Dr. Meryl Nass, M.D.

E-mail:  mnass@anthraxvaccine.org

September 10, 2000

Presented at the International Public Conference on Vaccination 2000

Anthrax vaccine was licensed by the Division of Biologic Standards at the National Institutes of Health in 1970, using limited safety data and efficacy data obtained in large part from a different anthrax vaccine.

The FDA began licensing vaccines several years later and at the time anthrax was licensed there was no requirement for demonstrating efficacy in humans. The vaccine was approved for two limited markets, workers exposed to imported animal products, and lab investigators using anthrax. Efficacy was demonstrated for cutaneous anthrax but not for inhalation anthrax in the studies. By the way, you don’t need to use a vaccine for cutaneous anthrax as it is not a fatal disease and is easily treated with antibiotics.

This 1960 paper by Brachman et al used a different, earlier vaccine, but this is the only efficacy study of an anthrax vaccine ever published, and has been used subsequently to justify vaccine effectiveness.

A New Hampshire goat hair mill had nine anthrax cases in persons who were not vaccinated. But only ¼ of the mill workers had received the vaccine, and it was found that the vaccinated workers worked in areas of the plant where there were lower spore counts, so they were at lower risk for anthrax than the placebo group.

Two years later the same authors published another evaluation of the vaccine using the same study population but this time included three additional mills. There were a total of 26 cases of anthrax at the four mills during the study. Five cases occurred in persons who had received some doses of vaccine and fifteen cases in persons who received placebo vaccine. Six cases occurred in workers who chose not to participate in the study.

However, the authors now reported that the vaccine was highly effective, and in performing the statistical analysis, they threw out four of the five anthrax cases in vaccinated workers for not having received enough doses of vaccine, to calculate a vaccine effectiveness of 92.5%, rather than an effectiveness of about 65%, had they included the other four cases. This 92.5% statistic, fallacious back in 1962, and generated by an older vaccine, has been used ever since to justify the anthrax vaccine program.

This is a table from the 1960's CDC observational study of the current vaccine, which was required to demonstrate safety so the vaccine could be licensed. There are several interesting things about this study. First, the investigators performed active surveillance for local vaccine reactions only, at 24 and 48 hours after giving the vaccine. They were careful to record local reactions, but paid only cursory attention to systemic reactions, and did not perform active surveillance for systemic reactions. In fact, at one mill a large number of systemic reactions were reported, but this was blamed on an over zealous nurse.

The physician working at that mill pointed out that the reaction rate was no greater than with other vaccines such as typhoid. No one noticed that typhoid was the most reactogenic vaccine in use then. Also, notice that the reaction rates are highly variable from one series to the other, which may suggest a large difference between the lots, or a major difference in the recording of the effects by the observers. Note also that they used both the old vaccine, used in the earlier trial, and the current anthrax vaccine, despite the fact that the old vaccine was 16 years old at the time the study was done.

Over the next 20 years, from 1970 to 1990, only a small number of persons were vaccinated with this vaccine: between 200 and 2,000, according to Dr. Kwai Chan's GAO report to Congress. “In our discussion with scientists at Fort Dietrich, the estimates of number of people who may have received this vaccine over a 30 years period range from somewhere between 200 to about 2,000 at the most. And we don’t know who those individuals are. There has been no follow up…” Vaccine recipients were never studied systematically and as far an anyone knew the vaccine was safe.

In 1985 the FDA was reviewing a number of products that had been licensed prior to the more stringent regulations, and anthrax vaccine was reviewed by an expert panel. FDA concluded, “Immunization with this vaccine is indicated only for certain occupational groups with risk of uncontrollable or unavoidable exposure to the organism". They also pointed out that “Inhalation anthrax occurred too infrequently to assess the protective effect of vaccine against this form of the disease.” Despite these qualifications the decision to vaccinate US troops against anthrax was made as we developed Operation Desert Shield and Operation Desert Storm.

A number of things were not taken into account then, and have yet to be taken into account, although 2.5 million military service members: active, reserve and Coast Guard are in the pipeline to be vaccinated, with 450,000 having already begun the series.

