Exploring Epitope-Focused Vaccine Development: Design of Epitope Scaffolds and Nanoparticle Presentation Platforms, and Computational Prediction of Conformational Epitopes
Thesis (Ph.D.)--University of Washington, 2013Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) evolved a number of defense strategies to evade protective mechanisms of the immune system. Classical vaccine approaches have failed to elicit a protective response for these targets. Epitope Scaffolding is a theoretically attractive immunogen design strategy, which isolates known protective epitopes from their environments while stabilizing relevant conformations, as defined by a neutralizing antibody. In this work, we extend previous epitope scaffolding methods to scaffold a known protective HCV epitope and introduce preliminary immunization results. Additionally, in light of several mixed, protein and glycan, epitopes described for HIV, we apply the scaffolding strategy to an anti-HIV broadly neutralizing antibody - PG9. Next, using a derivative of an HIV envelope glycoprotein, we describe the development of a novel multimerization platform and illustrate potential applications. Finally, a computational protocol was developed to identify antibody accessible epitopes on flexible, glycosylated proteins
