Rising to the Challenge

What exactly is biodefense?

The definition of “biodefense” has expanded over the years. Originally, it was limited to the idea of defending against a purposeful biological attack with a conventional infectious agent or toxin on military forces or civilians carried out by nation states, extremist groups, or a “lone wolf.” It is clear now that the term has broadened to include threats from engineered pathogens, emerging infectious diseases, new influenza strains, and even from laboratory accidents. An example of this expanded interpretation can be seen in the US 2018 National Biodefense Strategy, which was recently signed by President Trump. 

Though there is, of course, a tremendous focus on defense against conventional, chemical and nuclear weapons, offensive biological weapons remain a credible threat to both civilians and the military. Naturally occurring emerging biological agents, such as new influenza strains, multidrug-resistant bacteria, and viruses that cause diseases, such as MERS, Lassa fever, dengue fever and Nipah also present significant threats to human health in that they have the capacity to quickly incapacitate and/or kill large numbers of people before a viable intervention can be put into place.

Many people believe that these emerging diseases will become more problematic as  population density increases and international travel becomes even more frequent. The US has made significant investments in protecting citizens against such pathogens, but for most emerging disease threats, there are still no licensed vaccines or effective treatments.

Revolutionary changes in genetic engineering have led to more powerful and accessible methods of manipulating genetic elements. There have also been increasing concerns about the prospect that purposefully-engineered agents could be developed and effectively used, which could be designed to possess traits that the naturally-occurring agents do not normally have. Engineered traits could include increased pathogenicity, an increased ability to survive in the environment or even the ability to suppress immune responses while still generating a productive infection.

Military forces must also be prepared for attacks with biological agents. “Germ warfare” practices and programs have existed since antiquity, and sophisticated “weaponized” forms of some of the most lethal agents and toxins, as well as the means to deliver them, were developed during World War II and the Cold War era. Historically, weapons containing infectious agents or toxins have been attractive, owing to their ability to incapacitate or kill enemies, spread from individual to individual (in the case of bacterial or viral agents), and provoke chaos and terror. At present, there are countermeasures, including for anthrax and smallpox, which are licensed and used by military forces deployed to certain regions, but additional options for other agents are still needed.

What are the business challenges; for example, navigating the government contracting process or the regulatory process?

Many companies understandably do not want to risk developing such products solely at their own expense, and therefore they need to seek external funding. These products have a very limited market and customer base – in the US, for example, the only customer is the federal government. Development funding can be sought in the form of grants and contracts from the Department of Health and Human Services, or Department of Defense, but competition for these funds can be fierce! The process can also be bureaucratic and very intimidating for companies who have never held such contracts. Helping companies with this process is one of our strengths.

Recently in the US, the government has been experimenting with a new, less-complex form of agreement to attract new firms. These agreements, awarded under an “Other Transaction Authority,” carry the promise of a more rapid-funding process, reduced administrative burden, and fewer regulations overall. But it is not clear yet whether this change will have the desired effect, particularly in cases where the government’s product requirements are small or unknown.

Depending on whether a vaccine is intended for use in soldiers or civilians, are there different considerations?

To date, I have not seen a difference between the requirements for licensing products designed for civilians versus military personnel – whether it be from a manufacturing, safety or efficacy standpoint. The passage in the US of Public Law 115-92 from January 2018 may change this as the law requires the FDA to prioritize the development and availability of medical products intended to help save the lives of military personnel. Given that this law is new, and just being implemented, it remains to be seen whether the FDA will go as far as to redefine some of its risk/benefit analyses to expedite the delivery of such life-saving products.

Tell us about the DynPort Vaccine Company and what you focus on…

It’s quite a long, complicated story! DynPort Vaccine Company LLC (DVC) was founded in 1997 as an entity to bid on a US Department of Defense (DoD) “prime systems” contract to conduct biodefense vaccine development for the DoD Joint Vaccine Acquisition Program (JVAP) for an exclusive period of 10 years. The new company won the contract that year, and still performs work for JVAP. As part of a larger acquisition in 2003, DVC became part of the Computer Sciences Corporation (CSC). CSC’s government contracting business was subsequently split from their commercial business and at the same time merged with SRA, becoming the company CSRA. CSRA was purchased by General Dynamics in 2018 and today DVC is a managed affiliate of the General Dynamics Information Technology business unit. Even though we’ve had a few different parent companies, DVC still functions as an LLC and carries its own brand. We operate exclusively as a US government contractor, and have performed work for DoD and the Department of Health and Human Services. We have worked on a great variety of products over the years, including vaccines, other biologic products, and small molecule anti-infectives. In 2005, the company licensed vaccinia immune globulin for the treatment of adverse reactions in smallpox vaccines, in particular progressive vaccinia.

DVC manages product development programs for government agencies, primarily (but not exclusively) related to medical countermeasures. Unlike many other biotechs, DVC does not own the intellectual property for its products. Instead, we partner with government agencies and other companies who own IP of interest. We are also a virtual company, which means we do not own any labs or manufacturing facilities. All of those activities are contracted out, which means we can use the best performers at the best value to complete complex, long-term development projects.

What projects are you working on now?

DVC has active contracts to develop specific products through to FDA licensure; namely a recombinant botulinum vaccine, recombinant plague vaccine, and human butyrylcholinesterase (bioscavenger), which is designed to protect from the effects of exposure to highly lethal organophosphorus nerve agents. All of these products are intended to be administered to active military personnel, and all are to be licensed under the FDA’s Animal Rule. DVC also holds separate contracts that issue specific task orders – the scope of which may include development of assays, conducting cGMP manufacturing, or conducting clinical trials on specific products. Our vaccines are being developed for JVAP, and the bioscavenger product is being developed for the DoD’s Chemical Defense Pharmaceuticals. These products have specific requisite performance characteristics attached to them, which are outlined in a Capability Development Document (CDD). CDDs are very useful for the contractor, because companies know early on in development the performance requirements that have to be met for the product to be acceptable to the DoD. These requirements may be separate or unrelated to FDA requirements.

Regarding the plague vaccine, the clinical-stage product we are developing for DoD is a recombinant fusion protein, which makes use of the two most well-known and well-characterized protective antigens from Yersinia pestis, namely the F1 antigen and the V antigen. Right now there is no FDA-licensed plague vaccine. From the 1940s to the 1990s there was a killed whole cell vaccine available to prevent plague, but the vaccine, last manufactured by Greer Laboratories Inc., was rather reactogenic and did not protect against all forms of plague. There is published evidence that subunit vaccines can protect against all forms of disease (1).

DVC is also advancing the bioscavenger protein as a prophylactic countermeasure designed to protect against the potentially lethal effects of organophosphorus nerve agents. Over the years, there have been many attempts to make this molecule by various means, but no products have progressed. As a result, the decision was taken to purify butyrylcholinesterase directly from human plasma, where it is found in trace concentrations. DVC and our partners are doing just that, and this product has the potential to very nicely add to the chemical defense arsenal for the services (2).

What are the challenges when working on highly confidential projects?

Many of the products that we have worked on are regulated by either the US Department of State, or Department of Commerce, but are not classified as Secret or Top Secret. The most stringent controls of technical information that we work under are the International Traffic in Arms Regulations (ITAR), which govern materials that are on the US Munitions List. These regulations limit the sharing of technical information about our products to only US persons, which means we cannot present technical information at scientific conferences or publish our findings. This is a challenge because publication and presentations are important to scientists working in product development! We have also needed to establish an infrastructure to be compliant with all aspects of the ITAR – a huge effort that took over a year.