Anthrax-cover with Cont Ed.p65

Inside:

Continuing Medical Education for U.S. Physicians and Nurses

Use of Anthrax Vaccine in the

United States

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES

Centers for Disease Control and Prevention (CDC)

Atlanta, GA 30333

December 15, 2000 / Vol. 49 / No. RR-15

Recommendations

and

Reports

Inside:

Continuing Medical Education for U.S. Physicians and Nurses

Inside:

Continuing Education Examination

Recommendations of the Advisory Committee on

Immunization Practices (ACIP)

Centers for Disease Control and Prevention .................. Jeffrey P. Koplan, M.D., M.P.H.

Director

The material in this report was prepared for publication by

National Center for Infectious Diseases .................................. James M. Hughes, M.D.

Director

Division of Bacterial and Mycotic Diseases ..............................Mitchell L. Cohen, M.D.

Director

The production of this report as an

MMWR

serial publication was coordinated in

Epidemiology Program Office ............................................ Barbara R. Holloway, M.P.H.

Acting Director

Office of Scientific and Health Communications ...................... John W. Ward, M.D.

Director

Editor,

MMWR

Series

Recommendations and Reports ...................................

Suzanne M. Hewitt, M.P.A.

Managing Editor

Darlene D. Rumph-Person

Project Editor

Morie M. Higgins

Visual Information Specialist

Michele D. Renshaw

Erica R. Shaver

Technical Information Specialists

The

MMWR

series of publications is published by the Epidemiology Program Office,

Centers for Disease Control and Prevention (CDC), U.S. Department of Health and

Human Services, Atlanta, GA 30333.

SUGGESTED CITATION

Centers for Disease Control and Prevention. Use of anthrax vaccine in the United

States: recommendations of the Advisory Committee on Immunization Practices

(ACIP). MMWR 2000;49(No. RR-15):[inclusive page numbers].

Vol. 49 / No. RR-15 MMWR i

Contents

Introduction ......................................................................................................... 1

Disease ........................................................................................................... 2

Pathogenesis ....................................................................................................... 4

Control and Prevention

Reducing the Risk for Exposure ................................................................... 4

Vaccination ..................................................................................................... 5

Vaccine Efficacy ............................................................................................. 7

Duration of Efficacy ........................................................................................ 7

Vaccine Safety ................................................................................................ 7

Management of Adverse Events .................................................................. 11

Reporting of Adverse Events ....................................................................... 11

Precautions and Contraindications .................................................................. 11

Vaccination During Pregnancy .................................................................... 11

Vaccination During Lactation ...................................................................... 11

Allergies ....................................................................................................... 11

Previous History of Anthrax Infection ......................................................... 11

Illness ........................................................................................................... 11

Recommendations for Use of AVA ................................................................... 12

Preexposure Vaccination ............................................................................. 12

Bioterrorism Preparedness.......................................................................... 12

Postexposure Prophylaxis —

Chemoprophylaxis and Vaccination ........................................................ 12

Research Agenda .............................................................................................. 14

Immunogenicity ........................................................................................... 16

Evaluating Changes in the Current Vaccine Schedule

and Route .................................................................................................. 16

Human Safety Studies ................................................................................. 16

Postexposure Prophylaxis ........................................................................... 16

Safety of Anthrax Vaccine in Clinical Toxicology Studies

Among Pregnant Animals ........................................................................ 17

References ......................................................................................................... 17

Continuing Education Examination ............................................................. CE-1

ii MMWR December 15, 2000

Vol. 49 / No. RR-15 MMWR iii

Advisory Committee on Immunization Practices

Membership List, October 2000

EXECUTIVE SECRETARY

Dixie E. Snider, Jr., M.D., M.P.H.

Associate Director for Science

Centers for Disease Control

and Prevention

Atlanta, Georgia

CHAIRMAN

John F. Modlin, M.D.

Professor of Pediatrics and Medicine

Dartmouth Medical School

Lebanon, New Hampshire

MEMBERS

Dennis A. Brooks, M.D., M.P.H.

Johnson Medical Center

Baltimore, Maryland

Richard D. Clover, M.D.

University of Louisville School of Medicine

Louisville, Kentucky

Fernando A. Guerra, M.D.

San Antonio Metropolitan Health District

San Antonio, Texas

Charles M. Helms, M.D., Ph.D.

University of Iowa Hospital and Clinics

Iowa City, Iowa

David R. Johnson, M.D., M.P.H.

Michigan Department of Community Health

Lansing, Michigan

Chinh T. Le, M.D.

Kaiser Permanente Medical Center

Santa Rosa, California

Paul A. Offit, M.D.

The Children’s Hospital of Philadelphia

Philadelphia, Pennsylvania

Margaret B. Rennels, M.D.

University of Maryland School of Medicine

Baltimore, Maryland

Lucy S. Tompkins, M.D., Ph.D.

Stanford University Medical Center

Stanford, California

Bonnie M. Word, M.D.

State University of New York

Stony Brook, New York

EX OFFICIO MEMBERS

Dana Bradshaw, M.D., Col., USAF

Air Force Medical Operations Agency

Washington, D.C.

James E. Cheek, M.D., M.P.H.

Indian Health Service

Albuquerque, New Mexico

Geoffrey S. Evans, M.D.

Health Resources and Services

Administration

Rockville, Maryland

T. Randolph Graydon

Health Care Financing Administration

Baltimore, Maryland

Martin G. Myers, M.D.

Centers for Disease Control and Prevention

Atlanta, Georgia

Carole Heilman, M.D.

National Institues of Health

Bethesda, Maryland

Karen Midthun, M.D.

Food and Drug Administration

Bethesda, Maryland

Martin G. Myers, M.D.

Centers for Disease Control

Atlanta, Georgia

Kristin Lee Nichol, M.D., M.P.H.

VA Medical Center

Minneapolis, Minnesota

iv MMWR December 15, 2000

LIAISON REPRESENTATIVES

American Academy of Family Physicians

Martin Mahoney, M.D., Ph.D.

Clarence, New York

American Academy of Pediatrics

Larry Pickering, M.D.

Norfolk, Virginia

Jon Abramson, M.D.

Winston-Salem, North Carolina

American Association of Health Plans

Eric K. France, M.D.

Denver, Colorado

American College of Obstetricians

and Gynecologists

Stanley A. Gall, M.D.

Louisville, Kentucky

American College of Physicians

Pierce Gardner, M.D.

Stony Brook, New York

American Hospital Association

William Schaffner, M.D.

