Laboratory of Mycobacterial Diseases and Cellular Immunology

Center for Biologics Evaluation and

Research

Laboratory of Mycobacterial Diseases and Cellular Immunology

• Regulatory Responsibilities

• Research Accomplishments

• Activities within the Public Health Community

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

LMDCI – Regulated Products

• VACCINES

TB, malaria, tularemia, Lyme disease,

Q fever, leishmania

• IMMUNOTHERAPEUTICS

BCG, M. vaccae

• DIAGNOSTICSSkin test reagents, devices

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

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

Research Sections of the Laboratory of Mycobacterial Diseases and

Cellular Immunology

• Molecular Vaccines

• Mycopathogenesis

• Immune Mechanisms

LMDCI – Molecular Vaccines Section

Current staff

Sheldon Morris, P.I.

Steven Derrick

Amy Li Yang

JaeHyun Lim

Kris Kolibab

CollaboratorsAECOM

NIH/VRC

NIH/NCI

Aeras

PHRI

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

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

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

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

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

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.

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.

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

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

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

Summary of LMDCI Research Accomplishments (2003- 2007)

• Publications – 45

(Nature Med., PNAS, J. Exp. Med., J. Clin. Invest.)

• Invited Presentations – 55• External Funding - 15

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 ]

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

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