Surge Capable Vaccines

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Surge Capable Vaccines Therapeutics
Vaccine manufacture 1959
Vaccine Manufacture 2006

• Michael Callahan MD, DTMH, MSPH
• Infectious Disease/Massachusetts General Hospital
• CIMIT BioDefense Mass-Casualty Care
• U.S Dept of State Avian Influenza Surveillance
  Network.

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Problem Current Vaccine Manufacture

• The fastest current vaccine
• Protects against a characterized, annual threat
  .Not against a mass-casualty infection (stage
  IIIB outbreak)
• Uses established, traditional, egg-propagated,
  killed virus speed is determined by fixed
  metabolic processes. Capacity does not increase
  speed
• Requires 6.5-9 months to manufacture, test, fill
  and finish A human fit strain, mitigated using
  current WHO plans would reach all countries in
  82-145 (CONUS in 82-105 days)
• Requires refrigeration and intact supply chain
  the worlds poor will be the primary casualties
  of HPAI pandemic.

• What if
• SPF eggs were infected (NCD, 2002)
• U.S. health security supply chain were
  destroyed (case studies Katrina)
• Virus was non-cultivatable in eggs
  (A/H5N1/almaty) OR mammalian cells (2)
• Sequences for reverse-genetics could not be
  determined (H267Y a-2,4 A/H5N1 Indonesian Clade
  2 (Pereis and Henry et al. publication pending)

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Case Study Endemic A/H5N1/Almaty

• US Dept of State funded AI surveillance in the
  FSU found HPAI in 37 trans-Asian migratory bird
  species
• Anas ducks have L/HPAI
• Kamchatka waterfowl shorebirds breed with
  Aleutian/Alaskan mates
• Trans-Aleutian surveillance is starting now

Autumn 2007
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International Cooperation how good is the data?
There are economic, national security and
political reasons hampering international
disclosure and reporting of highly dangerous
influenza strains.
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Disincentives to Alternative Vaccine
Manufacturing Technologies
New Vaccine Technologies

• Why isnt itbeing done?
• COGS is optimal
• Supply currently meets demand (mAB)
• Share holders (several 1B vaccine factories just
  completed)
• Risk of adopting new technologies is too high for
  vaccine industry
• Not driven by USG agencies

New super-hubs allow for rapid spread of agents
via fomites vectors
Technology makes BW production easy This POP
proved 4M doses of anthrax could be produced for
190 reagents (2001)
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Accelerated Vaccine Candidates
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Solution Restructure Vaccine Critical
Therapeutics Manufacture
Promising Results A Erwinia fermentation system
is producing 2 gm/l of a human single chain
antibody in 72 hrs A cell-free system has
produced small proteins from ATP, amino acids,
and NTPs. The system produced 500 µg/ml of a 24
kD protein in 6 hrs
New Platforms
Large scale yeast fermentation
Artificial cells cell-free systems for protein
synthesis

• Limitations
• Complex proteins, such as functional AB (4
  chains), currently impossible to produce in
  alternate systems
• Alternate systems produce insoluble, in-correctly
  folded, or non-functional proteins
• Protein synthesis slows during scale-up

chloroplast
Commandeered Biological Platforms
arthropod
Marine
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Case 1 An agricultural enzyme system is
redirected to make vaccine antigen
Fungal Fermenter Train
Aspergillus

• Engineered Aspergillus
• a fast growing fungus with flexible gene
  cassettes
• Extensive, well-characterized genetic toolbox
• Achieves high protein concentrations in 3-4
  days
• Proteins produced with minimal fragments

Small proteins expressed at gt 30 g/L Amylase,
an industrial detergent (50 60 kD) Large
Proteins gt100 kD produced at 6 g/L ß-Galactosidase
, for cellulose degradation (116 kD correctly
folded intact N- C- terminals)
Recombinant, Engineered Proteins Commodity Based
Material 0.0001 -
0.005/gmConsumer Products 0.05 -
1/gmPersonal Care Products 0.05 -
10/gmPharmaceutical Products 100.00 -
10,000.00/gm
One company produced a single chain human-like
mAB within 72 hrs of gene insertion
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Case 2 Plant Based Protein Production

• Chloroplast genes are maternally-
  inherited10000X more abundant than chromosomal
  genes
• Expression gt 500X that of nuclear genes
• Freeze-drying allows RT C store stockpiling

• .8g/kg fresh biomass (lt 1/g crude protein under
  GMP compliant codes its lt 50/g)
• 80 total soluble protein
• (normal stable transgenic plants only get yields
  of lt100ug/g of fresh leaf mass, and have  lt1
  total soluble protein)

Dual use- Harvest plant for food and therapeutics
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Case 3 Soluble Protective Antigen from
Engineered Duckweed
Rapid High Protein Content 36 hours to
double biomass protein is 30 dry weight

• Protein secreted into media
• Plants are batch cultured in sealed vessels no
  containment worries
• inexpensive

• Expression of mAB
• Preliminary 2.8 soluble protein (5.6 g/kg dry
  weight)

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Case 4 single chain monoclonals produced using
a novel prokaryote system
Biological Threat (virus, bacterial, toxin,
synthetic BW, prion)
Complete Antibody Fab
Fc region
Single Chain Antibody Fragment (sc AB)
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Accelerating Delivery of New Therapeutics
What is Needed
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Key Challenges

• Post-translational events
• Glycosylation
• Folding
• Amidation

Sequence integration clone selection
Difficulties with scale-up from pilot to large
scale
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Established Novel Expression Systems
Established Systems
SPEED
Fast
Slow
E. coli
yeast
baculovirus
plant
mammalian cells
transgenic
COST


E. coli
yeast
mammalian cells
transgenic
baculovirus
plant
FDA Approval
Unlikely
Likely
plant
baculovirus
yeast
transgenic
E. coli
mammalian cells
Promising New Platforms
Nucleic acid
Cell free
crustacean
duckweed
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Re-evaluate upgrade select vaccines
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Summary Surge Vaccine Capability and Public
Health Security

• Replace large, static, costly vaccine stockpiles
  and supply chain with a fast, low-cost
  manufacturing system (multi-use, iterative,
  upgradeable)
• High efficiency platforms supported by profitable
  manufacture (e.g. anti-cancer biologics) and be
  redirected for public health vaccines
• Expanded capacity for orphan vaccine manufacture
• Transition of biological threat intelligence into
  an effective drug
• (years ? weeks)
• Potential benefits in speed and simplicity of FDA
  approval
• Restore U.S. health autonomy by eliminating
  reliance on foreign nations
• If necessary, an opportunity to keep target
  epitopes unpublished