1
Introduction

Anthrax is a disease caused by Bacillus anthracis, a spore-forming bacterium whose characteristics of stability and availability make it a feasible choice for biological warfare. Examples of weapons development programs using B. anthracis are well known, but the distribution of anthrax spores through the United States postal system in the fall of 2001 considerably heightened awareness of the risks from anthrax and brought additional interest in the disease and its prevention through the use of the vaccine Anthrax Vaccine Adsorbed (AVA). This report is a review of plans by the Centers for Disease Control and Prevention (CDC) for a congressionally mandated research program on the safety and efficacy of the anthrax vaccine.

As described below, the motivation for the CDC anthrax vaccine safety and efficacy research program was concerns about the vaccine among some military personnel and members of the public following the start of mandatory immunizations against anthrax for the military in 1998. However, the bioterrorist events of 2001 radically altered perspectives on the need for anthrax vaccine, making what had been a hypothetical risk—exposure to aerosolized anthrax spores—seem far more concrete. The bioterrorist events have had widespread ramifications, including vigorous government efforts to accelerate the development and licensure of a new anthrax vaccine.

The committee’s evaluation of the CDC anthrax safety and efficacy research program has necessarily been affected by this change in context. In particular, the timeline for the CDC research plan must be viewed in the context of plans for tremendously accelerated development of a new anthrax vaccine. While many of the planned studies would provide information that is relevant to the development and understanding of a new vaccine as well as the current one, some data about the safety and efficacy of the currently licensed vaccine could conceivably come too late to be useful. The committee acknowledges that the changed situation has put great demands upon CDC and hopes that this report will provide advice that will help optimize the usefulness of the research program.

The research program will also be affected by other circumstances beyond CDC’s control, such as the timing and extent of the resumption by the Department of Defense (DoD) of its anthrax vaccination program for the military. Similarly, the timeline for the availability of a new licensed vaccine is uncertain. Bearing in mind these uncertainties, the committee strove to focus on addressing the research questions that stand regardless of these circumstances.

ORIGIN OF THE STUDY

Concerned that biological weapons using anthrax might be directed against the U.S. military, in December 1997 DoD announced a program to vaccinate all service personnel against anthrax using the li-



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1 Introduction Anthrax is a disease caused by Bacillus anthracis, a spore-forming bacterium whose characteristics of stability and availability make it a feasible choice for biological warfare. Examples of weapons development programs using B. anthracis are well known, but the distribution of anthrax spores through the United States postal system in the fall of 2001 considerably heightened awareness of the risks from anthrax and brought additional interest in the disease and its prevention through the use of the vaccine Anthrax Vaccine Adsorbed (AVA). This report is a review of plans by the Centers for Disease Control and Prevention (CDC) for a congressionally mandated research program on the safety and efficacy of the anthrax vaccine. As described below, the motivation for the CDC anthrax vaccine safety and efficacy research program was concerns about the vaccine among some military personnel and members of the public following the start of mandatory immunizations against anthrax for the military in 1998. However, the bioterrorist events of 2001 radically altered perspectives on the need for anthrax vaccine, making what had been a hypothetical risk—exposure to aerosolized anthrax spores—seem far more concrete. The bioterrorist events have had widespread ramifications, including vigorous government efforts to accelerate the development and licensure of a new anthrax vaccine. The committee’s evaluation of the CDC anthrax safety and efficacy research program has necessarily been affected by this change in context. In particular, the timeline for the CDC research plan must be viewed in the context of plans for tremendously accelerated development of a new anthrax vaccine. While many of the planned studies would provide information that is relevant to the development and understanding of a new vaccine as well as the current one, some data about the safety and efficacy of the currently licensed vaccine could conceivably come too late to be useful. The committee acknowledges that the changed situation has put great demands upon CDC and hopes that this report will provide advice that will help optimize the usefulness of the research program. The research program will also be affected by other circumstances beyond CDC’s control, such as the timing and extent of the resumption by the Department of Defense (DoD) of its anthrax vaccination program for the military. Similarly, the timeline for the availability of a new licensed vaccine is uncertain. Bearing in mind these uncertainties, the committee strove to focus on addressing the research questions that stand regardless of these circumstances. ORIGIN OF THE STUDY Concerned that biological weapons using anthrax might be directed against the U.S. military, in December 1997 DoD announced a program to vaccinate all service personnel against anthrax using the li-

