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The Front-End of Vaccine Manufacturing:

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Presentation on theme: "The Front-End of Vaccine Manufacturing:"— Presentation transcript:

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 Eric Eisenstadt, Hervé Tettelin, Scott Peterson The Institute For Genomic Research Rockville, MD 20850 VaxDesign’s work was funded by DARPA/DSO in the Rapid Vaccine Assessment Program TIGR’s work was funded by NIH/NIAID & Novartis

2 Manufacturing Facilities Begin During Clinical Trials
High risk Large investment Ill-afford lost opportunity costs

3 Conventional Vaccine Development
DNA recombinant technology 5 – 15 years

4 Costs and Time Associated with Today’s 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 and antigen predictions
Steps 1 & 2: Produce the genome sequence, read it, and predict the vaccine candidates (reverse vaccinology) In silico comparisons and antigen predictions Whole genome sequence 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, Pizza et al. (2000) Science 287, Group B Streptococcus - GBS One genome sequenced - No candidate providing broad protection Tettelin et al. (2002) PNAS 99, Analysis of 8 genomes Highly diverse species Cocktail of 4 candidates confer broad protection Tettelin et al. (2005) PNAS 102, Maione et al. (2005) Science 309,

10 The Systems Vaccinology Pipeline

11 Step 3: Making the Vaccine Antigens via High 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?

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
Vaccination Site Collagen Module Lymphoid Tissue Equivalent Module

17 How To Create a Functional Ex Vivo AIS
Vaccination Site (VS) Lymphoid Tissue Equivalent (LTE) DC crossing endothelium Microbes and Infection (2003) 5:

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 VS (DCs) LTE (T/B) Humoral 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 R&D 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

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