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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 VaxDesign Corporation Orlando, FL 32826 www.vaxdesign.com Eric Eisenstadt, Hervé Tettelin, Scott Peterson

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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

VaxDesign Corporation

Orlando, FL 32826

www.vaxdesign.com

Eric Eisenstadt, Hervé Tettelin, Scott Peterson

The Institute For Genomic Research

Rockville, MD 20850

www.tigr.org

VaxDesign’s work was funded by DARPA/DSO in the

Rapid Vaccine Assessment Program

TIGR’s work was funded by NIH/NIAID & Novartis


  • High risk

  • Large investment

  • Ill-afford lost opportunity costs

Manufacturing Facilities Begin During Clinical Trials

http://www.vaccinealliance.org/site_repository/resources/21VacMarket.pdf


5 – 15 years

Conventional Vaccine Development

DNA recombinant technology


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?


Reverse Vaccinology: Applying Genomics, Immunology & Engineering To Rapidly Assess Vaccine Candidates

High Throughput Gene

Expression

~ 6 months - 1 year


Genomics tissue engineering automation provide a new approach
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



Whole genome sequence Approach

In silico comparisons

and antigen predictions

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


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



Step 3 making the vaccine antigens via high throughput expression
Step 3: Making the Vaccine Antigens via PartnershipHigh 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



Men B Vaccine: Genomic Approach Partnership

Bottleneck and relevance?

http://www.meningitis.org/uploads/C05_2_15_Rappuoli.pdf


The systems vaccinology pipeline2
The Systems Vaccinology Pipeline Partnership

  • Clinical trial in a test tube: high throughput in vitro assay system


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


Lymphoid Tissue human vaccine candidates

Equivalent Module

Vaccination Site

Collagen Module

Artificial Immune System Cell Interactions


How To Create a Functional human vaccine candidatesEx Vivo AIS

Lymphoid Tissue Equivalent (LTE)

Vaccination Site (VS)

DC crossing

endothelium

Microbes and Infection (2003) 5: 205-212


Example human vaccine candidates: Representative Ex-Vivo Immunogenicity Testing

Donor had a high anti-tetanus toxoid titer; yet, the industry standard PBMC assay failed to show protection


The artificial immune system construct supports the induction of naïve and recall human B cell responses


Predictive induction of naïve and recall human B cell responsesex 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


The systems vaccinology pipeline3
The Systems Vaccinology Pipeline induction of naïve and recall human B cell responses

Develop vaccines or fully human therapeutic mAbs


When thinking of vaccine manufacturing
When Thinking of Vaccine Manufacturing …. induction of naïve and recall human B cell responses

  • 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


When thinking of vaccine manufacturing1
When Thinking of Vaccine Manufacturing …. induction of naïve and recall human B cell responses

  • 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


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

http://www.bio-itworld.com/issues/2006/sept/2-billion-pill


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