Development of a live-attenuated, sublingual vaccine against diarrheal disease

Respiratory and diarrheal infections cause the majority of deaths in children under the age of 5 worldwide. In spite of this, vaccines targeting the most prevalent respiratory and diarrheal pathogens are either prohibitively expensive or non-existent. To fill this need, there is currently an intensive effort ongoing to develop vaccine platforms that can simultaneously, efficaciously, and inexpensively present multiple antigens to the mucosal immune system. With this in mind, we recently conceived of a novel antigen presentation platform that relies on genetic fusion of antigens to RbmA, a secreted protein that spontaneously adheres to the V. cholerae biofilm matrix. Our goal here is to vet our vaccine platform in an arena where there is great need and protective antigens have been identified. Therefore, we have first chosen to target the most common diarrheal infections. There is a need for a multivalent vaccine against diarrheal disease. 1.7 billion children worldwide contract a diarrheal infection each year, and 760,000 of these illnesses result in death. In the developing world, even non-fatal episodes of childhood diarrhea are correlated with life-altering sequelae such as undernutrition, growth delay, cognitive impairment, poor response to childhood vaccines, and increased risk of death from other causes. A recent study showed Shigella sp and enterotoxigenic Escherichia coli (ETEC) to be the most frequently isolated bacterial diarrheal pathogens at seven study sites in Asia and Africa, and history has shown us that epidemic cholera can be unpredictable, threatening populations that are unexpectedly displaced by natural disaster or civil unrest. However, there are no licensed vaccines against ETEC and Shigella. Protective antigens targeting ETEC and Shigella have been identified, and we now have preliminary evidence that a subset of these antigens is secreted and decorates the cell surface when fused to RbmA. In this proposal, we aim to establish that sublingual delivery of a live attenuated, whole cell V. cholerae vaccine decorated with ETEC and Shigella antigens elicits a robust and functional antibody response to these antigens. Our long-term goal is to participate in the effort to reduce mucosal infections worldwide by creating an easily modified, highly effective, conveniently delivered vaccine platform. Through the development of this diarrheal vaccine and the application of our vaccine platform to other prevalent mucosal infections, we hope to do our part to improve the quality of life worldwide.