Experts tend to arrange biological threats in tiers. And anthrax may very well have an entire shelf to itself. After all, it was a series of deadly letters containing anthrax sent through the mail just weeks after 9/11 that spawned the biodefense industry as it exists today.
On the heels of anthrax comes a string of deadly agents that scientists also fear can be used as weapons and spread with ease. These include small pox, botulism, plague and tularemia. Most of the medical countermeasures stockpiled by the government were engineered to combat anthrax and small pox. Scientists throughout the private sector and in university labs are racing to develop vaccines for the others before they can be used in a large-scale act of bioterrorism and before the natural consolidation of the industry whisks away funding opportunities for research and development.
Maryland’s DynPort Vaccine Co. has contracts with the Pentagon to develop vaccines for plague and botulinum neurotoxin. The former is of particular concern because it is passed so easily between people, and the latter is “one of the most potent threats known to mankind,” said DVC President Robert House. Botulinum neurotoxin can easily be turned into a weapon and used to contaminate water and food sources, he said. An attack with “bot-toxin” would have devastating effects far beyond the deaths of those exposed.
“It shuts down your breathing apparatus and it is necessary to use artificial ventilation and supportive therapy,” House said. “While death certainly is a bad outcome, when people become incapacitated in large numbers it creates a huge burden on the healthcare industry. That would make us more susceptible to other diseases because now all of our medical resources are being taken up.”
Plague, which wiped out a third to half of Europe’s population during one outbreak in the Middle Ages, also is attracting the attention of researchers in academia.
Data released by the Army a few years ago showed that vaccines currently undergoing clinical trials poorly protected African green monkeys from an aerosolized version of Yersinia Pestis, the gram-negative bacterium that causes plague. The reasons for the unsatisfactory results remain unclear, making it difficult to predict whether the vaccines will protect humans, said Stephen Smiley, adjunct professor of medicine at the University of Vermont and corporate relations director at the Trudeau Institute.
Smiley and a team of researchers are trying to create a vaccine that would protect members of the military and the public from a weaponized version of the plague. His laboratory aims to add “cell-mediated immunity defense” to plague vaccines. In one series of studies, his team is developing safe, live-attenuated vaccines. In another effort, Smiley and company seek to complement vaccine candidates developed by the Defense Department with antigens that activate T cells and trigger protective cellular responses.
Plague is one of the few agents that has been deployed as a weapon, Smiley said. The Japanese dropped ceramic bombs containing fleas carrying bubonic plague during World War II. It also was loaded onto intercontinental ballistic missiles during the Cold War. When inhaled, it manifests as pneumonic plague, a contagious disease that causes death within a few days. A 1970 World Health Organization study concluded that the detonation of “a plague bomb” over a city of 5 million could infect 150,000 people, of which 36,000 might die.
The government has spent a great deal of effort focusing on the development of antibiotics to protect against threats like plague, but some scientists in the research trenches consider vaccines a more suitable tool.
“I think the government prefers therapeutics over vaccines,” Smiley said. “They appear to want broad-spectrum therapeutics that work against multiple threats. However, broad-acting agents are difficult to produce and antibiotic-resistant threats exist, so vaccines may be our only viable option.”
Some university labs are investigating different ways to manipulate cells and boost immunity to biological threats. Texas A&M University researchers are looking inside the human body to study the details of cells under attack. Scientists want to know which genes allow toxins and microbes to hijack cells so they can eventually develop drugs to protect humans against biological attacks. The Defense Threat Reduction Agency is funding their work, which involves the screening of thousands of cell lines from mice, each with a missing gene. The strongest cells will be developed in living mice to test their resistance to deadly agents. The studies are focusing on rabies, brucella and botulinum. The latter paralyzes respiratory muscles, so “it’s not like we can just give them a shot of antibiotics and send them home,” said Deeann Wallis, a molecular geneticist and project manager for the research, which eventually could lead to vaccine candidates.
Researchers from the National Institute of Standards and Technology and the Weill Cornell Medical College have designed artificial cells that can lure, entrap and inactivate deadly viruses. These decoys will allow scientists to study the way viruses attack cells and may even lead to a new class of antiviral drugs.
The protocells, which scientists call “honey pots,” have successfully deactivated experimental versions of Nipah and Hendra, which are henipaviruses that cause fatal encephalitis. These viruses belong to a large class of human pathogens, which also includes mumps and measles.
