Year of Award

2021

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

David Burkhart

Commitee Members

Celine Beamer, Andrij Holian, Erica Woodahl, Kendal Ryter

Keywords

Adjuvants, C-type lectin receptor, Influenza, SARS-CoV-2, Toll-like receptor, Vaccine

Publisher

University of Montana

Abstract

Ligands for pattern recognition receptors (PRRs) have been isolated or synthesized for use as adjuvants in order to improve the magnitude and quality of the immune response of vaccines. In particular, basic research of toll-like receptor (TLR) and C-type lectin receptor (CLR) families has culminated in the production of novel ligands with agonist activity. To use these PRR agonists as vaccine adjuvants, it is necessary to properly formulate them in delivery systems to unlock their agonist activity. The objective of this work was to develop liposomal and oil-in-water (O/W) emulsion formulations for TLR4 and TLR7/8 agonists and to develop O/W emulsion formulations for CLR agonists for use as vaccine adjuvants. First, liposomal formulation of novel TLR4 and TLR7/8 agonists, delivered alone or in combination, were used to drive immune synergy for use in an influenza vaccine. Second, different novel TLR4 and TLR7/8 agonists were formulated in squalene-based O/W emulsions to create stable and efficacious adjuvants for use in a vaccine against SARS-CoV-2. Lastly, O/W emulsions were used to formulate novel agonists for macrophage inducible C-type lectin (Mincle) receptor for use in a vaccine against Mycobacterium tuberculosis. Collectively, these results demonstrate the importance of formulation of PRR agonists and demonstrate effective ways to increase vaccine adjuvant stability and efficacy using formulation.

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© Copyright 2021 Kristopher Kenneth Short