ON ERODING THE VALUES OF SCIENCE

THE INSTITUTE OF MEDICINE’S REPORT ON THE ANTHRAX VACCINE

Meryl Nass, MD

Nearly two years ago, Congress asked the National Academy of Sciences (NAS) to review the existing data on safety and efficacy of the anthrax vaccine (AVA).  A committee was created by the NAS Institute of Medicine (IOM) to do this, and the group met over the last seventeen months to review this complex and controversial issue.

I attended several of the open meetings, made an invited presentation, and supplied nearly 300 pages of supporting information to the committee.

The National Academy of Science's report ‘The Anthrax Vaccine: Is it safe? Does it work?’ was released March 6.  It claimed to be a thorough compilation of all the existing data, weighted by reliability, and included a number of recommendations and ideas for further research.

What did the report conclude?  Here is where it gets interesting.
 

The report's conclusions rely on ignoring many pieces of crucial information, and its recommendations give the Department of Defense everything it could have wanted. The report appears to be "spun" to support a number of DOD initiatives, and it provides the needed justification for restarting mandatory anthrax vaccinations over the objections of many in Congress.

Strong words.  Can I back them up?  Let's review the Executive Summary and see what the report concludes about efficacy, safety and vaccine manufacturing concerns (which closed the plant for four years, until it finally received FDA approval in January 2002). Several unexpected recommendations are also explored. I’ve excerpted from the text in bold, and used quotations.

EFFICACY

1.  "Because the vaccine exerts its protection via an antigen crucial to the action of the bacteria's toxins, AVA should be effective against anthrax toxicity from all known strains of B. anthracis, as well as from any potential bioengineered strains."

This particular fairly tale has been oft-repeated by a variety of DOD spokespersons over the last four years, in support of the anthrax vaccine immunization program.  Although it makes logical sense, the statement is contradicted by the data, in which thousands of vaccinated animals have succumbed to challenge with many strains of anthrax, despite generating high levels of antibody to the vaccine antigen in question, ‘protective antigen’ or PA. 

It furthermore ignores the work of Pomerantsev et al in Russia (published in the December 1997 issue of the journal Vaccine), in which a genetically engineered strain of anthrax had the PA antigen gene removed.  Another gene for cereolysin was inserted, making the engineered anthrax resistant to a PA-based vaccine like the current anthrax vaccine. 

How did the IOM report deal with this information? It claimed Pomerantsev’s study was ‘flawed’ because anti-PA antibody titres of vaccinated animals were not given. This is a specious argument, because antibody titres in mice and guinea pigs have shown no correlation with survival. Then the report complains that hamsters were used, and "little is known about hamsters as an animal model." The study was done in Russia, and the Russians who use hamsters as their model probably know plenty about hamsters and anthrax.

Pomerantsev works at NIH now, not far from IOM. If answers to these questions were really wanted, Pomerantsev could have been invited to come answer them.

The report also mentioned, but immediately ignored, the fact that DOD was so frightened about this type of engineered anthrax, that it contracted with Battelle Memorial Institute to genetically engineer a similar strain.  (See Miller J and Broad W. NYT September 4, 2001, page A1.) And who knows what Pomerantsev is concocting now at NIH?

Claims by IOM that a vaccine "should be effective" against all known strains and all potential bioengineered strains should be summarily dismissed as reckless optimism.

2. "The macaque and the rabbit are adequate animal models for evaluation of the efficacy of AVA for the prevention of inhalation anthrax."

Many animal models have been used in anthrax experiments.  DOD has found that only the rabbit and rhesus macaque show strong immunity after anthrax vaccine.  The macaque, not surprisingly, has an illness that is closest pathologically to the human version of inhalation anthrax.  The chimpanzee, however, which is normally considered closer to the human
than the macaque, develops an anthrax illness that more closely resembles that in guinea pigs and mice.

