SUPPLEMENT ARTICLE
Monitoring the Safety of a Smallpox Vaccination
Program in the United States: Report of the Joint
Smallpox Vaccine Safety Working Group of the
Advisory Committee on Immunization Practices
and the Armed Forces Epidemiological Board
John Neff,1,2 John Modlin,3 Guthrie S. Birkhead,4,5 Gregory Poland,8 Rose Marie Robertson,9,13 Kent Sepkowitz,6
Clyde Yancy,10 Pierce Gardner,7 Gregory C. Gray,14 Toby Maurer,15 Jane Siegel,10 Fernando A. Guerra,11 Tim Berger,15
W. Dana Flanders,16 and Robert Shope12,a
1
Children’s Hospital and Regional Medical Center and 2University of Washington, Seattle, Washington; 3Dartmouth Medical School, Lebanon, New
Hampshire; 4New York State Department of Health and 5School of Public Health, University of Albany, Albany, 6Memorial Sloan-Kettering Cancer
Center, New York, and 7Stony Brook University School of Medicine, Stony Brook, New York; 8Mayo Clinic, Rochester, Minnesota; 9American Heart
Association and 10University of Texas Southwestern, Dallas, 11San Antonio Metropolitan Health District, San Antonio, and 12University of Texas at
Galveston, Galveston, Texas; 13Vanderbilt University Medical Center, Nashville, Tennessee; 14University of Iowa College of Public Health, Iowa City;
15
University of California–San Francisco, San Francisco; and 16Emory University, Rollins School of Public Health, Atlanta, Georgia
In December 2002, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization
Practices and the Department of Defense Armed Forces Epidemiological Board formed a joint Smallpox Vaccine
Safety Working Group (SVS WG) to provide independent safety oversight for smallpox vaccination safetymonitoring systems. From January 2003 through June 2004, the SVS WG reviewed individual and aggregate
safety data on postvaccination adverse events. Serious adverse events were rare because of careful education,
prevaccination screening, and strict attention to vaccination-site management. Recent vaccinees safely cared
for high-risk patients, adhering to recommended site care. Human immunodeficiency virus–infected individuals
without severe immunosuppression had uncomplicated vaccination reactions. Epidemiological studies supported a causal relationship between myocarditis and/or pericarditis and smallpox vaccination. Data supported
neutrality regarding hypothesized causal associations between vaccination and dilated cardiomyopathy or
ischemic cardiac disease. The SVS WG concurs with recommendations to defer from vaccination any person
with ⭓3 ischemic cardiac disease risk factors.
The eradication of smallpox ranks among the modern
public health triumphs. The terrorist attacks of 11 September 2001 renewed concern that the smallpox virus
(variola) could be reintroduced by bioterrorists. In re-
The findings and conclusions in this report are those of the authors and do not
necessarily represent the views of the funding agency.
a
Deceased.
Reprints or correspondence: Dr. John Neff, Center for Children with Special
Health Care Needs, Children’s Hospital and Regional Medical Center, Metropolitan
Park West, M/S: MPW5-2, 1100 Olive Way, Ste. 500, Seattle, WA 98101
([email protected]).
Clinical Infectious Diseases 2008; 46:S258–70
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4606S3-0014$15.00
DOI: 10.1086/524749
S258 • CID 2008:46 (Suppl 3) • Neff et al.
sponse to President George W. Bush’s announcement
on 12 December 2002 of the intent to administer smallpox vaccine to key public health, health care, and Department of Defense (DoD) personnel [1–3], the DoD
began a vaccination program on 16 December 2002,
and the Department of Health and Human Services
(DHHS) on 24 January 2003. Both programs used dried
calf-lymph smallpox vaccine (Dryvax; Wyeth Laboratories) exclusively. The DHHS program targeted federal
and state smallpox response teams (including civilians
and commissioned officers in the US Public Health
Service) designated to investigate or provide medical
care to initial smallpox cases.
