A. Adverse Reactions to Vaccines

By far the most common reactions to vaccines are local reactions at the site of injection, usually soreness and swelling. Fever is also associated with some vaccines. These reactions generally last only a few hours or days, although the soreness and swelling occasionally may be more severe and prolonged. Some vaccines are more likely than others to produce these reactions. For example, influenza vaccines may cause mild soreness and fever in 20 to 30 percent of individuals;[94] the typhoid vaccine generally used by the military may have caused local soreness in 50 to 80 percent of recipients, and headache, muscle aches, and fever in up to 30 percent.[95] Serious reactions to vaccines are much less common. Most vaccines can cause allergic reactions that can be life-threatening (anaphylaxis), but this is rare.[96]

At the time of the Gulf War, joint guidance required that adverse reactions to vaccines be described in the individual’s medical record. Reactions requiring hospitalization or resulting in significant time lost from duty were also to be reported on a CDC form. The more common and limited reactions need not be reported unless contaminated lots of vaccines were suspected. [97]

While there are no detailed listings for all adverse reactions to vaccines experienced by servicemembers during the Gulf War deployment, a database maintained by the Army’s Center for Health Promotion and Preventive Medicine lists 58 vaccine reaction incidents for which servicemembers were hospitalized. Typhoid vaccine was the most frequent cause of reactions attributed to a single vaccine (rather than to combinations of vaccines or to various unidentified vaccines). Two incidents listed in this database might have been life threatening: a severe allergic reaction to typhoid vaccine (anaphylaxis) and a widespread skin rash from smallpox vaccine (generalized vaccinia).[98]

Information was also limited on adverse reactions to the biological warfare vaccines, anthrax and botulinum toxoid. A communication from mid-January 1991 indicated that there was no formal feedback program for gathering information on adverse reactions from anthrax vaccinations, but noted that about half of personnel vaccinated in the first week of the program developed local irritation that went away in three to four days, and that no serious reactions were observed.[99] A survey of 169 aircrew members found that 92 percent reported some reaction from the anthrax vaccine, primarily local tenderness and redness, while 30 percent reported fever, headache, and muscle aches; only 3 percent felt their reactions were serious enough to affect flying duties.[100] Adverse reactions from anthrax vaccine used before the Gulf War included local reactions in 30 percent with a tendency toward increased reactions with later doses in the series. This and other information about adverse reactions expected to occur with this vaccine was noted in the package insert that accompanied the vaccine.[101] We are aware of one hospitalization during the Gulf War possibly related to anthrax vaccine.[102]

We are not aware of any reports of severe reactions to the botulinum toxoid vaccine. A 1995 Institute of Medicine report notes that the 1st Marine Expeditionary Force conducted a postcard survey in August 1991 of 123 Marines who received one or more doses of the vaccine in the Gulf. Of the 121 who responded, 12 percent reported mild local reactions; 14 percent reported pain that limited use of the arm temporarily; and 2.5 percent reported systemic symptoms that did not limit activity.[103] By comparison, the CDC had noted reaction rates in earlier vaccine recipients of 5.8 percent for moderate and severe local reactions and 3 percent for systemic reactions.[104]

A system for reporting complaints about medical materiel to the Defense Personnel Support Center (DPSC) was also in place during the Gulf War (although this system was not designed primarily for vaccine reactions). Complaints about medical materiel included any of the following: Type I, complaints about materiel determined by use or tests to be harmful or defective enough to cause death, injury, or illness; Type II, complaints about materiel other than equipment suspected of being harmful, defective, deteriorated, or otherwise unsuitable for use; and Type III, complaints about equipment determined to be unsatisfactory because of malfunction, design, and defects.[105] The DPSC was to immediately notify the Defense Medical Standardization Board (DMSB) and the Food and Drug Administration of all Type I complaints. According to DMSB staff, the Board received no Type I complaints for any vaccines used during the Gulf War. Documentation was not available at the DMSB regarding Type II or Type III complaints involving vaccines for the same period.[106]