DOD has long claimed, without citing any data to support the claim, that because macaque anthrax looks like human anthrax, that the macaque is the best animal model for studying vaccine immunity.  But just because the disease may be similar pathologically does not mean the macaque immune response to vaccine is similar to the human response.  The IOM report entirely fails to explain this conceptual leap.

Another leap follows.  The rabbit happens to develop stronger immunity after anthrax vaccination than the rat, mouse or guinea pig.   Macaques are expensive, but rabbits are cheap.  So DOD wants to conduct its vaccine efficacy studies in rabbits, not macaques or chimps.  Rabbit anthrax does not resemble human anthrax closely.

IOM supplied DOD with the desired gold nugget to support rabbit experiments, based on the misleading argument that macaque anthrax looks like human anthrax, and the rabbit immune response to AVA looks like the macaque immune response, therefore rabbits are like humans!
 

We know rabbits get good immunity from anthrax vaccine, but the real question is do humans get good immunity?  Where is the evidence that rabbits provide a good model for human immunity?

The report’s assertion that these animals are good models for humans falls apart several paragraphs later.  The IOM report says, "The data from animal studies already developed suggest that serological correlates of human immunity can be developed in appropriate animal models. The committee commends this work and encourages its further development."

What that means is that at present, there is no way to compare the immunity developed by animals after vaccination, to the immune response of humans after vaccination.   Bottom line: the IOM gave DOD its imprimatur to use rabbits, with no supporting evidence or logic, because they are inexpensive and likely to provide the forgone conclusion desired.

3.  "The committee finds that the available evidence from studies with humans and animals coupled with reasonable assumptions of analogy, shows that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by any known or plausible engineered strains of B. anthracis."

Here the report makes several claims favorable to DOD, but unsupported by evidence, in a single sentence:

 a) AVA is effective in humans, even for inhalation

 b) The addition of the phrase "as licensed" appears to be an attempt to weigh in on the current case in Federal Court, which notes that the AVA license does not include an indication (an approved use) for inhalation, or biological warfare use. If a jury agrees, DOD will be prevented from forcing anthrax vaccine on troops.

 c) The vaccine will be effective for genetically engineered strains.

Despite all the report’s hand-wringing about PA, the main vaccine ingredient, there is clearly no way to know if the vaccine will be effective against engineered anthrax strains: it depends how they are engineered.

Ken Alibek’s book "Biohazard" says that vaccine resistant anthrax strains are possible and were under development in the former USSR. Alibek was one of this report’s reviewers. Were his concerns omitted too, or did he forget what he wrote 3 years ago?

A legal problem for the vaccine manufacturer, but ignored by FDA in its rush to license a vaccine to protect us from DOD-developed weaponized anthrax, released by God Only Knows Whom, and God Only Knows Why (the federal government hasn’t a clue who grabbed its anthrax), is that there exist no human data to support efficacy of this vaccine for any form of anthrax in humans: not for cutaneous anthrax, not for inhalation.  And under the regulations in place in 1970 when the vaccine was licensed, and still in place today, you had to have that data to obtain a license.

Is there reasonable evidence of efficacy?  Not really.  The vaccine works in some animals, but not in others.  An older, never-licensed anthrax vaccine had partial efficacy.  Maybe this one does too, but the data to show this in humans do not exist.

SAFETY

4.  "Local events, especially redness, swelling, or nodules at the injection site...are similar to the events observed following receipt of other vaccines..."

True, but they happen at a much higher rate than with other vaccines. Why wasn't this mentioned in the Summary?

5.  "Systemic events, such as fever, malaise and myalgia, are similar to the events observed following receipt of other vaccines currently in use by adults, but are much less common than local events."

Several studies gave 70-80% rates of local reactions, and 48% rates of systemic reactions for anthrax vaccines.  Is 48% much less common than 70%?  Both these rates are higher than for other vaccines.

6. "There are sex differences in local reactions following vaccination with AVA..."

Here the report parrots a misstatement of the facts first made by DOD.  The available data show that females have higher rates of both local and systemic reactions than males, by a factor of 2-3.

