The Biodefenders (1 of 2):
signalsmag.com
Although the United States gave up biological weapons many years ago, it never abandoned an interest in biodefense. That interest became a top priority in the 1990s, however, thanks to several chilling revelations. Saddam Hussein may not have had atomic weapons during the War in the Gulf, but he did have anthrax weapons -- and he deployed them. The Soviets' bioweapons arsenal was revealed to extend far beyond what U.S. intelligence imagined. After the Soviet Union broke up there were concerns that Russian scientists desperate for money would help other countries acquire these weapons. Not that weapons collectors didn't have alternatives: In 1998 it was reported that Iraq was helping Libya build a bioweapons production facility.
The Pentagon has committed itself to protecting the troops against biological warfare. Naturally, army researchers carry out much of the research aimed towards this goal. But to get access to the latest technologies, and to get biodefense products approved by the FDA, the military relies on a small group of biotechnology companies. And as sometimes happens with military-supported R&D, biodefense biotechnology could turn out to have benefits elsewhere, both commercial and peaceful.
In 1346, after years of riding on the backs of fleas and rats and men, the long westward journey of Yersinia pestis along Asiatic trade routes came momentarily to rest upon Europe's eastern doorstep, the Crimean peninsula on the Black Sea. Its arrival made for a memorable demonstration of biological warfare.
At first, the beleaguered residents of Kaffa (today, Feodosia) rejoiced as the bubonic plague fell upon the enemy who laid siege to their city. A Black Sea port belonging to the Genoese trading empire, Kaffa was being starved and bled into submission by the Tartar army of Kipchak khan Janibeg, an ally of Genoa's rival, Venice. Plague so decimated Janibeg's army that by the next year he had no choice but to lift his siege and withdraw. In his final act before leaving, Janibeg loaded the blackened, festering corpses of his dead soldiers into catapults, and hurled them over Kaffa's walls. Dumping the smashed bodies into the sea could not dispose of what the grisly assault had sown. Survivors of the siege, squalid and spent after their ordeal of boulder and fireball bombardment, were a ripe and easy harvest for the Black Death.
Today as then, biological weapons descend from the sky. As an intruder's flight path tracks across a target city, his aircraft spews pestilence in the form of a biological warfare agent carefully formulated to hang in the air in a colorless, odorless cloud. Particle size in this aerosol, between one and five microns, permits quick penetration down to the lung alveoli, one step away from entry into the bloodstream. In good war weather (low wind speeds in combination with an inversion to hold surface air down, common conditions for evening and dawn) the aerosol remains unbroken and suspended for hours.
A plague or anthrax attack starts filling hospitals within two days. Many doctors of course will have the same symptoms as their patients. Hardly any will have the medical training to recognize what they have until it is too late: If antibiotic treatment isn't started within 24 hours of symptoms, plague pneumonia is almost 100 percent fatal; the window for treating anthrax may be even smaller. A World Health Organization (WHO) study estimates that 50 kilograms of anthrax spores dispersed across a city of 500,000 would kill a quarter of the population within a week. Morticians, like physicians, would be overwhelmed. Dead bodies would pile up faster than mass graves could bury them. Stacks of human cordwood would be left to molder and putrefy, just as happened in the 14th century.
The United States no longer has biological weapons. At President Nixon's order, the U.S. biological arsenal was destroyed during 1971-72. (America's biodefense effort, which dates back to the 1950s, never stopped.) The arsenal was by no means comprehensive, but its diversity conveys an idea of the threat today's biodefenders face. America stocked lethal agents (Bacillus anthracis, Botulinum toxin, Francisella tularensis, Brucella suis), incapacitating agents (Coxiella burnetti, Staphylococcal enterotoxin B, Venezuelan equine encephalitis virus) and anticrop agents (Rice blast, Rye stem rust, Wheat stem rust).
What the U.S. discarded, others have stockpiled. In the aftermath of the Persian Gulf War, United Nations inspectors learned that fear of Saddam Hussein's biological weapons capabilities had been well founded: During the war the Iraqis deployed bombs and SCUD warheads filled with Botulinum toxin, anthrax, and aflatoxin.
In 1992 an even more fearsome threat came to light, when a defector revealed the vastness of the former Soviet Union's biological warfare enterprise. He explained how the legitimate activities of a pharmaceutical company called Biopreparat had been used to conceal investigations of dozens of pathogens as weapons. He described how the Soviets developed biological arms sufficient to dispatch millions to their graves. His most sensational revelation was that the Soviets produced variola virus by the ton. Let fools believe the 1970s eradication campaign made the world safe forever from smallpox. The Soviet biowarfare establishment knew better.
