8.2 Notebook annotated

smallpox, which is believed to have originated more than 3,000

years ago in India or Egypt, is one of the most devastating diseases

known to humanity. For centuries, repeated smallpox epidemics swept

across continents, decimating populations in their wake.

The disease, for which no effective treatment was ever developed,

killed as many as 30% of those infected. Between 65% and 80% of

survivors were marked with deep-pitted pockmarks, most prominently

on the face. Blindness was another complication. In 18th century Europe,

a third of all reported cases of blindness were because of smallpox.

As late as the 18th century, smallpox killed every 10th child born in

Sweden and France. During the same century, every 7th child born in

Russia died from smallpox. It wasn’t until 1798, when Edward Jenner

demonstrated that inoculation with pus from cowpox lesions could

protect against smallpox, that there was hope that the disease could be

contained through medical means.

In the early 1950s—150 years after the introduction of vaccination—

an estimated 50 million cases of smallpox occurred in the world each year,

a ﬁgure which fell to around 10 to 15 million by 1967 because of vacci-

nation. Based on these encouraging statistics, the World Health Organi-

zation (who) launched an intensiﬁed plan in 1967 to eradicate smallpox—

the “ancient scourge” that threatened 60% of the world’s population.

Through the success of the global eradication campaign, smallpox was

ﬁnally pushed back to the horn of Africa and then to a single last natur-

al case, which occurred in Somalia in 1977 (the last case in the United

States occurred in 1949 in Texas). There has been only one smallpox-re-

lated fatality since: a laboratory-acquired case that occurred in the Unit-

ed Kingdom in 1978. In 1979, who certiﬁed the global eradication of small-

pox—one of the greatest achievements in the history of public health.

With the end of smallpox, the virus went on to survive only in labo-

ratories in the United States and in Koltsovo, Siberia. After the Soviet

Union collapsed, reports surfaced alleging that the Soviets had produced

variola in large quantities and were attempting to weaponize the virus in

the 1970s, 80s, and 90s. Bioterrorism experts began to worry that the Rus-

sians might have let the virus slip into the wrong hands, with recent

media reports suggesting that at least four countries have hidden stocks

of variola. Still, most experts have long discounted the use of variola as a

biological weapon, given numerous safety and “effectiveness” consider-

ations. However, after the terrorist attacks on the World Trade Center and

the Pentagon on September 11, 2001, many of the nay-sayers did an

about-face and recognized that, in the hands of the wrong people, a lethal

and socially destabilizing attack using variola was possible, if not likely.

Because of the lingering threat of a terrorist attack involving vario-

la—an attack anywhere in the world could easily result in widespread dis-

semination before the ﬁrst case of smallpox is ofﬁcially diagnosed—a

number of health agencies throughout the world have begun the process

of reimplementing smallpox vaccination programs. In the United

States, both “pre-event” and “post-event” protocols have been set up and

there is now enough vaccine available to immunize every U.S. resident.

However, there are lingering concerns regarding the use of smallpox vac-

cination in the United States today, given that a much larger percentage

of the general population are immune compromised, including a size-

able percentage of hiv-infected individuals.

What follows is a detailed summary of smallpox and the smallpox

vaccine, including the anticipated adverse events (particularly those in

hiv-infected individuals with suppressed immune systems) and the

various contraindications that need to be considered. Also provided is

a review of the pre-event vaccination program currently under way in

New York City, along with encouraging smallpox vaccine safety data from

Israel and the United States Department of Defense.

Variola: The Basics

smallpox is caused by variola, a dna virus belonging to the

orthopoxvirus family. It is a brick-shaped virion, approximately 200

nm in diameter—roughly the size of a bacterial spore. Its dumbbell-

shaped core contains nucleic acid and is surrounded by a series of

membranes. Variola replicates in the cytoplasm of host cells, forming B-

type inclusion bodies—Guarnieri bodies—which, unlike many other

viruses, replicate in the nucleus.

In terms of its genetic composition, variola carries a single, linear,

double-stranded dna covalently closed at each end. The average vario-

la genome has 200,000 base pairs, which ranks among the largest of the

animal viruses.

Smallpox has two main forms: variola major and variola minor.

While both forms cause similar lesions, variola major is typically asso-

ciated with severe disease and high fatality rates, claiming the lives of ap-

proximately 30% of those infected. Variola minor, which includes the

strains kafﬁr and alastrim, tends to run a milder course of disease and

has a case-fatality rate of less than 1%.

Bioterrorism

and Smallpox

Vaccination:

Experience and

Considerations

THE PRN NOTEBOOK

| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG 3

Isaac B. Weisfuse, md, mph

Deputy Commissioner, Division of Disease Control

New York City Department of Health and Mental Hygiene

Kent A. Sepkowitz, md

Director, Infection Control

Memorial Sloan-Kettering Cancer Center

Associate Professor, Department of Medicine

Weill Medical College of Cornell University

Yehuda L. Danon, md

Director, Kipper Institute of Immunology

Schneider Children’s Medical Center

Professor of Medicine, Sackler School of Medicine

Tel Aviv University

Summary by Tim Horn

Edited by Susan Forlenza, md, mph, and Allon Moses, md

Reprinted from The prn Notebook

® |

june 2003 | Dr. James F. Braun, Editor-in-Chief | Tim Horn, Executive Editor. | Published in New York City by the Physicians’ Research Network, Inc.

4 THE PRN NOTEBOOK

| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG

Transmission and Clinical Picture

the usual route of variola entry is through the oropharyngeal

or respiratory mucosa. Secretions from the mouth and nose that become

airborne are the most important source of human-to-human trans-

mission, although this generally requires direct and prolonged face-to-

face contact (i.e., within six feet). Transmission is also possible through

direct contact with body ﬂuids and contaminated objects. Variola is

less contagious than measles or influenza and is not known to be

transmitted by insects or animals.

Twelve to 14 days after infection, the incubation period typically ends

and the ﬁrst phase of symptoms appear. These include high fevers; se-

vere body aches; abdominal pain, nausea, and vomiting; and ﬁnally sores

that develop in the mouth and pharynx, where they ulcerate, quickly re-

leasing large amounts of virus into the saliva. It is at this point that the

patient is considered to be highly infectious.

Approximately four days after the onset of the ﬁrst phase of symp-

toms, the second phase begins. It is during this phase that the hallmark

lesions of smallpox appear on the skin and become disseminated, with

umbilication of the lesions being a common feature. After the vesicu-

lar stage, the lesions become pustular. The pustules are characteristically

round, tense, and deeply embedded in the dermis.

