Laboratory of Bacterial Toxins
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Transcript of 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