Description:
OBJECTIVE: This topic solicits the development of serotype-specific, high-affinity monoclonal antibodies that target Burkholderia mallei and Burkholderia pseudomallei and/or O-polysaccharide and capsular polysaccharide. DESCRIPTION: Burkholderia mallei, causative agent of glanders, and Burkholderia pseudomallei, causative agent of melioidosis, are recognized as potential biological warfare threat agents. During World War I, glanders was believed to have been spread deliberately by German agents to infect large numbers of Russian horses and mules on the Eastern Front, which resulted in humans acquiring the infection. In addition, the Japanese deliberately infected horses, civilians, and prisoners of war with glanders at the Pinfang (China) Institute during World War II. The Soviet Union is also believed to have weaponized Burkholderia as a potential biological warfare (BW) agent after World War II. Currently, there are no licensed prophylactic countermeasures to prevent infections caused by these intracellular pathogens. Limited efforts to develop B. mallei and B. pseudomallei vaccines comprised of O-polysaccharide- (OPS) and capsular polysaccharide (CPS) have had limited success. However, given the importance of these targets in protective immunity, identification of alternative strategies to develop prophylactic countermeasures against Burkholderia is warranted. In particular, the development of methods to isolate high-affinity OPS- and CPS-specific monoclonal antibodies is anticipated to result in the development of a prophylactic countermeasure against these weaponizable agents. PHASE I: It is anticipated that studies in this initial phase will focus on the development of a reagents and an animal model system that will enable the production of B. mallei and/or B. pseudomallei OPS- and CPS-specific antibody responses. Use of attenuated or non-pathogenic strains of Burkholderia during this phase is recommended, so long as the selected strains expression antigenically-identical OPS and CPS to those expressed by wild-type B. mallei and B. pseudomallei. It is important that offerors ensure strain-specific antigenic epitopes in the B. mallei and B. pseudomallei OPS- and CPS are maintained. PHASE II: It is anticipated that this phase will focus on isolation of OPS- and CPS-specific hybridoma clones and demonstration of specificity using in vitro immunochemistry methods. Studies to enhance affinity OPS- and CPS-specific monoclonal antibodies are also within the scope of this phase. It is also envisaged that if an acceptable animal model is available, an initial challenge study will be conducted as part of a down-select process to identify antibodies with the highest affinity, specificity and potency. All animal studies will be conducted under the appropriate containment and review, and at an accredited location. PHASE III: Studies in this phase may focus on monoclonal antibody humanization and manufacturing process development. This phase is also expected to include a demonstration that the humanized monoclonal antibodies maintained specificity and affinity for the respective OPS and CPS targets. After successful completion of the aforementioned milestone and if the monoclonal antibodies merit further development, cGMP manufacturing will be conducted. Material produced during cGMP manufacturing will be used to assess toxicity and potency in an appropriate animal model. Proof-of-concept efficacy studies in non-human primates (NHPs), if an acceptable model is available, are also within the scope of this phase. Challenge studies will be conducted under appropriate biosafety containment conditions. Milestones: Each phase of the project will be milestone driven. The Principal Investigator will propose milestones prior to starting any phase of the project. Deliverables: Major milestone schedule and decision tree for project Monthly reports in the format of a slide deck and teleconference Quarterly written reports (in addition to slide deck and teleconference) Final report including major accomplishments and proposed path forward PHASE III DUAL USE APPLICATIONS: Successful development of effective B. mallei and B. pseudomallei monoclonal antibodies will provide important countermeasures for the warfighter and have broader commercial potential as a public health tool in diagnostics and prophylaxis in endemic regions to control the spread of this emerging pathogen.