The Centers for Disease Control and Prevention
Table 1. US National Smallpox Pre-Event Vaccination Program, as of 30 June 2004.
ulin (VIG) and cidofovir for any individual under the investigational new drug protocols for the NSVP.
Department of Defense
Department of Health
and Human Services
628,414
39,566
This article reports the safety profile of Dryvax vaccine as administered in the NSVP and as monitored by the SVS WG.
This effort represents a comprehensive review of smallpox vaccine safety in the modern era and provides a basis for future
medical and public health vaccination recommendations.
Value
No. vaccinated
Primary vaccinees, %
71
24
Revaccinees, %
29
75
Male, %
88
37
Female, %
12
63
Age, median years
26
48
(CDC) and state health departments established the Smallpox
Vaccine Adverse Events Monitoring and Response Activity [3–
12]. The DoD developed a similar system with military reporting channels. Both the CDC and the DoD conducted surveillance through the Vaccine Adverse Event Reporting System
(VAERS) and other surveillance mechanisms. The same screening and exemption criteria were used for military vaccinations
in the United States and among internationally deployed troops
[2, 4, 11, 12].
SMALLPOX VACCINE SAFETY WORKING
GROUP
The DoD and DHHS vaccination programs required (1) a system of screening to avoid vaccinating persons who themselves
or their close household contacts had a medical condition that
predisposed to vaccine-related adverse effects and (2) a system
of follow-up of vaccinees to determine whether adverse events
occurred and whether the rate of vaccine-related adverse effects
was elevated above expectations. To accomplish these goals, the
Director of the CDC and the Assistant Secretary for Defense
(Health Affairs) formed the Smallpox Vaccine Safety Working
Group (SVS WG), a combined working group of the CDC
Advisory Committee on Immunization Practices (ACIP) and
the DoD Armed Forces Epidemiological Board (AFEB), to
function as an independent, external review board. The SVS
WG included representatives of the ACIP, the AFEB, the
Healthcare Infection Control Practices Advisory Committee,
and the National Vaccine Advisory Committee and other specialists [13]. DHHS and DoD staff participated as ex officio
members. A representative of Wyeth (the manufacturer of
Dryvax smallpox vaccine) served as a consultant. The CDC’s
National Immunization Program and the Office of the Executive Secretary, AFEB, provided technical and administrative support.
The charge to the SVS WG was
1. to evaluate data on smallpox vaccine safety as well as
the vaccine safety monitoring and treatment system of the
DHHS and DoD National Smallpox Pre-Event Vaccination Program (NSVP) and
2. to monitor safety data for use of vaccinia immune glob-
METHODS
Case definitions and threshold rates that would trigger responsive actions were set by the SVS WG on the basis of data
on smallpox vaccine adverse reactions obtained during the
1960s [13–17] and were refined in collaboration with the DHHS
and DoD teams and clinical consultations. Case definitions
reported by Casey et al. [18] are the final consensus versions.
The CDC and DoD provided reports of individual and aggregate safety data to the SVS WG, including analyses of common
and sentinel postvaccination events and reports of VIG and
cidofovir requests, releases, and outcomes.
RESULTS
By 30 June 2004, the DHHS and DoD had vaccinated 39,566
persons and 628,414 persons, respectively (table 1 and figures
1 and 2); most were vaccinated by 31 May 2003. At the peak,
the DoD administered ∼50,000 vaccinations per week, employing group briefings and individual screening for adverse
event risk factors. The DHHS program provided more individualized screening but, compared with the DoD program,
lacked health background information on vaccinees before
screening [1–3].
The demographic profiles of DoD and DHHS vaccinees differed (table 1). The median age of DoD vaccinees was 26 years
(range, 17–79 years); 70.5% were primary vaccinees. The median age of DHHS vaccinees was 48 years (range, 17 to 165
years); 24% were primary vaccinees. Men comprised 88% of
the DoD vaccinees and 37% of the DHHS vaccinees [2, 3].
