1. 0 HHS Influenza Vaccine Projects for NVAC Meeting June 7, 2006 By: Dr. Robin Robinson Acting Assoc. Director ORDC/OPHEP/DHHS

2. 1 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. 2 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. 3 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. 4 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 oSP: 0.33 M doses @ 90 ug HA/dose Sept. 04; completed Nov. 04 oSP: 5.8 M doses @ 90 ug HA/dose Sept. 05; completed Dec. 05 oChiron: 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. 5 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. 6 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. 7 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. 8 Influenza Vaccine Cell Substrates  Vero cells (Baxter)  monkey kidney cell line  Non-tumorigenic cell line at limited passage  Adherent, flu virus titers -10 7 pfu/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 -10 8 pfu/ml  PER.C6 cells (SP)  Ad5 E1 gene transformed human fetal retinal cells  Weakly oncogenic cell line  Suspension, flu virus titers -10 8 pfu/ml

10. 9 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. 10 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. 11 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. 12 New Cell-based Contracts: Budgets CompanyFunding TermFunding Amt. GSK (ID Biomed)Full (5 yrs.)$274,752,168 MedImmuneFull (5 yrs.)$169,462,231 Novartis (Chiron)Full (5 yrs.)$220,507,491 DynPort (Baxter)thru Jul 07$40,971,895 SolvayFull (5 yrs.)$298,594,057 Total$1,004,287,842

14. 13 HHS Cell-based Contracts: Seasonal Influenza Vaccine Product Development CompanySource Pre- ClinicalPhase IPhase II Phase III Licensed GSK (ID Biomed)Egg U.S./E.U. CellE.UU.S. MedImmuneEgg U.S. CellU.S. Novartis (Chiron)Egg E.U. U.S CellU.S. E.U. DynPort (Baxter)Egg E.U. Cell E.U. SolvayEgg E.U. Cell U.S.E.U. sanofi pasteurEgg E.U. U.S Cell U.S.

15. 14 Pan Flu Vaccine Forecast: Egg- and Cell-based Vaccines

16. 15 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: oAdjuvants oImmune cytokines oAlternative delivery devices oOther delivery methods RFP issued Mar. 17, 2005 Contract awards expected in 3Q06