Vaccination News Home Page

31 JAN 2002

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Anthrax Vaccine Adsorbed, (BioThrax™) is a sterile, milky-white suspension (when mixed) made from

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.

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 in the environment and it is largely through the upt ake 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

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

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 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% 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% to

60%.

Inhalation (pulmonary) anthrax has been reported to occur from 1-43 days after exposure to

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

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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 U.S. is estimated to be approximately 45% to 90%. From 1900 to October 2001, there

were 18 identified cases of inhalation anthrax in the U.S., the latest of which was reported in 1976,

with an 89% (16/18) mortality rate. Most of these exposures occurred in industrial settings, i.e., textile

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 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

BioThrax, to the protection against anthrax has not been determined.

A controlled field study using an earlier version of a protective antigen–based anthrax vaccine,

developed in the 1950’s, that consisted of an aluminum potassium sulfate-precipitated cell free filtrate

from an aerobic culture, was conducted from 1955-1959. 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

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% (lower

95% CI = 65%).

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.

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

A randomized clinical study was conducted by the U.S. Army Medical Research Institute of Infectious

Diseases (USAMRIID) from 1996-1999 in 173 volunteers to evaluate changes to the vaccination

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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

and 65 years of age who come in contact with animal products such as hides, hair or bones that come

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 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 vaccination-related 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-Barré 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

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

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This product should be administered with caution to patients with a possible history of latex sensitivity

since the vial stopper contains dry natural rubber.

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

Safety and effectiveness in pediatric patients have not been established.

No data regarding the safety of BioThrax are available for persons aged > 65 years.

Studies). Over the course of the 5-year study, there were 24 reports (0.15% 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% of doses administered) of moderate local reactions (edema or induration greater

than 30 mm but less than 120 mm in diameter) and 1373 reports (8.63% of doses administered) of

mild local reactions (erythema only or induration measuring less than 30 mm in diameter).

Systemic Reactions- In the same open label study, four cases of systemic reactions were reported

reported to have been transient, included fever, chills, nausea and general body aches.

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Recently (1996-1999), an assessment of safety was conducted as part of a randomized clinical study

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), headac he (2), fever (1) and

elevated temperature (1). Of these events, a single patient reported the simultaneous occurrence of

Local Reactions- The most common local reactions reported after the first dose (n=28) in this study

were tenderness (71%), erythema (43%), subcutaneous nodule (36%), induration (21%), warmth

(11%) and local pruritus (7%). The most frequently reported local reactions after the second dose

(n=28) were tenderness (61%), subcutaneous nodule (39%), erythema (32%), induration (18%), local

pruritus (14%), warmth (11%) and arm motion limitation (7%). After the third dose (n=26), the most

frequently reported local reactions were tenderness (58%), warmth (19%), local pruritis (19%),

erythema (12%), arm motion limitation (12%), induration (8%), edema (8%) and subcutaneous nodule

(4%). Local reactions were found to occur more often in women. No abscess or necrosis was

observed at the injection site.

Systemic Reactions- 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%),

respiratory difficulty (4%) and fever (4%). After the second dose (n=28), the most frequently reported

systemic reactions were malaise (11%), myalgia (7%), fever (7%), headache (4%), anorexia (4%) and

nausea or vomiting (4%). After the third dose (n=26), the most frequently reported systemic reactions

were headache (4%), malaise (4%), myalgia (4%) and fever (4%). 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.

Data regarding potential adverse events following anthrax vaccination are available from the Vaccine

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 1850 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% 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

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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, Guillain-Barré 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.

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 5-35% 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 one-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.

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.

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.

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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.

2. Henderson, D.W., Peacock, S., Belton, F.C., 1956. Observations on the prophylaxis of

50:1077-9.

5. Brachman, P.S., & A. M. Friedlander. 1999. Anthrax. In Vaccines, Third Edition, Plotkin &

Orenstein (eds.), pp. 629-637.

Health, 52:632-645.

7. Centers for Disease Control and Prevention. General recommendations on immunization

Vol. 43 (No. RR-1).

542-550.

Revision: January 31, 2002

Manufactured by

Lansing, Michigan 48906

U.S. License No. 1260

50483-04