Nashville, Tennessee

American Medical Association

H. David Wilson, M.D.

Grand Forks, North Dakota

Association of Teachers of

Preventive Medicine

W. Paul McKinney, M.D.

Louisville, Kentucky

Advisory Committee on Immunization Practices

Membership List, October 2000 — Continued

Canadian National Advisory Committee

on Immunization

Victor Marchessault, M.D.

Cumberland, Ontario, Canada

Healthcare Infection Control Practices

Advisory Committee

Jane D. Siegel, M.D.

Dallas, Texas

Infectious Diseases Society of America

Samuel L. Katz, M.D.

Durham, North Carolina

National Immunization Council and

Child Health Program, Mexico

Jose Ignacio Santos, M.D.

Mexico City, Mexico

National Medical Association

Rudolph E. Jackson, M.D.

Atlanta, Georgia

National Vaccine Advisory Committee

Georges Peter, M.D.

Providence, Rhode Island

Pharmaceutical Research and

Manufacturers of America

Barbara J. Howe, M.D.

Collegeville, Pennsylvania

Vol. 49 / No. RR-15 MMWR v

The following CDC staff members prepared this report:

David A. Ashford, D.V.M., M.P.H., D.Sc.

Bradley Perkins, M.D.

Division of Bacterial and Mycotic Diseases

Lisa D. Rotz, M.D.

Office of Bioterrorism Preparedness and Response

National Center for Infectious Diseases

vi MMWR December 15, 2000

Vol. 49 / No. RR-15 MMWR 1

Use of Anthrax Vaccine in the United States

Recommendations of the Advisory Committee on

Immunization Practices

Summary

These recommendations concern the use of aluminum hydroxide adsorbed

cell-free anthrax vaccine (Anthrax Vaccine Adsorbed [AVA], BioPort Corporation,

Lansing, MI) in the United States for protection against disease caused by

Bacillus

anthracis

. In addition, information is included regarding the use of chemoprophy-

laxis against

B. anthracis

INTRODUCTION

Anthrax is a zoonotic disease caused by the spore-forming bacterium

Bacillus

anthracis

(

1,2

). The disease most commonly occurs in wild and domestic mammals (e.g.,

cattle, sheep, goats, camels, antelope, and other herbivores)(

). Anthrax occurs in

humans when they are exposed to infected animals or tissue from infected animals

or when they are directly exposed to

B. anthracis

(

3–5

). Depending on the route of

infection, anthrax disease can occur in three forms: cutaneous, gastrointestinal, and

inhalation (

B. anthracis

spores can remain viable and infective in the soil for many years. During

this time, they are a potential source of infection for grazing livestock, but generally do

not represent a direct infection risk for humans. Grazing ruminants become infected

when they ingest these spores. Consequently, humans can become infected with

B. anthracis

by skin contact, ingestion, or inhalation of

B. anthracis

spores originating

from animal products of infected animals. Direct skin contact with contaminated animal

products can result in cutaneous anthrax. Ingestion of infected and undercooked or raw

meat can result in oropharyngeal or gastrointestinal forms of the disease. Inhalation of

aerosolized spores associated with industrial processing of contaminated wool, hair, or

hides can result in inhalation anthrax. Person-to-person transmission of inhalation

anthrax has not been confirmed.

Estimation of the true incidence of human anthrax worldwide is difficult because

reporting of anthrax cases is unreliable (

). However, anthrax occurs globally and is

most common in agricultural regions with inadequate control programs for anthrax in

livestock. In these regions, anthrax affects domestic animals, which can directly or indi-

rectly infect humans, and the form of anthrax that occurs in >95% of cases is cutaneous.

These regions include South and Central America, Southern and Eastern Europe, Asia,

Africa, the Caribbean, and the Middle East (

). The largest recent epidemic of human

anthrax occurred in Zimbabwe during 1978–1980; 9445 cases occurred, including

141 (1.5%) deaths (

In the United States, the annual incidence of human anthrax has declined from

approximately 130 cases annually in the early 1900s to no cases during 1993–2000. The

last confirmed case of human anthrax reported in the United States was a cutaneous

case reported in 1992. Most cases reported in the United States have been cutaneous;

2 MMWR December 15, 2000

during the 20th century, only 18 cases of inhalation anthrax were reported, the most

recent in 1976 (

). Of the 18 cases of inhalation anthrax reported in the United States

since 1950, two occurred in laboratory workers. No gastrointestinal cases have been

reported in the United States.

Anthrax continues to be reported among domestic and wild animals in the United

States. The incidence of anthrax in U.S. animals is unknown; however, reports of animal

infection have occurred among the Great Plains states from Texas to North Dakota (

8–10

In addition to causing naturally occurring anthrax,

B. anthracis

has been manufac-

tured as a biological warfare agent, and concern exists that it could be used as a biologi-

cal terrorist agent.

B. anthracis

is considered one of the most likely biological warfare

agents because of the ability of

B. anthracis

spores to be transmitted by the respiratory

route, the high mortality of inhalation anthrax, and the greater stability of

B. anthracis

spores compared with other potential biological warfare agents (

11–14

). Anthrax has

been a focus of offensive and defensive biological warfare research programs for

approximately 60 years. The World Health Organization estimated that 50 kg of

B. anthracis

released upwind of a population center of 500,000 could result in 95,000

deaths and 125,000 hospitalizations (

The infectious dose of

B. anthracis

in humans by any route is not precisely known.

Based on data from studies of primates, the estimated infectious dose by the respiratory

route required to cause inhalation anthrax in humans is 8,000–50,000 spores (

7,16,17

The influence of the bacterium strain or host factors on this infectious dose is not com-

pletely understood.

Primary and secondary aerosolization of

B. anthracis

spores are important consider-

ations in bioterrorist acts involving deliberate release of

B. anthracis

. Primary aerosoliza-

tion results from the initial release of the agent. Secondary aerosolization results from

agitation of the particles that have settled from the primary release (e.g., as a result of

disturbance of contaminated dust by wind, human, or animal activities.) In the generation

of infectious aerosols, the aerosol is composed of two components that have differing

properties: particles larger than 5 microns and particles 1–5 microns in diameter. Par-

ticles >5 microns in diameter quickly fall from the atmosphere and bond to any surface.

