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Principal Investigator: Steven Bradfute
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $1,758,323
Funding agency: National Institute of Allergy and Infectious Diseases
In Project 2 (P2) we will use cutting-edge antigen engineering to refine vaccine antigen design strategies through
iterative assessments of immunogenicity and protective efficacy to generate optimized vaccine immunogens
against nairo-, hanta-, and paramyxoviruses. Our approach will establish a protective antigen engineering
blueprint for emerging bunyaviruses and paramyxoviruses with pandemic potential. We will interact with the other
PROVIDENT projects and cores for antigen production (CC), animal efficacy testing (CD), mRNA vaccines (P3,
CE), and sharing knowledge and resources (CB, P1, P3, P4). Aim P2.1: Structure-based antigen design. We
will utilize an in-depth understanding of structural biology of viral surface proteins to design and express
recombinant viral antigens from a prototype nairovirus (Crimean-Congo hemorrhagic fever virus, CCHFV),
hantavirus (Andes virus, ANDV), and paramyxovirus (Menangle virus). Following optimization of antigen designs
for prototype viruses, design strategies will be applied to related but genetically distant outgroup viruses
(nairoviruses: Hazara virus; hantaviruses: Sin Nombre virus and Hantaan virus; paramyxoviruses: Sosuga virus
and Nipah virus) to validate that our vaccine design approach is applicable within virus families. Aim P2.2:
Antigenicity and protective efficacy of engineered antigens. We will vaccinate animals with recombinant antigens
designed in P2.1 and produced by CC and evaluate immunogenicity and in vivo efficacy against viral infection.
Following down-selection, lead antigens will be incorporated into mRNA vaccine platforms optimized by P3.
Comparative immunogenicity and in vivo efficacy studies will evaluate recombinant- and mRNA-based vaccine
platforms head-to-head. Based on results obtained using prototype viruses from each family, we will apply
antigen design strategies to outgroup viruses and evaluate immunogenicity and protective efficacy of lead
candidates in existing and/or novel animal models being developed by CD. Aim P2.3: Characterization of
humoral immune responses to engineered antigens. We will evaluate humoral immune responses to engineered
antigens using samples collected from animal studies (P2.2) using high-throughput, well-characterized assays.
We will use authentic and surrogate virus assays to rapidly evaluate neutralization potential and Fc-mediated
activity of vaccine-elicited polyclonal antibodies. VH-VL antibody repertoires encoded by peripheral B cell
subsets will be identified using novel multivalent BCR-seq methodologies. We will also investigate correlates of
protection for lead CCHFV and ANDV vaccine antigens from P2.2 by executing B cell depletion studies with
support from CD. Aim P2.4: Evaluations of T cell responses to engineered antigens. We will perform in-depth
analyses of peripheral, tissue resident, and follicular memory T cell responses in vaccinated animals and will
conduct T cell receptor sequencing to identify the breadth and diversity of T cell responses post-vaccination. To
assess the role of T cells in protective efficacy, T cell depletion studies will be completed with support from CD.
This project will provide a roadmap to optimize vaccine immunogens for nairo-, hanta-, and paramyxoviruses.
Terms: <Amino Acids><Andes Virus><Animal Model><Animal Models and Related Studies><Animals><Antibody Binding Sites><Antibody Repertoire><Antibody Response><Antibody Specificity><Antigenic Determinants><Antigens><Assay><B blood cells><B cell><B cells><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B-cell receptor repertoire sequencing><B-cell receptor sequencing><BCR repertoire sequencing><BCR seq><BCR sequencing><BCRseq><Binding><Binding Determinants><Bioassay><Biological Assay><Body Tissues><Bunyavirus><Cell Body><Cell Function><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell Surface Antigens><Cell-Mediated Immunity><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Immunity><Cellular Physiology><Cellular Process><Clinical Treatment Moab><Complex><Congo Virus><Congo hemorrhagic fever virus><Crimean Hemorrhagic Fever Virus><Crimean-Congo Hemorrhagic Fever Virus><Crimean-Congo hemorrhagic fever orthonairovirus><Crystallographies><Crystallography><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Distant><ELISA><Engineering><Environment><Enzyme-Linked Immunosorbent Assay><Epidemic Hemorrhagic Fever Virus><Epitopes><Evaluation><Family><Four Corners Virus><Four Corners hantavirus><Goals><Hantaan virus><Hantavirus><Head><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemorrhagic Nephroso-Nephritis Virus><Humoral Immunities><Immune><Immune response><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Surface Markers><Immunological><Immunological Surface Markers><Immunological response><Immunologically><Immunologics><Immunotherapeutic agent><Inducer Cells><Inducer T-Lymphocytes><Investigation><Knowledge><Korean Hemorrhagic Fever Virus><Lead><M protein><Machine Learning><Maps><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methodology><Mice><Mice Mammals><Molecular Interaction><Monoclonal Antibodies><Muerto Canyon Virus><Murine><Mus><Nairovirus><Nipah Virus><Nipah henipavirus><Orthobunyavirus><Paramyxoviridae><Paramyxovirus><Paratopes><Pb element><Peptides><Peripheral><Position><Positioning Attribute><Process><Production><Protein Engineering><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RNA vaccine><RNA-based vaccine><Recombinants><Reference Standards><Research Grants><Research Project Grants><Research Projects><Research Resources><Resources><Role><Sampling><Sin Nombre hantavirus><Sin Nombre virus><Splenocyte><Structure><Subcellular Process><Surface><Surface Antigens><Surface Proteins><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T memory cell><T-Cell Depletion><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-cell depletion therapy><T-cell diversity><T-lymphocyte depletion therapy><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Tissues><Up-Regulation><Upregulation><Vaccinated><Vaccination><Vaccine Antigen><Vaccine Design><Vaccines><Viral><Viral Antigens><Viral Diseases><Viral Vaccines><Virus><Virus Diseases><Work><aminoacid><animal efficacy><antibody combining site><antibody-based immunity><comparative><cytokine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><efficacy study><efficacy testing><enzyme linked immunoassay><experience><genetic protein engineering><heavy metal Pb><heavy metal lead><host response><immune drugs><immune system response><immune-based therapeutics><immunogen><immunogenicity><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><in vivo><killer T cell><lead candidate><mAbs><mRNA vaccine><mRNA-based vaccine><machine based learning><memory T lymphocyte><model of animal><monoclonal Abs><multiple myeloma M Protein><novel><pandemic concern><pandemic potential><pandemic risk><pandemic threat><pathogenic virus><polyclonal antibody><protective efficacy><protein complex><protein design><prototype><resident memory T cell><social role><structural biology><thymus derived lymphocyte><tissue resident memory T cell><vaccine development><vaccine efficacy><vaccine platform><vaccine strategy><viral infection><viral pathogen><virus antigen><virus infection><virus pathogen><virus-induced disease>