Anthrax Vaccine: GAO's Survey of Guard and Reserve Pilots and	 
Aircrew (20-SEP-02, GAO-02-445).				 
                                                                 
GAO reviewed the views of pilots and aircrew members of the Air  
National Guard and Air Force Reserve regarding the Anthrax	 
Vaccine Immunization Program (AVIP) of the Department of Defense 
(DOD). In December 1997, the Secretary of Defense announced a	 
plan to inoculate U.S. forces against the potential battlefield  
use of anthrax as a biological warfare (BW) agent. In the context
of the conventional battlefield, the nature and magnitude of the 
military BW threat has not changed materially since 1990 in terms
of the number of countries suspected of developing BW capability,
the types of BW agents they possess, or their ability to	 
weaponize and deliver BW agents. In marked contrast to other	 
mandatory DOD immunization requirements, GAO's sample survey in  
2000 showed that AVIP was at that time adversely affecting the	 
retention of trained and experienced guard and reserve pilots and
aircrew members. Between September 1998 and September 2000, 16	 
percent of the pilots and aircrew members of the guard and	 
reserve had (1) transferred to another unit (primarily to	 
nonflying positions to avoid or delay receiving the anthrax	 
shots), (2) moved to inactive status, or (3) left the military.  
Additionally, one in five of those still participating in or	 
assigned to a unit in 2000 indicated their intention to leave in 
the near future. At the time of the survey, two-thirds of the	 
guard and reserve pilots and aircrew members did not support	 
DOD's mandatory AVIP or any future immunization programs planned 
for other BW agents. However, these negative views did not appear
to indicate a general antivaccine bias. On the basis of the	 
survey, GAO estimated that 37 percent of the guard and reserve	 
pilots and aircrew members had received one or more anthrax shots
as of September 2000. Of these recipients, 85 percent reported	 
experiencing some type of reaction. This overall rate reported	 
for adverse reactions following anthrax immunization was more	 
than double the rate published in the vaccine manufacturer's	 
product insert that was in use at the time of the survey.	 
Respondents to the survey indicated that they had not reported	 
most of the reactions they cited to the military chain of command
through official or informal channels and that they were not	 
reported to Food and Drug Administration's Vaccine Adverse Events
Reporting System (VAERS). Reasons survey respondents gave for not
reporting to the military chain of command included a lack of	 
awareness of VAERS, a concern about the loss of flight status, a 
possibly adverse effect on military or civilian career, and a	 
fear of ridicule.						 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-02-445 					        
    ACCNO:   A05107						        
  TITLE:     Anthrax Vaccine: GAO's Survey of Guard and Reserve Pilots
and Aircrew							 
     DATE:   09/20/2002 
  SUBJECT:   Aircraft pilots					 
	     Biological warfare 				 
	     Chemical and biological agents			 
	     Emergency preparedness				 
	     Health care planning				 
	     Health care services				 
	     Health hazards					 
	     Immunization programs				 
	     Immunization services				 
	     Infectious diseases				 
	     Military reserve personnel 			 
	     National Guard					 
	     Safety						 
	     Surveys						 
	     CDC/FDA Vaccine Adverse Events Reporting		 
	     System						 
                                                                 
	     DOD Anthrax Vaccine Inoculation Program		 

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GAO-02-445

Report to Congressional Requesters

United States General Accounting Office

GAO

September 2002 ANTHRAX VACCINE GAO*s Survey of Guard and Reserve Pilots
and Aircrew

GAO- 02- 445

Page i GAO- 02- 445 Anthrax Vaccine Letter 1

Results in Brief 3 Background 6 Scope and Methodology 8 The Anthrax Threat
Has Been Limited and Stable Since 1990 9 How the Anthrax Program Affected
Aircrew Members* Decisions to

Change Military Status 9 The Anthrax Vaccine Program Was Not Widely
Supported 13 Respondents Did Not Deem AVIP Information That DOD Provided

Credible 15 Respondents Reported More Adverse Events than Expected 18
Conclusions 22 Recommendations 24 Agency Comments 24

Appendix I Scope and Methodology 28 Questionnaire Development 28 Sample
Construction 28 Survey Administration 29 Weighting Responses and Potential
Nonresponse Bias 29

Appendix II Estimated Percentages of Vaccination Shot Recipients
Experiencing Local and Systemic Adverse Reactions 30

Appendix III The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number 31

Appendix IV Anthrax Vaccine Adsorbed Revised Product Insert (Jan. 31,
2002) 36

Description 36 Clinical Pharmacology 36 Clinical Studies 38 Indications
and Usage 39 Contraindications 39 Warnings 39 Precautions 40 Contents

Page ii GAO- 02- 445 Anthrax Vaccine

Adverse Reactions 41 Dosage and Administration 44 How Supplied/ Storage 45
Nonclinical Toxicology 45 References 46

Appendix V Comments from the Department of the Army 47

Related GAO Products 49

Tables

Table 1: Types of Anthrax Disease, Methods of Contraction, Symptoms, and
Outcomes 7 Table 2: Aircrew Who Had Changed Status and Reported Plans to

Change Status in the Near Future 12 Table 3: Pilots Who Had Changed Status
and Reported Plans to

Change Status in the Near Future 12 Table 4: Adverse Reactions Described
in the Anthrax Vaccine

Product Insert 18 Table 5: Adverse Events Exceeding 7 Days by Anthrax
Vaccination

Shot 21

Figures

Figure 1: Factors Influencing the Decisions of Pilots and Aircrew to
Change Status 10 Figure 2: Factors Influencing the Decisions of Pilots and
Aircrew to

Change Status in the Near Future 11 Figure 3: Extent of Support for AVIP
Reported by Pilots and

Aircrew 13 Figure 4: Aircrew Views on the Likelihood of Their Voluntarily

Taking Anthrax Vaccine 14 Figure 5: Aircrew Satisfaction with DOD*s
Information on Anthrax

Issues 15 Figure 6: Personnel with Moderate to Very Great Concern about

the Anthrax Vaccine and Health Issues 17 Figure 7: Estimated and Reported
Vaccine Reactions and Events 20

Page iii GAO- 02- 445 Anthrax Vaccine Abbreviations

AVIP Anthrax Vaccine Immunization Program BW biological warfare,
biological weapon CDC Centers for Disease Control and Prevention DOD
Department of Defense FDA Food and Drug Administration NIH National
Institutes of Health VAERS Vaccine Adverse Events Reporting System

Page 1 GAO- 02- 445 Anthrax Vaccine

September 20, 2002 The Honorable Dan Burton, Chairman Committee on
Government Reform House of Representatives

The Honorable Benjamin A. Gilman, Chairman Subcommittee on Middle East and
South Asia Committee on International Relations House of Representatives

The Honorable Walter B. Jones House of Representatives

As you requested, we address in this report the views of pilots and other
aircrew members of the Air National Guard and Air Force Reserve regarding
the Anthrax Vaccine Immunization Program (AVIP) of the Department of
Defense (DOD). We received your requests before the terrorist events of
September 11, 2001* the destruction of the World Trade Center towers in
New York City and the attack on the Pentagon in Washington, D. C. These
tragedies were followed in October 2001 by the mailing of anthrax- laced
letters that killed five people in the United States. The perpetrator*
individual, group, or other entity* responsible for sending the anthrax
letters has not yet been identified.

Most of the information in this report was derived from the results and
analyses of survey questionnaire responses received from selected pilots
and other aircrew members of the Air National Guard and the Air Force
Reserve before the events of September and October 2001. If the survey
questionnaire on AVIP were administered today, views on some issues
discussed in this report could be different, either negatively or
positively. However, since most of the questions were, at the time,
related to and report views on contemporaneous events (for example,
information provided in 1999 and 2000 or information about adverse
reactions experienced with inoculations given before 2000), we believe the
results of the survey are still valid and useful as a measure of the AVIP
program*s performance. This information should be of interest to DOD and
the Congress as they consider future anthrax vaccine programs.

In December 1997, the Secretary of Defense announced a plan to inoculate
U. S. forces against the potential battlefield use of anthrax as a
biological

United States General Accounting Office Washington, DC 20548

Page 2 GAO- 02- 445 Anthrax Vaccine

warfare (BW) agent. The mandatory AVIP* using the only available vaccine
produced by the BioPort Corporation* was officially launched in August
1998 as a high- priority commander*s program. This means that unlike other
mandatory vaccines routinely given to the military, AVIP received intense
attention from high command levels and was subject to exceptional
accountability requirements. It was intended to be compulsory for all 2.4
million DOD military service members* active duty and reserve component
members, including certain designated civilian and contractor personnel.
DOD still regards the biological agent anthrax, a disease that is usually
lethal if inhaled in sufficient quantity, as the single greatest BW threat
to U. S. military forces in the battlefield.

AVIP has been the subject of continuing controversy from its inception.
Public debate has centered on the vaccine*s safety and effectiveness, the
extent and severity of adverse reactions experienced by vaccine
recipients, and the adequacy and accuracy of the adverse reactions that
have been reported. In addition, some Gulf War veterans are suffering from
unexplained illnesses that they believe might have been caused by anthrax
vaccinations received during the war. We have reported on many of these
issues (see the list of related GAO products at the end of the report).

DOD temporarily restricted the mandatory anthrax program in 2000 to a very
small group (special mission individuals and researchers) because of
limited vaccine supply resulting from the closing of the vaccine
manufacturing plant. In January 2001, the Food and Drug Administration
(FDA) completed an approval and licensure process, allowing the
manufacturing plant to resume production of the anthrax vaccine. In May
2002, DOD announced the resumption of the anthrax immunization program,
limiting it to *at risk* troops. However, the identity of the troops
receiving the vaccine will not be disclosed for security reasons. DOD also
stated that substantial quantities of vaccine would be reserved for
civilian uses in homeland security.

Congressional concern continues about the potential effect of this program
on the retention of highly trained and experienced personnel in the Air
National Guard and Air Force Reserve.

Page 3 GAO- 02- 445 Anthrax Vaccine

As you requested, we examined 1. the nature and magnitude of the anthrax
battlefield threat over time, 2. AVIP*s impact on the retention of
experienced guard and reserve pilots

and aircrew members, 3. the level of support for AVIP among guard and
reserve pilots and

aircrew members, 4. the level of satisfaction that guard and reserve
pilots and aircrew

members expressed regarding the information provided to them on AVIP and
the anthrax vaccine, and

5. the number and severity of adverse events that vaccinated guard and
reserve pilots and aircrew members experienced and reported.

In the context of the conventional battlefield, the nature and magnitude
of the military BW threat has not changed materially since 1990 in terms
of the number of countries suspected of developing BW capability, the
types of BW agents they possess, or their ability to weaponize and deliver
BW agents. 1 This is particularly true regarding the ability to accumulate
and deliver sufficient quantities of processed agent to cause mass
casualties.

In marked contrast to other mandatory DOD immunization requirements, our
sample survey in 2000 showed that AVIP was at that time adversely
affecting the retention of trained and experienced guard and reserve
pilots and aircrew members. While many factors can and do influence an
individual*s decision to participate in the military, a significant number
of pilot and aircrew members cited the required mandatory anthrax
immunization as a key reason for reducing their participation or leaving
the military altogether in 2000.

