Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants
<p>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 agon...
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| Format: | Thesis |
| Language: | English |
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2014
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| _version_ | 1826290720051298304 |
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| author | Lynn, G |
| author2 | Seymour, L |
| author_facet | Seymour, L Lynn, G |
| author_sort | Lynn, G |
| collection | OXFORD |
| description | <p>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.</p> <p>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 <em>in vivo</em> 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 <em>in vivo</em>. 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.</p> |
| first_indexed | 2024-03-07T02:48:30Z |
| format | Thesis |
| id | oxford-uuid:acdb09f7-e690-4cf2-b0e4-3b1611750e49 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:48:30Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:acdb09f7-e690-4cf2-b0e4-3b1611750e492022-03-27T03:31:41ZPolymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvantsThesishttp://purl.org/coar/resource_type/c_db06uuid:acdb09f7-e690-4cf2-b0e4-3b1611750e49VaccinologyAdvanced materialsChemistry & allied sciencesPolymers Amino acid and peptide chemistryChemical biologyMaterials SciencesSupramolecular chemistryImmunologyNano-biotechnologyNanomaterialsEnglishOxford University Research Archive - Valet2014Lynn, GSeymour, L<p>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.</p> <p>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 <em>in vivo</em> 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 <em>in vivo</em>. 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.</p> |
| spellingShingle | Vaccinology Advanced materials Chemistry & allied sciences Polymers Amino acid and peptide chemistry Chemical biology Materials Sciences Supramolecular chemistry Immunology Nano-biotechnology Nanomaterials Lynn, G Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants |
| title | Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants |
| title_full | Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants |
| title_fullStr | Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants |
| title_full_unstemmed | Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants |
| title_short | Polymer carriers of toll-like receptor-7/8 agonists as vaccine adjuvants |
| title_sort | polymer carriers of toll like receptor 7 8 agonists as vaccine adjuvants |
| topic | Vaccinology Advanced materials Chemistry & allied sciences Polymers Amino acid and peptide chemistry Chemical biology Materials Sciences Supramolecular chemistry Immunology Nano-biotechnology Nanomaterials |
| work_keys_str_mv | AT lynng polymercarriersoftolllikereceptor78agonistsasvaccineadjuvants |