The Pacific-Southwest Center for Biodefense and Emerging Infectious Diseases Research will be a collaborative and synergistic consortium of investigators at several public and private institutions in Arizona, California, Hawaii, and Nevada. The overall goals of the Center are the following: (1) outstanding multidisciplinary and collaborative research on infectious diseases of biodefense or emerging public health importance; (2) secure dissemination of research findings and reagents within the Regional Centers for Excellence network and to local, state, and federal agencies; (3) timely translation of research findings into products and applications to detect, monitor, prevent, and treat these infections; (3) equitable provision of opportunities for new investigators to enter the field and development of innovative training programs to enhance biodefense readiness; and (4) on-call preparedness to respond to bioterrorism threats and emerging infectious disease emergencies. There will be eight program projects, each comprising 3-5 research projects, and six different core technology facilities in support of the programs. The research areas of the programs are anthrax vaccines, arboviruses, arenaviruses, botulinum toxin, Burkholderia, hantaviruses, plague, and tularemia. The cores facilities are animal models, clinical trials, mass spectroscopy and proteomics, DNA microarrays, new technologies for pathogen detection, and genome-wide protein arrays. The major criteria for outcome measurements are the following: (a) the quality and innovativeness of the science, as well as the extent to which new research funds and contracts are generated; (b) whether the milestones for translating research findings into products or other applications are attained; (c) the addition of new investigators in the field of biodefense research and the establishment of new collaborations with state and federal laboratories and industry; and (d) readiness for an emergency response. ? ? PROJECT 1: ANTHRAX: TARGETING THE BACILLUS ANTHRACIS CAPSULE FOR IMMUNOPROTECTION (Kozel, T. R.) ? ? PROJECT 1 DESCRIPTION (provided by applicant): Disseminated anthrax is characterized by both a massive bacteremia and toxemia. The bacteremic phase is made possible by the presence of a capsular polypeptide of poly-gamma-D-glutamic acid (PGA) that prevents phagocytosis of the bacterium. Current strategies for prevention of inhalation anthrax target the toxin through immunization with PA. There is a good possibility that targeting PA may be necessary but not sufficient for immunoprotection. This program targets PGA with the intent of reducing or eliminating the bacteremia that precedes toxemia. Thus, there is an opportunity for potent synergy between capsule- and toxin-targeted immunity. Preliminary studies developed monoclonal antibodies (mAbs) specific for PGA and demonstrated a high level of protection in a murine model of pulmonary anthrax. Additional preliminary studies demonstrated that PGA is a T-independent antigen whose immunogenicity is markedly increased by conjugation to an immunogenic protein carrier. Studies proposed for this program will examine further the immunologic basis of capsule-targeted immunity and the factors that influence such immunity. Project 1 (Kozel) will examine capsular architecture and the immunochemistry of capsule-antibody interactions using PGA-specific mAbs and will identify in vitro surrogates of protection in vivo. Project 2 (Lucas) will optimize formulation of a protein conjugate vaccine and will characterize the immune response to candidate vaccines. Project 3 (Murphy) will evaluate use of a CD40 agonist antibody to induce a rapid IgG antibody response to PGA for post-exposure immunization. Project 4 (Keim) will take advantage of the world's largest known and best characterized collection of B. anthracis isolates to examine strain diversity in capsule production and capsular gene expression. Project 5 will use murine and rabbit models of pulmonary anthrax to evaluate active and passive immunization that targets the capsule and the role of strain diversity in capsule-targeted immunity. Together, these studies will examine dramatically understudied aspects of the biology and immunology of anthrax-capsule structure, the molecular basis of antibody-capsule interactions, immunogenicity of the capsule, and the efficacy of capsule-targeted active, and passive immunization. ? ?
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