Rapid antibody screening systems to identify and engineer antiviral protection

PROJECT SUMMARY A detailed understanding of molecular and cellular adaptive immune responses is critical to accelerate progress in human immunology and drug development. However, available technologies for analyzing antiviral neutralizing antibody responses are slow and impractical for large-scale clinical sample analysis, and can provide limited information on the scope of neutralizing antibody features in human immunity. Importantly, current methods are also unable to engineer antibody molecules to directly improve neutralization potency, which is a major limitation to the discovery of potent and broadly reactive antibody-based interventions for viral diseases. Current methods also cannot engineer broad antibody neutralization against related viruses, which is critical for drug and vaccine development against diverse viral lineages. Important examples include the diverse viral lineages of betacoronaviruses and flaviviruses, where protection against evolved and expanded viral lineages is essential for effective clinical use. This project will develop a new in vitro platform for rapid analysis and engineering of antibody neutralization. We will establish methods to directly select antibodies desired antiviral properties at high throughput, including for neutralization breadth and potency. We will apply a custom platform for natively paired antibody heavy and light chain gene capture from human immune responses to map the neutralization capacity of antiviral antibodies elicited by natural infection or vaccination, and to select for broad antibody protection against related viruses. Aim 1 will establish our new assay techniques for antiviral antibody discovery and engineering against SARS- CoV-2, which is continuously evolving after its recent emergence into human populations. This project will identify antibody variants with high potency and breadth from the immune responses of convalescent COVID-19 patients. We will also engineer promising antibodies for enhanced neutralization breadth and potency against diverse SARS-CoV-2 strains. Aim 2 will establish antiviral antibody discovery and engineering strategies against flaviviruses, using yellow fever virus as a key model system. Antibody-dependent enhancement in flaviviruses makes potent antibody neutralization a critical feature for any antibody-based clinical interventions. We will identify potent neutralizing antibodies from patients vaccinated against yellow fever virus, and engineer improved neutralizing antibodies for high potency against multiple yellow fever virus strains This work will establish a new platform approach for potent antiviral discovery and antibody engineering. Our long-term objectives are to develop robust and rapid antiviral antibody discovery platforms that can accelerate progress in the development of medical interventions for viral diseases.