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Biomedicine

Attacking Anthrax

Promising new antibiotics, antidotes, and vaccines emerge.

Anthrax stands apart in the rogue’s gallery of bioterror diseases: the bacterial spores that cause it are relatively easy to acquire, mass-produce, and disseminate. They are extraordinarily lethal when inhaled, and antibiotic-resistant strains are easy to make. Moreover, as the five mail-attack deaths grimly demonstrated in 2001, modern medicine is powerless against late-stage anthrax, in which bacterial toxins cause deadly blood poisoning and organ damage.

“Biological weapons are the biggest national security threat facing the nation,” says Tara O’Toole, director of the Center for Civilian Biodefense Strategies at Johns Hopkins University. Anthrax, she adds, is “a much more serious threat than smallpox. I think it’s much easier to imagine terrorists getting hold of the bug, the technology, and disseminating anthrax than doing all this with smallpox.”

But against these realities, significant progress is afoot. A host of rapidly emerging approaches promises to save lives in future anthrax attacks, whether on the battlefield or on the home front. New treatments that kill the bacterium-Bacillus anthracis-and deactivate the deadly toxins it produces should become available within the next year or two. And better vaccines are on the way to replace the 18-month-long vaccination regimen that is already standard for hundreds of thousands of military personnel.

The first mission: combating antibiotic resistance. Anacor Pharmaceuticals in Palo Alto, CA, is developing a new class of antibiotics that block an enzyme certain bacteria-including Bacillus anthracis-need to replicate their DNA. Although the difference between this approach and the way some existing antibiotics work is subtle, it is significant enough to “increase the difficulty [for terrorists] by an order of magnitude,” says Anacor CEO David Perry. That’s because each new line of antibiotic attack makes it less likely that the bugs will have evolved the means to escape or that rogue states or terrorists will have engineered the right type of resistance, he says. Anacor, which last year won a $21.6 million grant from the U.S. Department of Defense to develop new compounds, has already started animal tests and expects to have drugs in human trials within three years.

Another antibiotic approach pits a virus against anthrax. Rockefeller University microbiologist Vincent Fischetti identified an enzyme from a virus that infects only anthrax-causing and closely related bacteria. In test-tube experiments, the enzyme kills about a hundred million bacteria in two minutes or less. “It drills a hole in the cell wall, and the organisms explode,” Fischetti says. He adds that the treatment should boost the power of existing antibiotics against anthrax, as well as kill resistant strains of the bacteria. His group is currently performing animal experiments to test the enzyme further.

Such superantibiotics could play a critical role should an anthrax attack use an antibiotic-resistant strain. But what’s needed most urgently is a treatment to counteract the potent toxins produced by Bacillus anthracis. These toxins attack the cells of those infected; in fact, researchers believe they are what killed the five anthrax victims in 2001, despite the patients’ treatment with powerful antibiotics. Experimental anthrax infections in monkeys show that “there comes a point of no return,” says Michael Mourez, who, as a postdoc in biochemist R. John Collier’s lab at Harvard Medical School, studied anthrax toxin. “You can treat the animal and get rid of the bacteria, and yet the disease will progress towards death.”

Collier’s group has developed several molecules that effectively protect animals against the toxins. Rats typically die within 90 minutes of being injected with anthrax toxin. If the rodents are given one of these antidotes, however, they survive. Even before the 2001 attacks, Collier had formed PharmAthene, a Potomac, MD-based company, to develop one such antidote into a drug. The treatment the company is testing is a mutant version of one of the proteins that make up the toxin; it binds to the other components to prevent the formation of active toxin. This protein could act as both a vaccine and a drug. If testing goes well, Collier anticipates that the treatment may be available in limited quantities next year.

That’s an optimistic timetable: drug development typically takes 10 years. But Collier may well meet his goal because last year the U.S. Food and Drug Administration moved to speed approval of treatments that improve the nation’s readiness to respond to bioterrorism. Rather than undergoing the usual extensive preclinical animal testing and three-phase human trials to establish drug safety and efficacy, treatments such as Anacor’s, Fischetti’s, and PharmAthene’s will have only to demonstrate effectiveness in two different animal models and safety in one human trial.

Improved vaccines are also critical. Current anthrax vaccines are safe and effective, but for full protection, recipients require six doses over 18 months, a delay that could be costly for military troops who will be the main beneficiaries of any new vaccines. But fast-acting vaccines could also allow civilians to live or work in contaminated areas after an attack. The anthrax spore is difficult to destroy: even now, the Washington, DC, postal facility that handled two contaminated letters in 2001 remains shut down.

In an effort to reduce both the number of doses and the time needed to protect people from anthrax, researchers at Frederick, MD-based DynPort Vaccine and Avant Immunotherapeutics in Needham, MA, have developed a vaccine they hope will induce protective antibodies more quickly. The current vaccine is basically a “soup” of bacterial cell parts; the new vaccine comprises only protective antigen, the same toxin subunit on which Collier’s treatment is based. This specificity should help avoid side effects while speeding the body’s immune response. Clinical trials started in October 2002.

Avant plans to go even further. It recently received a government subcontract to create a single-dose oral vaccine that will shield against both anthrax and plague, a flea-borne bacterial disease that could also be a bioweapon. Contracted through DynPort from the Defense Department’s Joint Vaccine Acquisition Program, the project’s costs may exceed $8 million over two years. “This isn’t just a research idea,” says Una S. Ryan, Avant’s president and CEO. “It’s pretty well down the development line.”

To start making this vaccine, Avant’s scientists have removed disease-causing genes from cholera and salmonella bacteria. They plan to insert genes that code for proteins made by anthrax- and plague-causing bacteria. The resulting proteins should prompt the body to produce disease-fighting antibodies. “You’ll get protection against cholera, anthrax, and plague with one swig-and-go,” says Ryan. Avant’s plans call for beginning human tests of this vaccine within two years, she adds.

Indeed, more effective vaccines and treatments for anthrax won’t be the only payoffs from the current surge of bioterror defense research. Anacor’s new antibiotics, for example, should work not only against anthrax and other bioweapons, but also against such common diseases as pneumonia and bacterial meningitis and staph infections. “All this money is not only going to be useful for biowarfare organisms,” Fischetti says. “It’s going to be a real shot in the arm for how we deal with infectious diseases.” But even without such medical windfalls, these new treatments for anthrax will help build much-needed defenses against this major bioterror threat.

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