1. Overview Laboratory of Bacterial Polysaccharides From cover - Science, 23 March, 2001

2. The Laboratory of Bacterial Polysaccharides The mission of this Laboratory is unified around the fact that: Most all invasive bacterial diseases in the young pediatric population are caused by bacterial species having polysaccharide capsules: Haemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae Streptococcus agalactiae (Group B Strep)

3. Licensed Vaccines for which the LBP has Product Responsibility Polysaccharides: Pneumococcal 23-valent Merck Meningococcal 4-valent Aventis Pasteur Typhoid Vi Aventis Pasteur Conjugates: Haemophilus influenzae type b (Hib) Wyeth Aventis Pasteur Merck (2 ) Pneumococcal 7-valent Wyeth Combination vaccines

4. Current Regulatory Activities in the Laboratory of Bacterial Polysaccharides O IND supplement review – over 125 active INDs o Product License application and supplement review Over 80 submissions since June 2000 o Meetings and conference calls with manufacturers o Lot release protocol review and lot release testing Approximately 400 protocols per year o Assist in training of reviewers and inspectors o Participate in inspections of manufacturing facilities o Presentations to VRBPAC

5. Major outside mission related activities by Laboratory of Bacterial Polysaccharides Personnel  Temporary consultants to CDC, PAHO, WHO and PATH  Help draft WHO requirements for conjugate vaccines  Review Red Book chapters on polysaccharide and conjugate vaccines  Journal review – multiple journals  Grant review for Meningitis Research Foundation  Review of Military Infectious Disease Research Program  On organizing committees for major workshops  Consult/train foreign laboratories in Quality Control

6. Research in the Laboratory of Bacterial Polysaccharides The LBP is responsible for:  Conducting basic and applied research on problems related to the preparation, purity, stability, and immunogenicity of investigational and licensed vaccines for encapsulated bacterial pathogens.  Evaluating host-parasite interactions for pathogenesis and protective immunity.

7. Organization of the Laboratory of Bacterial Polysaccharides Carl E. Frasch, Ph.D Laboratory Chief Pathogenic Neisseria Section Margaret C Bash, MD Medical Officer Lipopolysaccharide Section Chao-Ming Tsai, Ph.D. Biochemist Polysaccharide and Conjugate Vaccine QC Lot Release Chi-Jen Lee, Sc.D. Biochemist Polysaccharide Immunity Section Carl E. Frasch, Ph.D Microbiologist Cellular Immunology Section Mustafa Akkoyunlu, MD, Ph.D. Immunologist

8. Research Objectives: Polysaccharide Immunity Section Conducts research to evaluate the ability of polysaccharide and conjugate vaccines to induce protective immunity. Studies different conjugation chemistries to improve conjugate yields and to improve the immune response to native polysaccharide epitopes

9. Research Objectives: Cellular Immunity Section Focuses on the initial phase of polysaccharide vaccine/encapsulated bacteria interaction with host immunity. Seeks to define the interaction of polysaccharides with toll-like receptors (TLRs) on innate cells. The biological events resulting from this interaction may affect the development of adaptive immune responses against polysaccharides. Investigates the role of “A proliferation-inducing ligand” (APRIL) and B Lymphocyte Stimulator (BLyS) in infant and adult immune responses against bacterial polysaccharides.

10. Research Objectives: Pathogenic Neisseria Section Investigates the Por B proteins of Neisseria gonorrhoeae and Neisseria meningitidis.  Studies the natural epidemiology of Por variation using novel molecular typing methods  Evaluates the effects of Por variation on host-pathogen interaction including immune responses to Por, structure function restrictions on Por, and transmission patterns  Identifies the mechanisms of Por variation through investigation of mixed infections, diverse and clonal populations.

11. Research Objectives: Lipopolysaccharide Section Conducts research to evaluate chemically or genetically detoxified meningococcal LPS bound to protein as a potential vaccine for group B meningococcal disease. Studies the genetics of LPS biosynthesis in pathogenic and commensal Neisseria species and characterizes their LPS immunochemically.

12. Thank you