AAPS Anthrax vaccine controversy

[Guest guest]

http://www.aapsonline.org/

The Anthrax Vaccine Controversy ---

Questions About Its Efficacy, Safety, and Strategy

Garth L. Nicolson, PhD, Meryl Nass, MD, L. Nicolson, PhD

ABSTRACT Although all U.S. Armed Forces personnel have been ordered to

receive the anthrax vaccine, questions remain concerning its efficacy and safety

and

its intended use to counter a biological weapons attack. Since published data

on the anthrax vaccine are scarce, it is difficult if not impossible to

evaluate claims of its effectiveness and safety. In addition, questions

concerning

its safety have been raised, based on reports that associate the anthrax

vaccine with high frequencies of adverse reactions and chronic illnesses. The

chronic signs and symptoms associated with anthrax vaccination are similar to

those

found in Gulf War Illness patients, suggesting that at least some of the

chronic illnesses suffered by veterans of the 1991 Gulf War may have been caused

by vaccines. Some commercial vaccines have been found to be contaminated with

microorganisms, such as Mycoplasma species, and this type of microbe has been

found in the blood of a sizable subset of Gulf War Illness patients along with

antibodies against an unlicensed vaccine adjuvant. Given concerns about safety

and efficacy of the military's vaccines, the strategy of using multiple

vaccines to protect against biological warfare agents must be re-evaluated in

the

context of integrated warfare and the potential simultaneous exposure of forces

to chemical, biological and radiological agents along with conventional

warfare environmental (smoke, chemicals, etc.) exposures.

Introduction --- Anthrax Biological Warfare

To counter an increasing threat that anthrax spores could be used as a

biological warfare (BW) agent all U.S. Armed Forces personnel, including reserve

and

National Guard members, were ordered to receive anthrax vaccine. This

decision has resulted in disciplinary hearings among U.S. Armed Forces personnel

who

have refused, based on safety considerations, the anthrax vaccine.(1) Although

rarely found in North America, Bacillus anthracis is a relatively common

spore-forming, infectious soil bacterium in some areas of the world, and

exposure

to a lethal dose can cause death within one week of exposure.(2,3)

Spore-forming bacteria like Bacillus anthracis fulfill the most important

criteria for a

BW agent --- their spores are highly infectious, very pathogenic and stable in

the air and environment for effective dissemination and infection by

inhalation. Spores are relatively inactive metabolically and are much more

resistant

to sunlight, heat, dryness and chemicals than the replicating microorganism and

are thus more effective as BW agents.(4)

Bacillus anthracis is one of dozens of lethal and incapacitating (causing

nonlethal sicknesses) agents that have been produced for BW,(3) and it is one of

the few BW agents for which a vaccine exists that is capable of preventing

some (but not all) lethal infections.(2,4) Although weaponized (with enhanced

survival and pathogenicity over naturally occurring strains) bacterial, viral,

fungal and toxin BW agents have been produced by several countries,(3) Bacillus

anthracis is considered one of the greatest threats because of the ease of its

production, storage and dissemination as airborne spores.(3,4)

Three methods exist to counter microbial BW: (1) administration of

antibiotics or antivirals, (2) passive immunization using immune sera or

monoclonal

antibodies and (3) active immunization using vaccines.(1,2,4) Antibiotics and

antivirals must be administered shortly before or after exposure to known BW

agents to be effective,(2) and in the case of anthrax BW, they cannot prevent a

lethal infection once signs of illness have appeared.(4) Passive

immunoprophylaxis requires quantities of immune sera or monoclonal antibodies

not currently

available,(2,4) and their administration must usually occur in a monitored,

hospital setting.(4) In contrast, active immunization can be effective if the

vaccines are administered in an appropriate sequence, some for up to 18 months

before exposure, and if immunity is maintained.(1,2) Thus vaccines can be

effective as long as enough immunity exists to neutralize BW agents like

Bacillus

anthracis before they start rapidly replicating en masse from the inactive spore

form and producing lethal toxins.(2) From a practical standpoint, only

antibiotics, antivirals, and vaccines can protect the large numbers of people

who

could be exposed in a BW attack. Antibiotics and antivirals are more effective

when the BW agents and their antibiotic/antiviral sensitivities are known so

that the appropriate drug(s) and dose(s) can be used. Similarly, active and

passive immunity require some immunochemical knowledge about the BW agent(s)

that

patients have been exposed to.(1,4)

