Biodefense experts: vaccines 'at a crossroads'.

A budding U.S. biodefense industry--working largely without the major pharmaceutical companies--is working on medical countermeasures intended to treat deadly agents. But many of the companies seeking government funds for biodefense work are small firms with no experience in bringing a drug to market. They face a significant challenge.

"I see an emerging new industry, new capabilities" in the medical biodefense field, says Vidadi M. Yusibov, executive director of the Fraunhofer USA Center for Molecular Biotechnology in Newark, Del., who oversees work on vaccines and therapeutics administered in edible plants.

Ninety-five U.S. companies are working on vaccines or therapeutics to combat bioweapons, according to a 2005 report by BioAbility, a provider of biotechnology- related information services located in Research Triangle Park, N.C. However, a large portion of those biodefense products are still just in the pre-clinical stage of development.

Since the 9/11 attacks, the federal government has dramatically increased funding to help create such products. For instance, funding for biodefense by the National Institute of Allergy and Infectious Diseases (NIAID) increased from $3.2 million in fiscal year 2001 to an estimated $ 561.51 million in fiscal year 2005. Project Bioshield legislation enacted last year provided $5.6 billion over the next 10 years to help generate medical countermeasures.

The president's requested fiscal year 2006 budget calls for $4.77 billion for civilian biodefense for the Departments of Homeland Security and Health and Human Services, in addition to funds for biodefense provided under Project Bioshield.

Experts say at least 50 biological agents are potential bioweapons. The development of a medical response to protect against them is an expensive and slow process. The estimated cost of creating a new vaccine is about $800 million, and takes typically about 10 years or more.

Government officials have created priority lists of pathogens of greatest concern, and further assessment of threats is under way. The only licensed biodefense vaccines being manufactured in the United States are against anthrax and smallpox, and each of those has shortcomings that companies are working to overcome in new vaccines.

Only a few companies are working on biodefense countermeasures as their only product. Instead, they frequently are drawing upon work on their other products. For some, government funds available for biodefense have helped ensure their survival after recent years of bad economic times.

"I'm not yet convinced there is a sustainable industry only in biodefense," says Una S. Ryan, president and chief executive officer of Avant Immunotherapeutics, based in Needham, Mass., which is working on vaccine protection against anthrax and plague. "I don't think I would have set up a company just for anthrax and plague."

Her company has received commitments of about $10 million from the Defense Department for its work on a next-generation injectable anthrax vaccine and an oral vaccine that would protect against both anthrax and plague.

Avant is drawing upon technology the company uses for other products, including its protection against cholera. It employs genetically modified bacteria as "buses" to deliver plague and anthrax antigens to the immune system and stimulate it. Ryan says of its work on biodefense vaccines, "We're really manufacturing a cholera bus or a salmonella bus with different soldiers."

In Brisbane, Calif., VaxGen also is receiving federal funds. The Department of Health and Human Services awarded the company an $877.5 million contract to produce 75 million doses of its next-generation anthrax vaccine. Because it is being produced using modern manufacturing techniques, expectations are that it will be purer than the existing licensed vaccine. And it will take effect with fewer doses than the six injections over an 18-month period called for in the current vaccine.

VaxGen's contract provides BioShield funds for delivering doses of the vaccine starting early next year, even though the Food and Drug Administration will not have approved it by then. This and other unapproved products are being added to the Strategic National Stockpile for use in the event of an emergency. The contract requires that VaxGen continue developing the vaccine until its licensing.

In the meantime, the producer of the approved vaccine, BioPort Corp. of Lansing, Mich., has a $122.7 million BioShield contract to provide 5 million doses of its licensed anthrax vaccine.

Enough smallpox vaccine is now available for everyone in the United States, and new smallpox vaccines are being created. Stewart Simonson, assistant HHS secretary for public health emergency preparedness, informed a congressional subcommittee that efforts are under way for a next-generation smallpox vaccine.

Scientists are also working on countermeasures against other pathogens considered to be among the most likely bioweapons including botulism, tularemia, Venezuelan equine encephalitis and the Ebola virus as well as genetically engineered threats.

Many of the involved researchers are in the forefront of medical innovations.

"Vaccines really are at a crossroads," Ryan says, noting improvements under way that could make them less expensive and faster to produce as well as more stable in varying temperatures.

Companies are also working on different ways to administer vaccines including using inhaled drugs, patches and multi-agent vaccines. Ryan believes Avant might eventually be able to combine protection against three pathogens in one dose.

"It's very exciting and very interesting research," says Michael G. Kurilla, director of the Office of Biodefense Research Affairs and associate director for Biodefense Product Development for NIAID. "Small companies have gotten very innovative."

Some experts are raising concerns over a "one-bug, one-drug" approach because of the expense of developing countermeasures for each pathogen, the logistics of stockpiling and administering them and the potential adverse health effects from receiving so many vaccines. Researchers are exploring alternatives, including non-specific boosters of the immune system.

