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., EST 

Thursday,

April 29, 1999

MEDICAL READINESS

Safety and Efficacy of the 

Anthrax Vaccine

Statement of Kwai-Cheung Chan, Director, Special Studies 

and Evaluations, National Security and International 

Affairs Division

GAO/T-NSIAD-99-148

Page 1 GAO/T-NSIAD-99-148 Medical Readiness

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, which is 

being done at your request. My testimony presents preliminary findings on 

(1) the short- and long-term safety of the vaccine, (2) the efficacy of the 

vaccine, and (3) problems the Food and Drug Administration (FDA) found 

in the vaccine production facility in Michigan that could compromise the 

safety, efficacy, and quality of the vaccine. We plan to issue the final report 

on our review this fall.

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

Defense’s (DOD) anthrax immunization program since the Department 

began vaccinating the first of 2.4 million active duty and reserve members. 

For example, some Gulf War veterans are suffering from unexplained 

illnesses that they believe might have been caused by anthrax vaccines that 

they received during the war. Also, some active duty military personnel 

expressed concerns regarding the safety and efficacy of the anthrax 

vaccine after the FDA found problems during the inspection of the facility 

that was manufacturing the anthrax vaccine. With this background, I will 

discuss our results.

Results in Brief The anthrax vaccine being given to U.S. military personnel was licensed in 

1970. Before the vaccine was licensed, the vaccine and the manufacturing 

process were changed, creating a similar vaccine, produced by the 

Michigan Department of Public Health (MDPH), which was the one 

eventually licensed.2

 The safety study conducted before licensing used 

both the original vaccine and MDPH vaccine. Knowledge to date about the 

safety of the vaccine includes the results of the original study and a 1998 

DOD study of 500 vaccine recipients. While these studies identified varying 

1Safety means relative freedom from harmful effects to persons affected directly or indirectly by a 

product that has been prudently administered, taking into considerations the character of the product 

in relation to the condition of the recipient at the time. Efficacy is not an absolute term. It 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

The original license for the production of anthrax vaccine was issued to MDPH. In 1995, the facility 

changed its name to the Michigan Biologic Products Institute. In 1998, the facility was sold, and its 

name was change to BioPort. The term MDPH will be used to refer to the licensed facility throughout 

this testimony. 
Page 2 GAO/T-NSIAD-99-148 Medical Readiness

rates of adverse reactions, they did not question the safety of the vaccine. 

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

Prior to the time of licensing, no human efficacy testing of the MDPH 

vaccine was performed. However, a study was done on the efficacy of the 

original vaccine. This study concluded that the vaccine provided 

protection to humans against anthrax penetrating the skin. In the 1980s, 

DOD began testing the efficacy of the licensed vaccine on animals, focusing 

on its protection against inhalation anthrax. DOD recognizes that 

correlating the results of animal studies to humans is necessary and told us 

that it is planning research in this area. 

Careful control of the manufacturing process is essential to ensure the 

quality of the product. The FDA inspections of the facility where the 

licensed vaccine was manufactured uncovered numerous problems. 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 

in 1998 and is now being renovated. FDA requires the manufacturer to 

meet specifications for sterility, stability, purity, and potency. In addition to 

the lot release testing required by FDA, DOD is conducting supplemental 

testing of each lot from this plant before distributing the vaccine. 

Background The nature and magnitude of the military threat of biological warfare (BW) 

has not changed since 1990, both in terms of the number of countries 

suspected of developing BW capability, the types of BW agents they 

possess, and their ability to weaponize and deliver those BW agents. 

Inhalation anthrax is considered by DOD to be the primary BW threat 

because of its lethality, ease of production, and weaponization. 

The original anthrax vaccine was developed by George Wright in the 1950s 

and first produced on a large scale by Merck. After a 1962 study on the 

vaccine’s effects in mill workers, its manufacturing process was changed, 

and MDPH took over as the vaccine’s producer. This changed vaccine was 

licensed in 1970 by the Division of Biologics, National Institute of Health, 

to be manufactured by MDPH.

Vaccines have three distinguishing features that contrast with those of 

chemical drugs. First, either they have no clearly chemically defined 

composition, or simple chemical analysis is insufficient for effective 

characterization. Second, proper evaluation of them (qualitatively or 

quantitatively) is usually done by measuring their effects in vivo (in the 
Page 3 GAO/T-NSIAD-99-148 Medical Readiness

living organism). 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. 

Vaccine Safety Studies have been performed to examine the safety of both the original 

vaccine and the licensed vaccine. These two vaccines were made using 

different processes and have different data to support their safety. While 

these studies identified varying rates of adverse reactions, they did not 

question the safety of the vaccine. The long-term safety of the vaccine has 

not yet been studied.

Data on Safety of the 

Original Vaccine

A study on the original vaccine’s safety was done by Philip Brachman and 

published in 1962.3

 Brachman reported on 379 subjects that received this 

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

the inoculation series. Some recipients developed more severe edema that 

extended to the mid-forearm or wrist. Two individuals had systemic 

reactions in addition to the edema. The researchers actively collected data 

on adverse reactions to the vaccine, and the study concluded that 

individual reactions to the vaccine were relatively minor. 

Data on Safety of the 

Licensed Vaccine

After the original vaccine was developed, MDPH was granted a license for a 

similar vaccine that differed from the original vaccine in three ways. First, 

the manufacturing process changed when MDPH took over. Second, the 

strain of anthrax that Merck used to grow the original vaccine was 

changed, and another strain was used to grow the MDPH vaccine. Finally, 

to increase the yield of the protective antigen (which is believed to be an 

important part of the vaccine’s protective effects), the ingredients used to 

make vaccine were changed from the original vaccine.

