CDC Set To Begin Wide-Reaching Anthrax Vaccine Studies This Month

By Keith Costa

Inside The Pentagon

March 8, 2001

A key component of a multifaceted anthrax vaccine research project coordinated by the Centers for Disease Control and Prevention is set to begin later this month, the results of which could lead to a better understanding of the vaccine's capabilities and changes in the way it is administered to service members.

Under a CDC contract, researchers at Battelle Memorial Institute, Columbus, OH, are gearing up to begin a seven-month challenge study using rhesus monkeys, which will be given Food and Drug Administration-approved vaccine and exposed to anthrax, according to Nina Marano, coordinator of CDC's Anthrax Vaccine Research Program. The vaccine, called Anthrax Vaccine Adsorbed (AVA), is the same given by the Defense Department to troops to protect them from inhaled anthrax.

Battelle also will conduct a 30-month follow-on study, and Emory University in Atlanta is signed up to do related vaccine research with rhesus monkeys, although the latter effort will not involve challenge studies, Marano said in an interview late last month.

The start date for Battelle is March 25, "pending final approval by [the] CDC Institutional Animal Care and Use Committee," according to Marano. CDC is less certain about the start date for the Emory University project, but expects it to begin "by the end of April at the latest."

The purpose of these efforts is to "demonstrate that modified AVA vaccine regimens produce an immunologic response similar to the human immune response and provide clinical protection (i.e., survival) against aerosolized challenge with [anthrax] spores," among other things, states a Jan. 22 CDC fact sheet obtained by Inside the Pentagon.

The Battelle and Emory studies are just two elements of the congressionally mandated Anthrax Vaccine Research Program, established in June 2000 at CDC's National Center for Infectious Diseases. (CDC is a Department of Health and Human Services agency.) In addition to the rhesus monkey studies, the Anthrax Vaccine Research Program has let contracts with other research institutions to conduct a human clinical trial to study the
possibility of immunizing vaccine recipients using fewer doses than presently recommended by the Food and Drug Administration. CDC will solicit 1,300 volunteers to participate in the human clinical trial, Marano said.

As spelled out in policies endorsed by the Defense Department's Anthrax Vaccine Immunization Program, service members are required to receive a primary series of five shots within one year, and another six months later, before they are considered fully
immunized under FDA guidelines. Annual boosters are required after the primary shot series.

The National Center for Infectious Diseases' human clinical trial also will look into changing the route of administration by injecting the vaccine into muscle, as opposed to just under the skin, as typically done today, and the different reactions men and women have to the vaccine. Another CDC element, the National Immunization Program, is reviewing safety issues related to the anthrax vaccine and the system used to report adverse events. The National Center for Infectious Diseases and the National
Immunization Program are seeking $23 million in funding for fiscal year 2002 as a Health and Human Services appropriation, Marano said.

The Defense Department has agreed to give CDC 8,900 doses of FDA-approved anthrax vaccine at no cost from its dwindling stockpile to conduct the anthrax-related research, Marano said. "It's enough for what we need," she added.

Then-Defense Secretary William Cohen kicked off the mandatory anthrax vaccine program for all service members in 1998. But a supply shortage has forced the Pentagon to scale it back dramatically. In July 2000, DOD said it would reserve its available supply for those deployed for an extended time in certain high-risk regions (ITP, July 13, 2000, p2). All other DOD personnel will resume taking shots once quality control problems have been resolved at BioPort, the sole supplier of the vaccine, according to the revised policy.

Based in Lansing, MI, BioPort is awaiting FDA approval to resume production for the military at its renovated manufacturing plant. Such approval, though, means addressing problems cited in an October 2000 FDA plant inspection, which uncovered design problems with the facility's filling suite and raised concerns about employee practices in ensuring the sterility of vaccines. Another inspection in November 1999 found that the manufacturing process for AVA was not validated (ITP, Nov. 16, 2000, p3; Dec. 16, 1999, p1).

FDA is not expected to give the go-ahead for new vaccine production until the second quarter of this year at the earliest, according to company officials.

In the meantime, the anthrax vaccination effort continues to come under fire from a legion of critics, which includes lawmakers and a number of service members, some of whom have put their careers on the line to protest the mandatory program.

Magnet for criticism

Critics attack the vaccine program on several fronts.

