Understanding and Overcoming Barriers to Oral Immunization with Biomaterials and Applied Immunology

Thesis (Ph.D.)--University of Washington, 2019Immunization is an incredibly powerful intervention to provide protection from infectious diseases. The application of engineered materials for parenteral vaccination has illuminated pathways to increase vaccine uptake, traffic vaccines to lymphoid organs, and strategically activate cells, which may allow for the tailoring of specific immune responses and their magnitude. The importance of immunization at mucosal sites to generate protective immunity at the locations where pathogens most commonly invade the body is well-recognized. However, the majority of clinically licensed vaccines are not administered mucosally. Oral vaccines have the potential to reduce cost, improve compliance, and induce immunity at mucosal surfaces that are the first line of defense against infection. The gastrointestinal tract is highly evolved to efficiently digest and absorb nutrients without eliciting aberrant inflammation. Thus, these functions also limit the efficacy of immunization by the oral route. Specifically, these barriers include digestion of antigens and immunogenic epitopes by gastric and intestinal proteases, limited epithelial absorption of macromolecules, and the immunotolerant nature of the gut. While mechanisms responsible for the development of immunity or tolerance to ingested antigens are being illuminated, the application of materials with precise physiochemical properties may accelerate our understanding of immunity within the gastrointestinal tract. Insight into these immunological mechanisms can inform the design of next-generation oral vaccines. Here, we develop and evaluate a nanofiber vaccine platform to define and overcome immunological barriers associated with oral immunization. First, a drug delivery platform using emulsion electrospinning is developed for the oral delivery of protein therapeutics. We evaluate this platform for retention of protein bioactivity, pH-responsive protein release, and therapeutic shelf life. Next, we explore the use of adjuvants as a strategy to improve uptake of orally delivered vaccines through epithelial cell activation and recruitment of antigen presenting cells to the epithelium. In vivo immunization studies identify adjuvants capable of eliciting systemic and mucosal immune responses when delivered orally and also establish the initial differences in mechanism of action. Finally, the role of gastrointestinal digestion on immune responses to oral vaccines is investigated through the application of biomaterials carriers to provide selective protection of vaccines in certain gastrointestinal environments. We find that the susceptibility of immunogenic epitopes of a model protein antigen to be cleaved by gastrointestinal enzymes prevents the activation of epitope-specific T cell responses. The combination of protection from such cleavage through encapsulation in nanofibers and use of a potent mucosal adjuvant achieved expansion of epitope specific CD8+ T cells in the local intestinal tissue compared to digestion protection or adjuvant use alone. Overall, this project provides insight into the immunology of oral vaccines and develops a biomaterial-based strategy to elicit immune responses through the protection of immunogenic epitopes from digestion and co-delivery of specific mucosal adjuvants