About This ProjectOur ultra-low dose, synthetically-designed Influenza vaccines are highly immunogenic & vaccinate ferrets at a dose 1,000-fold lower than current shots. Potentially if current infrastructure yields 1,000 doses a Codagneix vaccine would generate 1,000,000 doses. Thus we could rapidly source vaccine for the entire globe in the event of a pandemic. Here we will design an H5N1 pandemic vaccine strain to show utility in combating a potential pandemic.
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What is the context of this research?
We have found the Achilles heel of all viruses. What is so unique about our approach is that our designer vaccines on the surface look IDENTICAL to the killer strain so they are extremely effective.
Our start-up is Codagenix and we have a Computer-Based technology that designs and constructs synthetic vaccines - this platform can be applied to ANY human virus.
We are currently developing a new Influenza vaccine that has multiple competitive advantages.
1t is a complete match to the target so may have higher efficacy and 2) it works at doses1,000-FOLD Lower than current vaccines in ferrets.
That means to manufacture 1,000 current flu-shot doses = one could manufacture 1,000,000 Codagenix doses, a true game changer in the field.
We have strong peer-reviewed publications in the top-scientific journals in the world (Science and Nature Biotechnology) as well a sNIH funding to support the development.
The support we seek will provide the initial funding to design and synthesize an H5N1 pandemic virus using our approach - providing a template for a future pandemic response with our ultra-low dose vaccine.
What is the significance of this project?
The 2009 pandemic highlighted the
inadequacies of the current Influenza vaccines as a means to respond to a pandemic – namely that they require large quantities of antigen/virus per dose (15ug of HA or 10^10 Influenza particles).
Nine months after the pandemic emerged, only sufficient doses (100 million) to protect 1.7% of the world’s population had been produced and most were the inactivated vaccine, which has low efficacy in high-risk populations.
This proposal seeks to move beyond the adage that we need to increase our manufacturing capabilities and source more embryonated eggs as a means to vaccine the world in the event of pandemic.
In order to provide sufficient vaccines for the globe in the event of a pandemic, the current infrastructure, making the current vaccines (at its “best case”), would take a year to yield a sufficient quantity (Collins et al., Vaccine 2009).
We present a vaccine platform capable of yielding highly immunogenic, live-attenuated influenza vaccines that are 100% antigenically to the target virus AND are capable of cross-protecting at an ultra low dose- a vaccinating dose that is 1,000-10,000 fold lower than current vaccines (Wang et al., PNAS 2013).
We have developed a rational, computer-aided approach to construct highly-efficacious live attenuated influenza virus vaccine candidates, termed Synthetic Attenuated Virus Engineering (SAVE), (Coleman et al., Science 2008). The custom attenuation via SAVE is achieved by designing hundreds of synonymous, silent nucleotide changes across the viral genome, de-optimizing the virus’s codon pair bias (Mueller et al., 2010. Nature Biotech).
This rational gene design approach allows Codagenix Inc. to maintain the amino acid sequences to be 100% identity to all viral proteins. Also maintaining a 100% amino acid sequence match to the vaccine target provides a characteristic of SAVE-attenuated vaccines that is not present in any currently available vaccine technology (Coffin J., New England Journal of Medicine 2008). SAVE-designed live attenuated influenza virus vaccine candidates have been shown to be cross-protective against heterologous challenge (Wang et al., PNAS 2013) and we have developed an ultralow-dose vaccine candidate for the clinically significant pandemic influenza strain, A/California/07/2009 (CA07). CA07 was the strain responsible for the 2009 pandemic.
What are the goals of the project?
In this proposal, we provide an inverse approach to solvng the threat of pandemic, which, if achievable, will present a new paradigm for influenza vaccinology and allow for rapid response to pandemic threats. Rather than increasing capacity – DECREASING the effective vaccine dose by 10,000 to 100,000-fold would achieve the goal of generating enough vaccine for an entire nation or globe – very cheaply and very quickly.
We believe this can only be done with a highly effective, yet very safe Live Attenuated Influenza Vaccine (LAIV). Codagenix’ core technology termed Synthetic Attenuated Virus Engineering (SAVE) is based on rational, computer-aided gene design to produce attenuated viruses through a process we call gene “deoptimization”. SAVE generates live-attenuated viruses that are 100% antigenically identical to wild type virus in all their proteins. SAVE was first developed in poliovirus (Coleman et al., 2008. Science), validated for live attenuated Influenza A vaccine candidates, (Mueller et al., 2010. Nature Biotech.), and shown to yield an Influenza A vaccine capable of protecting mice at ultra-low doses against wildtype and heterologous challenge (Yang et. al., 2013, PNAS).
