Written presentation to Independent Inquiry on GWS, London. Sept 1, 2004

[Guest guest]

My understanding of the safety of anthrax vaccine and its role in GWS

My name is Meryl Nass. I practice general internal medicine in a community

hospital in the US, and also see patients with the diagnoses Gulf War Syndrome

(GWS), Fibromyalgia, Chronic Fatigue Syndrome, and vaccine-associated illnesses.

I have been a student of anthrax and biological warfare for the past fifteen

years. I try to apply the tools of medicine, microbiology, immunology and

epidemiology to investigate phenomena that are hidden or poorly understood. I

am known for having analysed a major anthrax outbreak, which occurred in

ia during its civil war. I showed that none of the explanations for why

it was a " natural " event stood up to scrutiny, and that the epizootic was due to

biological warfare.[1] My work was discussed in a 1994 Royal Society

publication titled " Scientific Aspects of Control of Biological Weapons. "

My goal was to make it riskier for perpetrators to employ such agents, by

showing that science could be used to distinguish between natural epidemics and

deliberate dissemination of disease. My interest had been to promote biological

arms control, but I was sidetracked into scrutinizing bioterrorism vaccines

several years ago.

Being familiar with the anthrax literature, I was aware that, at the time the

US' Anthrax Vaccine Immunization Program was announced in late 1997, published

evidence for both safety and efficacy of the anthrax vaccine was lacking. Dr.

Turnbull, formerly head of anthrax research at Porton Down, and others had

made this information available in the open literature. Rodent challenge

studies showed poor efficacy of the UK and US killed human anthrax vaccines

against highly virulent strains, and there existed no published safety data,

save from a study of an earlier, unlicensed " Brachman " (aka " Merck " ) anthrax

vaccine. It contained little information on systemic adverse effects.[2] I

later found that the unpublished, CDC 'open label' study of the licensed US

anthrax vaccine, used to affirm vaccine safety, had employed report forms that

only collected information on local reactions. Although a nurse at the Alabama

factory where the bulk of the study's anthrax vaccinations were administered had

expressed concern about the adverse reactions, and these concerns reached the

CDC, she was overruled by the local doctor and the documentary evidence suggests

the matter was then dropped.[3]

I wrote a short piece for an internet mailing list of infectious disease

professionals, ProMed Mail, in late December 1997.[4] It suggested that in the

absence of existing vaccine safety data, and in the absence of a cause or causes

for Gulf War Syndrome (GWS), the US military should not begin a program to

vaccinate 2.4 million troops against anthrax until further research had been

performed. At the time I didn't know that the vaccine was a cause of GWS; it

simply seemed unwise to begin a massive peacetime vaccination program for a

disease that did not occur naturally, using a vaccine that had no track record.

My short piece grew legs. It bounced around the Internet, and if you read The

Lancet on-line, you could 'hot key' directly to my post.[5]

Before I knew it, I was contacted by large numbers of people who had concerns

about taking the anthrax vaccine, and then from soldiers and their families who

contacted me to ask whether illnesses that had developed in temporal

relationship to vaccination were due to the vaccine. I was also asked to write

a review of the issue.[6]

After telling the first 50 or 100 people who contacted me that their episodes of

malaise, fever, diarrhea, joint pains and an enormous number of odd complaints

were unlikely to be due to the vaccine, I began to see patterns in the

complaints they were reporting, and realized there might be something to their

suspicions after all. So I then set out to investigate the safety of anthrax

vaccine.

I reviewed the reports of several panels[7] [8] [9] in the US that had been

charged with investigating GWS, and had said the vaccine had nothing to do with

it. I was surprised to learn that the evidence they relied on to draw

conclusions about the role of anthrax vaccine was shaky at best. The reports

either cited no references to support their vaccine conclusions, or cited only

briefings by military officers, not scientific studies.

Furthermore, despite the finding by a Senate committee in 1994 that anthrax

vaccine was being considered as a possible cause of GWS,[10] and the statement

by the Persian Gulf Veterans Coordinating Board that " all potential causes [of

GWS] that have been identified are being investigated, " [11] when I reviewed the

full portfolio of federal research on GWS in 1999, I was surprised to find that

of 166 studies listed, none looked specifically at anthrax vaccine.[12] Only

because the Wessely/Unwin study was designed to investigate all potentially

noxious exposures that GW soldiers had faced, had data on anthrax vaccine been

captured. It seemed suspicious that so many of the federally funded studies

were designed to investigate psychological issues, and none the anthrax vaccine.

The 1999 report states that, " the RWG [Research Working Group] established the

development of treatment protocols for unexplained illnesses as a research

priority for future years. " [13] And in that same report was a discussion of

two proposed treatment trials for GWS. Yet since those trials commenced, not one

treatment trial for GWS has been sponsored by the federal government.

Both treatment trials, you may already know, were conducted by the same group,

and studied the effect of cognitive behavioural therapy, and of doxycycline use

for one year (for mycoplasma infection diagnosed by PCR). As I understand the

mycoplasma trial, after speaking with the principal investigator, Dr. Sam Donta,

approximately 450 veterans were enrolled and given either doxycycline or placebo

for one year. At three months there was a treatment benefit, but by 12 months

there had been a high number of dropouts, and so no benefit was demonstrated

statistically.[14] Instead of enrolling more veterans (there had been a lot of

interest on the part of veterans nationwide during initial enrollment) in order

to achieve a valid sample size, the authors instead concluded " Long-term

treatment with doxycycline did not improve outcomes of GWVs at one year. " The VA

sponsored this trial, and in the report I cited above, it says the trial was

projected to cost $12.4 million dollars, or $27,500 per subject. Yet Pfizer

donated the doxycycline and a matching placebo. The 1999 report states, " The

estimated size of this donation will exceed $5 million. "

I purchased generic doxycycline for a small number of uninsured patients, and it

cost $8.00 per month for the dose used in this study. Assuming that the placebo

pills cost the same, a one-year course of medication for each subject would cost

$96.00. The total cost for all trial participants would be $43,200, or less

than one per cent of the cost estimated by the Research Working Group. The

subjects were followed for a few visits during 18 months. It is hard to

understand why this trial was so expensive. Yet its cost was used to justify

the claim that additional treatment trials were too expensive to undertake.