During the 1990s, intense concern over biological weapons prompted the Department of Defense (DOD) to greatly increase its biodefense program. The DOD is now spending millions to defuse the Russian threat: It's not only destroying biological weapon stockpiles in Russia, but it's subsidizing Russian microbiologists to prevent them from working for rogue nations and beefing up security where they work. And to protect our forces, and aid the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID, at Fort Detrick, in Frederick, MD) in its biodefense mission, the DOD enlisted the skills and cooperation of a number of biotech companies, forming a corps of biotech biodefenders.
For the peculiar business of protecting soldiers against illnesses that in a better world would be unthinkable, the DOD in 1997 decided to engage a single company (what is called a prime systems contractor) to oversee development, licensing and manufacture of an essential group of biodefense vaccines. A 10-year contract for the job went to DynPort Vaccine Company, LLC, headquartered in Frederick, MD.
DynPort's 65 employees coordinate subcontractors across the United States to move the biodefense pipeline: vaccines for smallpox, plague, tularemia, Venezuelan equine encephalitis, and botulinum toxin. The only non-vaccine product is vaccinia immune globulin, a treatment for adverse events caused by the smallpox vaccine.
There was a time when DynPort's activities weren't seen as necessary. "It was accepted up until Desert Storm that these products would be maintained in IND status," explains Mike Langford, DynPort's technical director. The army had access to IND products made by various manufacturers, and "the intent was that during a national emergency or biowarfare the IND products could be used." DynPort is in business today because that thinking changed. FDA approval became desirable, and to get it, the army created the Joint Vaccine Acquisition Program (JVAP). In turn, JVAP awarded DynPort its $322 million contract.
All the vaccines will have Phase I clinical trials for safety. But to win FDA approval, says Langford, DynPort must "demonstrate efficacy to the level of confidence that would allow licensure without having to actually conduct efficacy trials in humans." In this language Langford captures the awkward problem every maker of biodefense medicine strives to solve. Efficacy trials are unethical for these unnatural diseases -- indeed, for smallpox are supposed to be impossible -- so how does one show these products work?
For smallpox, that actually won't be so hard. Viable stores of smallpox vaccine still exist, so DynPort will be able to compare its vaccine to the old ones in terms of the immune responses they generate. DynPort's strategy is essentially to do as much as ethically permissible to demonstrate bioequivalence. The smallpox vaccine is DynPort's most advanced project, a couple of years away from a Phase I trial. The real challenges, says Langford, are waiting farther down the road: "The ones that will be tough will be the ones that don't have surrogate markers like the development of antibodies or cell mediated immunity, or that don't have an animal model, or for which there is no endemic disease." The FDA's task of approving these products won't be easy either, he adds, since no single regulation exists that covers all the problems that arise in biodefense drug development.
JVAP has the option to add as many as 17 more vaccines to the flock DynPort will shepherd into the army's vaccine stockpiles. The one item not on that list is an anthrax vaccine, for the reason that one already exists. It was approved in 1970 based upon its benefit to wool workers (inhalational anthrax is also called Woolsorters' disease). It is the only FDA approved biodefense vaccine the army has, and it's produced by a single company, BioPort Corp., of Lansing, MI.
The Michigan Biologic Products Institute (MBPI) made the vaccine until 1998, when the state decided to privatize the operation and sold it to BioPort. To BioPort it must have seemed like a good deal. There certainly wouldn't be any lack of customers: That same year, the DOD started a program to vaccinate all of its 2.4 million active duty and reserve personnel against anthrax. (Click here for the DOD's official website for its anthrax vaccination program.)
Poor BioPort probably hasn't had a day of peace since.
Despite the FDA's reaffirmation that the anthrax vaccine has demonstrated good safety over millions of doses, BioPort's product has awful public relations problems. Vociferous objections from a few soldiers that the vaccine is unsafe have received widespread press attention. A Government Accounting Office study claims that fear of the vaccine has hurt reenlistment and caused early retirements. Closer to home, BioPort may have underestimated the time and money required to refurbish MBPI's manufacturing plant and increase its capacity. And while BioPort corrects manufacturing problems turned up by FDA inspectors, the Pentagon has temporarily suspended its vaccination program in order to save the limited stocks of vaccine. Presently, anthrax vaccines go only to troops bound for duty in Asia. BioPort has also asked the DOD for a new contract, claiming it did not know Michigan subsidized MBPI's operation at a $5 million-a-year loss.