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censed product AVA. The vaccination plan was to be phased in gradually, starting with service members judged most likely to encounter the threat. The first vaccinations under DoD’s Anthrax Vaccine Immunization Program (AVIP) took place in March 1998. As more members of the military received the mandatory vaccine doses, some raised concerns about the safety and efficacy of the vaccine being administered. Because of the importance of protecting service personnel from potential acts of biological warfare using B. anthracis, and because of concern among troops and their families about adverse events possibly associated with the anthrax vaccine, the U.S. Congress has also been interested in the anthrax vaccine and the DoD immunization policy. In its appropriations for the Department of Health and Human Services for fiscal year 2000, Congress provided funding for CDC to carry out a research program on vaccines used against biological agents. The request is found in Box 1-1 below. As it began planning a research program to respond to this mandate, CDC sought the input of the Institute of Medicine (IOM) regarding its developing plan. CDC contracted with IOM to establish an expert panel to review the completeness and appropriateness of the CDC anthrax vaccine safety and efficacy research program. The committee’s Statement of Task is found in Box 1-2. BOX 1-1 Congressional Request for CDC Anthrax Vaccine Research, FY 2000–1 Public Law 106-113 provided fiscal year 2000 funding “to the Centers for Disease Control and Prevention (CDC) for a collaborative effort to study the safety and efficacy of vaccines used against biological agents. The study would address: (1) the risk factors for adverse events, including differences in rates of adverse events between men and women; (2) determining immunological correlates of protection and documenting vaccine efficacy; and (3) optimizing the vaccination schedule and administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events. It is intended that NIH, CDC, and the Department of Defense will fully cooperate in this effort.” The excerpt of Public Law 106-113 above is the language that formed the basis of the contract for this project. In the succeeding year, Congress made additional comments as follows in the House–Senate conference report that was generated in conjunction with fiscal year 2001 appropriations legislation, with fiscal year 2001 funding provided by Public Law 106-554. “Regarding the anthrax study, the conferees understand that clinical studies will be greatly facilitated by the establishment of the Vaccine Healthcare Center Network, with the first site at Walter Reed Army Medical Center. This Network will facilitate data collection, standardization of the anthrax immunization, training and general data collection for this project.” BOX 1-2 Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program Statement of Task This committee will advise the Centers for Disease Control and Prevention (CDC) on the completeness and appropriateness of the CDC plan to respond to the Congressional mandate to study the safety and efficacy of anthrax vaccine, addressing: (1) risk factors for adverse reactions, including gender differences; (2) determining immunologic correlates of protection and documenting vaccine efficacy; (3) optimizing the vaccination schedule and routes of administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events. The CDC, the National Institutes of Health (NIH), and the Department of Defense (DOD) are directed by Congress to collaborate and cooperate fully in this effort.

