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1
Introduction and Background
l
Anthrax is a disease caused by a common ant! wiclespreact organism, Bacillus anthracis,
whose characteristics make it a feasible choice for biological warfare; examples of weapons
development programs using B. anthracis are well known. Because of the potential that
biological weapons using B. anthracis might be directed against the United States military, on
May 18, 1998, the Department of Defense (DoD) ordered all service personnel to be fully
vaccinated for protection against anthrax (the Anthrax Vaccine immunization Program, AV1P).
Limited availability of the anthrax vaccine forced at least a temporary siow-clown in attaining
this goal. But in acIdition to supply problems, the anthrax vaccine and AVTP have also been the
subject of an unusual degree of concern from service personnel, regarding possible adverse
events associated with the vaccine.
Because of the importance of protecting service personnel against biological warfare using B.
anthracis, and because of concern among troops and their families about adverse events possibly
associated with the anthrax vaccine, the Congress has also been interested in the policy and its
justification and ramifications. The DoD and the Centers for Disease Control and Prevention
(CDC) were directed to undertake additional research on the vaccine, both individually and
collaboratively.
The CDC contracted with the Institute of Medicine (IOM) to establish an expert pane] to
review the completeness and appropriateness of the CDC plan for responding to the
congressional mandate that CDC conduct research on the safety and efficacy of anthrax vaccine.
The committee's Statement of Task (Box 1-~) reflects the congressional appropriations language
(which became the Department of Health and Human Services Appropriations Act of 2000, now
Public I,aw 106-1 13) almost exactly, as comparison with Box I-2 shows. Congress (Erected the
CDC and the NIH and DoD to collaborate and cooperate fully in this effort. Meanwhile, the DoD
received congressional direction in the DoD Appropriations Act of 2000, now Public Law 106-
79, whose conference report language called for study of technical matters regarding the safety
and efficacy of the licensed anthrax vaccine. DoD therefore also contracted! with the lOM for a
separate study (see Box I-3 for that committee's Statement of Task). The DoD-sponsored study
is aimed at currently existing data on the safety and efficacy of the currently administerecl
vaccine. The CDC-sponsorect study was intenclec3 as a review of the CDC's plans for further
research into the safety, effectiveness, and acceptability of the anthrax vaccine. The CDC-
11
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12
CDC ANTHRAX VA CCINE SAFETY & EFFICA CY RESEARCH PROGRAM
sponsored study contract also called for this interim report. The full study is planner! for a total
duration of 24 months. This interim report sets out the committee's findings, eight months into
the project. Both the committee's review anti the CDC's research program are ongoing, and
further clevelopments are expected.
BOX 1-1 Statement of Task: Committee to Review
the CDC Anthrax Vaccine Safety and Efficacy Research Program
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 man-
date to study the safety and efficacy of anthrax vaccine, addressing (1) risk factors for ad-
verse 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 coop-
erate fully in this effort.
BOX 1-2 Congressional Language Regarding
Anthrax Vaccine Research, FY 2000-1
Public Law 106-1 13 provided fiscal year 2000 funding
"to the Centers for Disease Control and Prevention (CD CJ for a collaborative effort to study
the safety and efficacy of vaccines used against biological agents. The study shall address:
(1J the risk factors for adverse events, including differences in rates of adverse events be-
tween men and women; (2J determining immunological correlates of protection and docu-
menting vaccine efficacy; and (3J optimizing the vaccination schedule and administration to
assure efficacy while minimizing the number of doses recluired and the occurrence of ad-
verse events. It is intended that NIH, CD C, and the Department of Defense will fully coop-
erate in this effort."
This excerpt of PL 106-113 is the language that formed the basis of the contract for this
project. In the succeeding year, however, Congress made additional comment as follows in
the House-Senate conference report that was generated during fiscal year 2001 appropria-
tions legislation, with fiscal year 2001 funding finally 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. The Network will facilitate data collection, standardi-
zation of the anthrax immunization, training and general data collection for this project."
