Biofilm Matrix-based Vaccines

In the developing world, diarrheal disease is the second leading cause of death in children under 5. The World Health Organization estimates that there are 3-5 million cases of the severe, dehydrating diarrheal disease cholera per year, of which 100,000-120,000 result in death. In addition, non-lethal infections represent a major nutritional setback for malnourished children. Two cholera vaccines, Shanchol and Dukoral, are currently licensed. Both include killed, whole Vibrio cholerae cells. In addition, Dukoral is administered with the purified B subunit of cholera toxin (CTB). While Dukoral is more expensive and difficult to administer than Shanchol, it provides protection against enterotoxigenic Escherichia coli (ETEC), the third most common cause of childhood diarrhea in the developing world. V. cholerae responds to specific environmental conditions by synthesizing an adhesive, exopolysaccharide- based extracellular matrix. Through proteomic analysis, we recently identified four secreted proteins that are associated with this matrix and showed that antigens such as CTB can be concentrated in the biofilm matrix by translational fusion to these matrix proteins. We propose that this exopolysaccharide matrix might serve as a platform on which to present diverse antigens and, thus, expand the range of the whole cell killed cholera vaccine. Here we propose to engineer such a biofilm matrix-boosted vaccine and to test its ability to elicit a protective immune response in mice. Our goal is to develop an affordable whole cell vaccine platform that exploits the bacterial biofilm matrix to increase protection against cholera as well as other common diarrheal pathogens.