The primary charge is that there is not enough evidence to back DOD's claim that the anthrax vaccine is safe and effective. A similar concern is raised about the way the vaccine is administered to troops. (The vaccine has been licensed by FDA since
1970.)

Citing studies by the National Academy of Sciences' Institute of Medicine and DOD's inspector general, as well as testimony by General Accounting Office officials, some have raised questions about the amount of scientific research available to justify the Pentagon's sweeping vaccination effort (ITP, April 13, 2000, p1). And based on anecdotal evidence and congressional testimony, they say the number of vaccine recipients who have experienced adverse systemic reactions is increasing, while the
reporting system for adverse events may not reflect the damage done to service members. The vaccine program has hurt Pentagon recruiting and retention, they add.

In an internal legal memorandum, two Air Force Reserve judge advocates general have argued that the vaccine program is inconsistent with federal law. The memo says the vaccine is used in a manner inconsistent with its original license and should be
considered an investigational new drug under FDA regulations (ITP, April 20,
2000, p1).

Such concerns prompted a bipartisan group of lawmakers last year to demand the suspension of the mandatory program. Leading the charge were House Government Reform Committee Chairman Dan Burton (R-IN), House Government Reform national security subcommittee Chairman Christopher Shays (R-CT), then-House International Relations Committee Chairman Benjamin Gilman (R-NY) and Rep. John Conyers (D-MI), ranking minority member of the House Judiciary Committee (ITP, June 1, 2000, p1).

"I respectfully cannot agree to such a request," wrote Charles Cragin, then-principal deputy assistant defense secretary for reserve affairs, in a May 16, 2000, response. Cragin is now the acting under secretary of defense for personnel and readiness.

"To suspend the program would place thousands of [service members] in a vulnerable position where they would go to work every day in areas of the world where potential adversaries possess the ability to deliver deadly weaponized, aerosolized anthrax at any moment," Cragin said.

Anthrax Vaccine Adsorbed has been "validated" by CDC and the National Institutes of Health, he added. "The FDA has continuously stated that the vaccine is approved and has been since 1970, as such, [it] is not an investigational drug."

The anthrax vaccine effort has been attacked by some groups using misinformation, Cragin added.

"When you administer over 1.7 million doses of vaccine to over 440,000 people, some will get sick, for some reason, inevitably, at some point in time," he wrote. "Although opponents to the inoculation program would have you believe otherwise, most of these illnesses are not related to anthrax vaccine." Military and civilian hospitals, he continued, have found many of the illnesses are "due to other causes."

Of all those who have taken the vaccine, only 31 have required hospitalization, Cragin wrote. "Of these 31, only six have been determined to, more probably than not, have illnesses which have resulted from anthrax vaccination. . . . These personnel have
been granted waivers to not receive future vaccinations. These determinations were made by an independent panel of experts convened by the U.S. Department of Health and Human Services."

In addition to arguing that the vaccine is both safe and effective, DOD officials also say that Anthrax Vaccine Adsorbed is one of the more thoroughly studied vaccines in recent history. However, several studies, including ones conducted by the U.S. Army Medical Research Institute of Infectious Diseases, went unpublished for years. As part of its efforts to address concerns about the anthrax vaccine, the Pentagon's Anthrax Vaccine Immunization Program office in 1999 began an effort to get the USAMRIID studies and others published (ITP, Aug. 3, 2000, p1).

Other studies on the vaccine include an ongoing review of the Vaccine Adverse Event Reporting System by the so-called Anthrax Vaccine Expert Committee, a group of civilian doctors organized by Health and Human Services, and a long-term initiative, organized by DOD and the Department of Veterans Affairs, that will follow the health reports of 100,000 people over a 20-year period. Pilot testing for the latter study, which will look at a number of health issues in addition to those related to the anthrax vaccine, began this year under the aegis of the assistant defense secretary for health affairs office.

Research to date indicates that the rate of major disease among the military population taking the vaccine is no higher than the rates for the general population, according to military officials.

Getting ready for kickoff

The impending Anthrax Vaccine Research Program tests using rhesus monkeys -- the one coordinated by CDC's National Center for Infectious Diseases -- will garner more information about the anthrax vaccine than rhesus monkey tests previously
performed at USAMRIID, according to Marano.

