Title: The Front-End of Vaccine Manufacturing
1The 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
2Manufacturing Facilities Begin During Clinical
Trials
http//www.vaccinealliance.org/site_repository/res
ources/21VacMarket.pdf
3Conventional Vaccine Development
DNA recombinant technology
4Costs 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?
5Reverse Vaccinology Applying Genomics,
Immunology Engineering To Rapidly Assess
Vaccine Candidates
High Throughput Gene Expression
6 months - 1 year
6Genomics, 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
7The Systems Vaccinology Pipeline
8Steps 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
9Proof 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
10The Systems Vaccinology Pipeline
11Step 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
12The Gateway Cloning Platform
13Men B Vaccine Genomic Approach
Bottleneck and relevance?
http//www.meningitis.org/uploads/C05_2_15_Rappuol
i.pdf
14The Systems Vaccinology Pipeline
Clinical trial in a test tube high throughput in
vitro assay system
15Step 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
16Artificial Immune System Cell Interactions
17How To Create a Functional Ex Vivo AIS
Lymphoid Tissue Equivalent (LTE)
Vaccination Site (VS)
DC crossing endothelium
Microbes and Infection (2003) 5 205-212
18Example Representative Ex-Vivo Immunogenicity
Testing
Donor had a high anti-tetanus toxoid titer yet,
the industry standard PBMC assay failed to show
protection
19The artificial immune system construct supports
the induction of naïve and recall human B cell
responses
20Predictive 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
21The Systems Vaccinology Pipeline
Develop vaccines or fully human therapeutic mAbs
22When 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
23When 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
24Need 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