With the development of an effective immune response, healing be-

gins. The contents of the pustule become dried out, and reestablishment

of the epithelial cell layer occurs between the cavity of the pustule and

the underlying dermis. The pustule then becomes a crusty scab. It is not

until the scabs fall off that the patient is considered to be no longer in-

fectious, approximately 21 days after the infection was ﬁrst established.

Death caused by a variola infection is often the result of a cascade of

physiological events occurring as a result of overwhelming infection,

usually between days 10 and 16 of the illness. These events can lead to

disseminated intravascular coagulation, hypotension, and cardiovascular

collapse. Smallpox can lead to other serious complications, including res-

piratory diseases (e.g., bronchitis and pneumonia), bacterial infection

of skin lesions, encephalitis, scarring of the skin, and blindness.

Smallpox Vaccination

smallpox vaccination efforts date back to 10th century china and

India, where “variolation” became a popular public health initiative

among community healers. Variolation involved taking pus from the

pocks of someone suffering from smallpox and rubbing it into incisions

made in the skin of people who were not yet exposed to the disease. This,

of course, was associated with a number of unfavorable consequences,

including full-blown smallpox and death in a number of individuals who

underwent variolation.

It wasn’t until 1721 that variolation was introduced to the western

world. Lady Mary Wortley Montagu, a writer and the wife of the British

Ambassador to Turkey, learned of variolation while living in Constan-

tinople. After surviving a disﬁguring case of smallpox several years

earlier, she had her children inoculated through variolation and per-

suaded some of the British royal family to do the same.

In 1788, a smallpox epidemic erupted in the English county of

Gloucestershire. Dr. Edward Jenner, a military-trained doctor who set up

his practice in bucolic Berkeley, initiated a variolation campaign to stem

the spread of smallpox. However, this effort was met with a great deal of

resistance by many of the local residents. Dr. Jenner learned that many of

the residents, particularly dairy farmers and milkmaids, had suffered from

a mild form of cowpox and appeared to be immune to smallpox. In

turn, only a few residents saw the need for risky smallpox variolation.

These observations led to Dr. Jenner’s famous experiment in 1796.

Modifying the smallpox variolation method, he inserted pus extracted from

a cowpox pustule on the hand of a milkmaid, into an incision on the arm

of an eight-year-old boy named James Phipps. Roughly two weeks later,

he repeated varioloation on Phipps, this time with pus from a smallpox

pustule. Phipps developed cowpox but not smallpox, despite close and pro-

longed exposure to individuals with the disease. After conducting the ex-

periment on 23 different cases, he concluded that those who had suffered

cowpox were indeed immune to smallpox. Hence, the term “vaccine” was

coined by Dr. Jenner, stemming from the Latin vacca—cow.

The modern smallpox vaccine is made from live vaccinia virus—

the pathogen identiﬁed, many years after Dr. Jenner’s experiments, to be

the cause of cowpox. The smallpox vaccine does not contain variola

virus. Neutralizing antibodies induced by the smallpox vaccine are genus-

speciﬁc and cross-protective for other orthopoxviruses in addition to var-

iola virus. Although the efﬁcacy of the smallpox vaccine has never been

measured precisely in controlled clinical trials, epidemiologic studies

demonstrate that an increased level of protection against smallpox persists

for up to ﬁve years after primary vaccination and substantial but waning

immunity can persist for up to 10 years. Antibody levels after revaccina-

tion can remain high longer, conferring a greater period of immunity than

occurs after primary vaccination alone. Importantly, administration of the

smallpox vaccine within the ﬁrst three to four days after initial expo-

sure to variola can reduce symptoms or prevent smallpox disease.

Two vaccines will be used in the coming years: the calf-lymph vac-

cine and a tissue culture cell vaccine. Dryvax, the stored calf-lymph

vaccine manufactured in the 1970s by Wyeth Laboratories, is freeze dried

(lyophilized) and must be reconstituted before use. This vaccine was pro-

DAY 0 DAY 4 DAY 7 DAY 14

Figure 1. Successful Response to Smallpox Vaccination.

Photographs of vaccination site "takes" shot at different intervals over a two week period

Source: John D. Millar; U.S. Centers for Disease Control and Prevention

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| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG 5

duced by infection of skin of calves using a strain of vaccinia virus

collected by the New York City Board of Health—the nycboh strain.

Dryvax is now licensed in the United States. Before use, the vaccine

is reconstituted with a diluent that contains 50% glycerin and 0.25% phe-

nol. The licensed vaccine is packaged in multiple dose vials which,

when reconstituted, will yield 100 doses per vial.

The licensed vaccine will be used to immunize health-care workers

who volunteer to be members of the smallpox response teams being set

up around the United States (discussed in greater detail below). Dryvax

is also used to immunize laboratory workers who require vaccination to

safely conduct research activities involving vaccinia or other ortho-

poxviruses.

Currently in development are tissue culture cell vaccines, being pre-

pared by Acambis/Baxter Laboratories. Two cell lines were selected for

propagation of vaccinia virus; the nycboh strain was selected as seed virus.

Vero monkey kidney cells and a human ﬁbroblast cell line (mrc

)

were selected as host cells for the preparation of vaccine. Several lots of

both vaccines have been prepared and are undergoing testing. It is

anticipated that one of these vaccines will supplant calf-lymph vaccine

if a more extensive vaccination program is implemented.

The following sections review the ofﬁcial recommendations for us-

ing the Dryvax smallpox vaccine in a pre-event vaccination program, in-

cluding the vaccination program currently under way. These recom-

mendations, including descriptions of the adverse events and con-

traindications to watch for, were initially published by the Advisory

Committee of Immunization Practices in 2001 (cdc, 2001) and re-

cently updated, in their entirety, in April 2003 (cdc, 2003). acip re-

mains committed to reviewing these recommendations periodically

or more urgently, if necessary.

Vaccination Method

the skin over the insertion of the deltoid muscle or the posterior

aspect of the arm over the triceps muscle are the preferred sites for

smallpox vaccination. Alcohol or other chemical agents should not be

used for skin preparation for vaccination unless the area is grossly

contaminated. If alcohol is used, the skin must be allowed to dry thor-

oughly to prevent inactivation of the vaccine by the alcohol.

The multiple-puncture technique uses a presterilized bifurcated

needle that is inserted vertically into the vaccine vial, causing a droplet

of vaccine to adhere between the prongs of the needle. The droplet

contains the recommended dosage of vaccine, and its presence within

the prongs of the bifurcated needle should be conﬁrmed visually. Hold-

ing the bifurcated needle perpendicular to the skin, punctures are

rapidly made with strokes vigorous enough to allow a trace of blood to

appear after 15 to 20 seconds. For individuals being vaccinated for the

ﬁrst time, only three punctures are needed. For individuals who have re-

ceived the vaccine in the past, a total of 15 punctures are necessary. Any

remaining vaccine should be wiped off with dry sterile gauze and the

gauze disposed of in a biohazard waste container.

