Subject: The Possible Role Of Vaccine Adjuvants In Persian Gulf War Veterans' Illnesses
An immunologist, with experience in the fields of epidemiology, toxicology, immunopathology and general pathology, who is currently working in the area of rheumatology and silicone-gel breast implants, presented the theory of "human adjuvant disease" and its possible link to Persian Gulf War Veterans' Illnesses. The immunologist follows approximately 500 women with breast augmentation implants. This patient population shows signs and symptoms of atypical connective tissue disease (an autoimmune disease), with symptoms very similar to those seen in patients suffering from Persian Gulf War (PGW) Veterans' Illnesses. The primary hypothesis is that silicone adjuvant (an agent added to a vaccine to increase antigenic response) is responsible for PGW veterans' developing "human adjuvant disease" or HAD. HAD is described as a chronic illness resulting from the introduction or implantation of a foreign material into the body. HAD has been linked to prosthetic implants but not to vaccine adjuvants. There are similarities between the symptoms associated with HAD and PGW Veterans' Illnesses, however the development of HAD symptoms generally requires years to occur.
The FDA restricts vaccine adjuvant use in the United States to various aluminum salts (alum, aluminum phosphate, aluminum potassium sulfate and aluminum hydroxide), not silicone. These aluminum salts act to form a "depot", or a deposit of vaccine in the muscle tissue, which slowly releases/exposes immunogenic material to the general circulation. In the theory proposed, the immunologist cites the experimental and early developmental uses of silicone-based gels as vaccine adjuvants in the 1960s. The side effects of silicone-based gels resulted in their removal from use as a vaccine adjuvant in the United States. Aluminum adjuvants used today were present in three of the vaccines administered to U.S. troops (anthrax, Botulinum toxoid and the diphtheria & tetanus toxoids (DT)). This data was verified through literature sources and the United States Army Medical Research and Material Command (USAMRMC). Billions of DT doses administered world-wide have only resulted in some adverse reactions at the injection site without any autoimmune reactions. Therefore, there is no evidence supporting the relationship between aluminum salt adjuvants and the development of HAD. The possible relationship between silicone-based breast implants and autoimmune disorders is totally unrelated to the use of aluminum vaccine adjuvants.
The report produced by this immunologist was forwarded for review and evaluation by USAMRMC, as well as to an independent non-government recognized expert immunologist. The Investigation Team, USAMRMC and the independent expert's findings conclude that the theory of Persian Gulf War Veterans' Illnesses relationship to human adjuvant disease is generally unfounded.
Included with this overview is the USAMRMC review. Appendix A to the USAMRMC review is the analysis completed by the independent non-government recognized expert immunologist.
(1) Immunofacts, Facts and Comparisons, 1993: 34, 52, 93, 112a, 115, 135, 487b, 494
(2) Medical Toxicology, Diagnosis and Treatment of Human Poisoning, Ellenhorn & Barceloux, Elsevier, 1988: 1009-1010
(3) Adjuvants - a balance between toxicity and adjuvanticity, Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efrain S, Gupta CK, Vaccine, Vol 11, Issue 3, 1993: 293-306
(4) Multiple antibodies in patients with silicone breast implants, Bar-Meir E, Teuber SS, Lin HC, Alosacie I, Goddard G, Terybery J, Barka N, Shen B, Peter JB, Blank M, et al., Journal of Immunology 8(2):267-77. Apr 1995
(5) Immunotoxicity of silicone: implications of oxidant balance towards adjuvant activity, Yoshida SH, Teuber SS, German JB, Gershwin ME, Food and Chemical Toxicology 32(11):1089-1100. Nov 1994
(6) Silicon and silicone: theoretical and clinical implications of breast implants, Yoshida SH, Chang CC, Teuber SS, Gershwin ME, Regulatory Toxicology and Pharmacology 17(1):3-18. Feb 1993
(7) Silicone-Induced Human Adjuvant Disease?, Baldwin CM and Kaplan EN, Annals of Plastic Surgery 10 (4): 270-273. Apr 1983
(8) The American Heritage Dictionary, Second College Edition, Houghton Mifflin Company, Boston, 1982
13 October 1995
by (the author)
SYNOPSIS OF HYPOTHESIS PROPOSED
Overall the report on Gulf War Syndrome (GWS) written by (the author) lacks focus and fails to provide a viable hypothesis based on fact and not supposition. The central recurring theme in (the author's) report is that organosilicon, and a variety of other organic compounds have been implicated in the induction of atypical connective tissue disease, in particular, after these agents have been implanted into humans (primarily, for breast augmentation). This ill-defined disorder has been referred to as "human adjuvant disease" (HAD)1. There is no specific diagnosis for HAD, per se, and this term is typically used by the medical community in a descriptive sense and not as a specific disease. HAD is in essence a form of systemic response generated by the body to an implanted foreign substance, i.e., a "foreign body response."