Following the Gulf War, revised joint guidance on immunizations continued to require the recording and reporting of adverse reactions as before, but reactions previously reported to CDC were now to be reported to the FDA through the newer Vaccine Adverse Events Reporting System (VAERS).[107] VAERS is a combined FDA and CDC program that requires reporting of certain events (and encourages reporting of any other events considered important) that occur after the administration of vaccines. This system uses the term "adverse event" rather than "adverse reaction" to indicate that it is not always possible to make a causative connection between events experienced and vaccines administered. Medical personnel, vaccine manufacturers, and vaccine recipients submit reports through VAERS.[108]

Reactions to the anthrax vaccine used in the current DoD immunization program have been documented through surveys of military personnel. Because the program began in early 1998, the majority of the servicemembers had received fewer than the full series of doses at the time of these surveys. Most of the reported reactions have been localized, minor, and limited, but these reactions were more frequent in women.[109] The DoD’s Anthrax Vaccine Immunization Program office maintains a web site with updated information on this issue.[110]

The CDC and the FDA continue to monitor licensed and investigational vaccines closely, and to suspend use of vaccines whenever there is substantial evidence that they may cause serious side effects.

Currently there are no established connections between vaccines and the persistent and unexplained illnesses reported by some veterans, although research continues on this issue.  A recent report from the Institute of Medicine (IOM) reviewed the published scientific research in order to assess the potential adverse health effects of the biological warfare vaccines.  The report concluded that anthrax and botulinum toxoid vaccinations are associated with transient acute local and systemic effects (e.g., redness, swelling, fever) typically associated with other vaccinations, but that there is inadequate/insufficient scientific evidence to determine whether these vaccinations are associated with long-term adverse health effects.  It noted that the small number of published studies on this issue is not unusual, as few vaccines have been monitored for adverse effects over long periods of time.  The report recommended long-term studies of recipients of these vaccines.  The IOM also assessed the possible health effects of multiple vaccinations, and again concluded that there is inadequate/insufficient scientific evidence to determine whether multiple vaccinations are associated with long-term adverse health effects, with further research needed.[111]

B. Vaccine Adjuvants

Adjuvants are substances included in some vaccines in order to improve the immune response to these vaccines. Not all vaccines contain adjuvants; some don’t need them to produce protection in recipients. The addition of an adjuvant to a vaccine preparation can sometimes increase local reactions to the vaccine, but there is substantial benefit in producing an earlier, stronger, or more persistent protection from the vaccine. Aluminum compounds are common adjuvants in licensed vaccines and have been used safely for many years. Some of the vaccines given to servicemembers during the Gulf War deployment, including the anthrax, botulinum toxoid, hepatitis B, and tetanus-diphtheria vaccines, contained aluminum compounds as adjuvants.[112]

To improve the effectiveness of vaccines, research has continued on a large number of newer adjuvant formulations that appear stronger than the aluminum compounds. Some of these newer adjuvant formulations contain squalene as an oil component in the formulation. Squalene itself is commonly found in certain cosmetics and foods, and in the body as a part of normal human metabolism. Both the Department of Defense and the National Institute of Allergy and Infectious Diseases (a division of the National Institutes of Health) have sponsored research clinical trials of vaccines that include squalene-containing adjuvants. Some of these trials were done at the time of the Gulf War. Because these vaccines were investigational products, FDA guidelines required informed consent from the volunteers. (See also Investigational Vaccines, Section V.) The DoD has also conducted research with squalene-containing adjuvants in animals, including research on newer anthrax vaccines. The General Accounting Office noted that the DoD considered but did not use vaccines containing adjuvants other than aluminum during the Gulf War. According to DoD officials, the use of new adjuvant formulations for the anthrax vaccine was rejected because any alteration in the licensed vaccine would require re-licensure, and DoD would not receive FDA approval in time.[113]

Since the Gulf War, one group of researchers has reported finding antibodies to squalene in Gulf War veterans with unexplained illnesses and has suggested that squalene, or antibodies to squalene, may have contributed to these illnesses.[114] This research is preliminary and will require confirmation.[115]

C. Information Available to Servicemembers

Communication of information to servicemembers about the health hazards of war and about the benefits and risks of medical countermeasures like vaccines is essential, but problematic. The information must be made understandable to all vaccine recipients, yet it may be impossible to completely avoid technical concepts. The communication of complex risks might be particularly difficult when the information is presented during the hurried and stressful times of deployment.

