Delivery of anti-bacterial glycan vaccines to cells and subcellular compartments

Project 3: Formulation and Delivery of Multifunctional Glycan Vaccines Project Summary Virus-like particles (VLPs) are highly effective carriers of small-molecule structures that stimulate the immune system’s response to such epitopes. VLPs have repetitive structures and package TLR-activating RNA, are amenable to chemical and genetic modification, and are large enough to display different functional molecules in a manner that allows them to effectively their cellular targets. Our laboratories have developed Qb and PP7 capsid proteins for this purpose, learning the rules for effective glycan display to elicit the production of affinity-matured antibodies. We now seek to go beyond the limitations of previous designs by engaging various mechanisms of antigen presenting cell uptake, processing, and presentation, and by delivering VLP-based vaccines over extended periods of time to take advantage of feedback amplification of germinal center maturation by continuous antigen exposure. Exploratory studies will use a representative Staph. aureus trisaccharide conjugated to a robust class II peptide as the displayed unit, arraying this motif on VLPs engineered to simultaneously present ligands for DC-SIGN, Fcg receptors, or complement receptors known to enhance B cell response to peptide immunogens. We will also explore the recruitment of immune cells by the display of the natural antigen rhamnose as well as the release of glycopeptide or stimulatory molecules carried in the interior of the VLP. Simultaneously, we will develop and test a new class of degradable hydrogel materials that can be programmed to release vaccines over different periods of time. The outcome of this ambitious program should be a highly optimized and modular vaccine delivery platform that will be immediately applied to the generation of high-affinity antibodies against drug-resistant bacterial pathogens that pose immediate and long term threats to human health.