American Journal of Public Health May 2002; pp 715-721

The Anthrax Vaccine Program: An Analysis of the CDC’s Recommendations for Vaccine Use

Meryl Nass, MD

ABSTRACT

The anthrax vaccine was never proved to be safe and effective. It is one cause of Gulf War illnesses, and recent vaccinees report symptoms re­sembling Gulf War illnesses.

The vaccine’s production has been substandard. With­out adequate evaluation, the Food and Drug Administration recently approved (retrospec­tively) significant changes made to the vaccine’s compo­sition since 1990. The vac­cine’s mandatory use for in­halation anthrax is “off-label.”

A skewed review of the vac­cine literature by the Centers for Disease Control and Pre­vention (CDC) led to remuner­ative collaborative research with the army, involving civilian volunteers. Despite acknowl­edging possible fetal harm, the CDC offered the vaccine to children and pregnant women.

New trends could weaken prelicensure efficacy and safety review of medical products in­tended for biodefense and avoid manufacturer liability for their use. (Am I Public Health. 2002;92 :715—721)

INTRODUCTION

This commentary weaves together 2 stories: the checkered history of the Department of De­fense’s (DOD’s) compulsory An­thrax Vaccine Immunization Pro­gram and the role of the Centers for Disease Control and Preven­tion (CDC) in shoring up the fail­ing vaccine program.

A LICENSED VACCINE BUT AN OFF-LABEL USE

The US Army has considered an ambitious plan to vaccinate all military personnel against biolog­ical warfare “threat agents” since at least 1987.¹ Anthrax has been considered to be the number one threat. Anthrax vaccine was the only vaccine planned for biowar­fare prophylaxis that had a li­cense, and it was already stock­piled by the military in 1987. The vaccine, however, was not li­censed for aerosol exposure² (the form of anthrax that would be faced in an attack), since the li­cense was based only on the evidence of an earlier vaccine’s effi­cacy against cutaneous anthrax.^3-6

­A 1995 letter to the vaccine’s manufacturer from the director of the army’s Medical Chemical and Biological Defense Research Program included a study pro­posal that acknowledged, “This vaccine is not licensed for aero­sol exposure expected in a bio­logical warfare environment.”⁷ A 1995 report authored by the DOD’s anthrax vaccine project manager noted that “protect[ing] service members from aerosol exposure to anthrax can only le­gally be done if the FDA [Food and Drag Administration] li­censes the vaccine for that spe­cific schedule and indication.”⁸

These documents recognized that although individual physi­cians can employ licensed drags and vaccines for off-label uses, the pros and cons for indi­vidual patients must be consid­ered. However, mass vaccina­tion programs, and particularly compulsory programs, bypass the role of the physician in making risk—benefit decisions.⁹ Therefore, such programs must use vaccines only for FDA-approved indications.

In 1996, in anticipation of the vaccine’s use throughout the armed forces, the anthrax vac­cine’s manufacturer submitted an investigational new drug applica­tion (IND) to the FDA to expand the approved indications for vac­cine use.¹⁰ The IND, which had been prepared by the army, al­lowed the DOD to conduct re­search to support adding a spe­cific indication for aerosol exposure to the label, changing to an intramuscular injection, and reducing the number of vac­cine doses. (The current anthrax vaccine license calls for 6 initial doses over 18 months and then yearly boosters. A soldier em­barking on a 20-year military ca­reer would thus receive 24 an­thrax inoculations before retiring.)

Upon reading The Cobra Event, a novel about a biological attack on New York City, Presi­dent Clinton decided to do something soon about the bio­logical warfare threat.¹¹ Clinton may not have known that biolog­ical weapons, having been used at least since World War 1,^12,13 have never injured or killed a single American in baffle.¹⁴