The low rate of GWS in French troops, who were unvaccinated, had used

prophylactic doxycycline and consumed cleaner, bottled water, needed

explanation. The issue of whether small numbers of French troops who did

develop GWS were in liaison positions, and were vaccinated alongside US and UK

units, has been raised by the French Ministry of Defense, but to my knowledge

has not been resolved.[15]

Meanwhile, I met with several vaccinated but nondeployed, Gulf War 'era'

soldiers in the US, who had developed similar multisystem illnesses as the

deployed soldiers. Dr. Lea Steele was able to analyze this intriguing finding

in a study of Kansas Gulf War veterans.[16] She found that nearly 4% of the

veterans who had not been deployed, nor vaccinated in preparation for

deployment, met her GWS case definition. (She later concluded that this number

is approximately the prevalence rate of a similar condition in civilians. Since

it has been estimated that 3% of the US population has fibromyalgia, her

conclusion has some support.) But those who were vaccinated in preparation for

deployment, but never actually deployed, had a rate 3 times higher, nearly 12%.

In her study, the overall rate of GWS in those deployed ranged from 20% to 40%,

depending on a range of variables such as rank, branch of service, and time

spent in theater.

The US Institute of Medicine (IOM) committee on GWS under Dr. Harold Sox was

asked to review only published, peer-reviewed literature, and did a credible job

looking at the published literature on anthrax vaccine. In September 1999 the

committee concluded that no evidence existed to either support or refute anthrax

vaccine as a cause of chronic adverse health effects, including GWS.[17] (Since

then, a 2003 Cochrane review of anthrax vaccines drew the same conclusion:

" Further research should be carried out on the short and long term safety

effects of available vaccines and if possible their effectiveness. " [18])

However, the IOM committee overlooked several studies that linked anthrax

vaccine to GWS. The first study was performed by a contractor to the Canadian

Department of National Defense (DND), Goss-Gilroy, and was published on the DND

website in 1998.[19] The study used self-reports (as nearly all the GWS studies

have done) and found that immunization with biological warfare vaccines, which

for Canadian troops included only anthrax and plague vaccines, was associated

with chronic fatigue.

Chronic fatigue was a cardinal feature of GWS, as defined by the CDC in a

seminal paper by Fukuda et al in 1998.[20]

In January 1999 a groundbreaking paper by Unwin and Wesseley et al in The Lancet

showed that anthrax vaccine was associated with development of a GWS syndrome,

defined by the authors, in both veterans of the Gulf War, and also in a small

number of anthrax-vaccinated veterans of the Bosnia conflict.[21] Because of

the large number of veterans studied, and good statistical techniques, this

research is very convincing. It furthermore showed that multiple vaccinations

were independently associated with development of GWS.

During 1999 and 2000, nearly a dozen Congressional hearings were held that

involved anthrax vaccine. The House Committee on Government Reform published a

report of its findings, termed Unproven Force Protection.[22] Although the

Committee recommended that the vaccine be used by the military as an

experimental product, this recommendation was not followed by the Department of

Defense (DOD). Many active and reserve soldiers left the military to avoid

vaccination, and the media were filled with reports of court martials and other

legal challenges to vaccination.

The US Army, the lead vaccine agency for the Department of Defense, was under

the gun on the issue of safety and efficacy of the vaccine. It was also moving

forward to implement a parallel but much larger bioterrorism vaccine program,

termed the Joint Vaccine Acquisition Program, which could develop dozens of new

vaccines and cost many billions of dollars.

In 1999, Colonel Grabenstein, an army pharmacist who had just completed a

PhD in Pharmacoepidemiology, was chosen to serve as the clinical head and deputy

director of the anthrax vaccine program agency. He was charged with supervising

a portfolio of Army research to show the vaccine was as safe and effective as

DOD had reported to Congress. Col. Grabenstein was also a consultant and

trainer for Merck and Glaxo Kline, and chaired a committee of the American

Pharmacists' Association whose purpose was to train pharmacists to prescribe and

administer vaccines without a doctor's prescription, and to pass legislation

needed for them to do so in every state. He is on the Board of the Immunization

Action Coalition, an industry-sponsored advocacy organization. Col. Grabenstein

has written, " At present, about 50 serious vaccine-associated injuries occur

each year in the United States, in the course of protecting a population of 275

million into which 3.9 million children are born annually, " [23] yet the FDA says

that 15% of 12,000 reported yearly reactions are serious. His remarkable

ability to spin even the worst news has led to his promotion to clinical chief

and spokesperson for all military vaccinations. As quoted in the Washington

Post, " Grabenstein said vaccinations of 524,000 military personnel had found

only low risks such as sore arms, aches and fevers, with the rare serious

reaction for 1 in 100,000. " [24]

Col. Grabenstein was quoted in the NY Times on December 21, 2001 as saying, " If

people are getting sick, it is not due to the [anthrax] vaccine. " He has

misrepresented the conclusions of a number of other studies of anthrax vaccine,

claiming that eighteen studies prove the vaccine to be safe. He also worked

closely with the Institute of Medicine committee that produced the March 2002

report " The Anthrax Vaccine: Is It Safe? Does It Work? " [25] He is thanked in

the report's acknowledgments.

