# Presentation: 300213

## Division of Bacterial, Parasitic and Allergenic ProductsOVRR/CBER/FDA

**Division of Bacterial, Parasitic and Allergenic Products****OVRR/CBER/FDA**

## Laboratory Mission and Functions

- Research
- Review
- Post-licensure surveillance
- Inspection/compliance
- Lot release testing/protocol review
- Label/promotional activity review
- Consultations with outside organizations

**Assure Safe and Effective Products for Immunological**
**Control of Bacterial, Parasitic and Allergenic Agents **
**Affecting Human Health**

## DBPAP Role in Regulatory Review and Approval

**Pre-IND             IND                      ****	****	****License**

**Meeting with**
**sponsors to**
**provide guid-**
**ance**

**Rev. of orig. **
**Submission &**
**all subsequent**
**ammendments**
**Tech. Advice for**
**product and **
**assay development**
**Rev. product manf.**
**data & determin-**
**ation of prod. specs.**
**Meet with sponsors**

**Present prod.  To**
**Advisory Comm.**
**Meet with spon-**
**sors**
**Eval. Assays to **
**measure clinical**
**response to prod.**
**Eval.  product **
**characterization**
**methods & assays**

**Rev. of final prod.**
**manuf. process, in-**
**cluding in process**
**& final product specs.**
**Est. lot release protocols**
**for CBER product**
**release**
**Conduct pre-approval**
**inspection of the**
**facility**

## DBPAP Role in Regulatory Review and Approval

**Pre-IND             IND             License****	****	****Post Licensure**

**Review of Biological Deviation**
**reports from industry**
**Participation in biannual **
**inspections of licensed products**
**Review of post approval **
**commitments**
**Review of subsequent supplements**
**for changes to maufacture or**
**additional indications**
**Meet with sponsors**

## New or Improved Products Possible in the Next Ten Years

- Respiratory Pathogens
- Streptococcus pneumoniae
- Mycobacterium tuberculosis
- Pseudomonas aeruginosa
- Neisseria meningitidis A,B,C
- Group B Streptococci
- Bordetella pertussis
- Chlamydia pneumoniae
- Corynbacterium diphtheriae
- Non-typeable H. influenzae
- Moraxella catarrhalis
- Sexually Transmitted Pathogens
- Neisseria gonorrheae
- Chlamydia trachomatis

- Pathogens Encountered by Penetrating Inoculation
- Borrelia burgdorfi
- Plasmodium species
- Leishmania species
- Clostridium tetani
- Staphylococcus aureus
- Schistosoma species
- Trypanosoma cruzi
- Special Pathogens (BT)
- Bacillus anthracis
- Clostridium botulinum
- Franciscella tularensis
- Yersinia pestis

## New or Improved Products Possible in the Next Ten Years

- Diarrhea-Causing Pathogens
- Enterotoxigenic E. coli
- Shigella species
- Vibrio cholerae
- Campylobacter jejuni
- Other Mucosally-Trafficking Pathogens
- Clostridium difficile
- Salmonella typhi
- Mycobacterium leprae
- Helicobacter pylori
- STEC and EPEC

- Allergenic Antigens
- Latex
- Cockroach
- Short ragweed
- Skin Test Antigens
- PPD
- Coccoidian
- Leishmania

## Division of Bacterial, Parasitic and Allergenic Products (DBPAP)

**Laboratory of Immunobiochemistry**
**Jay Slater, M.D.-Chief**

**Immediate Office of the Director**
**Richard Walker, Ph.D.-Director**
**Vacant.-Deputy Director**
**Regulatory Staff      Administrative Staff**