Six months after the IND was filed, but before any supporting data to amend the original li­cense was submitted to the FDA, the assistant secretary of defense for health affairs, Dr Stephen Joseph, asked the act­ing deputy commissioner of the FDA, Dr Michael Friedman, for a go-ahead to use the vaccine, thus skirting the FDA’s normal regulatory procedures for amending a vaccine license.¹⁵ Less than 2 weeks into his new position, Friedman wrote back, “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.”¹⁶ However, Friedman’s words merely ex­pressed his personal opinion and did not comply with the re­quirements of the Code of Fed­eral Regulations for amending the vaccine’s label; therefore, they provided no legally accept­able justification for the vac­cine’s off-label use. 17 Anthrax Vaccine Adsorbed is approved by the FDA only for veterinari­ans and workers handling po­tentially infected animals or their products and for labora­tory workers researching anthrax.²’³

In 1997, the DOD finalized the decision to vaccinate all 2.5 million active and reserve military service members, members of the Coast Guard, and certain civilian employees, although no change in the an­thrax vaccine label had been approved. At the time, no re­search had been published that explored the link between an­thrax vaccine and Gulf War ill­nesses, although, in the ab­sence of evidence, expert committees reviewing these ill­nesses had expressed doubt about a vaccine etiology.¹⁸

IMMUNIZATIONS

PROCEED DESPITE

QUESTIONS

On December 15, 1997, the anthrax vaccine program was announced. A few weeks ear­lier, Secretary of Defense Wil­liam Cohen had held up a 5-pound bag of sugar on national television and warned that if the bag contained anthrax, it could kill half of Washington, DC. He also promised that 4 precondi­tions would be met before the program had his final ap­proval.¹⁹ It was later shown that at least 2 of the preconditions were substantially unmet.²⁰

Also in December 1997, a team of Russian researchers re­ported the creation of a geneti­cally engineered anthrax strain that could resist vaccine protec­tion.²¹ Later, Ken Alibek, former second-in-command of the So­viet biowarfare program, ex­pressed his concern that addi­tional vaccine-resistant anthrax chimeras had been created.²²

In March 1998, Secretary Cohen was publicly vaccinated, and mandatory mass vaccina­tions began. The science to support the program did not exist. There were no published studies documenting the safety or efficacy of this vaccine for any route of exposure in hu­mans,²³ although human studies are required under the Food, Drag and Cosmetic Act. Within weeks, military service members began reporting ill­nesses following vaccination, while others refused the vac­cine. The military leadership responded with court-martials, fines, and less-than-honorable discharges.

In response, an unprece­dented 13 congressional hear­ings explored these issues in depth. In early 2000, the House Committee on Govern­ment Reform recommended halting the mandatory program and using the vaccine “only pursuant to FDA regulations governing investigational testing for a new indication.” Its report also said, “The subcommittee finds the AVIP [Anthrax Vac­cine Immunization Program] a well-intentioned but over­wrought response to the threat of anthrax as a biological weapon.”²⁰

Also responding to congres­sional concerns, an Institute of Medicine committee, formed to investigate potential causes of Persian Gulf War illnesses, was asked to report on the anthrax vaccine’s safety for the DOD. The committee emphasized the lack of evidence for long-term vaccine safety and urged publi­cation of unpublished DOD vac­cine studies.²⁴ Subsequently, DOD investigators published a synopsis of the unpublished studies in the CDC’s Morbidity and Mortality Weekly Report,²⁵ glossing over safety concerns by omitting important data from the studies. Having previously reviewed these studies for the General Accounting Office, I noted the omissions in a com­mentary to ProMED Mail, an Internet mailing list for infec­tious disease professionals.²⁶

CDC OVERSEES ADDITIONAL

VACCINE RESEARCH

Three years after the anthrax immunization policy was an­nounced, and after half a mil­lion people had already been vaccinated as part of the An­thrax Vaccine Immunization Program, the CDC and its Advi­sory Committee on Immuniza­tion Practices reviewed existing research on anthrax vaccine and made recommendations for vac­cine use.²⁷ Prior to its publica­tion, David Ashford, a coauthor of the recommendations, had been quoted as saying, “We do not have specific information on the efficacy of the existing vac­cine for the prevention of in­halational anthrax and we prob­ably never will.”²⁸

Since the extent of the vac­cine’s benefit was uncertain, and the dimensions of the bio­logical warfare risk were un­known, the CDC had no easy task, as it attempted to develop appropriate recommendations for vaccine use. However, the CDC recommendations contain inaccuracies and omissions that compound this difficulty:

1. The recommendations state, “The potency and safety of the final [vaccine] product is confirmed according to US FDA regulations.” This statement ob­scures the fact that almost all existing lots of vaccine have been quarantined by the FDA²⁹ or held up for approval.³⁰ Fur­thermore, the FDA did not allow the rebuilt anthrax vac­cine manufacturing facility, completed in May 1999, to open until January 2002 be­cause of repeated significant de­viations from current good man­ufacturing practices.³¹ The renovated filling suite (where bulk vaccine is bottled) could not ensure sterility, so the man­ufacturer has contracted with another pharmaceutical com­pany to package the vaccine.³² Finally, potency cannot be de­termined, because the current standard, a guinea pig challenge test, has been shown to be un­reliable and irreproducible.³³’³⁴

2. The quoted 92.5% vac­cine efficacy figure was derived from a study of an unlicensed, precursor anthrax vaccine. It is also incorrect, having been cal­culated by improperly exclud­ing one or more of the vacci­nated participants who later developed anthrax.^4,35 Further­more, it reflected spore counts and strains randomly found in factories, not those likely to be encountered in a biological warfare setting. One might ex­pect to see higher spore con­centrations, more virulent an­thrax strains, uniform spore sizes, and use of excipients to promote deposition of particles in the terminal alveoli in a bioterrorism event. These fea­tures could additionally strain vaccine-induced immunity.²¹

3. The Vaccine Adverse Event Reporting System (VAERS), jointly managed by the CDC and the FDA, collected a very high rate of adverse event reports for anthrax vaccine relative to other vaccines: 1750 reports (from March 1998 to May 2001), or 1 report for every 300 vaccine re­cipients. Only 54% of these re­ports showed that there had been a resolution of the reaction when the report was filed.³⁶

VAERS is a voluntary, passive reporting system that does not provide actual reaction rates. In the case of military personnel, for whom a vaccine reaction can prevent deployments and career advancement, reporting an adverse reaction can end a career. General Accounting Office testi­mony before Congress noted that 6 0% of surveyed air crew mem­bers who had had a vaccine re­action did not report it to mili­tary medical facilities.³⁷

The DOD has now acknowl­edged that the systemic reaction rate, listed as 0.2% on the pack­age insert, is actually between 5% and 35%. Military vaccine studies have found systemic reac­tion rates up to 48%.³⁹ The rate of chronic, unresolved reactions remains unknown, but anecdo­tally is quite high (29% from an unpublished survey at Dover Air Force Base).⁴⁰

4. The CDC report states, ‘Analysis of VAERS data docu­mented no pattern of serious ad­verse events clearly associated with the vaccine.” However, in an unpublished analysis of 1660 VAERS reports performed by Thomas D. Williams of the Hart­ford Courant and by myself, 10% (168) of the reports) note that the vaccine recipient developed at least 2 of the following 3 symptoms: fatigue, muscle or joint pains, and cognitive or emo­tional impairment. This meets the CDC’s own case definition of Gulf War Syndrome.⁴¹ Since Gulf War Syndrome—like illnesses have been reported by vaccine recipients in 3 congressional hearings,^42~44 the CDC or the FDA would be expected to inves­tigate this pattern of illnesses fur­ther. However, according to the FDA’s Mark Elengold, such a re­view has not been initiated (writ­ten communication, January 16, 2001).

The best sources of informa­tion on anthrax vaccine’s long-term safety are studies of Gulf War veterans. The CDC report says that 2 CDC studies⁴¹’⁴⁵ of Gulf War illnesses have “examined a possible association with vaccinations, including anthrax vaccination.” The report, how­ever, then admits that for the first study, “the ability of this study to detect a significant dif­ference was limited,” and for the second study, “no specific ques­tions were asked about the an­thrax vaccine.”

Although the 2 cited CDC studies lacked the ability to iden­tify a relationship between an­thrax vaccine and Gulf War ill­nesses, the reports’ authors assert that “existing scientific evidence does not support an association between anthrax vaccine and PGW [Persian Gulf War] ill­nesses.” This is not true.

