Project 2 is dengue
virus type 2 (DENV2) because this serotype, which is widely distributed, is one of the most studied flaviviruses.
Lessons learned and vaccine platforms developed for DENV2 will be applicable to closely related pathogenic
flaviviruses (e.g., other DENV serotypes and Zika virus) as well as more distantly related flaviviruses. Project
2 has three independent Aims, where each Aim is based on a single design concept for developing a modular
vaccine platform. In Aim 1, we will further improve the E homodimer technology and obtain critical non-human
primate immunogenicity and protection data required for advancement of the platform to clinical trials with our
industry partner, Moderna. Aims 2 and 3 explore new and exciting vaccine design approaches for induction
of flavivirus cross-protective immunity using antigens that display complex structural epitopes on E that require
assembly of higher order E homodimers. Project 2 is closely linked to other Projects and Cores in the FLARE
Center. Project 2 will use animal models available through Core D, up-to-date immunological assays
developed by Core E, and engage with Core C to solve the structure of vaccine antigens and explore alternate
nanoparticle vaccine delivery platforms. Project 2 also will collaborate with Project 1 to design and test E
homodimer vaccines for flaviviruses that are distantly related to the DENV complex, and Project 5 to develop
DENV serotype cross-protective therapeutic mAbs.
Terms: <Address><Agreement><Alpha Virus><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigenic Determinants><Antigens><Architecture><Archives><Area><Arthropod Vectors><Binding><Binding Determinants><Bionomics><Blood Sample><Blood specimen><Breakbone Fever Virus><Chimera Protein><Chimeric Proteins><Clinical Trials><Collaborations><Complex><Country><DENV><DENV infection><DENV vaccine><Data Protection><Dengue Infection><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus infection><Dengue virus vaccine><Development><Distant><E protein><Ecology><Encapsulated><Engineering / Architecture><Envelope Protein><Epidemic><Epidemiology><Epitopes><Evaluation><Exposure to><Flavivirus><Fusion Protein><Future><Genetic Alteration><Genetic Change><Genetic defect><Goals><Group A Arboviruses><Group B Arbovirus><Health><Higher Order Chromatin Folding><Higher Order Chromatin Structure><Higher Order Structure><Hu-mABs><Human><Immune response><Immunity><Immunize><Immunological response><Immunology procedure><Infection><Lead><Link><Lipids><MAb Therapeutics><Maps><Messenger RNA><Methods><Mice><Mice Mammals><Minor><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Mutation><North Carolina><Orthoflavivirus><Pathogenicity><Pb element><Performance><Persons><Play><Protein Engineering><Protein Subunits><Proteins><RNA vaccine><RNA-based vaccine><Recombinant Proteins><Recombinants><Secondary to><Serotyping><Structure><Subunit Vaccines><Surface><T cell response><Technology><Testing><Therapeutic Monoclonal Antibodies><Tick-Borne Encephalitis Virus><Tickborne Encephalitis Virus><Transmission><Universities><Vaccination><Vaccine Antigen><Vaccine Design><Vaccines><Variant><Variation><Viral><Virion><Virus><Virus Assembly><Virus Particle><West Nile><ZIKV><Zika Virus><cross reactivity><deliver vaccines><dengue viral infection><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><dimer><env Antigens><env Gene Products><env Polyproteins><env Protein><epidemiologic><epidemiological><flaviviridae E protein><flavivirus E><flavivirus envelope protein E><flavivirus glycoprotein E><flaviviruses glycoprotein E><future epidemic><genetic protein engineering><genome mutation><heavy metal Pb><heavy metal lead><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immune system response><immunization strategy><immunogen><immunogenicity><immunologic assay><immunologic assay/test><immunoresponse><improved><industrial partnership><industry partner><industry partnership><mRNA><mRNA vaccine><mRNA-based vaccine><member><model of animal><monoclonal antibody drugs><monomer><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><next epidemic><non-human primate><nonhuman primate><novel><protein design><protein structure><protein structures><proteins structure><prototype><response><scaffold><scaffolding><screening><screenings><self assembly><technology platform><technology system><therapeutic mAbs><transmission process><vaccination strategy><vaccine against DENV><vaccine against dengue><vaccine candidate><vaccine candidate against dengue><vaccine delivery><vaccine development><vaccine platform><vector><vector-borne><vectorborne><viral assembly><viral testing><virus testing><zikav>