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STUDY PROCESS AND INFORMATION SOURCES The IOM convened the Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program in fall 2000. Reflecting elements in the charge to the committee, members brought expertise in microbiology; infectious diseases; vaccine research, development, and evaluation; postmarketing surveillance of adverse events; regulatory and licensing procedures; epidemiology; biostatistics; survey research and design; immunology; differences in disease between men and women; and health surveillance (see Appendix A for biographical sketches of the committee members). The charge to the committee did not include evaluation of the safety and efficacy of the current vaccine. This topic was the subject of a recent report of another IOM committee, the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine (IOM, 2002). Four members of that committee also served on the Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program. The charge to the present committee was limited to a review of the research program and did not encompass review of other aspects of the CDC anthrax vaccine program, such as clinical or operational efforts related to administering the anthrax vaccine. The committee based its evaluation of the CDC research plan primarily on information provided by CDC. At five open meetings, the committee heard presentations from CDC investigators about their developing research plans. CDC also provided written materials to the committee describing the research plans. To better understand the context in which the research was requested and planned, the committee also heard in one of its open meetings from service members and others with concerns about the safety or efficacy of the vaccine. The dates, locations, and agendas of the public workshops are provided in Appendix B. In addition to meetings held in conjunction with its public sessions, the committee met in two closed sessions and two telephone conferences to deliberate and to draft its report. Because CDC research plans continued to evolve during the first year of the committee’s work, the committee requested that CDC provide a document that described the complete research plan as of February 2002. The committee also requested other specific information, such as an integrated timeline and a comprehensive list of critical research questions in anthrax vaccine research. The document describing the research plan and the accompanying study protocols that CDC provided in response to the IOM request received significant emphasis in the committee’s evaluation of the research plan, supplemented by information gathered and discussed in the committee meetings. A subset of these documents is provided in Appendix C. The original timeline for the IOM review of the CDC research plan called for an interim report to be delivered by June 30, 2001, and a final report by the end of the original task order period (August 2002). The committee provided its interim report to CDC on June 25, 2001, and the report was publicly released in July 2001. Subsequently, the government’s response to the bioterrorist events of fall 2001 placed tremendous demands on CDC’s time and resources. Expertise that would otherwise have been applied to further development of the CDC anthrax safety and efficacy research plan was instead appropriately redirected in part toward response to the anthrax exposures and cases. CDC requested that IOM delay its activities for a period of several months, and the contract was extended to conclude on December 31, 2002. INTERIM REPORT The committee’s interim report of July 2001 (IOM, 2001) provided its findings and recommendations as of that time, which was fairly early in CDC’s planning and development of the research program. The committee found that the CDC had not yet developed—or not communicated—a comprehensive plan for the anthrax vaccine safety and efficacy research program. Nevertheless, the committee concluded that despite the absence of a comprehensive plan, the CDC program included appropriate and well-conceived scientific projects generally responsive to the congressional mandate. Many projects were still not fully developed and described at the time, however. The committee’s major recommendations in the interim report were that CDC should produce a comprehensive description of its research program, with a statement of its goals and how the plans would meet the goals. The report also recommended that CDC should

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consider engaging experts to provide immediate consultation on technical matters of study design and execution. Another recommendation was that CDC should continue and further strengthen the mandated collaboration with DoD and NIH, for example, by making more extensive use of DoD’s Defense Medical Surveillance System (DMSS). A full listing of the findings and recommendations from the interim report appears in Appendix F. The report can be found on the Internet at http://www.nap.edu/catalog/10157.html. RELATED REPORTS Because of the controversy surrounding the military’s mandatory vaccination program and heightened concerns regarding the use of anthrax as an agent of terrorism or warfare, two key reports have been released in recent years regarding the anthrax vaccine. While they are not directly related to the subject of this report on the CDC research plan, they provide context for the research needs discussed. ACIP Recommendations In December 2000, a report regarding recommendations for use of the anthrax vaccine was released by the Public Health Service’s Advisory Committee on Immunization Practices (ACIP) (CDC, 2000). In Use of Anthrax Vaccine in the United States, ACIP reviewed safety and efficacy data and recommended routine vaccination with AVA for those working with large quantities or concentrations of B. anthracis and those conducting activities with a high potential for production of aerosolized B. anthracis (CDC, 2000). ACIP did not recommend pre-exposure vaccination for emergency first responders, federal responders, medical practitioners, or private citizens for bioterrorism preparedness because “the target population for bioterrorist release of B. anthracis cannot be predetermined, and the risk of exposure cannot be calculated…. For the military and other select populations or for groups for which a calculable risk can be assessed, pre-exposure vaccination may be indicated” (CDC, 2000, p. 12). Since the release of that report, the intentional distribution of anthrax spores in letters in the fall of 2001 and the subsequent illnesses and deaths from anthrax have heightened interest in the use of AVA for a wider population. At the time of this writing, however, ACIP had not altered its recommendations regarding the populations for whom vaccination is indicated. IOM Report on the Anthrax Vaccine In March 2002, the IOM Committee to Assess the Safety and Efficacy of the Anthrax Vaccine released the report The Anthrax Vaccine: Is It Safe? Does It Work? From its review of both published and unpublished data, the committee concluded that AVA as licensed is an effective vaccine to protect humans against anthrax, including inhalational anthrax. Because the vaccine exerts its protection via antibodies to protective antigen, which is crucial to the action of B. anthracis toxins, the report states that AVA should be effective against anthrax toxicity from all known strains of the bacterium, as well as from any potential bioengineered strains. Regarding safety, the report describes the committee’s review of numerous case reports and many epidemiologic studies. From these data, the committee concluded that AVA is reasonably safe. Within hours or days following vaccination, it is fairly common for recipients to experience some local events (e.g., redness, itching, swelling, or tenderness at the injection site), while a smaller number of vaccine recipients experience some systemic events (e.g., fever and malaise). But these immediate reactions, and the rates at which they occur, are comparable to those observed with other vaccines regularly administered to adults. The committee found no evidence that vaccine recipients face an increased risk of experiencing life-threatening or permanently disabling adverse events immediately after receiving AVA, when compared with the general population. Nor did it find any convincing evidence that vaccine recipients face an elevated risk of developing adverse health effects over the longer term, although data are limited. Regarding the manufacture of AVA, the committee reviewed and evaluated the steps taken by BioPort to win FDA approval of its production process following the shutdown of its facilities for renovation.