Currently the method used to protect against BW, vaccines --- like the

anthrax vaccine --- may not be reliable. For example, although vaccines can

protect

against accidental exposure of relatively small doses of anthrax spores

infecting skin wounds, such as encountered occasionally in meat processing, it

remains unproven whether the anthrax vaccine will protect against a lethal

aerosol

dose of inhaled weaponized anthrax spores.(4-6) This problem may be compounded

if mixtures of BW agents are used instead of single agents.(1,3,4)

Safety Concerns - The Anthrax Vaccine

There are valid questions about the safety of the anthrax vaccine. It remains

unproven in its ability to stop a lethal dose of weaponized Bacillus

anthracis spores, and there are serious safety questions about the

vaccine.(1,4,7)

Although the anthrax vaccine used by the U.S. military was claimed to be safe,

and adverse reactions were originally said to occur at a rate of 1/10,000

doses,(8) the rate of chronic health problems after receiving the anthrax

vaccine

may be 7-10 percent or higher, based on reports from Dover Air Force Base. The

rate of acute adverse reactions has ranged from 30-70 percent.(9)

Assessing anthrax vaccine safety is dependent on how vaccine adverse effects

are reported.(4-10) Often individuals suffering from adverse anthrax vaccine

effects, especially in the military, are reluctant to seek medical care,

because they have seen their colleagues' concerns dismissed as due to depression

or

stress. There have also been losses in assignment duties because of

undiagnosed illnesses that began after receiving anthrax vaccinations.

Officially the

anthrax vaccine can produce adverse effects, such as soreness, redness, itching,

swelling, and lumps at the injection site, but these are claimed to last only

a short time.(11) Recently Department of Defense (DoD) spokespersons have

admitted that from 5-35 percent of vaccinees report muscle aches, joint aches,

headaches, rash, chills, fever, nausea, loss of appetite, malaise, or related

symptoms shortly after vaccination. More importantly, there have been no

completed studies of the long-term side effects of anthrax vaccine using active

surveillance.(1,9)

There is great variation between official DoD spokespersons and affected

service members regarding the likelihood of chronic illness following receipt of

the anthrax vaccine. The DoD claims that chronic adverse effects are

negligible.(1) However, after receiving the anthrax vaccine Armed Forces

personnel

report polyarthralgias, polymyalgias, cognitive problems, weakness and numbness,

fever, vomiting, diarrhea, splenic tenderness, among others, and these problems

can occur well after the usual reporting period. Patients with preexisting

autoimmune illnesses such as rheumatoid arthritis, lupus, multiple sclerosis and

other conditions, appear to be more likely to suffer a serious adverse

reaction, as are those with neurologic diseases, such as childhood illness

caused by

polio or other viral infections. Some anthrax vaccine recipients report

seizures, loss of consciousness, respiratory distress and other pulmonary

illnesses.

Few of those reporting illness have been subjected to an intensive medical

evaluation, including immunological testing, and thus the mechanisms by which

anthrax vaccine may be causing chronic signs and symptoms have not been

elucidated. The entire supply of anthrax vaccine is owned by the DoD, and it has

not

been made available for independent testing.(1)

Source of the Anthrax Vaccine

Obtaining specific information on the anthrax vaccine and its safety has

proven elusive. Most U.S. military vaccines are FDA-approved and from

sole-source

manufacturers that must fulfill strict production, efficacy and safety

requirements. However, the anthrax vaccine apparently has not met these

requirements.(4) The sole licensee and producer of the anthrax vaccine was

originally

state-owned Michigan Biologic Products, Inc. (MBPI), who obtained approval for

the

vaccine from the NIH Bureau of Biologics in 1970, two years before efficacy

data were required for licensing by the FDA. Long-term safety data were not

supplied with the license application, and evidently none have since been

supplied

to the FDA.(4) Moreover, the vaccine preparation procedures may be different

from the original approved vaccine, and this usually requires that the vaccine

and its altered preparation procedures be re-approved. The FDA has apparently

not examined or approved all modifications made to the current anthrax

vaccine.(1)