Between September 1998 and September 2000, about 16 percent of the pilots
and aircrew members of the guard and reserve had (1) transferred to
another unit (primarily to nonflying positions to avoid or delay receiving
the anthrax shots), (2) moved to inactive status, or (3) left the
military. Additionally, an estimated one in five (18 percent) of those
still

1 U. S. General Accounting Office, Medical Readiness: Safety and Efficacy
of the Anthrax Vaccine, GAO/ T- NSIAD- 99- 148 (Washington, D. C.: Apr.
29, 1999). Results in Brief

Page 4 GAO- 02- 445 Anthrax Vaccine

participating in or assigned to a unit in 2000* that is, those who had not
already changed their status* indicated their intention to leave in the
near future. Both groups, those who had already left and those indicating
their intention to leave, ranked AVIP as a key factor in their decision to
leave or change their participation. We estimated that about 24 percent of
those who had already left did so knowing they were doing so before
qualifying for military retirement benefits. A majority of those who had
changed status and those intending to do so were experienced pilots who
held crew qualifications of flight evaluators, flight instructors, and
aircraft commanders, representing the loss of a very seasoned workforce.
Both those who had changed status and those intending to change status had
accumulated an estimated individual average of more than 3,000 flight
hours.

At the time of our survey, two- thirds of the guard and reserve pilots and
aircrew members did not support DOD*s mandatory AVIP or any future
immunization programs planned for other BW agents. However, these negative
views did not appear to indicate a general antivaccine bias. To the
contrary, most had a positive view* in terms of both effectiveness and
safety* toward immunization in general. From our survey, we estimate that
77 percent would not have taken the anthrax vaccine if it had been offered
on a voluntary basis. Almost 9 of 10 reported that they would have safety
concerns if an additional vaccine for other BW agents were added to the
military*s required immunization program. Additional analysis showed that
officers were statistically more likely than enlisted personnel to report
that they would not have taken the anthrax vaccine voluntarily.

Overall, there was general dissatisfaction with the completeness and
accuracy of the information DOD provided about AVIP and the anthrax
vaccine. We estimated from our survey that only about 4 of 10 guard and
reserve pilots and aircrew members were satisfied with the information DOD
provided on the military threat from anthrax. Considerably fewer were
satisfied with the information DOD provided regarding the anthrax
vaccine*s effectiveness in battlefield exposures, the history and past
usage of the vaccine, the vaccine*s short- term safety and long- term
safety, and possible side effects caused by reactions to the anthrax
vaccine. We also found that officers were statistically more likely than
enlisted personnel to question information given to them concerning
specific issues such as the vaccine*s battlefield effectiveness and its
short- term and long- term safety.

On the basis of our survey, we estimated that 37 percent of the guard and
reserve pilots and aircrew members had received one or more anthrax shots
as of September 2000. Of these recipients, 85 percent reported

Page 5 GAO- 02- 445 Anthrax Vaccine

experiencing some type of reaction (local or systemic or both). 2 This
overall rate reported for adverse reactions following anthrax immunization
was more than double the rate published in the vaccine manufacturer*s
product insert that was in use at the time of our survey (84 percent
versus approximately 30 percent). Each shot generated an average of four
or more reported reactions. More importantly, almost onefifth of the
reported events were categorized as systemic and about onefifth of these
systemic reactions lasted for more than 7 days. Some of these reactions
could have negative implications for an individual*s work performance and
job safety. The systemic reaction rate reported through the survey
represents a level more than a hundred times higher than the 0.2 percent
published in the product insert. We were unable to determine why the AVIP
reaction rates so exceeded the product insert rates for the vaccine as
approved in 1970. However, we found two studies conducted by DOD that
looked at the short- term safety of the vaccine* one in Korea and one in
Hawaii. Both reported reaction rates similar to those reported in our
survey and disclosed a markedly higher rate of reaction for female shot
recipients. 3 Since we first reported these results from our survey in
September 2000, the manufacturer*s product insert has been revised to
include the adverse reaction rates reported in post licensure survey
studies. 4

Respondents to our survey indicated that they had not reported most of the
reactions they cited to the military chain of command through official or
informal channels (such as supervisors) and that they were not reported to
FDA*s Vaccine Adverse Events Reporting System (VAERS). 5 Reasons survey
respondents gave for not reporting to the military chain of command
included a lack of awareness of VAERS, a concern about the

2 A local reaction affects only the general area around the point of
injection and may be experienced as redness, itching, or the like. A
systemic reaction is more serious because it affects bodily systems after
absorption or ingestion and may be experienced as chills, fever, nausea,
dizziness, and so on.

3 The first DOD study of anthrax vaccine reactions was conducted in Korea.
A physician collected data for this study in 1997. The second study, in
Hawaii, was called the Tripler Army Medical Center Anthrax Survey (Tripler
survey). Both reported reaction rates considerably higher than the vaccine
product insert rates.

4 See appendix IV for the revised product insert. 5 VAERS is a passive
surveillance system to alert FDA and the Centers for Disease Control and
Prevention (CDC) of adverse events that may be associated with licensed
vaccines. Health care providers, patients, or families, who are encouraged
to report any adverse events after a person receives a vaccine, report
information voluntarily to VAERS.

Page 6 GAO- 02- 445 Anthrax Vaccine

loss of flight status, a possibly adverse effect on a military or civilian
career, and a fear of ridicule.

This report contains recommendations for DOD to direct the establishment
of an active surveillance program to identify and monitor adverse events
associated with each anthrax vaccine immunization. This program should
ensure that appropriate and complete treatment and follow- up is provided
to those who have experienced adverse events and to those who may
experience them in the future.

Anthrax is an acute infectious disease caused by the spore- forming
bacterium Bacillus anthracis. It can infect humans; however, it occurs
most commonly in warm- blooded animals (herbivores) in the agricultural
regions of countries with less standardized and less effective public
health programs. Human anthrax occurs only rarely in the United States
from natural causes. However, the anthrax attacks in October 2001 through
contaminated mail resulted in the death of five persons.

Human infection normally results from an occupational exposure to infected
animals or animal products. For example, workers may be exposed to dead
animals or to products such as wool, hides, leather, or hair products
(especially goat hair). There have been no reports, even now, of the
disease spreading from person to person; thus, anthrax is most likely not
spread in humans directly.

Anthrax infection can occur in three forms: (1) cutaneous, usually through
a cut or an abrasion; (2) gastrointestinal, by ingesting contaminated
meat; and (3) inhalation, by breathing anthrax spores into the lungs.
Symptoms depend on how the disease is contracted but usually appear within
7 days. The disease can be treated with antibiotics: tetracycline and
doxycycline are preferred, but penicillin, erythromycin, chloramphenicol,
or ciprofloxacin can also be used. To be effective, treatment should be
started early. The symptoms and forms of the disease are presented in
table 1. Background

Page 7 GAO- 02- 445 Anthrax Vaccine

Table 1: Types of Anthrax Disease, Methods of Contraction, Symptoms, and
Outcomes Disease form How contracted Symptoms Outcome

Cutaneous By bacteria entering skin cut or abrasion Begins as a raised
itchy bump resembling

an insect bite; develops in 1* 2 days into a vesicle with black center and
then a painless ulcer

Death is rare with appropriate treatment; untreated death rate is about
20%

Gastrointestinal By consuming contaminated meat Acute inflammation of the
intestinal tract Death in 20%* 60% of cases Inhalation By inhaling anthrax
spores

while handling contaminated animal products; anthrax spores can be sprayed
into atmosphere in biological warfare

First resembles a common cold or flu; after several days, acute symptoms
develop, such as severe breathing problems and shock

Death 1* 2 days after onset of acute symptoms

Source: Arnot Ogden Medical Center, www. aomc. org.

The Secretary of the Army is the executive agent for managing AVIP. The
dosing regimen or protocol for the anthrax vaccine calls for a series of
six shots over 18 months. An initial series of three shots is given at 2-
week intervals, followed by a series of three shots at 6- month intervals.
Annual boosters are required thereafter. As of early 2001, more than
520,000 service members had received at least one dose of the vaccine.
However, since late 2000, DOD has had to significantly reduce the
inoculation rate because of a dwindling supply of vaccine from the sole
source manufacturer.

The original anthrax vaccine in the United States was developed by George
Wright and others in the 1950s and was first produced on a large scale by
the pharmaceutical manufacturer Merck Sharp & Dohme. 6 A clinical study in
1962 evaluated the safety and effectiveness of the Merck vaccine in mill
workers. 7 This study formed the basis for subsequent licensure of a
modified vaccine in 1970. The Division of Biologics of the National
Institutes of Health (NIH) issued the original license for anthrax vaccine
to the Michigan Department of Public Health. 8 In 1995, the facility
changed its name to the Michigan Biologic Products Institute. In 1998, the
facility was sold, and its name was changed to BioPort Corporation.

6 Merck Sharp & Dhome is a subsidiary of Merck & Co., Inc. 7 Anthrax
infection has most commonly occurred in settings like wool mills, where
workers may be exposed to infected animal products. 8 Before FDA was
established as the licensing authority for vaccines, NIH performed that
function.

Page 8 GAO- 02- 445 Anthrax Vaccine

Over time, FDA has cited the facility for repeated deviations from
applicable manufacturing standards for the vaccine. The facility received
warning letters from FDA, including one in March 1997 stating its intent
to revoke the facility*s license. The facility closed its plant for
renovations in 1998 and since then has supported all AVIP requirements
with vaccine produced and stockpiled (some from the early to the middle
1990s) before the plant closed. DOD had to restrict the mandatory anthrax
program because of the shortage of anthrax vaccine. BioPort has now
received FDA*s approval to resume production. 9

To achieve our objectives, we developed, pretested, and validated a
questionnaire that we sent to a stratified random probability sample of
1,253 people from DOD*s list of Air National Guard and Air Force Reserve
personnel. These included pilots, flight engineers, loadmasters,
navigators, crew chiefs, and others. Collectively, these individuals
represented about 13,000 service members of the total fiscal year 1999 end
strength of approximately 176,000, which included about 29,000 officers
and 147,000 enlisted personnel. We selected a random sample in four
strata, defined by whether a person was currently active or had changed
military status as of March 1, 1998, and had been vaccinated or not as of
February 2000.

The overall response rate from the sample of 1,253 was 67 percent. Each
response was subsequently weighted in the analysis to account
statistically for all the members of the population, including those who
were not selected. Because our results are based on a sample and different
samples could provide different estimates, we express our confidence in
the precision of our particular sample*s results as a 95 percent
confidence interval (for example, plus or minus 5 percentage points). We
are 95 percent confident that each of the confidence intervals in this
report includes the true values in the study population. Unless we note
otherwise, all percentage estimates from the survey have a 95 percent
confidence interval of plus or minus 5 percentage points.

The overall survey results can be generalized to all guard and reserve
pilots and aircrew personnel. A more complete description of the scope and
methodology is in appendix I. We conducted our work between

9 FDA has revised the adverse reactions section in the product insert to
reflect a higher incidence of local and systemic reactions. Scope and

Methodology

Page 9 GAO- 02- 445 Anthrax Vaccine

May 2000 and July 2002 in accordance with generally accepted government
auditing standards.

DOD considers inhalation anthrax in an aerosolized form to be the greatest
mass destruction BW threat to U. S. military forces, and it bases the
scope of AVIP on this threat. According to DOD, this assessment is based
on several factors, including (1) the judgment that a few nations, hostile
to the United States, consider anthrax to be a potential weapon on the
battlefield, and (2) the lethality and relative ease of production and
battlefield use.

