DOCUMENTS REVEAL DOUBTS ABOUT DOD ANTHRAX VACCINE BEFORE APPROVAL

February 17, 2000

Four years ago, U.S. government officials preparing a massive initiative to immunize all military personnel against anthrax raised a number of fundamental questions about whether the existing vaccine -- as licensed by the Food and Drug Administration -- had been adequately tested for this use, according to U.S. government documents obtained by Inside the Pentagon.

At issue was whether the anthrax vaccine could be used in ways the FDA-approved label did not clearly spell out. Specifically, U.S. officials questioned whether a vaccine originally intended for workers who come into skin contact with anthrax-infected animals could be given to millions of members of the U.S. military who might contract anthrax in a whole new way: delivered by a terrorist or rogue nation in aerosol form through a bomb or crude weapon.

Ultimately, the FDA issued what many critics see as half-hearted approval to the Pentagon for its mandatory immunization program, without a requirement for further research or the informed consent of service members who must take the shots. But with concern about the program increasing among the military and on Capitol Hill, questions first raised behind the scenes in the medical and scientific community are beginning to surface.

Defense Secretary William Cohen approved the Anthrax Vaccine Immunization Program on Dec. 15, 1997, and launched it on May 18, 1998, citing an increased threat of biological warfare from terrorists and rogue nations. Since then, more than 400,000 soldiers, sailors, airmen and marines have received one or more anthrax shots, part of a six-injection regime over 18 months, with annual boosters after that. By about 2005, the entire military is to have received the vaccine.

But the program has spawned a growing rebellion among service members who have heard reports about how the vaccine manufacturer, BioPort, and its predecessor organizations have failed FDA inspections of their Lansing, Michigan, production facilities. And although the Defense Department says there have been fewer than 100 cases of significant side effects since the vaccine program started, program critics say serious adverse reactions are more common than that.

Reported side effects range from days or weeks of swelling at the vaccine site on the arm to headaches, nausea, fever and dizziness. Meanwhile, there have been some cases of life-threatening reactions possibly attributable to the vaccine. Critics say many service members are afraid to report health problems associated with the vaccine for fear of being labeled as troublemakers.

Those who have ducked the shots are essentially refusing an order, a serious military infraction. More than 30 such service members have been court-martialed. The Air Force just yesterday agreed to a non-judicial punishment for Maj. Sonnie Bates, the first officer called on the carpet for refusing to take the vaccine, avoiding a controversial court-martial (ITP, Jan. 20, p7). Critics say hundreds more have avoided the shots by taking desk jobs or even leaving the military.

Opponents of the vaccine program, including a vocal group of Republicans on Capitol Hill, have called on the Pentagon to suspend the initiative until more research can be done (ITP, Dec. 23, 1999, p7; and Nov. 11, 1999, p1). They say the anthrax vaccine should return to the status of an "investigational new drug," or IND, until scientists can reach a better understanding of how it interacts with the human body.

Today (Feb. 17) the House Committee on Government Reform's subcommittee on national security is expected to release a report demanding a pause in the mandatory anthrax immunization program until the Pentagon can identify a vaccine more suitable for military use (see related story).

Questions have lingered for years

The anthrax vaccine being administered was originally approved in November 1970 for use in immunizing veterinarians, laboratory personnel and wool mill workers at risk of getting anthrax through the skin when they came into contact with diseased animals or their parts, including fur or hair.

In contrast, the Defense Department is concerned about service members contracting anthrax if an adversary delivers the highly lethal disease using an aerosol weapon, which could infect -- and potentially kill -- nearly all of those who breathe it.

Is the current vaccine appropriate for this kind of threat? Although a similar vaccine appeared to protect goat hair mill workers against inhaled anthrax in a study conducted in the 1950s, "there was insufficient data to demonstrate protection against inhalational disease," according to a 1995 Army document obtained by Inside the Pentagon. Because anthrax occurs naturally only very rarely, and because any scientific studies of anthrax in humans would expose subjects to a highly lethal disease, recent research on the vaccine's efficacy against inhaled anthrax has focused almost exclusively on animal testing.