(The author) argues that the rapid deployment of personnel to the Gulf resulted in these individuals receiving a large number of vaccines in a short period of time. Since these vaccines contain adjuvant, they may have induced HAD. (The author) also infers that some of the vaccines given to personnel deployed to the Gulf contained experimental adjuvants; some may have been rapidly produced or contaminated foreign vaccines, or vaccines (in particular, botulinum toxoid vaccine) of unknown safety. (The author) suggests that the adjuvant or the vaccines may have induced a HAD-like disorder. (The author's) report also contains many peripheral issues to the primary topic. A complete review of all the literature in all of these areas would require a search encompassing hundreds of publications. This report will focus on the basic hypothesis - Gulf War Syndrome is "human adjuvant disease."
HUMAN ADJUVANT DISEASE
HAD was first "defined" in 1964 by Miyoshi et al.1 He described the development of a disease in two patients resembling adjuvant arthritis induced in rats, months or years after they had received breast augmentation using paraffin injection. It was postulated that the injected material was responsible for the pathogenesis of the disorder and, of significance, the signs and symptoms were relieved after mastectomy. The central feature of HAD is that autoimmune disease is induced as a result of the presence of a foreign material in the body. Examples of materials attributed to induce such reactions are silicone-gel implants, vinyl chloride, and oleoanilides (contaminant that caused the toxic Spanish Oil syndrome). Most cases of HAD would exhibit the following characteristics based on the initial description of the diseases:
1. Foreign material or materials in the body at some time prior to the development of the autoimmune disease.
2. Local reaction to the implanted material with any one or all of the following: encapsulation, pain, tenderness, heat, swelling or redness.
3. Some signs or symptoms generally associated with known autoimmune conditions to include, but not necessarily restricted to aches and pains in muscles and joints, stiffness, weakness, memory loss for recent events, and fatigue.
4. Clinical detection of at least one autoantibody after introduction of foreign material.
5. No other condition or disease that would explain the patient's condition, including infection, malignancy, or naturally occurring autoimmune disease. Exclusion of typical disease is important as HAD usually produces atypical autoirnmune disease.
6. Evidence is found for local immunological activation. This can range from foreign body giant cells to simple chronic inflammation with phagocytic cells marginated on or near the foreign material together with some lymphocytes or plasma cells.
7. Improvement following explanation of the foreign material when most or all of it is removed. In general, significant laboratory and clinical improvement is seen within 2 years.
It must be pointed out that most physicians have not accepted HAD as a true disease, and the term is generally discredited, though still used by some (Appendix A, Scientific Review). However, it has found an increased usage recently as the result of current breast implant litigation. The defining criteria for HAD, like the criteria for rheumatic disease in general, are empiric. Symptomatology develops with different time courses depending on the foreign material. For example, the average time for the development of the first systemic symptoms after silicone-gel implantation is about 6 years.
The primary difference between HAD patients and other patients is the presence of a foreign material in their body. At least 20 generic complaints are commonly found in these patients. Most patients indicate the presence of at least 50% of these complaints when questioned. The diversity of symptoms in these patients may result from a systemic immunological activation that affects many organ systems. It has not been demonstrated in controlled clinical testing what the underlying mechanism is in HAD. At least eight of these complaints overlap those commonly associated with GWS. It is the similarity between breast implant patient's (HAD?) symptomatology and GWS that has struck (the author).
At present the cause and effect association between silicone-gel implants and the variety of autoimmune findings in implant patients has not been established (Appendix A). For the most part, there are many anecdotal reports of a temporal association between implantation and the occurrence of clinical and laboratory findings of immunological disorders. The breast implant controversy has led to several retrospective studies on the association between breast implants and a variety of autoimmune and connective tissue diseases thought to be of autoimmune origin. Thirteen studies have so far shown no increased risk of developing these types of diseases in silicone gel breast implant individuals compared to populations without implants. Silicone, a very common compound in the environment, is found in prepared foods, medical equipment, lubricants and many other places. It has been estimated that diabetics, using silicone-treated syringes, inject more silicone over several years than is thought to leak from intact implants. At the present time, it is too early to draw any firm conclusions as to what role silicones may play in inducing the symptomatology associated with HAD in implant patients.
VACCINES AND ADJUVANT USED DURING GULF WAR DEPLOYMENT
Table 1 lists all vaccines that are currently given to military personnel on a regular basis.
