Burkholderia mallei, the etiologic agent of glanders, cause severe disease in humans and animals and are a potential agent of biological warfare and terrorism. At present, there are no human or veterinary vaccines available for immunization against disease. One of the long term objectives of our research is the investigator to identify and characterize protective antigens expressed by B. mallei and use them to develop novel glanders vaccine candidates. Previous studies have demonstrated that the O-polysaccharide (OPS) expressed by B. mallei is both a virulence determinant and a protective antigen. Consequently, this carbohydrate moiety has become an important component of the various glanders subunit vaccine candidates that we are currently developing in our lab. Recently, we have shown that Burkholderia thailandensis, a closely related but non-pathogenic species, can be genetically manipulated to express B. mallei-like OPS antigens. These observations provide the basis for the proposed research. We hypothesize that OPS-based glanders vaccine candidates can be constructed safely and cost-effectively using antigens isolated from B. thailandensis OPS mutants. The goal of the current research proposal is to synthesize a variety of OPS-based glycoconjugates and evaluate their protective capacity in an animal model of glanders. To test this hypothesis, we have formulated the following specific aims:
Specific Aim 1. Construct OPS-based glycoconjugates for immunization against glanders. This will be accomplished by covalently linking B. thailandensis-derived OPS antigens to a variety of well characterized carrier proteins.
Specific Aim 2. Characterize the humoral immune responses of mice immunized with the OPS- based glycoconjugates. This will be accomplished by immunizing groups of mice with the glycoconjugates. Pre- and post-immune serum immunoglobulin titers will be quantitated via antigen specific enzyme-linked immunosorbent assay. Serum bactericidal and opsonophagocytic activities will also be assessed.
Specific Aim 3. Determine the protective capacity of OPS-based glycoconjugates in an animal model of glanders. To accomplish this, groups of mice will be vaccinated with the two most immunogenic glycoconjugates identified in Specific Aim 2. Mice will then be challenged by aerosol with virulent B. mallei and their survival monitored over the course of the experiment. Collectively, these studies will significantly increase our understanding regarding the protective capacity of OPS antigens and yield important clues towards the rational design of future glanders vaccines candidates.

Public Health Relevance

Burkholderia mallei is a select agent and a potential agent of biological warfare and terrorism. At present, there are no human or veterinary vaccines available for immunization against glanders. The proposed research will explore the feasibility of using novel OPS-based glycoconjugates to vaccinate against disease caused by this bacterial pathogen as well as characterize the importance of anti-OPS polyclonal antibody responses in this regard.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI088418-01
Application #
7872402
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Zou, Lanling
Project Start
2010-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$210,089
Indirect Cost
Name
University of South Alabama
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Heiss, Christian; Burtnick, Mary N; Roberts, Rosemary A et al. (2013) Revised structures for the predominant O-polysaccharides expressed by Burkholderia pseudomallei and Burkholderia mallei. Carbohydr Res 381:6-11
Burtnick, Mary N; Heiss, Christian; Roberts, Rosemary A et al. (2012) Development of capsular polysaccharide-based glycoconjugates for immunization against melioidosis and glanders. Front Cell Infect Microbiol 2:108
Burtnick, Mary N; Heiss, Christian; Schuler, A Michele et al. (2012) Development of novel O-polysaccharide based glycoconjugates for immunization against glanders. Front Cell Infect Microbiol 2:148
Heiss, Christian; Burtnick, Mary N; Black, Ian et al. (2012) Detailed structural analysis of the O-polysaccharide expressed by Burkholderia thailandensis E264. Carbohydr Res 363:23-8