Evidence of Immunity

appearance of neutralizing antibodies after vaccination with live

vaccinia virus indicates an active immune response that includes the de-

velopment of antibodies to all viral antigens and increased vaccinia-spe-

ciﬁc cell-mediated immunity. In a person with normal immune func-

tion, neutralizing antibodies appear approximately 10 days after primary

vaccination and seven days after revaccination. Clinically, persons are

considered fully protected after a successful response or major reaction

is demonstrated at the site of vaccination (see Figure 1).

The vaccination site should be inspected six to eight days after vac-

cination and the response interpreted at that time. Two types of response

have been deﬁned by the World Health Organization (who) Expert

Committee on Smallpox. The ﬁrst type of response is a “major reaction,”

deﬁned as a vesicular or pustular lesion or an area of deﬁnite palpable

induration or congestion surrounding a central lesion that might be a

crust or an ulcer. A major reaction indicates that virus replication has

taken place and vaccination was successful. There is also an “equivocal

reaction,” deﬁned, somewhat vaguely, as all responses other than ma-

jor reactions. An equivocal reaction indicates a possible consequence of

immunity adequate to suppress viral multiplication or allergic reactions

to an inactive vaccine without production of immunity. If an equivocal

reaction is observed, vaccination procedures should be checked and the

vaccination repeated by using vaccine from another vial or vaccine lot,

if available.

Side Effects and Adverse Reactions

smallpox vaccination is generally considered to be a safe and

effective preventive measure against smallpox. However, in a number of

individuals, smallpox vaccination can result in untoward effects and ad-

verse reactions. Most are totally benign, if frightening in appearance. Some

are serious, but treatable. A few, which rarely occur, are potentially fatal.

Inadvertent Inoculation: In terms of less severe adverse events, inad-

vertent inoculation at other sites is the most frequent complication of

smallpox vaccination and accounts for approximately half of all com-

plications of primary vaccination and revaccination (see Figure 2). In-

advertent inoculation usually results from autoinoculation of vaccinia

virus transferred from the site of vaccination. The most common sites

involved are the face, eyelid, nose, mouth, genitalia, and rectum. While

most lesions heal without speciﬁc therapy, vaccinia immunoglobulin

(vig) can be used to manage cases of ocular implantation. However, if

Figure 2. Inadvertent Autoinoculation

Inadvertent autoinoculation of the cornea in a 12-year-old male.

Source: U.S. Centers for Disease Control and Prevention

6 THE PRN NOTEBOOK

| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG

vaccinial keratitis is present, vig is con-

traindicated because it might increase

corneal scarring.

Rash: Erythematous or urticarial rashes can

occur approximately 10 days after primary

vaccination and can be confused with gen-

eralized vaccinia. However, the vaccinee is

usually afebrile with this reaction, and the

rash resolves spontaneously within two to

four days. Rarely, bullous erythema multi-

forme (i.e., Stevens-Johnson syndrome) oc-

curs (see Figure 3).

Moderate and severe complications of

vaccinia vaccination include eczema vacci-

natum, generalized vaccinia, progressive

vaccinia, and postvaccinial encephalitis.

These complications are rare but are more

likely to occur among primary vaccinees

than among revaccinees and are more fre-

quent among infants than among older chil-

dren and adults.

Eczema Vaccinatum: Eczema vaccinatum is

a localized or systemic dissemination of

vaccinia virus among persons who have

eczema or a history of eczema or other

chronic or exfoliative skin conditions (e.g.,

atopic dermatitis). Usually, illness is self-

limited, but it can be severe or fatal (see

Figure 4).

Generalized Vaccinia: Generalized vaccinia is

the result of the systemic spread of virus

from the vaccination site (see Figure 5). De-

spite the appearance of the lesions, it is

usually a benign complication of primary

vaccination that is self-limited except in

some individuals with underlying immune

suppression. Other post-vaccination rash-

es—examples include nonspeciﬁc autoim-

mune rashes, eczema vaccinatum, and le-

sions of inadvertent inoculation—have been

diagnosed as generalized vaccinia, making

it difﬁcult to determine the true frequency of

this complication.

Progressive Vaccinia: Progressive vaccinia

(vaccinia necrosum) is a severe, potentially fatal illness characterized by

progressive necrosis in the area of vaccination, often with metastatic le-

sions (see Figure 6). If allowed to progress, progressive vaccinia can lead

to superimposed systemic fungal infections and/or bacterial infec-

tions, including bacteremia and endotoxic shock with or without dis-

seminated intravascular coagulation.

Massive doses of vig are necessary to control viremia in patients with

progressive vaccinia. Up to 10 ml/kg of intramuscular vig has been

used. In the event vig is not available or is not effective in managing pro-

gressive vaccinia, the cdc lists cidofovir (Vistide)—a intravenously ad-

ministered antiviral approved for the treatment of cytomegalovirus

disease—as an alternative. Studies evaluat-

ing the effectiveness of cidofovir in patients

with life-threatening vaccinia reactions are

not available; however, in vitro and animal

studies involving orthopoxviruses have yield-

ed encouraging results. Surgical removal

of massive lesions has also been performed

to reduce viral mass, usually following vig

treatment. And in patients with bacterial

or fungal superinfections, antibiotic thera-

py is often warranted.

Postvaccinial Encephalitis: Another serious

complication is postvaccinial encephalitis. In

the majority of cases, it affects primary vac-

cinees. According to the cdc, occurrence

of this complication was inﬂuenced by the

strain of vaccine virus and was higher in

Europe than in the United States. The prin-

cipal strain of vaccinia virus used in the

United States—the nycboh strain—was as-

sociated with the lowest incidence of post-

vaccinial encephalitis. Approximately 15% to

25% of affected vaccinees with this compli-

cation die, and 25% have permanent neu-

rologic complications. The risk of this seri-

ous complication is highest among chil-

dren less than one year of age.

Cardiac Complications: Finally, there are

possible cardiac complications to consider.

