Vaccine-adjuvant-carrier design against group A streptococcus and human papillomavirus type-16 infection

Moyle, Peter Michael (2006). Vaccine-adjuvant-carrier design against group A streptococcus and human papillomavirus type-16 infection PhD Thesis, School of Pharmacy, The University of Queensland.

       
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Author Moyle, Peter Michael
Thesis Title Vaccine-adjuvant-carrier design against group A streptococcus and human papillomavirus type-16 infection
School, Centre or Institute School of Pharmacy
Institution The University of Queensland
Publication date 2006
Thesis type PhD Thesis
Total pages 264
Collection year 2006
Language eng
Subjects L
Abstract/Summary Vaccination is one of the most successful and cost-effective public health interventions, with a plethora of vaccines marketed for disease prevention. Most vaccines require parenteral administration, potentially reducing patient compliance due to injection associated pain, as well as requiring administration by trained medical staff. The capacity to deliver vaccines via a mucosal route (e.g. via the nose or mouth) has therefore been subject to a large amount of research. Despite this interest, few mucosal vaccine candidates have successfully progressed to human clinical trials. The attachment of synthetic or bacterial lipids to peptide antigens has been shown to effectively increase the immune response to poorly immunogenic peptide antigens administered via parenteral or mucosal routes. Human clinical trials of lipopeptide vaccines suggest that they in general have a good safety profile, with few or no side effects reported. The lipid core peptide (LCP) system is a lipopeptide vaccine delivery system that incorporates a lipidic adjuvant, carrier, and peptide epitopes into a single molecular entity. The LCPsystem has been demonstrated to adjuvant peptide epitopes from several group A streptococcal (GAS) strains. Antibodies elicited following immunisation with these LCPsystems may potentially protect against challenge with homologous GAS strains. Despite this encouraging data, the LCP-system suffers the inability to be thoroughly characterised, or purified to homogeneity, thus limiting its capacity to be examined in human clinical trials. The ultimate aim of this research is to develop a human-compatible mucosal LCP-based GAS vaccine. The aim of this research was therefore to develop methods for the synthesis of readily characterisable, highly pure LCP-analogues, in decent yield. Techniques that were examined, both in solution and on a solid support, included native chemical ligation and fragment condensation. Both of these techniques suffered from solubility problems. For native chemical ligation, the addition of organic solvents to the ligation mixture helped solubilise species containing the LCP lipid adjuvant, although successful ligation was not observed. The addition of 1% (w/v) sodium dodecyl sulphate (SDS) to the ligation mixture however was capable of solubilising lipidic species and enabled successful ligation. The thesis describes the use of this technique for the synthesis of two tri-epitopic GAS LCP-analogues, and a monoepitopic, tetra-valent GAS LCP-system, with the two tri-epitopic LCP-analogues assessed for their capacity to elicit systemic antigen-specific IgG antibodies. Overall, the thesis describes the development of a successful technique for synthesising highly pure, multi-epitopic lipopeptide vaccines for possible use in human clinical trials. In addition, the developed technique should be applicable for the synthesis of lipopeptide vaccines targeting other microorganisms, particularly where a multi-epitopic vaccine approach is warranted. While many studies have examined the LCP-systems capacity to elicit antigen-specific antibodies against attached peptide epitopes, few studies have examined its ability to elicit antigen-specific cytotoxic lymphocytes (CTLs). The ability to elicit antigen-specific CTL responses is important for the development of therapeutic vaccines against viral infections and cancer. Described is the synthesis of a series of LCP-systems incorporating a human papillomavirus type-16 (HPV-16) peptide antigen [HPV-16 E7(44-62)], containing a CTL, Bcell, and T-helper epitope. The vaccines were synthesised in order to investigate their capability to be used for the prevention and/or treatment of HPV-16 associated cervical cancer. Four mannose residues, both in O-acetylated and de-O-acetylated form, were attached to the vaccines to investigate the effect of potential dendritic cell mannose receptor targeting. The vaccines were assessed using a murine HPV-16 tumour model (TC-1 cells). This model demonstrated the capacity of the HPV-16 LCP-systems to reduce or eradicate TC-1 tumours when administered prior to tumour challenge (prophylactic), with mannose containing vaccines exhibiting greater efficacy. Overall, this study suggested that HPV-16 E7(44-62) LCP-systems had the capacity to elicit antigen-specific CTLs capable of clearing HPV-16 associated tumours when administered prior to tumour development. Based on this data, further research should be conducted to examine whether these vaccines are capable of eliminating or reducing the size of developed tumours, why mannose conjugation improved vaccine efficacy, and whether this was due to mannose receptor targeting.

 
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Created: Fri, 21 Nov 2008, 15:01:26 EST