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

2. 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

3. 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

4. DBPAP Role in Regulatory Review and Approval Pre-IND IND LicensePost 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. Evaluation Components Review Individual Review Program Comment on Current and Future Directions Return to agenda