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 Products Responsibilities
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. Division of Viral Products Public Health Impact
DVP Influenza Vaccine Experts

6. Licensed Viral Vaccines
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

7. Viral Vaccines Under Development
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

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 Products Snapshot
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 Products Research 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. Division of Viral Products Laboratories
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

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 Hepatitis Viruses (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. 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
gp120 particles HBsAg particles

18. Laboratory of Immunoregulation (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 Method Development
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 Method Development (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 Retrovirus Research (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 DNA Viruses (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