Anthrax aftermath: Adverse drug reactions, vaccine controversy undercut CDC extended treatment offer

Some 8,000 people say thanks but no thanks

Bioterrorism
Watch

Despite the lingering possibility of late-onset anthrax infection, more than 8,000 people potentially exposed in the bioterrorism attacks of 2001 have turned down offers of additional antibiotics and immunization with the controversial vaccine, Bioterrorism Watch has learned. Faced with insufficient data to truly assess the risk, the Centers for Disease Control and Prevention (CDC) in Atlanta offered the additional measures but fell short of actually recommending them.

Additional treatment offered as an option’

Operating on a thin margin of data about anthrax exposures, incubation periods, and subsequent infections, the CDC concluded it couldn’t make a formal recommendation. The additional antibiotics and vaccine were made available as "options" to those exposed. "The feeling was that this was the best thing we could do for people, and at least, leave it up to them to make a decision," says Ian Williams, PhD, medical epidemiologist in the CDC national center for infectious diseases. "We don’t know what the answer is, but these are the options. We were really caught between a rock and a hard place on this one."

The 10,000 people potentially were exposed to anthrax in Connecticut, Florida, New Jersey, New York City, and Washington, DC. They were all originally recommended to take at least 60 days of post-exposure antibiotic prophylaxis, but emerging data suggest that there has been a surprising lack of compliance.

In some preliminary surveys, fewer than half of those exposed were fully adhering to their original 60-day regimen. The CDC now has undertaken a telephone survey of all 10,000 people to identify adverse reactions and other reasons for the lack of adherence. (See "Side effects undermine anthrax drug adherence" in this issue.)

The vaccine and additional antibiotic options were brought into play in part because the CDC knew it had large numbers of people who had not completed the original 60-day regimen. But the offer of additional care may have been undermined to some degree by prior adverse antibiotic reactions and fear of an anthrax vaccine that has been mired in controversy for years. Then again, many of those exposed may have felt they were no longer at risk and if their status changed, they would consult a physician.

Anthrax alive at 100 days

Though no known cases of anthrax have developed in any of the individuals who were prescribed the 60-day antibiotic course, the CDC also was aware of some disturbing data in animal studies. Traces of live anthrax spores have been detected in test animals’ lungs up to 100 days following exposure, raising the theoretical possibility that the spores remaining still could cause disease. In that regard, one of the additional options offered to the exposed people was to take antibiotics for another 40 days (bringing total therapy time out to 100 days).

The other option was to take the additional drug regimen and also be vaccinated against anthrax. The latter option included three doses of anthrax vaccine over a four-week period, but antibiotics still had to be taken as the vaccine took effect.

The vaccine was not designed for post-exposure prophylaxis, but the theory is that it may provide additional protection by inducing an immune response to anthrax. "People were unclear what the upper limit [for the onset of infection] was," Williams says. "That is what really drove both the vaccine and the antibiotic [offer]. We thought that 40 additional days to make 100 days looked sufficient based on our scant data. The vaccine was added because, is 100 days enough? I can’t tell you absolutely for sure that it is enough."

Thousands took their chances

Most people were willing to take their chances that late onset anthrax will not occur. Of the exposed cohort of some 10,000 people, 1,547 elected to receive more antibiotics after their 60-day regimen. Another 192 opted to be immunized with the anthrax vaccine and take additional antibiotics while the series of shots is given. Are the other 8,000-plus people at any real risk? "Our feeling is that there shouldn’t be any late cases of anthrax, based on what we know," Williams says. 

"But that very well might be dose-dependent. We can’t quantify the dose. If you go back and look at the animal studies that were done, they were actually done with probably lower doses than we have seen in the [U.S. Senate] Hart office building. But based on the data we can draw from animal models, it looks like there shouldn’t be late onset cases," he explains. If such an event occurred, the disease presumably still could be treated — provided the person seeks medical care. Still, making assumptions about anthrax can be tricky.

The CDC has been on a steep learning curve throughout the bioterrorism attack, with officials caught off guard by the ability of anthrax to disperse and spread during mail handling. In addition, the ability to predict risk of infection in an exposed individual remains elusive, said Julie Gerberding, MD, director of the CDC division of healthcare quality improvement. "We know that the exposure dose probably varies depending on how close you are to the source when it’s released and how long you are in the [area] of release," Gerberding reported at a recent CDC meeting on post-exposure prophylaxis for anthrax. "[But] despite our capacity to think about populations, we cannot accurately identify individual exposure, and we cannot accurately quantify individual risk," she explained.

Faced with that conundrum, the CDC put the same options on the table for all 10,000 people potentially exposed. "The risk was probably different in different places," Williams says. "If you look at Capitol Hill, the concentration of anthrax released was probably much higher than say, Connecticut, where a letter just went through a post office. But that’s group risk. Individual risk is different. [We] can’t tell you exactly what your risk is. We’ll give you the best available data, but you are going to have to make that decision."