Risk communication might be considered successful when "it raises the level of understanding of relevant issues for those involved and satisfies them that they are adequately informed within the limits of available knowledge." It most often involves a two-way exchange of information in order to maximize this level of understanding, but this dialogue may not be feasible or appropriate for all military situations. Sometimes a simple one-way briefing may suffice; at other times feedback and discussion may be necessary.[116] Successful risk communication, as applied to the use of vaccines, would make it clear that the scientific information is rarely complete, that the risks of the diseases and the vaccines are neither overstated nor understated, and that the decisions made are in the best health interests of the servicemembers. Such communications should lead to improvements in mutual respect and trust.

During the Gulf War, the policy for informing servicemembers about the biological warfare vaccines was contained in the CENTCOM guidelines and was classified in order to preserve operational security. Prepared statements were to be read to servicemembers at the time of vaccination, but were not to be distributed, and vaccine recipients were cautioned not to discuss the vaccinations with anyone.[117]

For the anthrax vaccine, the information in the statement included the reasons for the vaccine, the schedule of injections, and the expected reactions to the vaccine. It indicated that the vaccine was supplementary to the primary protection provided by masks and to treatment with available antibiotics.[118] For the botulinum toxoid vaccine, the information also included a brief description of botulism, indications that the vaccine was investigational, and details about the reactions that had occurred with previous uses of the vaccine.[119] An additional statement was added to the information sheet for botulinum toxoid vaccine for signature by the vaccine recipient. The statement indicated that the recipient had read and understood the information, and had voluntarily submitted to the vaccine series.[120]

These policies for vaccine information appear to have been implemented with varying consistency and success. A preventive medicine officer reported that "…despite the hush-hush nature of the [anthrax] vaccine's employment…, there developed some groundswell of unease and anxiety among units who were not on the distribution list…. I had to do some scrambling just to find out what the principles of prioritization were."[121] A medical detachment commander expressed similar concerns: "The reasons why some units were chosen to receive the [anthrax] vaccine and not other units was not made clear to all units. There was poor communication about the vaccine itself leading to many fears among those potentially receiving the vaccine. Many commanders made the immunization mandatory…. Other commanders made it optional…. There was a great deal of misinformation about the anthrax vaccine among the soldiers. Very many thought that the vaccine was not FDA approved and was an experimental drug. Many feared drastic systemic side effects."[122] Some servicemembers reported that they were provided no information on why the anthrax and botulinum toxoid vaccines were being given.[123]

Following the Gulf War, the Department of Defense developed policy that reflects a heightened awareness of the importance of informing personnel of health threats and risks associated with deployment.[124] The DoD now provides several web sites with information about vaccines and links to other governmental and non-governmental sources of information.[125] Each of these sites is an attempt by DoD to establish improved lines of communication with servicemembers about the role of vaccines in force health protection.

D. Investigational Vaccines

The administration of botulinum toxoid vaccine to US forces during the Gulf War highlighted the concerns and challenges surrounding the military use of investigational drugs and vaccines.[126] Generally speaking, the term "investigational" applies to drugs and vaccines that have not been fully approved and licensed by the Food and Drug Administration. Such is the case with the botulinum toxoid vaccine. Conversely, the anthrax vaccine used during the Gulf War had been licensed by the FDA for many years, and thus was not an investigational product.[127]