This report is a cynical whitewash of the safety and efficacy concerns about

anthrax vaccine, and makes a number of unsubstantiated and incorrect claims

regarding both.[26] [27] Furthermore, the report considers the DOD's Defense

Medical Surveillance System database's findings of a statistical association

between receiving anthrax vaccine and hospitalizations for diabetes, breast

cancer, asthma, Crohn's Disease, thyroid cancer and multiple sclerosis. It

acknowledged that these associations could be signals of a possible causal

relationship, especially for diabetes, Crohn's Disease and multiple sclerosis,

and recommends " additional follow-up " in the text. However, when the report

makes its final recommendations, it recommends against such follow-up, saying,

" DOD should develop systems to enhance the capacity to monitor the occurrence of

later-onset health conditions that might be associated with the receipt of any

vaccine; the data reviewed by the committee do not suggest the need for special

efforts of this sort for AVA. "

The National Academy of Sciences division in which this report was produced is

the Medical Follow-Up Agency, and it is 100% funded by the Department of Defense

and the Department of Veterans Affairs. Would this division have retained its

funding had the report provided an honest assessment of the vaccine?

Under Col. Grabenstein's oversight, the army has published at least four studies

purporting to show anthrax vaccine is safe and effective.[28] [29] [30] However,

the data reported in these studies leave much to be desired. The most important

study, the only one designed to learn about long-term reactions, was conducted

on 603 vaccinated medical staff at Tripler Army Medical Center.[31] According to

the principal investigator, " The objectives were to provide active surveillance

of self-reported side effects and the duration of symptoms. " [32] Soldiers were

asked to complete a questionnaire about symptoms that developed after their last

anthrax vaccination, whenever they presented for a subsequent inoculation, or

within two weeks of vaccination.

One case of multiple sclerosis and two other neurologic reactions developed in

vaccinees. One neonatologist developed a tremor and upper extremity weakness

associated with a CPK level over 1000. A pediatric cardiologist developed

numbness and fasciculations, suggesting a brachial plexopathy, which resolved.

Although the study was designed and initially advertised to seek persisting

adverse reactions, the forms completed by soldiers only specified whether

reactions lasted brief periods less than 72 hours, or more than 72 hours, and

the published paper provides no tables on side effect duration. The paper notes

that only local reactions could be linked to vaccination, and appears to dismiss

vaccine causality for other reactions without providing a rationale for doing

so. The exit questionnaire used was a general health questionnaire (Health

Enrollment Assessment Review Survey), rather than a questionnaire designed to

capture specific information related to vaccine adverse effects and their

duration. In fact, the questionnaire used made no reference to anthrax vaccine.

Other problems with this study include the fact that although 603 persons were

enrolled and originally reported on,[33] the published paper lists only 601

subjects. The abstract notes that localized reactions occurred more often in

women, but neglects to mention that systemic reactions did also, at

approximately twice the rate of men. Although the published paper notes that

one reason for enrollees to drop out was pregnancy, it omits mention that eleven

women became pregnant during their vaccine series, and the outcome of the

pregnancies remains unknown.

This is important because navy physician Cdr. has found that women

vaccinated for anthrax during the first trimester have a higher rate of birth

defects in offspring than unvaccinated women.[34] [35] Apparently this research

was compelling enough, despite an army study to the contrary, for the FDA in

2002 to change the pregnancy warning on the vaccine label from a C (no data on

risk) to a D (data suggests increased risk during pregnancy). However, the data

have not yet been published.

Dr. Araneta, also associated with the Naval Health Research Center and

University of California, has shown that GW veterans are also likelier than

controls to have children with certain birth defects.[36]

According to the Tripler study authors, " Women in the immunized cohort were more

likely to report (in their exit questionnaire) that their general health was

'poor or fair' compared with the unimmunized cohort (RR 4.4; 95% CI:

1.3-15.1).otherwise there were no notable trends or associations. " Regarding

the Tripler authors' claim that there were no notable trends in their data, one

would think that the high female reaction rates and poorer female health at the

study's conclusion would be notable, and that a serious neurologic reaction rate

of 0.5% in a vaccine study should have raised some eyebrows.

Because all the army studies claim to show the vaccine is safe, sometimes in

spite of evidence to the contrary, and all were supervised by the same

individual, while virtually all the research done elsewhere has found that

chronic illnesses are associated with anthrax vaccinations, I have chosen to

disregard the army research, which I believe has put the " mission " to vaccinate

soldiers before the science.

The FDA has similar criticisms of these army studies. In the vaccine's package

insert[37] under the title " Post Licensure Survey Studies " FDA included the

following statement: " In addition to the VAERS data, adverse events following

anthrax vaccination have been assessed in survey studies conducted by the

Department of Defense in the context of their anthrax vaccination program.

These survey studies are subject to certain methodological limitations, e.g.,

sample size, the limited ability to detect adverse events, observational bias,

loss to follow-up, exemption of vaccine recipients with previous adverse events

and the absence of unvaccinated control groups. "

Several years ago, in conjunction with the Hartford Courant newspaper, I

reviewed the first 1660 anthrax vaccine adverse events reports to FDA (found in

the Vaccine Adverse Effect Reporting System (VAERS)), and found that about 160

met the CDC's case definition for GWS. Most of those reporting had not been to

the Gulf. They had reported at least two of the following three problems:

musculoskeletal pain, fatigue, and a cognitive or emotional disorder. I wrote

to the FDA about this, and enclosed the Fukuda/CDC's case definition from the

JAMA. I was later gratified to learn that the revised January 2002 anthrax

vaccine package insert[38] includes the CDC's GWS case definition in the list of

reported adverse reactions, although the fact that this is the GWS definition is

not stated.

