BVS - Bacilligen Vector System/Vaccines
Bacilligen is developing vaccines for infectious diseases for delivery via BVS,
Bacilligen’s bacteriophage‐based vector system. BVS is unique in that, although
based upon bacteriophage (viruses that infect bacteria), the capsids can enter human/mammalian
cells where their double‐stranded RNA cargo is delivered and expressed to produce
proteins (or therapeutic RNA.) There are a number of RNA‐ and DNA-°©‐based vector
systems for delivery of genetic cargo to humans and animals, but BVS has many advantages
and none of the most serious disadvantages. These traits make BVS the vector of
choice where speed and efficiency are necessary, as in emergency preparedness/biodefense,
and veterinary applications. Bacilligen is currently funded via two NIH grants to
develop BVS-based vaccines for HIV and flu. Additionally, the Company has entered
into a collaborative research and development agreement with the U.S. Army Medical
Research Institute of Infectious Diseases (USAMRIID) at Ft. Detrick in Frederick,
MD to develop a single BVS vaccine against anthrax and plague.
Advantages
BVS possesses the utility of mammalian-derived and generated vectors such as adeno-associated virus or adenovirus since it can enter human cells, but is more easily and less expensively produced in bacteria. Other vector systems, since they are based on human or animal viruses, must be grown in mammalian cell culture. BVS can be grown in E. coli which is less expensive and substantially quicker.
Advantages of BVS over mammalian virus vectors or DNA plasmids include:
1. Pre-existing vector immunity
It has been shown that adenovirus vectors can present reduced efficiency at inducing immune responses in recipients to cargo antigens, and other complications can also result as was seen in recent results from an AIDS vaccine trial. Bacilligen has not extensively screened human sera, but based on our limited testing, and the fact that BVS is not a human virus, it is highly unlikely that there will be any pre-existing immunity to BVS.
2. Integration into recipient DNA
DNA vectors, plasmid or virus-based, can potentially integrate into the genome of the patient/recipient of vaccines or therapies based on them. Fear of insertional mutagenesis inducing oncogenesis or inadvertent activation or deactivation of critical genes in the host by the vector remains a concern. Since BVS is RNA-based, there is virtually no chance of integration into host genetic material.
3. Large cargo capacity
Some viral vectors have limited cargo capacity, thus limiting the size of the protein or the number of proteins encoded in the BVS RNA. Currently, BVS’ capacity is ~5 kilobases (kb). With further engineering, it is expandable to ~10 kb.
4. Flexibility
BVS can be constructed to directly deliver RNA encoding proteins for vaccination against infectious diseases, cancer and other disease states, therapeutic proteins, and functional RNA including interfering RNA (siRNA). In addition to direct administration of BVS capsids to humans, the capsids can be used to transiently transfect mammalian cells in culture for rapid cGMP recombinant protein production. For example, a single BVS can serve directly as a vaccine prime, and the same capsids used to drive production of a recombinant protein version of the same antigen(s) for subsequent boosting.
5. Faster
BVS is a rapid system — bulk directly administrable capsids can be ready in emergency situations within 7 days. The advantages for biodefense and pandemic flu are obvious. Further, because of this rapid turnaround, BVS will be useful in personalized medicine. While plasmid DNA offers similar speed advantages as BVS, DNA has shown difficulty in inducing immune responses andpresents the safety concerns noted above of potential integration into recipient DNA. Compared to other virus vector systems, BVS alleviates the need for mammalian cell culture to generate enough virus stock or the vaccine itself. In the case of the heralded cell culture based flu vaccine production scheme, time is lost to lengthy cell culture just to generate enough flu virus to infect another batch of mammalian cells to generate the actual flu vaccine taking in excess of 140 days. BVS production can be accomplished in 70 days, and could be reduced.
6. Less Expensive
BVS capsids are produced completely in bacteria, which are much less expensive to use as a substrate than mammalian cells. Further, the facilities are less expensive.
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How it Works
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Generation of BVS capsids with a specific cargo RNA sequence is shown in the adjacent figure. A sequence of interest, for example encoding antigens from a newly-emergent H5N1 flu strain, is synthesized chemically as DNA to drive invitro RNA synthesis. The resulting RNA is then electroporated into E. coli where the RNA directs production of BVS capsids containing the flu sequences. In an emergency situation, this producing E. coli strain will be used directly to initiate large scale production. In a conventional, non-emergency setting where a product will be made repeatedly, master and working seeds of the capsid-producing E. coli would be made for subsequent large scale production. After large scale production is complete, the capsids are purified, tested, filled, finished and lot release testing is performed.
For a more detailed discussion about the BVS family of bacteriophage and the technology inside BVS, please see the material following this overview, which includes references for further reading.
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Future Plans
Bacilligen continues to optimize the production and purification schemes for BVS capsids for direct use, and, to direct recombinant protein production in vitro,
to ensure greatest efficiency with respect to cost and time.
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Intellectual Property
Bacilligen has protected its intellectual property through a patent filing covering the technology and use of BVS.
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Partnering Opportunities
Bacilligen is interested in expanding the use of BVS for the delivery of vaccines for other indications, including cancer and patient-specific uses, as well as veterinary vaccines. Interested parties should contact Dr. Steve Bende, President and CEO of Bacilligen via email at
info@bacilligen.com or by phone at 301-217-9525.
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Details on the science behind BVS and literature citations