GAO

United States General Accounting Office

Testimony

Before the Subcommittee on National Security, Veterans’ 

Affairs, and International Relations, Committee on 

Government Reform, House of Representatives

For Release on Delivery 

Expected at 

10:00, a.m., EDT 

Wednesday, 

July 21, 1999

MEDICAL READINESS

Issues Concerning the 

Anthrax Vaccine

Statement of Kwai-Cheung Chan, Director Special Studies 

and Evaluations, National Security and International 

Affairs Division

GAO/T-NSIAD-99-226

Page 1 GAO/T-NSIAD-99-226 

Mr. Chairman and Members of the Subcommittee:

We are pleased to be here today to share the results of our work on the 

anthrax vaccine. As you know, questions have been raised about the 

Department of Defense’s (DOD) anthrax immunization program because 

of concerns related to (1) the safety and efficacy of the vaccine and 

(2) problems found over the past few years by the Food and Drug 

Administration (FDA) during its inspection of the facility that was 

manufacturing the vaccine. We reported our findings on these issues to 

you in previous testimonies.1

In December 1997, the Secretary of Defense announced that all U.S. forces 

would be inoculated against the potential use of anthrax on the battlefield. 

Although a version of the anthrax vaccine was shown to be effective 

against cutaneous exposure, the vaccine has not been tested against 

inhalation anthrax in humans. DOD has recognized that some of the 

concerns about using the current vaccine might be mitigated in the future 

through actions such as testing and research and adjustments to the 

program based on new data. 

As requested, we will discuss (1) the extent to which data support the need 

for six initial shots and an annual booster of the anthrax vaccine, (2) the 

relative merits and weaknesses of a passive surveillance system in 

determining adverse events,2

 (3) the available data on differences in 

adverse reaction rates between men and women receiving the anthrax 

vaccine, and (4) the disadvantages of the current vaccine and the status of 

federal efforts to develop an improved anthrax vaccine.

Results in Brief No studies have been done to determine the optimum number of doses of 

the anthrax vaccine. A study done during the early 1950s showed that 

animals could be protected against cutaneous anthrax using a three-dose 

schedule. However, the number of doses was increased to six when three 

people who had received three doses of the vaccine were infected after 

exposure to anthrax. In a study of the vaccine’s human efficacy published 

1

Medical Readiness: Safety and Efficacy of the Anthrax Vaccine (GAO/T-NSIAD-99-148, Apr. 29, 1999) 

and Contract Management : Observations on DOD’s Financial Relationship With the Anthrax Vaccine

Manufacturer (GAO/T-NSIAD-99-214, June 30, 1999).

2

Clinical events reported to a passive surveillance system are usually termed adverse events rather than 

adverse reactions because causally-related events to the vaccine is not usually possible. 

Letr
Page 2 GAO/T-NSIAD-99-226 

in 1962, a six-dose schedule was used, and the researchers concluded that 

the vaccine provided protection against cutaneous exposure to anthrax. 3

In 1998, the current manufacturer of the vaccine submitted an FDA 

application (Investigational New Drug) to determine whether the number 

of shots in the initial schedule could be reduced from six to five. Although 

annual boosters are given, the need for this frequency and the amount of 

the booster dose has also not been evaluated. 

DOD submits data on adverse events associated with the anthrax vaccine 

to the Vaccine Adverse Events Reporting System (VAERS).4

 This system 

has several advantages. It alerts FDA/CDC to previously unreported or 

unexpected increases in reported adverse events. It is also a relatively 

affordable way to supplement the data collected on vaccines before they 

are licensed. However, it is a passive surveillance system, which means 

that FDA/CDC must rely on vaccine recipients or their health care 

providers to report any adverse events after receiving the vaccine; studies 

show that adverse events are reported significantly less than they would be 

in an active surveillance system. In an active system, which is generally 

more costly to administer, vaccine recipients are monitored to find out if 

they had any adverse events after being inoculated. 

In addition to reporting data to VAERS, DOD has conducted three efforts to 

actively collect data on adverse reactions after servicemembers received 

the anthrax vaccine. Data from these efforts show that women reported 

twice the rate of adverse reactions than men for both local (e.g., swelling) 

and systemic (e.g., malaise and chills) reactions. In addition, a higher 

proportion of women than men reported making an outpatient medical visit 

after a vaccination, and more than twice the percentage of women reported 

that they missed one or more duty shifts after their vaccinations than did 

men. 

The anthrax vaccine has several disadvantages. The amount of protective 

antigen in the vaccine cannot be precisely measured, and it varies from lot 

to lot. Also, the requirement for a six-dose schedule and annual booster 

shots, rather than a smaller number of doses, complicates the logistics of 

inoculating all of DOD’s troops and increases the cost of the vaccine 

program. Knowledge of anthrax infection and studies of experimental 

3

P.S. Brachman et al., “Field evaluation of a human anthrax vaccine,” American Journal of Public 

Health, vol. 52 (1962), pp. 632-645.

4

The system is an FDA/Centers for Disease Control and Prevention (CDC) system.

Letr
Page 3 GAO/T-NSIAD-99-226 

anthrax vaccines indicate that a second-generation vaccine with a more 

precise amount of protective antigen could be developed and that fewer 

doses of the vaccine would be required. However, a second-generation 

vaccine has not been fully tested, and the testing required for licensing 

alone would take about 3 years. FDA approval of the manufacturing of the 

vaccine would take longer. In 1995, the U.S. Army Medical Research 

Institute of Infectious Diseases (USAMRIID)5

 developed a 

second-generation recombinant vaccine (that is, a vaccine produced 

through DNA extraction) against anthrax. The vaccine was tested on 

animals, but clinical trials were not conducted in humans. DOD currently 

considers such a vaccine an unfunded requirement. The Department of 

Health and Human Services recently funded several active research grants 

to develop a second-generation recombinant vaccine because of a 

perceived growing bioterrorism concern. In developing a new vaccine, 

researchers also believe they should consider the impact of new and 

engineered strains of anthrax.

Background DOD currently plans to vaccinate all 2.4 million servicemembers against 

anthrax using the vaccine licensed in 1970 by the Division of Biologics 

Standards, National Institutes of Health (NIH). As of July 14, 1999, more 

than 300,000 servicemembers had received at least one dose of the vaccine. 

Initial immunization consists of three shots given at 0, 2, and 4 weeks 

followed by three additional shots given at 6, 12, and 18 months. 

Some studies have been done on the short-term effects of the licensed 

vaccine. We previously testified that the number of adverse reactions 

reported in these studies partly depended on whether an active or passive 

surveillance system was used to monitor adverse reactions.6

 Also, we 

reported that the long-term safety of the vaccine has not been investigated 

but that DOD is considering a study to examine long-term effects of the 

vaccine. 

5

USAMRIID, an organization of the U.S. Army Medical Research and Materiel Command, conducts 

research to develop strategies, products, information, procedures, and training programs for medical 

defense against biological warfare threats and naturally occurring infectious diseases that require 

special containment. It is located at Fort Detrick, Maryland.

6

Medical Readiness (GAO/T-NSIAD-99-148, Apr. 29, 1999). 
Page 4 GAO/T-NSIAD-99-226 

Data on the Need for 

Six Shots Are Not 

Available

The original inoculation schedule of three doses was based on a regimen 

developed using animals in the early 1950s. However, three people (two in 

Fort Detrick and one in a private wool mill) who received three doses of 

the vaccine became infected after exposure to anthrax. The number of 

doses was then increased to six for the human efficacy study published in 

1962. The study did not provide enough information to determine whether 

the vaccine was effective against inhalation anthrax. There were no 

studies done to determine the optimum number of doses of the vaccine. 

Also, according to DOD researchers, the choice of six doses was arbitrary. 

The license for the vaccine, which was granted to the Michigan Department 

of Public Health (MDPH),7

 calls for the six-dose schedule and annual 

boosters used in the human efficacy study, and DOD has followed this 

regimen. In September 1998, BioPort submitted to FDA an application 

(Investigational New Drug) to determine whether the number of shots in 

the initial schedule could be reduced from six to five.

In November 1971, the Division of Biologics Standards, NIH, noted an 

apparent increase in reports of adverse reactions after individuals received 

booster shots. The Division considered it advisable to reevaluate the need 

for annual boosters and possibly the amount of the booster dose. Although 

the record is unclear as to whether or not NIH requested a reevaluation, to 

date, no such reevaluation has been done. 

The Relative Merits 

and Weaknesses of 

Passive Surveillance 

Systems in 

Determining Adverse 

Events

DOD submits data on adverse events associated with the anthrax vaccine 

to VAERS. VAERS is a passive surveillance system to alert FDA and CDC of 

adverse events that may be associated with licensed vaccines. Information 

is voluntarily reported to VAERS by health care providers, patients, or 

families, who are encouraged to report any adverse events after a person 

receives a vaccine. 

VAERS has several advantages. It is a relatively affordable way to 

supplement data on short-term adverse events that are collected using 

active means during the clinical trials before a vaccine is licensed. Most 

important, however, VAERS serves as a signal for the detection of 

previously unreported adverse events and/or unexpected increases in 

7

MDPH was granted the original license to produce the anthrax vaccine. 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.
Page 5 GAO/T-NSIAD-99-226 

reported events. Prelicensing clinical trials are limited in detecting the 

range of adverse reactions because of the small samples, short durations, 

and the homogeneous population used as subjects. In addition, both the 

general public and doctors can report adverse events to the system, and the 

data is open to public scrutiny.

VAERS also has several disadvantages. Studies show that adverse events 

are often underreported in a passive surveillance system.8

 A former FDA 

commissioner acknowledged the underreporting of adverse events in 

passive surveillance systems and cited one study showing that “only about 

1 percent of serious events” attributable to drug reactions are reported to 

FDA.9

 Reporting of adverse events appears to depend on several factors, 

such as the clinical seriousness of the event, the length of time between the 

shots and the event, and health care workers’ awareness of and obligation 

to report particular adverse events. Also, outcomes with delayed onset 

after vaccination or outcomes not generally recognized to be associated 

with vaccination are often underreported. According to the National 

Vaccine Information Center, there is no mechanism within VAERS for 

a 1-, 3-, or 10-year follow-up to evaluate vaccine reactions that have a long 

latency period. According to CDC, the limitations of VAERS data suggest it 

is not a valid source for assessing the rate of adverse events. 

In an active surveillance system, health care workers monitor people that 

have been vaccinated to find out if they have had adverse reactions. Such 

systems are generally used during clinical trials and are more costly to 

administer than passive systems because of the additional infrastructure 

and personnel required. However, such systems are sometimes used to 

obtain information when questions arise about the safety of a vaccine after 

licensing.

8

S. Rosenthal and R. Chen, “The Reporting Sensitivities of Two Passive Surveillance Systems for 

Vaccine Adverse Events,” American Journal of Public Health, vol. 85 (1995), pp. 1706-1709; R.T. Chen et 

al., “The Vaccine Adverse Event Reporting System (VAERS),” Vaccine, vol. 12 (1994), pp. 542-550; and 

R.T. Chen, “Special Methodological Issues in Pharmacoepidemiology Studies of Vaccine Safety,” Ed. 

B.L. Strom, Pharmacoepidemiology (Chicester: John Wiley and Sons, 1994).

9

D.A. Kessler, “Introducing MEDWatch: A New Approach to Reporting Medication and Devise Adverse 

Effects and Product Problems,” Journal of the American Medical Association, vol. 269 (1993), pp. 

2765-2768, and H.D. Scott, et al., “Rhode Island Physicians’ Recognition and Reporting of Adverse Drug 

Reactions,” Rhode Island Medical Journal, vol. 70 (1987), pp. 311-316.
Page 6 GAO/T-NSIAD-99-226 

Women Report More 

Adverse Reactions 

Than Men

In addition to DOD’s reporting of adverse events to VAERS, DOD has 

conducted three efforts to actively collect data that can be used to examine 

gender differences in adverse reactions after servicemembers have 

received the anthrax vaccine. The first effort, conducted by USAMRIID, 

included data on shots given at Fort Detrick during 1977-96. The second 

effort, conducted in 1999 by a DOD physician stationed in Korea, was a 

survey given to servicemembers when they reported for their initial 

six-dose schedule of shots; it asked questions about their reactions to the 

previous shot. Results from this effort reflect the researcher’s preliminary 

analysis of the data. The third effort, conducted in 1998-99 at Tripler Army 

Medical Center, Hawaii, included a survey on adverse reactions to the first 

three shots when individuals reported for their fourth shot and later 

included a follow-up survey on adverse reactions to the fourth shot. None 

of the efforts used a control group. Also, all three relied on self-reported 

data and were not adjusted for factors such as occupation, physical activity 

level, and age. Because of differences in the way data were collected, 

reaction rates are not strictly comparable among the different efforts. 

According to the data gathered in all three efforts, a higher proportion of 

females reported reactions to the anthrax vaccine than did their male 

counterparts. Tables 1 and 2 summarize the rates of reported reactions to 

the vaccine during the two efforts at Fort Detrick and in Korea. The 

researchers at Fort Detrick determined that the statistical difference was 

significant10 in the reported reaction rates of males and females after their 

second and subsequent shots. The researchers for the other two efforts did 

not report whether the difference in reported reaction rates was 

statistically significant. 

10Tests of significance deal with the question of whether a difference is real or just a chance variation. It 

does not deal with the question of how important the difference is or what caused the difference. The 

test does not check the design of the study. If a test is significant at the 99-percent level, the results 

could be due to chance 1 percent of the time. 
Page 7 GAO/T-NSIAD-99-226 

Table 1: Gender Differences in the Reported Rate of Reactions to the Anthrax 

Vaccine, From Fort Detrick Data (1977-96)

Note: As a result of GAO’s recalculation, the percentages reflect minor differences from those 

reported by the researcher.

a The gender difference in reported reaction rates is statistically significant at the 99-percent 

confidence level.

b The gender difference in reported reaction rates is statistically significant at the 99.99-percent 

confidence level. 

Source: DOD.

Table 2: Preliminary Data on Gender Differences in the Reported Rate of Reactions 

to the Anthrax Vaccine, From Korea Survey (1999)

Note: This represents a preliminary analysis of the data by the researcher, and at the time of our 

review, data on reactions to the third shot were not available.

Source: DOD.

The data gathered in Korea shows that after the first two shots, more than 

twice the proportion of women reported the systemic reactions of fever, 

malaise, or chills than men (see table 3). 

Dose number

Males percent

(number of doses)

Females percent

(number of doses)

First 3.75 (1,013) 3.86 (259)

Second 3.06a

 (979) 7.29a (247)

Third 1.71a

 (938) 5.06a (237)

Fourth and subsequent 3.40b

 (5062) 7.06b (737)

Dose number

Males percent

(number of doses)

Females percent

(number of doses)

First 42.1 (2036) 71.6 (495)

Second 44.4 (1953) 74.0 (474)
Page 8 GAO/T-NSIAD-99-226 

Table 3: Preliminary Data on Gender Differences in Systemic Reactions, From Korea 

Survey (1999)

Note: This represents a preliminary analysis of the data by the researcher, and at the time of our 

review, data on reactions to the third dose were not available.

Source: DOD.

The Tripler effort also demonstrates gender differences in reported 

reactions (see table 4). These data show that a higher proportion of 

women reported making an outpatient visit after a vaccination than their 

male counterparts. In addition, more than twice the proportion of women 

reported that they missed one or more duty shifts after their vaccinations 

than did males.

Numbers in percent

Fever Malaise Chills

Dose 

number Male Female Male Female Male Female

First 0.9 2.8 6.0 15.6 1.5 5.5

Second 1.7 4.8 7.1 15.4 1.9 4.0
Page 9 GAO/T-NSIAD-99-226 

Table 4: Gender Differences in Reported Local Reactions, Outpatient Medical Visits, 

and Missed Duty, From Tripler Army Medical Center Survey (1998-99)

Note: Between 421 and 471 men and between 74 and 83 women responded to each question on the 

survey.

a

Data were not available. 

Source: DOD.

Numbers in percent

Reaction Dose 1 Dose 2 Dose 3 Dose 4

Moderate to severe redness

Male 

Female

17.5

49.1

20.4

46.9

17.2

51.4

31.6

39.8

Swelling of lower arm

Male

Female

9.7

13.4

9.5

13.5

9.2

13.0

7.1

8.4

Pain limiting motion of elbow

Male 

Female

9.7

17.1

8.7

13.5

7.6

11.7

7.9

8.6

Localized itching

Male

Female

25.2

62.6

25.7

60.4

24.5

57.9

27.7

39.2

Lump or knot

Male

Female

63.9

89.9

64.4

87.8

60.5

83.6

65.5

73.2

Muscle soreness

Male

Female

66.6

79.7

64.7

76.4

61.8

70.8

60.4

61.6

Outpatient medical visit

Male

Female

5.3

10.0

2.0

13.8

2.7

3.9 a

Missed one or more shifts of duty

Male

Female

2.2

5.0

2.0

5.1

0.9

3.9 a
Page 10 GAO/T-NSIAD-99-226 

Status of Federal 

Efforts to Develop a 

Second-Generation 

Anthrax Vaccine

According to researchers and the Institute of Medicine of the National 

Academy of Sciences, the current anthrax vaccine has several 

disadvantages.11 The amount of protective antigen in the vaccine is variable 

from lot to lot because the manufacturing process cannot precisely 

quantify the antigen.12 Also, there is some evidence that the current 

anthrax vaccine may have diminished efficacy against certain virulent 

strains of anthrax (Bacillus anthracis). And the required six-dose schedule 

and annual boosters complicate the logistics of inoculating all of DOD’s 

troops and increase the cost of the vaccine program. 

According to DOD research, a second-generation recombinant vaccine 

created with a process that is fully defined, quantified, and controlled in 

terms of protective antigen, can be developed and that fewer doses could 

be required.13 DOD research also shows that a recombinant vaccine could 

be created using modern techniques to produce highly purified protective 

antigen. This process not only would remove unwanted bacterial proteins 

but also would enable precise amounts of the purified protective antigen to 

be incorporated into the vaccine. A further potential benefit is that, 

compared to the current vaccine, the protective antigen could be produced 

in a nonspore-forming organism. As a result, according to DOD officials, 

manufacturers could use their buildings and equipment to produce the 

anthrax vaccine as well as other vaccines. 

In 1995, USAMRIID developed a new recombinant protective antigen 

vaccine against anthrax. This vaccine was successfully tested in 

experiments using animals but has not been tested on humans. USAMRIID 

officials stated that this testing would take about 3 years, and FDA 

approval of the manufacturing of the vaccine could take years longer. DOD 

considers further development of this vaccine candidate an unfunded 

requirement. In response to the perceived threat of bioterrorism, the 

11P.S. Brachman and A. Friedlander, “Anthrax,” Vaccines, ed. S.A. Plotkin and E.A. Mortimer, Jr., 

(Philadelphia: W.B. Saunders Company, 1994), p. 737, and Chemical and Biological Terrorism:

Research and Development to Improve Civilian Medical Response, Institute of Medicine (Washington, 

D.C.: National Academy Press, 1999), p. 135.

12Chemical and Biological Terrorism: Research and Development to Improve Civilian Medical

Response, Institute of Medicine (Washington, D.C.: National Academy Press, 1999), p. 135.

13B. Ivins et al., “Immunization Studies with attenuated strains of Bacillius anthracis,” Journal of 

Infection and Immunity, vol. 52 (1986), pp. 454-458; B.E. Ivins, “The Search for a New-Generation 

Human Anthrax Vaccine,” Clinical Immunology Newsletter, vol. 9 (1988), pp. 30-32; and Y. Singh et al., 

“Study of Immunization Against Anthrax with the Purified Recombinant Protective Antigen of Bacillus 

anthracis,” Journal of Infection and Immunity, vol. 66 (1998), pp. 3447-3448. 
Page 11 GAO/T-NSIAD-99-226 

Department of Health and Human Services’ National Institute of Allergy 

and Infectious Diseases formed a working group to develop and test a 

second-generation anthrax vaccine. The Institute recently funded several 

active research grants in this regard. 

In developing a second-generation recombinant anthrax vaccine, 

researchers believe they will need to address the additional problem of 

whether strains of deliberately engineered or naturally occurring anthrax 

can overcome the protective immunity of such a vaccine. A variation in 

virulence among anthrax strains and a variation in relative resistance to 

vaccine-induced immunity has been observed in experiments on animals. 

However, the reasons for the variation have not been scientifically proven. 

Mr. Chairman, this concludes my formal statement. If you or other 

members of the Subcommittee have any questions, we will be pleased to 

answer them. 

Contacts and 

Acknowledgments

For future contacts regarding this testimony, please contact Kwai-Cheung 

Chan at 512-3652. Individuals making key contributions to this testimony 

included Sushil Sharma, Howard Deshong, and Nancy Ragsdale. 

(713043) Letr
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