As early as May 1999, 14 months after the start of the Anthrax Vaccine

Immunization Program, a group of military clinicians got together to identify

illnesses developing after anthrax vaccination, develop criteria for waiving

further vaccinations in certain ill individuals, and develop evaluation,

prevention and treatment strategies. Col. Grabenstein later joined this group,

which placed him in the interesting position of denying that chronic illnesses

are caused by anthrax vaccine, while also coauthoring credible reports of

vaccine adverse reactions, and coauthoring clinical guidelines for

vaccine-related disorders. The guidelines have undergone several revisions

since 1999, and can be found on the DOD website.[39]

It is interesting that the unexpected reactions seen by these military

clinicians in 1999, when they wrote the first draft of the guidelines, remain

important and continue to be addressed by the guidelines four years later: these

include neurological reactions, chronic fatigue, chronic pain syndromes and 8th

nerve dysfunction, among others.[40]

One of the clinicians in the forefront of responding to illnesses that develop

following military vaccinations is Col. Renata Engler, MD, the Army's chief

allergist- immunologist. She evaluated severely affected soldiers at Walter

from the beginning, and founded the National Vaccine Healthcare Center in

2001.[41] Subsequently the military's Vaccine Healthcare Network has expanded

to four sites, and its mission has expanded to include illnesses developing

after any vaccination. The centers have also treated smallpox vaccine

reactions, and developed screening criteria for waiving both anthrax and

smallpox vaccinations. They are involved in research on vaccine reactions.

Over 1,000 in depth case reviews and patient evaluations have been performed.

Despite the centers' successes, funding was about to be cut off in October 2004,

but has been reinstated for one year as a result of Congressional interest.

According to Walter National Vaccine Healthcare Center authors,[42]

" between May 1998 and July 2001, 82 patients were evaluated for complaints of

prolonged systemic clinical problems whose onset was associated or attributed to

anthrax vaccine exposure by the patient, referring provider or family

member...the spectrum of systemic symptoms in this group is heterogeneous with

the reasons for referral including (but not limited to) one or more of the

following features: non-injection site skin rashes (15%); persistent headaches

(12%); tinnitus (16%); other neurologic disease or symptoms (21%); prolonged

fatigue with 50% functional loss for > 60 days (21%). Specific diagnoses are

diverse with some patients manifesting prolonged disability...there continues to

be a need to improve our understanding of these clinical scenarios. "

In February of this year, Army Surgeon General B. Peake issued new

guidelines for treatment of soldiers' illnesses that do not respond to standard

treatments.[43] He suggested that vaccine reactions be considered, that vaccine

histories be taken, and that clinicians seek second opinions from the vaccine

healthcare centers. His memo followed publicity about the death of Lacy,

a 22 year old nursing student and army reservist who was called up for duty in

Iraq, given five vaccines in one day, including anthrax and smallpox, rapidly

became ill, and died 4 weeks later at the Mayo Clinic. Her autopsy revealed

adult respiratory distress syndrome and eosinophilic lymphocytic myocarditis.

Another military case of eosinophilic lymphocytic myocarditis was seen at Mayo

Clinic around the same time, also associated with five vaccines including

anthrax and smallpox, but the soldier lived to have an endomyocardial biopsy,

receive high dose prednisone treatment, and recover.[44]

The Surgeon General may also have been responding to media reports of over

twenty " mystery pneumonias " in soldiers that were non-infectious, associated

with eosinophils in blood or bronchoalveolar lavage fluid, and resulted in a

number of ventilator cases and several deaths.

After years of military physicians failing to report vaccine adverse reactions

to FDA, and failing to acknowledge in the patients' medical records that such

reactions have occurred, the Vaccine Healthcare Centers have begun to reverse

this unfortunate trend. One soldier who I recently evaluated had been

extensively worked up by the Vaccine Healthcare Center. His record there stated,

" Staff Sergeant ****** was a high functioning, decorated service member prior to

beginning the anthrax vaccine in 1998. He has had no disciplinary action. He

has functioned well in his duty assignments and is highly regarded even now.

Staff Sergeant ******'s life has been significantly altered due to his current

disability, and hope for recovery is uncertain. The lack of clinical findings

is discouraging and leaves his providers baffled and powerless as to an

effective treatment plan. His condition is not unique for us at the Vaccine

Health Care Center. We have treated many proficient service members with

debilitating conditions that cannot be diagnosed or medically substantiated,

conditions that have developed in close temporal association to having received

the anthrax as well as other vaccines. Hopefully future medical research and

discovery will provide some definitive answers to these perplexing medical

dilemmas and allow us to effectively treat individuals such as Staff Sergeant

******. " [45]

This statement was signed by Limone C. , MD, director of the Walter

Regional Vaccine Health Care Center and by Jeannette F. , FNP, case

manager, on January 14, 2004. It is gratifying to finally have these

clinicians, who see the greatest number of patients with post-vaccine illnesses,

acknowledge that they too are baffled by patterns of symptoms in many patients

who are debilitated and treatment resistant, and who have developed

undiagnosable illnesses following vaccinations, usually including anthrax.

Because the subset of illnesses that are readily diagnosable in soldiers I

evaluate often turn out to be endocrinopathies, connective tissue disorders,

vasculitides, and other autoimmune disorders such as multiple sclerosis, I have

begun to hypothesize that the difficult-to-diagnose illnesses are also

autoimmune, despite not fitting into usual diagnostic categories, nor having

classic laboratory findings of autoimmunity. The fact that so many GW veterans,

and many with anthrax vaccine-associated illnesses, have become chemically

sensitive, suggests that some poorly understood form of allergy comprises at

least part of their illness. I expect that further appropriate research will

yield lab markers, and accurate ways of understanding and treating these

disorders. The significant cognitive impairment in most of these veterans,

which may not show up on scans, will be shown to have physiological correlates

in future, as will their physical disabilities. Eventually, our understanding of

GWS will shed light on a variety of poorly understood syndromes like

fibromyalgia, chronic fatigue syndrome and chemical sensitivity.

Recent UK studies

Regarding the short-term adverse effects of recent anthrax vaccinations in the

UK, in soldiers vaccinated before the recent Gulf deployment, two small studies

have been done. The UK vaccine is given as a four dose series over one year,

with yearly boosters; the US vaccine is given in 6 doses over 18 months, with

yearly boosters.

