1. 1 Overview of the Laboratory of Hepatitis Viruses March 20, 2014 VRBPAC Discussion of the December 5, 2013 Site Visit for the Laboratory of Hepatitis Viruses Marian Major, Ph.D., Acting Chief LHV/DVP/OVRR/CBER/FDA

2. Personnel  Marian Major, Ph.D., Acting Chief  Dino Feigelstock, Ph.D., Staff Scientist  Iryna Zubkova, Ph.D., Visiting Scientist  Alla Kachko, Ph.D., Visiting Scientist  Frances Wells, Biologist  Hongying Duan, M.D., Ph.D. ORISE Fellow  Alexander Gutfraind, Ph.D. ORISE Fellow  Qingwen (Sam) Cui, B.S. ORISE Fellow  Tarah Woodle, B.S. ORISE Fellow  Other staff during the rating period who are no longer with LHV  Stephen Feinstone, M.D.  Kathleen Mihalik, Biologist  Abeba Tesfaye, Ph.D., ORISE Fellow  Haiyan Qin, Ph.D., Interagency Oncology Task Force (IOTF) Fellow  Wendy Tan, Ph.D., FDA Commissioner’s Fellow 2

3. LHV Regulatory Responsibilities Responsible for review of BLA and IND applications for new and licensed vaccines  Hepatitis A vaccines  Hepatitis B vaccines  Hepatitis B combination vaccines  Hepatitis C vaccine INDs  Hepatitis E vaccines INDs  Therapeutic HBV and HCV vaccines  Rotavirus vaccines  Norovirus vaccines  Manufacturer facility inspections (pre- and post-licensure) 3

4. LHV Regulatory Review Workload (2010-2013) Prior to September 2012 there were 8 scientists in LHV with regulatory review responsibilities, 2 PIs with supervisory overview of the work Currently 5 scientists in LHV have regulatory review responsibilities, 1 PI with supervisory overview. Pre-INDs14 IND files42 INDs amendments360 BLAs & supplements169 Facility Inspections4 4

5. 5 Other Public Health Responsibilities Participation in working groups and consultations with other public health agencies and vaccine stakeholders  HHS – Viral Hepatitis Action Plan (2014-2016)  CDC ACIP – Hepatitis Working Group

6. LHV Research Program Research complements and supports the regulatory mission of to ensure the safety and efficacy of hepatitis virus vaccines and facilitate the development of new viral vaccines The majority of the research focuses on hepatitis C virus 6

7. LHV Research Program – Challenges Addressed Examples of challenges/issues addressed by the LHV research program  What is an acceptable end point for HCV vaccine trials? Prevent infection? Prevent chronic infection? Research from LHV showed that despite reinfection following spontaneous recovery from HCV, protective immune responses are induced, viral kinetics are significantly different and clearance rates are significantly higher. Conclusion: Naturally acquired immunity occurs and prevention of chronic infection is an acceptable endpoint for HCV vaccines 7

8. LHV Research Program – Challenges Addressed (Continued)  Evaluation of existing data on HCV vaccine success  Meta-analysis of chimpanzee vaccine studies showed vaccination can reduce chronic infections but that target antigens may be important  Evaluation of assays for testing HCV vaccine immunogenicity and elucidating correlates or biomarkers of effective HCV vaccination  T-cell phenotypes or poly-functionality may be more reliable indicators of vaccine success than Elispot assay  Studies on neutralizing antibody mechanisms of action and T-cell induction with viral vectors 8

9. LHV Research Program – Challenges Addressed (Continued)  Immune escape or resistance from vaccines ?  LHV studies have shown that ineffective HCV vaccines can create greater immune pressure for viral mutation  How can clinical trials for HCV vaccines be designed in drug user populations?  Developing mathematical models to simulate spread of HCV in drug user populations to test effective intervention strategies in silico  Development and evaluation of mouse models for HCV/HBV infection and immune responses 9

10. 10 Research Program Support The research program has received support from internal FDA sources, external (non-FDA) sources and through royalties  CBER Targeted Research  Methods to target hepatitis C virus neutralizing epitopes in rE1E2  Studies on neutralizing antibodies against HCV in cell culture  Mathematical models for HCV clinical trial design  Use of a humanized mouse model for HCV infection  Biotechnology Engagement Program (BTEP)  Immunologic and structural studies on HCV rE1E2 Proteins  Medical Counter Measures Initiative (MCMi)  Mouse Systems to Develop Humanized Liver/Immune Chimeric Mice  Patent Royalties  Modified HCV peptide vaccines

11. 11 Site Visit Presentations December 5, 2013  Marian Major  Iryna Zubkova  Dino Feigelstock