1. Laboratory of Mycobacterial Diseases and Cellular Immunology Center for Biologics Evaluation and Research

2. Laboratory of Mycobacterial Diseases and Cellular Immunology Regulatory Responsibilities Research Accomplishments Activities within the Public Health Community

3. LMDCI – Regulatory Responsibilities Provide pre-clinical guidance Review IND submissions Review BLAs Inspect manufacturing facilities Review product labeling and advertising Review product lot release documents Assist in developing regulatory policy

4. LMDCI – Regulated Products VACCINES TB, malaria, tularemia, Lyme disease, Q fever, leishmania IMMUNOTHERAPEUTICS BCG, M. vaccae DIAGNOSTICS Skin test reagents, devices

5. Regulatory Accomplishments (2003 – 2007) Reviewed >700 IND submissions Participated in 12 pre-IND meetings Approved >30 BLA supplements Reviewed 20 Annual Reports Co-authored 3 FDA Guidance documents Made 18 presentations relevant to the regulatory process Co-organized a NIH/FDA workshop on TB vaccines

6. LMDCI Research Molecular basis of TB and Francisella pathogenesis Immune mechanisms associated with intracellular infections The effectiveness of novel TB vaccines Development of assays to characterize vaccine- related products

7. Research Sections of the Laboratory of Mycobacterial Diseases and Cellular Immunology Molecular Vaccines Mycopathogenesis Immune Mechanisms

8. LMDCI – Molecular Vaccines Section Current staff Sheldon Morris, P.I. Steven Derrick Amy Li Yang JaeHyun Lim Kris Kolibab Collaborators AECOM NIH/VRC NIH/NCI Aeras PHRI

9. LMDCI Research – Molecular Vaccines Section Characterization of live, attenuated M. tuberculosis strains Evaluation of novel TB DNA vaccines Development of assays to facilitate TB vaccine development

10. Molecular Vaccines – Significant Findings Demonstrated the effectiveness of the pro- apoptotic strategy for generating new attenuated M. tuberculosis vaccines Showed that BCG immunization protects against challenge by 10 different M. tuberculosis genotypes

11. Molecular Vaccines – Significant Findings (cont.) Developed pre-clinical assays for assessing the safety and potency of post-exposure and prophylactic TB vaccines Showed that the frequency of multifunctional T cells (expressing IFN- , TNF- , and IL2) correlate with the level of vaccine-induced protection against TB

12. LMDCI – Mycopathogenesis Section Current Staff Michael Brennan, P.I. Marcela Parra Nathalie Cadieux Prachi Singh Collaborators Institut Pasteur Univ. of MD Colorado State Univ. of Texas Catholic University

13. LMDCI Research – Mycopathogenesis Section Characterization of the Heparin-Binding Hemagglutinin cell surface protein of Mycobacterium tuberculosis Characterization of the novel PE/PE_PGRS multigene family of Mycobacterium tuberculosis

14. Mycopathogenesis Section – Significant Findings 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. 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.

15. Mycopathogenesis Section – Significant Findings (cont.) 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.

16. LMDCI – Immune Mechanisms Section Current staff Karen Elkins, P.I. Siobhan Cowley Anda Meierovics Roberto De Pascalis Alicia Chou Samantha Roberts Collaborators NIH/NIAID UNC – Chapel Hill UMD – Baltimore Univ. of Victoria UTSA Univ. of New Mexico

17. LMDCI Research – Immune Mechanisms Section Provide reagents and information for tularemia vaccine research Understand innate immune responses to intracellular bacteria, including F. tularensis and M. tuberculosis Define mechanisms by which B and T cells provide protection against intracellular bacteria, including F. tularensis and M. tuberculosis

18. Immune Mechanisms Section – Significant Findings 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. Non-CD4/CD8 “double-negative” T cells contribute substantially to adaptive immunity against Francisella and Mycobacteria in mice Francisella spp. contains a major pathogenicity island expressing ~25 virulence-related genes; important to the evaluation of LVS safety

19. Summary of LMDCI Research Accomplishments (2003- 2007) Publications – 45 (Nature Med., PNAS, J. Exp. Med., J. Clin. Invest.) Invited Presentations – 55 External Funding - 15

20. Involvement with the Public Health Community WHO GAVI committee WHO TB Vaccine Initiative Advisory Board WHO STOP/TB Working Group WHO Tularemia network Standard reagents for the WHO CDC skin test studies BTEP program [ US – Russia ]

21. Involvement with the Public Health Community NIH Study Sections NIH TB Vaccine Review Committee NIH Blue Ribbon Panels Advisory Committee for the Elimination of Tuberculosis Federal TB Task Force Editorial Boards for scientific journals Organization of major scientific meetings

22. LMDCI Outreach Activities Provide reagents and develop assays for tularemia and TB research Characterization and distribution of a Mtb challenge strain and standard BCG vaccine for pre-clinical vaccine testing Development of standard tuberculins Distribution of anti-HBHA Mabs and HBHA knock-out strains