by Guy Gugliotta, Washington Post
Six months after last fall’s deadly anthrax attacks, the Pentagon is scrambling to develop a new generation of vaccines to protect troops and perhaps the American populace from biological weapons.
But it will be years before any new vaccines are ready. And many experts inside and outside the armed forces say the rush could have been avoided if military planners had not ignored repeated warnings that the vaccine program was woefully inadequate, had not allowed the program to deteriorate for lack of funding and had avoided missteps in the few attempts that were made to develop, test and win approval for vaccines.
“There seemed to be no mechanism so that a good vaccine idea could be manufactured and clinically tested with all the assurances we associate with that,” said Franklin H. Top Jr., executive vice president of Medimmune Inc., a Gaithersburg biotech firm. Top chaired a Pentagon-funded panel that produced a highly critical report on the vaccine program just two months before Sept. 11. “You needed to set up some sort of management structure,” he said. “It was incoherent.”
The result is that the nation has only two vaccines licensed for use: a smallpox vaccine that was used to immunize every American until the naturally occurring disease began to disappear in the 1970s and a cumbersome anthrax vaccine that even supporters agree should be replaced.
Supplies of an imperfect plague vaccine have all but disappeared and there are no approved vaccines for a host of other “threat agents,” including botulism, tularemia, and many encephalitis viruses and hemorrhagic fevers. The failure to develop vaccines, experts say, has left the nation unnecessarily vulnerable to bioterrorists.
“Vaccines should be your bedrock; they give you solid protection against solid threats,” said Donald S. Burke, director for the Center for Immunization Research at Johns Hopkins University. “The decisions for management for this were badly run and could have been much better. Our vaccine vulnerability is much higher than it needs to be.”
The Pentagon declined comment, although Col. Edward M. Eitzen Jr., chief of the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick, the Pentagon’s research arm for biodefense vaccines, acknowledged, “There’s a new environment post-Sept. 11.”
The anthrax attacks that killed five people last fall imposed new urgency on military efforts to develop and test vaccines, win approval for vaccines that have languished for years as experimental remedies and explore ways to produce vaccines reliably and in large amounts.
It was not that planners were unaware of biological warfare. Worries that Iraq would use biological agents during Operation Desert Storm prompted the Pentagon in 1991 to distribute 300,000 doses of anthrax vaccine and 8,000 doses of botulism toxoid to U.S. forces in the Persian Gulf.
The Pentagon also had a civilian company under contract to produce limited supplies of vaccines classified as “investigational new drugs” -- remedies that had not obtained FDA approval.
Most of the experimental vaccines, however, were doomed never to win FDA license because the human trials required by law were impossible. Injecting people with experimental vaccines and then challenging them with lethal biological warfare agents is an ethical taboo. Still, experimental vaccines can be administered in emergencies as long as the patient gives written informed consentand accurate records are kept. The Pentagon relied on this regulatory loophole for years and used it during the Gulf War.
“The attitude was, ‘We’ll never use these vaccines, and if we have to use them, the risk would be so high, the benefit would far outweigh the risk,’ ” said Army Col. David L. Danley, project manager of the Pentagon’s Joint Vaccine Acquisition Program.
But that changed soon after the war, when some veterans complained of unusual illnesses they attributed to their Gulf service and suggested vaccines may have caused them. Investigators found the Pentagon had neither obtained informed consent from all of those injected nor kept accurate records.
By 1992, the Defense Department had all but abandoned the experimental drugs. Henceforth it would seek FDA approval for all its vaccines. This new policy, however, was not accompanied by adjusted regulatory requirements. As a result, the human trial ban became a Catch-22 that curtailed, and, in some cases, halted Pentagon-contracted vaccine research for years.
Nevertheless, in 1994, Pentagon biodefense researchers at Fort Detrick asked the civilian contractors at a now-defunct division of the Salk Institute for Biological Studies to seek FDA approval of experimental vaccine for tularemia, which causes flu-like symptoms and sometimes pneumonia.