Figure 1. Number of persons vaccinated by the US Department of
Defense between December 2002 and January 2004.
Smallpox Vaccine Safety Oversight Report • CID 2008:46 (Suppl 3) • S259
probable generalized vaccinia. One was confirmed by identification of vaccinia virus DNA by PCR of tissue samples from
peripheral lesions [23]. The rash in this confirmed case became
apparent only 2 days after vaccination [20, 22]. The patient
reported similar lesions monthly for ∼1 year after vaccination.
One reviewed case was excluded because of varicella DNA
identified by PCR. The remaining cases were judged to represent either nonspecific rashes or hypersensitivity reactions.
All suspected generalized vaccinia cases were mild and selflimited [22]. None of these case patients had atopic dermatitis
or underlying conditions that might be related to an impaired
immune system.
Figure 2. Number of persons vaccinated by the US Department of
Health and Human Services between December 2002 and January 2004.
Noncardiac Adverse Events
The reported counts of key adverse events are outlined in table
2. There were no cases of progressive vaccinia, eczema vaccinatum, fetal vaccinia, or occupational transmission. Two of 48
reports met the case definition for superinfection of vaccination
site; neither of these had a pathogenic organism isolated from
the site [19].
Adverse Dermatologic Events
Case definitions. The terminology for some dermatologic
conditions traditionally associated with smallpox vaccination
was inconsistently applied and does not reflect the current understanding of the underlying pathophysiology [20].
Response threshold. No thresholds can be established for
the mild dermatologic conditions because of confusing terminology. Any one case of eczema vaccinatum, progressive vaccinia, or health care–associated transmission represents a
screening failure and requires investigation.
Any case of erythema multiforme major (Stevens-Johnson
syndrome) requires evaluation to assess possible associated risk
factors. A rate of Stevens-Johnson syndrome that exceeds the
historically observed rate (1 per 1 million vaccinees) should be
investigated.
Reports of Adverse Dermatologic Events
Erythema multiforme major. Erythema multiforme major
(Stevens-Johnson syndrome) developed 20 days after primary
vaccination in a 19-year-old male military service member who
was concurrently immunized against anthrax, tetanus, and
diphtheria. He recovered after a 1-week stay in the hospital
[21].
Generalized vaccinia. A subset of 43 cases reported as suspect or probable generalized vaccinia were reviewed by a subcommittee of the SVS WG and separately by representatives of
the CDC National Immunization Program [22]. Only 2 of 15
cases with adequate photographs met the case definition for
S260 • CID 2008:46 (Suppl 3) • Neff et al.
Inadvertent Inoculation
Case definitions. Four types of inadvertent inoculations were
of concern: inadvertent vaccination of pregnant women, inadvertent vaccination of HIV-infected or immunosuppressed
persons, autoinoculation at sites other than the primary vaccination site, and transfer of vaccinia virus from vaccinees to
unvaccinated persons (contact vaccinia).
Response thresholds for inadvertent vaccination of pregnant
women and HIV-infected or immunosupressed persons.
Any inadvertent vaccination of a pregnant woman or HIVinfected or immunosuppressed person represents a screening
failure and requires evaluation. All outcomes of pregnancy
among vaccinated pregnant women require documentation.
Response threshold for contact vaccinia. An incidence of
12–6 cases of contact vaccinia per 100,000 primary vaccinees
exceeds a threshold based on Poisson modeling of historical
data and requires follow-up evaluations on vaccination-site
management [24].
Reports of Inadvertent Inoculation
Inadvertent vaccination of pregnant women. Approximately
74,000 women were vaccinated after being screened by selfreported history and urine pregnancy testing. Despite screening,
236 women (226 DoD and 10 DHHS) were inadvertently vaccinated while pregnant or within 28 days before conception.