**Laboratory of Methods Development and**
**Quality Control**
**Bruce Meade, Ph.D.-Chief**

**Laboratory of Respiratory and Special Pathogens**
**Drusilla Burns, Ph.D.-Chief**

**Laboratory of Bacterial Polysaccharides**
**Carl Frasch, Ph.D.-Chief**

**Laboratory of Enteric and Sexually **
**Transmitted Diseases**
**Dennis Kopecko, Ph.D.-Chief**

**Laboratory of Mycobacterial Diseases and **
**Cellular Immunology**
**Sheldon Morris, Ph.D.-Chief**

**Laboratory of Bacterial Toxins**
**Willie Vann, Ph.D.-Chief**

**Laboratory of Biophysics**
**Richard Pastor, Ph.D.-Chief**

## DBPAP Program Focus Areas

- Standardization of Assay Methods for Bacterial, Parasitic and Allergenic Substances
- LMDQC, LB, LIB, LP, LESTD, LBT, LRSP, LMDCI
- Pertussis and Other Toxin-Mediated Diseases
- LMDQC, LB, LBT, LRSP
- Mycobacterial and Other Intracellular parasites
- LMDCI
- Mucosal Pathogenesis and Immunization
- LESTD
- Allergenic Products and Allergenic Diseases
- LB, LIB
- Products to Combat Bioterrorism Agents
- LMDQC, LB, LESTD, LBT, LRSP, LMDCI

## Bioterrorism Program

- Research/Review for:
***B. anthracis***
***F. tularensis***
***Y. pestis***
- Botulinum toxin
- Research Areas:
- Genetic manipulation and regulation
- Virulence factors
- Vaccine improvement
- Immunologic assay standardization

-                 Cutaneous
-            anthrax infection

## Laboratory of Methods Development and Quality Control

**Areas of Research**
- Develop, standardize, and evaluate quality control methods for bacterial vaccines
- Develop, evaluate, and apply serological methods to measure immune response in vaccine trials
- Coordinate quality assurance activities within DBPAP and provide leadership in initiative to accredit CBER quality control testing laboratories

**                           ****Recent Milestones**
- Developed QC methods incorporated into WHO
-  acellular pertussis vaccines guidelines
- Leader effort to standardize pertussis immunoassays
- 9 publications evaluating safety and immunogenicity
-  of acellular pertussis vaccines

## Laboratory of Bacterial Polysaccharides

**Areas of Research**
- Characterization of immune responses to polysaccharide and conjugate vaccines
- Standardization of methods for relevant clinical application
- Development of novel physical and chemical methods for improved evaluation of licensed and experimental vaccines
- Characterization of innovative approaches to vaccine development, and evaluation of epidemiologic aspects of vaccine candidates

**                       ****Recent Milestones**
- Genetic typing method for gonococcal epidemiology
- Discovery of new gene in LPS biosynthesis
- Found that T cell peptides can serve as carrier
- protein in conjugate vaccine
- Found conjugation method can modify epitopes in
- polysaccharide conjugate vaccines

**Notes:**
Quantitation of antibody responses to:
Pneumococcal polysaccharides
Group B streptococcal polysaccharides
Development and distribution of international reference sera/reagents
Quantitation of polysaccharides in Haemophilis b and pneumococcal vaccines
Molecular typing methods for the pathogenic Neisseria

## Laboratory of Biophysics

**Areas of Research**
- Characterization of biopolymers (polysaccharides, proteins DNA) and macromolecular assemblies (vaccine/adjuvant complexes, membranes, micelles).
- High-end instrumentation, including  NMR, light scattering, mass spec.
- Computer simulation methods for molecular modeling and analysis of complex data.

**Recent Milestones**
** **Simulation of aquaporin in membrane
-  NMR based  3-D structure determination of carbohydrates and of peptides in micelles
- Synthesis of multiple antigen peptide (MAP)

## Laboratory of Respiratory and Special Pathogens

**Areas of Research**
***Bordetella pertussis*****, *****Bacillus anthracis*****, and *****Yersinia***** spp.**
- Characterization of Virulence Factors and
- 	Studies on Mechanism of Action
- Studies on Regulation of Gene Expression
- Animal Models of Infection