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INTRODUCTION & BACKGROUND
13
BOX ~ -3 Statement of Task: DoD-Sponsorec' Committee
to Assess the Safety ant! Efficacy of the Anthrax Vaccine
The committee will analyze available information, hold workshops, and make specific rec-
ommendations on technical aspects regarding the safety and efficacy of the licensed an-
thrax vaccine. The issues include the types and severity of adverse reactions, including
gender differences; long-term health implications; inhalational efficacy of the vaccine
against all known anthrax strains; correlation of animal models to safety and effectiveness
in humans; validation of the manufacturing process focusing on, but not limited to discrep-
ancies identified by the Food and Drug Administration in February 1998; definition of vac-
cine components in terms of the protective antigen and other bacterial products and con-
stituents; and identification of gaps in existing research.
ANTHRAX DISEASE AND PREVENTION
Anthrax Disease
Anthrax disease is caused by an infection with Bacillus anthracis (Brachman ant!
Friediander, 1999; Dixon, 19991. The endospores of B. anthracis remain dormant in soil and are
very resistant to physical and chemical conditions like heat, dryness, and disinfectants to which
many organisms are susceptible. This hardiness is one characteristic that makes the organism
practical as a weapons component (Tnglesby, 1999; Zilinskas, 1997~. B. anthracis can cause
cutaneous, gastrointestinal, or inhalational anthrax disease, ciepencling on the route of entry into
the body (Brachman and FriedIander, 19991. Grazing animals can become infected and, in turn,
can infect humans, but transmission of inhalational anthrax between human beings has not been
documented. Cutaneous anthrax is generally associates! with handling infected animals or their
products, and is manifested as lesions that form vesicles and finally ulcers marked by a
characteristic black eschar. Patients can be treated with antibiotics, and the survival rate is then
over 95%. Gastrointestinal anthrax can be causer! by eating infected meat. The fatality rate is
variable, estimated at 25 to 75%. Inhalational anthrax is usually, if not always, fatal, even with
aggressive treatment, within a matter of (lays after onset of symptoms (Brachman and
FriedIander, ~ 9991. Inhalational anthrax is the primary focus of the current United States military
immunization program because this clisease manifestation is of interest as a possible outcome of
biological warfare. Tnhalational anthrax depends on aerosolization of the endospores, which does
not normally occur in nature but can happen under industrial conditions (as in goat hair, wool
and hicle processing plants) or by means of weapons.
B. anthracis infection and pathogenesis begin with the introduction of endospores through
abrasions in the skin, or by ingestion or inhalation. The endospores then are phagocytosecl by
macrophages, wherein they germinate and are released as vegetative bacilli, which multiply in
lymph nodes and then may enter the blood stream in great numbers, causing massive septicemia.
The latter condition is more likely in inhalational anthrax than in the other forms. The virulence
of the anthrax bacilli depends on expression of both bacterial capsule and toxins, the genes for
which are carried on two plasmids. The loss of either the plasmid bearing the genes for the
toxins, or the capsule gene plasmitl, attenuates the bacterium such that it becomes unable to
cause disease. It is the effects of those toxins that actually cause human disease, but the capsule
inhibits the phagocytosis of vegetative bacteria. The plasmid carrying the toxin genes actually
codes for three distinct proteins: protective antigen (PA), edema factor (EF), and lethal factor
(LF). These factors then combine to form two toxins, each with an active domain and a binding
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14
CDC ANTHRAX VACCINE SAFETY & EFFICACY RESEARCH PROGRAM
domain. The toxins are eclema toxin, comprising PA and EF, and lethal toxin, composed of PA
and EF. In both cases, PA seems to mediate binding of the toxin to the target cell and its
translation to the cell's interior. The eclema toxin includes an actenylate cycIase, which causes
increased levels of cAMP and interferes with the cell's water balance, resulting in edema. The
lethal toxin includes a protease that stimulates the release from macrophages of tumor necrosis
factor or and interIeukin-1 0, which along with other cytokines may be the specific effect of lethal
toxin in mortality (Brachman and FriedIander, 1999; Dixon, 1999; Little and Ivins, 19991.