In the first paper by and World, 129 soldiers working in a military field

hospital were offered vaccine, and 76% (98 soldiers) accepted and began the

series.[46] Initially, 63% had adverse reactions. " Forty-five percent of

these caused incapacity. " Approximately 22% of reactors had arm pain that

prevented lifting or driving for 48 hours. Twenty-one percent of reactions were

designated severe. Only 27 of the 98 soldiers who began the vaccinations

completed the four dose series. The authors noted, " Although the old vaccine is

considered safe, the number of adverse reactions and incapacity reported by a

military medical unit was unexpected. "

The second paper looked at vaccine acceptance and adverse reactions in personnel

at five RAF bases.[47] " Those completing the [vaccine] course as a percentage

of those starting it varied from 22% at base 2 to 3.7% at base 4. " Yet these

authors reported that only 11% of vaccinees had side effects, and that these

were mild.

Neither set of authors was able to explain the dropoff in vaccine uptake. Both

studies were supported by the MOD.

What questions should be resolved regarding the contribution of anthrax vaccine

to GWS, and what data exist to answer them?

1.. Did the vaccine alone, in the absence of other noxious exposures, cause

GWS? Nondeployed GW 'era' soldiers and recent vaccinees who had no additional

noxious exposures should be formally studied for chronic illness effects.

However, studies and individual reports from recent US and UK vaccinees, and

Wesseley's vaccinated Bosnia cohort are very suggestive that anthrax vaccine

alone may cause GWS. Additional support comes from the presence of many ill,

vaccinated, nondeployed veterans. There exist no reliable negative studies of

which I am aware. What the incidence of GWS is in those with only an anthrax

vaccine exposure is unknown, and may be difficult to determine, because veterans

had variable numbers of doses, and the composition of the vaccine from lot to

lot varies enormously, so reactions rates may also. A recent unpublished study

of reactions and their persistence at Dover Air Force Base suggests that in some

circumstances, chronic illness rates may be very high, up to 30%.[48]

Furthermore, although we have estimates of vaccine uptake (provided by the US

and UK governments) in GW veterans, I have seen no documentary evidence that

supports the accuracy of these estimates. Therefore in my opinion the number of

US GW veterans with anthrax vaccine exposure is unknown, and the information

that DOD has produced regarding the vaccination status of a few thousand GW

veterans is similarly unreliable. The fact that DOD policies were established

at the time of the GW to omit recording certain vaccinations, particularly

anthrax, leads to concerns that persisting adverse reactions were anticipated.

2.. Did the anthrax vaccine, in conjunction with other administered vaccines,

cause or contribute to GWS? The reports by Wesseley, Steele and Cherry on

multiple vaccinations are in agreement about this. Is it more dangerous to give

other vaccines at the same time as anthrax vaccine, compared to giving the

vaccine individually? The US' Armed Forces Epidemiology Board has considered

this issue, but decided multiple vaccines were safe with anthrax (in the absence

of good data), and the British MOD did establish a policy to inoculate for

anthrax without other vaccines being used simultaneously. Whether this policy

remains in place and whether it was followed I do not know, nor am I privy to

additional evidence, if any, upon which the MOD and DOD concerns were based.

3.. Did the anthrax vaccine in conjunction with other toxic exposures (other

than immunizations) contribute to GWS? There is no population data or

experimental data, to my knowledge, that addresses this question. It is an

important question, particularly because chemical and pharmacological exposures

can predispose to autoimmune disorders similar to some that appear to be caused

by the vaccine alone. Dr. Abou Donia has expressed interest to me in pursuing

this in the animal model. From my perspective, it is quite likely that the

combination of exposures increased the risk of illness in veterans. Whether

combined exposures led to additive, synergistic or other effects is worthy of

study.

4.. What information is available regarding specific reactions following

vaccination?

1.. The Vaccine Adverse Event Reporting System (VAERS), a joint FDA-CDC

undertaking, has collected approximately 3,000 reports from medical

professionals and vaccinees regarding adverse events following anthrax

vaccination. The database is limited by lack of follow-up for most of the

reports, absence of verification using medical records, the fact that reporting

is voluntary, use of cumbersome terminology, and the presumption that reactions

are under-reported by a factor of 10 to 100. I made the following calculation

in July 2002, using data supplied to me by FDA, that one in 250 vaccine

recipients had had an anthrax VAERS report filed, and FDA noted then that 25% of

these VAERS reports were serious. Subsequently, some of these reactions have

been down-coded by FDA and are no longer labeled as serious. This database

needs to be mined.

2.. The VAERS database is designed to capture 'signals.' Because it is felt

by FDA that causality cannot be assessed on the basis of VAERS reports alone,

such signals are then investigated with a directed epidemiologic study. Such a

study to establish or refute causality for anthrax vaccine reactions has not

been performed, to my knowledge.

3.. Dr. Mark Geier and his son Geier have manipulated their own copy

of the VAERS database, and established a method by which they compare adverse

event reporting rates from one vaccine to another, in order to estimate a

" baseline " level of symptoms that are not causally related to vaccination. They

have shown that levels of reporting for joint[49] and

gastrointestinal-related[50] complaints are much higher for anthrax vaccine than

for other killed vaccines.

4.. Approximately ten case reports of illnesses following anthrax

vaccination have been published in the medical literature. It should be of

interest that all these reported reactions could be autoimmune effects.

5.. Which component(s) of the vaccine are responsible for illness?