Companies are also working on a variety of other biodefense products and services. For example, Logistics Health, with headquarters in La Crosse, Wis., has been selling logistical support, including overseeing anthrax vaccinations for military personnel and vaccine and antibiotics for civilians exposed to anthrax in the 2001 mail incidents.

While many companies are struggling with navigating the bureaucracy and finding the best way to seek support from federal agencies, Logistics Health can draw upon the experience of former secretary of Health and Human Services Tommy Thompson, whom it hired as its president in February.

Detectors are also a growing market. For example, U.S. Genomics of Woburn, Mass., has a $7.5 million contract from DHS to develop a sensor that could detect and identify any airborne pathogen. DHS also is seeking technology to detect infection through breath checks, and a preservative that would neutralize anthrax spores in food and treated clothing.

But despite innovative research and billions of federal dollars, few new medical countermeasures have yet to be produced. "It's too early to see massive industry change," says Mark D. Dibner, president of BioAbility. "Although there are a few things on the market, most of these things are in the early stage of development."

Critics are calling for more results. They question the speed at which the government is signing up contractors.

Michael Greenberger, director of the University of Maryland Center for Health and Homeland Security, criticized the time it is taking for DHS to determine the agents that are a threat to the United States, a step required before other agencies can spend BioShield funds.

"DHS has employed an opaque, highly bureaucratized, relatively lengthy process for determining material threats," he charged in a written statement.

Experts disagree on which agency should have the lead in providing medical countermeasures to protect civilians. Some maintain it should be HHS while others say Homeland Security should have the major procurement role because they see HHS as having a contentious relationship with the industry.

Critics have raised concerns about the progress in the development of medical countermeasures to protect military personnel. The Defense Department is continuing work on medical countermeasures with its own researchers and its Joint Vaccine Acquisition Program, with DVC, of Frederick, Md., as its prime contractor. But with the growing concern over protection of civilians from potential bioterrorism, other departments, especially HHS and Homeland Security, are also now playing significant roles.

Last year the Institute of Medicine issued a report calling for the creation of a new Medical Biodefense Agency within the Defense Department to handle military activities and help avoid fragmentation of responsibilities. It urged that the Medical Biodefense Agency focus on unique needs for military protection and coordinate its efforts with the National Institutes of Health to minimize redundancies.

Other concerns are being raised by doubters who wonder whether the small biotech companies have the funds, experience and infrastructure to get the job done.

Eventually many of the smaller companies may partner with large ones. Authorities are exploring options to try to lure large pharmaceutical companies to participate and help speed up the process.

The problem is not new. The Defense Department faced similar resistance during the first Persian Gulf War when it tried to get companies to produce vaccines to protect against biological weapons. Efforts extended even to those making animal drug products, but BioPort emerged as the sole producer of the anthrax vaccine.

Thus far, large companies have shown reluctance to produce biodefense products for civilians. Vaccines don't offer the same promise of profits as lifestyle drugs or medicines for chronic diseases, which are taken repeatedly throughout long periods of time.

"There's a real lack of development of drugs and vaccines for infectious diseases of all types," says Brad T. Smith, a University of Pittsburgh medical professor and an associate at the school's Center for Biosecurity.

In addition, companies worry about having the government as the only customer. They point to the government's treatment of Bayer AG. The company was pressured to sell its Cipro antibiotic at a discount after the 2001 anthrax incidents.

Alan Goldhammer, associate vice president of the Pharmaceutical Research and Manufacturers of America, sees "a lot of technical and regulatory hurdles." Among his main concerns is the liability the companies might incur in producing biodefense products. Though the Safety Act would provide liability protection during a bioterrorism emergency, it does not cover products administered before an attack.

Goldhammer views biodefense vaccines as especially risky. Because it is considered unethical to expose trial participants to a disease that generally does not occur naturally in the United States, researchers may now use animals to test the drugs. As a result, Goldhammer says, people might be vaccinated during an emergency with a drug that has not been tested for effectiveness on humans.

"The challenge of liability protection is potentially very expensive," Smith says. Private insurers are reluctant to provide coverage. It is among the issues Congress is struggling with as it considers proposed BioShield legislation that supporters hope will encourage large companies to participate in medical biodefense.

Goldhammer says his other main concern is that antitrust regulations prevent companies from working together in responding to the challenge. Many of the industry, academic and government leaders who were interviewed during a 2004 study conducted by the Center for Biosecurity and the Sarnoff Corp. of Princeton, N.J., said they would like to see a single organization created to facilitate collaboration.

According to the Biosecurity and Bioterrorism journal, "the measures the U.S. government has taken to date, including the passage of the BioShield legislation, will not be enough to entice pharmaceutical industry leaders into that field and will not produce the countermeasures the nation needs for a truly effective biodefense."

Margaret Davidson is a medical journalist and a professor at the University of Wisconsin-Oshkosh.