Local reactions are considered minor, and invariably resolve.  But systemic reactions that occur after vaccination may be harbingers of chronic illnesses to come.  Therefore, DOD is unwilling to acknowledge what its own data show about systemic reactions, and in particular to admit the existence of a rate disparity between the sexes. Acknowledging the gender difference in systemic reactions could result in women being exempted from vaccination, something DOD very much wants to avoid. (Another case based on gender differences is also winding its way through the courts.)

7.  "The available data are limited but show no convincing evidence at this time that personnel who have received AVA have elevated risks of later-onset health events."

Every reference cited to support this statement was to a DOD briefer, with the exception of three citations to a series of papers looking at Fort Detrick personnel who each received many different vaccinations. The problem with these three papers (dated 1958, 1965 and 1974) is that the research was done on all of them prior to 1971. The anthrax vaccine was licensed in 1970; therefore, the anthrax vaccine received almost exclusively by these Detrick personnel was a different anthrax vaccine. 

The problem with using only DOD briefers should be obvious.

What did the report scrupulously avoid in order to draw the above conclusion?

a) Preliminary data from the Navy were provided to the IOM shortly before the report was completed. A Navy study had found higher rates of birth defects in the offspring of vaccinated, as opposed to non-vaccinated sailors. The IOM report emphasized the preliminary nature of these data and other limitations in the Navy database, and did not mention the study in its recommendations.

b) Five studies of Gulf War syndrome found a statistically significant association between anthrax vaccine, or multiple vaccines given for the Gulf deployment, and the development of Gulf War Syndrome. No studies exist that refute this association. These studies were done by five separate groups of researchers.

This is a major omission, especially since three of the five groups studied veterans who had received AVA, the identical vaccine being studied; the other two studies were of British veterans who received a different anthrax vaccine. The results were similar, however. How did the IOM report justify this oversight?

First, it claims that the Gulf War studies "were not designed to study the effects of vaccine exposure." That is nonsense. Then the report criticizes the fact that multiple vaccinations were given. But some of the studies did look at the multiple vaccination issue, and got positive results. This tells you that at least one of the vaccines is likely causing problems, or that multiple vaccinations interacted to cause illness. Finally, the report criticizes the need to rely on self-reports of vaccine exposure. But since DOD did not put the vaccinations into US soldiers’ shot records, all that researchers can do is use self-reports. That is, unless DOD decides to find the Gulf War vaccination records it conveniently lost ten years ago.

These pretexts do not justify junking this research, which has been published in top medical journals: The Lancet, American Journal of Epidemiology, and Occupational and Environmental Medicine.

Instead, the report says that unpublished DOD studies, in most cases done by young military scientists with little experience in epidemiology, and which were neither peer-reviewed nor published, were the "best available" sources of data on AVA and health outcomes.

The available data would not have been limited had IOM chosen to consider the Gulf War studies, done by seasoned and respected professionals. 

I gave each committee member a published anthrax vaccine study done at a military base in England in 2000. Of 100 soldiers who volunteered to take anthrax vaccine, 71% dropped out of the vaccine series before their fourth dose. The author was not sure why so many who accepted the initial dose refused later doses, but the initial adverse reaction rate was extremely high, and prevented 28% of recipients from lifting or driving for at least 48 hours following vaccination. This paper also got no mention in the report.

c) IOM refused to draw any conclusions from the VAERS data (VAERS is a voluntary adverse event reporting system overseen by FDA and CDC) or from the Anthrax Vaccine Expert Committee (AVEC), which was formed by DHHS at DOD’s request, to review every VAERS report on anthrax vaccine.  IOM pointed out that the VAERS data should be used to generate hypotheses about vaccine effects, which should then be tested using methods that have
statistical validity, which VAERS lacks.

However, VAERS has to be studied in order to generate hypotheses: that is its purpose.  FDA did this and put the information in the current anthrax vaccine's package insert.  IOM prefers to imply that no chronic symptoms reported to VAERS are due to the vaccine, whereas FDA properly noted that some symptoms are reported with sufficient frequency after vaccination to be included in the vaccine's label.