Rhesus monkeys are small -- about 20 pounds -- and in previous tests were given "human-size doses" of the anthrax vaccine, leading to an "enormous antibody response," Marano told ITP in a July 2000 interview.

"Because of their size, it would have been better if they were given a dose that corresponds to their body weight," she said. "We want to know what happens when they are given the right dose for their body weight. . . . It will give us a better model for
evaluating the vaccine."

The purpose of the seven-month study involving rhesus monkeys is to "establish what that dose is that could be comparable with the human dose," Marano said during last month's interview. The information provided by such a study will be of great interest to FDA officials, she added.

This study, along with others conducted by the Anthrax Vaccine Research Program, could inform a future decision to cut back on the number of doses considered necessary to achieve immunity from inhalational anthrax.

"What we want to do is reduce the number of doses" required for human vaccine recipients, Marano said. "We don't think it takes that many doses to protect people," she added, referring to the FDA-approved shot regimen for humans: six doses over 18 months followed by annual boosters thereafter.

A critical first step in reaching such a conclusion is finding out whether past studies involved "overimmunizing the monkeys with that human dose," Marano said. "It could very well be that the human dose may be totally appropriate for a monkey, but that's
the purpose of the first study. We're going to give progressively diluted vaccine to the monkeys, and see how the monkeys that get the diluted vaccine compare to those who get the full vaccine dose -- from a blood work standpoint and a survival standpoint."

Past studies involving rhesus monkeys "have constituted two doses, given four weeks apart, and then these animals were challenged two years later," she said. "That's a long time. They're challenged, and they have very high survival rates."

The survival rates raise questions about the FDA-approved shot regimen. This schedule "reflects the feeling that people have to maintain very high antibody titers in order to be protected. Now that doesn't compare to the monkeys because what you see is their antibody titers before challenge two years later is almost nondetectable. That does not compare to what we're saying we have to do in humans," she said.

The researchers will examine whether something other than high antibody levels produced by the vaccine protects against anthrax exposure. It could be that protection is achieved because of the body's ability "to have memory of the vaccine," Marano said. "In other words, people get a couple of priming doses, but then they can go a long time without the vaccine. But if they get exposed, God forbid, they will respond [because] their bodies will know how to appropriately respond. That's what we see in monkeys."

In addition to looking into changing the recommended number of anthrax vaccine doses and the route of administration, better understanding "correlates of protection for inhalational anthrax" is a key part of the Anthrax Vaccine Research Program effort,
Marano said.

In other words, she added, this part of the program will look into "what it is about the anthrax vaccine that actually protects against the threat." Researchers will ask if it's high antibody levels or something more complex taking place at the cellular level that offers protection against anthrax.

"We also want to more fully characterize the immune response to protective antigen," Marano told ITP in the July 2000 interview. The anthrax vaccine contains small amounts of protective antigen (PA), which theoretically 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 at the time. "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 bottom line is the research could lead to a better understanding of the efficacy of the vaccine and how it works, Marano told ITP last month.

Further, the research will be useful in validating the use of tests like the ELISA (enzyme linked immunoabsorbent assay) and TNA (toxin neutralization assay) as correlates of protection, according to the Jan. 22 CDC fact sheet. Both are "primary assays CDC will be using to measure the antibody response" to the anthrax vaccine, Marano said. ELISA measures antibody titers and concentration and TNA evaluates the ability of a person's immune system "to neutralize lethal toxin, the primary toxin produced by bacillus anthracis," she explained.

Gaining a better understanding of how Anthrax Vaccine Adsorbed works will also lead to the "development of new strategies for predicting clinical protection against inhalational disease in humans following vaccination with current and newly developed anthrax vaccines," the fact sheet states.

The United States is likely between five and 10 years away from developing a recombinant anthrax vaccine, one made using genetic engineering, Marano said. Recombinant vaccines are considered more effective and less likely to cause adverse
reactions than those manufactured using traditional methods. Fewer doses may
be needed to achieve immunity against anthrax using the recombinant vaccine than with Anthrax Vaccine Adsorbed.

Knowledge gained from the CDC-funded Anthrax Vaccine Research Program studies can be applied to any new anthrax vaccines in the works, as well as any vaccines being developed to fight bacterial diseases, she added.