The outcomes of 222 of these pregnancies were known as of
31 May 2004. No cases of fetal vaccinia were identified. Identified spontaneous pregnancy losses and preterm births did not
exceed expected rates (observed rate, 10.6%–11.2%; expected
rate range, 9%–30%) [25–31]. No clusters of congenital anomalies with a common embryologic origin or increases above the
expected birth defects prevalence rate of 3%–4% were identified. Each of 2 cases of sudden infant death syndrome (SIDS)
among 185 live births had known risk factors for SIDS and
negative postmortem testing for vaccinia [31–33].
Inadvertent vaccination of individuals with HIV infection.
Ten DoD vaccine recipients had undiagnosed HIV infections:
3 primary vaccinees, 5 revaccinees, and 2 with unknown vac-
Table 2. Number of adverse events reported in the US National Smallpox Pre-Event Vaccination Program,
as of 30 June 2004.
Department of Defense
vaccinees
(n p 628,414)
Department of Health
and Human Services
vaccinees
(n p 39,566)
Pregnant women
HIV-infected persons
Transmission to contacts
Health care–associated transmission
226
10
45 secondary; 2 tertiary
0
10
0
0
0
Generalized vaccinia
40 suspected or
probable; 0 confirmed
2 suspected; 1 confirmed
Inadvertent inoculation
Nonocular
59
21
Ocular
Postvaccinial encephalitis
14
1
3
1
Eczema vaccinatum
Progressive vaccinia
0
0
0
0
Fetal vaccinia
Erythema multiforme major (Stevens-Johnson syndrome)
0
1
0
0
Event
Inadvertently vaccinated
cination histories [34]. The mean CD4 cell count at diagnosis
of HIV infection (1–3 months after vaccination) was 483 cells/
mm3 (range, 286–751 cells/mm3). All had major reactions to
smallpox vaccination, with normal healing and no adverse
reactions.
Autoinoculation. Seventeen of 97 reports of autoinoculation were ocular infections. None involved the cornea.
Contact vaccinia. Two of 47 reports of transmission of
vaccinia virus from DoD male primary vaccinees to personal
contacts were ocular infections. None involved the cornea.
Clinically, these ocular noncorneal infections were characterized
by areas of edema and inflammation surrounding a vaccination
lesion.
Presence of vaccinia virus was confirmed by viral culture or
PCR in 31 recipients. Thirty-seven of the infected contacts were
young adult women, unvaccinated spouses or partners who had
known or presumed intimate contact. Seven person-to-person
transmissions resulted from contact sports. None occurred in
the workplace, despite intercontinental mass movement of many
vaccinees and close living conditions on airplanes and ships and
in austere field conditions. No transfers occurred from vaccination sites covered with intact semipermeable transparent dressings over gauze. No contact transfers resulted in eczema vaccinatum. All contact vaccinations resolved without sequelae. Two
tertiary transfers were reported separately [35, 36].
A confirmed diagnosis requires demonstration of CNS inflammation by histopathology or neuroimaging. A suspected diagnosis is made by clinical features alone [18, 37, 38].
The pathophysiology of adverse CNS reactions attributed to
smallpox vaccination is incompletely understood. Direct infection of the CNS by vaccinia virus may result in acute cytotoxic
neuronal damage and inflammation. However, laboratory evidence of virus replication is often lacking; inflammatory
changes are attributed instead to immunopathological mechanisms. Histopathological findings are often similar to those
found with acute disseminated encephalomyelitis (or postinfectious encephalomyelitis). The distinction between these 2
pathologic mechanisms is difficult. A diagnosis of acute disseminated encephalomyelitis is favored by a longer interval of
onset after immunization and MRI findings suggesting acute
demyelination (multifocal areas of increased signal on T2, fluid
attenuation inversion recovery, and diffusion weighted imaging
sequences) [39].
