Overview of the Division of Viral Products

Jerry P. Weir, Ph.D.Director

Division of Viral Products/OVRR/CBER/FDA

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

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

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

DVP Influenza Vaccine Experts

Division of Viral ProductsPublic Health Impact

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

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

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

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)

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

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

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., ChiefLaboratory 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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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