1.. Microbiological contamination is a possibility.

i. Many lots

had visibly contaminated bottles, which were thrown away without extra testing

of the remaining vials; some lots and sublots had to be destroyed due to

bacterial or fungal contamination.

ii. The only

sterilizing step in vaccine production was filtration. For several years the

manufacturer used a tetanus vaccine filter for anthrax vaccine that had not been

validated for anthrax.

iii. Even after

the manufacturer rebuilt its entire anthrax manufacturing facility, the bottling

suite was not sterile, and the manufacturer has had to ship all vaccine to a

company in the state of Washington, Hollister-Stier, for bottling since 2002.

iv. Only two

types of plates were used to incubate aliquots of vaccine to determine whether

there was microbiological contamination. The plates were held for 5 days. This

was insufficient to identify bacterial L-forms such as mycoplasma, spirochetes

that could pass through the pores of the filter, or slow-growing bacteria. It

was inadequate to identify viruses. It would also miss many fungi.

v. Studies of

other human and animal vaccines have found viral and mycoplasma contamination.

vi. A

DOD-sponsored study designed to address the issue of high mycoplasma levels by

PCR in GW veterans, originally found by Dr. Garth Nicholson and others,

identified no mycoplasma in vials of anthrax vaccine;[51] however, because the

DOD has refused to provide vaccine vials for independent study, and because it

would be easy for DOD to inactivate microorganisms in the killed vaccine, to

select an uncontaminated sublot for testing, or refilter the vaccine, without

revealing that such had taken place, I do not believe this study rules out

mycoplasma contamination in anthrax vaccine.

vii. Many lots

were found to have low (out of specification) levels of benzethonium (phemerol)

during supplemental testing of the vaccine stockpile in 1997-1999; Benzethonium

was used for its antimicrobial effects; low levels increased the chance of

microbial contamination.

viii. Microbial

contamination (or simply chronic occult infection) is one of the few theories of

the origin of GWS that could explain the transmission of GWS to some spouses and

children of affected veterans.

2.. Intrinsic toxicity of PA is another possibility.

i. Both the

British and US vaccines' primary immunizing ingredient, and main protein

component, is PA (Protective Antigen). The British vaccine seems to cause

similar problems as the US vaccine, even though the two vaccines use different

anthrax strains, a different culture system, and slightly different adjuvants

(aluminum phosphate [alum] in the UK, and aluminum hydroxide [alhydrogel] in the

US). However, both countries have had manufacturing problems that led to both

manufacturing facilities being refurbished in the past five years, so it is

possible that manufacturing flaws are contributory.

ii. ii. In the

1960s, prior to licensing the current anthrax vaccine, at least two studies done

at Fort Detrick looked at the effect of PA, in the absence of lethal factor or

edema factor, injected into monkeys. In the first study, levels of blood

glucose and liver glycogen dropped markedly with injection of PA.[52] In the

second study, PA was injected into the monkeys' cerebrospinal fluid. The authors

had the following to say: " Within 30 to 60 seconds, a marked decrease in

cortical [brain] electrical activity was noted, followed in some animals by

complete electrical silence at approximately 3 to 5 minutes. " [53] Thus some

inherent toxicity of this compound has been established, but no research has

been published in the open literature to expand on these observations in the

intervening thirty-six years.

3.. Excessive amounts of PA and other (expected but uncharacterized) anthrax

fermentation products may be contributing to toxicity.

i. The

pre-Gulf War I lots were tested by Dr. Bruce Ivins at Fort Detrick, and found to

vary in concentration of PA by a factor of forty. Perhaps the more concentrated

lots caused problems in susceptible individuals.

ii. After the

Michigan vaccine fermenters were changed from glass to stainless steel, and the

filters were changed from three dimensional ceramic filters to two dimensional

nylon filters, Dr. Ivins discovered that the newer lots were one hundred times

more concentrated than the lots made with the earlier fermenters and

filters.[54] You might wonder how FDA allowed this to occur, but FDA was simply

not notified of these changes by the manufacturer.

iii. The

vaccine is manufactured by growing an attenuated strain of anthrax in culture,

heat-shocking it to kill the bacteria, filtering the culture medium, adding

aluminum hydroxide gel, stirring to promote protein binding by the gel,

centrifuging the mixture, discarding the supernatant and resuspending the

pellet, adding formaldehyde and benzethonium, and the resulting mixture is the

vaccine. Thus any components of anthrax, including cell membrane, DNA, and even

undefined virulence factors, may become part of the vaccine. Because this mix

has not been characterized, and because the concentrations of PA as well as

other components vary greatly between different sublots (each individual

fermentation product becomes a sublot of about 10,000 vaccine doses), other

virulence factors remaining in the vaccine could be problematic. Also, these

extraneous materials probably further stimulate an immune response.

iv. Recombinant

PA vaccines, with very low concentrations of other materials, were developed

even before the first Gulf War, and at least one (rPA102) is in clinical trials

in the US. I have been told informally that high concentrations of these purer

vaccines are needed in order to generate sufficient immunity in vaccinees. In

its initial Phase 1 clinical trial, the rate of systemic reactions reported for

the rPA102 vaccine was 39%, compared to an 18% systemic reaction rate for

Biothrax.

4.. Might other vaccine components be responsible for toxicity?

i. The level

of aluminum in each vaccine dose, and the number of doses used, does produce a

high body burden of parenteral aluminum.

ii. Rumors of

the use of experimental anthrax vaccines at the time of the first Gulf War

abound. Because two Fort Detrick commanders acknowledged in early 1990 that

unlicensed anthrax and other vaccines were used in selected military units,[55]

it appears to have been standard practice to use unlicensed anthrax vaccines in

some troops. I have collected several documents for the Inquiry that relate to

the US use of unlicensed (experimental) medical products in soldiers, and after

reviewing this subject, and the memorandum of understanding about the use of

such products between the FDA and DOD, I have come to believe that clinical

trials of experimental medical products were regularly conducted in the military

without the knowledge of troops. I further believe that use of such products

outside of a clinical trial setting also routinely occurred. (The US National

Strategic Stockpile of drugs and vaccines now includes unlicensed products, and

recent laws passed in the US would allow such experimental products to be

mandated for civilians as well, in the event of a designated bioterrorism

emergency.) How experimental anthrax vaccines may have differed from the

licensed vaccine at the time of the GW is unknown.

iii.