Yet, prior to Cohen's decision to launch the immunization campaign, a number of officials in the government's medical and scientific community began asking whether there had been sufficient animal testing to justify the specifics of the anthrax vaccination program. Questions included how many shots should be given to each individual to provide adequate immunity, whether the shots should be given into the muscle or just beneath the skin, and -- perhaps most importantly -- whether this vaccination regime is appropriate to combat a variety of anthrax strains that might be delivered by an aerosol weapon.

On Oct. 20, 1995, the Army's Joint Program Office for Biological Defense hosted a meeting of Defense Department and industry officials to discuss, among other things, the possible expansion of the licensed anthrax vaccine "to include protection against an aerosol challenge of spores," according to meeting notes issued the following month by the program office.

Labeling for the vaccine, which lays out its approved uses, does not specifically say whether the vaccine protects against inhaled anthrax, but it also does not preclude this use. The license does describe the occupations that may involve anthrax exposure and understandably omits the military, given the time frame in which it was issued. But lawmakers have pointed out that an FDA-approved package insert notes, "Since the risk of exposure to anthrax infection in the general population is slight, routine immunization is not recommended."

Col. Arthur Friedlander, then chief of the bacteriology division of the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) and a top expert on anthrax, is said to have raised questions at the 1995 Army meeting about whether the medical community -- in the absence of much human test data -- had a sufficient understanding of how animal research on the anthrax vaccine correlates to humans.

In characterizing Friedlander's comments at the meeting, the Nov. 13, 1995, Army memo says "the current thinking is that antibodies against 'protective antigen (PA)' are important for immunity against anthrax infection." Yet animal tests "fail to demonstrate a correlation between PA antibody levels and immunity," the memo states. In other words, the medical community had not yet developed a clear understanding of how much vaccine is needed to provide immunity against inhaled anthrax.

A briefing by an SAIC consultant to the program at the October 1995 meeting noted that initially workers exposed to anthrax took a three-shot vaccine. But after two lab technicians and a wool mill worker developed anthrax anyway, the medical community "arbitrarily added three more doses at six-month intervals," according to the briefing.

Adding to the complexity of the issue is the fact that the vaccine given to the wool mill workers and others in the 1950s, which was produced by Merck, is different in some respects from the one later licensed for production by the Michigan Department of Public Health -- production that was ultimately assumed by the private company BioPort.

The General Accounting Office has said that differences in the two vaccines may raise safety issues. Those differences include changes in the manufacturing process when MDPH took over production from Merck, differences in the anthrax strain used to grow the vaccine, and changes in the ingredients used to make the vaccine that were intended to increase the yield of the protective antigen.

Friedlander, who currently serves as the USAMRIID commander's senior military scientist, was unavailable for comment this week. But he has said recently he thinks the animal tests do provide enough foundation for the Defense Department's immunization campaign. "We have 62 of 65 animals that have survived a lethal aerosol challenge against this disease," he told PBS' "NewsHour with Jim Lehrer" last October. "That's a 95 percent survival rate."

Asked if he was satisfied with that research as a basis for the current program, Friedlander said, "It's good enough for me. I don't see how it's not good enough for anybody. Given the threat, in fact, I think it would be medical malpractice not to offer and give that vaccine."

How much antibody is enough?

If Friedlander's earlier concerns have abated, that is not the case for all experts in the field. "How much antibody in your bloodstream is enough?" remains a question to the current day, acknowledges Lt. Col. John Grabenstein, deputy director of the Anthrax Vaccine Immunization Program agency. "The optimum dosage is unknown here." But Grabenstein counts himself among those who think the question should not be a show-stopper for the military's vaccine program; he believes additional research should continue in parallel with the existing immunization effort.