These particles require large amounts of energy to be resuspended. Even with use of

highly efficient dissemination devices (i.e., devices able to disseminate a high concentra-

tion of agent into the environment), the level of environmental contamination with the

larger, bound particles is estimated to still be too low to represent a substantial threat of

secondary aerosolization (

18–20

). Particles 1–5 microns in diameter behave as a gas

and move through the environment without settling. Environmental residue is not a

concern from this portion of the aerosol (

Disease

The symptoms and incubation period of human anthrax vary depending on the route

of transmission of the disease. In general, symptoms usually begin within 7 days of

exposure (

Cutaneous

Most (>95%) naturally occurring

B. anthracis

infections are cutaneous and occur

when the bacterium enters a cut or abrasion on the skin (e.g., when handling contami-

nated meat, wool, hides, leather, or hair products from infected animals). The reported

Vol. 49 / No. RR-15 MMWR 3

incubation period for cutaneous anthrax ranges from 0.5 to 12 days (

1,6,22

). Skin infec-

tion begins as a small papule, progresses to a vesicle in 1–2 days, and erodes leaving a

necrotic ulcer with a characteristic black center. Secondary vesicles are sometimes

observed. The lesion is usually painless. Other symptoms might include swelling of adja-

cent lymph glands, fever, malaise, and headache. The case-fatality rate of cutaneous

anthrax is 20% without antibiotic treatment and <1% with antibiotic treatment (

1,23,24

Gastrointestinal

The intestinal form of anthrax usually occurs after eating contaminated meat and is

characterized by an acute inflammation of the intestinal tract. The incubation period for

intestinal anthrax is suspected to be 1–7 days. Involvement of the pharynx is character-

ized by lesions at the base of the tongue or tonsils, with sore throat, dysphagia, fever, and

regional lymphadenopathy. Involvement of the lower intestine is characterized by acute

inflammation of the bowel. Initial signs of nausea, loss of appetite, vomiting, and fever are

followed by abdominal pain, vomiting of blood, and bloody diarrhea (

). The case-

fatality rate of gastrointestinal anthrax is unknown but is estimated to be 25%–60%

(

1,26,27

Inhalation

Inhalation anthrax results from inspiration of 8,000–50,000 spores of

B. anthracis

Although the incubation period for inhalation anthrax for humans is unclear, reported

incubation periods range from 1 to 43 days (

). In a 1979 outbreak of inhalation anthrax

in the former Soviet Union, cases were reported up to 43 days after initial exposure. The

exact date of exposure in this outbreak was estimated and never confirmed, and the

modal incubation period was reported as 9–10 days. This modal incubation period is

slightly longer than estimated incubation periods reported in limited outbreaks of inhala-

tion anthrax in humans (

). However, the incubation period for inhalation anthrax might

be inversely related to the dose of

B. anthracis

(

30,31

). In addition, the reported admin-

istration of postexposure chemoprophylaxis during this outbreak might have prolonged

the incubation period in some cases. Data from studies of laboratory animals suggest

that

B. anthracis

spores continue to vegetate in the host for several weeks postinfection,

and antibiotics can prolong the incubation period for developing disease (

28–30,32

These studies of nonhuman primates, which are considered to be the animal model that

most closely approximates human disease, indicate that inhaled spores do not immedi-

ately germinate within the alveolar recesses but reside there potentially for weeks until

taken up by alveolar macrophages. Spores then germinate and begin replication within

the macrophages. Antibiotics are effective against germinating or vegetative

B. anthracis

but are not effective against the nonvegetative or spore form of the organism. Conse-

quently, disease development can be prevented as long as a therapeutic level of antibi-

otics is maintained to kill germinating

B. anthracis

organisms. After discontinuation of

antibiotics, if the remaining nongerminated spores are sufficiently numerous to evade or

overwhelm the immune system when they germinate, disease will then develop. This

phenomenon of delayed onset of disease is not recognized to occur with cutaneous or

gastrointestinal exposures.

Initial symptoms can include sore throat, mild fever, and muscle aches. After several

days, the symptoms can progress to severe difficulty breathing and shock. Meningitis

frequently develops. Case-fatality estimates for inhalation anthrax are based on incom-

plete information regarding the number of persons exposed and infected. However, a

4 MMWR December 15, 2000

case-fatality rate of 86% was reported following the 1979 outbreak in the former Soviet

Union, and a case-fatality rate of 89% (16 of 18 cases) was reported for inhalation an-

thrax in the United States (

8,28,29

). Records of industrially acquired inhalation anthrax

in the United Kingdom, before the availability of antibiotics or vaccines, document that

97% of cases were fatal.

PATHOGENESIS

B. anthracis

evades the immune system by producing an antiphagocytic capsule. In

addition,

B. anthracis

produces three proteins — protective antigen (PA), lethal factor

(LF), and edema factor (EF) — that act in binary combinations to form two exotoxins

known as lethal toxin and edema toxin (

33–35

). PA and LF form lethal toxin; PA and EF

form edema toxin. LF is a protease that inhibits mitogen-activated protein kinase-kinase

(

). EF is an adenylate cyclase that generates cyclic adenosine monophosphate in the

cytoplasm of eukaryotic cells (

37,38

). PA is required for binding and translocating LF and

EF into host cells. PA is an 82 kD protein that binds to receptors on mammalian cells and

is critical to the ability of

B. anthracis

to cause disease. After binding to the cell mem-

brane, PA is cleaved to a 63 kD fragment that subsequently binds with LF or EF (

). LF

or EF bound to the 63KD fragment undergoes receptor-mediated internalization, and the

LF or EF is translocated into the cytosol upon acidification of the endosome.

After wound inoculation, ingestion, or inhalation, spores infect macrophages, germi-

nate, and proliferate. In cutaneous and gastrointestinal infection, proliferation can occur

at the site of infection and the lymph nodes draining the infection site. Lethal toxin and

edema toxin are produced and respectively cause local necrosis and extensive edema,

which is a major characteristic of the disease. As the bacteria multiply in the lymph

nodes, toxemia progresses, and bacteremia may ensue. With the increase in toxin pro-

duction, the potential for widespread tissue destruction and organ failure increases (

CONTROL AND PREVENTION

Reducing the Risk for Exposure

Worldwide, anthrax among livestock is controlled through vaccination programs,

rapid case detection and case reporting, and burning or burial of animals suspected or

confirmed of having the disease. Human infection is controlled through reducing infec-

tion in livestock, veterinary supervision of slaughter practices to avoid contact with po-

tentially infected livestock, and restriction of importation of hides and wool from countries

in which anthrax occurs. In countries where anthrax is common and vaccination cover-

age among livestock is low, humans should avoid contact with livestock and animal

products that were not inspected before and after slaughter. In addition, consumption of

meat from animals that have experienced sudden death and meat of uncertain origin

should be avoided (

1,4

Vol. 49 / No. RR-15 MMWR 5

Vaccination

Protective Immunity

Before the mechanisms of humoral and cellular immunity were understood, research-

ers demonstrated that inoculation of animals with attenuated strains of

B. anthracis

led to

protection (

41,42

). Subsequently, an improved vaccine for livestock, based on a live

unencapsulated avirulent variant of

B. anthracis

, was developed (

43,44

). Since then, this

vaccine has served as the principal veterinary vaccine in the Western Hemisphere.