The new owner of the anthrax vaccine license is Bioport, Inc., led by Admiral

Crowe, Jr., former head of the Joint Chiefs of Staff, DoD, and Faud

El-Hibri, a German citizen (now naturalized American) of Lebanese descent. The

facility was sold to Bioport after the DoD decided to vaccinate all of its

forces against anthrax.1 Recently Bioport ran into financial problems and

negotiated changes in its DoD contract that increased by three-fold the per dose

price of the anthrax vaccine.(12) The financial relationship between DoD and the

new owners of Bioport has been questioned.(1)

The FDA and Anthrax Vaccine Safety

Problems with the anthrax vaccine have raised questions about previous

military vaccine programs. Unlicensed anthrax vaccines were used on DoD

personnel

before the Gulf War,(13) but there is, of course, no established record of

safety available for unlicensed vaccines. Even for the licensed anthrax vaccine

there are no published studies of safety or efficacy in humans. Although some

safety information about the anthrax vaccine has been recently published, the

paper refers to previously unpublished data that are not available for

evaluation.(14)

The FDA reviews adverse reactions from approved vaccines through the Vaccine

Adverse Event Reporting System (VAERS). Adverse events are usually recorded

independently by an FDA-approved contractor, which then sends its data to the

FDA, whereupon the FDA assembles a committee that evaluates adverse events for

the likelihood that the vaccine might have caused them. It can then recommend

further studies.(10) However, in the case of the DoD's anthrax vaccine,

military physicians were instructed that only certain adverse effects could be

vaccine-related (classic allergic reactions), and others, such as

polyarthralgias,

polymyalgias, cognitive disturbances, etc. were not vaccine-related.

Unfortunately, physicians treating these patients had no access to published

data on

anthrax vaccine adverse effects. The package insert for the vaccine is based on

data collected from an earlier anthrax vaccine, and it does not list the

possible reactions that could occur.(2,11) None of the vaccine's long-term

chronic

effects were reported until recently. Only reactions that resulted in

hospitalization or immediate loss of 24-hour duty time were reported to a

military

clearing-house for vaccine reactions.(15) This has now been changed, and it

appears adverse vaccine effects should now be reported to the military's vaccine

program, but it remains questionable whether they will always be reported to the

FDA. Traditional and accepted means of FDA vaccine evaluation must be

implemented for the DoD's vaccines, just as they are required for commercial

vaccines.(4) The anthrax vaccine must be treated like other commercial vaccines

and not

given special waivers or treatment in the evaluation process.(1)

Quality of the Anthrax Vaccine

For years the FDA warned MBPI of intent to revoke its license to produce

vaccines because of " good manufacturing practice " (GMP) violations in vaccine

production and testing. MBPI received formal written notification they had not

complied with FDA-mandated requirements, but since MBPI was the only

manufacturer

of anthrax vaccine, they were allowed to remain open, pending FDA compliance.

However, vaccine lots continued to be distributed to the DoD, and in 1998

some of these vaccine lots were retested, and only 6/31 lots passed initial

supplemental testing.(8) Most of the retested vaccine lots had expired and had

been

redated for an additional 3-year period once or even twice.(16) Lot release

criteria require that every lot must be tested, but these tests may not be

comprehensive enough to find potential contaminants and other problems.

Were expired or failed vaccine lots used for vaccinating DoD personnel during

the Gulf War? Since supplemental testing on anthrax vaccines used in the Gulf

War was not undertaken, and some of these lots apparently had previously

expired and had been redated, some DoD personnel could have received out-of-date

and/or contaminated vaccines. Thus some of the health problems associated with

the Gulf War could be related to possible vaccine contamination.(1)

Vaccines and Operation Desert Shield/Storm

Before military personnel were deployed to Desert Shield/Storm, they had to

pass physical examinations and be fit for active duty. Those who passed

received several vaccinations, mostly with commercial vaccines. In the Persian

Gulf

theater this was usually done by administering as many as two dozen vaccine

doses within a few days,(17) even if they were normally required to be given

over

a course of several months to over a year. In contrast to previous wars, DoD

personnel were not allowed to keep a record of some of these vaccinations, and

the shot records of hundreds of thousands of deployed personnel have since

disappeared. Although some soldiers became sick after receiving the vaccines,

medical personnel were not always allowed to report vaccine adverse effects,

unless hospitalization occurred. Most personnel had to return to active duty,

even if they suffered adverse effects directly attributable to the vaccines.(1)