Anthrax Vaccine
Anthrax is among the first diseases for which the protective efficacy of vaccination was
evaluated (Turnbull, 19914. The human efficacy data for the currently licensed vaccine comes
from a field study of a similar vaccine in mill workers (Brachman et al., 1962, and see
FriedIander, et al., 1999 for review). The stucly (which was randomized and placebo-controlled)
was conducted among the workers in four northeastern United States mills that were engaged in
the processing of raw goat hair. Cutaneous anthrax was a problem in the mills, and the results of
the study showed 92.5% protection against cutaneous anthrax among vaccinees (gastrointestinal
anthrax was not a problem in the mills, and the number of cases of inhalational anthrax was too
small to serve as evidence for or against vaccine efficacy). That vaccine has been shown to be
effective in protecting animals from aerosolized B. anthracis anthrax spores.
The licensed anthrax vaccine is a sterile filtrate, the major active ingredient being PA, from
cultures of an avirulent, non-encapsulated strain of B. anthracis. The V770-NPl-R strain of
anthrax bacilli is grown in a chemically cleaned culture medium. The whole bacteria in the
culture are removed by filtration from the culture medium. The antigen is then adsorbed onto
aluminum hydroxide, and the product is caller! Anthrax Vaccine Adsorbed, or AVA. The current
vaccine differs slightly from the initial field trial tested vaccine in that it starts with a different
avirulent strain cultured under different conclitions, and uses a different aluminum preparation
(Myers, presentation, 2001~. There have been no randomizes! placebo-controlled clinical trials of
the efficacy of this vaccine, but its protective efficacy has been demonstrated in several animal
species. AVA is not at this time being procluced, but is licensed to be manufactured by Bioport
Corporation of Michigan. (Bioport, ~ 9991.
The composition of the filtrate includes PA, possibly with traces of lethal toxin (and perhaps
previously edema toxin, as mentioned in Brachman and FriedIander, ~ 999, though not according
to recent company information) and other materials. The amount of protective antigen and other
proteins per 0.5 m! dose is variable, approximately 50 micrograms of protein, of which 10 to 20
micrograms are PA, per dose (Bioport, presentation, 2001~. The vaccine contains no more than
0.83 mg of aluminum per (lose, 0.0025% benzethonium chloride as a preservative, and
formaldehyde in final concentration not to exceed 0.02%. The potency and safety of the product
comply with Focal and Drug Administration (FDA) regulations. The content (purity) of PA
averaged 50% with a standard deviation of 7%. Some data suggest that immunity is largely, if
not entirely, a response to PA (On relevance of PA, see, for example, Gladstone, 1946; Dixon et
al., 1999; Little and Ivins, 1999; and on aluminum hydroxide as an adjuvant, see for example,
Wright et al., 1954, 1962; Ivins et al., 19951.
Modification of the current dosage and route of administration for the licensed product might
improve its acceptability. AVA is given subcutaneously, a route that is typically associated with
greater reactogenicity relative to intramuscular administration (ACIP, 19941. AVA is an unusual
vaccine product because it is the only licensed vaccine to include aluminum hydroxide and to be
labeled for subcutaneous administration. The immunization schedule of multiple doses and
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INTRODUCTION & BACKGROUND
15
boosters that is currently specified in the package insert was based on the number of
immunizations found to afford protection against cutaneous anthrax in the field study by
Brachman et al. (1962), and this inoculation schedule was not evaluated against other possible
scheclules. The dosage schedule is currently a 0.5 m! injection at 0, 2, and 4 weeks, again at 6, 12
and 18 months, and annually thereafter. The number of inoculations alone can be objectionable
to some vaccinees.
