Moschos, Stergios Athanasios;
(2004)
Design and analysis of adjuvanticity for new vaccine strategies.
Doctoral thesis (University College London), University College London.
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Abstract
The future of vaccine design relies on three major areas of research a) the characterisation of vaccine components with regards to immunostimulatory capacity and biological effects to ensure and predict safety and efficacy b) the development of novel adjuvants and vaccine delivery systems and c) the identification of new targets that can elicit protective immunity. In this thesis a series of studies were conducted addressing aspects of these issues. There is a defined requirement for the development of in vitro systems for the evaluation of the safety and efficacy of vaccines. The modified horizontal Ussing chamber was evaluated as a tissue culture tool for the rapid in vitro screening of candidate vaccines for mucosal delivery. With limitations identified, recommendations for future design improvements and areas of application are proposed. It is postulated that future vaccines will incorporate multiple adjuvants to induce appropriate, protective types of immunity. To this end, the effect of co-administration of secondary adjuvants with alum and chitosan were investigated in the context of the clinically relevant Helicobacter pylori antigen urease (rUre). It was found that chitosan enhanced the adjuvanticity of the B subunit of cholera toxin (CTB) as well as muramyl di-peptide (MDP), although MDP was ineffective when administered intramuscularly or intranasally. In addition, co-administration of alum with Quil-A or, more so, MDP enhanced immunogenicity and introduced type I response elements suggesting a synergistic mode of action between the adjuvants. In an effort to introduce a simple application approach for double stranded RNA (dsRNA) as an adjuvant in subunit vaccine research, a plasmid-based dsRNA expression system was investigated. Although such a plasmid was constructed, problems over scalable preparation due to palindrome-mediated inviability non-viability were encountered. Alternative approaches based on dual vector systems are discussed. The Staphylococcus aureus RNA III Activating Protein (RAP), a quorum sensing (QS) ligand that controls virulence and adhesion, which has been described as a protective antigen against staphylococcal disease, even antibiotic resistant strains (such as MRSA), was investigated in the context of known effective adjuvants. This data support clinical evaluation of this antigen as it was found that alum and poly-L-lactide (PLA) nanoparticles administered intramuscularly were capable of eliciting immunity similar to that obtained in protective studies; this was achieved with a fraction of the antigen quantity previously used and with non-toxic adjuvants. As elicitation of systemic immunity was not detected following nasal vaccination, the potential role of tolerance to RAP is discussed.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | University College London |
| Title: | Design and analysis of adjuvanticity for new vaccine strategies. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis Digitised by Proquest. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10121721 |
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