How BioPort will solve its problems isn't clear (the company declined to be interviewed). But as busy as they are with today's concerns, BioPort's executives must be giving some thought to the huge problem looming several years ahead -- losing out to a better vaccine. "The major concern about the vaccine is the number of doses required," says Col. Arthur Friedlander, a physician and scientific advisor at USAMRIID. BioPort's vaccine requires six shots delivered over 18 months, and yearly boosters thereafter. Friedlander hopes the new vaccine being developed at USAMRIID will protect soldiers after just two doses. It is based on purified Protective Antigen, one of the three anthrax toxins. Protective Antigen is toxic only in conjunction with one of the other toxins, Edema Factor and Lethal Factor. By itself, Protective Antigen confers protection against anthrax in animal experiments, and is considered a good candidate for a safe vaccine. It may be in Phase I trials in about a year, says Friedlander.
The defector who unveiled Biopreparat's activities was no low-level functionary with compartmentalized knowledge of one or two weapons. Ken Alibek was an altogether different sort of man. Alibek could describe the Soviet program in detail because he was the man who ran it
It is hard to think of anyone surpassing Alibek's knowledge of biological weapons. His experience is extraordinary. He worked on developing weapons with tularemia, brucellosis, glanders, plague and anthrax, and directed research for smallpox, Marburg, and Ebola weapons. Alibek was chief scientist and first deputy director of Biopreparat. The weapons programs he directed employed thousands of people.
Ken Alibek
After spending more than a year debriefing U.S. officials, Alibek started a new life for himself. He changed his name (from Kanatjan Alibekov) to accommodate American English. After a research stint at NIH, he took a couple of positions as a biodefense consultant, published a memoir (Biohazard, Random House, 1999), and became a U.S. citizen. In 1999, Alibek became president of a biodefense company, Advanced Biosystems, a subsidiary of Hadron, Inc., located in Alexandria, VA.
Advanced Biosystems is run according to Alibek's belief that biodefense depends on understanding the fundamentals. "To develop something to protect against biological weapons," he states, "you need to understand three important things: First, how they work. Second, the actual pathogenesis. Third, how the infections differ from major natural infections."
The company's research programs focus on immunology. "We know so little about these infections in terms of the immune system response," he says. That is especially true for anthrax, a problem he hopes Advanced Biosystems can do something about with support from a $2.6 million contract from the U.S. Army Medical Research and Materiel Command. Company scientists are systematically studying the duet between B. anthracis and the immune response at each stage of infection: incubation, prodrome, manifestation and outcome (severe hypoxia, septic shock, massive cytokine dysfunction and death). The aim is to find better antibiotic therapies and ways to combat anthrax sepsis and septic shock.
Therapy for anthrax is severely limited. Except when taken at the inception of infection, antibiotics merely hasten death, as bacterial lysis simply pours more anthrax toxins into the bloodstream. Antibodies, too, have to be used early. Otherwise, effective doses would be higher than the body could tolerate, causing "concentrations of circulating immune complexes so high that you shut down the kidneys."
Work on this project has already suggested an idea for a better anthrax vaccine, which Alibek says he plans to propose soon to the Army. He is skeptical that subunit vaccines based on soluble anthrax factors will work, claiming they aren't likely to protect against infection or work against all anthrax strains. What is needed, he says, is a vaccine that blocks infection from its earliest stage.
A second project concerns the early immune response when a warfare microbe is still in the lungs. The Defense Advanced Research Projects Agency (DARPA) is supporting a proof-of-principle demonstration that enhancing non-specific mucosal immunity in the respiratory tract can protect against a broad spectrum of bioweapons.
When a warfare microbe is breathed in, it doesn't go immediately into the bloodstream. Instead, it remains in the lung alveoli for a period (hours to days) that depends on the organism. Alibek hopes to stimulate alveolar macrophages, monocytes, neutrophils and NK cells to eliminate the invaders before they enter the circulation. The research will test different stimulants' ability to enhance non-specific immunity, delivering them to the lungs of animals with a nebulizer. Stimulants to test include low-toxicity cytokines, cytokine mimics and what Alibek calls polysaccharide-peptide structures. Animal tests will begin soon using vaccinia virus, yellow fever and anthrax as model infections.
Non-specific immune enhancement is a prevention project, not therapy, he says. But it could be enormously helpful for national defense if it works: A man who should know says there are too many weapons and too many people for vaccination to offer complete protection.
Alibek hopes that success with these projects will let his company branch out into treatments for natural infections. "The general idea is that we don't develop anything that could be used only in biodefense," he says, sounding a common theme for biodefense companies. Almost all of them hope that by advancing military medicine they will help themselves in the civilian market.
A different anthrax defense harnesses the widely unappreciated immune function of red blood cells. This requires hybrid antibodies developed by EluSys Therapeutics Inc., of Pine Brook, NJ. |
