Evaluations Of Severe Acute Respiratory Syndrome Coronavirus Therapeutics And A Viral Capacity For Plasticity And Escape. Public Deposited

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  • March 19, 2019
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  • Bolles, Meagan Elise
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emerged in 2002/2003, causing the deaths of almost a tenth of the 8000 individuals infected worldwide before it was controlled by public health measures. While the 2003 epidemic strain is likely extinct, the importance of coronaviruses as emergent zoonotic viruses was again realized with the emergence of a novel human coronavirus in Saudi Arabia in 2012. Despite a decade of research on SARS-CoV no approved vaccine or therapeutic yet exists, and development of broadly neutralizing and effective therapeutics for coronaviruses remains a priority. Neutralizing antibodies targeting the Spike glycoprotein (S) are both necessary and sufficient for protection against SARS-CoV, but the high genetic diversity and mutability of SARS-CoV in natural infections presents a challenge to both vaccine- and antibody-based therapeutics. Thus, an effective SARS-CoV therapeutic should provide S-specific immunity that is nonetheless broad enough to counter heterologous and derivative S variants. This work was designed to assess immunization strategies towards SARS-CoV, to explore the plasticity and neutralization networks of the Spike glycoprotein, and to assess the utility of molecular models to predict host range and antibody neutralization. In the first study we explored the limitations of a doubly inactivated SARS-CoV vaccine, identifying a vaccine-induced immunopathology and emphasizing the importance of rigorous challenge viruses and animal models that accurately recapitulate age-associated lung pathology. Second, in two collaborative studies we assessed multi-generational monoclonal antibodies designed to be broadly neutralizing or escape resistant, and extended our characterization of the Spike receptor binding domain (RBD) as a highly plastic antiviral target. Finally, we characterized ten recombinant Combinatorial Escape Viruses (CEVs) engineered from a database of antibody escape substitutions in the RBD. These CEVs were designed to assess the plasticity of the S-RBD, the utility of predictive modeling, and the neutralization networks across the RBD. The tools developed this study will assist in the development of predictive models and standardized platforms for combination monoclonal antibody immunotherapies for emergent viruses. These studies of SARS-CoV have extended our understanding of a key neutralizing target and have provided a valuable foundation for the rapid characterization of novel coronaviruses and potential therapeutics.
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  • In Copyright
Advisor
  • Baric, Ralph S.
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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