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In a message dated 02/09/2000 6:55:25 PM Eastern Standard Time,
gnicimm@ix.netcom.com writes:
<< Subj: Recent Publications on Anthrax
Vaccine
Date: 02/09/2000 6:55:25 PM Eastern Standard Time
From: gnicimm@ix.netcom.com (Prof. Garth L. Nicolson)
To: VetCenter@aol.com
The Medical Sentinel 2000
The Anthrax Vaccine Controversy
Questions about its Efficacy, Safety and Strategy
Garth L. Nicolson,1* Meryl Nass2 and Nancy L. Nicolson1
1 The Institute for Molecular Medicine, Huntington Beach, CA 92649 and
2 Parkview Hospital, Brunswick, ME 04011
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 F3their 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
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
Although currently the method of choice to protect against BW, vaccines like the anthrax vaccine may not be a reliable method of protection. 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% or higher, based on reports from Dover Air Force Base. The rate of acute adverse reactions has ranged from 30-70%.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% 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 servicemembers 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., lead by Admiral William 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 have 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 establishedrecord 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 a 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 EDs 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 EDs long-term chronic effects were reported until recently.
Only reactions that resulted in hospitalization or immediate loss of 24 h duty time were reported to a military clearing-house for vaccine reactions.15 This has now been changed, and it appears that adverse vaccine effects will be entered in patients’ medical records, 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 EDs 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 EBgood manufacturing practice ED (GMP) violations
in vaccine production and testing. MBPI received formal written notification
that 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 or 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 that 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 sydnrome, 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 ~77% of spouses and ~65% 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% 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 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 that future terrorists will choose BW agents over other weapons.
The DoD EDs 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 that 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.
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 EDs financial
relationship with the anthrax vaccine manufacturer, Report GAO/NSIAD-99-214,
1999.
13. Takefuji ET, Russell PK. Inf. Dis. Clin. North Amer. 1990;4:156-170.
14. Friedlander AM, Pittman PR, Parker 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.
*Correspondence: Prof. Garth L. Nicolson and Dr. Nancy L. Nicolson are affiliated with The Institute for Molecular Medicine, 15162 Triton Lane, Huntington Beach, CA 92649; Tel: (714) 903-2900; Fax: (714) 379-2082; Website: www.immed.org; Email: gnicimm@ix.netcom.com.
Dr. Meryl Nass is affiliated with Parkview Hospital, 331 Main Street,
Brunswick, ME 04011; Tel: (207) 865-7000; Fax (207) 865-6975; Website:
www. anthraxvaccine.org; Email: mnass@anthraxvaccine.org
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