Response thresholds. Separate curves were developed for
primary vaccination and revaccination by using a Poisson
model for the vaccinated age groups. The thresholds for responsive action were 12.1 cases of postvaccinia encephalitis
(PVE) per 100,000 primary vaccinees and 10.01 cases of PVE
per 100,000 revaccinees.
Adverse Neurological Events.
Reports of Adverse Neurological Events
Case definitions. Encephalitis and myelitis are inflammation
of the parenchyma of the CNS (brain and spinal cord, respectively), generally due to an infectious or postinfectious etiology.
A total of 214 VAERS reports described neurological signs or
symptoms. No concerning patterns were identified [37, 38, 40].
Headache (44%) was the most common neurological symptom
Smallpox Vaccine Safety Oversight Report • CID 2008:46 (Suppl 3) • S261
reported. Two cases classified as possible PVE were both complex and may represent alternate etiologies [37, 38].
Adverse Cardiac Events
Case definitions. Myo/pericarditis represents a pathologic
spectrum of disease characterized by inflammation of the myocardium and/or the pericardium [41, 42]. Dilated cardiomyopathy (DCM) is defined by the World Health Organization
as a disease of the heart characterized by dilatation and impaired contraction of the left ventricle or both ventricles [43].
Standard diagnostic criteria were used for ischemic heart
disease.
Response threshold. Any ischemic, inflammatory, or other
cardiac event occurring within 30 days after vaccination or any
death associated with a postvaccination cardiac event merits
investigation.
Reports of Adverse Cardiac Events
Myo/pericarditis. Myo/pericarditis, identified among vaccinees, clustered during the first 7–12 days after vaccination [44–
52] (table 3 and figure 3). Primary vaccinees and men were
disproportionately present among DoD cases but were underrepresented among DHHS cases [44, 49] (table 3).
One of 2 DoD female case patients was a 22-year-old who
died 33 days after receiving 5 deployment immunizations, including smallpox. Objective findings of carditis were noted 29
days after vaccination. This case met the myo/pericarditis case
definition criteria [13, 18]. However, her clinical course was
more consistent with lupus-induced serositis associated with
low-grade pericarditis than with the course of the inflammatory
cardiac events recognized as myo/pericarditis after smallpox
vaccination.
Follow-up through April 2005 of 66 DoD case patients has
not documented residual cardiac damage on the basis of electrocardiogram, echocardiogram, graded exercise stress test, and
functional status, although 12.5% reported atypical nonlimiting
persistent chest discomfort [51, 52]. Electrocardiogram, echocardiogram, graded exercise stress test, and/or functional status
of 21 DHHS myo/pericarditis case patients followed for a mean
of 40.2 weeks after diagnosis all improved. Fourteen percent
reported some persistent mild symptoms [50].
Ischemic cardiac conditions. Ten cases of ischemic cardiac
disease (3 fatal) occurred among 410,000 military and civilian
smallpox vaccinees before the end of the first week in April
2003 [53]. As of 30 June 2004, the DHHS reported 10 ischemic
cardiac events (2 fatal) [53]; the DoD reported 16 ischemic
cardiac events (3 fatal) (table 4). Cases did not cluster temporally after vaccination. An age-stratified epidemiological
analysis identified no difference in rates of ischemic events
among DoD smallpox vaccinees and a similar unvaccinated
cohort. DHHS analysis of available data did not support an
excess of ischemic cardiac events among recent smallpox vaccinees [53]. Cases did not cluster temporally after vaccination.
Nevertheless, in March 2003, this signal led to deferral from
vaccination of persons with ⭓3 risk factors for ischemic heart
disease [54].
DCM. Seven cases of DCM were reported in people vaccinated through 30 June 2004. Four DoD case patients ranged
in age from 34 to 44 years, and 3 DHHS vaccinees with DCM
ranged from 53 to 56 years. DCM was recognized 5–40 weeks
after vaccination. Four DCM case patients recovered sufficiently
to return to work; 2 achieved a return to baseline exercise
capacity [49, 50]. Two DoD DCM case patients received disability discharges and successful heart transplants.
