Our broad, long-term objectives are to develop human vaccines for the prevention of glanders caused by Burkholderia mallei, and for melioidosis caused by B. pseudomallei. In the currently proposed studies, we will examine the immune response to B. mallei and B. pseudomallei vaccine candidates in small animals and in the horse, and we will determine the efficacy of immunotherapeutic interventions in challenge studies with an aim toward developing plans for extending the results to a human vaccine. The major hypothesis being evaluated is that immunotherapeutic intervention is a viable approach for the prevention of glanders caused by B. mallei and for the prevention of melioidosis caused by the closely related organism, B. pseudomallei. We have made significant progress in the last number of years in the identification of the virulence determinants of B. mallei and B. pseudomallei which we hypothesize will be excellent candidates as components of conjugate vaccines. Of particular note are two polysaccharide structures present on the surface of both of these organisms which are critical for the virulence of both of these. These are an extracellular polysaccharide capsule (CPS) and lipopolysaccharide O-antigen (OPS). We propose to conjugate the CPS and OPS polysaccharides to six carrier proteins shown or predicted to play important roles in pathogenesis by B. pseudomallei and B. mallei. CPS and OPS will also be conjugated to recombinant exotoxin A, a proven efficacious carrier protein of polysaccharide-based vaccines. We believe that this strategy will identify a vaccine that will protect against B. mallei challenge in a mouse model of infection as well as against B. mallei challenge in the horse which is the natural host for the organism. If shown to be successful in preventing glanders, this vaccine will be subsequently used in human trials to investigate protection against melioidosis in Australia and Thailand.
Our specific aims are: 1. To evaluate the immune response to CPS and OPS conjugated to the carrier proteins in mice and in the horse. 2. To determine the ability of CPS and OPS conjugated to the carrier proteins to protect against B. mallei challenge in a BALB/c mouse model of infection. 3. To test the hypothesis that CPS and OPS conjugates which are protective in BALB/c mice will also protect the horse against B. mallei challenge. We believe that immunotherapeutic intervention is a viable approach for the prevention of glanders caused by B. mallei and for the prevention of melioidosis caused by the closely related organism, B. pseudomallei. Since B. mallei and B. pseudomallei are of significance as agents of bioterrorism (Category B, Centers for Disease Control, U.S.) and biological warfare, the development of effective vaccines are of particular concern. Vaccines will also have considerable multi-use potential since the diseases caused by these organisms are recognized as emerging infectious diseases in various areas of the world.
|Mulye, Minal; Bechill, Michael P; Grose, William et al. (2014) Delineating the importance of serum opsonins and the bacterial capsule in affecting the uptake and killing of Burkholderia pseudomallei by murine neutrophils and macrophages. PLoS Negl Trop Dis 8:e2988|
|Woodman, Michael E; Worth, Randall G; Wooten, R Mark (2012) Capsule influences the deposition of critical complement C3 levels required for the killing of Burkholderia pseudomallei via NADPH-oxidase induction by human neutrophils. PLoS One 7:e52276|