Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.640071
Title: Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants
Author: Lynn, Geoffrey M.
ISNI:       0000 0004 5346 2305
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Abstract:
There is currently a need for vaccine adjuvants that are effective for eliciting Th1-type CD4 and CD8 T cell responses when formulated with protein and peptide-based subunit vaccines. Some of the most promising adjuvants in this regard are combined small molecule Toll-like receptor-7/8 agonists (TLR-7/8a). However, poor pharmacokinetic properties have precluded TLR-7/8a for use in vaccines. In this thesis, polymer carriers were used to control pharmacokinetics and to modulate activity of TLR-7/8a for use as vaccine adjuvants. Combinatorial synthesis and in vivo structure-activity studies were used to evaluate how properties of Polymer-TLR-7/8a conjugates (Poly-7/8a) influence innate immune activation in lymph nodes that drain the site of vaccine administration. The most striking finding was that particle formation by Poly-7/8a strongly enhances the magnitude and duration (>14 days) of innate immune activation in lymph nodes by restricting agonist biodistribution and promoting uptake by dendritic cells. Particle-forming Poly-7/8a optimized for activity were found to induce only local innate immune activation (not systemic) and were effective for eliciting Th1-type CD4 and CD8 T cells that mediated protection against infectious challenge. Based on the importance of particle formation for activity of Poly-7/8a, thermo-responsive Poly-7/8a were developed that exist as single water-soluble macromolecules in solution but undergo temperature-driven particle formation in vivo. In conclusion, polymer carriers of TLR-7/8a represent a versatile and effective platform for modulating innate immune activity and warrant further investigation as a class of adjuvants for vaccines.
Supervisor: Seymour, Leonard W. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.640071  DOI: Not available
Keywords: Nano-biotechnology ; Immunology ; Vaccinology ; Chemistry & allied sciences ; Advanced materials ; Chemical biology ; Nanomaterials ; Polymers Amino acid and peptide chemistry ; Supramolecular chemistry ; Materials Sciences ; vaccines ; drug delivery ; polymer chemistry ; adjuvants ; cellular immunology ; nanobiotechnology
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