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    1. 1. Laboratory of Mycobacterial Diseases and Cellular Immunology <ul><li>Center for Biologics Evaluation and Research </li></ul>
    2. 2. Laboratory of Mycobacterial Diseases and Cellular Immunology <ul><li>Regulatory Responsibilities </li></ul><ul><li>Research Accomplishments </li></ul><ul><li>Activities within the Public Health Community </li></ul>
    3. 3. LMDCI – Regulatory Responsibilities <ul><li>Provide pre-clinical guidance </li></ul><ul><li>Review IND submissions </li></ul><ul><li>Review BLAs </li></ul><ul><li>Inspect manufacturing facilities </li></ul><ul><li>Review product labeling and advertising </li></ul><ul><li>Review product lot release documents </li></ul><ul><li>Assist in developing regulatory policy </li></ul>
    4. 4. LMDCI – Regulated Products <ul><li>VACCINES </li></ul><ul><li>TB, malaria, tularemia, Lyme disease, </li></ul><ul><li>Q fever, leishmania </li></ul><ul><li>IMMUNOTHERAPEUTICS </li></ul><ul><li>BCG, M. vaccae </li></ul><ul><li>DIAGNOSTICS </li></ul><ul><ul><li>Skin test reagents, devices </li></ul></ul>
    5. 5. Regulatory Accomplishments (2003 – 2007) <ul><li>Reviewed >700 IND submissions </li></ul><ul><li>Participated in 12 pre-IND meetings </li></ul><ul><li>Approved >30 BLA supplements </li></ul><ul><li>Reviewed 20 Annual Reports </li></ul><ul><li>Co-authored 3 FDA Guidance documents </li></ul><ul><li>Made 18 presentations relevant to the regulatory process </li></ul><ul><li>Co-organized a NIH/FDA workshop on TB vaccines </li></ul>
    6. 6. LMDCI Research <ul><li>Molecular basis of TB and Francisella pathogenesis </li></ul><ul><li>Immune mechanisms associated with intracellular infections </li></ul><ul><li>The effectiveness of novel TB vaccines </li></ul><ul><li>Development of assays to characterize vaccine-related products </li></ul>
    7. 7. Research Sections of the Laboratory of Mycobacterial Diseases and Cellular Immunology <ul><li>Molecular Vaccines </li></ul><ul><li>Mycopathogenesis </li></ul><ul><li>Immune Mechanisms </li></ul>
    8. 8. LMDCI – Molecular Vaccines Section <ul><li>Current staff </li></ul><ul><li>Sheldon Morris, P.I. </li></ul><ul><li>Steven Derrick </li></ul><ul><li>Amy Li Yang </li></ul><ul><li>JaeHyun Lim </li></ul><ul><li>Kris Kolibab </li></ul><ul><li>Collaborators </li></ul><ul><li>AECOM </li></ul><ul><li>NIH/VRC </li></ul><ul><li>NIH/NCI </li></ul><ul><li>Aeras </li></ul><ul><li>PHRI </li></ul>
    9. 9. LMDCI Research – Molecular Vaccines Section <ul><li>Characterization of live, attenuated </li></ul><ul><li>M. tuberculosis strains </li></ul><ul><li>Evaluation of novel TB DNA vaccines </li></ul><ul><li>Development of assays to facilitate TB vaccine development </li></ul>
    10. 10. Molecular Vaccines – Significant Findings <ul><li>Demonstrated the effectiveness of the pro-apoptotic strategy for generating new attenuated M. tuberculosis vaccines </li></ul><ul><li>Showed that BCG immunization protects against challenge by 10 different M. tuberculosis genotypes </li></ul>
    11. 11. Molecular Vaccines – Significant Findings (cont.) <ul><li>Developed pre-clinical assays for assessing the safety and potency of post-exposure and prophylactic TB vaccines </li></ul><ul><li>Showed that the frequency of multifunctional T cells (expressing IFN-  , TNF-  , and IL2) correlate with the level of vaccine-induced protection against TB </li></ul>
    12. 12. LMDCI – Mycopathogenesis Section <ul><li>Current Staff </li></ul><ul><li>Michael Brennan, P.I. </li></ul><ul><li>Marcela Parra </li></ul><ul><li>Nathalie Cadieux </li></ul><ul><li>Prachi Singh </li></ul><ul><li>Collaborators </li></ul><ul><li>Institut Pasteur </li></ul><ul><li>Univ. of MD </li></ul><ul><li>Colorado State </li></ul><ul><li>Univ. of Texas </li></ul><ul><li>Catholic University </li></ul>
