# Presentation: 096413

## 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***
**DIAGNOSTICS**
**Skin 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**

_**Collaborators**_
**AECOM**
**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**