The use of livestock vaccines was associated with occasional animal casualties, and

live vaccines were considered unsuitable for humans. In 1904, the possibility of using

acellular vaccines against

B. anthracis

was first suggested by investigators who discov-

ered that injections of sterilized edema fluid from anthrax lesions provided protection in

laboratory animals (

45,46

). This led to exploration of the use of filtrates of artificially

cultivated

B. anthracis

as vaccines (

47–51

) and thereby to the human anthrax vaccines

currently licensed and used in the United States and Europe today. The first product — an

alum-precipitated cell-free filtrate from an aerobic culture — was developed in 1954

(

52,53

). Alum is the common name for aluminum potassium sulfate. This vaccine pro-

vided protection in monkeys, caused minimal reactivity and short-term adverse events in

humans, and was used in the only efficacy study of human vaccination against anthrax in

the United States. In the United States, during 1957–1960, the vaccine was improved

through a) the selection of a

B. anthracis

strain that produced a higher fraction of PA

under microaerophilic conditions, b) the production of a protein-free media, and c) the use

of aluminum hydroxide rather than alum as the adjuvant (

50,51

). This became the vac-

cine approved for use in the United States — anthrax vaccine adsorbed (AVA [patent

number 3,208,909, September 28, 1965]).

Passive immunity against

B. anthracis

can be transferred using polyclonal antibodies

in laboratory animals (

); however, specific correlates for immunity against

B. anthracis

have not been identified (

55–57

). Evidence suggests that a humoral and cellular re-

sponse against PA is critical to protection against disease following exposure (

49,57–59

Anthrax Vaccine Adsorbed

AVA, the only licensed human anthrax vaccine in the United States, is produced by

BioPort Corporation in Lansing, Michigan, and is prepared from a cell-free filtrate of

B. anthracis

culture that contains no dead or live bacteria (

). The strain used to prepare

the vaccine is a toxigenic, nonencapsulated strain known as V770-NP1-R (

). The filtrate

contains a mix of cellular products including PA (

) and is adsorbed to aluminum hy-

droxide (Amphogel, Wyeth Laboratories) as adjuvant (

). The amount of PA and other

proteins per 0.5–mL dose is unknown, and all three toxin components (LF, EF, and PA) are

present in the product (

). The vaccine contains no more that 0.83 mg aluminum per

0.5–mL dose, 0.0025% benzethonium chloride as a preservative, and 0.0037% formalde-

hyde as a stabilizer. The potency and safety of the final product is confirmed according to

U.S. Food and Drug Administration (FDA) regulations (

). Primary vaccination consists

of three subcutaneous injections at 0, 2, and 4 weeks, and three booster vaccinations at

6, 12, and 18 months. To maintain immunity, the manufacturer recommends an annual

booster injection. The basis for the schedule of vaccinations at 0, 2, and 4 weeks, and 6, 12,

and 18 months followed by annual boosters is not well defined (

52,62,63

; Table 1).

6 MMWR December 15, 2000

Because of the complexity of a six-dose primary vaccination schedule and frequency

of local injection-site reactions (see Vaccine Safety), studies are under way to assess the

immunogenicity of schedules with a reduced number of doses and with intramuscular

(IM) administration rather than subcutaneous administration. Immunogenicity data were

collected from military personnel who had a prolonged interval between the first and

second doses of anthrax vaccine in the U.S. military anthrax vaccination program. Anti-

body to PA was measured by enzyme-linked immunosorbent assay (ELISA) at 7 weeks

after the first dose. Geometric mean titers increased from 450 µg/mL among those who

received the second vaccine dose 2 weeks after the first (the recommended schedule,

n = 22), to 1,225 for those vaccinated at a 3-week interval (n = 19), and 1,860 for those

vaccinated at a 4-week interval (n = 12). Differences in titer between the routine and

prolonged intervals were statistically significant (p <0.01).

Subsequently, a small randomized study was conducted among military personnel to

compare the licensed regimen (subcutaneous injections at 0, 2, and 4 weeks, n = 28) and

alternate regimens (subcutaneous [n = 23] or intramuscular [n=22] injections at 0 and

4 weeks). Immunogenicity outcomes measured at 8 weeks after the first dose included

geometric mean IgG concentrations and the proportion of subjects seroconverting (de-

fined by an anti-PA IgG concentration of

>25 µg/mL). In addition, the occurrence of local

and systemic adverse events was determined. IgG concentrations were similar between

the routine and alternate schedule groups (routine: 478 µg/mL; subcutaneous at 0 and

4 weeks: 625 µg/mL; intramuscular at 0 and 4 weeks: 482 µg/mL). All study participants

seroconverted except for one of 21 in the intramuscular (injections at 0 and 4 weeks)

group. Systemic adverse events were uncommon and similar for the intramuscular and

subcutaneous groups. All local reactions (i.e., tenderness, erythema, warmth, induration,

and subcutaneous nodules) were significantly more common following subcutaneous

vaccination. Comparison of the three vaccination series indicated no significant differ-

ences between the proportion of subjects experiencing local reactions for the two subcu-

taneous regimens but significantly fewer subcutaneous nodules (p<0.001) and

significantly less erythema (p = 0.001) in the group vaccinated intramuscularly (P. Pittman,

personal communication, USAMRIID, Ft. Detrick, MD).

Larger studies are planned to further evaluate vaccination schedule and route of

administration. At this time, ACIP cannot recommend changes in vaccine administration

because of the preliminary nature of this information. However, the data in this report do

support some flexibility in the route and timing of anthrax vaccination under special

circumstances. As with other licensed vaccines, no data indicate that increasing the

TABLE 1. Recommended vaccination schedule and contraindications for Anthrax Vaccine

Adsorbed (AVA)

Recommended vaccination schedule Subcutaneous injections at 0, 2, and

4 wks, then 6 mos, 12 mos, and 18 mos.

Annual booster injection if immunity is to

be maintained.

Contraindications a) Previous history of anthrax infection.

or b) Experiencing an anaphylactic

reaction following a previous dose of AVA

or any of the vaccine components.

Postponement of vaccination Moderate or severe acute illness.