Table 1. Standard Vaccines for U.S. Military Personnel
Immunizing Agent - Scheduled - Recommended for Deployment (Manufacturer) Recipients during OD Shield/Storm Adenovirus - All recruits - No (WyethAyerst) (includes reserves) Cholera - Only when required by - No (WyethAyerst) host country Hepatitis B - Only to health care - Health care workers only, (Merck & Co.) workers booster or as needed Influenza - All active duty - Current year strain (WyethAyerst and personnel Connaught Labs) Measles - All recruits - No; booster not required (Merck & Co.) Meningococcus - All recruits - Yes, required by Saudi (Connaught Labs) Arabia for troops in their country. Not required for Navy personnel. Mumps - All recruits - No; booster not required (Merck & Co.) Plague - Alert and Special - Booster for Alert and (Miles Forces Special Forces only, as Biologicals) needed. Polio - All active duty - Only if booster not received (Lederle Labs) personnel as an adult Rabies - Special Forces only - No (Pasteur Merieux, dist. by Connaught Labs) Rubella - All recruits - No; booster not required (Merck & Co.) Tetanusdiphtheria - All active duty - 10-year booster, if required (Connaught Labs, personnel Lederle Labs and WyethAyerst) Typhoid Vaccine, - Alert Forces and when - Yes, for all deployed troops Injectable deployed to high risk (WyethAyerst) areas Yellow fever - Alert and Special - Not by Army. (Connaught Labs) Forces, Booster if required for all Navy and Marine Alert and Special Forces and Forces Navy/Marines
During deployment to the Gulf, all personnel are assumed to have received in the past the basic immunization series during basic/advanced training, i.e., adenovirus, measles, meningococcus, mumps, polio, rubella, diphtheria/tetanus toxoid (DT) and influenza (annual). Saudi Arabia also required that troops in that country be current with meningococcus immunization (Naval personnel for the most part were exempt from this requirement). An additional vaccine beyond the standard series received during basic training and required for deployment to the Gulf was typhoid. Many active duty personnel would have received the typhoid vaccine while serving on routine overseas duty prior to the Gulf War. There were estimates of 5% to 50% of personnel among the services, including the reserves, who required either a typhoid booster or the initial 2-dose series. Hepatitis A vaccine was not approved by the FDA at the time of the Gulf War and was not given to military personnel. The Navy, Marines and Coast Guard also routinely immunize for yellow fever. Special Forces components and Alert Forces routinely receive plague, rabies (Special Forces), typhoid (Alert Forces) and yellow fever vaccines. Boosters for plague, DT, typhoid and yellow fever were given as required to those troops previously immunized with these vaccines (e.g., all troops are kept current for DT and Special Forces and Alert Forces for the additional vaccines they receive).
All of the standard vaccines used by the military are licensed by the FDA for safety and efficacy, and most have been in use for many years, e.g., the DT and typhoid vaccines. Just before the Gulf ground war started, 150,000 troops received one or two doses of the licensed anthrax vaccine. Another 8,000 service members, components of the U.S. Marine Corps, First Marine Division, and US. Army VII Corps received at least one injection of the Botulinum toxoid (BotTox) vaccine. The BotTox vaccine was used as an investigational new drug (IND) product and reviewed by the FDA. It has been tested for safety and immunogenicity in over 3,000 people; however, it has not yet been licensed. The IOM report indicates that no forces received both anthrax and BotTox. Both of these vaccines have been used worldwide for the protection of military, public health, and industrial laboratory personnel for many years. The anthrax vaccine is also used to protect workers in some animal product trades. No evidence has been found of chronic, adverse effects of either of these vaccines that resembles the symptomatology of Gulf War veterans. The epidemiology of GWS has been examined in regard to the anthrax/BotTox vaccinated cohorts and no correlation was found.
ADJUVANTS USED DURING ODS/S
Alum (includes both aluminum hydroxide and phosphate forms) is the only FDA licensed adjuvant and the only adjuvant incorporated into vaccines used by the military. Of those vaccines that may have been given to deployed personnel, the anthrax, BotTox, and DT vaccines contain alum. Hepatitis B vaccine also contains alum, but its use was primarily restricted to health care personnel. It must be pointed out that the only vaccine required for deployment beyond the standard vaccines received by all active duty personnel was the typhoid vaccine, and it does not contain adjuvant. In addition to typhoid, 150,000 troops received the anthrax vaccine and 8,000 received at least one dose of the BotTox vaccine. A small number of personnel may have also required a 10-year DT booster. Therefore, for the majority of personnel deployed to the GW, the alum-adjuvant load was small, if any.