VACCINE RELATED ADVERSE EVENTS
Adverse events following immunization with the licensed vaccine include local and systemic
reactions. The most common local reactions are erythema (raciness), subcutaneous nodules at the
site of injection, ant! less commonly, forearm swelling due to eclema. Frequent systemic reactions
include malaise and lassitude, and less commonly fever anct chills.
Such local and short term systemic reactions are common to a number of different bacterial
vaccines in current routine use. The standard regulatory terms for any undesirable effect of a
vaccine (or other biologic or drug) are adverse event or adverse reaction. Adverse events can
range from mile! to serious or life threatening. The stanciard term uses! by regulatory agencies to
describe the characteristic profile of a product and its associated adverse events is the safety of
the pro cluct. We have used the term "aclverse events" wherever possible, as "safety" may seem to
over-emphasize serious or life threatening events.
The primary means of learning of adverse events associated with any licensee! vaccine is the
Vaccine Adverse Event Reporting System (VAERS), aciministered by the CDC and the Food and
Drug Administration (FDA). VAERS collects and analyzes information from reports of possible
adverse events following immunization (http://www.vaers.org, accessed 8/29/001. The VAERS
program encourages reporting of any clinically significant adverse event following any
immunization, anct anyone can file a report to VAERS. VAERS is a passive surveillance
system- it accepts reports but does not actively seek out vaccinees or health care providers to
make inquiries and as with any such system, it is safe to presume that the rate of reporting is
low relative to the rate of events (though it is ctifficult to estimate how low), and varies due to the
rate of events but also due to other factors such as awareness of alleged problems with a
particular vaccine (Singleton et al., ~ 9991. Between January ~ 990 and August 2000, ~ 544 reports
of adverse events following administration of the anthrax vaccine were filed with VAERS.
During that time period, 1,859,500 closes were given to 463,000 people (Mootrey, presentation,
10/31/001. VAERS is not designed to track the absolute rate of adverse events experienced per a
given number of doses administered. Rather it is a signal-capturing or hypothesis-generating
system: for example, if VAERS should receive a significant increase in reports of adverse events
associated with some particular product, then that serves as a signal to investigate possible
causes such as perhaps a particular lot or batch of the product that might be unusually
reactogenic (see also Tilson, 19921. In the special case of the anthrax vaccine, the VAERS
reports receive indiviclual review by an inclependent civilian committee of medical experts, the
Anthrax Vaccine Expert Committee (AVEC), which considers causality and forwards
conclusions to the DoD. The AVEC had reviewed some 1 530 reports as of March 15, 2001, but
their first report has not yet been published (Caserta, presentation, 2000; personal
communication; and http://www.anthrax.osd.mil, accessed 4/6/011.
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16
CDC ANTHRAX VACCINE SAFETY & EFFICACY RESEARCH PROGRAM
POLICY CONTEXT OF REPORT
Beginning in 1970 anct continuing through today, the licensed anthrax vaccine has been
routinely administered to United States workers with occupational exposure to anthrax bacteria
or spores. Although human anthrax due to contact with infected animals or their products
remains a health problem in some areas, currently in the United States the licensed anthrax
vaccine is in use primarily by the military to protect troops from weaponized anthrax (Brachman
and Friec3lander, 1999; Mazzuchi et al., 20001. In 1979, an outbreak of human anthrax occurred
in SverdIovsk, U.S.S.R. (Abramova et al., 1993' Meselson et al., 1994; Jackson et al., 19984.
Although initially it was officially blamed on consumption of contaminated meat, subsequent
investigations of a series of cases shower} pathologic lesions diagnostic of inhalational anthrax
(Abramova et al., 1993), which is now admitted by the Russian government. The admission that
Iraq haci produced weapons containing anthrax spores during the 1991 Gulf War confirmed fears
of the potential use of anthrax as a biological weapon (Zilinskas, 19971. Approximately 268,000
doses of the vaccine were distributed to troops in ~ 990 (IOM, 2000b).