The FDA grants licensure for drugs and vaccines that have been shown to be both safe and effective (generally for a specific use). Products developed to protect against biological warfare agents can be shown to be safe in humans using fairly well established procedures. However, the human trials usually required by the FDA to prove vaccine effectiveness are not possible when the disease does not occur naturally with sufficient frequency, or when studies in humans are too dangerous (i.e., exposure to harmful doses). Consequently, a number of much-needed products under development in military research programs cannot satisfy the current requirements for licensure by the FDA and remain in an investigational status.[128]

Investigational drugs and vaccines are tested in volunteer subjects under FDA-approved guidelines. Use and study of these investigational products require review by an institutional review board, informed consent from the recipients of the products, and the maintenance of detailed records of the products’ administration and test results.[129]

In assessing countermeasures to Iraq's biological threats during the Gulf War, the DoD determined that it needed to be prepared to use investigational products such as the botulinum toxoid vaccine. At the same time, the DoD was concerned that the rules for administering investigational products could not be followed under battlefield conditions. Therefore, in late October 1990, the DoD recommended that the FDA provide a mechanism for waiving informed consent requirements for investigational products that might be considered the best preventive or therapeutic treatments available for US military personnel serving in the Gulf. In its recommendation, the DoD noted that "…In all peacetime applications, we believe strongly in informed consent and its ethical foundations…. But military combat is different. If a soldier's life will be endangered by nerve gas, for example, it is not acceptable from a military standpoint to defer to whatever might be the soldier's personal preference concerning a preventive or therapeutic treatment that might save his life, avoid endangerment of other personnel in his unit, and accomplish the combat mission."[130]

The FDA responded to the DoD recommendation by publishing an interim rule in the Federal Register in December 1990. This rule permitted the FDA to determine that obtaining informed consent from military personnel for the use of an investigational drug or biologic is not feasible in certain battlefield or combat-related situations, and that withholding treatment would be contrary to the best interests of military personnel. The published rule stated that "…FDA will consider investigational products proposed for military use on a case-by-case basis, and the agency is prepared to waive the requirement of informed consent where it can be documented that use of these agents in combat-related situations serves the best interests of individual soldiers and the military combat units in which they serve."[131]

As required by this interim rule, the DoD then submitted a written request to the FDA, asking for a determination that obtaining informed consent would not be feasible for the botulinum toxoid vaccine because of the military combat exigencies associated with Operation Desert Shield.[132] The FDA Commissioner concurred and provided a written determination to the Assistant Secretary of Defense for Health Affairs in late December 1990, noting that "…I find that there is no available satisfactory alternative therapy for the prevention of botulism, and I concur with your assessment that informed consent is not feasible and that withholding treatment would be contrary to the best interests of military personnel."[133] (A detailed discussion of the issues surrounding this interim rule may be found in a 1999 RAND report.[134] Information on vaccine record keeping is included in the following subsection of this paper.)

Media reports about "experimental" vaccines, combined with limited vaccine supplies, were apparently key factors in a decision by CENTCOM to modify the agreed-upon protocol and allow servicemembers the choice of declining the botulinum toxoid vaccine. In post-Gulf War testimony before the Presidential Advisory Committee on Gulf War Veterans' Illnesses (PAC), the CENTCOM Surgeon expressed concern about the impact of media-fueled rumors on the morale of military personnel. He further stated that since there was not enough botulinum toxoid vaccine for all servicemembers, it seemed reasonable to give them the information and let them make the choice.[135] In subsequent correspondence with the FDA, the DoD commented that while this decision had been made without notice to the Pentagon until after the fighting stopped, "…in retrospect, it was quite proper to give the responsible military command the option to decide whether actual military circumstances unfolding in the theater of operations truly required the standardized use of the vaccine."[136]

Other investigational vaccines were also considered for use during the Gulf War. In December 1990, the DoD briefly considered establishing a "Manhattan-like project" to accelerate the testing and development of several new vaccines in an operational setting.[137] The proposed project was evaluated by a tri-service medical working group, which felt that the timing was not right at that point in the conflict, although such a proposal might be possible if the Gulf War became prolonged.[138] The project was referred for further consideration, but was not supported and a draft memorandum establishing a project task force was never signed by the Army Surgeon General.[139]