Vol. 49 / No. RR-15 MMWR 7

interval between doses adversely affects immunogenicity or safety. Therefore, interrup-

tion of the vaccination schedule does not require restarting the entire series of anthrax

vaccine or the addition of extra doses.

Vaccine Efficacy

The efficacy of AVA is based on several studies in animals, one controlled vaccine trial

in humans (

), and immunogenicity data for both humans and lower mammalian spe-

cies (

47,49,57,65

). Vaccination of adults with the licensed vaccine induced an immune

response measured by indirect hemagglutination in 83% of vaccinees 2 weeks after the

first dose and in 91% of vaccinees who received two or more doses (

57,65

). Approxi-

mately 95% of vaccinees seroconvert with a fourfold rise in anti-PA IgG titers after three

doses (

57,65

). However, the precise correlation between antibody titer (or concentra-

tion) and protection against infection is not defined (

The protective efficacy of the alum-precipitated vaccine (the original form of the PA

filtrate vaccine) and AVA (adsorbed to aluminum hydroxide) have been demonstrated in

several animal models using different routes of administration (

49–52,57,62,63,66–69

Data from animal studies (except primate studies) involve several animal models, prepa-

rations, and vaccine schedules and are difficult to interpret and compare. The macaque

model (Rhesus monkeys,

Macaca mulatta

) of inhalation anthrax is believed to best

reflect human disease (

), and the AVA vaccine has been shown to be protective

against pulmonary challenge in macaques using a limited number of

B. anthracis

strains

(

52,62,70–73

) (Table 2).

In addition to the studies of macaques, a study was published in 1962 of an adjuvant

controlled, single-blinded, clinical trial among mill workers using the alum-precipitated

vaccine — the precursor to the currently licensed AVA. In this controlled study,

379 employees received the vaccine, 414 received the placebo, and 340 received nei-

ther the vaccine nor the placebo. This study documented a vaccine efficacy of 92.5% for

protection against anthrax (cutaneous and inhalation combined), based on person time

of occupational exposure (

). During the study, an outbreak of inhalation anthrax

occurred among the study participants. Overall, five cases of inhalation anthrax

occurred among persons who were either placebo recipients or did not participate in the

controlled part of the study. No cases occurred in anthrax vaccine recipients. No data are

available regarding the efficacy of anthrax vaccine for persons aged <18 years and

>65 years.

Duration of Efficacy

The duration of efficacy of AVA is unknown in humans. Data from animal studies

suggest that the duration of efficacy after two inoculations might be 1–2 years (

57,62,72

Vaccine Safety

Data regarding adverse events associated with use of AVA are derived from informa-

tion from three sources. These sources are a) prelicensure investigational new drug data

evaluating vaccine safety, b) passive surveillance data regarding adverse events associ-

ated with postlicensure use of AVA, and c) several published studies (

64,74,75

8 MMWR December 15, 2000

TABLE 2. Summary of efficacy studies of acellular filtrate vaccines against inhalation anthrax in macaques

Route of vaccine

Vaccine* No. doses administration Challenge dose

†

Challenge strain

Duration

Survival p-value

Alum

3 Subcutaneous 50 x LD50 Vollum 16 days seven of seven p=0.0001

Alum

2 Subcutaneous 100 x LD50 Vollum 16 days four of four p=0.008

34 days four of four p=0.008

Alum

2 Subcutaneous 10 x LD50 M36 (Vollum) 7 days 10 of 10 p= 0.00001

1 yr 10 of 10 p= 0.00001

2 yrs six of seven p=0.01

AVA

2 Intramuscular 200 x LD50 Ames 8 wks 10 of 10 p= 0.0002

38 wks three of three

100 wks seven of eight p=0.02

AVA

2 Intramuscular 200 x LD50 Ames 12 wks 10 of 10 p=0.0001

* Alum=aluminum potassium sulfate; AVA=Anthrax Vaccine Adsorbed.

†

In multiples of macaque LD50. LD50=a lethal dose of 50% (defined as the dose of a product that will result in the death of 50% of a population exposed to that product).

Route of challenge was inhalation.

Duration of challenge following vaccination.

Vol. 49 / No. RR-15 MMWR 9

Prelicensure Adverse Event Surveillance

Local Reactions. In AVA prelicensure evaluations, 6,985 persons received 16,435

doses: 9,893 initial series doses and 6,542 annual boosters (

). Severe local reactions

(defined as edema or induration >120 mm) occurred after 1% of vaccinations. Moderate

local reactions (defined as edema and induration of 30 mm–120 mm) occurred after

3% of vaccinations. Mild local reactions (defined as erythema, edema, and induration

<30 mm) occurred after 20% of vaccinations. In a study of the alum precipitated precur-

sor to AVA, moderate local reactions were documented in 4% of vaccine recipients and

mild reactions in 30% of recipients (

Systemic Reactions. In AVA prelicensure evaluations, systemic reactions (i.e., fever,

chills, body aches, or nausea) occurred in <0.06% (in four of approximately 7,000) of

vaccine recipients (

). In the study of the alum precipitated precursor to AVA, systemic

reactions occurred in 0.2% of vaccine recipients (

Postlicensure Adverse Event Surveillance

Data regarding potential adverse events following anthrax vaccination are available

from the Vaccine Adverse Event Reporting System (VAERS) (

). From January 1, 1990,

through August 31, 2000, at least 1,859,000 doses of anthrax vaccine were distributed in

the United States. During this period, VAERS received 1,544 reports of adverse events;

of these, 76 (5%) were serious. A serious event is one that results in death, hospitaliza-

tion, or permanent disability or is life-threatening. Approximately 75% of the reports

were for persons aged <40 years; 25% were female, and 89% received anthrax vaccine

alone. The most frequently reported adverse events were injection-site hypersensitivity

(334), injection-site edema (283), injection-site pain (247), headache (239), arthralgia

(232), asthenia (215), and pruritis (212). Two reports of anaphylaxis have been

received by VAERS. One report of a death following receipt of anthrax vaccine has been

submitted to VAERS; the autopsy final diagnosis was coronary arteritis. A second fatal

report, submitted after August 31, 2000, indicated aplastic anemia as the cause of death.

A causal association with anthrax vaccine has not been documented for either of the

death reports. Serious adverse events infrequently reported (<10) to VAERS have

included cellulitis, pneumonia, Guillain-Barré syndrome, seizures, cardiomyopathy, sys-

temic lupus erythematosus, multiple sclerosis, collagen vascular disease, sepsis,

angioedema, and transverse myelitis (CDC/FDA, unpublished data, 2000). Analysis of

VAERS data documented no pattern of serious adverse events clearly associated with

the vaccine, except injection-site reactions. 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.