Back in 1995, Friedlander was not the only scientist mulling whether sufficient testing had been done to allow the approved vaccine to be used against an inhaled threat. Dr. Robert Myers, head of the organization that later became BioPort, said at the Army meeting that "extensive problems exist in demonstrating vaccine efficacy against an aerosol challenge" in the absence of much human data, according to the meeting notes. "There are no precise serological or cellular correlates linking immunization with protection in humans, and extrapolation from animal studies to humans is complicated by the same fact," the document states.

Grabenstein said this week that the animal studies, begun in the late 1980s, produced mixed results. The combined results from a number of different tests during the 1990s of vaccinated rhesus monkeys, challenged with aerosolized anthrax, showed that 62 of 65 primates tested survived -- a success rate of 95 percent, Grabenstein said in a Feb. 14 interview. Rabbits exhibited similar protection from the vaccine: 114 of 117 vaccinated rabbits survived a lethal dose of anthrax, a success rate of 97 percent, he said.

Guinea pig testing offered less encouraging results: only 19 of 88 vaccinated animals survived exposure to aerosolized anthrax, which translates to 22 percent. But even those figures encourage Grabenstein, who believes guinea pigs are not as analogous to humans as monkeys and rabbits are. "That's not bad when compared to zero-percent survival," he said, referring to odds of surviving anthrax without vaccination or post-exposure treatment with antibiotics.

Grabenstein said the animal research provided enough evidence that the vaccine works against inhaled anthrax to give the Pentagon leadership confidence the immunization program should proceed.

Still, GAO has said the animal tests continue to leave pressing questions about the vaccine unresolved. "Research using monkeys showed for the first time that monkeys could be protected against aerosol exposure," the agency said in April 1999 testimony before Congress. "However, in both the guinea pig and monkey studies, protection did not correlate with levels of antibodies to a protective antigen. Several studies have shown no direct comparison of immunity in humans to that in monkeys."

Eyeing changes to an FDA-approved label

Eleven months after the Army meeting at which questions were raised about whether the vaccine could be given to the military without a change in the licensed label, Myers -- the director of the Michigan Biologic Products Institute, BioPort's predecessor -- applied to the FDA to use the anthrax vaccine as an investigational new drug.

The purpose of the IND application, Myers wrote in a Sept. 20, 1996, letter obtained by ITP, was "to conduct clinical investigations designed to investigate changes in the approved labeling for the [already] licensed product." The "potential labeling changes," Myers wrote, would pertain to the "specific clinical indication" for the vaccine, which experts say refers to the type of disease against which the vaccine is intended to protect: cutaneous versus inhaled anthrax.

The IND would also allow testing to be done on the "route and vaccination schedule" for the product, which refers to whether the vaccine might be given in the muscle instead of beneath the skin -- which may be more effective and reduce side effects -- and whether fewer than six shots might be sufficient to provide immunity, which would save taxpayer dollars and also potentially reduce side effects.

An FDA spokeswoman said last week the agency does not comment on INDs because they involve trade secrets in the drug industry. But a recent letter sent by an FDA official to Capitol Hill refers to a pilot study the Pentagon has conducted on alternative "routes of administration" and "dosing schedules" for the anthrax vaccine, using "a BioPort IND" and requiring the "informed consent" of participants.

Grabenstein this week confirmed that pilot studies were carried out in 1998 using the IND, leading up to an anticipated launch this summer of major studies on intramuscular injections and alternative dosing for the anthrax vaccine.

Regarding the third issue for which Myers applied for IND status -- clinical indication -- Grabenstein referred to statements made by Kathryn Zoon, director of FDA's Center for Biologics Evaluation and Research. She has told lawmakers she views the vaccine as effective against anthrax, regardless of the way in which the disease is introduced into the human body, through the skin or the lungs, Grabenstein said.

But he also acknowledged that some "statisticians" remain unconvinced there is sufficient research data to demonstrate the approved vaccine should be used to protect against inhaled anthrax. He said a working group that includes representatives from the Defense Department, FDA, the Centers for Disease Control, the National Institutes of Health and BioPort continues to wrestle with what additional research may still be needed.