Following the Gulf War, progress in resolving the issues surrounding the military’s use of investigational drugs under deployment conditions has been slow. The PAC noted that the DoD and the FDA had "deliberated carefully" before allowing the use of investigational products without informed consent during the Gulf War. However, the DoD was unable to produce records of who received these products and had not been responsive to the recommendation that it routinely inform servicemembers about the possible use of investigational products for chemical and biological warfare defense; the FDA had failed to devise better long-term methods governing military use of these products and had taken too much time before soliciting public comment on alternatives to the interim rule.[140] In a summary report, the PAC again noted the FDA’s slowness in making progress on these issues, as well as DoD's acknowledgement of its failures to comply with federal regulations pertaining to these investigational products in both the Gulf War and in the subsequent deployment to Bosnia.[141]

In 1998, Congress passed legislation stipulating that only the President, at the request of the Secretary of Defense, can waive the requirement for informed consent involving investigational products. The law states that for informed consent to be waived, it must be found to be not feasible, contrary to the best interest of the servicemember, or not in the best interests of national security.[142] In 1999, a presidential order expanded on the requirements of the 1998 law, and called for the DoD to provide ongoing training and health risk communication to servicemembers on investigational drugs in support of military operations. [143] The FDA then revoked its 1990 (Gulf War) interim ruling and published a new interim rule that establishes criteria for the President to apply in making a determination that informed consent is not feasible or is contrary to the best interests of the individual servicemember.[144]

The military will likely have need for investigational vaccines in future deployments, but use of these vaccines will be difficult. As noted, some investigational vaccines cannot be adequately tested in humans in order to satisfy current requirements for licensure, and all investigational vaccines have proven difficult to administer under deployment conditions.

E. Vaccine Record Keeping

Documentation of health care (including immunizations) during the Gulf War is addressed in detail in an earlier information paper released by the Office of the Special Assistant.[145] Guidance on documentation of immunizations during the Gulf War was complicated by the need for operational security in the use of the biological warfare anthrax and botulinum toxoid vaccines, and by special record keeping requirements for the investigational botulinum toxoid vaccine.

In January 1991, CENTCOM and Army messages—originally classified SECRET and since declassified—provided guidelines for the theater-wide anthrax and botulinum toxoid vaccination programs. These messages stated that the vaccinations may be recorded on the yellow shot record (PHS 731), or on the Immunization Record (SF 601), as Vacc A and Vacc A-2 for the anthrax series, and Vacc B, Vacc B-2, and Vacc B-3 for the botulinum toxoid series.[146] A later memorandum indicated these vaccines may also have been recorded as "Anthrax," "A Vaccination," "A-Vax," "Botulinum," "Bot-Tox," "B Vaccination," "B-Vax," or something similar.[147] For the anthrax vaccine, it appears that a roster of personnel receiving the vaccine was required. For the botulinum toxoid vaccine, personnel were required to sign an information sheet about the vaccine, indicating that they had read and understood the information and had voluntarily submitted to this immunization.[148]

Whatever the initial guidance, there appeared to be substantial confusion about where, even whether, these vaccinations were to be recorded. Additional guidance, issued after the cease-fire and termination of the vaccination program, specifically required that the vaccinations be entered in the individual health records, and that rosters of immunized personnel be forwarded through the chain of command.[149] Post-conflict discussions with Gulf War veterans further indicated that documentation of anthrax and botulinum toxoid immunizations was irregular, perhaps owing to the need for operational security in the administration of both vaccines, and to the uncertain guidance regarding the documentation of the investigational (botulinum toxoid) vaccine.[150]