Still, the “800-pound gorilla is clearly anthrax,” House said. Though it is widely considered the most serious threat to troops and civilians alike, House and other researchers said that the United States is in fairly good shape to deal with the effects of anthrax. There currently is a vaccine licensed by the Food and Drug Administration to protect against the disease. BioThrax was developed by Emergent BioSolutions, and it has been administered in more than 10 million doses to some 2.5 million people, mostly members of the military and other high-risk government employees.
Even though the BioThrax program has been around for more than a decade, the company is trying to figure out ways to make it more efficient. BioThrax is currently administered over five doses and an annual booster. The government has expressed an interest in accelerating the effects of the drug, said company president Daniel J. Abdun-Nabi. The firm has an application in to the FDA to reduce the requirement to three doses with a booster every three years. It also is developing an antibody to use as a life-saving therapeutic once someone has been infected with the disease.
Though the company had focused some attention on botulinum in the past, it is now completely zeroed in on anthrax. “The government has prioritized what it thinks are the top threats and it has to work within budgets,” Abdun-Nabi said. “It has to deal with the ones that are most weaponizable and easiest to deploy. In that respect, anthrax is clearly number one on the list.”
Quoting a former Department of Health and Human Services official, he added: “The top three threats facing the nation today are anthrax, anthrax and anthrax.”
Companies like Emergent BioSolutions and DVC, which already have lucrative relationships with the government, have staked out fertile territory in the biodefense market landscape. Others, especially smaller companies, may never be so lucky, executives said.
The next decade or so will be key for the slew of firms playing in this space, industry representatives said. As products prove successful, the government can begin to work with just a handful of companies to stockpile the effective drugs. The consolidation of this market is inevitable, executives said.
Unlike commercial medicines, vaccines against bio-threats are not depleted as they are produced. They are stockpiled until they expire and then replenished. And at the end of the day, all of the companies seeking to develop pharmaceutical countermeasures to biological threats have one customer — the government.
“We’re still trying to figure out how this will all play out in the future, because this is not a model that can sustain most of the smaller companies that are currently engaged in this space,” House said. “Eventually it will mature to the point that the government and probably just a few companies are going to be producing these products.”
Abdun-Nabi calls this impending amalgamation a natural evolutionary part of any industry. “When you think about the real commercial players out there, it eventually shrinks down to a handful of them, somewhere in the single digits, maybe low double digits,” he said. “I don’t think the biodefense arena is much different than the commercial arena.”
In late 2009, market research firm Business Insights published a report on the biodefense industry and its future. The study showed that the main driver of the market, the U.S. government, had spent about $50 billion on countermeasures since 9/11. The report warned that the growth of the industry would slow as the initial funding surge for vaccines under President Bush had ended. A lagging economy also could spell doom for some companies in the biodefense space.
“As many of the active participants are small-scale and reliant on outside funding to maintain operations, reduced credit options could force them out of business,” said one of the report’s key findings. It also states that a “single serious bioterrorist incident in the U.S. could spur another round of government spending as happened after the 2001 anthrax attacks.”
It takes years to develop and test vaccines, and a small percentage of the process, just like the future of the industry, will always be a guessing game. Because companies cannot ethically expose humans to these deadly agents, they can never be completely sure that a drug or vaccine works against a specific threat. Human tests are generally for safety purposes only. So scientists rely on experiments with animals and judgments based on biology and immunity to create a delicate bridge back to the human angle.
“You then do this tricky dance in which you combine the data generated in animal studies and the data in human safety trials and come up with a story to tell the FDA whereby you give a high degree of certainty that these vaccines will work in humans,” House said. But no vaccine has yet been licensed using this approach. And most animal models are not that great at predicting how a human would respond to diseases like anthrax or plague and the drugs meant to combat them.
Add to that the possibility of a disease that comes out of the blue. What happens when an attack makes use of a threat that is not on anybody’s radar? That question haunts House and other scientists.
“One of the scariest threats we face is the potential of engineered or synthetic diseases,” House said. “We are rapidly approaching the time where the creation of novel diseases that have never existed will become a reality.”
Weapons could be created from micro-organisms that would bypass antibiotic therapy and resist any effects from vaccines. They could be made so pathogenic and dangerous that they would quickly kill those infected no matter what type of medical countermeasure is employed, House said.
“These are things that we have to be prepared for, just as we have to be prepared for natural disasters like hurricanes and earthquakes,” he said. “We can’t wait until they happen and then decide what to do.”
In that sense, Abdun-Nabi said, these drugs and vaccines are as important to national security as tanks, fighter jets and submarines.