    13. 13. LMDCI Research – Mycopathogenesis Section <ul><li>Characterization of the Heparin-Binding Hemagglutinin cell surface protein of Mycobacterium tuberculosis </li></ul><ul><li>Characterization of the novel PE/PE_PGRS multigene family of Mycobacterium tuberculosis </li></ul>
    14. 14. Mycopathogenesis Section – Significant Findings <ul><li>Differences in expression of certain PE_PGRS genes during infection indicate that they provide a novel mechanism of antigenic variation used by M. tuberculosis to evade the host immune response . </li></ul><ul><li>PE-PGRS proteins interact with mitochondria which may lead to host cell injury and death and provides M. tuberculosis with a mechanism for escaping macrophages and other infected host cells. </li></ul>
    15. 15. Mycopathogenesis Section – Significant Findings (cont.) <ul><li>A PE antigen has been identified that elicits a strong TH1-like response and protects against M. tuberculosis challenge in an aerosol TB mouse model. This PE antigen (MaPE) is being pursued as a new TB vaccine candidate. </li></ul>
    16. 16. LMDCI – Immune Mechanisms Section <ul><li>Current staff </li></ul><ul><li>Karen Elkins, P.I. </li></ul><ul><li>Siobhan Cowley </li></ul><ul><li>Anda Meierovics </li></ul><ul><li>Roberto De Pascalis </li></ul><ul><li>Alicia Chou </li></ul><ul><li>Samantha Roberts </li></ul><ul><li>Collaborators </li></ul><ul><li>NIH/NIAID </li></ul><ul><li>UNC – Chapel Hill </li></ul><ul><li>UMD – Baltimore </li></ul><ul><li>Univ. of Victoria </li></ul><ul><li>UTSA </li></ul><ul><li>Univ. of New Mexico </li></ul>
    17. 17. LMDCI Research – Immune Mechanisms Section <ul><li>Provide reagents and information for tularemia vaccine research </li></ul><ul><li>Understand innate immune responses to intracellular bacteria, including F. tularensis and M. tuberculosis </li></ul><ul><li>Define mechanisms by which B and T cells provide protection against intracellular bacteria, including F. tularensis and M. tuberculosis </li></ul>
    18. 18. Immune Mechanisms Section – Significant Findings <ul><li>Membrane TNF-  is a major mediator of the T-cell mediated control of Francisella or M. tuberculosis intramacrophage growth, but IFN-  has only a modest role and is unlikely to be a reliable correlate. </li></ul><ul><li>Non-CD4/CD8 “double-negative” T cells contribute substantially to adaptive immunity against Francisella and Mycobacteria in mice </li></ul><ul><li>Francisella spp. contains a major pathogenicity island expressing ~25 virulence-related genes; important to the evaluation of LVS safety </li></ul>
    19. 19. Summary of LMDCI Research Accomplishments (2003- 2007) <ul><li>Publications – 45 </li></ul><ul><li>(Nature Med., PNAS, J. Exp. Med., J. Clin. Invest.) </li></ul><ul><li>Invited Presentations – 55 </li></ul><ul><li>External Funding - 15 </li></ul>
    20. 20. Involvement with the Public Health Community <ul><li>WHO GAVI committee </li></ul><ul><li>WHO TB Vaccine Initiative Advisory Board </li></ul><ul><li>WHO STOP/TB Working Group </li></ul><ul><li>WHO Tularemia network </li></ul><ul><li>Standard reagents for the WHO </li></ul><ul><li>CDC skin test studies </li></ul><ul><li>BTEP program [ US – Russia ] </li></ul>
    21. 21. Involvement with the Public Health Community <ul><li>NIH Study Sections </li></ul><ul><li>NIH TB Vaccine Review Committee </li></ul><ul><li>NIH Blue Ribbon Panels </li></ul><ul><li>Advisory Committee for the Elimination of Tuberculosis </li></ul><ul><li>Federal TB Task Force </li></ul><ul><li>Editorial Boards for scientific journals </li></ul><ul><li>Organization of major scientific meetings </li></ul>
    22. 22. LMDCI Outreach Activities <ul><li>Provide reagents and develop assays for tularemia and TB research </li></ul><ul><li>Characterization and distribution of a Mtb challenge strain and standard BCG vaccine for pre-clinical vaccine testing </li></ul><ul><li>Development of standard tuberculins </li></ul><ul><li>Distribution of anti-HBHA Mabs and HBHA knock-out strains </li></ul>

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