Rettig wrote a formal study for the RAND Corporation about the use of (eight)

unlicensed drugs and vaccines during the Gulf War.[56] At the time of the GW,

the DOD only acknowledged using two unlicensed products, pyridostigmine bromide

(NAPS) and botulinum toxoid vaccine.

iv. Squalene has

been cited as a possible unlicensed adjuvant added to anthrax vaccine at the

time of the Gulf War. Pertussis vaccine is known to have been used to adjuvant

the anthrax vaccine in the UK. Numerous studies by Drs. Turnbull, Ivins, Welkos

and and others explored the use of novel adjuvants in boosting the

efficacy of anthrax vaccines, which was known to be poor in the face of highly

virulent anthrax strains. These researchers found that a variety of adjuvants,

including Bordetella pertussis and synthetic adjuvants containing squalene and

other highly immunogenic materials, were capable of profoundly boosting vaccine

efficacy after only one dose.[57] However, none of these adjuvants were

licensed for human use in the US. Might they have been used at a time our

nation was facing possible attack with anthrax, when vaccine availability was

limited, and when the FDA gave the DOD the right to use a number of experimental

products on troops?

5.. Might there be problems with storage, shipping or shelf life of vaccine?

i. We know

that in 1998, some FDA-approved lots of vaccine had been in storage since the

Gulf War, well past their putative 3-year expiration period. The manufacturer

had a policy of simply retesting potency of expired lots and then redating the

lots for an additional three-year period. FDA was not aware of this procedure

until 1997.[58]

ii. The DOD

had a policy in place, apparently approved by FDA, that all vaccine stored in

bulk would have no expiration date. Such vaccine would be tested only for

potency at the time it was bottled, and then issued a standard shelf life. No

testing for degradation of the product, or for toxicity, took place at the time

of bottling. This extended expiration dates by ten years or more.

iii.

Investigational New Drug (IND or unlicensed) products were covered by a similar

but different policy. They have no expiration date at all, and can be stored

indefinitely either in bulk or in vials and ready for immediate use, with no

potency or other testing required before they are used.

iv. The

alhydrogel adjuvant has only a two-year shelf life, according to the

manufacturer, after which there is increased desorption of protein.[59] How

this affected vaccine subjected to long periods in storage is unknown.

v. The FDA

recalled anthrax vaccine lot 016 due to stopper deterioration; the problem was

discovered by the presence of visible particulates in the vaccine. Whether

other lots contained rubber particles is unknown. Whether stopper deterioration

allowed entry of late microbial contaminants is also unknown.

vi. No anthrax

vaccine stability testing was done prior to 1998.

vii. No published

studies have addressed any issues of prolonged vaccine storage, shipping and/or

holding of vaccine outside the temperature limits established in the product

license, or other issues of product degradation. Yet we know that vaccine was

shipped by the military using 'polar packs' only, without refrigeration or

climate control, and that it did not always remain within the temperature limits

specified in the product license.[60]

6.. The FDA issued a NOIR (Notice of Intent to Revoke the establishment

license of Michigan Biologic Products Institute) in March 1997, due to a large

number of failures of cGMP by the manufacturer.[61] Possibly other quality

control failures not discussed above led to illness.

7.. Possibly GW 1 soldiers are ill from receiving unlicensed anthrax vaccines,

not the Michigan vaccine product. Possibly they had unlicensed adjuvant added

to what had been an acceptable product. However, the fact that large numbers of

soldiers have become ill after receiving this vaccine over the past 6 years,

during which no convincing evidence has surfaced that unlicensed vaccines were

being used, or that unlicensed adjuvants were being added to the vaccine, weighs

against that possibility being the complete explanation for anthrax vaccine

toxicity.

What research should be done to resolve whether and how anthrax vaccine causes

chronic illnesses?

1. A large prospective case-control active surveillance safety trial should be

done using soldiers who are required to be vaccinated by the US military, and

comparable controls, for as long a period of follow-up as possible. (I believe

it would be unethical to vaccinate volunteers due to the high rate of serious

reactions.) Gulf War veterans often developed their illnesses slowly, sometimes

years after leaving the service. The recent safety studies of anthrax vaccine,

as opposed to studies of GW veterans, have all been short-term, generally

concluding about one month following vaccinations.

a) The vaccine lot(s) they are receiving should be characterized as

comprehensively as possible; the concentrations of PA, aluminum, benzethonium

and formaldehyde should be measured; and the presence of known anthrax virulence

factors should be identified.

Both bottled vaccine and individual vaccine components should undergo

comprehensive toxicity testing in animals, especially pregnant animals, which

according to the package insert has not been done.

c) The VAERS database of approximately 3,000 adverse event reports should

be mined to collect the most common complaints, and develop a reporting form for

this clinical trial that will elicit whether any of these complaints develop,

but also will allow for 'penciling in' of any other symptoms or illnesses

experienced by vaccinees over the period of follow-up.

d) This entire study must be carried out by independent researchers who

have no ties to the DOD or VA, and no other conflicts of interest.

2. Several rare, serious illnesses have been linked anecdotally to anthrax

vaccine. These include pemphigus vulgarus (currently being investigated by the

Walter National Vaccine Healthcare Center) aplastic anemia, leukemia,

lymphoma, multiple sclerosis, glomerulonephritis, and others.

a) Independent researchers should review the records of all soldiers who

have received a bone marrow transplant in the military, and see if there is a

disproportionate number who have received anthrax vaccine, as alleged by one

marrow recipient.

All cases of new onset of multiple sclerosis, glomerulonephritis, and

other serious autoimmune diseases and lymphoproliferative disorders should be

similarly reviewed, to see if the rate of development of these disorders in the

vaccinated is different than the rate in a comparable unvaccinated cohort.