Table 3. Summary of myocarditis and/or pericarditis (myo/pericarditis) reports after smallpox vaccination, as of 30 June 2004.
Measure
Department of Defense
vaccinees
(n p 628,414)a
Department of Health
and Human Services
vaccinees
(n p 39,566)b
6
73
16
5
4
0
97
14
97
33
No. of cases with disease classification
Suspected
Probable
Confirmed
Characteristic, %
Primary vaccinee
Male
Time from vaccination to onset of symptoms, days
Median (range)
Mean SD
a
b
Total of 79 cases of myo/pericarditis.
Total of 21 cases of myo/pericarditis.
S262 • CID 2008:46 (Suppl 3) • Neff et al.
10 (1–25)
11 (2–42)
9.5 7.78
10.2 3.9
Figure 3. Cases of myocarditis and/or pericarditis among smallpox vaccinees by day of onset after vaccination, December 2002–June 2004. CDC,
Centers for Disease Control and Prevention; DoD, US Department of Defense.
Treatment with VIG and Cidofovir
Three vaccinees were given VIG, a ratio of 1 per 222,660 vaccinations. VIG was administered prophylactically to a 21-yearold vaccinee who developed accidental burns across 45% of his
body surface area, including his vaccination site, 5 days after
vaccination. During recovery, he developed vesicles on his
torso, which tested negative for vaccinia virus by culture and
PCR assay. One vaccinee and one contact received VIG after
ocular (noncorneal) vaccinia inoculation [55, 56]. No cases
warranted experimental treatment with cidofovir.
DISCUSSION
Smallpox vaccine enabled eradication of smallpox, a medical
and public health triumph, yet smallpox vaccine carries the risk
of severe adverse effects. This was accepted historically because
the impact of disease was much greater than that of the vaccine.
The current NSVP, begun in December 2002, presented both
opportunity and obligation to study the safety profile of the
currently available vaccine in a well-controlled, well-screened
adult population.
The NSVP demonstrated that most adverse events can be
prevented through carefully instituted educational and screening programs, with attention to vaccination-site management.
Only 2 possible encephalitis cases were reported; other known
serious complications, such as eczema vaccinatum, progressive
vaccinia, and health care–associated transmission, were not observed. This experience provided reassuring data on the risk
from inadvertent vaccination of both pregnant women and
persons asymptomatically infected with HIV, a population that
did not exist during the previous smallpox vaccine era. Before
the 2002–2004 experience, disseminated vaccinia was reported
in 1 military recruit with HIV disease [57]. Several hundred
military personnel with HIV infection were estimated to have
received smallpox vaccine before routine HIV screening of all
incoming recruits [58].
Many states reported substantial time spent per person for
screening and vaccination. The pressures from an actual outbreak could shorten this time and reduce the screening effectiveness. However, most persons deferred from vaccination during pre-event use of smallpox vaccine would not be deferred
under guidelines for vaccination in a postoutbreak situation in
which disease risk is substantially increased [59, 60]. Mass
smallpox vaccination programs conducted by the DoD during
2003 and 2004 had rates of adverse events comparable to those
of the smaller DHHS program that targeted primarily health
care professionals. The military health care system screened
vaccinees more efficiently while allowing extensive questionand-answer opportunities for individual vaccinees. The DoD
program used a short (2–3 page) screening form [61] and
benefits from having available extensive health data on vaccinees and a younger, healthier population than the general civilian population. The efficiency of the civilian screening process should be improved in preparation for an actual smallpox
outbreak.
Common Systemic Symptoms
The CDC administered Dryvax reconstituted with a new diluent
(1:1) to a cohort of 1006 persons under an investigational new
drug protocol from October 2001 through December 2002. The
frequency of mild-to-moderate adverse events was assessed
Smallpox Vaccine Safety Oversight Report • CID 2008:46 (Suppl 3) • S263
Table 4.
