The U.S. military has been on the vanguard of defending the United States against biological weapons for over half a century, with USAMRIID at its core. Before the anthrax attacks of 2001, USAMRIID was largely the only “game in town” in the United States developing countermeasures against biological weapons threats, from the bench top through animal models of disease and ultimately testing in humans. That has changed, as the United States has invested billions of dollars to build new laboratories and fuel research in other government laboratories, universities, and pharmaceutical companies.
Despite the popular impression that the military can get around the rules, U.S. Army programs aren’t permitted to take any shortcuts when making new products and must answer to the FDA, just like everyone else.
Over decades the USAMU (U.S. Army Medical Unit) and USAMRIID have developed an array of vaccines against numerous infectious diseases like tularemia, Q fever, Rift Valley fever virus, Staphylococcal enterotoxin B, and chikungunya.1 Some of these were tested in the 1950s and 1960s under the classified “White Coat Program.” Seventh Day Adventists who wanted to serve their country but not carry weapons volunteered as research subjects to receive experimental vaccines and undergo exposure to some of the agents. Despite the ominous sound of this testing, the program’s ethical standards for informed consent of human volunteers were ahead of their time.
Hidden behind a cluster of buildings on Fort Detrick stands one of the few remaining vestiges of the United States’ biological weapons program during the Cold War: a one-million-liter stainless-steel sphere, referred to as the 8 Ball, that looks like a spaceship hovering three stories above the ground. Researchers released aerosols of pathogens inside the 8 Ball to test vaccines, and the White Coat volunteers stood on a catwalk and put their faces up to external portals. As they breathed, they inhaled agents like Q fever and tularemia. Afterward doctors monitored and treated them for illness in Fort Detrick’s hospital. No one died. The 8 Ball is now on the National Register of Historic Places, although some might prefer to tear it down and disavow that part of U.S. history.
Although multiple countermeasures were developed, few made it to full licensure (approval by the FDA), but the vaccines continued to demonstrate potency in regular animal testing. We continue to vaccinate laboratory workers with some of them through USAMRIID’s Special Immunizations Program, which fell under my purview as chief of the Medicine Division. Multiple agencies, including elite military units and laboratory personnel elsewhere (the National Institutes of Health [NIH], the CDC, universities), have sought our vaccines to protect their laboratory workers.
Demonstrating whether a new compound works starts in the lab using tissue culture or bacterial growth inhibition. Next we move to small animals (mice, rats, guinea pigs), then maybe rabbits or monkeys to see the impact on their behavior, appetites, weight, or kidney and liver function, and whether the compound treats or protects them against infection. This can take years, but once the compound passes these major hurdles, we are not even halfway to the finish line. Now comes the much harder part: taking the compound through rigorous testing in humans to licensure by the FDA. No matter how good something looks in animals, we cannot predict how humans will react or whether the compound works. Most countermeasures fail, so licensing new drugs or vaccines can cost $1 billion and take years or decades. Large pharmaceutical companies have little enthusiasm to invest billions of dollars in vaccines or treatments against rare, high-consequence events. The low potential for profit is one reason we don’t have many FDA-approved biodefense countermeasures. Developing drugs that treat chronic illnesses, like hypertension or diabetes, which must be taken long-term offer much greater profit potential.
Testing in humans runs through four phases, with increasing numbers of people receiving the new compound at each phase until we can prove the compound is safe and effective. This is a unique challenge and a significant vulnerability in biodefense and contributes to why we have few licensed vaccines and treatments against the highest bioweapon threat agents. In order to demonstrate proof of effectiveness in humans, we have to have enough people with the disease or at risk for the disease in whom we can test the product, but many of the biodefense diseases are rare. Medical ethics prevent us from doing tests such as giving people an anthrax vaccine and then infecting them purposely with deadly anthrax to see if the vaccine works.
The FDA developed the “Animal Rule” that offers a different pathway to approval, but the FDA has set a high bar. The scientific developers must produce an infection in animals that looks similar to human disease; the countermeasure has to work in animals the way we expect it to work in humans; and the countermeasure must be safe in humans. This might sound simple to achieve. It is not. Only a few compounds have been approved this way so far.
The work developing countermeasures continues, but it remains an uphill battle because our techniques are limited, the process takes years, and we can’t predict what a terrorist or adversary might reach for. We have done poorly at predicting the next infectious disease challenge—even those from Mother Nature. No one envisioned a massive Ebola outbreak like the one in West Africa from 2014 to 2016, nor did we suspect Zika virus would be lurking around the corner. Everyone in public health and pandemic preparedness continues to fear that a new, deadly strain of bird flu could adapt for rapid spread between humans and cause a major pandemic like the one that killed millions in 1918.
Although we have had some recent success with promising countermeasures against Ebola, back in 2004 when Dr. Kelly Warfield accidentally stuck herself with a needle that was possibly contaminated with Ebola virus, we had very few options to choose from. We scrambled as best we could to respond.