Overview of Laboratory of Bacterial Polysaccharides By Willie F. Vann, Chief LBP
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.
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.
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
Current Organization of the Laboratory of Bacterial Polysaccharides
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
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.
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.
Some Significant Achievements • Development of Efficient Method for Meningococcal Group A Conjugate Vaccine Synthesis • Vaccine in MVP/WHO Sponsored Phase II Clinical Trial
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
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
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
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.
Some Significant AchievementsStructural 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 m=monomer p=polymer 2. Carbohydrate 3D Structure: Sucrose
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
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