Published Studies About Adverse Events

Adverse events following anthrax vaccination have been assessed in several studies

conducted by the Department of Defense in the context of the routine anthrax vaccina-

tion program. At U.S. Forces, Korea, data were collected at the time of anthrax vaccina-

tion from 4,348 service personnel regarding adverse events experienced from a previous

dose of anthrax vaccine. Most reported events were localized, minor, and self-limited.

After the first or second dose, 1.9% reported limitations in work performance or had

been placed on limited duty. Only 0.3% reported

>1 day lost from work; 0.5% consulted a

10 MMWR December 15, 2000

clinic for evaluation; and one person (0.02%) required hospitalization for an injection-site

reaction. Adverse events were reported more commonly among women than among

men. A second study at Tripler Army Medical Center, Hawaii, assessed adverse events

among 603 military health-care workers. Rates of events that resulted in seeking medi-

cal advice or taking time off work were 7.9% after the first dose; 5.1% after the second

dose; 3.0% after the third dose; and 3.1% after the fourth dose. Events most commonly

reported included muscle or joint aches, headache, and fatigue (

). However, these

studies are subject to several methodological limitations, including sample size, the

limited ability to detect adverse events, loss to follow-up, exemption of vaccine recipients

with previous adverse events, observational bias, and the absence of unvaccinated

control groups (

No studies have definitively documented occurrence of chronic diseases (e.g., cancer

or infertility) following anthrax vaccination. In an assessment of the safety of anthrax

vaccine, the Institute of Medicine (IOM) noted that published studies reported no signifi-

cant adverse effects of the vaccine, but the literature is limited to a few short-term

studies (

). One published follow-up study of laboratory workers at Fort Detrick, Mary-

land, concluded that, during the 25-year period following receipt of anthrax vaccine, the

workers did not develop any unusual illnesses or unexplained symptoms associated with

vaccination (

77,78

). IOM concluded that, in the peer-reviewed literature, evidence is

either inadequate or insufficient to determine whether an association exists between

anthrax vaccination and long-term adverse health outcomes. IOM noted that few vac-

cines for any disease have been actively monitored for adverse effects over long periods

and encouraged evaluate of active long-term monitoring studies of large populations to

further evaluate the relative safety of anthrax vaccine. Such studies are under way by

the Department of Defense.

CDC has conducted two epidemiologic investigations of the health concerns of

Persian Gulf War (PGW) veterans that examined a possible association with vaccina-

tions, including anthrax vaccination. The first study, conducted among Air Force person-

nel, evaluated several potential risk factors for chronic multisymptom illnesses, including

anthrax vaccination. Occurrence of a chronic multisymptom condition was significantly

associated with deployment to the PGW but was not associated with specific PGW expo-

sures and also affected nondeployed veterans (

). The ability of this study to detect a

significant difference was limited. The second study focused on comparing illness among

PGW veterans and controls. The study documented that the self-reported prevalence of

medical and psychiatric conditions was higher among deployed PGW veterans than

nondeployed veterans. In this study, although a question was asked about the number of

vaccinations received, no specific questions were asked about the anthrax vaccine. How-

ever, the study concluded that the relation between self-reported exposures and condi-

tions suggests that no single exposure is related to the medical and psychiatric conditions

among PGW military personnel (

). In summary, current research has not documented

any single cause of PGW illnesses, and existing scientific evidence does not support an

association between anthrax vaccine and PGW illnesses. No data are available regard-

ing the safety of anthrax vaccine for persons aged <18 years and >65 years.

Management of Adverse Events

Adverse events can occur in persons who must complete the anthrax vaccination

series because of high risk of exposure or because of employment requirements.

Several protocols have been developed to manage specific local and systemic adverse

Vol. 49 / No. RR-15 MMWR 11

events (available at www.anthrax.osd.mil). However, these protocols have not been

evaluated in randomized trials.

Reporting of Adverse Events

Adverse events occurring after administration of anthrax vaccine — especially events

that are serious, clinically significant, or unusual — should be reported to VAERS, regard-

less of the provider’s opinion of the causality of the association. VAERS forms can be

obtained by calling (800) 822-7967. Information about VAERS and how to report vaccine

adverse events is available from http://www.vaers.org>, <http://www.fda.gov/cber/vaers/

vaers.htm> or <http://www.cdc.gov/nip/>.

PRECAUTIONS AND CONTRAINDICATIONS

Vaccination During Pregnancy

No studies have been published regarding use of anthrax vaccine among pregnant

women. Pregnant women should be vaccinated against anthrax only if the potential

benefits of vaccination outweigh the potential risks to the fetus.

Vaccination During Lactation

No data suggest increased risk for side effects or temporally related adverse events

associated with receipt of anthrax vaccine by breast-feeding women or breast-fed chil-

dren. Administration of nonlive vaccines (e.g., anthrax vaccine) during breast-feeding is

not medically contraindicated.

Allergies

Although anaphylaxis following anthrax vaccination is extremely rare and no ana-

phylaxis deaths associated with AVA have been reported, this adverse event can be life

threatening. AVA is contraindicated for persons who have experienced an anaphylactic

reaction following a previous dose of AVA or any of the vaccine components.

Previous History of Anthrax Infection

Anthrax vaccine is contraindicated in persons who have recovered from anthrax

because of previous observations of more severe adverse events among recipients with

a vaccine history of anthrax than among nonrecipients. The vaccine is also contraindi-

cated in persons with a history of an anaphylactic reaction to the vaccine.

Illness

In the context of the routine preexposure program, vaccination of persons with mod-

erate or severe acute illness should be postponed until recovery. This prevents superim-

posing the adverse effects of the vaccine on the underlying illness or mistakenly attributing

a manifestation of the underlying illness to the vaccine. Vaccine can be administered to

persons who have mild illnesses with or without low-grade fever.

12 MMWR December 15, 2000

RECOMMENDATIONS FOR USE OF AVA

Preexposure Vaccination

Occupational and Laboratory Exposures

Routine vaccination with AVA is indicated for persons engaged a) in work involving

production quantities or concentrations of

B. anthracis

cultures and b) in activities with a

high potential for aerosol production (

). Laboratorians using standard Biosafety Level

2 practices in the routine processing of clinical samples are not at increased risk for

exposure to

B. anthracis

spores.

The risk for persons who come in contact in the workplace with imported animal

hides, furs, bone meal, wool, animal hair, or bristles has been reduced by changes in

industry standards and import restrictions (

). Routine preexposure vaccination is rec-

ommended only for persons in this group for whom these standards and restrictions are

insufficient to prevent exposure to anthrax spores.

