Laboratory of Mycobacterial Diseases and Cellular Immunology

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Laboratory of Mycobacterial Diseases and Cellular
Immunology

• Center for Biologics Evaluation and Research

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Laboratory of Mycobacterial Diseases and Cellular
Immunology

• Regulatory Responsibilities
• Research Accomplishments
• Activities within the Public Health Community

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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

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LMDCI Regulated Products

• VACCINES
• TB, malaria, tularemia, Lyme disease,
• Q fever, leishmania
• IMMUNOTHERAPEUTICS
• BCG, M. vaccae
• DIAGNOSTICS
• Skin test reagents, devices

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Regulatory Accomplishments (2003 2007)

• Reviewed gt700 IND submissions
• Participated in 12 pre-IND meetings
• Approved gt30 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

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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

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Research Sections of the Laboratory of
Mycobacterial Diseases and Cellular Immunology

• Molecular Vaccines
• Mycopathogenesis
• Immune Mechanisms

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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

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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

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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

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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-g, TNF-a, and IL2)
  correlate with the level of vaccine-induced
  protection against TB

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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

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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

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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.

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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.

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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

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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

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Immune Mechanisms Section Significant Findings

• Membrane TNF- a is a major mediator of the T-cell
  mediated control of Francisella or M.
  tuberculosis intramacrophage growth, but IFN-g
  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

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Summary of LMDCI Research Accomplishments (2003-
2007)

• Publications 45
• (Nature Med., PNAS, J. Exp. Med., J. Clin.
  Invest.)
• Invited Presentations 55
• External Funding - 15

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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

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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

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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