According to DOD and other, unclassified sources, we found that in terms
of conventional battlefield use, the nature and magnitude of the anthrax
threat has been stable since 1990 and has not changed materially in terms
of the number of countries suspected of developing a BW capability, the
types of biological agents they possess, or their ability to weaponize and
deliver such agents. We have previously reported that the use of most
biological agents would require a relatively high degree of
sophistication, in terms of both expertise and equipment, to successfully
cause mass casualties. 10 Specialized knowledge would be needed to acquire
the right biological agent, process it, improvise a weapon or device, and
effectively disseminate it to cause mass casualties. However, as clearly
demonstrated in October 2001, the mailing of just a few letters
contaminated with refined anthrax spores can cause death and severely
disrupt business and government operations.

The anthrax program adversely affected the retention of trained and
experienced pilots and aircrew members in the guard and reserve. While
many factors can and do influence an individual*s decision to participate
in the military, pilots and other aircrew respondents cited the required
anthrax immunization as a key reason for (1) leaving the military
altogether, (2) reducing their involvement or participation in the
military, and (3) otherwise changing their military status. According to
our survey, between September 1998 and September 2000, when AVIP was
mandatory, about 16 percent of the guard and reserve pilots and aircrew
members had transferred to another unit (primarily to nonflying
positions), moved to inactive status, or left the military altogether. In
addition, 18 percent of

10 GAO/ T- NSIAD- 99- 148. The Anthrax Threat

Has Been Limited and Stable Since 1990

How the Anthrax Program Affected Aircrew Members* Decisions to Change
Military Status

Page 10 GAO- 02- 445 Anthrax Vaccine

those still participating in units indicated their intention to transfer,
move, or leave in the near future. About one- fifth of those who had
already left did so knowingly before qualifying for military retirement.

As shown in figure 1, we estimate that more than two- thirds, or 69
percent, of those who changed their status reported that the anthrax shot
was the major influence behind their decision to do so* more even than
those reporting family reasons as an important factor. Of those who
changed their status, 27 percent reported that anthrax immunization was
the most important factor influencing their decision to leave or transfer.
In addition, the general military immunization program was not an
important factor in their decision to change status.

Figure 1: Factors Influencing the Decisions of Pilots and Aircrew to
Change Status

Source: GAO 2000 survey.

Further, according to our survey, an estimated 44 percent of those who had
already changed their military status or who were no longer in military

Percent 0 10

20 30

40 50

60 70

80 Other immunizations

Unit morale Individual morale

Workload Other employment

Retirement Family

Anthrax shot

29 1

53 3

52 5

56 8

42 12

32 16

61 16

69 27

Major influence Most important influence

Page 11 GAO- 02- 445 Anthrax Vaccine

flying status because of AVIP indicated that they probably would consider
returning to a unit or to military flying status if AVIP were not
mandatory.

Our survey results also indicated that an estimated 18 percent of those
who were still participating in guard and reserve units reported that they
planned to leave the military or change their military status within 6
months. As shown in figure 2, when asked to indicate the most important
factors for their planned decision to leave, an estimated 72 percent
reported that anthrax immunizations influenced their decision from a
moderate extent to a very great extent, followed by heavy unit workload,
individual morale, and family reasons.

Figure 2: Factors Influencing the Decisions of Pilots and Aircrew to
Change Status in the Near Future

Source: GAO 2000 survey.

Our survey indicated that the majority of guard and reserve pilots who had
already changed their military status or who were intending to do so in
the near future were experienced pilots. These were individuals who held

Percentage 0 10

20 30

40 50

60 70

80 Other employment Otherimmunizations Unit morale Family

Individual Workload

Retirement Anthrax shot

28 72

44 56

51 49 51 49 55

45 60

40 71

29 73

27 None or some Moderate to very great

morale

Page 12 GAO- 02- 445 Anthrax Vaccine

crew qualifications of flight evaluator, flight instructor, or aircraft
commander and had each accumulated an average of more than 3, 000 flying
hours, thus representing a trained and experienced workforce.

Table 2 reflects the composition of the pilots and aircrew members who had
already changed status and those indicating plans to do so in the near
future. For the same categories* those who had changed status and those
indicating plans to do so* table 3 reflects the percentages of pilots with
the qualifications of flight evaluator, flight instructor, and aircraft
commander that require higher qualifications than the positions of pilot
or copilot.

Table 2: Aircrew Who Had Changed Status and Reported Plans to Change
Status in the Near Future

Status Pilot Nonpilot

Changed: past loss 51% 49% Intending to change: future loss 69 31

Source: GAO 2000 survey.

Table 3: Pilots Who Had Changed Status and Reported Plans to Change Status
in the Near Future

Role Status Evaluator, instructor,

commander Pilot or copilot

Changed: past loss 87% 13% Intending to change: future loss 95 5

Source: GAO 2000 survey.

Table 2 shows that more than half of the experienced losses, as well as
the potential future losses, of aircrew members in the guard and reserve
were pilots. Table 3 discloses that the majority of the pilots served or
serve in the more experienced positions of flight evaluator, flight
instructor, and aircraft commander. In summary, in both groups* those who
had left and those intending to leave* most of the pilot losses
represented a very seasoned and experienced workforce.

Page 13 GAO- 02- 445 Anthrax Vaccine

Most survey respondents reported fairly negative views concerning AVIP and
any additional biological vaccines DOD planned in the future as well. A
substantial majority of all respondents* 66 percent* reported supporting
AVIP to little or no extent, as shown in figure 3. About 9 percent
supported the program to a great or very great extent.

Figure 3: Extent of Support for AVIP Reported by Pilots and Aircrew

Source: GAO 2000 survey.

We performed additional analyses to determine whether there were
statistically significant differences in responses about the extent of
AVIP support between Air Force Reserve and Air National Guard members,
personnel who had changed their military status and those who had not, and
nonrecipients of the vaccination shot versus vaccinated personnel. We
found that Air Force Reserve personnel were considerably more likely than
Air National Guard personnel to report limited or no support for AVIP.
Further, people who had already changed military status were a little more
than twice as likely as those who had not changed status to indicate
limited support for AVIP. The same ratio held true for a nonshot recipient
when compared with an anthrax shot recipient. The Anthrax Vaccine

Program Was Not Widely Supported

Percent 0 10

20 30

40 50

60 70

Little or none Some Moderate

Great Very great

66 14

11 5 4

Page 14 GAO- 02- 445 Anthrax Vaccine

Overall, a large majority of the respondents* 77 percent* indicated that
they would not or probably would not have taken the anthrax vaccine shots
if AVIP were a voluntary program. Just 11 percent of the respondents
reported that they would have taken or probably would have taken the shot
on a voluntary basis; about 13 percent were uncertain. These data are
reflected in figure 4.

Figure 4: Aircrew Views on the Likelihood of Their Voluntarily Taking
Anthrax Vaccine

Source: GAO 2000 survey.

We also found that officers (compared with enlisted personnel), members of
the reserve (compared with the guard), those who had changed their
military status (compared with those who had not), and nonrecipients of
the vaccine (compared with recipients) were statistically more likely to
indicate that they probably would not have taken the anthrax shot
voluntarily. For example, officers were more than twice as likely as
enlisted personnel to indicate they would not or probably would not have
taken the anthrax vaccine voluntarily. Similarly, reserve personnel were
almost twice as likely as guard personnel to answer *no* or *probably no*
to taking the anthrax vaccine voluntarily.

Percent 0 10

20 30

40 50

60 70

80 90

No or probably no

Uncertain Yes or probably yes

77 13 11

Page 15 GAO- 02- 445 Anthrax Vaccine

In addition, an estimated 86 percent, or almost 9 of 10, *would have had
concerns* or *probably would have had concerns* about safety if additional
vaccines for other BW agents were added to military immunization
requirements in the future. About three- fourths of guard and reserve
personnel reported they had immediate family and co- workers who agreed
with their views on the military*s AVIP.

Overall, our survey disclosed a general dissatisfaction with the
respondents* perception of the completeness and accuracy of information
DOD provided to the guard and reserve about AVIP before 2000. This
dissatisfaction appeared to be especially high concerning such key factors
as the military threat from anthrax, the anthrax vaccine*s battlefield
effectiveness, the vaccine*s history and past usage, the short- term and
long- term safety risks of the vaccine, and the possible side effects from
and reactions to the vaccine. Fewer were satisfied with the information
provided on other factors, as shown in figure 5.

Figure 5: Aircrew Satisfaction with DOD*s Information on Anthrax Issues

Source: GAO 2000 survey.

Respondents Did Not Deem AVIP Information That DOD Provided Credible

Percent 0 1000

2000 3000

4000 5000

6000 7000

8000 9000

Side effects Long- term safety Short- term safety History Vaccine
effectiveness

Threat

Dissatisfied Neither satisfied nor dissatisfied Satisfied 69

18 13

69 20

11 62

33 15

55 23 22

62 20 18

41 78

37

Page 16 GAO- 02- 445 Anthrax Vaccine

Our analysis also disclosed that reserve personnel were uniformly less
satisfied with the information provided to them about AVIP than were guard
personnel. Further, we found that officers were more likely than enlisted
personnel to question the information on certain issues, such as the
vaccine*s battlefield effectiveness and its short- term and long- term
safety.

Although DOD employed a high- visibility information campaign on AVIP and
took various steps to address the controversy surrounding it, we reported
in October 1999* about a year after the official start of AVIP* that
service members were not satisfied with the information DOD had provided
to them at the time. 11

Subsequently, DOD expanded its communications efforts by updating the
program*s Internet web site, opening a toll- free anthrax information
telephone line, and forming a speaker*s bureau of anthrax experts. In
addition, DOD updated briefings for installation leaders and medical
personnel to provide more detailed information on the anthrax threat and
vaccine.

Despite DOD*s efforts, we found that relatively few survey respondents had
visited DOD*s Web site at the time of our survey, and few respondents
reported being satisfied with the information posted. For example, of
those who visited the Web site, 20 percent were moderately to very
satisfied with the completeness of the information, 19 percent were
moderately to very satisfied with the information*s accuracy, and 27
percent were moderately to very satisfied with its timeliness. Just 12
percent were moderately to very satisfied that the information was
unbiased.

Concerns were also expressed about the anthrax vaccine and its possible
effects on certain health issues such as fertility and the risk of
increased autoimmune disease. These issues and respondents* concerns are
summarized in figure 6.

11 U. S. General Accounting Office, Medical Readiness: DOD Faces
Challenges in Implementing Its Anthrax Vaccine Immunization Program, GAO/
NSIAD- 00- 36 (Washington, D. C.: Oct. 22, 1999).

Page 17 GAO- 02- 445 Anthrax Vaccine

Figure 6: Personnel with Moderate to Very Great Concern about the Anthrax
Vaccine and Health Issues

Note: Percentages are estimates, based on GAO*s 2000 survey.

Although the survey disclosed that the respondents* basic views regarding
AVIP and the anthrax vaccine were quite negative, the survey did not
indicate a general antivaccine bias. On the contrary, most respondents
expressed a positive attitude toward immunization in general in terms of
both effectiveness and safety. Overall, 73 percent, or close to
threefourths, believed that immunization is effective, and 59 percent, or
about three- fifths, believed it to be safe.

