What the future may hold for the Strategic National Stockpile for Biodefense

In the year 2001, shortly after the events of 9/11, letters containing anthrax spores appeared in the offices of senators and news outlets. The nation was scared, but within 12 hours, medical countermeasures were rushed, under armed guard by US Marshals, to New York City and Washington, DC—the sites of what was later described as an anthrax terrorist attack.

A few years later, in 2005, after Hurricanes Katrina and Rita struck the coasts of Louisiana and Mississippi, medical equipment and supplies were immediately dispatched to the scene in “12-hour push packages,” or pre-configured caches of 130 containers of antibiotics, oxygen tubing, and syringes—enough to fill a widebody plane’s belly. This scenario was repeated after Superstorm Sandy.

In each case, the cavalry that came to the rescue was a $7 billion agency, operating largely below the radar, from 5-story-high warehouses in undisclosed locations outside of Washington, DC.

Its name: the Strategic National Stockpile for Biodefense.

And this organization is likely the first thing that the country will turn to in the event of a biological attack, relying on the massive quantities it has on hand of shrink-wrapped boxes of life-saving medicines, to combat everything from smallpox to influenza. And the stockpile’s team spends years in planning, training, and conducting exercises, so that responders will know what to do if 100,000 cases of some new disease with pandemic potential appears—what global health officials have sometimes dubbed as “Disease X.”

Yet many people have not heard of this stockpile—even though the Washington Post estimates that “[n]ationwide, the repository contains enough medical countermeasures to add up to more than 133,995 pallets. Laid flat, they’d cover more than 31 football fields—or 41 acres of land.”

So what, exactly, is the Strategic National Stockpile for Biodefense? What are some of the possibilities for the stockpile’s future, and how might they affect the way these supplies are delivered to the site of a biological attack and used in the future? And how could they deal with engineered or antibiotic-resistant variants of known biothreat agents? The answers may lie in  new technologies that uses gene-based approaches—based upon the nucleic acids DNA and RNA. They could be used as therapies that are straightforward to produce, cheap and easy to store, and in quantities large enough for a massive number of doses to be maintained within a small footprint at several different sites scattered across the country.

Preparing for the unexpected. The idea behind the stockpile is that if a biological attack occurs, enough resources will be available to ensure that exposed populations have rapid access to medical countermeasures, including the antibiotics, anti-toxins, and vaccines stored in its vast warehouses. Although the cost of maintaining this vast array of countermeasures is small in light of the impact of the large-scale release of some biothreat agents, the cost is still significant partially because one cannot simply squirrel away a pile of these materials and forget about them; things degrade and their potency diminishes over time. This is one reason why the drugs found in everyday household medicine cabinets are stamped with expiration dates—even including a bottle of aspirin.

Consequently, one of the most surprising features about the stockpile is that in all likelihood, it is probably incomplete. The reason for this is that although the stockpile includes what are presumed to be the best medical countermeasures for a broad range of potential biothreats—we don’t know the exact inventory because the identity of the contents are closely held —there is an even broader range of potential biothreat agents that an adversary could use in an attack. And stockpiling countermeasures for every conceivable individual agent is currently not feasible because countermeasures for some biothreat agents do not even exist yet—and even if they did, the continuous maintenance of copious countermeasures may not be logistically or financially feasible. There is also the possibility that an adversary could select or engineer an agent that is simply resistant to all-known medications.

To address this problem, future stockpiles may benefit from an emerging approach to disease treatment: shifting countermeasures from today’s emphasis on protein-based vaccines and antitoxins to a new system primarily focused on nucleic acid (DNA and RNA) coding for genes that help the body protect itself from myriad infectious diseases and toxins. This approach offers the long-term prospect of a stockpile that could simultaneously be more comprehensive and vastly cheaper to establish and maintain. Such a future is conceivable because of the accelerated pace of molecular biology research and development of methods to safely transfer (or what specialists refer to as “deliver”) synthetic genes into people.

DNA vaccines, for example, are based on the delivery of synthetic genes that code for individual proteins found on a bacteria or a virus—instead of using the whole pathogen itself as a basis for the vaccine. (A pathogen is a biological agent—such as a parasite, bacterium, or virus—that causes disease or illness in its host.) This emerging approach is akin to the current trend toward the use of “sub-unit” vaccines, which contain only the proteins known to activate the immune system.

Both approaches are safer than traditional vaccination methods that use a weakened or “attenuated”—but still live—strain of the pathogen, which is generally much more dangerous by comparison. For example, the live oral polio vaccine is no longer used in the United States because of the risk of its reversion—however small—to a strain of the virus that can cause paralysis. Consequently, recent research efforts have been focused on vaccines that contain only the harmless parts of the pathogen that can be recognized by the body’s immune system as belonging to potentially dangerous foreign agents. Once the immune system has established a long-term memory of these recognizable markers, the next time the same pathogen protein appears (now in the context of an infection), the body can immediately identify it as foreign and begin producing large quantities of protective antibodies to fight it.

More tantalizing for a future Strategic National Stockpile than improved vaccines—which would still have a lag time of one-to-two weeks until protection—is the possibility of bypassing the requirement for immune “education” entirely, and directly delivering genes that code for pathogen-specific antibodies, thereby achieving more rapid protection. The process involves determining the genetic sequence for an antibody that is known to offer protection against a pathogen and then delivering that gene to cells. The body’s own cells re-use their existing protein production machinery and become antibody factories, a method termed “antibody gene transfer.” It is a form of immunotherapy that has been garnering significant attention lately as a new approach for treating some chronic diseases, such as cancer. Optimistically, the approach may be ideal for emergency use when drugs are not effective—in other words, a single medical countermeasure that protects populations whose exposure status is unknown, as well as those needing treatment to clear an incubating or clinical infection following a biological attack.