Funding for the program, according to Marano, "is not only money well spent for the current generation of people having to be vaccinated; it's money well spent because everything we learn with this vaccine can be applied to the new, recombinant vaccine.

"And we're hoping at the very least that we will never have to use animals again for anthrax protective efficacy research," she said. "I think we're going to learn what we need to learn from these studies."

Headed for trial

To conduct non-human primate studies and a human clinical trial, CDC's Anthrax Vaccine Research Program signed contracts and interagency agreements with seven institutions: Walter Reed Army Medical Center, Washington, DC; the National
Institutes of Health, Bethesda, MD; Baylor College of Medicine, Houston, TX;
the Mayo Clinic, Rochester, MN; as well as USAMRIID, Emory University and Battelle.

The Anthrax Vaccine Research Program will "coordinate the studies, perform serologic assays to support the primary trial end points, and will collate, enter and analyze all the data produced" by the various efforts, the fact sheet says.

Ohio State University in Columbus, OH, and the Centre for Applied Microbiology and Research in the United Kingdom, which makes the British anthrax vaccine, are subcontractors working for Battelle and will conduct in-vitro studies with samples from
the rhesus monkey tests.

In addition to providing advice to CDC on setting up lab tests, USAMRIID will obtain serum for the ELISA assay, according to Marano. "You need a large amount of reference serum from people already vaccinated. USAMRIID is helping us obtain those volunteers," she said. Furthermore, "the National Institutes of Health will help us to produce recombinant PA that is also needed to go into these laboratory tests."

Walter Reed, Emory University, Baylor and the Mayo Clinic are performance sites for the human clinical trial. The Defense Department's Anthrax Vaccine Immunization Program will make staggered shipments of anthrax vaccine to each site.

Marano expects to sign up 1,300 civilian volunteers for the trial, which is designed to answer questions about changing the route of administration by injecting the vaccine into muscle, instead of just under the skin. In addition, the trial effort will study eliminating shots required by the FDA at two weeks and 12 weeks, and giving service members boosters every other year instead of annually, according to the fact sheet.

The human clinical trial could begin May 1, Marano said, pending approval of trial protocols by FDA, CDC and local ethics committees set up by the institutions conducting the study. Marano expects to submit the protocols by mid-March. If enrollment for the trial begins in May, the Anthrax Vaccine Research Program could have data to submit to the FDA in September 2002, she said.

The local ethics committees, called Institutional Review Boards, are comprised of physicians, statisticians, health educators and bioethicists. They will review the protocols in detail "to make sure that what we're proposing to do takes into account the protection of human subjects," Marano said. Also, "they want to make sure the participants are fully informed . . . and that we are providing enough financial incentive to cover their costs to travel to the sites."

The enrollment period could last as long as nine months, she said, and participants are expected to remain in the program for 43 months. How much they get paid will vary from site to site, but some could receive $50 a visit for 20 visits.

Program officials expect to recruit members of the first-responder community --firefighters and police officers, for example -- for the human clinical trial. "We wouldn't take exclusively from this group, but we think those people might be more motivated
to take the vaccine," Marano said.

In addition, volunteers will be solicited by mail and radio announcements, she said. Participants will receive a medical examination. Pregnant women are not allowed to participate.

The Anthrax Vaccine Research Program is "very interested" in studying the differences between how men and women react to the vaccine, according to Marano.

Women have a higher rate of short-term adverse reactions to the vaccine. Up to 30 percent of women have nodule development in the arm where the shot was administered, and they experience more pain and redness than men.

"The study will look at some of these differences," she said. "What we expect to find is when you go to the intramuscular route [of administration], all those short-term side effects will go away. We think that almost all those short-term reactions are related to the fact that it's being given subcutaneously."

Whether study officials will be able to enroll the required number of participants is unclear, Marano said. However, "I think there's a lot of interest . . . [from] people who feel they need to be protected," particularly in the first-responder community, she added.

"It's the only way right now for a civilian to get anthrax vaccine," Marano said. "A number of investigators [at CDC] are planning to enroll. I'm planning to enroll. Mayo did a survey of their personnel and asked, 'If we did this, would you be interested to join up?' There was a 40 percent 'yes' response rate."

DOD's Anthrax Vaccine Immunization Program office receives a number of calls from civilians asking where they can get vaccinated. Those calls will be directed to the research sites, Marano said.