Percentage 0 10

20 30

40 50

60 70

80 90

Other Autoimmune Effect on offspring Male fertility Female fertility

84 16

80 20

63 37

51 49 44

56 Moderate to very great None or some

Page 18 GAO- 02- 445 Anthrax Vaccine

According to our survey results, the reported rate and severity of adverse
events experienced by personnel who had received the anthrax shots were
considerably higher than those published in the vaccine manufacturer*s
product insert in use at the time of the survey or reported by DOD. 12 For
example, an estimated 84 percent of the personnel who had had anthrax
vaccine shots between September 1998 and September 2000 reported having
side effects or reactions. This rate is more than double the level cited
in the vaccine product insert. Further, about 24 percent of all events
were classified as systemic* a level more than a hundred times higher than
that estimated in the product insert. The reaction rates from our survey
were also consistent with the results of two earlier DOD studies of the
anthrax vaccine. In addition, we found that most events were not being
reported to either official or informal DOD channels, partly because most
individuals were unaware of the reporting process for documenting any such
occurrences.

According to the anthrax vaccine product insert in use at the time of our
survey, a number of reactions can be expected from the anthrax vaccine.
Table 4 summarizes the type and severity of adverse events reported in the
product insert.

Table 4: Adverse Reactions Described in the Anthrax Vaccine Product Insert
Type Percentage

occurrence Description Additional Information

Mild local 30 Consists of small erythema, 1* 2 cm in diameter; occurs
within 24 hours and begins to subside by 48 hours

Erythema may increase to 3* 5 cm; severity tends to increase by 5th
injection

Moderate local 4 Inflamed reactions greater than 5 cm in diameter; nodules
may occur at injection site and may persist for several weeks in a few
persons

More severe reactions are less frequent and consist of extensive edema of
forearm

Systemic 0.2 Characterized by malaise and lassitude; chills and fever have
been reported in only a few cases

Immunization should be discontinued in such instances

Source: Anthrax Vaccine Product Insert, 1999.

As reflected in the table, at the time of our survey 34. 2 percent of all
anthrax vaccine recipients were estimated to report experiencing a

12 While the accuracy of memory may degrade over time, in this case this
effect was minimized because of the highly publicized nature of the
program, and our survey was administered while respondents were still
receiving the shots. Respondents

Reported More Adverse Events than Expected

Page 19 GAO- 02- 445 Anthrax Vaccine

reaction* generally fairly mild and short lived. The vast majority, or 30
percent, of such reactions should consist of an area of redness 1 to 2
centimeters in diameter at the injection site. Moderate local reactions,
consisting of increased redness and the possible appearance of persistent
nodules, were expected in about 4 percent of shot recipients. A rate of
only 0.2 percent for systemic reactions was anticipated. According to the
insert, immunization should be discontinued when systemic reactions occur.
The duration of most reactions, other than the development of a nodule,
was expected to be short and to dissipate in a few days.

According to our survey, 37 percent of guard and reserve personnel
received one or more anthrax vaccine shots. Of these, 84 percent reported
side effects or adverse events* a rate more than double that expected or
cited in the product insert. On the basis of our survey, each anthrax shot
generated more than four reported events, and each respondent had received
close to four shots of anthrax vaccine. Thus, the average respondent had
reported experiencing about 17 reactions or events thought to be
attributable to the vaccine. Figure 7 compares the estimated percentages
of vaccine reactions in the product insert with the experience reported in
our survey.

Page 20 GAO- 02- 445 Anthrax Vaccine

Figure 7: Estimated and Reported Vaccine Reactions and Events

Source: GAO 2000 survey.

We estimate that almost 44 percent of anthrax shot recipients reported
experiencing minor local redness, about 24 percent experienced the
enlarged redness associated with a moderate local reaction, and about 69
percent experienced the development of nodules. These data considerably
exceed the levels in table 4. The rates, however, are similar and
consistent with the Korea and Hawaii studies that DOD conducted after AVIP
started. For example, the Hawaii study (the Tripler survey) disclosed a
reaction rate for moderate to severe redness ranging from 18 percent to 32
percent for shots one through four. Our survey indicated rates ranging
between 21 and 24 percent for the same shots. The Hawaii study also
reported that between 64 percent and 66 percent of the vaccine recipients
experienced a lump or knot* our survey disclosed a range of 64 to 68
percent for the same shots. Both the Hawaii and Korea studies found that
women experienced a reaction rate substantially higher than men did* in
some instances double or more. Our survey did not include a sufficient
number of women to address this issue.

Percentage 0 10

20 30

40 50

60 70

80 90

Total Local Systemic

34 84

34 76

24 0.2 Estimated Reported

Page 21 GAO- 02- 445 Anthrax Vaccine

These two DOD studies found a higher incidence of systemic reactions than
estimated in the product insert and also found that women experienced
higher rates than men did. Our survey estimated that almost 24 percent of
all the events experienced were systemic* a rate more than a hundred times
that expected in the product insert in effect at the time of our survey.
Almost 19 percent of all reported reactions in our guard and reserve
survey exceeded 7 days. The rate for local reactions lasting longer than 7
days was 17 percent and slightly greater than 23 percent for systemic
reactions. The rate of event or reaction per shot appeared to be fairly
consistent, with some drop- off as the shot series progressed, as shown in
table 5.

Table 5: Adverse Events Exceeding 7 Days by Anthrax Vaccination Shot
Vaccination shot Event type 1 2 3 4 5 6 Average

Local 19.0% 17.1% 16.6% 14.3% 13.6% 30.0% 17.0% Systemic 26.5 25.8 23.1
20.6 12.3 5. 5 23.4

Total 20.7% 19.1% 18.2% 15.9% 13.4% 26.7% 18.6%

Source: GAO 2000 survey.

Some of these reactions could have implications for safety and effective
work performance* for example, conditions such as arm pain with limited
motion, extreme fatigue, joint pain, and memory loss lasting more than 7
days.

We found that most of the reactions were not reported to the military
chain of command through official channels (military medical personnel),
informal channels (supervisors), or FDA*s VAERS. Since most individuals
were not reporting their reactions to military medical personnel, their
supervisors, or VAERS, the actual duration, extent, or impact on units and
individuals and the ultimate resolution of reactions are unknown.

We estimated that about 67 percent of those who experienced side effects
or reactions were unaware of VAERS. As a result, about 6 percent of those
who experienced a reaction reported it to this system* altogether 18
individuals reported submitting VAERS reports on their own, and another 6
reported that the military submitted a report for them. Moreover, DOD had
initially limited reporting anthrax vaccine events to VAERS to only
reactions leading to either hospitalization or the loss of 48 hours or
more of duty time. This restriction was subsequently removed. In addition,
our survey estimated that about 57 percent of those who

Page 22 GAO- 02- 445 Anthrax Vaccine

experienced an adverse reaction did not discuss it with anyone in military
health care or their individual supervisors. Some 49 percent cited concern
about the loss of flight status, possible adverse effects on their
military or civilian careers, and the fear of ridicule as reasons for not
discussing vaccination shot reactions with others. Another 49 percent
indicated that the reactions they experienced were not severe enough to
seek medical help or to tell their supervisors about.

DOD continued to use data from VAERS to monitor adverse events or
reactions to anthrax vaccination, even though it is a *passive*
surveillance system that relies on vaccine recipients or their health care
providers to report adverse events after vaccination. Studies show that
significantly fewer adverse events are reported under such a system when
compared to an active surveillance approach in which vaccine recipients
are actively monitored to identify and track any adverse reactions to a
vaccine or medication. 13 For example, we estimated that almost three-
fourths of vaccinated guard and reserve personnel experienced burning in
the vaccinated arm and a knot or lump in the vaccinated arm, compared with
DOD*s report that 0.007 percent had such reactions. In November 2001, DOD
reported that after more than 2 million doses of anthrax vaccine had been
administered to more than 522,000 people, only 1,685 VAERS reports were
submitted for possible adverse events associated with the vaccine. In
contrast, the approximately 380 shot recipients in our survey disclosed
more than 6,000 reactions (almost 1,300 of which were systemic) from
slightly more than 1,300 shots.

According to DOD, inhalation anthrax is the greatest BW threat to U. S.
military forces. To counter this threat, DOD officially established the
mandatory AVIP in August 1998 to inoculate all 2.4 million of DOD*s
service members, including active duty and reserve component personnel,
along with some DOD civilian and contractor employees. This major
undertaking involved scheduling and administering more than 14 million
shots to satisfy the vaccine*s initial dosage requirements of six shots
per individual over an 18- month period, followed by an annual booster.

13 S. Rosenthal and R. Chan, *The Reporting Sensitivities of Two Passive
Surveillance Systems for Vaccine Adverse Events,* American Journal of
Public Health 85, no. 12 (1995): 1706- 09; R. T. Chan and others, *The
Vaccine Adverse Event Reporting System (VAERS),* Vaccine 12 (1994): 542*
50; R. T. Chan, *Special Methodological Issues in Pharmacoepidemiology
Studies of Vaccine Safety,* in Pharmacoepidemiology, ed. B. L. Strom (New
York: John Wiley & Sons, 1994). Conclusions

Page 23 GAO- 02- 445 Anthrax Vaccine

Accordingly, DOD initiated a large, high- visibility campaign to
communicate its views and to inform service members about the anthrax
threat and the anthrax vaccine. Among other things, DOD established a Web
site, opened a toll- free anthrax information telephone service, formed a
speakers* bureau of experts, and provided briefings and other materials
for installation leaders and medical personnel to use at unit and base or
installation levels.

Our findings suggest that DOD*s communications efforts were largely
unsuccessful in convincing most guard and reserve pilots and aircrew
members that the anthrax threat was as serious as alleged or to support
AVIP as an appropriate response. Overall, there was a general and
pervasive degree of dissatisfaction among guard and reserve pilots and
aircrew members about the completeness and accuracy of most of the
information DOD provided on the anthrax vaccine and AVIP. In addition to
their response to military threat, surveyed pilots and aircrew members
expressed significant dissatisfaction with such key factors as the
battlefield effectiveness of the anthrax vaccine, its history and past
usage, its short- term and long- term safety risks, and the possible side
effects from the vaccine.

In addition, although DOD has maintained from AVIP*s outset that the
anthrax vaccine is very safe and causes minimally adverse effects, our
survey disclosed that a significantly large number of vaccine recipients
reported experiencing adverse events. Further, the results of two DOD
studies on anthrax vaccine reactions* both of which used active monitoring
systems, as opposed to a passive system such as VAERS, for gathering
information on adverse events* are consistent with and support the results
of our survey. The rates disclosed in the survey and the DOD studies are
each significantly higher than those stated in the vaccine product insert
until recently. Such marked variances from the product insert data suggest
the possibility of change in the composition of the vaccine from the
vaccine originally approved in 1970.

In summary, AVIP appears to have adversely affected the Air National Guard
and Air Force Reserve in terms of retaining needed experienced personnel.
Sixteen percent of our survey respondents either left the military or
significantly reduced their level of participation, citing the anthrax
immunization program as an important factor in their decision to do so.
Interestingly, 45 percent of these individuals indicated that they would
consider returning if AVIP were made voluntary. Further, at the time of
our survey, 18 percent of those still participating indicated their
intention to leave in the near future, again citing AVIP as an important

Page 24 GAO- 02- 445 Anthrax Vaccine

factor in that decision. Unfortunately, the actual losses and expected
losses as a result of this program represented some of the most
experienced and highly trained individuals in these services and are
people not easily replaced. It takes time and a great deal of money and
other resources to develop trained, experienced pilots and other aircrew
members to support the important missions of these reserve components,
particularly in light of the current battle against terrorism.

We recommend that the Secretary of Defense direct the establishment of an
active surveillance program (unlike the passive VAERS) to identify and
monitor adverse events associated with each anthrax vaccine immunization.
This program should ensure that appropriate and complete treatment and
follow- up are provided to those who have experienced adverse events and
to those who may experience them in the future.

