Progress in Stabilizing Vaccines

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Progress in Stabilizing Vaccines

• Debra Kristensen
• PATH
• TECHNET Consultation Tunis, Tunisia
• 3 December, 2008

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Presentation overview

• Background on PATHs project
• Progress in vaccine stabilization efforts
• Lyophilization
• Spray drying
• Liquid formulation
• Expectations for future products

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PATHs Vaccine Stabilization Project

• Supported by the Bill Melinda Gates Foundation
• September 2003December 2010
• Goal Assess the technical and commercial
  feasibility of converting vaccines used in
  developing-country health programs to
  thermostable formats

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Project Team

• Dexiang Chen, Technical lead
• Hugh Chang, Business
• Birute Curran, Clinical trials coordinator
• Abra Greene, Program assistant
• Mark Guy, Program associate
• Jeff Huentelman, Administrator
• Debra Kristensen, Team leader
• Manjari Lal, Technical officer
• Emily Lindsay, Project administrator
• Carol Levin, Economic analyses
• Heidi Plzak, Laboratory research
• Scott Priddy, Laboratory research
• Amy Wales, Communications

PATH Seattle Lab
PATH
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Project Collaborators

• Technology companies
• Ace BioSciences (Denmark)
• Arecor Ltd. (UK)
• Aridis (US)
• Aktiv-Dry (US)
• BD (US)
• Cambridge Biostability Ltd (UK)
• Glide Pharma (UK)
• HTD Biosystems (US)
• Nektar Therapeutics (US)
• Stabilitech (UK)
• University of Colorado (US)

• Contract services
• PPD Development (US)
• Niro A/S (Denmark)
• Spring Valley Laboratories (US)
• Statens Seruminstitut (Denmark)
• Vaccine producers/projects
• Crucell (S.Korea, Switzerland)
• Enterics Vaccine Initiative (US)
• Indian Immunologicals Ltd (India)
• Meningitis Vaccine Project (France)
• Novartis Vaccines (Italy)
• Panacea Biotech (India)
• Serum Institute of India (India)
• Shantha Biotechnics (India)

Current collaborators
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Reference document
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Lyophilization

• Efforts by
• Celldex, formerly Avant Immunotherapeutics (US)
• Sapporo University (Japan)
• Stabilitech (UK)
• University of Groningen (Netherlands)
• Vaccine producers

• Progress
• Influenza vaccine stable for 26 weeks at room
  temperature1 (University of Groningen)
• Typhoid vaccine (Ty800) stable for 12 months at
  25C2 (Celldex)
• Amorij JP, et al. Rational design of an influenza
  subunit vaccine powder with sugar glass
  technology preventing conformational changes of
  haemagglutinin during freezing and freeze-drying.
  Vaccine. 2007 Aug 2925(35)6447-6457.
• Avant Immunotherapeutics. VitriLife - a long
  term preservation method for biological samples.
  Company
• information release.

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Lyophilization

• Benefits
• Well established readily available process and
  equipment
• Often best method for unstable antigens,
  especially bacterial and viral vaccines
• Challenges
• Not appropriate for vaccines containing aluminum
  adjuvant
• Batch limited, process takes days
• No flexibility, final product is dried cake or
  foam
• Require storage in the cold chain
• Reconstitution required

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Spray-drying

• Efforts by
• Aktiv-Dry (US)
• Aridis Pharmaceuticals (US)
• BD Technologies (US)
• Cambridge Biostability Limited (UK)
• MEND (US)
• PATH (US) internal research and collaboration
  with all groups listed above except MEND

Laboratory-scale spray drier at PATH

• Progress
• Hepatitis B vaccine stable for greater than 24
  months at 37C1
• Meningitis A vaccine stable for gt 16 weeks at
  40C1
• 1) PATH unpublished data.

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Spray-dried hepatitis B vaccine
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Spray-dried meningitis A vaccine
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Spray-drying

• Benefits
• Works with vaccines containing aluminum adjuvant
• Possibility of blending spray-dried components to
  make a multivalent vaccine
• Free flowing powder
• Flexibility with regard to doses per container
• Amenable for new delivery technologies
• Capsule/tablet for oral delivery
• Inhalation
• Skin patch
• Single dose reconstitution devices

Spray dried hepatitis B vaccine
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Spray-drying

• Challenges
• Difficulties applying technology to viral
  vaccines (e.g. years of work with measles vaccine
  have not yielded results superior to
  lyophilization)
• No commercial products yet produced by aseptic
  spray-drying
• Vaccine producers reluctant to adopt new
  production methods

Niro A/S
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Liquid formulations

• Efforts by
• Arecor (in collaboration with PATH)
• Havana University
• PATH
• Vaccine producers
• Progress
• Synthetic Hib vaccine stable for 3 months at
  37C1 (Havana University)
• Hepatitis B vaccine stable for gt 6 months at 37C
  and 45C2
• Freeze protection technology developed by PATH3
• Verez-Bencomo V, et al. A synthetic conjugate
  polysaccharide vaccine against Haemophilus
  influenzae type b. Science. 2004 Jul
  23305(5683)522-525.
• Jezek J et al. A heat stable hepatitis B vaccine
  formulation. Vaccine. In press.
• Jones Braun L, et al. Vaccine. 2008. E-pub ahead
  of print.

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Freeze protection technology overview

• Benefits
• Straightforward formulation Addition of a freeze
  stabilizer.
• Safe excipients Stabilizers are already widely
  used in licensed products, including parenteral
  medications and vaccines for infants.
• Broadly applicable All vaccines and diluents
  containing aluminum adjuvant.
• Low cost excipients The cost of stabilizers is
  negligible US0.0001 per dose of vaccine.
• Challenges
• Introduction into existing vaccines requires
  reformulation, clinical trials and regulatory
  approvals.
• Status
• Clinical trials planned for two existing vaccines
  (hepatitis B and DTP-HepB-Hib) for registration
  purposes.

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Freeze- and heat-protected hepatitis B vaccine
(liquid) 12-month stability
FT Three cycles of freezing (-20C, 24 hrs) and
thawing (24C, 4 hrs)
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Freeze-protection technology placed in the public
domain
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Vaccines with potential for high temperature
storage
Illustrative estimates based on best stability
data for each vaccine.
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Maximizing the availability and benefits of
thermostable vaccines

• Industry and vaccine development projects
• Incorporate stabilization methods during vaccine
  development
• Obtain stability and other data required to
  support vaccine storage temperatures other than 2
  to 8C.
• Public sector
• Develop out of cold chain procedures, policy and
  equipment (WHO, Technology and Logistics Advisory
  Committee)
• Provide input to industry with regard to
  desirable target product profiles (VPPAG, vaccine
  introduction projects