In the two years leading up to Cohen's decision to go forward with the vaccination initiative, another variation of this same question was being asked. Given the limitations in understanding the vaccine, could the Pentagon begin vaccinating millions of service members without doing additional research? Would changes to the FDA-approved label prove necessary, which in turn would require significantly more testing and more time?

"There had been some questions about whether or not the vaccine labeling was permissive for use to protect against pulmonary anthrax, or whether it applied only to use for prevention of cutaneous anthrax," stated an interoffice memo issued on Feb. 18, 1997, by the director of FDA's vaccines division. "The military is mostly concerned about the threat posed by aerosol anthrax exposure," continues the memo, obtained by Inside the Pentagon.

This official concluded that despite the questions, the FDA-approved vaccine could indeed be used as protection against inhaled anthrax. "My interpretation of the anthrax vaccine labeling is that it IS permissive for use to prevent pulmonary/inhalation anthrax," the memo continues. "Also, there are now some excellent animal data available to indicate vaccine efficacy for the inhalation route of challenge," the document states, calling special attention to the good results demonstrated by vaccinated monkeys challenged with lethal doses of anthrax.

A decision is made

Two weeks later, on March 4, 1997, Dr. Stephen Joseph, then assistant secretary of defense for health affairs, wrote to FDA to ascertain whether the Defense Department could use the approved vaccine to prevent inhaled anthrax, delivered by a weapon, despite the lack of specificity on the label.

"While the package insert for this vaccine is nonspecific as to the route of exposure, DOD has long interpreted the scope of the license to include inhalation exposure, including that which would occur in a biological warfare context," Joseph wrote. "Please advise whether the FDA has any objection to our interpretation of the scope of the licensure for the anthrax vaccine."

Dr. Michael Friedman, FDA's lead deputy commissioner, responded on March 13, 1997, with a letter that laments the limitations in research data but ultimately accedes to DOD's interpretation. "While there is a paucity of data regarding the effectiveness of anthrax vaccine for prevention of inhalation anthrax, the current package insert does not preclude this use," he wrote.

The memo goes on to note how the human data gathered in the 1950s demonstrated the efficacy of the vaccine against skin exposure to anthrax, but shed little light on its use against an inhaled threat.

"These data alone are insufficient to allow definitive statistical conclusions," Friedman wrote. He added, though, that "results from animal challenge studies have also indicated that pre-exposure administration of anthrax vaccine protects against inhalation anthrax.

"Therefore, I believe your interpretation is not inconsistent with the current label," Friedman wrote. Officials say this statement paved the way for the Defense Department's mammoth immunization program using the already-approved vaccine, without additional research or any alteration to the labeling.

To Grabenstein, the lingering questions after the fact reflect a natural desire on the part of the medical and scientific community to better understand how a vaccine works and how it can be improved. But he says he believes, as Friedlander recently stated, that given the anthrax threat, the government had enough understanding of the vaccine to go forward with the program.

"The information cup is not 100-percent full," he told ITP in this week's interview. "We all wish there was more data." But, he said, "you must make a decision based on incomplete knowledge."

Others are looking at that same body of knowledge, and, given additional concerns about BioPort's production process and the side effects that have cropped up, judge it as an insufficient foundation for a mandatory program to vaccinate millions of service members.

"Administration of the anthrax vaccine for mass prophylaxis against biological warfare should be considered an off-label use of the product to treat an indication for which it is not explicitly licensed," according to the House Government Reform panel report, set for release today. Deviations from the uses specifically indicated on the label "should be undertaken only pursuant to FDA regulations governing clinical trials of investigational new drugs," the report says.

The Pentagon's policy states that service members will be given a "suitable" vaccine to immunize them against anthrax, one congressional aide said Feb. 14. "The question is, 'Is this a suitable vaccine?'" -- Elaine M. Grossman