HHS Influenza Vaccine Projects for NVAC Meeting June 7, 2006

1. HHS Influenza Vaccine Projects for NVAC Meeting June 7, 2006 By: Dr. Robin Robinson Acting Assoc. Director ORDC/OPHEP/DHHS

2. Overview • Key Winter/Spring Events • H5N1 Vaccine: Pre-Pandemic Vaccine Stockpile • H5N1 + Alum Adjuvant Vaccine Candidates • Egg-based Influenza Vaccine Contract: H7 & H5 Vaccines • Cell-based Influenza Vaccine Contracts • RFP 05-08 Optimization of Influenza Vaccine Antigen

3. Key Winter/Spring Influenza Events • National & HHS Pandemic Influenza Plans released (11/05) • Clinical results of alum adjuvant on H5N1 vaccine immunogenicity • Molecular pathogenesis of H5N1 virus in lower respiratory tree • Continued spread and genetic “drift” of H5N1 viruses in birds from Asia to Europe & Africa • HHS awards multiple contracts to advance development of cell-based influenza vaccines for U.S. licensure & capacity building in U.S. • Further emergence of H5N1 virus clade 2 isolates in Eurasia • More H5N1 vaccine + adjuvant clinical trials • Plans to manufacture H5N1 clade 2 vaccine candidates for clinical trials • Continued U.S. stockpiling of flu antiviral drugs & H5N1 clade 1 vaccine

4. HHS Pandemic Vaccine Goals • Goal #1: To establish and maintain a dynamic pre-pandemic influenza vaccine stockpile available for 20 million persons: H5N1 stockpiles • Goal #2: To provide pandemic vaccine to all U.S. citizens within six (6) months of a pandemic declaration • Basis: two doses/person x 90 ug HA/dose (antigen alone) x 300 million persons = 600 million doses = 54 kilograms H5 antigen = 160 kg inactivated virus vaccine • Method: To expand and diversify influenza vaccine types, increase number of domestic manufacturers, and enlarge pandemic influenza vaccine manufacturing surge capacity • Possible Substrate Sources: eggs, mammalian cells, recombinant vaccines

5. H5N1 Vaccine: Pre-Pandemic Vaccine Stockpiles • HHS Pandemic Plan goal: establish & maintain pre-pandemic vaccine stockpile for 20 M persons in critical workforce & high priority groups • Contracts awarded for commercial scale production of egg-based inactivated monovalent split H5N1 bulk vaccine during seasonal vaccine manufacturing off-season to establish stockpile • SP: 0.33 M doses @ 90 ug HA/dose Sept. 04; completed Nov. 04 • SP: 5.8 M doses @ 90 ug HA/dose Sept. 05; completed Dec. 05 • Chiron: 1.3 M doses @ 90 ug HA/dose Oct. 05; completed Feb. 06 • Manufacturing virus reference strain: reverse genetics reassortant avian influenza A/H5N1/Vietnam/2004/1203 x PR8 (St. Jude) • Indemnification & licensure issues await resolution in summer 2006 • Formulation and fill finish of H5N1 vaccine for DOD set for summer 2006 • Remaining H5N1 vaccine await results of NIAID/NIH clinical studies using adjuvants in 2006

6. H5N1 + Alum Adjuvant Vaccine Candidates • Six formulations of H5N1 +/- alum vaccine (SP) completed in Nov. 05 • NIAID/NIH commenced clinical studies with H5N1 +/- alum vaccine in Mar. 2006 for safety and immunogenicity • Other NIAID/NIH clinical studies with H5N1 vaccine administered as antigen alone or with alum or MF-59 adjuvant at bedside

7. Egg-based Influenza Vaccine Contract: H7N7 & H5N1 clade 2 Vaccine Candidates • Contract awarded Sept. 2004 to Sanofi Pasteur for establishment of secure, year-round embryonated hen’s eggs and other essential supplies for five years • Final testing of pilot investigational lots of H7N7 + alum adjuvant vaccine in progress for safety & immunogenicity evaluation in clinical trials by NIAID/NIH VTEUs later in 2006 • Several H5N1 clade 2 virus reference strains will be studied for production & antigenicity to produce clinical lots for safety & immunogenicity evaluation in clinical trials by NIAID/NIH

