In vitro and in vivo evaluation of novel biodegradable polymer adjuvants for vaccine delivery

摘要

Infectious disease remains a constant threat to the health of man and his animals. Vaccination has been declared one of the medical triumphs of the twentieth century. For man or animal, vaccination remains the best and most cost effective means for the prevention of disease. Many novel vaccine antigens are rationally designed peptides and recombinant proteins which require the use of adjuvants or other immune enhancers to increase efficacy. Currently, there is a need not only for single dose vaccines (to improve patient compliance and improve animal welfare by reducing livestock handling) but also adjuvants that preserve the immunogenicity of the protein during encapsulation, storage and release and enhance the host\u27s immune response to the antigen. Biodegradable polyanhydrides have shown many characteristics that fulfill these ideals but further study is needed. The studies presented in this dissertation were undertaken with the intent to define the interaction(s) between novel biodegradable polyanhydride microspheres and the host immune system. In order to address the role of polyanhydride chemistry on murine dendritic cells (DCs) in vitro, DC activation by polyanhydride microspheres was evaluated by surface marker expression and cytokine secretion. Several murine models, including a transgenic T cell transfer model, were used to evaluate the induction of antigen-specific immune response by immunizing mice with microsphere adjuvanted ovalbumin. The in vivo studies using ovalbumin encapsulated microspheres were carried out in three mouse strains to evaluate the memory or recall response induced by a single microsphere vaccination and to evaluate strain differences in response to the polyanhydride microspheres. Finally, microspheres loaded with the protease digested vaccine antigen derived from Brachyspira hyodysenteriae was used to vaccinate mice and pigs prior to disease challenge studies designed to evaluate the induction of protective immunity. Taken together, this body of work further adds to our knowledge of polyanhydride microspheres and their potential use as vaccine carriers.