Since 1998, each of the 4 groups reporting on whether spe­cific deployment vaccines⁴⁶’⁴⁷ or

anthrax vaccine^48-51 cause symp­toms of Gulf War illnesses found a statistically significant, positive association between the two. So has a large Veterans Administra­tion study, in data that have been presented but not yet pub­lished.⁵² Among nondeployed but vaccinated Gulf War—era vet­erans from Kansas who received deployment vaccines in prepara­tion for Gulf duty, the rate of Gulf War illness was 3 times higher than in other nonde­ployed Gulf War—era veterans who did not receive these vacci­nations.⁴⁶ These nondeployed veterans had no other Gulf War exposures to account for their symptoms.

Making the claim that anthrax vaccination is not related to Gulf War illnesses by citing research that lacked the power to discern a relationship, and ignoring all studies that did show a relation­ship, does not enhance confi­dence in the vaccine. It also calls into question the independence of this CDC vaccine review.

The CDC subsequently under­took supervision of a large body of research on anthrax vaccine for the DOD, funded at $23 mil­lion, involving several of the CDC recommendation’s authors.⁵³’⁵⁴ Will similar questions be asked about the scientific integrity of this new research program?

Despite these issues, the CDC recommendations conclude with little support for anthrax vaccination:

Although groups initially con­sidered for preexposure vacci­nation for bioterrorism pre­paredness included emergency first responders, federal respon­ders, medical practitioners, and private citizens, vaccination of these groups is not recom­mended. Recommendations re­garding preexposure vaccination should be based on a calculable risk assessment. At present, the target population for a bioter­rorist release of B. anthracis cannot be predetermined, and the risk of exposure cannot be calculated. In addition, studies suggest an extremely low risk for exposure related to second­ary aerosolization of previously settled B. anthracis spores. Be­cause of these factors, preexpo­sure vaccination for the above groups is not recommended. For the military and other select populations or for groups for which a calculable risk can be assessed, preexposure vaccina­tion may be indicated.

The CDC tries to have it both ways. The vaccine is not appro­priate for civilians when risk— benefit considerations are taken into account, even for bioterror­ism “first responders.” But the vaccine is acceptable for military personnel. The CD C’s conclusion ignores the fact that all military personnel, independent of their specific job or whether they will be deployed to a “high threat” area, are ultimately slated for vaccination. Thus, the decision to vaccinate all service members ig­nores risk—benefit assessment, the heart of preventive medicine practice. In acquiescing to the needs of the military, the CDC has established a double stan­dard for the practice of military as opposed to civilian medicine, even in peacetime.

The CDC’s recommendations were given wide exposure, being reprinted in the Journal of the American Medical Association and the Journal of Toxicology:Clinical Toxicology, in addition to Morbidi(y and Mortality Week(y Report. Garnering further atten­tion, free continuing education credits were available for physi­cians who read the report. Yet, given its failure to evenhandedly review existing information on this vaccine, the report hardly de­serves to create the national prac­tice standard to which it aspires.

LEGAL AND ETHICAL CONCERNS

In June 2001, the fourth “slowdown” of the vaccine pro­gram was announced, due to lim­ited supplies of vaccine.^{55 56} The FDA had not approved release of any vaccine lots for more than a year. The only people then slated for vaccination included potentially exposed research lab­oratory personnel and special forces troops—the same 2 groups who received the vaccine before the Anthrax Vaccine Immuniza­tion Program was initiated. How­ever, vaccine is being held in re­serve for the CDC-supervised vaccine trials, which will use ci­vilian volunteers

Those who refused the vac­cine continued to be prosecuted until the Anthrax Vaccine Immu­nization Program was effectively halted. In May 2001, Capt John Buck, a military physician who refused to receive or administer the vaccine, was court-martialed. Precluded by the military judge from presenting evidence to the jury about the vaccine’s IND sta­tus, manufacturing problems, or safety and efficacy concerns, he was found guilty.

At his sentencing, Dr Buck said, “I was at the crossroads be­tween the oath of an officer and the oath of a physician. The only way I could have peace about the apparent conflict was to do what I knew to be right as a phy­sician and to stare down the bar­rel of the gun with the courage of an officer.”⁵⁷ It is lamenta­ble that physicians have been or­dered to abandon good medical practice in aid of a failed vaccine program. Buck, with an exem­plary record as a physician, had a pending promotion reversed, was fined $21 000, and was confined to his base for 2 months.

