Overview of the Division of Viral Products

1. Overview of the Division of Viral Products Jerry P. Weir, Ph.D.Director Division of Viral Products/OVRR/CBER/FDA

2. The Division of Viral Products • Overview of the Division’s Mission, Responsibilities, and Public Health Impact • Overview of the Division’s Research Programs, Priority Areas of Focus, and Examples of Recent Accomplishments and Impact

3. Mission • Regulate viral vaccines and related biological products, ensuring their safety and efficacy for human use • Facilitate the development, evaluation, and licensure of new viral vaccines that positively impact the public health

4. Division of Viral ProductsResponsibilities • Investigational New Drug (IND) and Biologics License Application (BLA) review, and other pre-marketing activities (e.g., pre-IND) • BLA supplement review, lot release review and testing, and other post-marketing activities (e.g., Biological product deviations) • Manufacturer inspections (pre- and post-licensure) • Consultation with other public health agencies (e.g., WHO, CDC, NIBSC) • Conduct research related to the development, manufacturing, evaluation, and testing of viral vaccines

5. DVP Influenza Vaccine Experts Division of Viral ProductsPublic Health Impact

6. Hepatitis Viruses Hepatitis A Hepatitis B HepA/HepB HepB-Hib DTaP-HepB-IPV Vector-Borne Viral Diseases Yellow Fever Japanese Encephalitis Virus DNA Viruses Varicella Virus Smallpox Childhood Viruses Inactivated poliovirus Measles, Mumps, rubella Rotavirus Respiratory Viruses Inactivated Influenza Live attenuated influenza Other Viral Vaccines Rabies Licensed Viral Vaccines

7. Hepatitis Viruses Hepatitis C Hepatitis E Vector-Borne Viral Diseases Dengue West Nile Virus DNA Viruses Human Papillomavirus Herpes Simplex Cytomegalovirus New smallpox vaccines Childhood Viruses New Rotavirus vaccines HIV Respiratory Viruses New Influenza vaccines Pandemic influenza vaccines Respiratory Syncytial Virus Parainfluenza virus Vaccines for Emerging Diseases and agents of Bioterrorism Ebola and other hemorrhagic fevers Venezuelan Equine Encephalitis Virus and other encephalitis causing viruses Viral Vaccines Under Development

8. The Division of Viral Products • Overview of the Division’s Mission, Responsibilities, and Public Health Impact • Overview of the Division’s Research Programs, Priority Areas of Focus, and Examples of Recent Accomplishments and Impact

9. Division of Viral ProductsSnapshot • 7 Laboratories • 17 Tenured Principal Investigators • 67 Full-time equivalent staff (April 2006) • > 50 Contract staff (e.g., post-doctoral fellows) • ~ 140 publications (last 2 years) • > $3,000,000 grants and contracts (FY05) • Researcher/Reviewer Model • Review workload (e.g., INDs, BLAs, post-marketing) • Mission-relevant research • Outreach and collaboration (e.g., expert consultants to WHO)

10. The Role of Research in the Division of Viral Products • Research and laboratory activities complement the regulatory mission • Address issues related to regulated viral vaccines • Anticipate and address issues related to the development and evaluation of new viral vaccine products • General issues applicable to many products or product classes (e.g., cell substrate issues, improved test methods, etc.) • Specific product issues (correlates of protection necessary for efficacy evaluation, animal models necessary for animal rule implementation, etc.) • Research efforts prioritized to maximize impact • Availability of expertise • Appropriateness of effort • Competing demands

11. Division of Viral ProductsResearch Activities • Vaccine safety (e.g., evaluation of cell substrates) • Vaccine efficacy (e.g., identification of correlates of protection, development of animal models predictive of efficacy) • Reagent preparation (e.g., influenza vaccines) • Development and evaluation of new methods and assays for product characterization • Issues related to vaccine development for emerging diseases (e.g., pandemic influenza, HIV, West Nile virus) and Bioterrorism agents • Novel vaccination strategies and technologies

12. Jerry P. Weir, Ph.D., Director Phil Krause, M.D., Deputy Director Laboratory of Hepatitis Viruses Steve Feinstone, M.D., Chief Laboratory of Vector-Borne Viral Diseases Lewis Markoff, M.D., Chief Laboratory of Retroviruses Hana Golding, Ph.D, Chief Laboratory of DNA Viruses Andrew Lewis, M.D., Chief Laboratory of Respiratory Viral Diseases Zhiping Ye, M.D., Chief (Acting) Laboratory of Immunoregulation Ira Berkower, M.D., Chief Laboratory of Methods Development Konstantin Chumakov, Ph.D., Chief Division of Viral Products Laboratories

13. Laboratory of Vector Borne Viral Diseases • Areas of Research • Characterization of candidate live, attenuated dengue and West Nile virus vaccines. • Mechanism by which flaviviruses repair attenuating 3'terminal deletions of genome RNA. • Virion morphogenesis. • Effect of quasi-species character on phenotype. • Development of an ELISA-based potency assay for rabies vaccines.

