CORE C: Structure & Protein Engineering Core

For pandemic preparedness, structural biology and structure-based vaccine design are critical to the prototype pathogen approach. Vaccine developers must select the viral protein(s) to be included in the vaccine based on knowledge gained from studying the prototype viruses in each family. They must also determine the optimal presentation of these viral proteins to effectively stimulate the immune system and elicit the desired immune response. Structural biology guides these decisions and provides the blueprint for rational design of engineered vaccine antigens. It also aids characterization of the antigens, defines the epitopes of potently neutralizing antibodies, and provides insight into the mechanisms of antibody-mediated neutralization, all of which enables iterative optimization of the antigen designs. To support the Research Projects in achieving their objectives, Core C: Structure and Protein Engineering will provide services encompassing protein engineering and production, characterization, and structural biology. Dr. Jason McLellan (UT Austin), an expert in structural virology and the development of structure- based interventions for viral pathogens, will lead Core C. His laboratory is well known for their ability to determine viral protein structures and antibody complexes via X-ray crystallography and cryo-EM. Furthermore, the McLellan laboratory has a wealth of experience in protein engineering, expression, and purification. Dr. Jimmy Gollihar (Houston Methodist) and his team will contribute to Core C their proficiency in synthetic biology, laboratory automation, and high-throughput screening and selection technologies. Core C will perform high-throughput protein engineering and production, allowing hundreds of designed protein constructs to be biophysically characterized for thermal stability, conformational homogeneity, and antibody reactivity. Select protein antigens meeting pre-specified criteria will be provided to the Research Projects and Cores to facilitate their studies, including immunogenicity experiments, antibody isolation, and assay development. Core C will also determine structures of wildtype and variant viral proteins, including complexes with antibody fragments. These structural insights will provide the atomic-level information necessary for designing effective vaccine antigens, and the reagents and data generated by Core C will aid the development of vaccine and antibody strategies for emerging enveloped RNA viruses in the Nairoviridae, Hantaviridae, and Paramyxoviridae families.