Summary of ischemic cardiac events after smallpox vaccination, as of 30 June 2004.
Measure
Department of Defense
vaccinees
a
(n p 628,414)
Department of Health
and Human Services
vaccinees
b
(n p 39,566)
3
5
8 (3)
4
0
6 (2)
5 1.41
13.1 10.6
No. of cases of disease
Angina
Atherosclerotic cardiovascular disease
Myocardial infarction (fatal cases)
Characteristic
Time from vaccination to initial evaluation, mean SD days
Male, %
Primary vaccinee, %
Age, mean SD years
a
b
94
28
44.9 8.8
60
10
55 7.5
Total of 16 ischemic cardiac events.
Total of 10 ischemic cardiac events.
from diary cards collected from 936 of these vaccinees for 28
days after vaccination [62]. Outcomes of this CDC study, described in table 5, informed the efforts of the SVS WG [62].
In a prospective analysis of 5951 DoD vaccinees from January
to April 2003, common systemic symptoms were self-reported
after return for assessment of the vaccination site at 6–8 days
after vaccination. Despite differences in vaccinated populations
and methodology, results were similar to those of the CDC
study (table 5). Between March and August 2003, 1254 DoD
vaccinees described their vaccination-site appearance and
symptoms by telephone or internet. Self-description of the vaccination site was matched with a health care provider’s assessment of a major reaction after vaccination (the vaccine “take”),
with a high positive predictive value. In these DoD populations,
2.4% reported diminished work activities, 0.4% missed work,
and 0.1% were hospitalized [63].
These studies, combined with VAERS reports of nonserious
smallpox vaccine–associated adverse events, provided information on the occurrences of common systemic reactions. Fever, myalgias, headaches, and sore arms were expected. Most
reports of superinfection of vaccination sites were actually robust but normal vaccine reactions [19]. Unexpectantly, up to
11% of vaccinees had joint pain [62, 63], and up to 11% had
abdominal pains [62, 63]. Further studies might elucidate the
etiology of these events.
Generalized Vaccinia
Most reported generalized vaccinia reactions probably represent
hypersensitivity or another nonspecific reaction [22, 64, 65].
Actual dissemination of the vaccinia virus is probably rare in
persons who are immunocompetent and do not have atopic
dermatitis [16, 17]. When systemic spread is documented, underlying immunocompromise should be sought.
The term “generalized vaccinia” should be reserved for cases
with virologic confirmation of the systemic dissemination of
S264 • CID 2008:46 (Suppl 3) • Neff et al.
vaccinia virus (e.g., virus recovery or PCR identification of viral
DNA from sites distant from vaccination). The lesions of other
cases lacking a specific etiology should be described clinically
(e.g., as papular, macular, or vesicular), should be biopsied for
histological and, if appropriate, virologic examination, and
should be photographed.
Transfer (Contact) Vaccinia and Success of Site-Care
Recommendations
Similar to observations in the 1960s, transmission of vaccinia
virus from vaccinated persons occurred predominately from
intimate body contact [24, 35, 36]. Transmission did not occur
in the workplace, did not involve persons with risk factors for
adverse outcomes, and did not result in long-term adverse
effects.
Despite the decline of immunity within the general population after more than a generation without either natural disease or routine vaccination, the rate of transfer vaccinia was
not substantially increased above that observed during the last
national experience with smallpox vaccination. Transfer vaccinia continued throughout the program at a consistent rate
of !10 cases per 100,000 primary vaccinees. The rates observed
in the United States in the 1960s were 2–6 cases per 100,000
primary vaccinees [24]. More than half of the 1960s cases were
eczema vaccinatum. Current surveillance for adverse events is
more comprehensive than it was in the 1960s; persons with
household contacts with atopic dermatitis are now deferred
from vaccination, and more attention is given to vaccinationsite management [66–69]. Virologic studies of vaccination sites
during 2003–2004 confirm the effectiveness of semipermeable
dressings over gauze to contain vaccinia virus [66–69].
