U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. Overview of the Laboratory of Respiratory Viruses (DVP) Jerry P. Weir, Ph.D., Director Division of Viral Products/OVRR/CBER/FDA

3. Laboratory of Respiratory Viruses • Reorganized from the previous Laboratory of Pediatric and Respiratory Viral Diseases • Previous portfolio too broad and diverse • Designed to focus research and regulatory activities on respiratory viruses and vaccines • 4 Research Teams • Influenza Virus Molecular Biology • Zhiping Ye, M.D., Ph.D., Team leader • Influenza Pathogenesis and Immunity • Maryna Eichelberger. Ph.D., Team Leader • Influenza Vaccine Technologies • Jerry Weir, Ph.D., Acting Team Leader • Antigenic Structure and Function Team • Judy Beeler, M.D., Team Leader

4. Influenza Virus Molecular Biology • Personnel • Zhiping Ye, M.D., Ph.D., Team leader • Hang Xie, Ph.D. • Olga Zoueva, Ph.D. • Ewan Plant, Ph.D. * • Xianghong Jing, Ph.D. * • 1 ORISE fellow • Major Regulatory Responsibilities • Influenza virus vaccines • Areas of Research • Molecular mechanisms of influenza virus attenuation & virulence • Molecular & genetic approaches to improving influenza vaccine candidates • Previous Site Visit – 11/04

5. Influenza Virus Molecular BiologyResearch Update • Optimizing Influenza Vaccine Candidates by Modification of Specific Influenza Genes • Modify the NA gene of pandemic influenza vaccine candidates to increase virus yields • Adamo, et. al., 2009. Optimizing Viral Protein Yield of Influenza Strain A/Vietnam/1203/2004 by Modification of the Neuraminidase Gene. Journal of Virology, 83:4023-4029. • Studies being extended to address yields of A/California/07/2009-like viruses • Modify the M gene of A/PR8 donor virus to optimize virus yields • Enhanced association of M and NP improved replication of a low-yielding H3N2 strain • Studies being extended to address yields of A/California/07/2009-like viruses • Establish an animal model of pandemic H1N1 virus pathogenesis to evaluate the safety of pandemic vaccine candidates • Suggested age-dependent pathogenesis of pandemic H1N1 in the mouse model

6. Influenza Virus Molecular BiologyResearch Update – Cont. • Support Influenza Vaccine Development and Production • Construct pandemic H1N1 vaccine candidates suitable for manufacture • Provided CBER-RG2 (pandemic H1N1) to over 20 WHOccs and manufactures worldwide • Ongoing studies to investigate antigenic stability after passage • Conduct human serology studies to support WHO influenza vaccine strain selection • SH studies in Sept 2009/NH in Feb 2010 • Evaluate a murine infection model to explore the mechanisms of cross-protection against pandemic influenza viruses • Xie et al 2009. A live attenuated H1N1 M1 mutant provides broad cross-protection against infleunza A viruses, including highly pathogenic A/Vienam/1203/2004 in mice. Journal of Infectious Diseases, 200:1874-83.

7. Influenza Pathogenesis and Immunity • Personnel • Maryna Eichelberger, Ph.D., Team leader • Katie Harris, B.S. • Jin Gao, M.S. • Matthew Sandbulte, Ph. D. • 3 ORISE fellows • Major Regulatory Responsibilities • Influenza virus vaccines • Areas of Research • Role of neuraminidase (NA)-specific immunity • Contribution of cell-mediated immunity to protection against disease • Previous Site Visit – New Research Team – 9/06

8. Influenza Pathogenesis and ImmunityResearch Update • Contribution of NA-specific Immunity to Influenza Vaccine Efficacy • Develop practical assays to measure functional NA-specific antibody titers • Sandbulte et al. A miniaturized assay for influenza neuraminidase inhibiting antibodies utilizing reverse genetics-derived antigens. Influenza and other Respiratory Viruses 3: 233-240, 2009 • Hassantoufighi et al. A Practical Influenza Neutralization Assay to Simultaneously Quantify Hemagglutinin and Neuraminidase-Inhibiting Antibody Responses. Vaccine 28:790-797, 2010 • Evaluate role of NA-specific antibodies/inhibitors in selection of escape variants • Memoli et al. Rapid selection of a transmissible multi-drug resistant influenza A/H3N2 virus in an immunocompromised host. J Inf Dis, in press.

9. Influenza Pathogenesis and ImmunityResearch Update – Cont. • Cell Mediated Immunity to Influenza • Develop practical assays to evaluate cell-mediated immunity • Eichelberger et al. Comparison of Human Immune Responses to Live , Attenuated and Inactivated Influenza Vaccines. In preparation • Studies are in progress to evaluate human CD4+ T cell responses to pandemic 2009 H1N1 infection and vaccination • Characterize early factors that initiate cell mediated immunity • Harris et al. Intramuscular immunization of mice with live influenza virus results in robust antibody and CD8+ T cell responses. In preparation. • Studies are in progress to compare early inflammatory responses to pandemic 2009 H1N1 and other H1N1 viruses in mice

10. Antigenic Structure and Function • Personnel • Judy Beeler, M.D., Team Leader • Lynne Crim, B.S. • Susette Audet, B.S. • Major Regulatory Responsibilities • RSV, PIV3, and other respiratory virus vaccines • Measles virus vaccines and immunoglobulins (OBRR consult) • Areas of Research • RSV-Host Cell Interactions • Measles Immunity • Previous Site Visit – 6/06

11. Antigenic Structure and FunctionResearch Update • Identification of Epitopes in the F and G Envelope Glycoproteins of RSV Involved in Receptor Binding and Eliciting a Protective Immune Response • Identified Linear Domains within F and G that bind to cells, inhibit virus infection, and block virus attachment to cells (Crim RL, et al., J Virol, 2007, 81:261) • Mapped cell binding domains on pre-fusion model of RSV-F • Studies being extended to identify epitopes recognized during human RSV infection

12. Antigenic Structure and FunctionResearch Update – Cont. • Optimizing the Age and Schedule for Measles Immunization and Assessing the Persistence of Measles Immunity in Vaccinated Populations • Measles neutralizing antibody titers increase 2-3 fold after a second dose and return to baseline within 6 months of immunization. In the post- elimination environment, titers decline steadily so that by age 30 (~25 years after dose 2), approximately 1/3 of the adult population can be expected to have antibody titers <120mIU/mL based on current models. (LeBaron, Beeler, et al., 2007. Persistence of measles antibodies after 2 doses of measles vaccine in a postelimination. Arch Pediatr Adolesc Med. 2007 Mar;161(3):294-301)