The administration of multiple vaccines all at once can result in

immune-suppression and susceptibility to opportunistic infections.(17) To be

effective,

the vaccines used in the Gulf War should have been given in several steps, over

months to over a year to maximize immunity. Since this could not be done,

they were given within a short time period. If given all at once, these vaccines

are more likely to cause adverse reactions and may produce diminished

immunity.(1)

Vaccines and Gulf War Illnesses

Gulf War Illnesses (GWI) are characterized by complex, multi-organ chronic

signs and symptoms, including chronic fatigue, headaches cognitive problems,

nausea, gastrointestinal problems, vomiting, diarrhea, polyarthralgias, fever,

splenic tenderness, polymyalgias, among other signs and symptoms.(19,20) Often

these patients show the appearance of rheumatic and other autoimmune signs and

symptoms. The signs and symptoms of GWI closely overlap with Chronic Fatigue

Syndrome (CFS) or Myalgic Encephalomyelitis (ME),(18,19) and often they meet

the criteria for diagnosis of CFS/ME or a related syndrome, Fibromyalgia

Syndrome (FMS). Often included in this complex clinical picture are increased

sensitivities to various environmental agents and enhanced allergic

responses.(19)

There are other clinical problems in these patients, including impaired cardiac

function, increases in spontaneous abortions and other chronic signs.

Importantly, the signs and symptoms reported by many anthrax vaccine recipients

strongly overlap with those that characterize GWI.(1,8)

In some cases GWI has apparently spread to immediate family members,

suggesting an infectious nature. Although incomplete, a U.S. Senate committee

found

that approximately 77 percent of spouses and 65 percent of children born after

the war developed the chronic signs and symptoms of GWI,(20) indicating that at

least a subset of GWI patients have an illness that is being transmitted to

spouses and children. These GWI cases cannot be explained solely on the basis

of chemical or radiological exposures, or battlefield stress leading to Post

Traumatic Stress Disorder.(19) Although stress can induce some illness, the link

between stress and GWI has not been established.(21) Of course, stress can

exacerbate chronic illness, and in the absence of physical or laboratory tests

that could identify possible origins of GWI, many physicians accepted that

stress was the cause of GWI or that it was caused by combinations of chemical

exposure and stress. However, a recent psychiatric study indicates that patients

with GWI do not fit the classical picture of a stress-related illness.(22)

If stress, chemical, biological and other toxic exposures are added to

multiple vaccines given at once, then immune suppression and opportunistic

infections could be a likely outcome in at least a subset of GWI patients.

Infection(s)

would also explain in some cases the apparent transmission of illness to

immediate family members and the occurrence of GWI in some vaccinated forces

that

were not deployed.(1)

Vaccine Contamination and Gulf War Illnesses

Contamination can and does occur in commercial vaccines.(23) Common

commercial vaccine contaminants are Mycoplasma species, small cell

wall-deficient

bacteria lacking many of the genes involved in macromolecular and lipid

synthesis.

Mycoplasmas have now been implicated in a variety of chronic illnesses,

including CFS/ME, FMS, Rheumatoid Arthritis, GWI, respiratory diseases, among

others.(24) When we examined GWI patients for blood mycoplasmal infections, we

found

them in about one-half of GWI cases. One species in particular, Mycoplasma

fermentans, was found at high incidence.(25,26) M. fermentans has been examined

for its role in causing a progressive, non-HIV AIDS-like fatal disease that

has many of the hallmarks of GWI.(27) In addition, the presence of antibodies to

an unlicensed vaccine adjuvant in over 90 percent of the GWI patients

evaluated suggests that experimental vaccines may have been used in the Gulf

War.(28)

Microorganisms like M. fermentans in commercial and experimental vaccines

could be involved in the transmission of GWI to immediate family members. When

tested for the presence of mycoplasmal infections in their blood, sick family

members were found to have the same species of mycoplasma as found in the

related veteran. In addition, most of these patients responded to the

appropriate

antibiotics and eventually recovered from their illness, albeit slowly, similar

to CFS/ME, FMS and Rheumatoid Arthritis patients with mycoplasmal infections.