Of the 190 people receiving anthrax vaccine, 80 had some political connection in Washington, DC, and 44 were postal workers in that city. Another 49 people in New Jersey were vaccinated; and the remainder were in New York City (12), Florida (four), and Connecticut (three). Of those who chose additional antibiotics only, 849 were in Washington, DC; 354 in New Jersey; 248 in New York City; 55 in Connecticut; and 41 in Florida.

A mixed message?

The CDC has drawn criticism for its approach, particularly for making a controversial vaccine available but leaving the immunization decision up to patients and their providers. "It would have been much better if they had come out and said, Yes, we think in order to have as much protection as possible against the potential of developing disease, you should receive both antibiotic and vaccine,’" says Phillip Brachman, MD, a professor in the Rollins School of Public Health at Emory University in Atlanta.

The vaccine has been embroiled in a safety dispute since the military began a mandatory immunization policy several years ago, with some veterans saying it made them sick and others refusing to take it. "A number of [the exposed people] undoubtedly read about the problems some of the military folks claimed they had experienced after having the vaccine," Brachman says. "They associated their problem with the vaccine. Remember, that those people in the military who have made those complaints are a very small number, considering the total number of doses given," he adds. "So there are very few voices creating a lot of concern."

Brachman did what remains the only clinical trail on the safety and efficacy of an anthrax vaccine precursor when he worked for the CDC in the 1950s.

In a study of goat’s-wool workers — which was once an occupational risk group for anthrax in the United States — he found the vaccine safe and effective. He reported few side effects to vaccination and an efficacy rate of 92.5%.1 The vaccine used in the study was a protective-antigen variety similar to the current vaccine. However, the manufacturing process has since changed and a different strain of anthrax is now used. "There have been a few minor changes, and some people make a lot more out of it then it really should be," he says. "A different strain is being used to prepare the vaccine, but that should make no difference because the organism is not in the vaccine. It is the protein product from the organism."

Dearth of data

An Institute of Medicine committee that convened to look at the current anthrax vaccine cited a dearth of data in concluding: "The published studies have found transient local and systemic effects (primarily erythema, edema, or induration) of the anthrax vaccine.

"There have been no studies of the anthrax vaccine in which the long-term health outcomes have been systematically evaluated with active surveillance. . . . The committee concludes that in the peer-reviewed literature, there is inadequate/insufficient evidence to determine whether an association does or does not exist between anthrax vaccination and long-term adverse health outcomes. . . . To date, published studies have reported no significant adverse effects of the vaccine, but the literature is limited to a few short-term studies,"2 the committee said.

For its part, the CDC would not have made the vaccine an option for those exposed if it had any doubts about its safety, Williams says. "It seems to be a very safe, efficacious vaccine," he says. "[The] CDC reviewed the data with the military, which has the most experience with this."

Still, some people may have been confused because the CDC did not roll out the vaccine right after the exposures occurred. Thus, the response was somewhat tepid to a vaccine "add-on" option 60 days after the potential exposure. One problem is that the U.S. military, which controls the dispersal of anthrax vaccine, did not release any stocks in the immediate aftermath of the bioterror attacks, he says. "One of the lessons we have learned is that if the vaccine had been available when this first started, I think the post-exposure prophylaxis would have been approached much differently," Williams says.

With the military now more amicable on the issue, if a bioterrorist strikes again with anthrax, the vaccine could play an important role from the onset, he emphasizes. "If this should happen again, the vaccine might be used closer to day zero," Williams says. "After a series of doses over a month or so, most people will develop an antibody response, so it would obviate the need for additional antibiotics. It will be used in more of a true post-exposure fashion."

Those who have been recently vaccinated will be followed over time. Indeed, the CDC is discussing following the whole cohort of 10,000 people. It is an interesting group, having been potentially exposed to anthrax, taken prolonged antibiotic regimens, and in some cases, received a vaccine whose long-term safety is in some question.

Another curious fact — as with other post-exposure regimens for diseases — is that no one will ever know if the additional measures taken by 1,739 of these people actually prevent a late-onset anthrax infection. "This is not an experiment to help us later," Brachman says. "We don’t have a control group. All we are doing is using the best science we have, which suggests that this is best way to give protection to people."

References

1. Brachman PS, Gold H, Plotkin S, et al. Field evaluation of a human anthrax vaccine. Am J Public Health 1962; 52:632-645.

2. Committee on Health Effects Associated with Exposures during the Gulf War. An Assessment of the Safety of the Anthrax Vaccine: A Letter Report. Washington, DC: Institute of Medicine; March 30, 2000.