HHS Influenza

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 _at_ 90 ug HA/dose Sept. 04
  completed Nov. 04
• SP 5.8 M doses _at_ 90 ug HA/dose Sept. 05
  completed Dec. 05
• Chiron 1.3 M doses _at_ 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
  hens 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)

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RFP ORDC VB 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.

• 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

• Contracting office ORDC/OPHEP/HHS
• Project Management ORDC/OPHEP/HHS
• Funding OPHEP FY06 1 B

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
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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