In comments on a draft of this report (reprinted in app. V), DOD did not
concur with our recommendation to establish a surveillance program. In
support of its position, DOD cited the following statement from the
Institute of Medicine*s report: The Institute of Medicine *committee

observes that no data that indicate the need for the continuation of
special monitoring programs for anthrax vaccine have emerged, but it
recognizes the real concerns for service members ordered to take the
vaccines.* 14 In addition, DOD stated that data from the Defense Manpower
Data Center about actual pilot separations did not support the statements
in the report in that the center*s data show that pilot separations before
the beginning of the anthrax program in 1998 were similar to the rates
during the time of the survey. DOD further stated that our report did not
address the normal or expected rates of turnover known to occur among
personnel in the Air National Guard and the Air Force.

DOD*s selective use of a conclusion from the Institute of Medicine report
that *a separate AVA monitoring program is not necessary* is misleading.
This response, while technically correct, ignores the comprehensive
recommendations that the institute*s report actually made to DOD.
Specifically, the institute recommended that DOD (1) use VAERS data to
generate hypotheses to study further, using DOD*s new unified service

14 Institute of Medicine, The Anthrax Vaccine: Is It Safe? Does It Work?
(Washington, D. C.: 2002). Recommendations

Agency Comments

Page 25 GAO- 02- 445 Anthrax Vaccine

medical reporting system; (2) regularly study those data for new trends;
(3) work with the Department of Veterans Affairs to encourage
participation in the Millennium Cohort study to better get a handle on all
the problems associated with the Gulf War and other actions; and (4)
regularly do ad hoc unit- based population monitoring of reactions to all
vaccines. 15 In addition, the Institute of Medicine report recommended
that anthrax vaccine lots produced after renovations at the BioPort
vaccine production facility should continue to be monitored for
immunogicity and stability and that individuals receiving these lots
should be monitored for possible acute or chronic events of immediate or
later onset. Adoption of these recommendations would satisfy our
recommendation.

More importantly, DOD did not address two major findings from our survey:
(1) some of the adverse reactions that our respondents reported persisted
for more than 7 days and (2) given that a large proportion of respondents
were not reporting the symptoms to VAERS or their DOD health care
practitioners, we do not know whether these reactions were resolved over
time. Also, active monitoring would result in a more comprehensive
database for conducting specific analysis to test whether the adverse
reactions lasting for more than 48 hours are occurring among older
recipients, as suggested by a study conducted in the United Kingdom. 16 In
that study, older recipients of the anthrax vaccine experienced
significant incapacity (inability to lift or drive), which according to
the author, would be critical for some military populations, such as
aviators. Further, several studies in the United States and the United
Kingdom now show a relationship between anthrax vaccine and

15 The Millennium Cohort Study is a survey sponsored by DOD. It will
monitor a total of 140, 000 U. S. military personnel during and after
their military service for up to 21 years to evaluate the health risks of
military deployment, military occupations, and general military service.

16 M. J. World, *Anthrax Immunization in the Older Warrior,* North
Atlantic Treaty Organization: RTO Meeting Proceedings 33, Operational
Issues of Aging Crewmembers,

Oct. 11* 14, 1999.

Page 26 GAO- 02- 445 Anthrax Vaccine

Gulf War syndrome. 17 We recommended an active monitoring system not for
the sole purpose of identifying adverse reaction rates, since FDA has
already recognized much higher local and systematic reaction rates and the
recent product insert has been revised accordingly, but also to
proactively monitor, identify, and treat individuals experiencing adverse
reactions. Our recommendation should lead to better lines of
communications in the chain of command and help overcome any fear or
mistrust of communicating reactions or symptoms to those responsible for
medical care. In addition, since the anthrax vaccine will be offered to
civilian first responders or health care workers, civilian doctors would
need information on adverse reactions that can be expected to follow. 18
DOD could be instrumental in providing information to civilian and medical
doctors about how these symptoms are resolved over time and effective
treatment approaches but only if an active monitoring program or the
recommendations of the Institute of Medicine are fully implemented.

With regard to our survey*s findings on pilot attrition, DOD had not
provided data to support its statement that there was no difference
between pilot separations before and during the mandatory AVIP program by
the time this report was issued. However, DOD*s response uses the term
*separations* while our report uses the term *change of status,* which is
a much broader term. We reported on percentages of pilots who changed
their status (for example, transferred to another unit, left the military
in a *separation,* or moved to inactive status) to avoid anthrax vaccine.
In any event, although the overall separation rates may be the same before
and after the onset of the mandatory anthrax vaccine program, it is clear
that the losses among the most experienced pilots (in bases where AVIP was
implemented) resulting from change of status were

17 L. Steele, *Prevalence and Patterns of Gulf War Illness in Kansas
Veterans: Association of Symptoms with Characteristics of Person, Place,
and Time of Military Service,* American Journal of Epidemiology 152
(2000): 992* 1002; W. R. Schumm and others, *Self- Reported Changes in
Subjective Health and Anthrax Vaccination as Reported by Over 900 Persian
Gulf War Era Veterans,* Psychological Reports 90 (2002): 639* 53; P. B.
Asa and others,

*Antibodies to Squalene in Gulf War Syndrome,* Journal of Experimental and
Molecular Pathology 68 (2000): 55* 64, and *Antibodies to Squalene in
Recipients of Anthrax Vaccine,*

Journal of Experimental and Molecular Pathology 73 (2002): 19* 27; N.
Cherry and others,

*Health and Exposures of United Kingdom Gulf War Veterans, Part II, The
Relation of Health to Exposure,* Journal of Occupational and Environmental
Medicine 58 (2001): 299* 306; C. Unwin and others, *Health of U. K.
Servicemen Who Served in Persian Gulf War,* Lancet 353 (1999): 169* 78.

18 D. A. Geier and M. R. Geier, *Anthrax Vaccination and Joint Related
Adverse Reactions in Light of Biological Warfare Scenarios,* Journal of
Clinical Experimental Rheumatology

20 (2002): 217* 20.

Page 27 GAO- 02- 445 Anthrax Vaccine

significant at some bases, resulting in the loss of an extremely seasoned
workforce.

As we agreed with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution of it until 30
days from its issue date. We will then send copies of the report to other
interested congressional members and committees. In addition, the report
will be available at no charge on the GAO Web site at http:// www. gao.
gov.

If you or your staff have any questions about this report or would like
additional information, please call me at (202) 512- 2700 or Sushil K.
Sharma, Assistant Director, at (202) 512- 3460. Penny Pickett, Laurel
Rabin, and Foy Wicker also made key contributions to this report.

Nancy R. Kingsbury, Managing Director Applied Research and Methods

Appendix I: Scope and Methodology Page 28 GAO- 02- 445 Anthrax Vaccine

The best way to reliably assess the pulse and views of military personnel
is by surveying a representative sample. We developed and administered
such a survey that was designed to obtain the views of selected Air
National Guard and Air Force Reserve personnel regarding issues associated
with AVIP. The survey, which was both voluntary and confidential, was
mailed in May 2000 to a random sample of 1,253 personnel. As of September
7, 2000, 828 individuals had completed and returned the survey. Follow- up
efforts yielded an additional 15 responses. A total of 843 responses were
returned, of which 833 provide useful information.

In addition, we performed logistic regression analyses for selected
questions in our questionnaire to determine odds ratios to evaluate the
responses of certain groups in our survey population. These groups
included enlisted personnel and officers, Air National Guard and Air Force
Reserve personnel, shot recipients and nonshot recipients, and individuals
who had changed their military status and those who had not. We conducted
our work in accordance with generally accepted government auditing
standards.

We developed the survey with the assistance of discussion groups made up
of pilots and other aircrew members of the Air National Guard and Air
Force Reserve. It was pretested at Andrews Air Force Base, Maryland, and
further pretested and refined at guard and reserve units at March Air
Reserve Base, California; Travis Air Force Base, California; Hartford,
Connecticut; Battle Creek, Michigan; Newburg, New York; Memphis,
Tennessee; and Madison, Wisconsin.

The sample consisted of 1,253 Air National Guard and Air Force Reserve
aircrew personnel who were in the service at any time between September
1998 and February 2000. Our sample was drawn from pilot and aircrew member
populations provided by the Air National Guard and Air Force Reserve in
early 2000. In addition, the AVIP office provided information as to
vaccination status. For the sample design, we categorized personnel in our
universe by two factors: military status (left versus onboard) and vaccine
status (shot versus no shot). The sample was adjusted for groups with
differing expected rates of survey completion and adjusted to provide a
level of precision of plus or minus 5 percentage points. Appendix I: Scope
and Methodology

Questionnaire Development

Sample Construction

Appendix I: Scope and Methodology Page 29 GAO- 02- 445 Anthrax Vaccine

As of September 6, 2001, we had received 843 responses from eligible
respondents, an overall response rate of 67 percent. We used a contractor
to key in the data reported in the responses. We validated the data
provided to us by the contractor to ensure accuracy.

The survey responses were weighted to reflect the Air National Guard and
Air Force Reserve population for the survey. This weighting procedure
adjusts for the different proportions of individuals sampled from each
cell and the actual response rate for that cell in the sample design. The
survey results assumed that nonrespondents would have answered as the
respondents did. This assumption involves some unknown risk of nonresponse
bias. Weighting can be used to statistically adjust for differing sampling
rates and response rates. However, weighting cannot adjust for possible
differences between those who do and those who do not respond to a survey.
Survey Administration

Weighting Responses and Potential Nonresponse Bias

Appendix II: Estimated Percentages of Vaccination Shot Recipients
Experiencing Local and Systemic Adverse Reactions

Page 30 GAO- 02- 445 Anthrax Vaccine

Vaccination shot Reaction 1 2 3 4 5 6

Average % experiencing

reaction Local

Redness 2. 5 inches or less 39.6% 33.5% 32.7% 33.5% 29.2% 42.6% 35.2%
Redness 2. 5 inches or more 16.9 19.7 19.4 17.6 16.8 26.2 19.4 Swelling in
arm 37.7 37.8 36.3 34.5 29.2 31.5 34.5 Burning in arm 60.7 60.6 58.1 57.8
57.0 63.4 59.6 Arm pain or limited motion 36.1 35.5 36.0 33.2 29.2 26.2
32.7 Itching in arm 27.6 28.3 29.0 27.4 25.6 26.8 27.4 Knot or lump in arm
54.5 55.3 55.3 51.7 52.1 63.4 55.4

Systemic

Chills 7. 7 6.8 8. 2 8.4 6. 5 5.7 7. 2 Fever 9. 3 9.6 10.3 9. 6 6.6 5. 7
8.5 Extreme fatigue 14.5 16.6 16.4 13.8 8. 9 0.6 11.8 Dizziness 3. 1 2.8
3. 3 4.3 2. 6 0.6 2. 8 Headaches 9.6 8. 4 9.8 8. 5 5.2 0. 6 7.0 Blurred
vision 2.3 2. 4 2.9 2. 5 1.4 0. 3 2.0 Numbness in extremities 3. 6 3.3 3.
4 3.2 1. 7 6.3 3. 6 Joint pain 16.1 16.3 17.3 18.0 13.0 16.7 16.2 Memory
loss 4.0 3. 7 4.3 4. 3 3.7 0. 6 3.4 Blackouts 0. 8 0.4 0. 4 0.6 1. 2 0 0.
6 Ringing in ears 5. 4 4.5 4. 6 3.1 2. 7 0.6 3. 5 Insomnia 4.3 3. 7 3.4 2.
5 3.8 0 2.9 Nausea 4.3 4. 5 4.7 5. 5 6.4 5. 7 5.2 Other 4.1 3. 5 4.9 5. 3
5.0 0 3.8

Source: GAO analysis.