Anthrax Vaccination Policy
Secretary of Defense William Cohen decided in late ~ 997 to proceed with a plan to vaccinate
all United States service members against anthrax, ant! immunizations began in 1998. By March
15, 2001, 2.l million closes of anthrax vaccine had been administered to approximately 505,000
military personnel (http://www.anthrax.osct.mil, accessed 4/6/014. The DoD's AV1P has had, and
continues to have, many formidable difficulties to manage. The licensee! anthrax vaccine was
only produced by one company, which is not in itself unusual, but the facility changed hands in
1998 and the company, now called BioPort, has had difficulty meeting regulatory requirements
for good manufacturing practices. In fact, the product has not been manufactured since the winter
of 1997. The DoD has been able to continue immunizations in spite of the limited supply of
vaccine, but not at the rate first planned. In July 2000, then more officially in November 2000,
the DoD slowed dramatically its immunization program, focusing only on troops thought to be at
greatest potential risk (http://www.anthrax.osd.mil, accessed 9/5/00; Marshall, 20001.
In addition to supply problems, some vaccinees have objected to the immunization policy.
There have been, for example, complaints among Gulf War veterans of chronic multisystem
clinical conditions that still lack definable relationship to anthrax vaccine and to other events in
the Gulf War experience (for farther information on Gulf War experience and concerns, see, for
example, Presidential Advisory Committee, 1996; Iowa Persian Gulf Study Group, 1997; Fukuda
et al., 1998; Hotopf et al., 2000; lOM, 1996, 2000a, 2000b). Even though there is no definable
relationship of anthrax vaccine to illnesses of long-term late appearance or duration, there has
been a perception in a small minority of military personnel that the anthrax vaccine is dangerous.
The AV]P, and the anthrax vaccine itself, have become a focal point of great concern on the
part of at least a segment of the military and interested public. The Congress has responded to
that concern, and several hearings have been held by relevant committees. The Congress also
appropriated funds to the DoD and to the CDC for the further study of the anthrax vaccine (see
Figure I).
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INTRODUCTION & BACKGROUND
DoD-sponsorec! study to evaluate
the safety and efficacy of anthrax
vaccine
17
CDC-sponsorec! study to evaluate
CDC research plan on safety and ef-
ficacy of anthrax vaccine
Congressional actions regarding IOM study of anthrax vaccine research
T T
DoD Appropriations Act 2000
PL 106-79
DoD is directed to enter into a contract
with the IOM to independently study
the effectiveness and safety of the
anthrax vaccine
IOM letter report an anthrax |
~t vaccine afety3/3012000
DoD contracted With IOM to study
the safety and efficacy of the an-
thrax vaccine
1
IOM Committee to Assess the Safety and
Efficacy of the Anthrax Vaccine
Meetings to date: October 3, 2000
January 29-30, 2001
April 17-18, 2001
!
Final Report due June 2002
l
DHHS Appropriations Act, 2000
PL 106-113
CDC is provided $20 million for a
collaborative effort to study the
safety and efficacy of anthrax
vaccine
L
CDC requested that IOM review
the CDC research plan
IOM Committee to Review the CDC Anthrax
Vaccine Safety and Efficacy Research Program
Meetings to date:
October 31, 2000
February 8-9, 2001
April 18-19, 2001
Interim Report due June 2001
| Final Report due August 2002 |
FIGURE ~ Origins of TOM Activities Related to the Anthrax Vaccine
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18
CDC ANTHRAX VA CCINE SAFETY & EFFICA CY RESEARCH PROGRAM
CDC'S REPONSE TO CONGRESS
The CDC intends to comply with the congressional mandate to stucly adverse events and the
efficacy of the anthrax vaccine by conducting various activities inclucling studies by two of its
subsidiary units, the National Center for Infectious Disease (NCID) and the National
Immunization Program (NIP). The CDC's research program addresses various and interwoven
aspects of the licensee! anthrax vaccine (anthrax vaccine adsorbecI, or AVA) on a variety of
levels. On the level of the immunological properties of the vaccine, for example, the CDC plans
include studies to determine the amount of specific types of antibodies produced in response to
immunization. On the level of the medical symptoms that some vaccinees may experience, and
that may influence acceptability of the vaccine, the CDC plans include studies of the effects of
different routes of administration on the frequency and extent of such adverse reactions. On the
level of perceptual factors that affect the acceptability of a vaccine, the CDC plans include a
survey to assess service members' knowledge, attitudes, and beliefs about the anthrax vaccine.