What was not considered when the decision to vaccinate troops against anthrax was made?

• First, long-term safety of the vaccine has never been established.
• Second, the old efficacy rate was fallacious and came from an older vaccine-- no one knew how effective this newer vaccine would be.
• Third, the stockpile was old and many lots had expired but been re-dated, as if they were new, with only a retest of potency.
• Fourth, the lots were extremely heterogeneous, with variable side effects and potency.
• Fifth, the manufacturer was far out of compliance with good manufacturing practices, and had never had its anthrax line properly inspected. Sixth, use for prophylaxis against biological warfare was not an FDA approved indication.

Even if the efficacy rate for this vaccine in mill workers were known, it would probably bear very little relationship to efficacy in a bio warfare setting, where spore counts would be much higher and anthrax strains would be specially selected for virulence. The fact that genetically engineered anthrax had been shown to evade vaccine protection was ignored. Monkey data were cited but guinea pig data, which showed very poor efficacy against virulent strains, was ignored.

Although the stockpile was old there was no FDA approved standard operating procedure for re-using expired lots, and no retesting for degradents, preservatives or sterility took place before approving the use of expired vaccine. It is now known that the potency test is unreliable and unreproducible. Finally, there had never been a protocol added to the vaccine license, which was required before reusing expired vaccine, yet FDA had permitted the manufacturer to continually redate old vaccine stocks since 1970.

This appears to have been no aberration. The military had a policy of storing vaccines for very long periods. In fact, they knew that if licensed vaccines were stored in bulk rather than in small vials they would legally last indefinitely, and if they were investigational vaccines they would never expire, no matter how stored, according to FDA regulations.

It turned out that some lots were 40 times as potent as other lots. The manufacturing process had never been required to demonstrate lot-to-lot product consistency, although that is part of FDA’s normal requirement for vaccines. The result is that studies performed on one lot might not be applicable to other lots, and that problems and side effects from one lot could not be predicted from studies on a different lot.

Although FDA was legally required to inspect the anthrax portion of the manufacturing plant every two years, it did not fulfill this obligation, and appears to have allowed the Army to perform its own inspections. When FDA finally went in and did a thorough inspection one month before the current vaccine program began, they found so many problems that they immediately quarantined 11 lots of vaccine, and the manufacturer "voluntarily" shut down for major repairs and renovations. Although those renovations have since been completed, the FDA has not allowed the manufacturer to reopen, and new lots of vaccine that have been made in the last 15 months remain under quarantine.

Because prophylaxis against biological warfare was not an FDA approved indication for the vaccine, such use both during the Gulf War and presently should only have been conducted using an investigational new drug protocol. This would have required the informed consent of vaccine recipients. The Defense Department actually did obtain an IND for adding inhalation to the vaccine indications in 1996.

Although they claim it does not affect the current use, the IND's existence opens up an interesting legal question of whether troops receiving vaccine to protect against inhalation anthrax should be covered by IND protection. This will likely be resolved in the courts.

After the vaccine was used on 150,000 US troops in the Gulf War one would expect that we would now have a good idea about safety of the vaccine. However, that is not the case. The very large question of whether Gulf War Illness is related to anthrax vaccination has not yet been resolved. Why is that?

Although the Defense Department and Veteran’s Administration have spent over 150 million dollars sponsoring over 120 studies of Gulf War Illness, not a single one of these studies in the United States has examined the relationship between anthrax vaccine and Gulf War Illness, although sixteen other Gulf War exposures have been studied. Instead the Defense Department has used a different strategy. A number of expert scientific panels were convened between 1994 and 1996. They were asked to comment on whether anthrax and botulinum toxoid vaccines could perhaps contribute to Gulf War Illness. None of the panels presented here, with the exception of the Presidential Advisory Committee, cited any references.