Appendix II: Estimated Percentages of Vaccination Shot Recipients
Experiencing Local and Systemic Adverse Reactions

Appendix III: The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number

Page 31 GAO- 02- 445 Anthrax Vaccine

Estimated number receiving each vaccination shot Reaction type and
duration 1 2 3 4 5 6 Total number

of reactions 4,678 4,492 4,316 2,933 1,389 336 Local Redness 2.5 inches or
less

Less than 24 hours 663 605 570 376 142 38 2,394 1* 3 days 680 538 502 356
173 52 2,301 4* 7 days 290 250 195 159 35 17 946 7 days or more 217 112
146 91 55 36 657

Total weighted number 1, 850 1,505 1,413 982 405 143 6,298 % 7 days or
more 11.7% 7.4% 10.3% 9.3% 13.6% 25.2% Redness 2.5 inches or more

Less than 24 hours 112 158 112 91 38 2 513 1* days 282 334 350 228 140 69
1,403 4* 7 days 220 200 181 126 54 17 798 7 days or more 176 192 194 71 2
0 635

Total weighted number 790 884 837 516 234 88 3,349 % 7 days or more 22.3%
21.7% 23.2% 13.8% 0.9% 0% Swelling in arm

Less than 24 hours 463 446 477 301 157 35 1,879 1* 3 days 537 617 513 334
104 0 2, 105 4* 7 days 349 294 291 181 55 0 1, 170 7 days or more 413 339
288 197 90 71 1,398

Total weighted number 1, 762 1,696 1,568 1,013 406 106 6,551 % 7 days or
more 23.4% 20.0% 18.4% 19.4% 22.2% 67.0% Burning sensation in arm

Less than 24 hours 2, 211 2,099 1,995 1,304 702 194 8,505 1* 3 days 498
498 406 301 90 19 1,812 4* 7 days 41 58 55 55 0 0 209 7 days or more 90 69
52 35 0 0 246

Total weighted number 2, 840 2,724 2,508 1,695 792 213 10,772 % 7 days or
more 3.2% 2.5% 2.1% 2.1% 0% 0% Arm pain or limited motion

Less than 24 hours 524 455 573 334 142 35 2,063 1* 3 days 564 592 491 359
157 36 2,199 4* 7 days 356 337 332 194 87 0 1, 306 7 days or more 247 209
156 87 19 17 735

Total weighted number 1, 691 1,593 1,552 974 405 88 6,303 % 7 days or more
14.6% 13.1% 10.1% 8.9% 4.7% 19.3%

Appendix III: The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number

Appendix III: The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number

Page 32 GAO- 02- 445 Anthrax Vaccine

Estimated number receiving each vaccination shot Reaction type and
duration 1 2 3 4 5 6 Total number

of reactions 4,678 4,492 4,316 2,933 1,389 336 Local Itching in arm

Less than 24 hours 567 572 554 340 145 19 2,197 1* 3 days 324 307 375 211
69 17 1,303 4* 7 days 231 247 178 145 71 19 891 7 days or more 167 145 145
109 71 35 672

Total weighted number 1, 289 1,271 1,252 805 356 90 5,063 % 7 days or more
13.0% 11.4% 11.6% 13.5% 19.9% 38.9% Knot or lump in arm

Less than 24 hours 548 465 461 249 157 35 1,915 1* 3 days 337 381 345 282
192 19 1,556 4* 7 days 553 624 653 499 159 36 2,524 7 days or more 1,110
1,013 929 485 216 123 3,876

Total weighted number 2, 548 2,483 2,388 1,515 724 213 9,871 % 7 days or
more 43.6% 40.8% 38.9% 32.0% 29.8% 57.7% Systemic Chills

Less than 24 hours 167 77 159 140 54 17 614 1* 3 days 107 124 106 71 19 2
429 4* 7 days 71 71 71 36 0 0 249 7 days or more 17 35 17 0 17 0 86

Total weighted number 362 307 353 247 90 19 1,378 % 7 days or more 4.7%
11.4% 4.8% 0% 18.9% 0% Fever

Less than 24 hours 203 167 197 157 54 0 778 1* 3 days 180 178 176 72 38 19
663 4* 7 days 19 36 19 36 0 0 110 7 days or more 35 52 52 17 0 0 156

Total weighted number 437 433 444 282 92 19 1,707 % 7 days or more 8.0%
12.0% 11.7% 6.0% 0% 0% Extreme fatigue

Less than 24 hours 159 213 211 139 36 2 760 1* 3 days 233 213 211 71 35 0
763 4* 7 days 72 88 54 54 36 0 304 7 days or more 214 231 231 140 17 0 833

Total weighted number 678 745 707 404 124 2 2, 660 % 7 days or more 31.6%
31.0% 32.7% 34.7% 13.7% 0%

Appendix III: The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number

Page 33 GAO- 02- 445 Anthrax Vaccine

Estimated number receiving each vaccination shot Reaction type and
duration 1 2 3 4 5 6 Total number

of reactions 4,678 4,492 4,316 2,933 1,389 336 Local Dizziness

Less than 24 hours 57 39 38 38 36 0 208 1* 3 days 36 54 88 52 0 2 232 4* 7
days 17 17 0 0 0 0 34 7 days or more 35 17 17 35 0 0 104

Total weighted number 145 127 143 125 36 2 578 % 7 days or more 24.1%
13.4% 11.9% 28.0% 0% 0% Headaches

Less than 24 hours 184 146 178 123 52 0 683 1* 3 days 124 106 175 71 19 0
495 4* 7 days 71 54 36 19 2 0 182 7 days or more 71 71 36 36 2 2 218

Total weighted number 450 377 425 249 75 2 1, 578 % 7 days or more 15.8%
18.8% 8.5% 14.5% 2.7% 0% Blurred vision

Less than 24 hours 55 55 55 36 17 0 218 1* 3 days 0 0 35 0 0 0 35 4* 7
days 19 19 19 19 2 1 79 7 days or more 35 35 17 17 0 0 104

Total weighted number 109 109 126 72 19 1 436 % 7 days or more 32.1% 32.1%
13.5% 23.6% 0% 0% Numbness in extremities

Less than 24 hours 60 41 39 54 17 17 228 1* 3 days 2 2 19 3 2 2 30 4* 7
days 35 35 36 36 2 0 144 7 days or more 71 71 52 0 2 2 198

Total weighted number 168 149 146 93 23 21 600 % 7 days or more 42.3%
47.7% 35.6% 0% 8.7% 9.5% Joint pain

Less than 24 hours 180 164 180 175 71 54 824 1* 3 days 178 140 175 106 17
0 616 4* 7 days 128 161 161 126 38 0 614 7 days or more 268 265 230 121 54
2 940

Total weighted number 754 730 746 528 180 56 2,994 % 7 days or more 35.5%
36.3% 30.8% 22.9% 30.0% 3.6%

Appendix III: The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number

Page 34 GAO- 02- 445 Anthrax Vaccine

Estimated number receiving each vaccination shot Reaction type and
duration 1 2 3 4 5 6 Total number

of reactions 4,678 4,492 4,316 2,933 1,389 336 Local Memory loss

Less 24 hours 55 38 55 54 17 0 219 1* 3 days 2 19 2 0 17 0 40 4* 7 days 35
35 35 17 0 0 122 7 days or more 93 76 93 54 17 2 335

Total weighted number 185 168 185 125 51 2 716 % 7 days or more 50.3%
45.2% 50.3% 43.2% 33.3% 0% Blackouts

Less 24 hours 19 19 19 19 17 0 93 1* 3 days 0 0 0 0 0 0 0 4* 7 days 0 0 0
0 0 0 0 7 days or more 17 0 0 0 0 0 17

Total weighted number 36 19 19 19 17 0 110 % 7 days or more 47.2% 0% 0% 0%
0% 0% Ringing in ears

Less 24 hours 107 107 55 38 19 2 328 1* 3 days 36 36 54 0 17 0 143 4* 7
days 19 19 19 2 2 0 61 7 days or more 91 38 71 52 0 0 252

Total weighted number 253 200 199 92 38 2 784 % 7 days or more 36.0% 19.0%
35.7% 56.5% 0% 0% Insomnia

Less 24 hours 39 38 38 19 17 0 151 1* 3 days 19 3 3 0 17 0 42 4* 7 days 55
55 38 19 19 0 186 7 days or more 87 69 69 35 0 0 260

Total weighted number 200 165 148 73 53 0 639 % 7 days or more 43.5% 41.8%
46.6% 47.9% 0% 0% Nausea

Less 24 hours 90 106 106 87 69 17 475 1* 3 days 39 57 76 54 3 2 231 4* 7
days 52 36 17 19 17 0 141 7 days or more 19 2 2 2 0 0 25

Total weighted number 200 201 201 162 89 19 872 % 7 days or more 9.5% 1.0%
1.0% 1.2% 0% 0%

Appendix III: The Weighted Numbers of Local and Systemic Adverse Reactions
by Vaccination Shot Number

Page 35 GAO- 02- 445 Anthrax Vaccine

Estimated number receiving each vaccination shot Reaction type and
duration 1 2 3 4 5 6 Total number

of reactions 4,678 4,492 4,316 2,933 1,389 336 Local Other

Less 24 hours 19 20 36 17 0 0 92 1* 3 days 35 35 35 17 35 0 157 4* 7 days
69 69 88 52 0 0 278 7 days or more 69 35 54 69 34 0 261

Total weighted number 192 159 213 155 69 0 788 % 7 days or more 35.9%
22.0% 25.4% 44.5% 49.3% 0%

Source: GAO analysis.

Appendix IV: Anthrax Vaccine Adsorbed Revised Product Insert (Jan. 31,
2002)

Page 36 GAO- 02- 445 Anthrax Vaccine

Anthrax Vaccine Adsorbed (BioThrax*) is a sterile, milky- white suspension
(when mixed) made from cell- free filtrates of microaerophilic cultures of
an avirulent, nonencapsulated strain of Bacillus anthracis. The production
cultures are grown in a chemically defined protein- free medium consisting
of a mixture of amino acids, vitamins, inorganic salts and sugars. The
final product, prepared from the sterile filtrate culture fluid, contains
proteins, including the 83kDa protective antigen protein, released during
the growth period. The final product contains no dead or live bacteria.
The final product is formulated to contain 1.2 mg/ mL aluminum, added as
aluminum hydroxide in 0.85% sodium chloride. The product is formulated to
contain 25 mg/ mL benzethonium chloride and 100 mg/ mL formaldehyde, added
as preservatives.

Anthrax occurs globally and is most common in agricultural regions with
inadequate control programs for anthrax in livestock. Anthrax is a
zoonotic disease caused by the Gram- positive, spore- forming bacterium

Bacillus anthracis. The spore form of Bacillus anthracis is the
predominant phase of the bacterium in the environment and it is largely
through the uptake of spores that anthrax disease is contracted. Spore
forms are markedly resistant to heat, cold, pH, desiccation, chemicals and
irradiation. Following germination at the site of infection, the bacilli
can also enter the blood and lead to septicemia. Antibiotics are effective
against the germinated form of Bacillus anthracis, but are not effective
against the spore form of the organism.

The disease occurs most commonly in wild and domestic animals, primarily
cattle, sheep, goats and other herbivores. In humans, anthrax disease can
result from contact with animal hides, leather or hair products from
contaminated animals, or from other exposures to Bacillus anthracis
spores. It occurs in three forms depending upon the route of infection:
cutaneous anthrax, gastrointestinal anthrax and inhalation anthrax.

Cutaneous anthrax is the most commonly reported form in humans (> 95% of
all anthrax cases). It can occur when the bacterium enters a cut or
abrasion on the skin, such as when handling contaminated meat, wool,
hides, leather or hair products from infected animals or other Appendix
IV: Anthrax Vaccine Adsorbed

Revised Product Insert (Jan. 31, 2002) Description

Clinical Pharmacology

Epidemiology

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2002)

Page 37 GAO- 02- 445 Anthrax Vaccine

contaminated materials. The symptoms of cutaneous anthrax begin with an
itchy reddish- brown papule on exposed skin surfaces and may appear
approximately 1* 12 days after contact. The lesion soon develops a small
vesicle. Secondary vesicles are sometimes seen. Later the vesicle ruptures
and leaves a painless ulcer that typically develops a blackened eschar
with surrounding swollen tissue. There are often associated systemic
symptoms such as swollen glands, fever, myalgia, malaise, vomiting and
headache. The case fatality rate for cutaneous anthrax is estimated to be
20 percent without antibiotic treatment.

Gastrointestinal anthrax usually begins 1* 7 days after ingestion of meat
contaminated with anthrax spores. There is acute inflammation of the
intestinal tract with nausea, loss of appetite, vomiting and fever
followed by abdominal pain, vomiting of blood and bloody diarrhea. There
can also be involvement of the pharynx with sore throat, dysphagia, fever,
lesions at the base of the tongue or tonsils and regional lymphadenopathy.
The case fatality rate is unknown but estimated to be 25 percent to 60
percent.

Inhalation (pulmonary) anthrax has been reported to occur from 1 to 43
days after exposure to aerosolized spores. 1 Studies in rhesus monkeys
indicate that a small number of inhaled spores may remain viable for at
least 100 days following exposure. 2 However, information on how long
spores remain viable in the lungs of humans is unavailable and the
incubation period for inhalation anthrax is unknown. Initial symptoms are
non- specific and may include sore throat, mild fever, myalgia, coughing
and chest discomfort lasting up to a few days. The second stage develops
abruptly with findings such as sudden onset of fever, acute respiratory
distress with pulmonary edema and pleural effusion followed by cyanosis,
shock and coma. Meningitis is common. The fatality rate for inhalation
anthrax in the United States is estimated to be approximately 45 percent
to 90 percent. From 1900 to October 2001, there were 18 identified cases
of inhalation anthrax in the United States, the latest of which was
reported in 1976, with an 89 percent (16/ 18) mortality rate. Most of
these exposures occurred in industrial settings* i. e., textile mills. 3
From October 4, 2001 to December 5, 2001, a total of 11 cases of
inhalation anthrax linked to intentional dissemination of Bacillus
anthracis spores were identified in the United States. Five of these cases
were fatal. 4

Virulence components of Bacillus anthracis include an antiphagocytic
polypeptide capsule and three proteins known as protective antigen (PA),
lethal factor (LF) and edema factor (EF). Individually these proteins are
not cytotoxic but the combination of PA with LF or EF results in the
Mechanism of Action

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2002)

Page 38 GAO- 02- 445 Anthrax Vaccine

formation of the cytotoxic lethal toxin and edema toxin, respectively.
Although an immune correlate of protection is unknown, antibodies raised
against PA may contribute to protection by neutralizing the activities of
these toxins. 5 The contribution of Bacillus anthracis proteins other than
PA, that may be present in BioThrax, to the protection against anthrax has
not been determined.

A controlled field study using an earlier version of a protective
antigenbased anthrax vaccine, developed in the 1950s, that consisted of an
aluminum potassium sulfate- precipitated cell free filtrate from an
aerobic culture, was conducted from 1955 to 1959. This study included
1,249 workers (379 received anthrax vaccine, 414 received placebo, 116
received incomplete inoculations [with either vaccine or placebo] and 340
were in the observational group [no treatment]) in four mills in the
northeastern United States that processed imported animal hides. 6 During
the trial, 26 cases of anthrax were reported across the four mills* five
inhalation and 21 cutaneous. Prior to vaccination, the yearly average
number of human anthrax cases was 1.2 cases per 100 employees in these
mills. Of the five inhalation cases (four of which were fatal), two
received placebo and three were in the observational group. Of the 21
cutaneous cases, 15 received placebo, three were in the observational
group, and three received anthrax vaccine. Of those three cases in the
vaccine group, one case occurred just prior to administration of the
scheduled third dose, one case occurred 13 months after an individual
received the third of the scheduled 6 doses (but no subsequent doses), and
one case occurred prior to receiving the scheduled fourth dose of vaccine.
In a comparison of anthrax cases between the placebo and vaccine groups,
including only those who were completely vaccinated, the calculated
vaccine efficacy level against all reported cases of anthrax combined was
92.5 percent (lower 95 percent CI = 65 percent).

From 1962 to 1974, based on information reported to Centers for Disease
Control and Prevention (CDC), 27 cases of anthrax occurred in mill workers
or those living near mills in the United States. Of those, 24 cases
occurred in unvaccinated individuals, one case occurred after the person
had been given one dose of anthrax vaccine and two cases occurred after
individuals had been given two doses of anthrax vaccine. No documented
cases of anthrax were reported for individuals who had received the
recommended six doses of anthrax vaccine. These individuals received
either an earlier version of a protective antigen- based anthrax vaccine
or BioThrax. Clinical Studies

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2002)

Page 39 GAO- 02- 445 Anthrax Vaccine

In an open- label safety study conducted by the CDC, BioThrax was
administered in 0.5 mL doses according to a 0, 2, 4 week initial dose
schedule followed by additional doses at 6, 12 and 18 months to complete
the 6 dose vaccination series. Annual boosters were administered
thereafter. In this study, 15,907 doses of BioThrax were administered to
approximately 7, 000 textile employees, laboratory workers and other at-
risk individuals and the incidence rates of local and systemic adverse
reactions were recorded. (See ADVERSE REACTIONS)

A randomized clinical study was conducted by the U. S. Army Medical
Research Institute of Infectious Diseases (USAMRIID) from 1996 to 1999 in
173 volunteers to evaluate changes to the vaccination schedule and route
of vaccine administration. Of those, 28 were enrolled into the study arm
to receive the licensed schedule (initial injections at 0, 2 and 4 weeks
followed by additional doses at 6, 12 and 18 months) and were subsequently
monitored for the occurrence of local and systemic adverse events. (See
ADVERSE REACTIONS)

BioThrax is indicated for the active immunization against Bacillus
anthracis of individuals between 18 and 65 years of age who come in
contact with animal products such as hides, hair or bones that come from
anthrax endemic areas, and that may be contaminated with Bacillus
anthracis spores. BioThrax is also indicated for individuals at high risk
of exposure to Bacillus anthracis spores such as veterinarians, laboratory
workers and others whose occupation may involve handling potentially
infected animals or other contaminated materials.

Since the risk of anthrax infection in the general population is low,
routine immunization is not recommended.

The safety and efficacy of BioThrax in a post- exposure setting has not
been established.

The use of BioThrax is contraindicated in subjects with a history of
anaphylactic or anaphylactic- like reaction following a previous dose of
BioThrax, or any of the vaccine components.

Preliminary results of a recent unpublished retrospective study of infants
born to women in the U. S. military service worldwide in 1998 and 1999
suggest that the vaccine may be linked with an increase in the number of
Indications and Usage

Contraindications Warnings

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2002)

Page 40 GAO- 02- 445 Anthrax Vaccine

birth defects when given during pregnancy (unpublished data, Department of
Defense). Although these data are unconfirmed, pregnant women should not
be vaccinated against anthrax unless the potential benefits of vaccination
have been determined to outweigh the potential risk to the fetus.

Animal reproduction studies have not been conducted with BioThrax. Before
administration, the patient*s medical immunization history should be
reviewed for possible vaccine sensitivities and/ or previous
vaccinationrelated adverse events, in order to determine the existence of
any contraindications to immunization.

Pregnant women should not be vaccinated against anthrax unless the
potential benefits of vaccination clearly outweigh the potential risks to
the fetus.

BioThrax should not be administered to individuals with a history of
Guillain- Barre Syndrome (GBS) unless there is a clear benefit that
outweighs the potential risk of a recurrence.

History of anthrax disease may increase the potential for severe local
adverse reactions.

Patients with impaired immune responsiveness due to congenital or acquired
immunodeficiency, or immunosuppressive therapy may not be adequately
immunized following administration of BioThrax. Vaccination during
chemotherapy, high- dose corticosteroid therapy of greater than 2- week
duration, or radiation therapy may result in a suboptimal response.
Deferral of vaccination for 3 months after completion of such therapy may
be considered. 7

The administration of BioThrax to persons with concurrent moderate or
severe illness should be postponed until recovery. Vaccination is not
contraindicated in subjects with mild illnesses with or without low- grade
fever. 7

This product should be administered with caution to patients with a
possible history of latex sensitivity since the vial stopper contains dry
natural rubber. Precautions

Appendix IV: Anthrax Vaccine Adsorbed Revised Product Insert (Jan. 31,
2002)

Page 41 GAO- 02- 445 Anthrax Vaccine

Epinephrine solution, 1: 1000, should always be available for immediate
use in case an anaphylactic reaction should occur.

PREGNANCY CATEGORY D. See Warnings.

It is not known whether exposure of the mother to BioThrax poses a risk of
harm to the breast- feeding child. However, administration of non- live
vaccines (e. g., anthrax vaccine) during breast- feeding is not medically
contraindicated. 7

Safety and effectiveness in pediatric patients have not been established.
No data regarding the safety of BioThrax are available for persons aged >
65 years.

In an open- label safety study, 15,907 doses of BioThrax were administered
to approximately 7,000 textile employees, laboratory workers and other
atrisk individuals (see Clinical Studies). Over the course of the 5- year
study, there were 24 reports (0.15 percent of doses administered) of
severe local reactions (defined as edema or induration measuring greater
than 120 mm in diameter or accompanied by marked limitation of arm motion
or marked axillary node tenderness). There were 150 reports (0.94 percent
of doses administered) of moderate local reactions (edema or induration
greater than 30 mm but less than 120 mm in diameter) and 1,373 reports
(8.63 percent of doses administered) of mild local reactions (erythema
only or induration measuring less than 30 mm in diameter).

In the same open label study, four cases of systemic reactions were
reported during a 5- year reporting period (< 0.06 percent of doses
administered). These reactions, which were reported to have been
transient, included fever, chills, nausea and general body aches.
Pregnancy

Nursing Mothers Pediatric Use Geriatric Use

Adverse Reactions Pre- Licensure Local Reactions

Systemic Reactions

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2002)

Page 42 GAO- 02- 445 Anthrax Vaccine

Recently (1996- 99), an assessment of safety was conducted as part of a
randomized clinical study conducted by the U. S. Army Medical Research
Institute of Infectious Diseases (USAMRIID) (see Clinical Studies). A
total of 28 volunteers were enrolled to receive subcutaneous doses of
BioThrax according to the licensed schedule. Each volunteer was observed
for approximately 30 minutes after administration of AVA and scheduled for
follow- up evaluations at 1- 3 days, 1 week and 1 month after vaccination.
Four volunteers reported seven acute adverse events within 30 minutes
after the subcutaneous administration of BioThrax. These included erythema
(3), headache (2), fever (1) and elevated temperature (1). Of these
events, a single patient reported the simultaneous occurrence of headache,
fever and elevated temperature (100DEG F).