Alum containing vaccines (e.g., DT) have been used in millions of people with no known longterm effects. Typically, many vaccines will cause shortterm reactions such as mild local inflammation, pain, or systemic symptoms such as malaise or fever. These typically last 1 or 2 days. The anthrax and BotTox vaccines likewise produced similar relatively mild, though somewhat stronger reactions than many other. No reports of chronic soreness or inflammation associated with vaccination sites by military personnel have been reported by either of the three Gulf War Task Forces. It should be pointed out that chronic inflammation at the site of alum deposition would be a requisite to meet the working definition of HAD.
It is important to note that no experimental adjuvants were used in any vaccine given during deployment, in particular, the MF59 adjuvant discussed by (the author)
RECOMMENDATIONS OF THE IOM REGARDING FURTHER STUDIES ON ROLE OF VACCINES IN GWS
All three review panels have stated that no long-term adverse effects of the vaccines used have been documented or would be expected. None of the committees has recommended further studies of the potential adverse effects of vaccines in the GW population, nor have such studies been endorsed in the current working plan. The IOM (Institute of Medicine) has, however, recommended that the DoD maintain its lists of those individuals receiving the anthrax and botulinum vaccines for the purpose of conducting follow-up studies on these cohorts in the future.
The basic hypothesis and supporting evidence presented by (the author) are flawed or inaccurate. Available information strongly argues against (the author's) hypothesis:
1. All vaccines used during the GW have a long history of safety and all, except BotTox which was used under an IND, were licensed by the FDA at the time of the Gulf War.
2. Since the standard immunization series is given to individuals in basic and advanced training, only a relatively small number of additional vaccines were given during deployment to the Persian Gulf, and the previous use of these vaccines has not resulted in problems similar to those reported by GW veterans.
3. All vaccine lots are individually licensed for safety and efficacy. The vaccines used, therefore, are unlikely to be contaminated or of low quality.
4. The only adjuvant used in the vaccines given to GW personnel was alum. Alum is an FDA approved adjuvant with a long history of safety. It has been given to millions of people world-wide without significant problems. No experimental adjuvants were used by the military.
5. There are no reports of alum causing HAD or any other chronic disease.
6. There are no reports of chronic inflammatory responses at the sites of immunization with vaccines containing alum as would be expected if HAD were to occur.
7. Several recent studies (13 reports to date) have failed to show any association between silicone-gel implants and increased incidence of connective tissue disease. There is little supporting evidence, other than anecdotal reports, that silicone-gel implants cause an increase in connective tissue diseases or HAD.
1 Miyoshi K, Miyamura T, Kobakyoshi Y, et al. Hypergammaglobulinemia by prolonged adjuvanticity in man: disorder developed after augmentation mammoplasy. Jpn Med J 1964; 2122 914
Independent Non-Governmental Medical Expert
September 13, 1995
"REPORT ON GULF WAR SYNDROME" by (the author)
(The author) has assembled a large amount of anecdotal data concerning the symptoms and illnesses reported by veteran's returning from the Gulf War conflict. (The author) concludes that these illnesses are attributable to a single etiology - autoimmune disease. (The author) further suggests that the initiation of this disease is associated with the effects of vaccines administered to the troops, in particular the adjuvants used. (The author's) arguments are based upon the unproven premise that the diverse illnesses associated with service in the Persian Gulf represents a single disease, and upon an incomplete and inaccurate understanding of the role of adjuvants in autoimmune disease.
2. Summary of (the author's) views
Veterans returning from the Gulf War conflict first started to report a variety of illnesses as early as late 1991. (The author) states that (the author) became interested in this "Gulf War syndrome" in April 1994, apparently based on reports in the popular press. (The author) drew a parallel between the symptoms reported by the veterans and those described by patients with silicone breast implants. It is (the author's) view that both groups of patients suffer from "human adjuvant disease." (The author) believes this disease was induced by the adjuvants given with vaccines used to immunize members of the military.
3. Human adjuvant disease
The term human adjuvant disease was coined by a Japanese physician who encountered several patients with vague symptoms associated with rheumatic and connective tissue diseases. These patients had had injections into their breasts of mineral oil, silicone oil or other unknown materials for purposes of mammary augmentation. Based on the erroneous impression that this disease in humans resembles adjuvant arthritis, an experimentally induced disease in rats, the term adjuvant disease was invented. Although adopted by a few investigators in the 1980s, the term has been discredited and the concept is rarely invoked by informed physicians or scientists.