8. Egg vs. Cell-based Influenza Vaccines • Egg-based production • FDA-licensed with good safety and decent efficacy profile • Incumbent business market model (50+ yrs.) • Historically cheap method • Domestic capacity – 60 M trivalent doses (100 M licensed doses) • Global capacity – 325 M trivalent doses • Requires adaptation of human flu vaccine virus strains to eggs • Egg product allergies • Dependent on egg availability & specialized egg-handling equipment • Cell-based production • Only licensed (registered) in The Netherlands • Oncogenicity/Tumorigenicity issue of cell lines • Adventitious agent issue for cell banks • Cell bank consistency • Flexible surge capacity • Equipment amenable to multi-product operations

9. Influenza Vaccine Cell Substrates • Vero cells (Baxter) • monkey kidney cell line • Non-tumorigenic cell line at limited passage • Adherent, flu virus titers -107pfu/ml, febrile SAE in humans • MDCK cells [MedImmune, GSK (IDB), Solvay, Novartis (Chiron)] • Darby Canine kidney cell line • Tumorigenic cell line • Adherent/Suspension, flu virus titers -108 pfu/ml • PER.C6 cells (SP) • Ad5 E1 gene transformed human fetal retinal cells • Weakly oncogenic cell line • Suspension, flu virus titers -108 pfu/ml

10. Cell-based Influenza Vaccine Contract: PER.C6 Cell Line • Contract awarded Apr. 2005 to sanofi pasteur over five years to facilitate advanced development of a PER.C6 human cell-based influenza vaccine U.S. towards U.S. licensure in U.S. mfg facilities with surge capacity of 300 M monovalent doses of pandemic vaccine (15 ug/dose) • Manufacturing of pilot investigational lots completed in France for safety & immunogenicity clinical evaluation in U.S. • Phase I studies scheduled for 2006

11. RFP 05-04 Cell- & Recombinant-based Influenza Vaccines • Goal: Expansion and acceleration of influenza vaccine surge capacity & diversification of influenza vaccine • Solicitation for contract proposals to facilitate development of cell- or recombinant-based seasonal and pandemic influenza vaccines towards U.S. licensure and manufacturing • Surge capacity of 150 M doses of pandemic vaccine • RFP issued April 29, 2005 • Proposals evaluated for technical merit • Contract awards awarded (May 1, 2006)

12. RFP ORDC V&B 05-04:Contract Solicitation Facts • RFP intent is to facilitate advanced development of cell- or recombinant-based seasonal and pandemic influenza vaccines towards FDA licensure and commitment to U.S.-manufacturing site at a pandemic surge capacity of 150 M doses/6 mos. • Contracting office – ORDC/OPHEP/HHS • Project Management – ORDC/OPHEP/HHS • Funding – OPHEP FY06 $1 B Support Activities • Clinical manufacturing • Product assay develop. • Clinical evaluation • Clinical assay develop • Process/Scale-up mfg develop • Product-related equipment • Process validation • Mfg facility concept design Deliverables • Product Develop Plan • Clinical & Regulatory Plan • Facility Plan • Feasibility Plan • Pan Vaccine Dev Milestones • Seasonal Vaccine Dev Milestones

13. New Cell-based Contracts: Budgets

14. HHS Cell-based Contracts: Seasonal Influenza Vaccine Product Development

15. Pan Flu Vaccine Forecast: Egg- and Cell-based Vaccines

16. RFP 05-08 Optimization of Influenza Vaccine Antigen • Solicitation for contract proposals to facilitate development of adjuvant and biological products, medical devices, and/or methods that optimize influenza HA antigen in vaccines to stretch the influenza vaccine supply • Scope includes: • Adjuvants • Immune cytokines • Alternative delivery devices • Other delivery methods • RFP issued Mar. 17, 2005 • Contract awards expected in 3Q06