In the absence of data they drew the following conclusions: The NIH Technology Assessment Workshop said, “no long term adverse effects have been documented”. The VA said “both vaccines, anthrax and botulinum toxoid have been used for many years without adverse effects. All three review panels, The Institute of Medicine, Presidential Advisory Committee and the Defense Science Board Review panels all stated that no long-term adverse effects have been documented or would be expected. Further study of the potential adverse effects of vaccines in this population is not recommended by any of the three panels nor is it endorsed in this plan."

The Presidential Advisory Committee produced a series of final reports as further information about Gulf War exposures continued to come to light. In 1996 they said, “The Committee concludes it is unlikely that health effects reported by Gulf War Veterans today are the result of exposure to the botulinum toxoid or anthrax vaccines, used alone or in combination”. They cited five references for this claim, all of which were to Defense Department briefers. The Institute of Medicine said, “The Committee knows of no evidence of any chronic effect.” The Defense Department attempted to sidestep any actual study of anthrax vaccine and Gulf War veterans’ illnesses. They said it was impossible to do a study because the Gulf War vaccination records have all been lost.

However, the document cited here indicates that the Gulf War vaccine records had actually been classified rather than lost. It says “All original records and documents used in identifying units and personnel immunized during Operation Desert Storm are still considered classified information.” But Dr. Philip Pittman at Fort Detrick studied the effect of booster doses of anthrax and botulinum toxoid vaccines several years after the Gulf War. To do this, he was able to identify 400 service members at Fort Bragg who had received anthrax and botulinum vaccinations during the Gulf War. Somehow, the names of vaccine recipients, the dates of vaccination and the numbers of doses for all 400 participants at Fort Bragg were found.

The results of his study were interesting. They showed that systemic reactions occurred in 44% of the recipients of vaccine. However, subjects received botulinum vaccine in one arm and anthrax in the other, so it is uncertain how many of these reactions are due to the anthrax vaccine alone. This study also showed that after 30 days, 3% of the subjects continued to have adverse systemic reactions. Whether their problems resolved is unknown. This appears to be an unprecedented rate of long term reactions, but it was ignored.

What then can be said about Gulf War Illness and anthrax vaccination? There has only been one study done and it was performed in England on service members who had received the British anthrax vaccine, which is similar but not identical to the one used on US troops. This study was published in the Lancet in January of 1999 and the authors wrote, “vaccination against biological warfare and multiple routine vaccinations were associated with this CDC multi-symptom syndrome, (which is a definition of Gulf War Syndrome) in the Gulf War cohort”. An accompanying commentary, written by Dr. Stephen Straus of the NIH, said “vaccination against plague and anthrax before deployment to the Gulf correlated highly with illness.

The investigators speculate that these vaccines more so than the routine ones given to service personnel had unanticipated effects.” Therefore we do not yet know conclusively whether anthrax vaccine caused or contributed to the development of Gulf War Illness, but we suspect it. Further evidence comes from the large number of gulf era service members who received anthrax vaccine, but were never sent to the Gulf, and subsequently developed typical Gulf War Illnesses. They all received more than one vaccination so we can’t say which has caused their illness, but they had no other Gulf exposures, so the vaccine connection is very significant.

Despite all these unanswered questions, the decision was made to begin vaccinating all US service members against anthrax in early 1998. And not only anthrax: vaccines against a number of other biological warfare threat agents are in development. Recently the military's Joint Vaccine Acquisition Program, the umbrella program under which all these vaccines will be developed, has talked about a total of 40-50 new vaccines for all service members. This program was initially funded in 1997 by Congress with 322 million dollars, and it has subsequently received additional appropriations.

There might be a relationship between the military’s interest in vaccinating troops, and the pharmaceutical industry's interest in vaccinating civilians. After passage of a Federal law in 1986, which made vaccine manufacturers no longer liable for adverse effects unless there was a production error, the financial climate for vaccine manufacturers started to improve. Furthermore, advances in genetic engineering made it much easier to create new antigens and microorganisms for vaccines. It is conceivable that the military vaccine program will be developing new techniques and possibly new vaccine adjuvants that will be tested on the military population and used later in civilian vaccines.