In this application we seek support to apply the SAVE technology to develop a pandemic influenza vaccine program, based on SAVE-deoptimized strains that that are highly effective at ultra-low doses and thus quickly and cheaply produced when needed, rather than stockpiled.
Specifically we will pursue to following Goal: Apply the SAVE-platform to 'de-optimize' a pandemic H5N1 strain and then recover this attenuated strain from cells in culture.
Note: There is large follow-on support to test the strain recovered from this project in animals at no-cost under a contract with the National Institutes of Health. The contract covers testing of our ultra-low dose influenza vaccines in animals. We just do not have the funds to design, synthesize, and recover an ultralow dose H5N1 pandemic virus
Synthetic DNA construction: This is the basis of this project. Although the current price of DNA synthesis has dropped to below $1 per bp, the industry still relies on the “classical” oligonucleotide-based synthesis that is still quite costly. The budgeted amount will gives us the ability to synthesize 7.5kb of DNA, a sufficient quantity to ‘de-optimize’ a pandemic H5N1 influenza strain.
Cloning: This synthetically customized DNA needs to be cloned into a suitable vector that will allow us to "re-boot' the synthetic virus from cells.
This synthetic DNA will be transfected into cells and then replicating - H5N1-vaccine strain virus will be recovered.
Salaries: of research scientists to design the "optimized" pandemic strain using the SAVE software platform and then performing the cloning step
Recovery of the Strains: will occur in the BSL-3 laboratory at Utah State University as a fee for service and will follow all safety procedures
Meet the Team
Team BioTogether Dr. Coleman, Dr. Wimmer, and Dr. Mueller have spun-out of Dr, Wimmer's lab at Stony Brook University where they co-invented SAVE, a rational computer-aided approach of designing synthetic, attenuated pathogens.
Mueller, Wimmer and Coleman co-founded Codagenix Inc. to develop improved live attenuated human vaccines of medical need. Dr. Wimmer was recently inducted into the National Academy of Sciences in recognition of his accomplishments as a molecular biologist who has been an expert on viral pathogenesis for over forty years. Dr. Coleman’s cross-functional skill set (strong science and finance) is capable of enhancing and expediting R & D milestones and will allow him to lead all facets of the project. Dr. Mueller is a skilled, driven scientist that has served as primary investigator on multiple externally funded projects, leading teams of postdoctoral fellows and technicians.
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Additional InformationDr. Wimmer was recently inducted into the National Academy of Sciences in recognition of his accomplishments as a molecular biologist who has been an expert on viral pathogenesis for over forty years. In the course of these studies Dr. Wimmer has deciphered the genome sequence and genetic structure of poliovirus, the antigenic structure of the poliovirion, and the viral IRESs. Recently, he has co-developed the SAVE platform strategy of whole genome synthesis that allows for the modification of a pathogen’s genetic information to an extent that was hitherto impossible. Dr. Wimmer’s unmatched scientific acumen, experience as an independent investigator, and creativity will be an invaluable asset to this project. As a co-founder and senior advisor to Codagenix, he will provide continually scientific direction on research approaches and project milestones attainment.
Dr. Coleman, together with Dr. Wimmer and Dr. Mueller co-discovered the SAVE technology and co-founded Codagenix, Inc. His work focuses on rational gene design for vaccine construction. He has multiple high impact publications, is the primary investigator on externally funded research projects, and has project management skills in small business and biotechnology. Dr. Coleman completed his MBA in finance while simultaneously co-founding Codagenix Inc., conducting research as a postdoc, and teaching/researching as an Assistant Professor. Dr. Coleman’s cross-functional skill set (strong science and finance) is capable of enhancing and expediting R & D milestones and will allow him to lead all facets of the R & D process.
Dr. Mueller is a skilled, driven scientist that has served as primary investigator on multiple externally funded projects, leading teams of postdoctoral fellows and technicians. He has experience working hands-on, and simultaneously managing projects, involving multiple unrelated viruses - poliovirus, Influenza A, and other viruses. This simultaneous management experience has left him ideally suited to excel as PI this project, leading the applying of SAVE to H5N1
1. Coleman JR, Wimmer E, Mueller S. Virus
attenuation by genome-scale changes in codon pair bias. Science, 2008. 320(5884): p. 1784-7.
2. Attenuation by a thousand cuts. Coffin JM. New England Journal of Medicine. 2008 Nov 20;359(21):2283-5
3. Mueller S., Coleman JR., Wimmer, E. et al. Live attenuated influenza virus vaccines by computer-aided rational design. Nature Biotechnology. 2010 Jul;28(7):723-6.
4. Yang C, Skiena S, Futcher B, Mueller S, Wimmer E.
Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):94
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