Routine vaccination of veterinarians in the United States is not recommended

because of the low incidence of animal cases. However, vaccination might be indicated

for veterinarians and other high-risk persons handling potentially infected animals in

areas with a high incidence of anthrax cases.

Bioterrorism Preparedness

Although groups initially considered for preexposure vaccination for bioterrorism

preparedness included emergency first responders, federal responders, medical practi-

tioners, and private citizens, vaccination of these groups is not recommended. Recom-

mendations regarding preexposure vaccination should be based on a calculable risk

assessment. At present, the target population for a bioterrorist release of

B. anthracis

cannot be predetermined, and the risk of exposure cannot be calculated. In addition,

studies suggest an extremely low risk for exposure related to secondary aerosolization

of previously settled

B. anthracis

spores (

28,83

). Because of these factors, preexposure

vaccination for the above groups is not recommended. For the military and other select

populations or for groups for which a calculable risk can be assessed, preexposure

vaccination may be indicated.

Options other than preexposure vaccination are available to protect personnel work-

ing in an area of a known previous release of

B. anthracis

. If concern exists that persons

entering an area of a previous release might be at risk for exposure from a re-release of

a primary aerosol of the organism or exposure from a high concentration of settled

spores in a specific area, initiation of prophylaxis should be considered with antibiotics

alone or in combination with vaccine as is outlined in the section on postexposure

prophylaxis.

Postexposure Prophylaxis — Chemoprophylaxis and

Vaccination

Penicillin and doxycycline are approved by FDA for the treatment of anthrax and

are considered the drugs of choice for the treatment of naturally occurring anthrax

(

14,83,84

). In addition, ciprofloxacin and ofloxacin have also demonstrated in vitro activ-

ity against

B. anthracis

(

14,85

). On the basis of studies that demonstrated the effective-

ness of ciprofloxacin in reducing the incidence and progression of inhalation anthrax in

Vol. 49 / No. RR-15 MMWR 13

animal models, FDA recently approved the use of ciprofloxacin following aerosol expo-

sure to

B. anthracis

spores to prevent development or progression of inhalation anthrax

in humans. Although naturally occurring

B. anthracis

resistance to penicillin is rare, such

resistance has been reported (

). As of November 2000, no naturally occurring resis-

tance to tetracyclines or ciprofloxacin had been reported.

Antibiotics are effective against the germinated form of

B. anthracis

but are not

effective against the spore form of the organism. Following inhalation exposure, spores

can survive in tissues for months without germination in nonhuman primates (

30,87

This phenomenon of delayed vegetation of spores resulting in prolonged incubation

periods has not been observed for routes of infection other than inhalation. In one study,

macaques were exposed to four times the LD50 dose* of anthrax spores, and the pro-

portion of spores that survived in the lung tissue was estimated to be 15%–20% at

42 days, 2% at 50 days, and <1% at 75 days (

). Although the LD50 dose for humans is

believed to be similar to that for nonhuman primates, the length of persistence of

B. anthracis

spores in human lung tissue is not known. The prolonged incubation period

reported in the Soviet Union outbreak of inhalation anthrax suggests that lethal amounts

of spores might have persisted up to 43 days after initial exposure. Although postexposure

chemoprophylaxis with tetracycline was reportedly initiated during this outbreak, the

duration of therapy was not reported.

Currently, ciprofloxacin is the only antibiotic approved by FDA for use in reducing the

incidence or progression of disease after exposure to aerosolized

B. anthracis

. Although

postexposure chemoprophylaxis using antibiotics alone has been effective in animal

models, the definitive length of treatment is unclear. Several studies have demonstrated

that short courses (5–10 days) of postexposure antibiotic therapy are not effective at

preventing disease when large numbers of spores are inhaled (

7,30

). Longer courses of

antibiotics may be effective (

). The study findings indicate that seven of 10, nine of

10 and eight of nine macaques exposed to 240,000–560,000 anthrax spores (8 times the

LD50) survived when treated for 30 days with penicillin, doxycycline, or ciprofloxacin,

respectively. All animals survived while undergoing antibiotic prophylaxis. Three ani-

mals treated with penicillin died on days 9, 12, and 20 after antibiotics were discontinued

(days 39, 42, and 50 after exposure). A single animal in the doxycycline group died of

inhalation anthrax 28 days after discontinuing treatment (day 58), and one animal in the

ciprofloxacin group died 6 days after discontinuation of therapy (day 36).

In addition, studies have demonstrated that antibiotics in combination with

postexposure vaccination are effective at preventing disease in nonhuman primates

after exposure to

B. anthracis

spores (

30,87

). Vaccination alone after exposure was not

protective. Because the current vaccine is labeled for use in specifically defined

preexposure situations only, no FDA-approved labeling addresses the optimal number

of vaccinations for postexposure prophylaxis use of the vaccine. An estimated 83% of

human vaccinees develop a vaccine-induced immune response after two doses of the

vaccine and >95% develop a fourfold rise in antibody titer after three doses (

57,65

Although the precise correlation between antibody titer and protection against disease is

not clear, these studies of postexposure vaccine regimens used in combination with

antibiotics in nonhuman primates have consistently documented that two to three doses

of vaccine were sufficient to prevent development of disease once antibiotics were

discontinued.

*LD50=a lethal dose of 50%; defined as the dose of a product that will result in the death of

50% of a population exposed to that product.

14 MMWR December 15, 2000

Only one study has directly compared antibiotics plus vaccine with a longer course of

antibiotics following aerosol exposure (

). This study documented no significant differ-

ence in survival for animals treated with doxycycline alone for 30 days or animals treated

with 30 days of doxycycline plus two doses of anthrax vaccine postexposure (nine of

10 versus nine of nine, p = 0.4). However, the study suggests a possible benefit of

postexposure combination of antibiotics with vaccination.

Following Inhalation Exposure

Postexposure prophylaxis against

B. anthracis

is recommended following an aerosol

exposure to

B. anthracis

spores. Such exposure might occur following an inadvertent

exposure in the laboratory setting or a biological terrorist incident. Aerosol exposure is

unlikely in settings outside a laboratory working with large volumes of

B. anthracis

textile mills working with heavily contaminated animal products, or following a biological

terrorism or warfare attack. Following naturally occurring anthrax among livestock,

cutaneous and rare gastrointestinal exposures among humans are possible, but inhala-

tion anthrax has not been reported. Because of the potential persistence of spores fol-

lowing a possible aerosol exposure, antibiotic therapy should be continued for at least

30 days if used alone, and although supporting data are less definitive, longer antibiotic

therapy (up to 42–60 days) might be indicated. If vaccine is available, antibiotics can be

discontinued after three doses of vaccine have been administered according to the stan-

dard schedule (0, 2, and 4 weeks) (Table 3). Because of concern about the possible

antibiotic resistance of

B. anthracis

used in a bioterrorist attack, doxycycline or

ciprofloxacin can be chosen initially for antibiotic chemoprophylaxis until organism sus-

ceptibilities are known. Antibiotic chemoprophylaxis can be switched to penicillin VK or

amoxicillin once antibiotic susceptibilities are known and the organism is found to be

penicillin susceptible with minimum inhibitory concentrations (MICs) attainable with oral

therapy.