I'd like to speak briefly about reporting and reviewing adverse events. The anthrax vaccine program began vaccinating service members in March of 1998. In eleven months 550,000 vaccine doses had been administered but only 39 VAERS (Vaccine Adverse Effects Reporting System) reports had been filed with the FDA. When Congressman Shays asked the Defense Department about the vaccine program, because of the large number of reports of serious illnesses that had reached Congress, he was presented with this slide and was told that the total adverse reaction rate was only .007%, and that anthrax vaccine was safer than childhood vaccines. What DOD did was to take the total number of reports to FDA of adverse effects and call it the sum total of all adverse events.

However, it turned out that the military had instituted a policy to limit the reports of adverse events before the first vaccination was ever given! Although normally physicians and vaccine recipients are encouraged to report to FDA any adverse reaction they choose, military medical personnel were told that only adverse reactions which resulted in hospitalization, or more than 24 hours of lost duty time could be reported to FDA. This kept the reporting rates remarkably low. When the difficulties in reporting adverse effects to FDA were reported in Congressional testimony in July 1999, the policy immediately changed. There are now about 1500 reports of adverse reactions to anthrax vaccine received by FDA, and approximately one in every three hundred vaccine recipients has officially reported an adverse reaction, despite continuing stories of obstructions being placed in the way of reporting.

What kinds of reactions are being seen? Data from a study conducted by Dr. Pittman in 1998 on Seventh Day Adventists who had served as human guinea pigs at Fort Detrick in the 1960’s and the 1970’s. Many of these people received anthrax vaccine and had never been followed up. However, 25 years after the program, named “Operation White Coat” ended, all the alumni were invited back to Fort Detrick for a weekend of fellowship, and asked to participate in the following study. What questions were asked regarding their symptoms?

The following list of twelve symptoms was given to each participant and they were asked to comment on frequency and severity. Please note that all of these symptoms are what is seen in Gulf War Illness, and now these are the chronic symptoms most commonly seen in those reporting problems after anthrax vaccination. While I'm on this subject, vaccine recipients also report a variety of neurologic disorders, especially tremors, and endrocrine disorders. We suspect these to have an autoimmune basis. A recent autopsy of a vaccine recipient showed death to be due to coronary artery vasculitis, or what appears to be a series of heart attacks occurring shortly after vaccination, and due to autoimmunity.

With 1500 VAERS filed why hasn’t FDA stopped the program?

Well, this is one page from a list of the VAERS reports received by FDA that I got through the Freedom on Information Act. This report lists seven people who have filed adverse event reports. You can see that it is extremely difficult to tell what the severity of the symptoms is and what the duration is. Two of these people report severe fatigue but fatigue is a very subjective symptom. The FDA has not paid it a lot of attention, although chronic fatigue syndrome and fibromyalgia are commonly seen in both Gulf War Illness and the post anthrax vaccine syndrome. FDA has its own list of terms that are used to describe adverse reactions.

The system is called COSTART and the terms that are used, tend to confuse, rather than illuminate the adverse reactions. For instance, the term asthenia, used twice on this page, is one that has been out of use for a century. The term " Immune system disorder," is not specific enough to be useful, and thus likely to be ignored. I have reviewed hundreds of these VAERS reports and it is my belief that this system makes it impossible to tell whether different people are reporting the same types of illnesses, and it is therefore impossible to tell whether their reactions are due to the vaccine.

The VAERS reports are received by a private company working as a contractor for FDA, and put into this format, then reviewed by FDA personnel. I think that the only way for FDA experts to get an accurate idea of vaccine reactions is for them to review more detailed reports, contact treating physicians directly, or investigate sufficient numbers of actual cases. Currently they are required only to investigate deaths.