3. The Institute of Medicine's 2002 report on anthrax vaccine contains

information from the Defense Medical Surveillance System database on

hospitalizations pre and post vaccination in military facilities. One half

million person-years of vaccinees are included. Although overall

hospitalizations in the anthrax-vaccinated are only about 2/3 as frequent in the

unvaccinated, hospitalizations for several diagnoses are significantly higher in

the vaccinated cohort. However, this result is confounded by the fact that only

the healthiest soldiers receive anthrax vaccine for deployments. Better data

would compare the rates of these disorders in anthrax vaccinees with a matched

cohort of non-vaccinated servicemembers. This comparison should be done by

independent researchers who have access to servicemembers' complete medical

records.

4. All US servicemembers have blood serum frozen every 1-2 years. Because many

of the chronic illnesses being reported appear autoimmune in nature, analyzing

stored serum samples to identify if/when autoimmune markers developed, and

whether this occurred in proximity to vaccination, is important. Examination of

stored serum for autoantibodies has been done for a number of soldiers seen at

the Vaccine Healthcare Centers, although a compilation of results has not been

published.

5. Cohorts of nondeployed, vaccinated GW veterans and unvaccinated control

veterans should be examined clinically to determine whether vaccination is

associated with subsequent illnesses, and whether serum markers of autoimmunity

or other markers, such as lower levels of endocrine hormones, higher rates of

mucocutaneous candidiasis, etc. exist that might distinguish between the two

groups.

6. More research in animal models needs to be done using combinations of

exposures. Anthrax vaccine has not yet been included in these studies, and

because the vaccine is impossible to obtain for research, and the entire vaccine

stockpile is owned by the DOD, such research will have to be mandated by

Congress in order to be carried out. Combinations should include

organophosphates, pyrethrin, pyridostigmine bromide, jet fuel, solvents

routinely used by the military, other inhalants, other vaccines, etc. It is

very important to learn whether certain combinations of chemical or

pharmaceutical exposures promote vaccine toxicity.

7. HLA typing of those who develop vaccine-associated illnesses should be done,

to determine whether a genetic predisposition to these illnesses can be

identified. Cytokine release patterns post vaccination should also be studied.

8. The Defense Medical Surveillance System database tells us that women who

have received anthrax vaccine are several times as likely to be hospitalized for

carcinoma in situ of the breast or genitourinary system after being vaccinated,

as they were before vaccination. Reports of abnormal PAP tests in female Gulf

War veterans abound, and there are reports that female Vietnam veterans were

similarly affected. Differentiating between a viral and toxic etiology for

cervical carcinoma in situ, and seeking information on synergism between viral

and toxic exposures in military women would be valuable.

Other thoughts on GWS exposures:

1. DU-Reports over the past several years have indicated that byproducts of

fission from nuclear reactors have been mixed with pure depleted uranium[62] to

create munitions and armor that are radioactively much more hazardous than would

be expected from pure DU. This lends credibility to reports of illness from this

exposure. The cancer risk and other risks, especially in those with high body

burdens of inhaled DU, must be established.

2. I believe the increased accidental death rate in GW veterans is due to

problems of cognition, slowed reaction times and impaired judgment. These

sequellae of their GW service are present in the majority of GW veterans I have

treated. Several who have undergone formal neuropsychiatric testing showed

clear deficits in cognition, especially of executive function.

3. Certainly the reports from both US and UK soldiers that they received

several more inoculations than are documented in their medical records raise

questions, and neither Rettig's RAND report nor any other information in my

possession answer them.

4. Economic modeling of the costs of vaccine-associated illnesses in

soldiers and veterans should be done, so that society can better calculate the

risk/benefit equation for using anthrax and other new vaccines, and embarking on

massive bioterrorism vaccination programs.

5. The Department of Defense medically retires soldiers who become

chronically ill following vaccinations. This shifts the costs of medical care

and disability pensions to the Veterans Administration, which is financed

through a separate Congressional appropriation. The DOD is thus protected from

the financial pain resulting from its use of highly reactogenic vaccines. Were

the VA to be funded out of a common appropriation along with the Defense

Department, the decision to use reactogenic vaccines and to expose soldiers to

other dangerous substances would probably be made much more judiciously.

6. Because the DOD is the employer of all those receiving anthrax vaccine,

is the employer of all physicians treating ill vaccinees at military facilities,

owns the entire vaccine stockpile, is the indemnifier (insurer) of the vaccine

manufacturer, is the holder of the vaccine patent, and has created policies that

demand mandatory vaccinations with not only anthrax but smallpox vaccine (which

is no longer given to civilians due to a high rate of serious adverse events),

and a host of new vaccines sponsored by DOD are in product development, the

Defense Department cannot be expected to change its course on vaccine policy

now, despite overwhelming evidence demonstrating serious safety concerns.

Instead, only the Congress, the Judiciary or the President can apply the

restraint needed to end the mandatory use of dangerous and questionably

effective vaccines by the military. US military medicine has become the

handmaiden of vaccination policies designed by non-medical officers, and both

the DOD leadership and most military physicians have turned a blind eye to the

medical consequences of these policies. So far, neither has paid a price for

doing so. Instead, it is the ill themselves who pay the price for developing

vaccine-induced diseases, which are often impossible to diagnose or treat. Many

of those who develop these disorders lose their military career, their

employability, their health, and even their self-respect, as they are try to

understand what has happened to them, and then convince an uninformed medical

establishment that they are truly very ill.

We physicians, who are unable to return these soldiers and veterans to health,

must at least believe in them, work to educate our colleagues about them, and

find a place in our textbooks for them. And encourage research designed to

enlighten us about these obscure but devastating syndromes.

Thank you very much for allowing me to make this presentation.

Meryl Nass, MD

Mount Desert Island Hospital

--------------------------------------------------------------------------------

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[33] GAO/T-NSIAD-99-226

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[41]

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[58] An FDA Memorandum attesting to this is included for the inquiry.

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