When recovered patients were retested for mycoplasmal blood infections, they

were no longer positive, suggesting that mycoplasmal infections could be

causing at least some, if not most, of the signs and symptoms of GWI.(26)

Were the vaccines used in the Gulf War the source of the mycoplasmas found in

veterans' blood? Although listed as our number one possible source of the

chronic infections found in GWI patients, vaccines were not the only possible

source.(17) The Iraqis were known to have extensive stockpiles of BW agents and

the potential to deliver these weapons offensively, at short range in modified

Italian-made biological sprayers and at long range in modified SCUD-B (SS-1)

missiles with 'airburst' warheads or sprayers carried by aircraft. Many of the

storage and factory facilities where BW agents were stored were destroyed

immediately up to, during and after the Desert Storm ground offensive, releasing

plumes that could have caused 'blow-back' exposures.(17) These and other

possible mechanisms of potential exposure must be carefully examined.

Protection Against BW Attacks

If BW agents are ever deployed in modern war or terrorist attacks, many times

the lethal (human) dose could be encountered in an aerosolized BW-chemical

mixture (Russian Doll Cocktails) designed to inhibit and overwhelm the body's

defensive abilities. The pulmonary immune system, particularly the pulmonary

macrophage, is one of the first levels of defense against inhaled foreign

microorganisms and its suppression could result in systemic infection. Future BW

use

will likely involve multiple BW agents and chemical mixtures to heighten

virulence and confuse the diagnosis and treatment of casualties.(17) BW can be

developed and produced at a fraction of the cost of other weapons of mass

destruction, making it likely future terrorists will choose BW agents over other

weapons.

The DoD's defensive strategy against BW agents is prior immunization using

multiple vaccines. This can only be successful if the exact agent(s) likely to

be encountered is known in great detail and for some time in advance of

exposure. Obviously, this strategy requires advance knowledge of the threat and

careful long-term preparation. To prepare for new threats that arise requires

time:

years or decades. Recent reports indicate the Russians have developed anthrax

strains for which it is claimed protective vaccines do not exist.(6) This

poses a problem for our vaccines if they will not protect against all known

anthrax strains.(4)

Strategies other than the vaccine approach to BW defense exist and have been

used successfully. During the Gulf War the French forces did not use vaccines

as a primary defense against Iraqi BW and did not use anti-nerve agents as a

defense against Iraqi Chemical Warfare agents. Instead, they used prophylactic

antibiotics to counter BW agents, and they depended on protective suits to

counter chemicals. The French Armed Forces were the only nation in the Coalition

Forces that did not report any cases of GWI. Interestingly, certain U.S. units

were issued antibiotics like ciprofloxacin and doxycycline, and these

antibiotics would be expected to be effective in preventing infections of at

least

two of the agents identified in veterans with Gulf War Illness (Mycoplasma

fermentans and Brucella spp.). Examination of deployments and types of

casualties

in the units administered antibiotics before and during the Gulf War could tell

us if this approach was more effective than administering multiple vaccines

to prevent BW casualties.(17)

If prophylactic antibiotic or antiviral agents are used for BW defense, can

these be defeated? Certainly BW agents can be modified or constructed that

possess antibiotic- or antiviral-resistance genes. Similar to the engineering of

more lethal BW agents to circumvent known vaccines, such microorganisms can be

engineered to resist specific antibiotic or antiviral agents.(1)

Vaccines and Disease

What assurances do we have that future vaccines will be free of microbial

contamination that could cause disease? The purity and safety of vaccines depend

on their ability to remain free of contamination by microorganisms.(23) Unless

each lot of vaccine is routinely tested for possible contamination, including

animal testing, there remains a possibility that vaccines could be

contaminated with viruses or slow-growing microorganisms that promote chronic

illnesses

in humans.

References

1. Nicolson GL, Nass M, Nicolson NL. Antimicrob. Infect. Dis. Newsl.,

2000;18: in press.