At the February 2003 prn meeting, when

the notable adverse events of smallpox vac-

cination were reviewed by Drs. Weisfuse,

Sepkowitz, and Danon, reports of cardiac

problems among vaccinees had not yet sur-

faced. However, on March 28, the cdc de-

scribed cases of cardiac adverse events

among vaccinated persons in the Morbidity

& Mortality Weekly Report (mmwr) (cdc,

2003a). At the time of this report, a total of

10 cases of myopericarditis had been docu-

mented among approximately 240,000 pri-

mary vaccinees in the military vaccination

program, and two such cases (one of my-

ocarditis and one of pericarditis) had been

reported among civilian vaccinees. No cas-

es of myopericarditis had been reported

among approximately 110,000 military revaccinees. Patients whose

cases were reported to the U.S. Department of Defense had onset sev-

en to 12 days after vaccination and had illness diagnosed based on

clinical features, laboratory studies, and electrocardiographic or echocar-

diographic features. Compared with the rate reported in an unvaccinated

military population during 1998 to 2000, the rate of myopericarditis is

substantially elevated.

As for cardiac ischemic events, a total of ﬁve reports had been re-

ported to the cdc as of March 28, including three patients with my-

ocardial infarctions and two patients with angina. The ﬁve patients

with ischemic events ranged in age from 43 to 60 years, and four of the

Figure 3. Erythema Multiforme

This eight-month-old patient displayed erythema mul-

tiforme lesions two weeks after his primary smallpox

vaccination.

Souce: Arthur E. Kaye; U.S. Centers for Disease Control and Prevention

Figure 4. Eczema Vaccinatum

A 22-year-old woman with eczema vaccinatum ac-

quired from her boyfriend. She became critically ill, with

nearly total involvement of her body, and required

thiosemicarbazones, as well as large doses of vig.

Source: U.S. Centers for Disease Control and Prevention

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| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG 7

ﬁve were aged >54 years; four were women.

Four of the ﬁve had underlying cardiovas-

cular risk factors. One had known cardio-

vascular disease, and two others had histo-

ries of chest pain (not clearly identiﬁed as

cardiac in origin on the basis of available in-

formation). Two patients died, both from

myocardial infarctions with out-of-hospital

cardiac arrests. Onset of cardiac symptoms

occurred 4, 4, 5, 9, and 17 days after vacci-

nation in the ﬁve patients; the patient who

experienced a cardiac arrest 17 days after

vaccination had symptoms of nausea, dizzi-

ness, shortness of breath, fever, and pro-

ductive cough ﬁve days after vaccination.

Two patients were revaccinees, but the pre-

vious vaccination status of the other pa-

tients is unknown; all were children at a

time when the majority of children in the

United States received smallpox vaccine.

The two deaths due to cardiac disease

among civilian vaccinees are similar to the

numbers expected among persons in these

age groups in the general population in the

absence of vaccination. The military re-

ported an additional case of a myocardial in-

farction and out-of-hospital cardiac arrest

in a man aged 55 years with multiple cardiac

risk factors; the cardiac arrest occurred ﬁve

days after vaccination.

These data are consistent with a causal

relation between myocarditis/pericarditis

and smallpox vaccination, but no causal as-

sociation between the ischemic cardiac

events and smallpox vaccination has been

identiﬁed.

In summation, fatal complications

caused by smallpox vaccination have his-

torically been considered rare, with ap-

proximately one death per million primary

vaccinations and 0.25 deaths per million

revaccinations—usually because of either

progressive vaccinia or postvaccinial en-

cephalitis. However, there are lingering con-

cerns that the risk of serious adverse events, including death, will be

higher today, given the larger proportion of patients with immune

suppression currently living in the United States (and elsewhere) than

in decades past.

Contraindications

according to the acip, the smallpox vaccine should not be ad-

ministered for pre-event indications if any of the contraindications re-

viewed below are present or if the vaccinee lives with or has close

physical contact (e.g. persons with prolonged intimate contact with

the potential vaccinee, including the potential for direct contact with the

vaccination site) with someone who has one of these conditions (cdc,

2003). However, in the event of a smallpox outbreak, if exposure to the

variola virus has occurred or there is a high

risk of exposure to a patient, these con-

traindications would not apply. In these sit-

uations, the beneﬁt of vaccination outweighs

the risks of potential adverse events.

Eczema, Atopic Dermatitis, Darier’s Disease,

or Other Skin Conditions: Because of the

increased risk for eczema vaccinatum, the

smallpox vaccine should not be adminis-

tered to persons with eczema or any degree

of atopic dermatitis, to those with a past

history of eczema or atopic dermatitis, or to

those whose household contacts have ac-

tive eczema or atopic dermatitis or a histo-

ry of these skin conditions. Persons with

other acute, chronic, or exfoliative skin con-

ditions (e.g., burns, impetigo, or varicella

zoster) might also be at higher risk for

eczema vaccinatum and should not be vac-

cinated until the condition resolves.

Pregnancy: Because of the remote possibili-

ty of intrapartum vaccinia infection of the

infant, the smallpox vaccine should not be ad-

ministered to pregnant women for routine

pre-event immunization indications. Women

who are vaccinated should avoid getting preg-

nant for four weeks after vaccination.

Immune Suppression: Replication of vaccinia

virus can be enhanced among persons with

hiv infection and other immunodeﬁciency

diseases, including those being treated with

immunosuppressive drugs (e.g., as occurs

with leukemia, lymphoma, generalized ma-

lignancy, solid organ transplantation, stem

cell transplantation, cellular or humoral im-

munity disorders, or therapy with alkylating

agents, antimetabolites, radiation, or high-

dose corticosteroid therapy). Persons with

such conditions or whose household con-

tacts have such conditions should not re-

ceive the smallpox vaccine.

hiv Infection: Risk for severe complications after smallpox vaccination

for persons infected with hiv is unknown and there hasn’t been any ev-

idence concluding that smallpox vaccination accelerates the progres-

sion of hiv-related disease, particularly among patients with unde-

tectable hiv-rna levels. However, the degree of immune suppression that

would place an hiv-infected person at greater risk for adverse events is

unknown. Because of this uncertainty, until additional information be-

comes available, not vaccinating persons—under routine pre-event con-

ditions—who have hiv infection is advisable.

Allergy to Vaccine Components: The currently available smallpox vaccine

contains trace amounts of polymyxin B sulfate, streptomycin sulfate,

chlortetracycline hydrochloride, and neomycin sulfate. Persons who ex-

perience anaphylactic reactions (e.g., hives, swelling of the mouth and

Figure 5. Generalized Vaccinia

This child manifested generalized vaccinia after re-

ceiving a primary smallpox vaccination.

Arthur E. Kaye; U.S. Centers for Disease Control and Prevention

Figure 6. Progressive Vaccinia

This adult manifested progressive vaccinia, shown

here as progressive necrosis of the vaccination area, af-

ter receiving a primary smallpox vaccination.

