Overview of Laboratory of Bacterial Polysaccharides

1
Overview of Laboratory of Bacterial
Polysaccharides

• By
• Willie F. Vann, Chief LBP

2
Description of the Laboratory of Bacterial
Polysaccharides

• The Laboratory of Bacterial Polysaccharides
  investigates the biochemistry, biology,
  chemistry, and immunology of virulence factors of
  encapsulated bacteria.
• These virulence factors include capsular
  polysaccharides, lipopolysaccharides, and outer
  membrane proteins.

3
Description of the Laboratory of Bacterial
Polysaccharides (continued)

• The Laboratory of Bacterial Polysaccharides has
  review responsibility for submissions related to
  polysaccharide and polysaccharide conjugate
  vaccines in addition to non-capsular immunogens
  of encapsulated pathogens.

4
Chronology of Laboratory of Bacterial
Polysaccharides

• 2002
• Last Site Visit
• 2004
• CE Frasch steps down as Lab Chief
• MS Blake becomes Acting Lab Chief
• 2006
• WF Vann appointed Lab Chief
• Glycobiology Group of Lab of Bacterial Toxins
  joined Lab of Bacterial Polysaccharides
• NMR and Mass Spectrometry groups of Lab of
  Biophysics joined Lab of Bacterial Polysaccharides

5
Current Organization of the Laboratory of
Bacterial Polysaccharides
6
CURRENT RESEARCH STAFF
7
(No Transcript)
8
(No Transcript)
9
Areas of Research

• Structure and conformation of capsular
  polysaccharides
• Biosynthesis of capsular polysaccharides
• Role of non-capsular antigens in protection
• Interaction of the capsular polysaccharides with
  the immune system
• Development of methodology for analysis of
  conjugate vaccines

10
Relevance of Research Program to CBER Mission

• The Laboratory of Bacterial Polysaccharides has
  regulatory responsibility for vaccines against
  encapsulated bacteria and products containing
  bacterial polysaccharides
• The overall goal of the research program of the
  LBP is to understand the virulence factors that
  are components of vaccines against bacterial
  pathogens.

11
Relevance of Research Program to CBER Mission
(continued)

• The research program of the Laboratory of
  Bacterial Polysaccharides is directed toward
  understanding the physical, chemical, and
  immunological properties of bacterial
  polysaccharides, and polysaccharide conjugate
  vaccines
• The knowledge and expertise gained in this
  research endeavor provide a scientific basis for
  our decisions related to the review of
  manufacturing, purity, potency, and safety of
  carbohydrate containing vaccines.

12
Some Significant Achievements

• Development of Efficient Method for Meningococcal
  Group A Conjugate Vaccine Synthesis
• Vaccine in MVP/WHO Sponsored Phase II Clinical
  Trial

13
Meningococcal Group A Conjugate Vaccine
Projectmanaged by CE Frasch - CBER M. LaForce
MVP
Gates Foundation
Daron Freedberg and Scott Norris contributed to
analysis during development
14
Some Significant AchievementsAnalytical
Biochemistry ChaoMing Tsai, PI

• Developed HPAEC method for quantitation of
  phosphate and acetylation in polysaccharide
  vaccines
• Characterized the lgtH gene of Neisseria LOS gene
  cluster
• Demonstrated that the LOS of commensal N.
  polysaccharea is similar to LOS of meningococcal
  pathogen

15
Some Significant AchievementsMolecular
Epidemiology Margaret Bash

• Developed and applied molecular methods to study
  PorB diversity
• Horizontal genetic exchange (mosaicism)
  predominates
• Persistence of PorB variable region sequence
  types indicates diversification is constrained
• Identified survival advantages associated with
  PorB types
• Relevant to development and evaluation of broadly
  protective OMP vaccines

16
Some Significant AchievementsCellular
Immunology-Mustafa Akkoyunlu, PI

• Interactions of bacterial capsular
  polysaccharides with innate immune system.
• Neisseria meningitidis type C polysaccharide
  binding to CD14 and LBP inhibits meningococcal
  LPS mediated cell activation
• Modulation of BAFF/APRIL system molecules by
  microbial products.
• Decreased expression of TACI on newborn mouse B
  cells may to be responsible for the impaired
  response of newborns to polysaccharide antigens.
• Toll-like receptor agonists, CpG DNA and LPS,
  strongly upregulate TACI expression on B cells.

17
Some Significant Achievements Structural
Biology-Daron Freedberg, PI

• 1. On cell NMR In-vivo antigen characterization
  by NMR
• Mening B PS structure on cells Mening B PS
  structure in vaccine

mmonomer ppolymer
2. Carbohydrate 3D Structure Sucrose
18
Licensed Product Responsibility
Vaccine Class Product Manufacturer
Polysaccharide Pneumococcal 23-valent Wyeth
Merck
Meningococcal tetravalent Sanofi Pasteur
Typhoid Vi Sanofi Pasteur

Conjugate Haemophilus influenzae type b Wyeth
Sanofi Pasteur
Merck (2)
Pneumococcal heptavalent Wyeth
Meningococcal tetravalent Sanofi Pasteur

19
Regulatory Responsibilities
20
Regulatory Accomplishments

• Licensing Tetravalent Meningococcal Conjugate
  Diphtheria Toxoid Vaccine against groups A,C,
  Y, and W-135
• Reviewers included Frasch, Tsai, Lee, Bash, Lynn,
  Blake
• Significant Changes in Analytical Methodology for
  Lot Release
• Reviewers included Tsai, Freedberg

21
Other Regulatory Accomplishments

• IND Supplement Reviewed 350
• BLA BLA Supplement Review -85
• Participated in International and CBER Policy
  Working Groups
• Distributed Reference Material for Haemophilus
  and Pneumococcal Antibody Assays