2. Brachman PS, Friedlander AM. In: Plotkin SA and Mortimer EA (eds),

Vaccines, 2nd Ed., WB Saunders, 1994, Philadephia, PA, 729-740.

3. Geissler E. Biological and Toxin Weapons Today. Oxford University Press,

1986, Oxford.

4. Nass M. Inf. Dis. Clin. North Amer. 1999;13:187-208.

5. Brachman PS, Gold H, Plotkin SA, et al. Am. J. Pub. Health.

1962;52:632-645.

6. Pomerantnsev AP, Startsin NA, Mockov YV, et al. Vaccine 1997;15:1846-1850.

7. Nass M. Def. Systems Intern. 1998; 37-39.

8. U.S. Congress, House Committee on Government Reform, Subcommittee on

National Security, Veterans Affairs and International Relations, Testimony of

Meryl

Nass, MD, April 29, 1999 (available at

http://www.house.gov/reform/ns/hearings/testimony/nass2.htm).

9. U.S. General Accounting Office, Medical readiness: Safety and efficacy of

the anthrax vaccine, Report GAO/NSIAD-99-148, 1999.

10. Ellenberg S, Chen R. Pub. Health Rep. 1997;112:10-20.

11. Anthrax Vaccine Package Insert (available at

http://www.Bioportcorp.com/anthraxIns.htm).

12. U.S. General Accounting Office, Observations on DoD's financial

relationship with the anthrax vaccine manufacturer, Report GAO/NSIAD-99-214,

1999.

13. Takefuji ET, PK. Inf. Dis. Clin. North Amer. 1990;4:156-170.

14. Friedlander AM, Pittman PR, GW. JAMA 1999;282:2104-2106.

15. Anthrax Vaccine Implementation Plan, Secretary of the U.S. Navy, Annex C,

p. 5 (available at http://www.neds.nebt.daps.mil/Directives/6230_4.pdf).

16. FDA Inspection Reports: MBPI, February 1998; Bioport, November 1999

(available at htpp://www.anthraxvaccine.org).

17. Nicolson GL, Nicolson NL. Med. Confl. Surviv. 1998;14:156-165.

18. Nicolson GL, Nicolson NL. J. Occup. Environ. Med. 1996;38:14-16.

19. Nicolson GL, Nasralla M, Haier J, Nicolson NL. In: War and Health, H.

Tapanainen, ed., Zed Press, Helinsiki, 2000; in press.

20. U.S. Congress, Senate Committee on Banking, Housing and Urban Affairs, U.

S. chemical and biological warfare-related dual use exports to Iraq and their

possible impact on the health consequences of the Persian Gulf War, 103rd

Congress, 2nd Session, Report May 25, 1994.

21. U.S. General Accounting Office, Gulf War Illnesses: improved monitoring

of clinical progress and reexamination of research emphasis are needed. Report

GAO/NSIAD-97-163, 1997.

22. Lange G, Tiersky L, DeLuca J, et al. Psychiat. Res. 1999;89:39-48.

23. Thornton D. Vaccine 1986;4:237-240.

24. Nicolson GL, Nasralla MY, Haier J, et al. Med. Sentinal 1999;4:172-176.

25. Nicolson GL, Nicolson NL. Int. J. Occup. Med. Immunol. Tox. 1996;5:69-78.

26. Nicolson GL, Nasralla M, Nicolson NL. Intern. J. Med. 1998;1:72-90.

27. Lo S-C, Wear DJ, Shih W-K, et al. Clin. Infect. Dis 1993;17(Suppl.

1):S283-S288.

28. Asa PB, Cao Y, Garry RF. Exp. Mol. Pathol. 2000;68:55-64.

Prof. Garth L. Nicolson and Dr. L. Nicolson are affiliated with The

Institute for Molecular Medicine in Huntington Beach, CA. Website:

www.immed.org;

Email: gnicimm@.... Dr. Meryl Nass is affiliated with Parkview

Hospital, Brunswick, ME. Email: mnass@....

Originally published in the Medical Sentinel 2000;5(3):92-95. Copyright ©2000

Association of American Physicians and Surgeons.