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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 ChiefLHV/DVP/OVRR/CBER/FDA

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

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LHV Regulatory Responsibilities

Responsible for review of BLA and IND applications for new and licensed vaccinesHepatitis 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

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-INDs 14

IND files 42

INDs amendments 360

BLAs & supplements 169

Facility Inspections 4

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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

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

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LHV Research Program – Challenges Addressed

Examples of challenges/issues addressed by the LHV research programWhat 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

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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

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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

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Research Program SupportResearch Program Support

The research program has received support from internal FDA sources, external (non-FDA) sources and through royalties

CBER Targeted ResearchMethods to target hepatitis C virus neutralizing epitopes in rE1E2Studies 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

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Site Visit Presentations Site Visit Presentations December 5, 2013 December 5, 2013

Marian Major

Iryna Zubkova

Dino Feigelstock