Document text
Principal Investigator: Jason Scott McLellan
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $4,043,107
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY - Core C: Structure Core
Structure-based vaccine antigen design is a key component of the prototype pathogen approach to pandemic
preparedness. For each prototype pathogen, vaccine developers must choose which viral protein(s) to include
in the vaccine as well as which form of the viral proteins to present to the immune system to elicit the optimal
immune response. Structural biology provides atomic-level information on viral glycoproteins, which is essential
for initiating the rational design of engineered vaccine antigens. Structural information is also crucial for
evaluating the engineered antigens, ensuring that the modifications and stabilizing substitutions produce the
intended effect. Additionally, structural biology plays a vital role in elucidating the epitopes and binding
mechanisms of monoclonal antibodies. This knowledge guides the design of antigens capable of binding to the
most promising antibodies, thereby eliciting an effective immune response. Antigen design, production,
characterization and structural biology will be performed in Core C: Structure as services to enable the Research
Projects to accomplish their objectives.
Core C will be led by Dr. Jason McLellan at the University of Texas at Austin, who is an expert in structural
virology and the development of structure-based interventions for viral pathogens. His laboratory has expertise
in the determination of viral protein structures and antibody complexes by X-ray crystallography and cryo-EM.
The McLellan laboratory also has extensive experience in protein engineering, expression, and purification. Dr.
Daisy Leung and her team will contribute to the biophysical characterization of antigens and antigen–antibody
complexes, and Dr. Anne Moscona and Dr. Tara Marcink will perform cryo-ET studies on whole virions to provide
structural information on higher-order glycoprotein assemblies and antibody interactions. One of the key services
provided by Core C is the rational and computational design of viral proteins to serve both as vaccine
antigens as well as bait for antibody isolation efforts. The second key service is the determination of structures
of viral glycoproteins, both alone and in complex with antibodies. These structures will provide the atomic-level
information required for structure-based antigen design, aid the characterization of antigen variants, define
antibody epitopes, and provide insights into mechanisms of antibody-mediated neutralization. As part of the
antigen design and development process, Core C will also express and purify viral proteins and variants
thereof. These proteins will also be rigorously assessed by Core C via biophysical methods, and those deemed
to be of sufficient quality and stability will be provided to the Research Projects and Cores to facilitate their
investigations. Collectively, the services provided by Core C will directly contribute to the development of vaccine
concepts, antigens, and antibodies that will inform development of medical countermeasures against
paramyxoviruses and bunyaviruses.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Address><Antibodies><Antigen-Antibody Complex><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Binding Proteins><Bunyavirus><COVID-19 virus><COVID19 virus><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Surface Glycoproteins><Cell membrane><Chimera Protein><Chimeric Proteins><Chromatography><Clinical Treatment Moab><CoV-2><CoV2><Complex><Computing Methodologies><Consultations><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasmic Membrane><Deuterium><Development><Diagnostic Reagent><Electron Cryomicroscopy><Engineering><Ensure><Epitopes><Fusion Protein><Glycoproteins><H element><H2 isotope><Hydrogen><Image><Immune Complex><Immune response><Immune system><Immunological response><Interferometry><Intervention><Intervention Strategies><Investigation><Knowledge><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Machine Learning><Mammalian Cell><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Membrane><Membrane Glycoproteins><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methods><Mission><Modeling><Modification><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Machines><Molecular Stereochemistry><Monoclonal Antibodies><Orthobunyavirus><Paramyxoviridae><Paramyxovirus><Plasma Membrane><Play><Process><Production><Protein Binding><Protein Engineering><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RSV Vaccines><Receptor Cell><Receptor Protein><Research Grants><Research Project Grants><Research Projects><Resolution><Respiratory Syncytial Virus Vaccines><Respirovirus><Role><Rubulavirus><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scanning><Services><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><Structure><Subunit Vaccines><Surface><Surface Glycoproteins><Surface Proteins><Techniques><Texas><Therapeutic antibodies><Universities><Vaccine Antigen><Vaccines><Variant><Variation><Viral><Viral Activity><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Physiology><Viral Proteins><Virion><Virus><Virus Particle><Visual><Work><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><biophysical approaches><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical methodology><biophysical methods><biophysical parameters><biophysical properties><biophysical techniques><bound protein><cell sorting><computational methodology><computational methods><computer based method><computer methods><computing method><conformation><conformational><conformational state><conformationally><conformations><consultation><coronavirus disease 2019 virus><coronavirus disease-19 virus><cryo-EM><cryoEM><cryogenic electron microscopy><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><experience><experiment><experimental research><experimental study><experiments><flexibility><flexible><genetic protein engineering><hCoV19><host response><imaging><immune system response><immunogen><immunogenicity><immunoresponse><insight><interventional strategy><light scattering><mAbs><mRNA delivery><machine based learning><medical countermeasure><membrane structure><messenger RNA delivery><monoclonal Abs><nCoV2><pandemic disease preparedness><pandemic planning><pandemic preparedness><pandemic readiness><particle><pathogen><pathogenic virus><plasmalemma><protein complex><protein design><protein purification><protein structure><protein structures><proteins structure><prototype><rational design><receptor><resolutions><social role><structural biology><vaccine antibodies><vaccine development><vaccine induced antibodies><vaccine-induced antibodies><viral pathogen><virology><virus pathogen><virus protein>