For service members who ac­cept vaccination and subse­quently become ill, things are no rosier. Many have been forced to leave the service as a result of their medical problems and have limited ability to earn an income. Moreover, the Feres Doctrine, a body of legal opinion that pre­vents recovery under the Federal Tort Claims Act [28USC §2674], bars service members from claims against the government for any illness or injury incurred incident to military service.⁵⁸

Anthrax vaccination is only the first vaccine in a planned and funded armed forces—wide pro­gram of additional mandatory vaccinations for biological warfare threats, termed the Joint Vaccine Acquisition Program.⁵⁹ A military-sponsored National Research Council study released in June 2001 recommended that the army “seek exemptions from some regulatory approval processes to speed up the development of new medical treatments.”⁶⁰

Further erosion of existing regulatory protections appears imminent. The FDA has even suggested eliminating human safety testing of medical prod­ucts designed for chemical and biological warfare prophylaxis, although they are normally re­quired for licensure.^61,62 Al­though efficacy testing of such products in humans may not be feasible, this certainly does not preclude safety testing in hu­mans. Animal testing does not ensure human safety. There is no acceptable reason to elimi­nate human safety testing of any product that the FDA will li­cense for human use.

If a passive FDA continues to allow the DOD to avoid normal scrutiny, as it assumes responsibility for all aspects of develop­ment, testing, licensure, manufac­ture, administration, and adverse event surveillance of future mili­tary vaccines and medical prod­ucts, more military medical disas­ters almost certainly await us.

CONCLUSIONS

Strong-arm tactics by the DOD, coupled with inadequate oversight and politically driven behavior by CDC and FDA, have resulted in the following prob­lems. The final four points iden­tify needed reforms.

I. The safety and efficacy of the currently used anthrax vac­cine have never been estab­lished, either for cutaneous or in­halation exposure in humans.

2. FDA standards for use of an IND (experimental) product. which apply equally to civilian and military vaccines, were by­passed because of pressure from the DOD.

3. Anthrax vaccination ap­pears to be one of the causes of Gulf War illnesses.

4. Vaccine manufacture has been substandard. For years, the vaccine manufacturer failed to meet current Good Manufactur­ing Practices requirements but was allowed to continue produc­tion. Over 6 million vaccine doses have been quarantined by the FDA, have failed the army’s supplemental testing, or both.

5. Service members have been subjected to a CD C-sanctioned double standard of medical prac­tice in which risk—benefit analy­sis does not apply.

6. The ability of military physi­cians to exercise their medical judgment has been suppressed.

7. Ill, recently vaccinated ser­vice members, who rely on mili­tary medical care and who are barred from filing suit against the government, find themselves re­living the plight of ill Gulf War veterans.

8. Medical professionals, who expect information from the CDC to meet the highest stan­dards, have instead received mis­representations concerning an­thrax vaccine.

9. The CDC is supervising the conduct of safety and efficacy tri­als of the current vaccine, but its ability to be objective is in ques­tion. Furthermore, because the safety issues are unresolved, con­ducting a large trial of this vac­cine in previously unvaccinated individuals is unethical. Retro­spective surveillance to assess safety should be performed first on the recent vaccinees, as rec­ommended by the Committee on Government Reform.²⁰

10. Medical defense measures for biological warfare, including the Joint Vaccine Acquisition Program, need independent civilian oversight, so that balanced med­ical decisionmaking can occur, free of the influence of the chain of command.

11. The same regulatory re­quirements imposed on civilian vaccine and drug manufacturers must be met for military products.

12. Anthrax vaccine should be used only in the most dire cir­cumstances. When employed for prophylaxis or treatment of in­halation anthrax, it should be under the conditions required for “off-label” use, including ac­tive surveillance for adverse re­actions and obtaining free in­formed consent.

ADDENDUM: THE STORY CONTINUES

Irresponsible decisions by fed­eral agencies have led to over 2 million mandatory anthrax vacci­nations in the past four years. Events following September 11 may be leading us further down the slippery vaccine slope.