NCID's projects to identify risk factors and improve use of the vaccine itself are also very
relevant to the vaccine's adverse event profile. The NCID's effort is the investigation of vaccine
immunogenicity and effectiveness, while the NIP concentrates on vaccine adverse events and
acceptability. The NCID, in collaboration with the DoD-USAMRIlD, issued a three-part request
for proposals for studies acIdressing the dosage, route of administration, and immunologic
correlates of protection of the AVA. The acceptability of the vaccine wouict improve, and acute
local reactions would likely decrease, if it could be administered intramuscularly and if fewer
closes were required. Recent data suggest that these changes may be possible (Pittman et al.,
submitted for publication), and the NCID studies are clesignect to further evaluate these changes.
If the studies support the reduction in doses or change in route of administration, then the results
couIc! support a supplementary application to change the labeling of the AVA product.
Although the FDA does not regulate medical practice, and specifically does not oversee
whether health care providers prescribe regulated products according to the directions in the
product labeling, the administration of medical products by the Uniter! States military is a special
situation. The Gulf War was the occasion of issuance of special rules that allowed! the
administration of investigational products, such as pyridostigmine bromicle, for specific wartime
indications, as cleemect necessary to protect troops from chemical or biological weapons (note,
however, that while the anthrax vaccine was administered} during the Gulf War, it was a licensed,
not investigational, vaccine). The intervening decade has seen a great clear of policy and
regulations development related to the use of new medical products in the military (see Raub,
1999, and FDA, 19991. In general, the military is not in a position to adopt a policy endorsing
uses of drugs or vaccines in ways other than directecl in the FDA-approved product labeling. Any
such usage is called "off-label" use. Concern in the FDA (and the DoD) about officially
sanctioned off-label use of medical products was underscored in a letter in response to
unspecified! reports of off-label anthrax vaccine administration, from Dr. Katherine Zoon,
Director of FDA's Center for Biologics Evaluation and Research to Dr. Sue Bailey, Assistant
Secretary of Defense for Health Affairs (Zoon, ~ 9991. In sum, in orcler for the DoD to administer
the anthrax vaccine by a different route or with a reduction in total closes, it is first necessary that
the product labeling be formally changed.
The NIP is, as noted, concerned with tracking vaccine adverse events and improving vaccine
acceptability. In order to assess the vaccine adverse event profile' the NIP hopes to improve the
detection of true adverse events, and in orcler to improve vaccine acceptability, the NIP hopes to
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INTRODUCTION & BACKGROUND
19
improve eclucation ant! communication about the vaccine, anc} confidence among vaccinees that
adverse events will be registered and prevented or treated.
The plans of the NIP to improve the adverse event profile ant! the acceptability of the vaccine
include research and programmatic components, with only the former (research) to be actUressed
in this interim report. As part of the research effort, the NIP will be conducting focus groups and
knowledge, attitudes, and beliefs (KAB) surveys among military personnel who have or will
receive the anthrax vaccine, with a view to improving education and communications. The NIP
is also proposing to stu(ly KAB among health care providers about VAERS reporting. The NIP is
working to develop strategies and techniques for more complete analysis of the (lata ("clata-
mining") in VAERS as well. In ad(lition, the NIP is working on several other projects in support
of the NCID-directed human clinical trials.
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Representative terms from entire chapter:
adverse events