Source: Arthur E. Kaye; U.S. Centers for Disease Control and Prevention

8 THE PRN NOTEBOOK

| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG

throat, difﬁculty breathing, hypotension, and shock) to any of these an-

tibiotics should not be vaccinated. The smallpox vaccine does not con-

tain penicillin. Future supplies of the smallpox vaccine will be refor-

mulated and might contain other preservatives or stabilizers. Refer to

the manufacturer’s package insert for additional information.

Infants and Children: Before the eradication of smallpox, smallpox vac-

cination was administered routinely during childhood to those over 12

months of age. However, smallpox vaccination is no longer indicated for

infants or children for routine immunization.

Cardiovascular Problems: While not a part of the original list of con-

traindications published by the acip, it is now recommended that per-

sons be excluded from the pre-event smallpox vaccination program

who have known underlying heart disease, with or without symptoms,

or who have three or more known major cardiac risk factors (i.e., hy-

pertension, diabetes, hypercholesterolemia, heart disease at age 50

years in a ﬁrst-degree relative, and smoking) (cdc, 2003a). In response

to these updated recommendations, prevaccination screening forms and

other materials have been revised and provided to state health depart-

ments. At the present time, there are no recommendations for special

medical follow-up for persons with cardiovascular risk factors who

have been vaccinated. Persons with risk factors or known atherosclerotic

coronary artery disease should be cared for and monitored by their

physicians.

HIV

and Smallpox Vaccination

the heightened risks of smallpox vaccination among hiv-positive

people are not hypothetical. In April 1984, a 19-year-old African-Amer-

ican male from the mid-southwestern United States began basic train-

ing at an Army military base (Redﬁeld, 1987). He received multiple im-

munizations—adenovirus 4 and 7, measles, rubella, bivalent inﬂuenza,

trivalent poliomyelitis, tetravalent meningococcal, tetanus, and diph-

theria—within the ﬁrst three days of basic training, followed by a pri-

mary smallpox vaccination at the end of the ﬁrst week.

He participated fully in basic training until two and a half weeks af-

ter the smallpox vaccination, when fever, headache, neck stiffness, and

night sweats developed. The diagnosis was cryptococcal meningitis

and, after further evaluation, it was determined that he had a cd

count of fewer than 25 cells/mm

. hiv was then isolated from pbmcs and

antibodies to the virus were detected by Western blot.

Four weeks after receiving the smallpox vaccination, while the con-

script was being treated for cryptococcal meningitis at the Walter Reed

Army Medical Center, an ulcer approximately 4 centimeters in diame-

ter developed at the vaccination site, with a smaller satellite ulceration

developing nearby. Over the next two to three days, approximately 80 to

100 pustular lesions appeared on the buttocks and the legs, many of

which became ulcerated. Generalized vaccinia was determined to be the

cause and 12 weekly doses of vig were prescribed. The ulcers gradual-

ly epithelialized and were completed healed by mid-August. The patient

subsequently died, probably as a result of progressive neurological dis-

ease, in December 1985.

Another noteworthy report was published in 1991 in The Lancet

(Guillaume, 1991). The report involved the experiences of 12 hiv-pos-

itive patients who underwent therapeutic administration of autologous

lymphocytes that were infected with a recombinant hiv-vaccinia virus.

Eight of the 12 patients had fewer than 150 cd4+ cells/mm

and three

of them developed symptoms of progressive vaccinia and subsequent-

ly died. These complications were not recognized as such and vig was

not administered.

As explained by Dr. Kent Sepkowitz, of the ﬁve notably adverse

events of smallpox vaccination—autoinoculation, generalized vaccinia,

eczema vaccinatum, progressive vaccinia, and encephalitis—generalized

vaccinia and progressive vaccinia are the most likely to occur in greater

frequency in hiv-positive vaccinees.

“Simply put, we don’t know what the risks are and I sincerely hope

that we won’t ever ﬁnd out.” As for autoinoculation, Dr. Sepkowitz

does not foresee an increased risk compared to hiv-negative persons.

There is also no reason that exzema vaccinatum would be more com-

mon in hiv, except in someone with sustained chronic dermatitis of

some sort. “We don’t see as much folliculitis as we used to,” he said. “We

don’t see as many chronic skin conditions as we did in pre-haart days.

That said, one can imagine that someone with diffused Kaposi’s sarcoma

or diffused skin conditions could get into big trouble from being vac-

cinated. But the biology of hiv would not, in itself, predispose someone

to higher rates of vaccinatum.” There’s also little reason to believe that

encephalitis rates would be any higher among hiv-positive vaccinees

than hiv-negative vaccinees.

In terms of generalized vaccinia, Dr. Sepkowitz reckons that there

would almost certainly be increased rates among hiv-positive vacci-

nees. “However, this is very manageable with vig and is not one of

those oh-my-God-drop-everything sort of infections. They can become

that, but they sound much more cinematic that they actually are in the

clinic.” Progressive vaccinia remains Dr. Sepkowitz’s biggest fear. “Any-

one with underlying immune dysfunction can develop this,” he warned.

“Progressive vaccinia has occurred, in the past, in one in a million vac-

cinees. We’d expect a much higher rate in a million immune-suppressed

vaccinees. While we might be able to determine which of our diag-

nosed hiv-positive patients have suppressed immune systems, we also

know that there are many people walking around with undiagnosed

hiv infection and possible immune suppression. We can pretty much

bank on increased progressive vaccinia in today’s day and age.”

Because of these fears, hiv-positive individuals, irrespective of their

+ cell counts, are being excluded from the current pre-event smallpox

vaccination program. However, there are encouraging data to suggest that,

in the event of a “pre-event” to “post-event” vaccine strategy that includes

the immunization of hiv-positive people, the adverse event rate will re-

main relatively low. Dr. Sepkowitz pointed out that the Department of De-

fense (dod) and the cdc have estimated that between 500 and 1,000 un-

diagnosed hiv-positive conscripts received smallpox vaccination in the

1980s, with an adverse event rate of less than 0.2%. “However,” Dr. Sep-

kowitz added, “most people who join the army are relatively healthy, so

this estimate doesn’t accurately reﬂect what we’d expect to see in sicker

hiv-positive individuals with suppressed immune systems.”

The possible scenario doesn’t end with data from the dod. Dr. Sep-

kowitz reminded prn members that hiv-positive individuals with well-

controlled infection safely beneﬁt from mmr, yellow fever, and Varivax im-

munizations—all live-virus vaccinations—with adverse event rates on a

par with hiv-negative individuals.

