Laboratory of Bacterial Toxins

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 ImmunologicalControl of Bacterial, Parasitic and Allergenic Agents Affecting Human Health

DBPAP Role in Regulatory Review and Approval

Pre-IND IND License

•Meeting withsponsors toprovide guid-ance

•Rev. of orig. Submission &all subsequentammendments

•Tech. Advice forproduct and assay development

•Rev. product manf.data & determin-ation of prod. specs.

•Meet with sponsors

•Present prod. ToAdvisory Comm.

•Meet with spon-sors

•Eval. Assays to measure clinicalresponse to prod.

•Eval. product characterizationmethods & assays

•Rev. of final prod.manuf. process, in-cluding in process& final product specs.

•Est. lot release protocolsfor CBER productrelease

•Conduct pre-approvalinspection of thefacility

DBPAP Role in Regulatory Review and Approval

Pre-IND IND License Post Licensure

•Review of Biological Deviationreports from industry

•Participation in biannual inspections of licensed products

•Review of post approval commitments

•Review of subsequent supplementsfor changes to maufacture oradditional indications

•Meet with sponsors

Possible New or Improved Products

• Respiratory Pathogens– Streptococcus pneumoniae– Mycobacterium tuberculosis– Pseudomonas aeruginosa– Neisseria meningitidis A,B,C,Y,W125– 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

Possible New or Improved Products

• 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

– Coccidioidin

– Leishmania

Division of Bacterial, Parasitic and Allergenic Products (DBPAP)

Laboratory of ImmunobiochemistryJay Slater, M.D.-Chief

Immediate Office of the Director

Richard Walker, Ph.D.-DirectorMilan Blake, Ph.D.-Deputy Director

Regulatory Staff Administrative Staff

Laboratory of Methods Development andQuality Control

Bruce Meade, Ph.D.-Chief

Laboratory of Respiratory and Special Pathogens

Drusilla Burns, Ph.D.-Chief

Laboratory of Bacterial Polysaccharides

Milan Blake, Ph.D.- Acting 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 BiophysicsRichard Pastor, Ph.D.-Chief

Laboratory of Methods Development and Quality Control

Research activities:• Develop and evaluate

– Quality control methods for bacterial vaccines

– Serological methods for immune response measurement

– Animal models• Gastrointestinal anthrax• Bioassays for potency

and toxicity

• Issues and observations– Recruiting for 1 position– Lab chief

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.

Issues and Observations•Integration as CBER high technology resource under review

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

Issues and Observations•Polysaccharide immunology group added•Mucosal immunity effort recommended•Lab go-away to develop focus and transition strategy

LABORATORY OF BACTERIAL TOXINS

Areas of Research• Neurotoxins Group

– Mechanism of toxin entry into nerve cells

– Interaction toxin with cellular components

– Mechanism of toxin persistence• Corynebacteria Group

– Identification and characterization of iron regulated virulence factors in C. diphtheria

• Glycobiology Group

– Mechanism of bacterial capsular polysaccharide biosynthesis

– Binding of neurotoxins to glycolipid receptors

Issues and Observations•Development of neurotoxin assays•Decreased emphasis on B. anthracis•Increased emphasis on vaccine design

Laboratory of Respiratory and Special Pathogens

Areas of Research• Bordetella pertussis, Bacillus anthracis, and Yersinia spp.

• Characterization of Virulence Factors andStudies on Mechanism of Action

• Studies on Regulation of Gene Expression

• Animal Models of Infection

The Laboratory of Mycobacterial Diseases and Cellular Immunology

Areas of Research

• Evaluation of protective innate and adaptive immune responses to intracellular bacteria

• Assessment of live attenuated TB vaccine strains and DNA vaccination strategies against tuberculosis

• Characterization of a unique family of tuberculosis proteins Issues and Observations

•Malaria effort lacks investigator•SVC recommended recruitment of MDwith research background in human immuneresponse to study correlations of human andanimal responses

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

Issues and Observations•Mucosal Immunity group added•STD work moved to LBP

Laboratory of Immunobiochemistry

Areas of Research

• Allergen structure and function

• Immunomodulation of allergic

responses

• Chemokines and chemokine

receptors in the modulation of

immune responses

Issues and Observations• Cockroach allergen standardization: collaboration with NIAID• Increased attention to

human T cell responses to allergensrole of endotoxin in the safety and efficacy of allergen vaccineshuman antibody responses to cockroach allergens

• Decreased emphasis onlatex allergenshymenoptera allergens

Promotion Plan

S e n io r B io m e d ica l R e sea rch S e rv iced o c to ra l sc ie n tis ts o f e xce p tio n a l d is t inc tion

a b ove G S -15 leve l

S e n io r Inve s tig a to rd o c to ra l, G S -1 3 to G S -15

In de pe nd ent

S e n io r S ta ff F e llowp o st d oc to ra l up to 7 ye a rs

S ta ff F e llowp o st d oc to ra l up to 4 ye a rs

S ta ff S c ien tistd o c to ra l o r n o n-d o cto ra l

G S -1 3 a n d a bo ve

S u p po rt S c ien tistn o n -d o cto ra lG S -1 2 m a x.

In d ep e nd en t an d N o n-Ind e pe n de n t C are er T ra cks

DBPAP Funding

• Salary and OVHD from FDA base

• Expendibles and Equipment– General FDA Appropriation

• Division operating funds• Special needs funds• Per capita distribution of remainder evenly among staff involved

– CT Funds• Handled similarly to general appropriation• Divided among CT staff

– Extramural Funds• Go directly to recipient

– Year End Funds

Challenges and Realities Facing Researcher/Reviewers

• Funding levels uncertain from year to year; dependent upon appropriation process

• Bureaucratic hurdles

• Timing of workload determined by sponsor submissions, not by CBER

Evaluation Components

• Review Individual

• Review Program

• Comment on Current and Future Directions

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

• New Technologies for Characterization of Biologics– LB

Laboratory of Methods Development and Quality Control

Areas of Research

• Develop and evaluate

– Quality control methods for bacterial vaccines

– Serological methods for immune response measurement

– Animal models

• Gastrointestinal anthrax

• Bioassays for potency and toxicity

Issues and Observations•Recruiting for 1 position•Lab Chief

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