The Defense Department did initiate its own study to resolve the question of long-term safety of the vaccine in September of 1998 amidst all of the controversy. This was done at Tripler Army Medical Center and 603 medical personnel were enrolled in an observational study. These data were presented in April 1999 to Congress. 43% of vaccine recipients had mild systemic reactions, and 5% had moderate or severe systemic reactions after one of the first four vaccine doses

This is a later GAO report to Congress, from July of 1999. It shows that over 60% of males reported muscle soreness after each vaccination and 60-80% of females reported the same thing. It shows that 2-5% of males and 4-14% of females sought medical attention after one of their first three vaccinations, and that 1-2% of males, but 4-5% of females missed at least one shift of work after receiving a vaccine dose. This vaccine causes adverse reactions in females at three times the rate of males. However, follow-up information on this study has not been released, so even though the Defense Department knows what happened to these 603 people, Congress and the rest of us have no information.about any persisting medical problems, which was the question this study was designed to resolve.

In March 2000, at the request of the Defense Department, an Institute of Medicine Committee investigating Gulf War Illness exposures reported on the evidence for safety of the anthrax vaccine. They said, “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. This finding means that the evidence reviewed by the committee is of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of an association between the vaccine and a health outcome in humans."

Does vaccination of troops against biological warfare agents even make sense strategically? This slide from DARPA, the military's Defense Advanced Research Projects Agency, lists over 65 known biological warfare agents, which are naturally occurring. In addition, there are an infinite number of microorganisms that may be created using genetic engineering. There are less than 10 vaccines effective against these agents. It takes an estimated ten years, once one is aware of a microbial pathogen, to develop an effective and safe vaccine against it.

The fact that we did not have an effective and safe anthrax vaccine at the time of the Gulf War, and now 10 years later we still do not have one, makes this perfectly clear. Furthermore, if we vaccinate against anthrax, an enemy can just pick a different microorganism to use. If an enemy genetically engineers a new virulent organism, we will not even be able to begin developing a vaccine against it until after it has presented itself--in other words, after if has been used. For these simple reasons, the use of vaccines against the threat of biological warfare will never provide an effective defense.

Dr. Ken Alibek, formerly the number two man in the Soviet Union’s biological warfare program, has made this perfectly clear. “We need to stop deceiving people that vaccines are the most effective protection and start developing new therapeutic and preventive approaches and means based on a broad spectrum protection.”

How has the FDA responded to the question of vaccines for the biological warfare threat? They have bought into the Defense Department’s plan completely. In fact, FDA itself is helping to develop newer vaccines against anthrax and other threat agents.

This new DNA plasmid encoding anthrax vaccine was developed at the Center for Biologics Evaluation and Research, FDA’s center for vaccine oversight. How can FDA provide proper oversight for vaccines developed by its own staff? Shouldn't FDA's scientists be helping the Defense Department to understand that vaccines are not "the answer", rather than helping them stitch together the emperor's new clothes?

Katherine Zoon, the Director of the FDA's CBER, the woman in charge of vaccine oversight for every vaccine used in the United States, has served on an Advisory Board for Biological Warfare for DARPA and has advocated rapid approval of new biological warfare vaccines. In this recently published article, she implies that the FDA review process may be limited to only six months for such products. She also says, “After these vaccines are licensed and administered, the safety and adverse reactions of these vaccines should be assessed.”

Ignoring Federal law, Dr. Zoon is suggesting that biowarfare vaccines be licensed and used on humans and only afterwards should their safety profile be ascertained. We have already learned that for the current anthrax vaccine, post marketing surveillance is essentially limited to VAERS reporting, and VAERS reporting is close to useless. Should the military be given carte blanche to field biowarfare vaccines and then determine whether they cause adverse reactions? Clearly, if the case of anthrax vaccine is any example, the military will do their best to prevent meaningful oversight and cover up adverse reactions.

Dr. Katherine Zoon, Director of the Center for Biologics Evaluation and Research at FDA, who is in charge of assuring that federal laws are followed and that public health is protected with respect to vaccines, has forgotten where her primary responsibilities lie. For advocating that vaccines be administered before their safety and adverse reactions are known she should immediately lose her job.

The FDA has focused more on assisting the Defense Department, than in assuring the public health. It is critical that FDA’s priorities be immediately turned around, or the repercussions will have grave effects on the health of both our military and civilians of the United States.

Originally posted on the Anthrax Vaccine Home Page http://www.anthraxvaccine.org/