An October 23, 2001, con­gressional hearing revealed that changes initiated since 1990 to anthrax vaccine’s fermenters and filters were not submitted to the FDA for approval until 2000 and may have led to lev­els of protective antigen, the vaccine’s main immunizing com­ponent, one hundred times greater than in the approved

preparation.⁶³ These changes prove that the current anthrax vaccine is not the same vaccine that was licensed in 1970 and should have undergone full safety and efficacy testing to be­come licensed.

Just days earlier (but after I wrote the article), anthrax was first used offensively in the United States. Its use resulted in 5 deaths, additional infections, and tremendous expenditures and turmoil. The Hart Senate of­fice building remained closed for 3 months pending spore decontamination.

The Ames strain of anthrax was used in the attack. This highly virulent strain was used by the army for vaccine chal­lenge studies²³ but possibly also for other purposes. When used in vaccine experiments, Ames was prepared as a slurry. How­ever, Ames had also been pre­pared in dry form, in extremely high concentrations, using an ad­ditive to promote spore separa­tion and aerosolization. It was this anthrax preparation—made by a highly secret US military process, one for which no defen­sive use has been given—that was placed in letters to a variety of news media and 2 senators.

This powder’s existence, cou­pled with additional disclosures of attempts to make an anthrax production facility and create a vaccine-resistant strain,⁶⁴ strongly suggest that the United States may be violating the Biological and Toxin Weapons Convention. This may help explain the US government’s intransigent opposi­tion to strengthening the treaty and the US delegation’s walking out of negotiations in July 2001.

US military scientists and con­tractors seem to have been the only people with access to this powdered, “weaponized” anthrax preparation, although the strain itself was shared with the de­fense establishments of Canada and the United Kingdom, as well as some universities and private laboratories, including the an­thrax vaccine manufacturer. Thus, the source of the attacks is thought to be domestic, someone with access to the military prepa­ration or its secret manufacturing process.

What possible motivation could lead a military scientist to send anthrax in letters that were disguised as those of an Islamic terrorist but that warned that they contained anthrax and that suggested antibiotics? The perpe­trator clearly intended to frighten but not to kill. The motive was probably the desire to elevate the status of the biological defense establishment, resulting in in­creased government funding and attention.⁶⁵ After the Clinton presidency’s emphasis on the bio­logical weapons threat, the Bush administration’s perceived lack of interest may have been seen as a problem in need of a solution. The anthrax vaccine program, for instance, was undergoing a high-level review last summer and might have been minimized or shut down had the attacks not occurred.

Publicly known details of the FBI investigation of the anthrax attacks make it appear half­hearted. The very existence of the powdered preparation, and who had access to it, took months to be reported.

The anthrax attacks gave the CDC an opportunity to study postexposure use of the anthrax vaccine. In this study, the CDC offered the anthrax vaccine to pregnant women and children, although the vaccine was li­censed only for those aged 18 to 65 years and was not approved for pregnant females. Prospective vaccinees were offered only 3 doses and received vaccine from a pilot lot that had not been ap­proved for licensed use by the FDA. For these reasons, vaccina­tion was considered experimental and required informed consent.

The consent form said that if study subjects became ill after vaccination, they would not be cared for by the Department of Health and Human Services. The form further noted that prelimi­nary data indicated the vaccine might cause an increased risk of birth defects. Knowing this infor­mation, yet offering the vaccine to pregnant women who had re­ceived effective prophylaxis with antibiotics, might seem unethical behavior. It could, however, pro­vide the defense department with data they sorely wanted, since so many servicewomen had become pregnant during the an­thrax series. The DOD may have hoped the CDC’s pregnant co­hort would yield evidence of vac­cine safety.

After the September attacks, the CDC as a whole received $450 million for bioterrorism preparedness, and the anthrax group received additional fund­ing for their collaborative an­thrax vaccine research with the army.

About the Author

Meryl Na.ss is with Parkview Hospital and

Midcoast Hospital, Brunswick, Me, and

Maine Medical Center, Portland, Me. Requests for reprints should be sent to

Menfl Nass, MD, 124 Wardtown Rd. Freeport, ME 04032.

This commentarg was accepted October17, 2001.

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