Refusing to consider the VAERS data is another example of how the IOM report overlooks evidence that might lead in the wrong direction.

New Manufacturing Process

8.  "AVA will now be produced by a newly validated manufacturing process under strict controls, according to current FDA requirements.  As a result, the post-renovation product has greater assurance of consistency than that produced at the time of original licensure."

If lack of consistency had been shown to be the reason AVA has not demonstrated safety or effectiveness, this would be good news.  Since that is not the case, we remain in the dark about the ‘newly licensed’ vaccine's safety and efficacy, and how it compares to the previously licensed vaccine.

Previously manufactured lots of AVA vary in the concentration of their components by a factor of 40 from lot to lot: some lots have 40 times as much active ingredient (PA) as others.

Last year, GAO informed Congress of filter changes at the vaccine manufacturer which led to a 100 fold increase (10,000 per cent increase) in the level of PA in anthrax vaccine. The series of filter changes began in 1990, but were not submitted to FDA for required approval. FDA only learned of these changes from GAO in 2000, and retroactively approved them several months later.

Somehow, the IOM report fails to mention the marked recent increase in vaccine potency, which might be an explanation for the higher reaction rates reported after 1990. Some newer lots may have 4,000 (40 x 100) times the potency of earlier lots.

This is a curious omission, since the current supply of vaccine is extremely limited. Anthrax vaccine might be effective at 1/100^th the dose, or perhaps be effective at even larger dilutions. The US is planning to dilute its existing inventory of 15 million doses of smallpox vaccine to 1/5^th its current strength: why not anthrax?

It would also be useful to learn whether the increases in PA and other vaccine components, which could now be 4,000 times greater than in lots of anthrax vaccine manufactured during the
1980s, affect vaccine safety and efficacy. 

The IOM report fails to suggest any investigation of whether the anthrax vaccine potency changes have affected safety, efficacy or the optimal dose, although there is a glaring need for research in these areas.

Surprising Gifts to DOD Found in the Report
 

9. "DOD should continue to support the efforts of CDC to study the reactogenicity and immunogenicity of an alternative route of AVA administration and of a reduced number of vaccine doses."

This is another nugget IOM threw to DOD, which wants a vaccine license amendment to permit deeper, intramuscular injections that will hide some of the local reactions.

10.  "The committee finds no scientific reason for the continued operation of AVEC in its present form.  The IOM committee's observations about AVEC reflect no fault with the members of AVEC or its performance as that committee is constituted; rather, the IOM committee observes that AVEC was designed to pay extra attention to safety concerns
regarding the safety of AVA and that the data do not warrant the continuation of such exceptional attention...

"DOD should disband AVEC in its current form and instead assist FDA and CDC in establishing an independent advisory committee charged with overseeing the entire process of evaluating vaccine safety."

 a) This recommendation was a big surprise.  Commenting on the continued existence of AVEC is way beyond what the IOM committee was charged to do.  Why did IOM overstep its guidelines to come up with this slap at AVEC?  Is it possible that AVEC began identifying problems with the vaccine?

AVEC gave a CDC group investigating anthrax vaccine a list of adverse reactions to look for in subjects receiving anthrax vaccine. Could its acknowledgement of adverse vaccine reactions have earned AVEC the coup de grace?

 b) Why did IOM ask DOD to assist FDA and CDC in the evaluation of vaccine safety? This recommendation has its origins in the twilight zone. Nothing in the committee charter could possibly be construed as inviting a recommendation like this one. Does the public want the Defense Department entering the civilian vaccine arena?

 DOD's ‘interest’ in vaccine safety has been demonstrated by the following:

1. giving experimental vaccines to military service members without informed consent or with inadequate information
    
2. storing vaccines for decades before use, and redating expired vaccines multiple times without proper testing
3. generating bad science to cover up the role of its vaccines and therapeutics in illnesses such
   as Gulf War Syndrome. 

Offering DOD a place at the vaccine safety table can only result in confounding the assessment of safety for civilian, as well as military, vaccines.