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It took BioPort several years to receive FDA approval, and during that time supplies of the vaccine ran low, necessitating suspension of the military’s vaccination program. With the newly validated manufacturing process being used in a renovated facility, AVA will be produced under strict controls that are in accord with current FDA requirements. The report states that the newly produced vaccine is expected to have greater assurance of consistency than the vaccine produced at the time of its original licensure. The committee emphasized the importance of continued and improved monitoring efforts to detect any adverse health effects caused by AVA and other vaccines. In addition, studies are needed to quantify and correlate protective levels of antibodies in animals with antibody levels in humans after full immunization. Direct tests of the efficacy of AVA are neither feasible nor ethical in humans. However, correlates of protection can be derived from studies that use animal models to test the efficacy of AVA, as well as new vaccines against anthrax. Both passive and active protection studies have important roles. The report stressed that production, testing, and licensure of a new vaccine requiring fewer doses and producing fewer local reactions is needed. The findings and recommendations of the report are presented in Appendix G. The full report can be found on the Internet at http://www.nap.edu/catalog/10310.html. ORGANIZATION OF THE REPORT CDC has organized its Anthrax Vaccine Safety and Efficacy Research Plan into components of efficacy, safety, and acceptability. Accordingly, this report follows that structure to some extent. Chapter 2 provides background material about the disease known as anthrax, the licensed anthrax vaccine, and the questions regarding the efficacy and safety of AVA that prompted the congressional request for the CDC research program. Chapter 3 summarizes CDC’s plan for the anthrax vaccine research program. In Chapter 4, the CDC research regarding the efficacy of AVA is described and the committee’s findings and recommendations regarding this aspect of the research plan are presented. Chapter 5 describes the CDC research that is to address the safety of the anthrax vaccine, followed by the committee’s discussion and evaluation. Chapter 6 reviews the research planned by CDC to address the acceptability of AVA and the committee’s findings and recommendations about this research. In Chapter 7, the committee discusses and evaluates the completeness and appropriateness of the research plan as a whole. REFERENCES CDC (Centers for Disease Control and Prevention). 2000. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR (Morbidity and Mortality Weekly Report) 49(RR-15):1–20. IOM (Institute of Medicine). 2001. CDC Anthrax Vaccine Safety and Efficacy Research Program. Interim Report. Washington, D.C.: National Academy Press. IOM. 2002. Joellenbeck LM, Zwanziger LL, Durch JS, Strom BL, eds. The Anthrax Vaccine: Is It Safe? Does It Work? Washington, D.C.: National Academy Press.