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The Front-End of Vaccine Manufacturing

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The Front-End of Vaccine Manufacturing: Getting Good Candidates from the Get-Go William Warren, Donald Drake, Janice Moser, Haifeng Song, Eric Mishkin – PowerPoint PPT presentation

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Title: The Front-End of Vaccine Manufacturing


1
The Front-End of Vaccine Manufacturing Getting
Good Candidates from the Get-Go
William Warren, Donald Drake, Janice Moser,
Haifeng Song, Eric Mishkin VaxDesign
Corporation Orlando, FL 32826 www.vaxdesign.com E
ric Eisenstadt, Hervé Tettelin, Scott
Peterson The Institute For Genomic
Research Rockville, MD 20850 www.tigr.org
VaxDesigns work was funded by DARPA/DSO in
the Rapid Vaccine Assessment Program TIGRs work
was funded by NIH/NIAID Novartis
2
Manufacturing Facilities Begin During Clinical
Trials
http//www.vaccinealliance.org/site_repository/res
ources/21VacMarket.pdf
3
Conventional Vaccine Development
DNA recombinant technology
4
Costs and Time Associated with Todays Vaccine
Product Lifetime Cycle
  • Challenges
  • Can we obtain possible vaccine candidates faster?
  • Can we reduce the time to get vaccines to the
    marketplace?
  • Can we reduce the associated costs?
  • Can we make a more predictive and representative
    readout?
  • Can we have greater success in clinical trials?

5
Reverse Vaccinology Applying Genomics,
Immunology Engineering To Rapidly Assess
Vaccine Candidates
High Throughput Gene Expression
6 months - 1 year
6
Genomics, Tissue Engineering, Automation
Provide a New Approach
  • Genomics analysis of DNA sequence information
    identifies vaccine candidates that can be used
    alone or in combination
  • Tissue engineering provides direct access to
    predictive human immune response without using
    people
  • High throughput automation for repeatable,
    reproducible and rapid processes

7
The Systems Vaccinology Pipeline
8
Steps 1 2 Produce the genome sequence, read
it, and predict the vaccine candidates (reverse
vaccinology)
TIGR rapid sequencing technologies that have
allowed us to clone thousands of open reading
frames derived from the genomes of a variety of
infectious agents, including influenza virus
9
Proof of Principle for Reverse Vaccinology via
TIGR/Chiron Partnership
Serogroup B Neisseria meningitidis - MenB No
vaccine candidate in 40 years of classical
vaccinology Genome sequence 7 novel
candidates Antigenic, Accessible, Highly
Conserved Specific and Bactericidal Tettelin
et al. (2000) Science 287, 1809-1815 Pizza et
al. (2000) Science 287, 1816-1820 Group B
Streptococcus - GBS One genome sequenced - No
candidate providing broad protection Tettelin et
al. (2002) PNAS 99, 12391-12396 Analysis of 8
genomes Highly diverse species Cocktail of 4
candidates confer broad protection Tettelin et
al. (2005) PNAS 102, 13950-13955 Maione et al.
(2005) Science 309, 148-150
10
The Systems Vaccinology Pipeline
11
Step 3 Making the Vaccine Antigens viaHigh
Throughput Expression
  • Directly from the pathogen genome via
    high-throughput technology that clones and
    translates the gene
  • Indirectly by synthesizing the gene de novo and
    then translate it

12
The Gateway Cloning Platform
13
Men B Vaccine Genomic Approach
Bottleneck and relevance?
http//www.meningitis.org/uploads/C05_2_15_Rappuol
i.pdf
14
The Systems Vaccinology Pipeline
Clinical trial in a test tube high throughput in
vitro assay system
15
Step 4 High-throughput testing of proteins as
possible human vaccine candidates
  • ex vivo models of human immunity that are
    functionally equivalent to the human immune
    system
  • Meld immunology with engineering to find elegant,
    practical solutions to complex biological problems

16
Artificial Immune System Cell Interactions
17
How To Create a Functional Ex Vivo AIS
Lymphoid Tissue Equivalent (LTE)
Vaccination Site (VS)
DC crossing endothelium
Microbes and Infection (2003) 5 205-212
18
Example Representative Ex-Vivo Immunogenicity
Testing
Donor had a high anti-tetanus toxoid titer yet,
the industry standard PBMC assay failed to show
protection
19
The artificial immune system construct supports
the induction of naïve and recall human B cell
responses
20
Predictive ex vivo Clinical Research For Influenza
  • Representative high-throughput ex vivo clinical
    research model that can assess initiation through
    neutralization immune responses of
    influenza/pandemic vaccine candidates
  • Rapid, predictive influenza/pandemic strain
    selection
  • Test immunity to circulating strains
  • Vaccine selection
  • Strains in which there are deficiencies or
    inappropriate responses

HA-FITC
Humoral
VS (DCs)
LTE (T/B)
Neutralizing Ab
Cellular
21
The Systems Vaccinology Pipeline
Develop vaccines or fully human therapeutic mAbs
22
When Thinking of Vaccine Manufacturing .
  • Companion diagnostics to better design clinical
    trials
  • e.g., Herceptin only donors with Her2 receptors
    respond
  • HBV works on 80-90 of population
  • Couple in vitro culture techniques with rapid
    sequencing and expression technologies to create
    an automatable, high-throughput system for
    assessing clinical viral isolates to elicit
    specific immunity in the population at large

23
When Thinking of Vaccine Manufacturing .
  • In-line immunogenicity with new manufacturing
    processes
  • e.g., Eprex EPO induced immunity to EPO in some
    patients, which caused severe anemia
  • e.g., Biogenerics
  • e.g., New formulations
  • Generate wholly human mAbs
  • Use the AIS as an Ab biofactory

24
Need for New Predictive Representative Vaccine
Candidates Earlier in the Vaccine Development
Pipeline
  • 51B spent for drug and vaccine discovery and
    development in 1995
  • Increases by 7 each year
  • 1B in RD cost for each new drug and vaccine
    approved, including failures
  • Predicted to reach 2B by 2010
  • Manufacturing is an intimate part of these costs
  • Reverse Vaccinology may reduce costs to bring
    drugs to the market

Reverse vaccinology
http//www.bio-itworld.com/issues/2006/sept/2-bill
ion-pill
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