McHugh, Catherine Jane; (2004) The delivery of DNA vaccines using particulate and non-particulate adjuvants. Doctoral thesis (Ph.D.), University College London.

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Abstract

The use of DNA for vaccination has many potential advantages over conventional vaccines. However, one of the drawbacks associated with this type of vaccination is the apparent lack of immunogenicity of plasmid DNA itself. Traditional aluminium-based adjuvants (alum) have been used to augment the immune response to DNA vaccines, however they have been implicated in allergic responses and the emerging condition macrophagic myofasciitis. The use of zinc oxide as an alternative to alum was investigated for protein antigens and plasmid DNA. An adjuvant effect was observed when zinc oxide was used in combination with other known adjuvants (polymeric microparticles or chitosan) to deliver protein antigen. Prime / boost strategies; priming with plasmid DNA and boosting with protein antigen have been shown to augment cellular and humoral immune responses to many antigens. The coadministration of plasmid DNA and protein antigen as either the priming or booster dose elicited a mixed humoral / cellular response, which was superior to the responses generated by the use of either component alone. Microparticles have been shown to augment the immune response to DNA vaccines, however the plasmid DNA can be degraded within the microparticles as a result of the acidic microclimate generated during polymer degradation. In this study, the co-encapsulation of magnesium hydroxide was observed to increase the stability of plasmid DNA inside the microparticles during polymer degradation. Microencapsulated MUC1 plasmid DNA was investigated for use as a cancer vaccine. Naked DNA has previously been shown to suppress tumour growth when administered intramuscularly. In this study, microencapsulated plasmid DNA delivered subcutaneously led to the greatest suppression of tumour growth. These studies show the initial feasibility of the approaches discussed to deliver plasmid DNA for vaccination and to act as potential adjuvants as an alternative to alum for DNA vaccines.

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