Discovery of subunit vaccine candidates against glanders

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Glanders is a severe disease that already has a history of use as an effective bioweapon. It is naturally an equine disease but zoonotically transmits to humans. Even if quickly diagnosed as Burkholderia mallei, antibiotic treatments have shown low efficacy and disease control requires long regimes with multiple drugs. Even if the acute phase is survived, chronic infection can be suffered for as many as 20 years. The most rational plan of defense is a vaccine but to date none have been successfully developed. The immune evading tactics, including genomic fluidity, of this complex pathogen have rendered the performance of even live vaccines disappointing. New approaches are warranted. Therefore, we propose to identify a vaccine against glanders that is both more efficacious and safer than any previous ones. It will be designed from a collection of pathogen subunits that will include antigens that stimulate protective host immune responses yet exclude those that are immune evading or superfluous. This conceptually solves the problem that whole pathogen vaccines are likely to provide too many components (dilution of useful ones by not useful ones) and the problem of subunit vaccines which are likely to provide too few components (limited antigenic coverage). We will accomplish this by engaging in a genomic-scale search of all B. mallei coding sequences for protective antigens by expression library immunization in a murine model of glanders disease. Our specific approach to identifying this condensed filtrate of protective antigens is to 1) establish optimal molecular and animal-model protocols for conducting protection assays on a large-scale 2) build all of the coding sequences of B. mallei into a library of expression constructs for genetic immunization and 3) directly assay the protective capacity of every B. mallei coding sequence in vivo. At the conclusion of this project we will have generated protective subunits and that will be ready for delivery and modality optimization studies. Development of a B. mallei vaccine is anticipated to greatly facilitate development of a 8. pseudomalliei and 6. cepacia vaccines against these ancient diseases.