Although the shortened vaccine regimen has been effective when used in a

postexposure regimen that includes antibiotics, the duration of protection from vaccina-

tion is not known. Therefore, if subsequent exposures occur, additional vaccinations

might be required.

Following Cutaneous or Gastrointestinal Exposure

No controlled studies have been conducted in animals or humans to evaluate the use

of antibiotics alone or in combination with vaccination following cutaneous or gastrointes-

tinal exposure to

B. anthracis

. Cutaneous and rare gastrointestinal exposures of humans

are possible following outbreaks of anthrax in livestock. In these situations, on the basis

of pathophysiology, reported incubation periods, current expert clinical judgment, and

lack of data, postexposure prophylaxis might consist of antibiotic therapy for 7–14 days.

Antibiotics could include any of those previously mentioned in this report and in Table 3.

RESEARCH AGENDA

The following research priorities should be considered regarding anthrax vaccine:

immunogenicity, evaluation of changes in use of the current vaccine, human safety stud-

ies, postexposure prophylaxis, antibiotic susceptibility and treatment studies, and safety

of anthrax vaccine in clinical toxicology studies among pregnant animals.

Vol. 49 / No. RR-15 MMWR 15

TABLE 3. Suggested postexposure antibiotic prophylaxis following confirmed or suspected exposure to

Bacillus anthracis

Drug Adults Children

†

(aged <9 yrs)

One of the following

Oral fluoroquinolones

Ciprofloxacin 500 mg orally twice daily 10–15 mg/kg/day orally divided every 12 hrs

Ofloxacin 400 mg orally twice daily Not recommended

Oral tetracyclines

Doxycycline 100 mg orally twice daily 5 mg/kg/day orally divided every 12 hrs

Oral penicillins

Penicillin VK 7.5 mg/kg orally four times daily 50 mg/kg/day orally divided four times daily

Amoxicillin 500 mg orally three times daily 80 mg/kg/day orally divided into two or

three doses

* Prophylaxis should continue until exposure to

B. anthracis

has been excluded. If exposure is confirmed and vaccine is available, prophylaxis should continue for

4 weeks and until three doses of vaccine have been administered or for 30–60 days if vaccine is not available.

†

Use of tetracyclines and fluoroquinolones in children have potential adverse effects including staining of teeth and cartilage damage, respectively. However, these

risks must be weighed carefully against the risk for developing anthrax. If a release of

B. anthracis

is confirmed, children should receive oral amoxicillin 80 mg per

kg of body mass per day divided every 8 or 12 hours (not to exceed 500 mg three times daily) or oral penicillin VK 50 mg/kg/day divided into four times daily as soon

as penicillin susceptibility of the organism has been confirmed.

Data are limited regarding the use of ofloxacin or other fluoroquinolones in children (except for ciprofloxacin).

16 MMWR December 15, 2000

Immunogenicity

Regarding the immunogenicity of AVA, priority research topics include a) identifying

a quantitative immune correlate(s) of protection in relevant animal species (especially

rabbits and nonhuman primates) and b)defining the quantitative relation between the

vaccine-elicited immune response in these animal species and humans. Specifically,

such information could help to provide scientific justification for changing the schedule

and route of administration of the existing vaccine.

Evaluating Changes in the Current Vaccine Schedule and

Route

Studies evaluating the effects of variations in use of the current anthrax vaccine

should include a definitive clinical evaluation comparing the intramuscular and subcuta-

neous routes of administration and an assessment of the effects of reducing the number

of inoculations required for protection. Both immunogenicity and safety of these changes

should be evaluated. Information about the efficacy and safety of AVA use in children and

elderly persons is needed. Information about safety of the vaccine during pregnancy is

also needed. In addition, research to develop the next generation of anthrax vaccines

should continue.

Human Safety Studies

To assess the safe use of anthrax vaccine in humans, the Advisory Committee on

Immunization Practices (ACIP) recommends several areas of research. Adverse event

surveillance through VAERS should be enhanced, which could include development of

electronic reporting capability and implementation of strategies to facilitate reporting. In

addition, the influence of lot-to-lot variations in the vaccine on rates of adverse events

should be evaluated. Other safety issues related to use of anthrax vaccine that should be

addressed include development and evaluation of pretreatment strategies to decrease

short-term adverse events; assessment of risk factors for adverse events, including sex

and preexisting antibody levels; and analysis of differences in rates of occurrence of

adverse events by route of anthrax transmission and method of vaccine administration

(intramuscular, subcutaneous, or jet injector). Because the role of repeated inoculations

in local and systemic reactions remains unclear, further research is needed regarding

this subject. In addition, the feasibility of studies to evaluate longer term and systemic

adverse events should be determined.

Postexposure Prophylaxis

Although a substantial benefit of postexposure antibiotics in preventing development

of inhalation anthrax has been demonstrated in macaques, further research is needed to

determine the optimal number of days of administration of those antibiotics and any

additional benefit of receiving the anthrax vaccine in combination with antibiotics. This is

a high priority for the current federal initiative regarding bioterrorism preparedness.

Determining alternative antibiotics for children and pregnant women should be an

important part of this research.

Vol. 49 / No. RR-15 MMWR 17

Antibiotic Susceptibility and Treatment Studies

Studies are needed that assess in vitro susceptibility of

B. anthracis

strains to

azithromycin, erythromycin, and other antibiotics that are practical for children and eld-

erly persons. In addition, treatment trials in animals for antibiotic alternatives to penicillin

and doxycycline are recommended.

Safety of Anthrax Vaccine in Clinical Toxicology Studies

Among Pregnant Animals

To assess the safety of anthrax vaccine use during human pregnancy, ACIP recom-

mends that regulatory toxicology studies be conducted in pregnant animals. The study

findings could provide baseline data for further studies of the safety of AVA use in

pregnant women.

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Recommendations

and

Reports

Continuing Education Activity