While numerous steps—including hiv-antibody testing—are in place

to prevent hiv-infected individuals from erroneously receiving the small-

pox vaccine as a part of the pre-event smallpox vaccination program,

there is still some concern that hiv-infected individuals will be inadver-

tently infected with the vaccinia virus through contact with a recently vac-

cinated person. Fortunately, Dr. Sepkowitz suspects that contacts of vac-

cinees—even those with suppressed immune systems—are unlikely to

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| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG 9

experience either progressive vaccinia or encephalitis if they are infected.

“What we’re likely to see are cases of inoculation, eczema vaccinatum, and

possibly generalized vaccinia,” Dr. Sepkowitz said.

To better understand nosocomial spread of vaccinia virus, Dr. Sep-

kowitz performed a literature search spanning 100 years of smallpox vac-

cination and yielded 12 key reports from around the world (Sepkowitz,

2003). In short, these reports detailed the experiences of 85 secondary

cases of vaccinia infection, 23 of which involved direct contact with a vac-

cinee. Approximately 75% of these secondary cases were children and

9/85 (11%) died of complications related to secondary vaccinia infection.

Information regarding the vaccinees—the sources of the secondary

vaccinia cases—was provided in the 12 reports reviewed by Dr. Sep-

kowitz. In ﬁve of the reports, the sources were children experiencing

eczema vaccinatum. “A child with eczema vaccinatum is simply oozing

virus,” he said. “The child is misdiagnosed and is put on to a ward with

other children with eczema. From there, it spreads from person to

person by the hands of a health-care worker. It’s very easy to see how this

can happen.” As for the other seven sources, two cases were adults with

generalized/disseminated vaccinia, one was a burn patient, one in-

volved a contaminated urinary catheter (an infant with dysuria received

a urinary catheter, which was subsequently removed and placed into a

pan with other catheters, resulting in vaccinia infection of 23 other

children), and two cases involved individuals participating in a com-

munity vaccination program. Only in one report was information in-

volving the vaccinee not known.

In terms of risk factors associated with secondary infection, all of the

cases reviewed by Dr. Sepkowitz involved individuals with an underly-

ing skin disorder. For example, a large percentage of secondary vaccinia

cases were in patients with eczema at the time of infection. Pemphigus

foliaceous was a preexisting condition in some adults with secondary

vaccinia disease. Other documented skin disorders believed to increase

suspectibility to secondary vaccinia infection included burns, Mycosis

fungoides, scabies, secondary syphilis, impetigo, and acne.

All in all, Dr. Sepkowitz believes that hiv-infected individuals with

well-controlled disease will tolerate smallpox vaccination, as well as

other live vaccines. “However,” he added in his concluding remarks,

“there are lessons from tb to be learned here. Even though we’re deal-

ing with an extremely familiar and predictable disease, it’s always pos-

sible that it will become extremely unfamiliar and unpredictable in

people with hiv infection.”

The New York City Smallpox Vaccination Program

given the concerns that smallpox may used by terrorist groups or

rogue nations as a component of biological warfare, the federal gov-

ernment announced plans on December 13, 2002, for a voluntary

smallpox vaccination program for hospital-based health care personnel

who, in the event of an outbreak, would be available and willing to

care for the initial patients with suspected or conﬁrmed smallpox. In ad-

dition to these smallpox response teams, the federal government also

announced plans to begin vaccinating public health response teams and

select military personnel.

There’s little doubting the need for a vaccination campaign to protect

“ﬁrst response” health-care workers. For evidence of this, one doesn’t need

to look much further than the sars epidemic. A number of health-care

workers have come down with symptoms of sars after treating patients

with the disease and have subsequently gone on to infect others. As a re-

sult, some hospitals have been forced to shut down or to reduce vital ser-

vices—including those intended for hiv-infected patients—in order to

grapple with the spread of sars. Clearly, little good can come of health-

care providers being unprotected against a contagious disease.

The pre-event smallpox vaccination plan outlined by the federal

government consists of three waves. The ﬁrst wave involves the vacci-

nation of 500,000 hospital-based health-care workers and public health

response teams nationwide. [Editor’s Note: According to a New York

Times editorial published on May 12, 2003, federal health ofﬁcials are now

suggesting that perhaps 50,000 vaccinated health care workers will be enough

to complete the ﬁrst wave of vaccinations.] The second wave currently

calls for the vaccination of 10 million health-care workers, along with ﬁrst

responders (e.g., police, ﬁreﬁghters, and emergency medical service staff)

not covered in the ﬁrst wave. In the third wave of the program, vacci-

nation will be made available to the general population.

In the event of a smallpox attack, it is impossible to predict where

the ﬁrst cases may present for their care. Therefore, the goal of this

smallpox vaccination program is to ensure that all acute-care hospitals

who volunteer to participate in this program have pre-vaccinated staff

ready to respond if a patient with smallpox presents to their institution.

Each hospital’s health-care smallpox response team consists of vol-

unteer health-care worker staff who would be prevaccinated against

smallpox and have agreed to be available to 1) evaluate and manage pa-

tients who present to their hospital with suspected smallpox, and 2) pro-

vide in-room medical care for the ﬁrst 7 to 10 days for these initial sus-

pected or conﬁrmed smallpox patients until additional hospital staff have

been successfully vaccinated.

The initial plans in New York City called for approximately 100 to 200

health-care workers at each of the 74 acute-care hospitals—between

750 to 1500 vaccinations in total—to be included in the New York City

Department of Health and Mental Hygiene (nyc dohmh) smallpox

vaccination plans. The workers are being recruited to serve on these

health-care smallpox response teams as a part of the ﬁrst wave of the vac-

cination program. Health-care workers are being selected based on

those job categories that would be required to care for the initial small-

pox cases (e.g., medical and nursing staff who work in the emergency de-

partment, intensive care unit, adult and pediatric wards, as well as res-

piratory therapists, radiology technicians, security, housekeeping, and oth-

er clinical support staff). The vaccine is voluntary; however, any person

agreeing to be vaccinated should be willing to serve on the hospital’s

health-care smallpox response team to provide direct care for the initial

suspected or conﬁrmed smallpox case(s) in the event of an outbreak. As

the incidence of vaccine adverse effects is less among persons who

have previously received smallpox vaccine, efforts are being made to tar-

get persons who have received at least one prior dose of smallpox vaccine.

The nyc dohmh, working closely with hospitals, began adminis-

tering smallpox vaccinations in March. As of May 9, 2003, a total of 319

persons have received the smallpox vaccination in New York City. As ex-

plained by Dr. Weisfuse in a recent interview, there has been very low

acceptance of the vaccinations, with the number of volunteers being sub-

stantially lower than expected. “This experience mirrors that in the

rest of the country,” he said. Participating in and plans for the second

wave of vaccinations will be reassessed after completion of the ﬁrst wave.