Four safety studies have been done that include the licensed vaccine. The 

results of those studies are presented in table 1. The Center for Disease 

Control collected data on the Investigational New Drug (IND) study, DOD 

collected data for both the Pittman study and the Tripler Army Medical 

Center (TAMC) Anthrax Survey, and DOD is currently collecting reports on 

3

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

vol. 52 (1962), pp. 632-645.
Page 4 GAO/T-NSIAD-99-148 Medical Readiness

adverse events. The number of adverse reactions appears to depends, in 

part, upon whether the mechanism for monitoring reactions is active or 

passive. (Active monitoring means that the vaccine recipients are 

contacted to ascertain any adverse reactions after vaccine administration; 

passive monitoring means that the onus is on the vaccine recipients to 

report any adverse reactions after vaccine administration.) None of the 

studies questioned the vaccine’s safety.

Table 1: Reactions to Licensed Anthrax Vaccine Reported in Various Studies

aThis number represents the number of study participants who received the first dose of the licensed 

vaccine. 

bThese figures represent the percentage of people who experienced this type of reaction during the 

study, even if they had previously been inoculated with the Merck vaccine. 

cThis figure also includes persons who had reactions of “unknown” severity.

dThis figure represents the frequency of the most common side effect, myalgia. 

eDOD testified that as of March 16, 1999, more than 223,000 servicemember have been immunized. 

There had been 42 reports on adverse effects submitted to the FDA and CDC. Only seven 

servicemembers required hospitalization or experienced loss of duty for more than 24 hours. 

Vaccine Efficacy Studies on the efficacy of the original and the licensed vaccines have been 

limited to a study of the efficacy of the original vaccine for humans, and 

studies of the efficacy of the licensed vaccine for animals. The study on the 

original vaccine concluded that the vaccine offered protection against 

anthrax penetrating human skin. The studies on the licensed vaccine 

focused on the efficacy of the vaccine in protecting animals against 

inhalation of anthrax. These studies, while showing some positive results, 

may not be extrapolated to humans. DOD is planning to conduct such 

correlating studies.

Local reactions

(percent)

Systemic reactions

(percent)

Study

Type of 

reporting

Number

vaccinated

(or doses) Mild

Moderate/

severe Mild

Moderate/

severe

IND Active/passive 3,984a 6 – 20b 1 – 10b Noneb .05b

Pittman (1997) Active 508 16 5 29c 14

TAMC

(1998)

Active 536 Not addressed Not addressed 43d 5

DOD (Current 

monitoring)

Passive 223,000e ee e e
Page 5 GAO/T-NSIAD-99-148 Medical Readiness

Human Efficacy Study 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. 

Because the vaccine used in the Brachman study was different from the 

licensed vaccine, additional data were submitted to the Division of 

Biologics, Department of Health, Education, and Welfare (HEW), to 

support the license application for the MDPH vaccine. In a February 1969 

memorandum, an HEW committee concluded that based on the data, the 

assumption of efficacy appeared speculative. Similarly, a 1991 Army 

document noted that “it would be scientifically incorrect to assume that 

this (licensed) vaccine would be totally efficacious under different 

circumstances, that is, beyond the parameters of the study design.” Thus, 

assuming that the epidemiological evidence from the original vaccine is 

applicable to the licensed vaccine, we can conclude that the licensed 

vaccine is efficacious against cutaneous exposure but that testing still 

needs to be conducted on inhalation anthrax. In the absence of a specific 

study, efficacy of the licensed vaccine for 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.

Animal Efficacy Studies of 

Licensed Vaccines

Beginning in the late 1980s, DOD began studying the efficacy of vaccines 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 (both the U.S. and U.K. 

versions) but are protected by the live spore veterinary vaccine.4

4

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.
Page 6 GAO/T-NSIAD-99-148 Medical Readiness

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

protected against aerosol exposure.5

 However, in both the guinea pig and 

monkey studies, protection did not correlate with levels of antibodies to a 

protective antigen. Several studies have shown no direct comparison of 

immunity in humans to that in monkeys. Study findings suggest that “the 

importance of various specific immune mechanisms against inhalation 

anthrax may vary in different animal species or . . . the ability of the 

licensed human vaccine to stimulate cell-mediated immunity may be 

greater in some species than others.” A 1998 study comes to the same 

conclusion and emphasizes the need for further studies. In animals, the 

lack of correlation of protection with antibodies to protective antigen has 

some important consequences. 

DOD recognizes the importance of establishing a correlate of immunity in 

humans. Recently, it has sought to develop a serologic correlate of 

immunity in an animal model to use for humans.

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 reproducible and consistent quality. 

In general, quality is achieved by applying the current good manufacturing 

practice. This process is not static but involves manufacturers and 

regulators in a continuing process of assessment and upgrades as scientific 

progress, technical development, and experience help to identify 

deficiencies and make improvements possible. Such principles also apply 

to the facilities and equipment in which products are manufactured. 

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. 

FDA’s inspections of the MDPH facility found a number of deficiencies. 

The deficiencies that FDA identified in its February 1998 inspection fall 

5

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

challenge in rhesus monkeys, in “Proceedings of the International Workshop on Anthrax, Salisbury 

Medical Bulletin, Special Supplement no. 87 (1996) pp. 125-126.
Page 7 GAO/T-NSIAD-99-148 Medical Readiness

broadly into two categories: those that, although serious, might affect only 

one or a limited number of batches that were produced when the 

deficiency was extent and those of a generic nature that could compromise 

the safety and efficacy of any or all batches. DOD had also identified 

deficiencies during a March 1992 inspection, including the absence of 

stability studies. In 1998, MDPH closed its plant, which is now being 

renovated. DOD has directed that supplemental testing be done on the lots 

of vaccine in the current inventory. 

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

questions you or members of the Subcommittee may have.

(713030) Letr
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