The most current (1995, but being revised) joint guidance covering the Armed Forces immunization program, along with service-specific medical record keeping directives, reflect the post-Gulf War policies for documenting immunizations. According to these directives, immunizations for Army, Navy, and Marine Corps personnel continue to be recorded on both the Immunization Record (SF 601) in the individual health record and the International Certificates of Vaccination (PHS 731). Air Force immunizations are recorded on the Adult Preventive and Chronic Care Flowsheet (AF 1480A) in the member’s health record as well as on the PHS 731.[151] These policies, in turn, have been affected by the 1998 issuance of an Adult Preventive and Chronic Care Flowsheet (DD 2766). The Navy[152] and the Army[153] now direct that immunizations be documented in the individual health record using the DD 2766 instead of the SF 601, and the Air Force has designated the DD 2766 as a replacement for the AF 1480A,[154] as well as a record for documenting medical care during deployments.[155]

The documentation of investigational drugs and vaccines remains a difficult issue. In its 1997 request for comments on the rule that waived the requirements for informed consent for investigational products taken during the Gulf War, the FDA recognized that the rule did not work as anticipated. The FDA specifically mentioned problems with record keeping, and requested comments on whether and how record keeping should be addressed in the rule.[156] In its reply, the DoD indicated that it believed existing FDA regulations on record keeping were adequate, and noted ongoing initiatives to develop automated record keeping and immunization tracking systems.[157]

Recognizing that increasing the number of vaccines and the complexity of immunization schedules require more efficient methods of recording and tracking immunizations, the DoD has established an interim tracking system for its anthrax vaccination program. Currently, the Army uses the Medical Occupational Data System (MODS), the Air Force uses its Military Immunization Tracking System (MITS), and the Navy and the Marine Corps use the Shipboard Automated Medical System (SAMS). Each system transmits a core set of information to the DoD’s Defense Eligibility Enrollment System (DEERS), allowing decentralized confirmation of an individual’s vaccination status and updating the servicemember’s immunization record.[158]

Responding to the Secretary of Defense’s direction to establish an anthrax vaccination program,[159] each of the services has developed plans to emphasize the importance of command-level support.[160] These plans, along with a subsequent Army regulation,[161] provide guidance on the medical record keeping and documentation of anthrax immunization program information.

F. Vaccine Use by Coalition Forces

While all coalition partners had vaccination programs, only some of them used vaccines directed against biological warfare agents. As part of the coalition response to Iraq’s invasion of Kuwait, the United Kingdom (UK) also conducted an immunization program against biological warfare agents. Details of the UK program are contained in two reports published by the Ministry of Defence in October 1997 and January 2000.[162]

The British program, like the US program, was classified SECRET at the time of the Gulf War. It consisted of an anthrax vaccine and a plague vaccine for use against the UK-assessed threat of Iraq’s biological warfare agents, and a pertussis vaccine for use as an adjuvant to accelerate the immunization effect of the anthrax vaccine.[163] The anthrax vaccine was produced from a strain of the bacteria different from that used for the US vaccine and was to be delivered in a series of four injections rather than six. This schedule was reduced to three doses and combined with pertussis vaccine in order to complete the vaccination series in the limited time available.[164] Instead of a botulinum toxoid vaccine, the UK procured botulinum antitoxin for use as a post-attack therapy.[165] The vaccines were intended to be voluntary and their usage was to be recorded. British troops were also to be briefed on the reasons for the vaccine program as well as characteristics of the vaccines.

The British estimate that over 75 percent of all personnel deployed to the Gulf region, and close to 100 percent in many units, received the first anthrax-pertussis injection. Fewer personnel received the second dose of anthrax-pertussis vaccine, which was often accompanied by the first plague vaccine injection. Additional doses of these vaccines were rare. Similar to the US vaccination program, implementation varied: vaccine information was not always made available to UK service personnel, medical officers, or commanders; the voluntary nature of the program was not universally understood or fully implemented; and documentation of immunizations was inconsistent.[166]

Recently, researchers have reported an association in UK veterans between multiple vaccinations given after arriving in the Gulf and later ill health. This work is subject to limitations noted by the authors and others, and will require additional research. [167]

Canada was another coalition partner that had a vaccination program against biological warfare agents during the Gulf War. Like the British forces, Canadian forces used a plague vaccine as well as an anthrax vaccine with pertussis vaccine as an adjuvant.[168]

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