Title:
Directing the immune response using nanoparticle vaccines and drug delivery systems
Directing the immune response using nanoparticle vaccines and drug delivery systems
Author(s)
Chapman, Asheley Poole
Advisor(s)
Finn, M. G.
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Abstract
Virus-like particles (VLPs) are icosahedral protein nanoparticles with inherent immunogenicity qualifying them as ideal carrier proteins for conjugate vaccines. These vaccines have both prophylactic potential and can be used to generate monoclonal antibodies (mAbs) against a wide array of targets. VLPs derived from bacteriophage Q and PP7 are formed from 180 copies of coat protein expressed in Escherichia coli that self-assemble nanoparticles ~30 nm in diameter. Reactive amino acid side chains can be modified to display synthetic antigens using bioconjugation techniques or can be genetically engineered as C-terminal extensions forming multivalent VLP-conjugate vaccines. This dissertation will describe the optimization of several design features of VLP-conjugate vaccines including linker length connecting antigen to carrier protein, route of vaccine administration, and adjuvant incorporation. These findings were incorporated into subsequent VLP-conjugate vaccine design and strategy. The antigenicity of several molecular classes of VLP-presented antigens were evaluated and ultimately produced libraries of rare mAbs targeting bacterial and tumor-associated glycans, fentanyl small molecules, cyclic peptides toxins, and SARS-CoV-2 peptides and proteins. Hybridoma-produced mAbs were characterized and assessed for binding specificity, affinity, cross-reactivity, and function, including their diagnostic potential for incorporation into immunoassays for use at Centers for Disease Control and Prevention. Additionally, a multistage nanoparticle drug delivery platform was explored in order to improve access to adaptive lymphocytes residing in the lymph nodes. This work builds upon previous work exploring the utility of VLP conjugates for vaccine development and polymeric nanoparticles that target lymph nodes for drug delivery, all of which demonstrate promise as technologies for use in the clinic and in diagnostic reagent development.
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Date Issued
2021-04-28
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Text
Resource Subtype
Dissertation