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Title page for ETD etd-06162016-165300


Type of Document Dissertation
Author Flyak, Andrew I.
Author's Email Address flaandrew@gmail.com
URN etd-06162016-165300
Title The Analysis of the Human Antibody Response to Filovirus Infection
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
James W. Thomas Committee Chair
D. Borden Lacy Committee Member
James E. Crowe, Jr. Committee Member
Melanie D. Ohi Committee Member
Terence S. Dermody Committee Member
Keywords
  • Glycoprotein
  • Neutralization
  • Cross-reactivity
  • Bundibugyo virus
  • Ebola virus
  • Marburg virus
  • Vaccines
  • Antibodies
  • Antigenic sites
Date of Defense 2016-03-01
Availability unrestricted
Abstract
Filoviruses cause a highly lethal disease in humans, with untreated mortality rates approaching 90%. Most of our knowledge about neutralizing antibody responses against filovirus infections has come from studies of monoclonal antibodies (mAbs) that recognize Ebola virus (EBOV). As a result, there is little information available about human antibodies that neutralize other filoviruses, such as Marburg virus (MARV) or Bundibugyo virus (BDBV). Using peripheral blood B cells from individuals who contracted MARV or BDBV infections, I isolated large panels of neutralizing antibodies that bind to filovirus glycoproteins (GPs). I determined that MARV GP-specific neutralizing mAbs bind to the receptor-binding site, revealing a mechanism of MARV inhibition. Using a panel of mAbs isolated from BDBV survivors, I determined that a large proportion of BDBV-specific neutralizing mAbs cross-react with multiple Ebolavirus species. Cross-reactive neutralizing mAbs targeted conserved antigenic sites in the glycan cap or near the membrane proximal region of BDBV GP. Collectively, this work reveals mechanisms of filovirus neutralization by human mAbs and provides information about conserved epitopes on GP that can be used to inform the development of vaccines effective against multiple filoviruses. The new knowledge gained from this study could help develop broad-spectrum protective mAbs and detection capabilities for existing filoviruses, and new viral strains that may emerge in the future.
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