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 ...