11.  "DOD personnel have used DMSS (Defense Medical Surveillance System) to conduct valuable analyses in response to concerns about health effects that might be associated with
vaccination with AVA...

"DOD should actively support and advance the development of DMSS data resources and staffing of units that will allow the continuing rapid and careful analysis of these data, including but not limited to the proposed collaboration between CDC and the Army Medical Surveillance Activity."

The DMSS database could have been a wonderful resource for studying an enormous variety of medical issues in active duty men and women.  It collects diagnostic data from every outpatient visit and hospitalization of each service member within military treatment facilities.  It does not capture data from the VA or non-military medical centers.

However, serious problems exist with DMSS, at least insofar as anthrax vaccine is concerned.

When three million person-years of non-anthrax-vaccinated service members were compared with 500,000 person-years of vaccinated service members, the results were unreal.  It turned out that if you had received any vaccine doses, you were only about 60% as likely to report a huge variety of medical problems than if you were never vaccinated. These results were highly statistically significant.

Since not even DOD can come up with a plausible explanation for these results, which imply that anthrax vaccine is the greatest health enhancer known to man, the results are due to either:

 a)  flawed statistical methodology

 b)  medical providers’ fears of documenting illnesses in recipients of this ‘safe’ vaccine, the centerpiece of military medicine’s biological warfare defense, or

 c)  vaccine recipients’ apprehension that symptoms ascribable to the vaccine may lead to forced medical retirement, so they avoid seeking help for illnesses, or seek help elsewhere.

This is the database the IOM report applauds.

On the other hand, the DMSS database does suggest that anthrax vaccine is associated with an increased risk of diabetes, breast cancer, asthma, Crohn’s Disease, thyroid cancer and multiple sclerosis. The IOM report acknowledged that these associations could be signals of a possible causal relationship, especially for diabetes, Crohn’s Disease and multiple sclerosis. These are all autoimmune disorders, which are the kinds of long-term reactions to a vaccine that might be predicted, since vaccines act as immune stimulants.

The report recommends "additional follow-up."

12.  "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."

So despite the fact that data on long-term effects are very limited, despite the concerns about the birth defect data and DMSS data on diabetes, multiple sclerosis and Crohn’s Disease, despite the refusals of further vaccine doses by many in the UK and US, and despite the five Gulf War Syndrome studies, the report specifically recommends against any special efforts in vaccine safety monitoring for AVA, and wants to shut down the one committee designated to perform this. So much for the concept of "additional follow-up."

Should we be surprised?  After all, at least three past expert panels that were formed to debate the illnesses appearing in Gulf War veterans, including one from the Institute of Medicine, gratuitously recommended against performing any research into the possible role of anthrax vaccine in Gulf War illnesses.

There is still only limited reliable information about the effects of dioxin (the most potent toxin in Agent Orange) in humans, thirty years after the US stopped using Agent Orange due to health concerns.

When have you previously seen scientists recommend against further research? Only in two cases: when an issue has been unquestionably resolved, or when someone is trying to hide something. Unfortunately, this report is a replay of a tawdry old tune. Esteemed expert panel meets to resolve complex scientific question. But read the report, and science is the one thing that’s missing. Instead, it’s politics (and coverup) as usual.

The book "Science, Money and Politics: Political Triumph and Ethical Erosion" by Daniel Greenberg recounts the history of lies and egregious behaviors by scientists that have eroded the values underpinning science in our society. Maybe one has to look no farther than to Greenberg to learn how reports like this one come to be.

IOM approval was what DOD had been waiting for, in order to restart the mandatory vaccination program, according to the vaccine manufacturer (March 7 NY Times, Sheryl Stolberg). With billions of dollars on the line for military biodefense vaccines, and the need to appear to be doing something meaningful about the bioterrorism threat, could this report possibly have produced any other conclusion?

If the government may be culpable for making its own soldiers sick, don’t hold your breath waiting for the government-sponsored science that will prove it.