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Principal Investigator: Aaron Gregory Schmidt
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $4,728,047
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Emerging and re-emerging arthropod-vectored viruses pose a significant threat to human health. Tick- and
mosquito-transmitted viruses can cause encephalitis and hemorrhagic fever leading to significant morbidity and
mortality. West Nile virus (WNV), tick-borne encephalitis virus (TBEV), and Zika virus (ZIKV) all have tropism for
neuronal cells, which can lead to infection and injury in the central nervous system. Several emerging and re-
emerging neurotropic flaviviruses represent a growing health concern due to their epidemic potential. New
rational immunogen design strategies are necessary to elicit protective responses that confer durable protection
against current and future flavivirus threats. Project 1 of our Flavivirus and Alphavirus ReVAMPP (FLARE)
Center uses iterative immunogen design cycles to develop, optimize, and advance next-generation vaccine
candidates using WNV and TBEV as prototype neurotropic flaviviruses. Our approaches focus on the major
surface envelope (E) glycoprotein, and we hypothesize that the structural conservation of the E glycoprotein will
enable a ‘plug and play’ modular workflow of immunogen and vaccine platform pairs that can be deployed for
other emerging or re-emerging neurotropic flaviviruses. In Aim 1, we design protein-based nanoparticles for
multivalent display of E-subdomains, E-DI and E-DIII. In Aim 2, we use protein engineering strategies to
covalently and non-covalently stabilize E dimers to display complex, conformation-specific epitopes present on
the virion that are the target of potently neutralizing and protective immune responses. In Aim 3, we implement
two immune-focusing strategies, epitope scaffolding and hyperglycosylation, to elicit responses to conserved E-
DIII epitopes. Initial down-selection will occur using protein-based immunogens with some candidates advancing
to mRNA-based delivery with our industry partner, Moderna. Vaccine candidates will be tested for
immunogenicity, antigenicity, and immune focusing with optimal candidates advancing to protection studies
using lethal WNV and TBEV murine challenge models in Aim 4. After down-selection and rigorous Go/No-Go
decision criteria, the top vaccine candidates will be transitioned to Animal Core D for further evaluation in mice
and non-human primates. Project 1 will work closely with Structural Core C to accomplish these objectives and
is conceptually and scientifically linked to FLARE Projects 2 and 3, which are focused on endemic flaviviruses
and alphaviruses, respectively.
Terms: <Alpha Virus><Animals><Antibodies><Antigenic Determinants><Antigens><Architecture><Arthropod Vectors><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Blood Serum><Brain Inflammation><CNS Nervous System><Cell Body><Cell surface><Cells><Central Nervous System><Clinical Treatment Moab><Complex><Computing Methodologies><Cryo-electron Microscopy><Cryoelectron Microscopy><Culicidae><Cysteine><Diffusion><Directed Molecular Evolution><Disulfides><Dose><E protein><Egypt 101 virus><Electron Cryomicroscopy><Electron Microscopy><Encephalitis><Engineering><Engineering / Architecture><Ensure><Epitope Mapping><Epitopes><Evaluation><Ferritin><Flavivirus><Flavivirus Infections><Future><Glycans><Glycoproteins><Group A Arboviruses><Group B Arbovirus><HAP2><Half-Cystine><Health><Human><Huntingtin-Associated protein 1><Immune><Immune response><Immunes><Immunological response><In vivo analysis><Infection><Injury><Ixodida><L-Cysteine><Link><Mammalian Cell><Maps><Membrane><Messenger RNA><Metabolic Glycosylation><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Mosquitoes><Murine><Mus><Negative Staining><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neurons><Orthoflavivirus><Play><Polysaccharides><Powassan><Powassan virus><Protein Engineering><Proteins><Serum><Single Crystal Diffraction><Site><Structure><Surface><Testing><Tick-Borne Encephalitis Virus><Tickborne Encephalitis Virus><Ticks><Tropism><Vaccine Design><Vaccines><Viral Hemorrhagic Fevers><Virion><Virus><Virus Particle><WNV><West Nile virus><Work><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><Yeasts><ZIKV><Zika Virus><computational methodology><computational methods><computer based method><computer methods><computing method><conformation><conformational><conformational state><conformationally><conformations><crosslink><cryo-EM><cryoEM><cryogenic electron microscopy><design><designing><diffused><diffuses><diffusing><diffusions><dimer><directed evolution><epidemic concern><epidemic potential><epidemic risk><epidemic threat><genetic protein engineering><glycosylation><hemorrhagic fever><host response><immune system response><immunogen><immunogenicity><immunoresponse><improved><in vivo><in vivo evaluation><in vivo testing><industrial partnership><industry partner><industry partnership><injuries><iterative design><light scattering><lumazine><mAbs><mRNA><membrane structure><monoclonal Abs><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neuronal><neurotropic><new vaccines><next generation vaccines><non-Native><non-human primate><nonhuman primate><nonnative><novel><novel vaccines><pandemic concern><pandemic potential><pandemic risk><pandemic threat><particle><pathogen><protein design><prototype><response><scaffold><scaffolding><vaccine candidate><vaccine efficacy><vaccine platform><vaccine strategy><viral transmission><virus transmission><zikav>