**          ****Recent Milestones**
** **Led the effort to license acellular
- pertussis vaccines
- Licensure of anthrax vaccine supplements
- Discovered secretion mechanism for
- pertussis toxin
- Elucidated mechanism of regulation of
*bvg*-repressed genes in *B. pertussis*

## Laboratory of Bacterial Toxins

**Areas of Research**
**Neurotoxins**
**Mechanism of toxin entry into nerve cells**
**Interaction of toxin with cellular components**
**Mechanism of toxin persistence**
**Corynebacteria**
**Identification and characterization of iron-regulated virulence factors in *****C. diphtheriae***
**Identification of iron utilization systems in *****Bacillus anthracis***
**Glycobiology**
**Mechanism of bacterial capsular polysaccharide biosynthesis**
**Binding of neurotoxins to glycolipid receptors**

**Recent Milestones**
** **Licensure of Botulinum type B for cervical dystonia
- Discovery of Heme oxygenase in *C. diphtheriae*

## The Laboratory of Mycobacterial Diseases and Cellular Immunology

**Areas of Research**
- Evaluation of protective innate and adaptive immune responses to intracellular bacteria
- Assessment of DNA vaccination strategies against tuberculosis
- Characterization of a unique family of tuberculosis proteins

-              **Recent Milestones**
- Development of in vitro culture systems for
- examining lymphocyte-mediated control of TB
-  and LVS growth
- Development of an effective combination
- TB DNA vaccine
- Identification of a TB protein involved in
- dissemination

## Laboratory of Enteric and Sexually Transmitted Diseases

**Laboratory of Enteric and Sexually Transmitted Diseases**

-            **Areas of Research**
**Invasion mechanisms of enteric pathogens**
**Genetic regulation of bacterial virulence genes**
**Mucosal immunity, dosing and adjuvants**
**Anthrax and *****Shigella***** - Genetic analysis and development of live attenuated *****Salmonella*****-vectored vaccines**

**                      ****Recent Milestones**
- Defined host and bacterial requirements of novel MT-dependent *C. jejuni *intestinal invasion system
- Defined DNA sites and transcriptional activator residues involved in BvgA-controlled virulence gene regulation
- Found evidence to refute Nanobacteria existence as putative pathogen and adventitious agent
- Constructed and patented oral anti-*S. sonnei *vaccine in *S. typhi *Ty21a live vector

## Laboratory of Immunobiochemistry

**Areas of Research**
**Allergen structure and function **
**Immunomodulation of allergic**
** ****	****responses**
**Chemokines and chemokine**
**	****receptors in the modulation of**
**	****immune responses**

- Development of a provisional US standard for latex
- Isolation and characterization of latex allergen Hev b 5
- Grass pollen allergen extract standardization
- Re-validation of competition ELISA to determine
-  potency of grass & mite allergen extracts
- Statistical basis for assignment of release limits
-  for standardized allergens
- Criteria for prioritization of allergens for standardization
- Assessment of potency of current cockroach allergen extracts

**Recent Milestones**

**Notes:**
Allergen structure and function
Structure of a new bee venom allergen, acid phosphatase
Role of glycosylation in immune responses to the bee venom allergen hyaluronidase
Improved physico-chemical methods of characterizing allergens (MALDI-TOF, circular dichroism)
Improving the stability of reference extracts

Immunomodulation of allergic responses
Epitopes of latex allergen Hev b 5
Role of lipopolysaccharides in allergic immune responses
Potency of commercially available cockroach allergen vaccines
Characterization of cockroach allergens
Multidrug resistance proteins and T-cell activation

Chemokines and chemokine receptors in the modulation of immune responses

## Challenges and Realities Facing Researcher/Reviewers

**Timing of workload determined by sponsor submissions, not by CBER**
**Funding levels uncertain from year to year; dependent upon appropriation process**
**Bureaucratic hurdles**

## Evaluation Components

**Evaluation Components**

**Review Individual**
**Review Program**
**Comment on Current and Future Directions**

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