In order to minimize the number of adverse events, all potential vol-

unteers are being educated about the contraindications to the vaccine.

The nyc dohmh is currently working with hospitals to ensure that ed-

ucational sessions are offered to all potential vaccinees prior to starting

smallpox vaccinations. The nyc dohmh is also providing information

on where potential volunteers may obtain free, conﬁdential, or anony-

mous hiv counseling and testing, and pregnancy testing, if indicated.

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| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG

hiv counseling and testing is strongly recommended for all persons con-

sidering smallpox vaccination in New York City.

Monitoring for any vaccine-related adverse events and arranging for

rapid treatment will be an essential component of the nyc dohmh

vaccine program. The nyc dohmh has mailed information to all New

York City health-care providers and posted information on the nyc

dohmh website (http://www.nyc.gov/health/smallpox) that highlights

the recognition, clinical management, and reporting of suspected

smallpox vaccine adverse events, all of which have been reviewed in this

article. Prevaccination of health-care smallpox response teams is just one

component of the nyc dohmh smallpox preparedness. Also important

has been the ability of health-care workers to rapidly recognize and re-

spond to the initial suspect cases of smallpox. New York City hospitals

are expected to implement measures outlined in a nyc dohmh and New

York State Department of Health document, “Guidelines for Manage-

ment of a Suspect Case of Smallpox in Acute Care Hospitals in New York

City,” which is available through the nyc dohmh Web site cited above.

These guidelines provide detailed information on measures that

should be put into place to ensure rapid recognition, isolation, and

appropriate management of suspected smallpox patients, including

the need for strict adherence to infection control measures. Isolation of

suspected or conﬁrmed smallpox patients and ensuring that all staff ad-

here to appropriate infection control precautions will also help pre-

vent transmission of the variola virus and protect those who can not, or

chose not to, be vaccinated.

The Israeli Experience

routine vaccination against smallpox in israel was initiated in

1924 and subsequently halted in July 1980. In August 2002, the Israeli

Ministry of Health dusted off its stockpile of smallpox vaccines and be-

gan immunizing thousands of citizens, most of them health-care per-

sonnel—ﬁrst responders who would likely be involved in an immedi-

ate response to a biological attack. At the time of Dr. Yehuda Danon’s prn

presentation, 17,700 Israeli citizens had received the vaccine and safe-

ty data were available for more than 7,000 vaccinees.

The smallpox vaccine being used by the Israeli Ministry of Health

is based on the Lister strain of the vaccinia virus, grown on the chorioal-

lantoic membrane of fertilized eggs. The bifurcated needle approach

used in the United States to administer the vaccine is considered to be

too costly in Israel, where the administration equipment of choice is the

helicopter pipette. “The helicopter pipette is widely available, has high

utilization in routine medical practice, and is associated with good

take results,” Dr. Danon explained.

Vaccine contraindications in Israel are similar to those in the Unit-

ed States. These include individuals with diseases or conditions that

cause immunodeficiency, such as hiv, aids, leukemia, lymphoma,

generalized malignancy, agammaglobulinemia, or are being treated

with alkylating agents, antimetabolites, radiation, or large doses of cor-

ticosteroids. Also excluded are individuals who have ever been diagnosed

with eczema—even if the condition is mild or not presently active—as

well as individuals with acute or chronic skin conditions such as atopic

dermatitis, burns, impetigo, or varicella zoster.

Much like the pre-event vaccination program in the United States, Is-

raeli health-care workers who receive the vaccine will be permitted to con-

tinue direct patient care, provided that vaccination site remains covered.

To date, roughly 70% of vaccinees have exhibited signs of a suc-

cessful take, which is on a par with take rates observed in the past. Dr.

Danon pointed out that all of the Israeli residents who have received the

vaccine had been vaccinated in the past. “We did not want to use a vac-

cine-naive population,” Dr. Danon explained. “We didn’t have any vig

in Israel. The only vig available was through the World Health Orga-

nization, and there was concern that some of these were infected with

hepatitis B or hepatitis C. Because of this, we needed to make sure that

we were being very careful about who received the vaccine in order to

reduce the risk of adverse events.”

To replenish its vig stock, the Israeli Ministry of Health has asked

that all successfully vaccinated individuals donate plasma—two or

three times—three to six weeks after vaccination. Plasma samples col-

lected any sooner than three weeks increase the risk of viremia, where-

as plasma collected more than 90 days post-vaccination won’t likely

contain high enough titers of antibodies to be of therapeutic beneﬁt.

The most common symptoms accompanying vaccination in 7,100

evaluable vaccinees were fatigue and weakness (31%), headaches (28%)

muscle pain (22.5%), nausea (12%), shivering (12%), and fever (8%).

Looking at the larger population of vaccinees, only ten adverse events

were documented as of early May 2003. No vaccine-related deaths have

thus far been reported to the Israeli Ministry of Health. In terms of ad-

verse events, there have been two cases of contact vaccinia, one of

which resulted in disseminated vaccinia. There have been two cases of

erythema multiforme among vaccinees, one case of polymyalgia, one

case of Stevens-Johnson optic neuritis, once case of peripheral neu-

ropathy, two cases of myopericarditis, and one case involving a patient

with both optic neuritis and vasculitis.

In terms of successful vaccine takes, there were no differences among

patients who had received either one, two, three, or four vaccinations in

the past. Also of interest, the rates of successful takes were similar in all

age groups. In terms of serologies, Dr. Danon noted that individuals

who had high vaccinia antibody titers on the day of vaccination were the

least likely to have successful takes. In contrast, 93% of those who had low

titers on the day of vaccination went on to have successful takes.

The Israeli Ministery of Health still has its work cut out for it.

“Ever since we began the vaccination program in August 2002, we’ve had

a low level of motivation and compliance among physicians,” Dr.

Danon reported. “We can’t explain why this is, because many of the doc-

tors who have experience in administering the smallpox vaccine and are

wary of its side effects are now in retirement. We have many younger

physicians who do not have much experience administering the small-

pox vaccine and are now being trained, but they’re still wary of the po-

tential for adverse events. Conversely, we’ve had a relatively high level

of motivation among nurses.”

The Department of Defense Experience

data involving the u.s. armed force’s experience with smallpox

vaccinations were not available at the time of the February 2003 prn meet-

ing but have since been released by the Department of Defense (dod,

2003). As of March 28, 2003, the dod has vaccinated 350,000 opera-

tional forces and military health-care workers against smallpox—many of

whom were naive to the vaccine prior to vaccination. Similar to the Israeli

experience, dod smallpox vaccine recipients have experienced the tem-

porary symptoms expected after smallpox vaccination (e.g., itching,

swollen lymph nodes, fever, malaise). Approximately 1% of vaccine re-

cipients developed “ﬂat” rashes that are not dangerous and not contagious.

