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.

Public Health Relevance

In the developing world, diarrheal disease is the second leading cause of death in children under 5. Our goal is to develop a general diarrheal vaccine platform based on a technology that exploits the bacterial biofilm matrix. If successful, our vaccine could save the lives of millions of children in the developing world.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI115303-01A1
Application #
8969239
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Hall, Robert H
Project Start
2015-05-04
Project End
2017-04-30
Budget Start
2015-05-04
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Liao, Julie; Smith, Daniel R; Brynjarsdóttir, Jóhanna et al. (2018) A self-assembling whole cell vaccine antigen presentation platform. J Bacteriol :
Liao, Julie; Gibson, Jacob A; Pickering, Bradley S et al. (2018) Sublingual Adjuvant Delivery by a Live Attenuated Vibrio cholerae-Based Antigen Presentation Platform. mSphere 3: