GAO

United States General Accounting Office

Testimony

Before the Committee on Government Reform, House of 

Representatives

For Release on Delivery

Expected at 1:00 p.m., EDT

Tuesday,

October 12, 1999

ANTHRAX VACCINE

Safety and Efficacy Issues

Statement of Kwai-Cheung Chan, Director, Special Studies 

and Evaluations, National Security and International 

Affairs Division

GAO/T-NSIAD-00-48

Page 1 GAO/T-NSIAD-00-48

Mr. Chairman and Members of the Subcommittee:

We are pleased to be here today to discuss the results of our ongoing 

examination of the safety and efficacy1

 of the anthrax vaccine. My 

testimony is based on previous studies2

 we have conducted to determine 

(1) the need for a six-shot regimen and annual booster shots, (2) the 

long- and short-term safety of the vaccine, (3) the efficacy of the vaccine 

and (4) the extent to which problems the Food and Drug Administration 

(FDA) found in the vaccine production facility in Michigan could 

compromise the safety, efficacy, and quality of the vaccine. Finally, I would 

like to discuss the effects of the anthrax vaccine on children, pregnant 

women or lactating women.

As you know, concerns have been raised about the Department of 

Defense’s (DOD) anthrax immunization program since DOD began 

vaccinating its 2.4 million active duty and reserve members in 1998. For 

example, some active and reserve military personnel expressed concerns 

regarding the safety and efficacy of the anthrax vaccine after the FDA 

found problems during the inspection of the vaccine production facility. 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. 

The original anthrax vaccine was developed in the 1950s and was first 

produced on a large scale by the Merck Pharmaceutical Corporation. After 

a 1962 study on the vaccine’s effect on mill workers, its manufacturing 

process was changed and the Michigan Department of Public Health took 

over as the vaccine’s producer. This changed vaccine, which is the vaccine 

being given to U.S. military personnel, was licensed in 1970 by the Division 

of Biologics Standards, National Institutes of Health. FDA is currently 

responsible for licensing new vaccines and ensuring vaccine safety.

1

Safety means relative freedom from harmful effects to persons affected directly or 

indirectly by a product that has been prudently administered, taking into consideration the 

character of the product in relation to the condition of the recipient at the time. Efficacy is a 

measure of a product’s ability to produce a given response. An effective vaccine will provide 

a certain degree of protection for a certain period of time.

2

See Medical Readiness: Issues Concerning the Anthrax Vaccine (GAO/T-NSIAD-99-226,

July 21, 1999) and Medical Readiness: Safety and Efficacy of the Anthrax Vaccine

(GAO/T-NSIAD-99-148, April 29, 1999).
Page 2 GAO/T-NSIAD-00-48

Summary No studies have been done to determine the optimum number of doses of 

the anthrax vaccine. Although annual boosters are given, the need for a 

six-shot regimen and annual booster shots have not been evaluated.

The long-term safety of the licensed vaccine has not been studied. 

However, DOD is designing studies to examine the vaccine’s long-term 

effects. Data on the prevalence and duration of short-term reactions to the 

vaccine are limited but suggest that women experience a higher rate of 

adverse reactions than do men. FDA’s system for collecting data on adverse 

events associated with the vaccine, which DOD uses, relies on vaccine 

recipients or their health care providers to report adverse events.3

 Studies 

have shown that such systems may not accurately reflect the incidence of 

events due to underreporting. However, data from two recent DOD efforts 

to identify the prevalence of adverse events associated with anthrax 

vaccine show that a higher proportion of women reported both local and 

systemic reactions to the vaccine 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. 

A study on the efficacy of the earlier vaccine concluded that it provided 

protection to humans against anthrax penetrating the skin but did not 

provide information to determine its effectiveness against inhalation 

anthrax. In the 1980’s, DOD began testing the efficacy of the licensed 

vaccine in animals, focusing on its protection against inhalation anthrax. 

The studies showed that the vaccine protected some animals against 

inhalation anthrax. However, the level of protection varied for different 

species and the results cannot be extrapolated to humans. DOD recognizes 

that correlating the results of animal studies to humans is necessary and 

told us that it is planning research in this area. DOD also plans to develop a 

second generation anthrax vaccine and, as part of this effort, will need to 

address whether strains of deliberately engineered or naturally occurring 

anthrax can overcome the protective immunity of such a vaccine.

FDA’s inspections of the vaccine production facility in 1997 and 1998 found 

a number of deficiencies. The deficiencies that FDA identified in its 

February 1998 inspection fall broadly into two categories: those that might 

3

Clinical events reported to a passive surveillance system such as FDA’s are usually termed 

adverse events rather than adverse reactions because there is usually insufficient evidence 

that the vaccine, rather than other health conditions, caused the reported events.
Page 3 GAO/T-NSIAD-00-48

affect only one or a limited number of batches that were produced and 

those that could compromise the safety and efficacy of any or all batches. 

The facility was shut down in early 1998. A new company, which purchased 

the facility in mid-1998, is addressing these issues.

Finally, you expressed concerns about the effects of the anthrax vaccine on 

children, pregnant women, or lactating women. The anthrax vaccine is not 

intended to be administered to children, pregnant women, or lactating 

women. No studies have been conducted on the vaccine’s effects on these 

groups.

Background 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. 

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. 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.

The inspection process for ensuring vaccine safety is more stringent and 

complex than for chemical drug because vaccines have three distinguishing 

features. First, either they have no clearly chemically defined composition, 

or chemical analysis is extremely difficult. Second, proper evaluation of 

vaccines generally requires measuring their effects in animals. Finally, 

quality cannot be guaranteed from final tests on random samples but only 

from a combination of in-process tests, end-product tests, and strict 

controls of the entire manufacturing process.

From the 1970s until 1998, DOD had been procuring the anthrax vaccine 

from a facility owned by the State of Michigan, the only facility in the 

country licensed to produce the vaccine. In 1997 and 1998, FDA identified 

numerous manufacturing problems at the facility. In response to concerns 

about the potential loss of anthrax vaccine production, DOD began funding 

renovation of the facility. Production facilities were shut down in early 

1998. In the summer of 1998, the State of Michigan sold the facility to the 

BioPort Corporation for $25 million. DOD contracts were then transferred 

to BioPort. BioPort is addressing manufacturing problems.
Page 4 GAO/T-NSIAD-00-48

Data on the Need for 

Six Shots and Annual 

Boosters Are Not 

Available

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

the anthrax vaccine. The immunization schedule of three doses used for 

the earlier vaccine was based on a regimen developed using animals in the 

early 1950s. However, the number of doses was arbitrarily increased to six 

when three people (two at Fort Detrick and one in a private wool mill) who 

received three doses of the vaccine became infected after exposure to 

anthrax. In a study of the vaccine’s human efficacy published in 1962, a 

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

vaccine provided protection against anthrax penetrating the skin. The 

study did not provide enough information to determine whether the 

vaccine was effective against inhalation anthrax. The license for the 

vaccine, which was granted in 1970, calls for the six-dose schedule and 

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

this regimen. In September 1998, the manufacturer submitted an 

Investigational New Drug application to FDA 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, National Institutes 

of Health, 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 the 

Division requested the manufacturer to conduct a reevaluation, no such 

reevaluation has been done to date.

Vaccine Safety The long-term safety of the licensed vaccine has not been studied. 

However, DOD is designing studies to examine the vaccine’s long-term 

effects.

With regard to short-term safety, data on the prevalence and duration of 

short-term reactions to the vaccine are limited but suggest that women 

experience a higher rate of adverse reactions than men. A study on the 

earlier vaccine’s safety was done by Philip Brachman and published in 

1962.4

 Brachman reported on 379 subjects that received this vaccine. The 

study concluded that individual reactions to the vaccine were relatively 

minor. About 35 percent had local reactions, a figure that varied during the 

4

P.S. Brachman et al., “Field Evaluation of a Human Anthrax Vaccine,” American Journal of 

Public Health, vol. 52 (1962), pp. 632-645.
Page 5 GAO/T-NSIAD-00-48

inoculation series. Some recipients developed more severe edema, or 

swelling, that extended to the mid-forearm or wrist. Two individuals had 

systemic reactions in addition to the edema. In addition to this study, some 

data was collected to support licensing of the vaccine but is of limited use 

because some participants had already received the earlier vaccine and it is 

not possible to identify who received which vaccine.

Post-licensing data are limited because only a limited number of doses—

about 68,000—were distributed by the manufacturer from 1974 through 

1989. Also, FDA did not establish its Vaccine Adverse Event Reporting 

System until 1990. This system, which DOD uses, alerts FDA and the 

Centers for Disease Control to increases in adverse events. However, it is a 

passive surveillance system, which means that FDA and the Centers for 

Disease Control 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 frequently with 

passive surveillance systems than they would be in an active system where 

vaccine recipients are monitored to find out if they had any adverse effects.

Since DOD’s mandatory inoculation program began in 1998, DOD has 

conducted two efforts to actively collect data on the short-term safety of 

the vaccine. These data also allow one to examine gender differences in 

adverse reactions after servicemembers have received the anthrax vaccine. 

The first effort, conducted in 1999 by a DOD physician stationed in Korea, 

was a survey given to service members 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 second 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.

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

females reported reactions to the anthrax vaccine than did their male 

counterparts. Table 1 summarizes the rates of all reported reactions to the 

vaccine in Korea. The data show that a higher proportion of females 

reported reactions than males.
Page 6 GAO/T-NSIAD-00-48

Table 1: Preliminary Data on Gender Differences in the Reported Rate of Adverse 

Reactions to the Anthrax Vaccine, From Korea Survey (1999)

Source: DOD 1999.

The data gathered in Korea also show that after the first two shots, more 

than twice the proportion of women than men reported systemic reactions 

of fever, malaise, or chills than did men (see table 2).

Table 2: Preliminary Data on Gender Differences in Systemic Reactions, From Korea 

Survey (1999)

Source: DOD.

The Tripler survey also demonstrates gender differences in reported 

reactions (see table 3). 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. In light of the fact no gender specific data were available 

from the pre-licensure studies, these findings underscore the need for 

monitoring to better understand the specific effects of this vaccine in 

different groups.

Dose 

Males

Percent (number of doses)

Females

Percent (number of doses)

First 42.1 (2036) 71.6 (495)

Second 44.4 (1953) 74.0 (474)

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.

Fever Malaise Chills

Dose 

number

Male

(percent)

Female

(percent)

Male

(percent)

Female

(percent)

Male

(percent)

Female

(percent)

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

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.
Page 7 GAO/T-NSIAD-00-48

Table 3: Gender Differences in Reported Local Reactions, Outpatient Medical Visits, 

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

a

Data were not available

Source: DOD.

Vaccine Efficacy Studies on the efficacy of anthrax vaccine have been limited to a study of 

the efficacy of the earlier vaccine for humans, and studies of the efficacy of 

the licensed vaccine for animals. The only study of the efficacy of the 

vaccine for humans was performed by Brachman, using the original 

vaccine. The Brachman study claimed that the vaccine gave 93 percent 

(and a lower confidence limit of 65 percent) protection against anthrax 

penetrating the skin. It found that the number of individuals who 

contracted anthrax by inhalation was too low to assess the efficacy of the 

vaccine against this form. There has been no specific study of the efficacy 

of the licensed vaccine in humans. Rather, its efficacy in humans has been 

inferred from other data, including a reduction in the incidence of anthrax 

following immunization of at-risk individuals and from animal experiments.

Reaction 

Dose 1

(percent)

Dose 2

(percent)

Dose 3

(percent)

Dose 4

(percent)

Moderate to severe redness (m) 17.5 20.4 17.2 31.6

(f) 49.1 46.9 51.4 39.8

Swelling of lower arm (m) 9.7 9.5 9.2 7.1

(f) 13.4 13.5 13.0 8.4

Pain limiting motion of elbow (m) 9.7 8.7 7.6 7.9

(f) 17.1 13.5 11.7 8.6

Localized itching (m) 25.2 25.7 24.5 27.7

(f) 62.6 60.4 57.9 39.2

Lump or knot (m) 63.9 64.4 60.5 65.5

(f) 89.9 87.8 83.6 73.2

Muscle soreness (m) 66.6 64.7 61.8 60.4

(f) 79.7 76.4 70.8 61.6

Outpatient medical visit (m) 5.3 2.0 2.7 a

(f) 10.0 13.8 3.9

Missed one or more shifts of duty (m) 2.2 2.0 0.9 a

(f) 5.0 5.1 3.9

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

survey.
Page 8 GAO/T-NSIAD-00-48

Beginning in the late 1980s, DOD began studying the efficacy of the 

licensed anthrax vaccine on animals, using guinea pigs, rabbits, and 

monkeys. All of these studies support the view that in these animals, the 

licensed vaccine can protect against exposure to some strains of anthrax 

either by inoculation or inhalation. It is clear, however, that animal species 

differ in their susceptibility. Studies of guinea pigs show that some anthrax 

strains are more or less resistant to vaccines for humans but are protected 

by the live spore veterinary vaccine.5

Research using monkeys showed for the first time that monkeys could be 

protected against aerosol exposure.6

 However, several studies have shown 

no direct comparison of immunity in humans to that in monkeys. DOD 

officials recognize that correlating the results of animal studies to humans 

is necessary and told us that DOD is planning research in this area. DOD 

also plans to develop a second generation anthrax vaccine, and as part of 

this effort, it will need to address 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 have 

been observed in experiments on animals. However, the reasons for the 

variation have not been scientifically proven.

Vaccine Manufacturing 

Process

The quality of a vaccine is closely linked to its manufacturing process, 

which must be rigorously controlled to ensure that batches of vaccines 

produced on different occasions are of consistent quality. Accordingly, 

vaccine production is very highly regulated to ensure that the products are 

of consistent quality and safe and effective for the purpose(s) for which 

regulatory approval was granted. Until 1993, FDA inspectors did not 

inspect the MDPH facility where the anthrax vaccine was made. According 

to FDA, access was not granted because its inspectors had not been 

vaccinated against anthrax. DOD conducted inspections, however, and 

identified deficiencies during a March 1992 inspection, including the 

absence of stability studies.

5

P.C.B Turnbull, et al., “Development of antibodies to protective antigen and lethal factor 

components in humans and guinea pigs and their relevance to protective immunity,” 

Infectious Immunology, vol. 52 (1988) pp.356-363.

6

B.E. Ivins, et al., “Efficacy of a standard human anthrax vaccine against Baccillus anthracis 

aerosol challenge in rhesus monkeys,” Proceedings of the International Workshop on 

Anthrax, Salisbury Medical Bulletin, Special Supplement no. 87 (1996) pp.125-126.
Page 9 GAO/T-NSIAD-00-48

FDA’s subsequent inspections of the production facility in 1997 and 1998 

found a number of deficiencies. The deficiencies that FDA identified in its 

February 1998 inspection fall broadly into two categories: those that might 

affect only one or a limited number of batches and those of a generic nature 

that could compromise the safety and efficacy of any or all batches. The 

facility received warning letters from FDA, including one in March 1997 

stating its intent to revoke the facility’s license. In 1998, the manufacturer 

closed its plant, which is now being renovated. DOD has directed that 

supplemental testing for purity, potency, sterility and safety be done on the 

lots approved by FDA before the current vaccination program began.

Effects of the Vaccine 

on Children and 

Pregnant and Lactating 

Women

The anthrax vaccine is not intended to be administered to children, 

pregnant or lactating women, and consequently no studies have been 

conducted to determine the specific effects of administering the anthrax 

vaccine to these groups. Before approving vaccines or drugs for marketing, 

FDA currently requires the submission of clinical data broken down by 

(among other things) gender and age. FDA then evaluates these data to 

determine efficacy and safety for specific subgroups of the general 

population. In addition, depending on FDA’s assessment of clinical data, 

specific labeling requirements pertaining to potential effects on pregnant 

women, nursing mothers and pediatric use may also be required. However, 

the Division of Biologics, National Institutes of Health, which licensed the 

vaccine in 1970, did not require the submission of data broken down this 

way.

Mr. Chairman, this concludes my statement. I will be happy to answer any 

questions you may have.

Contacts and Acknowledgments

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

Chan at (202) 512-3652. Individuals making key contributions to this 

testimony included Sushil K. Sharma, Jonathan R. Tumin, and Howard 

Deshong.

(713049) Letr
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