14. Laboratory of Vector Borne Viral Diseases (continued) • Recent Accomplishments • Determined that processing of dengue structural proteins, envelope (E), pre-M (M), and capsid (C), requires the cellular enzyme signal peptidase • Identified structures in the 3’ non-coding region of the Dengue genomic RNA required for viral RNA replication • Demonstrated that the virus encoded RdRp contains an activity to repair 3'terminal deletions of virus RNA • Demonstrated that specific mutations in the capsid protein abrogate attachment, entry, or uncoating in monkey cells but not mosquito cells

15. Laboratory of Hepatitis Viruses • Areas of Research • Vaccine strategies to prevent HCV infection • Development of mouse models for HCV infection to replace the chimpanzee • Development of in vitro culture systems to study antibody neutralization of HCV • Biomarkers for HCV protection and HBV/HCV related hepatocellular carcinoma • Rotavirus-cell interactions • Rotavirus attenuation markers

16. Laboratory of HepatitisViruses (continued) • Recent Accomplishments • Defined pathogenesis and immune responses to HCV in chimp model • Demonstrated that protective T-cell mediated immunity occurs in chimpanzees that spontaneously clear HCV infection • Established that neutralizing antibody to HCV does not play a role in clearance of virus but can control viral replication in vaccinated chimpanzees • Established in vitro culture systems and transgenic mouse models for HCV study • Demonstrated that T-cell vaccines can modify HCV infections and that CD4+ T cell escape is a mechanism of T-cell vaccine failure • Demonstrated that the N- and C-terminal regions of rotavirus NSP5 are determinants of viroplasm formation and that VP4 translocates to cellular peroxisomes by PTS1

17. gp120 particles HBsAg particles Laboratory of Immunoregulation • Areas of Research • Structure-function analysis of HIV envelope glycoproteins • Vaccination strategies to enhance vaccine immunogenicity • Dissecting the neutralizing antibody response to vaccinia virus

18. Laboratory ofImmunoregulation (continued) • Recent Accomplishments • Developed a novel method for forming virus-like particles • Expressed HIV gp120 and gp41 at a lipid-water interface • Identified forms of gp120 with increased antigenicity and immunogenicity • Identified a novel mechanism of resistance to HIV fusion inhibitors • Evaluated the role of antibodies to A27 in Dryvax-induced protection

19. Laboratory of Respiratory Viral Diseases • Areas of Research • Prepare and distribute influenza virus reagents to determine purity and strength of influenza vaccines • Perform serology studies in support of influenza strain selection • Develop new high growth influenza virus strains for vaccines and determine properties for optimal growth in eggs and tissue culture • Evaluate new vaccine strategies • Identify cellular receptors for respiratory syncytial virus (RSV) and determine antigenic structure of RSV glycoproteins • Develop serological methods for vaccine trial evaluation

20. Laboratory of Respiratory Viral Diseases (continued) • Recent Accomplishments • Prepared potency reagents (e.g., strain-specific antisera) for seasonal influenza vaccine and possible pandemic strains • Developed attenuated donor influenza virus that can be used for preparation of pandemic vaccines • Demonstrated improved efficacy of influenza DNA vaccines by co-expression of multiple genes • Identified amino acid motifs that contribute to high growth of influenza B in eggs • Demonstrated that HSPGs bind RSV glycoproteins and identified binding domains that block attachment

21. Laboratory of MethodDevelopment • Areas of Research • Microarrays and other molecular methods for analysis of pathogens • Genotyping of viruses and bacteria • Identification of Mycoplasmas • Genetic stability of live viral vaccines • Immunological test methods development • New animal model development • Neurotoxicity assay development

22. Laboratory of MethodDevelopment (continued) • Recent Accomplishments • Identified mutation hot-spots in vaccine-derived poliovirus (OPV) • Assessed the mucosal immune response to IPV by direct PCR analysis of stool samples of vaccinees • Used Block-ELISA profiling of IPV to monitor consistency of IPV production and to study antigenic properties • Evaluated immunogenicity of new Sabin IPV (with and without adjuvants) in Tg-mouse potency test • Developed rapid microarray-based genotyping of influenza virus strains • Developed new neurotoxicity test for mumps virus • Developed mumps virus neutralization assay for assessing protective immune responses

23. Laboratory of Retrovirus Research • Areas of Research • Development of assays for HIV and smallpox clinical trial evaluation • Identification and characterization of adjuvants • Activity and safety of DNA vaccines and CpG oligodeoxynucleotides • Safety and evaluation of cell substrates used for vaccine production • Retrovirus transmission

24. Laboratory of RetrovirusResearch (continued) • Recent Accomplishments • Developed a method to distinguish HIV infection from vaccine response in clinical trials • Developed a method for rapid measurement of neutralizing antibody following smallpox vaccination • Demonstrated that administration of CpG oligodeoxynucleotides preferentially activates IFNγ secreting cells, increases antigen-specific antibody responses, and improves the protective efficacy of pathogen-specific vaccines • Developed assays to assess DNA oncogenicity • Established induction conditions for detecting occult retroviruses in cell substrates

25. Laboratory of DNA Viruses • Areas of Research • Evaluation of cell substrates used for vaccine manufacture • Developing methods to evaluate the risks posed by the use of neoplastic cells for production of viral vaccines • Detection of adventitious agents • Mechanisms of viral latency • Immunogenicity and pre-clinical efficacy of new-generation smallpox vaccines • Evaluation of novel herpesvirus vaccination strategies

26. Laboratory of DNAViruses (continued) • Recent Accomplishments • Developed methods to evaluate neoplastic cells used in viral vaccine production (e.g., tumorigenicity and oncogenicity assays) • Developed standardized Q-PCR assays for detection of specific polyomaviruses • Developed novel methods for the detection of non-specific adventitious agents • Identified the major antigens of the humoral immune response to smallpox vaccination • Demonstrated that new-generation smallpox vaccines (e.g., MVA) elicit levels of protective immunity comparable to traditional smallpox vaccines in animal models of efficacy • Demonstrated that novel vaccination strategies (e.g., prime-boost immunization) result in enhanced immune responses

27. Summary • The research programs and laboratory activities in the Division of Viral Products support the regulatory mission of the Office of Vaccines and CBER • Ensures the safety and efficacy of regulated viral vaccine products, and • Facilitates the development and evaluation of new virus vaccine products