The most common local reactions reported after the first dose (n = 28) in
this study were tenderness (71 percent), erythema (43 percent),
subcutaneous nodule (36 percent), induration (21 percent), warmth (11
percent) and local pruritus (7 percent). The most frequently reported
local reactions after the second dose (n = 28) were tenderness (61
percent), subcutaneous nodule (39 percent), erythema (32 percent),
induration (18 percent), local pruritus (14 percent), warmth (11 percent)
and arm motion limitation (7 percent). After the third dose (n = 26), the
most frequently reported local reactions were tenderness (58 percent),
warmth (19 percent), local pruritis (19 percent), erythema (12 percent),
arm motion limitation (12 percent), induration (8 percent), edema (8
percent) and subcutaneous nodule (4 percent). Local reactions were found
to occur more often in women. No abscess or necrosis was observed at the
injection site.

All systemic adverse events reported in this study were transient in
nature. The systemic reactions most frequently reported after the first
dose (n = 28) were headache (7 percent), respiratory difficulty (4
percent) and fever (4 percent). After the second dose (n = 28), the most
frequently reported systemic reactions were malaise (11 percent), myalgia
(7 percent), fever (7 percent), headache (4 percent), anorexia (4 percent)
and nausea or vomiting (4 percent). After the third dose (n = 26), the
most frequently reported systemic reactions were headache (4 percent),
malaise (4 percent), myalgia (4 percent) and fever (4 percent). There was
one report of delayed hypersensitivity reaction beginning with lesions 3
days after the first dose. The subject was reported to have diffuse hives
by day 17, 3 days after the second dose, and had swollen hands, face and
feet by day 18 and discomfort swallowing. The subject did not receive any
subsequent scheduled doses. Post- Licensure

Local Reactions Systemic Reactions

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2002)

Page 43 GAO- 02- 445 Anthrax Vaccine

Data regarding potential adverse events following anthrax vaccination are
available from the Vaccine Adverse Event Reporting System (VAERS). 8 The
report of an adverse event to VAERS is not proof that a vaccine caused the
event. Because of the limitations of spontaneous reporting systems,
determining causality for specific types of adverse events, with the
exception of injection- site reactions, is often not possible using VAERS
data alone. The following four paragraphs describe spontaneous reports of
adverse events, without regard to causality.

From 1990 to October 2001, over 2 million doses of BioThrax have been
administered in the United States. Through October 2001, VAERS received
approximately 1, 850 spontaneous reports of adverse events. The most
frequently reported adverse events were erythema, headache, arthralgia,
fatigue, fever, peripheral swelling, pruritus, nausea, injection site
edema, pain/ tenderness and dizziness.

Approximately 6 percent of the reported events were listed as serious.
Serious adverse events include those that result in death,
hospitalization, permanent disability or are life- threatening. The
serious adverse events most frequently reported were in the following body
system categories: general disorders and administration site conditions,
nervous system disorders, skin and subcutaneous tissue disorders, and
musculoskeletal, connective tissue and bone disorders. Anaphylaxis and/ or
other generalized hypersensitivity reactions, as well as serious local
reactions, were reported to occur occasionally following administration of
BioThrax. None of these hypersensitivity reactions have been fatal.

Other infrequently reported serious adverse events that have occurred in
persons who have received BioThrax have included: cellulitis, cysts,
pemphigus vulgaris, endocarditis, sepsis, angioedema and other
hypersensitivity reactions, asthma, aplastic anemia, neutropenia,
idiopathic thrombocytopenia purpura, lymphoma, leukemia, collagen vascular
disease, systemic lupus erythematosus, multiple sclerosis, polyarteritis
nodosa, inflammatory arthritis, transverse myelitis, GuillainBarre
Syndrome, immune deficiency, seizure, mental status changes, psychiatric
disorders, tremors, cerebrovascular accident (CVA), facial palsy, hearing
and visual disorders, aseptic meningitis, encephalitis, myocarditis,
cardiomyopathy, atrial fibrillation, syncope, glomerulonephritis, renal
failure, spontaneous abortion and liver abscess. Infrequent reports were
also received of multisystem disorders defined as chronic symptoms
involving at least two of the following three categories: fatigue, mood-
cognition, musculoskeletal system. Post- Licensure Adverse

Event Surveillance

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Page 44 GAO- 02- 445 Anthrax Vaccine

Reports of fatalities included sudden cardiac arrest (2), myocardial
infarction with polyarteritis nodosa (1), aplastic anemia (1), suicide (1)
and central nervous system (CNS) lymphoma (1).

In addition to the VAERS data, adverse events following anthrax
vaccination have been assessed in survey studies conducted by the
Department of Defense in the context of their anthrax vaccination program.
These survey studies are subject to several methodological limitations* e.
g., sample size, the limited ability to detect adverse events,
observational bias, loss to follow- up, exemption of vaccine recipients
with previous adverse events and the absence of unvaccinated control
groups. Overall, the most reported events were localized, minor and self-
limited and included muscle or joint aches, headache and fatigue. Across
these studies, systemic reactions were reported in 5 to 35 percent of
vaccine recipients and included reports of malaise, chills, rashes,
headaches and low- grade fever. Women reported these symptoms more often
than men.

Adverse events following immunization with BioThrax should be reported to
the Medical Affairs Division of BioPort Corporation (517) 327- 1675 during
regular working hours and (517) 327- 7200 during off hours. Adverse events
may also be reported to the U. S. Department of Health and Human Services
(DHHS) Vaccine Adverse Event Reporting System. Report forms and reporting
requirement information can be obtained from VAERS through a toll free
number 1- 800- 822- 7967.

Immunization consists of three subcutaneous injections, 0.5 mL each, given
2 weeks apart followed by three additional subcutaneous injections, 0.5 mL
each, given at 6, 12, and 18 months. Subsequent booster injections of 0.5
mL of BioThrax at 1- year intervals are recommended.

Use a separate 5/ 8- inch, 25- to 27- gauge sterile needle and syringe for
each patient to avoid transmission of viral hepatitis and other infectious
agents. Use a different site for each sequential injection of this vaccine
and do not mix with any other product in the syringe. Post- Licensure
Survey

Studies Reporting Adverse Events Dosage and Administration

Dosage Administration

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2002)

Page 45 GAO- 02- 445 Anthrax Vaccine

1. Shake the bottle thoroughly to ensure that the suspension is
homogeneous during withdrawal and visually inspect the product for
particulate matter and discoloration. If the product appears discolored or
has visible particulate matter, DISCARD THE VIAL.

2. Wipe the rubber stopper with an alcohol swab and allow to dry before
inserting the needle.

3. Clean the area to be injected with an alcohol swab or other suitable
antiseptic.

4. Holding the needle at a 45DEG angle to the skin, inject the vaccine
subcutaneously.

5. DO NOT inject the product intravenously. Follow the usual precautions
to ensure that you have not entered a vein before injecting the vaccine.

6. After injecting, withdraw the needle and briefly and gently massage the
injection site to promote dispersal of the vaccine.

Anthrax Vaccine Adsorbed (BioThrax TM ) is supplied in 5 mL multidose
vials.

THIS PRODUCT IS TO BE STORED AT 2.2DEG C TO *15DEG C (36DEG TO 4DEG F). Do
not freeze. Do not use after the expiration date given on the package.

Animal studies have not been performed to ascertain whether BioThrax has
carcinogenic action, or any effect on fertility. How Supplied/ Storage

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Appendix IV: Anthrax Vaccine Adsorbed Revised Product Insert (Jan. 31,
2002)

Page 46 GAO- 02- 445 Anthrax Vaccine

1. Meselson, M., and others. 1994. The Sverdlosk Anthrax Outbreak of 1979.
Science 266: 1201* 8.

2. Henderson, D. W., S. Peacock, and F. C. Belton. 1956. Observations on
the Prophylaxis of Experimental Pulmonary Anthrax in the Monkey.

J. Hygiene, 54: 28* 36. 3. Brachman, P. S. 1980. Inhalation Anthrax. Ann.
NY Acad. Science,

353: 83* 93. 4. Update: Investigation of Bioterrorism- Related Anthrax*
Connecticut,

2001. MMWR 2001; 50: 1077- 9. 5. Brachman, P. S., and A. M. Friedlander.
1999. Anthrax. In Vaccines, 3rd

ed., Plotkin and Orenstein (eds.), pp. 629* 37. 6. Brachman, P. S., and
others. 1962. Field Evaluation of a Human

Anthrax Vaccine. Amer. J. Public Health, 52: 632* 45. 7. Centers for
Disease Control and Prevention. General

Recommendations on Immunization Recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR 1994;

43 (No. RR- 1). 8. Chen, R. T., and others. 1994. The Vaccine Adverse
Event Reporting

System (VAERS). Vaccine 12( 6): 542* 50. Revision: January 31, 2002. Rx
Only* Federal (U. S. A.) law prohibits dispensing without a prescription.

Manufactured by Bioport Corporation Lansing, Michigan 48906 U. S. License
No. 1260

50483- 04 References

Appendix V: Comments from the Department of the Army

Page 47 GAO- 02- 445 Anthrax Vaccine

Appendix V: Comments from the Department of the Army

Appendix V: Comments from the Department of the Army

Page 48 GAO- 02- 445 Anthrax Vaccine

Related GAO Products Page 49 GAO- 02- 445 Anthrax Vaccine

Anthrax Vaccine: Changes to the Manufacturing Process. GAO- 02- 181T.
Washington, D. C.: Oct. 23, 2001.

Anthrax Vaccine: Preliminary Results of GAO*s Survey of Guard/ Reserve
Pilots and Aircrew Members. GAO- 01- 92T. Washington, D. C.: Oct. 11,
2000.

Medical Readiness: DOD Continues to Face Challenges in Implementing Its
Anthrax Vaccine Immunization Program. GAO/ T- NSIAD- 00- 157. Washington,
D. C.: Apr. 13, 2000.

Medical Readiness: DOD Faces Challenges in Implementing Its Anthrax
Vaccine Immunization Program. GAO/ NSIAD- 00- 36. Washington, D. C.: Oct.
22, 1999.

Anthrax Vaccine: Safety and Efficacy Issues. GAO/ T- NSIAD- 00- 48.
Washington, D. C.: Oct. 12, 1999.

Medical Readiness: Issues Concerning the Anthrax Vaccine.

GAO/ T- NSIAD- 99- 226. Washington, D. C.: July 21, 1999..

Contract Management: Observations on DOD*s Financial Relationship with the
Anthrax Vaccine Manufacturer. GAO/ T- NSIAD- 99- 214. Washington, D. C.:
June 30, 1999.

Medical Readiness: Safety and Efficacy of the Anthrax Vaccine.

GAO/ T- NSIAD- 99- 148. Washington, D. C.: Apr. 29, 1999.

Gulf War Illnesses: Questions about the Presence of Squalene Antibodies in
Veterans Can Be Resolved. GAO/ NSIAD- 99- 5. Washington, D. C.: Mar. 29,
1999. Related GAO Products

(460501)

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