“We had terrible misgivings,” said Ron Arndt, a former Salk scientist. Researchers hadn’t done enough trials or testing of the vaccine and “we never got to first base,” Arndt said.
In the mid-1990s, Fort Detrick scientist Michael Langford thought he had devised a way to circumvent the restriction on human trials by demonstrating that botulism toxin could be neutralized in mice using human antibodies. The experiment foundered, however, because Langford could not demonstrate measurable levels of immunity in the mice after one year.
“People may well have been protected,” said Langford, now chief scientific officer at Frederick-based DynPort Vaccine Co. “But we couldn’t show it.” The research was abandoned.
Similarly, a new generation anthrax vaccine has never been approved because of the FDA’s arduous and time-consuming requirements for testing and data collection. People “didn’t consider that to license [a new vaccine] you would have to to do a number of things, and there was no strong data,” said Michael Gilbreath, former medical project officer at the Pentagon’s Joint Program Office for Biological Defense who is now a vaccine specialist at the National Institutes of Health. “There was also a lot of evidence of a safety profile with the old vaccine, something that would have taken years to get for a new one.”
The old vaccine is impractical because it requires a six-shot injection regime. Pentagon scientists suspected they could get by with fewer shots but they had not done the research “because the attention was always on the new vaccine,” said one scientist with direct knowledge of the program.
Closer attention to licensing over the past decade also led the FDA to look more carefully at existing vaccine facilities to see whether they were complying with guidelines. Often they weren’t.
BioPort Corp., of Lansing, Mich., nearly went bankrupt and needed a four-year renovation before the FDA allowed it to resume making anthrax vaccine in January.
Other vaccines disappeared altogether. In 1995, the FDA demanded that Greer Labs Inc., of Lenoir, N.C., retest its plague vaccine, a remedy licensed as a treatment for infectious disease but also used by the armed forces in biodefense. Greer closed the facility after the Defense Department refused to help with funding.
“They lost plague . . . because of really shortsighted decisions,” said Alexandria-based consultant James G. Kenimer, a vaccine specialist.
To avoid these problems, Defense planners after the Gulf War proposed that the Pentagon build its own vaccine factory. It would take five to seven years to complete and would cost nearly $400 million, but it would guarantee vaccine supplies.
The idea was approved but then discarded in late 1993 when Congress and the Pentagon decided it was “not cost-effective,” said Anna Johnson-Winegar, deputy assistant to the secretary of defense and a leading advocate of the plan.
Instead, the Pentagon in 1997 hired DynPort as an outside contractor for $322 million, giving the company the task of moving as many as 17 different vaccines to licensing. Four years later, after staggering in its initial stages, DynPort has seven vaccines in research. The closest to being licensed is a new smallpox remedy, projected for 2005.
But Top’s committee report damned the DynPort approach as “insufficient,” and Top called it “a high-risk strategy.”
“If you want a vaccine in five to seven years, you go with the big guys,” Top said. “If you have 15 years, then you can do it small.”
Meanwhile, Johnson-Winegar is chairing an interagency panel examining the desirability of a government-owned facility, but Defense Secretary Donald H. Rumsfeld told Congress in January “I don’t know of a time frame” on the panel’s making a decision.
In the meantime, anthrax vaccine research appears finally on track. New generation vaccines are in development again, although FDA licensing is years away, and government scientists are testing the old vaccine with the aim of reducing the shot regime, perhaps beginning in 2004. Studies have also resumed on tularemia and botulism vaccines in hopes that both will be licensed -- tularemia in 2009 and botulism in 2012.
And finally, the FDA is readying a new regulation that will describe how researchers might substitute animal test data for human trials, thus circumventing the regulatory bottleneck that discouraged biodefense vaccine licensing. The first draft of this “animal rule” was written five years ago.