Pentagon Moving Closer To Publishing Past Anthrax Vaccine Studies

by Keith J. Costa

Inside the Pentagon

August 3, 2000

The Defense Department is moving closer to conducting and publishing a number of anthrax vaccine studies that the Pentagon hopes will put to rest concerns of service members and their families about the vaccine's safety and efficacy. A set of past safety studies on the anthrax vaccine performed at the U.S.Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD, will be published for the first time in the September issue of Vaccine, a medical journal, according to Army Lt. Col. John Grabenstein, deputy director for clinical operations at the Anthrax Vaccine Immunization Program agency.

In late September, the Centers for Disease Control and Prevention will award a contract to a major research institution to study the consequences of reducing the number of vaccine shots given to service members and changing the route of vaccine administration, Nina Marano, coordinator of CDC's anthrax vaccine research project, told Inside the Pentagon last week. Today, service members are given an initial series of six vaccine shots, which are followed by annual boosters. The shots are administered subcutaneously, but the Pentagon has expressed interest in injecting the shots directly into muscle, in part to reduce skin irritation.

CDC received "multiple proposals from both civilian and military institutions" in response to a request for such proposals published May 15 in the Commerce Business Daily, Marano said. The center cannot release the identity of the bidders at this time, she added. "The proposals were all very strong. The institutions that responded all have experience doing this kind of work on this scale."

The CDC study is scheduled to begin early next year and will "address the risk factors for adverse events between men and women . . . and optimizing the vaccination schedule and administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events," the CBD notice states.

Getting all the unpublished studies done at USAMRIID has been an important goal for the AVIP agency. In August 1999, AVIP set up a "longitudinal study concept committee" to plan studies that would help bolster the Pentagon's claim that the vaccine is both safe and effective. The group proposed getting completed studies published and worked with other federal agencies to plan new health-related studies for the program (ITP, Aug. 26, 1999, p1). The Pentagon's mandatory anthrax vaccination program, which was scaled back last month because of supply problems, came under fire by critics in March
after the National Academy of Sciences' Institute of Medicine released a report highlighting a lack of published, peer-reviewed data on the vaccine (ITP, April 13, p1). The institute concluded that "in peer-reviewed literature there is inadequate [and] insufficient evidence to determine whether an association does or does not exist between anthrax vaccination and long-term health outcomes. To date, published studies have reported no significant adverse effect of the vaccine, but the literature is limited to a few short-term studies." One study the Pentagon is counting on to help it better grasp the long-term health effects of the vaccine is being conducted by a civilian group of doctors organized by the Department of Health and Human Services. Established in 1998, the group, called the Anthrax Vaccine Expert Committee, has been evaluating reports from the 1990s on anthrax vaccine use provided by the Vaccine Adverse Event Reporting System, which is jointly managed by the Food and Drug Administration and the Centers for Disease Control and Prevention.

The committee's work is "60 percent done," but the results so far bode well for the anthrax vaccine program, Grabenstein told Inside the Pentagon July 20. The results will put debate about vaccine safety "on a more objective plane," he said. Some opponents of the AVIP effort, citing anecdotal evidence and testimony from service members whose health has apparently deteriorated since beginning the six-shot dosing schedule, say taking the vaccine has led to incidents of thyroid disease and other maladies.

The Defense Department, on the other hand, has said there is no evidence to suggest that the military population taking the vaccine has higher rates of such diseases than the population at large, and the AVEC results buttress the claim, Grabenstein said. "Before we said there's no reason to believe there are higher incidents in the vaccinated population," he said. "Now we have good evidence that there is no such problem."

The Army is conducting another study using existing health data from anthrax vaccine use to look at hospitalization and outpatient visit rates, comparing them with data on the non-vaccinated population. At the same time, this study is focused on hospitalization and outpatient visit rates to see whether women are at greater risk from using the vaccine than men. Given the results so far, "we can say the data shows no gender effect for hospitalization," Grabenstein said. "They're still working on results for [a] gender effect related to outpatient visits." Two additional studies are expected to begin next year. First, a long-term study initiative, organized by DOD and the Department of Veterans Affairs, will attempt to enroll 100,000 people, starting in 2001, and follow their health reports for 20 years.

The second will be the one conducted by the Centers for Disease Control and Prevention -- a Department of Health and Human Services agency -- with DOD cooperation. With money provided by HHS, the congressionally mandated study "will cover a broad range of research, including the human clinical trial for reducing the number of doses in the shot regime and changing the route of administration, non-human primate studies and correlates of protection for inhalational anthrax," according to Marano.

The correlates of protection for inhalational anthrax will examine "what it is about the anthrax vaccine that actually protects against the threat," she said. In other words, this aspect of the research will examine whether high antibody levels or "something more complex taking place at the cellular level" offers protection against anthrax. "Is it just the antibodies or is something else happening?" Marano asked.

"We also want to more fully characterize the immune response to protective antigen," Marano said. The anthrax vaccine -- licensed by the Food and Drug Administration and considered by DOD to be safe and effective for use against inhaled anthrax -- contains small amounts of protective antigen (PA), which allegedly stimulates the body to produce antibodies that can protect against the PA, thereby providing a protection against anthrax infection, she said. The study will test that theory. "All we know for sure is that when vaccinated the body gets high antibody levels," Marano said. "What we want to know is whether the protective antigen is producing the immune response. Or are other factors contributing to the immune response?" The non-primate studies are needed to provide more information about the anthrax vaccine than was provided in previous tests at USAMRIID using rhesus monkeys, Marano said (ITP, March 2, p3). Rhesus monkeys are small, weighing about 20 pounds, and in previous tests they were given "human-size doses" of the vaccine, leading to an "enormous antibody response."

"Because of their size, it would have been better if they were given a dose that corresponds to their body weight," Marano said, adding that some officials expressed concern adult-size vaccinations may have led to erroneous conclusions. "We want to know what happens when they are given the right dose for their bodyweight," she said. "It will give us a better model for evaluating the vaccine." All the lab work for the study will be performed by CDC "to give us greater confidence we can interpret the data," she added. CDC will consult with USAMRIID when setting up the lab work and for advice on getting military personnel to participate in the study. The study is expected to last 43 months. Along with the contractor that will manage the study's logistics, CDC will begin enrolling participants as early as January. Marano expects most participants will come from the "first responder community" -- civilian firefighters, police officers and paramedics. The goal is to enroll 1,600 people and give them vaccinations.

"There will be seven subgroups to examine, each with a different shot schedule," Grabenstein said of the study. "The main thing is to see if we remove dose two . . . do we get as good an antibody response with that shot included? Then they'll look subsequently at whether there's no change if we go to boosters every two years instead of annually. "They'll take blood samples and examine the antibody response to the vaccine," he added. "Based on the amount of antibodies people have, they'll make a decision on the main issue: If there are fewer doses, is there no less of an antibody response?" As for changing the route of administration, the study will look at injecting doses an inch deep into muscle as opposed to a half-inch deep into skin, as they are administered today, Grabenstein said.

Grabenstein added that most participants probably will be civilians because DOD personnel "move around too much to be good subjects for study." Also, it may be better for a university to conduct this effort than a military institution because it will then be seen by many as a more independent and open process, he said.