4. Adjuvant arthritis
Adjuvant arthritis is a well-characterized disease produced in certain strains of rats following injection of complete Freund's adjuvant. The pathological signs of this disease, including joint deformities and erosive arthritis, bear little or no resemblance to the signs described in veterans returning from the Persian Gulf. The preponderance of evidence shows that the disease occurs primarily in genetically predisposed strains of rat and requires injection of complete Freund's adjuvant. Complete Freund's adjuvant contains a mineral oil emulsion and killed mycobacteria. There is substantial evidence that the disease itself is due to a component of the mycobacteria, namely, a 65 kDa heat-shock protein. Adjuvant disease has never been associated with the adjuvant alum.
5. Autoimmune disease
Autoimmune disease can be defined as a pathological consequence of an autoimmune response. The autoimmune response is an immune response directed to an antigen present in the body of the host. Autoimmune responses are relatively common and are generally not the cause of autoimmune disease. In order to establish a connection between the autoimmune response and autoimmune disease, a number of steps are necessary. The autoimmune response must be relevant to the disease and must be capable of producing the characteristic pathological changes. Because this evidence is difficult to amass using human subjects, investigations of autoimmune disease often depend upon developing animal models. Translation of results obtained with such models to humans, however, must be done with caution. It is particularly important to understand that many diseases of unknown origin are associated with autoimmune responses, but that there is little or no evidence that autoimmunity is the cause of the disease. Autoimmune diseases may affect many different sites in the body, including the blood cell, eye, brain. endocrine organs, nerve junctions, heart, liner, and so forth. The manifestations of autoimmune disease, therefore, are quite dependent upon the location of the pathological process.
6. Connective tissue disease
(The author) frequently and incorrectly uses the terms connective tissue disease or collagen/vascular disease, as synonymous with autoimrnune disease. As explained previously, autoimmune disease refers to the origin and pathological process of a disease. Connective tissue disease or collagen-vascular disease are anatomical diagnoses depending upon the tissue affected. Some autoimmune diseases may affect connective tissue; others affect other tissues. Similarly, some connective tissue disease is attributed to autoimmune responses, whereas many others are due to genetic, metabolic, infectious or other causes. Mixing these two terms leads to a great deal of muddy thinking.
7. Laboratory parameters of autoimmunity
(The author) places great stress on the use of laboratory tests to detect autoimmune diseases. Very few tests, however, are specific for a particular disease and are only used appropriately to confirm or exclude a clinical diagnosis. It is particularly important to realize that if a large number of tests are carried out, a certain number will inevitably be "outside of the normal range." Since autoimmunity is a common phenomenon found in normal individuals, most of the laboratory tests are set up on the basis of normal distribution curves. Statistically, a certain proportion of normal individuals (generally 5%) will fall outside of the so-called normal range on the basis of chance alone. If twenty laboratory tests are carried out, therefore, it is statistically very likely that at least one "abnormal" finding will be discovered. No qualified physician would take such a finding as evidence of an immune disorder.
8. Silicone-associated autoimmune disease
In the 1980s, several case series were reported, suggesting that certain autoimmune diseases, such as lupus, rheumatoid arthritis, scleroderma, and mixed connective tissue disease or fibromyalgia, are associated with the use of silicone-gel-filled breast implants. These reports have now been investigated through controlled epidemiological studies. The evidence clearly shows that there is no association of autoirnrnune disease with silicone-gel breast implants. In addition, a number of experimental studies have been completed. They failed to show that silicone oil or silicone elastomer have adjuvant effects, but do show that silicone gel mixed with foreign antigens acts as a potent adjuvant. Silicone gel, however, has not been shown to induce autoimmune disease, acting either alone or in concert with a self-antigen.
9. Induction of autoimmunity by vaccines
Vaccines may be composed of living attenuated microorganisms, killed microorganisms, or products of microorganisms. In order to heighten their immunological potency, some vaccines are combined with an adjuvant. In the case of human use, only alum has been approved in the United States. Despite millions of doses given to large populations over the past century, there is no evidence that any of these vaccines is capable of inducing autoimmune disease.
10. Gulf War syndrome
Veterans returning from the Persian Gulf area have manifested a number of symptoms and illnesses. They include both physical and psychological disorders. There is no evidence and no reason to believe, however, that all of these diseases have a single etiology. Persuasive evidence, such as that assembled by the Institute of Medicine, shows that this syndrome represents a number of unrelated disorders with no evidence of a common origin. Studies have not yet shown that these illnesses, separately or collectively, are more prevalent among Gulf War veterans than appropriate controls.
(The author's) "Report on Gulf War Syndrome" is based on a series of erroneous assumptions and unsupported conjectures.