Using antibodies to treat an infectious disease, or to provide temporary protection against future near-term exposure to biothreat agents, is not new. Scientists have mature laboratory-based manufacturing and production processes to produce and harvest protein antibodies similar to those made by the immune system. As therapeutics (meaning that they are concerned with the treatment of a disease as opposed to the prevention of one), these products can already be injected into people to rapidly neutralize pathogens and boost the immune system. There are, however, challenges related to their large-scale production, purification, cold storage, and shelf life that have limited wide-scale adoption of antibodies for prophylactic and therapeutic treatment, except for diseases without alternative treatment options such as for Ebola virus disease and botulinum neurotoxin poisoning.

What’s next? Over the past year, many articles in peer-reviewed journals have described early-stage success with a new way to prevent infectious disease: artificially initiating antibody production via antibody gene transfer. In this process, cells that do not play a significant role in the immune system—including muscle cells (following injection) or nose and lung cells (following inhalation)—have been coaxed into producing large quantities of specific antibodies to fight the pathogen. Furthermore, in some instances they excrete large enough quantities of the antibody to protect against lethal infection. The process works whether or not the individual has been previously exposed to the pathogen or not, because antibody production via gene transfer bypasses the entire immune system. As such, it should work effectively even in populations taking immunosuppressive drugs—a group left vulnerable with many traditional medical countermeasures. Some animal studies show that the process can work within a matter of hours, an aspect which could be vital during the crucial, limited time window available to respond to a biological attack.

Antibody gene transfer can also be used to take advantage of recent advances in bioengineering, so that antibody characteristics can be developed that are not found in nature. Recent research has demonstrated that novel antibody genes could be produced with the key properties of multiple different antibodies fused into one—meaning that one hybrid antibody could offer protection against multi-strain pathogens or those that mutate frequently, such as influenza. This ability to design custom antibodies bodes well for the development of future countermeasures, offering broad-based protection from even engineered or antibiotic-resistant variants of known biothreat agents.

A switch to countermeasures based on nucleic acid instead of protein could massively simplify components of countermeasure stockpile management. DNA and RNA are straightforward to produce, cheap and easy to store, and material enough for a massive number of doses can be maintained within a small footprint. As such, management of local strategic stockpiles, as opposed to a national warehouse, may be possible. Local maintenance would ensure that at a minimum, emergency medical countermeasures against known threat agents are located closer to population centers, reducing transportation-related delays during an emergency.

At the same time, it might be possible to develop a standardized platform for the rapid development of countermeasures—one capable of quickly identifying and producing genes “on-demand” that code for antibodies against emerging biological threats. This approach would allow for standardized production procedures, thereby streamlining highly-varied manufacturing steps or reagents, and reducing costs. Gene-based countermeasures containing only nucleic acid would vastly simplify large-scale manufacturing, because individual antibody genes would be nearly identical, varying only by a small portion of the genetic sequence from countermeasure to countermeasure. Furthermore, the gene packaging and delivery mechanisms could be made identical to further streamline a platform-based development process.

The Defense Advanced Research Projects Agency has been investing heavily in this area, with the goal of reducing the time to develop treatments from 30 weeks with traditional antibodies to eight weeks using antibody gene transfer approaches. To protect against novel threats during an emergency, however, the complicated process for determining the specific antibodies that confer protection will need to be reduced to days, not months—a feat that may eventually be achieved when computer modeling and simulation of antibody interactions improves. Nonetheless, if upcoming clinical trials using antibody gene transfer techniques to target an infectious disease show success, it may finally pave the way for a standardized platform for production of gene-based countermeasures.

As with any therapeutic, a primary concern is ensuring that gene transfer products can be safely tolerated in people. Recent basic research into antibody gene transfer approaches to protect against influenza, Ebola virus, and Zika virus are promising; however, there are long-standing safety concerns stemming from gene therapy. Although antibody gene transfer differs from gene therapy in that integration of a new gene within the cell’s genome is not necessary or desirable, all therapeutic gene delivery research slowed after a volunteer in a gene therapy clinical trial tragically died in 1999 due to immune hyperactivation—an immune response so massive and acute that it led to multiple organ failures. Fortunately, the gene therapy research field has seen immense progress in the last 20 years—to the point where the US Food and Drug Administration (FDA) has recently approved several gene therapies, and the National Institutes of Health no longer requires federal oversight of each clinical trial. Progress includes safer gene delivery mechanisms that do not unintentionally activate the immune system, and techniques that minimize or eliminate the risk that transferred genes will integrate into the host cell—which in extreme cases can cause diseases such as cancer.

To further improve safety, there are prospects for also including genes with a genetic “off-switch,” that could be activated if the recipient shows adverse effects from the treatment. The switch could be triggered by consumption of a benign drug, and would have the effect of shutting down only the cells that received the synthetic gene that caused the adverse reaction. In a large-scale biological attack, the use of such novel approaches may be necessary if decision-makers are forced to consider deploying incompletely tested or non-FDA-approved countermeasures, potentially under FDA’s compassionate use rules.

Although still years away, the prospect of local stockpiles of DNA- or RNA-based countermeasures that can protect large cities and military bases against known biothreat agents is appealing. Eventually these stockpiles could be more comprehensive and cheaper to maintain than what is currently available at the national scale. Importantly, with a common approach to the production and utilization of nucleic acids, as opposed to one-off vaccines and antitoxins, the grand vision for a truly standardized platform approach for rapid countermeasure production against novel biological threat agents may finally be achievable.