These vaccinees have been treated according to their symptoms (such as

itching) and have remained on the job with their units. These rashes are

consistent with known responses after smallpox vaccination.

There have been 29 cases of inadvertent auto-inoculation, none of

which were severe. There have also been 25 cases of generalized vaccinia,

most of which were treated as outpatients. There have been two in-

stances in which vig was prescribed, both of which involved patients with

generalized vaccinia. There have been 14 cases of myocarditis and/or peri-

carditis among the 350,000 smallpox vaccinees, with symptoms ranging

from mild to severe (all have since recovered). No cases of eczema vac-

cinatum or progressive vaccinia have been reported, and there have

been no deaths associated with smallpox vaccination. There have been 10

cases of vaccinia being transferred to contacts. However, none of these cas-

es were severe and primarily involved inadvertent inoculation.

“Our smallpox vaccination program expanded rapidly and effec-

tively to include more than 350,000 people,” says Dr. William Winken-

werder, Jr., Assistant Secretary of Defense for Health Affairs. “The pro-

gram continues to go well, and has been administered in a thorough,

careful and professional manner. We continue to experience the types of

reactions that we expected overall. Close monitoring has afforded these

individuals prompt, effective care. We have adjusted our screening

guidelines to defer those with a history of cardiac disease, based on

guidance from the cdc and other medical experts. dod’s Smallpox Vac-

cination Program provides service members and the Nation an en-

hanced level of preparedness against the threat of smallpox.”

Conclusion

although the campaign to vaccinate 500,000 health-care work-

ers against smallpox appears to getting off to an unexpectedly slow

start, adverse event data collected thus far paint an encouraging picture

(see Sidebar). hiv-infected civilians are still being excluded from the pre-

event smallpox vaccination program. At the present time, the greatest

threat to hiv-infected patients is secondary vaccinia transmission by a

vaccinee. However, as this issue of The prn Notebook went to press, no

cases of vaccinia transmission to contacts have been reported to the

cdc—an indication that correct measures are being taken to reduce the

risk of adverse events.

It is with hope that smallpox never reemerges from the shadows of his-

tory. Should the day come, it is comforting that mechanisms are in place

to curtail the spread of disease and to protect those who have long been

at the greatest risk of walking onto the frontlines of epidemics in their ear-

liest stages: health-care providers and other emergency personnel.

References

Department of Defense. dod smallpox vaccination program: Safety summary, as of March 31, 2003.

http://www.smallpox.army.mil/event/SPSafetySum.asp. Accessed May 19, 2003.

Guillaume JC, Saiag P, Wechsler J, et al. Vaccinia from recombinant virus expressing hiv genes. Lancet

337(8748):1034-5, 1991.

Redﬁeld RR, Wright DC, James WD, et al. Disseminated vaccinia in a military recruit with human im-

munodeﬁciency virus (hiv) disease. N Engl J Med 316:673-6, 1987.

Sepkowitz KA. How contagious is vaccinia? N Engl J Med 348:439-46, 2003.

U.S. Centers for Disease Control and Prevention (cdc). Vaccinia (smallpox) vaccine: recommendations of

the Advisory Committee on Immunization Practices (acip), 2001. mmwr 50(RR10):1-25, 2001.

U.S. Centers for Disease Control and Prevention. Recommendations for Using Smallpox Vaccine in a Pre-

Event Vaccination Program. Supplemental Recommendations of the Advisory Committee on Immuniza-

tion Practices (acip) and the Healthcare Infection Control Practices Advisory Committee (hicpac). mmwr

52(RR07):1-16, 2003.

U.S. Centers for Disease Control and Prevention. Notice to Readers: Supplemental Recommendations on

Adverse Events Following Smallpox Vaccine in the Pre-Event Vaccination Program: Recommendations of

the Advisory Committee on Immunization Practices. mmwr 52(13):282-4, 2003.

THE PRN NOTEBOOK

| VOLUME 8, NUMBER 2 | JUNE 2003 | WWW.PRN.ORG 11

Status of the Smallpox Vaccination Program

Source: U.S. Centers for Disease Control Prevention. State-by-state vaccination numbers and

adverse events numbers will be updated every Thursday by 12:00 pm est and can be accessed

through the World Wide Web (http://www.cdc.gov/od/oc/media/spadverse.htm).

Adverse Total number of

Event Cases (as of 5|9)

Eczema vaccinatum 0

Erythema multiforme/

Stevens-Johnson syndrome 0

Fetal vaccinia 0

Generalized vaccinia 2

Inadvertent inoculation,

nonocular 13

Myocarditis/pericarditis 24

Adverse Total number of

Event Cases (as of 5|9)

Ocular vaccinia 3

Postvaccinial encephalitis 1

Progressive vaccinia 0

Pyogenic infection of

vaccination site 0

Vaccinia transmission to contacts

In health-care settings 0

In other settings 0

State/ No. of Individuals

Program Vaccinated

Alabama 481

Alaska 95

American Samoa 0

Arizona 39

Arkansas 976

California 1,509

Chicago 56

Colorado 224

Connecticut 634

Delaware 107

District of Columbia 98

Florida 3,623

Georgia 135

Guam 0

Hawaii 181

Idaho 200

Illinois 228

Indiana 765

Iowa 486

Kansas 448

Kentucky 767

Los Angeles 219

Louisiana 1,107

Maine 39

Marshall Islands 0

Maryland 719

Massachusetts 94

Michigan 716

Micronesia 0

Minnesota 1,475

Mississippi 404

State/ No. of Individuals

Program Vaccinated

Missouri 1,253

Montana 101

Nebraska 1,457

Nevada 10

New Hampshire 323

New Jersey 657

New Mexico 158

New York 659

New York City 330

North Carolina 1,235

North Dakota 414

No. Mariana Islands 0

Ohio 1,760

Oklahoma 335

Oregon 95

Palau 0

Pennsylvania 198

Puerto Rico 9

Rhode Island 29

South Carolina 859

South Dakota 735

Tennessee 2,429

Texas 4,145

Utah 282

Vermont 121

Virgin Islands 0

Virginia 843

Washington 512

West Virginia 734

Wisconsin 745

Wyoming 409

Total Number of Individuals Vaccinated (as of May 16, 2003) 36,662

Adverse Events Associated with Smallpox Vaccination

Among Civilians

(Total number of adverse events associated

with smallpox vaccination, as of May 9, 2003.)

State-by-state vaccination numbers, as of May 16, 2003