Autoinoculation
None of 97 accidental autoinoculations resulted in serious longterm consequences. It is difficult to compare this rate (∼1 case
Table 5. Comparison of primary vaccinees versus revaccinees who reported
specific adverse events after smallpox vaccination through active surveillance
in a civilian program.
CDC vaccinees who
reported event, %
All DoD
vaccinees who
reported event, %
Primary
vaccinees
Revaccinees
P
Swollen lymph nodes
Swelling at site
71
58
33
33
!.0001
23
!.0001
62
Pain at injection site
Muscle pain
48
46
30
19
.0018
NA
!.0001
Fatigue
Headache
43
40
29
25
.0161
.0088
27
NA
23
Itching on body
Joint pain
31
25
17
11
.0048
.0011
11
NA
Fever
Backache
Abdominal pain
20
17
11
9
7
2
.0047
.009
.0012
6.6
NA
NA
Adverse event
a
NOTE. The vaccine administered was Dryvax reconstituted with a new diluent (1:1). Data
are from [62] and J. Grabenstein, personal communication. CDC, Centers for Disease Control
and Prevention; DoD, US Department of Defense; NA, not available.
a
Local site symptoms were itching.
per 6,500 vaccinations) with rates from the 1960s [14–17].
Current surveillance is more complete, and vaccination is exclusively for adults. The majority of 1960s vaccinations were
of children with uncovered vaccination sites. Careful attention
to the vaccination procedure and site management should prevent autoinoculation.
Inadvertent Vaccination of Pregnant Women
The expected rate of unknown pregnancy (i.e., pregnancies
of !4 weeks gestation or !6 weeks obstetrical dating) and the
estimated rate of conception of reproductive-age women during a 4-week period is ∼12 per 1,000 women in the general
population [25, 70]. With adjustment of this rate to the older
age distribution of the civilian health care workers vaccinated
during this program, ∼8 per 1,000 would be expected to be
inadvertently exposed in the absence of screening and education [70].
The observed rate of inadvertent exposure to smallpox vaccination during pregnancy among women of reproductive age
vaccinated in the DoD and DHHS populations was ∼3 per
1,000. Three-quarters of the women in the registry were exposed to vaccination before a standard pregnancy test could
have yielded a positive result, either because vaccination preceded conception or because vaccination followed so closely
after conception that tests either were or would have been
negative [25]. The lack of vaccinia-related adverse outcomes
after vaccination of pregnant women supports the earlier understanding that fetal vaccinia is rare and that fetal deformities
may not be associated with vaccinia [25, 70].
Neurological Cases
Because risk factors for PVE have not been defined, it is impossible to design education or screening practices intended to
decrease the risk. The low rate of encephalitis observed during
2002–2004 may indicate that 1960s data included cases unrelated to vaccination. Improved current diagnostic techniques
may allow more-accurate identification of rates. Alternately, in
the 1960s, young children were vaccinated populationwide.
Current programs target vaccination to adults and may have
unmasked a previously unrecognized age differential in the occurrence of PVE. The careful program of education, screening,
and deferral to avoid vaccination of persons with risk factors
for other smallpox vaccine–associated adverse events (e.g.,
those with altered immunity or history of atopic dermatitis)
may have had a collateral benefit of reducing susceptibility to
PVE among vaccinees by elimination of as-yet-unidentified risk
factors.
Cardiac Adverse Events
Myo/pericarditis. Cardiac complications among smallpox
vaccinees were unanticipated events, although postvaccinia myocarditis and pericarditis have been documented in the medical
literature [44–49]. Among the vaccinated military population,
inflammatory cardiac disease occurred almost entirely in young,
primary vaccinees and may have a predilection for white men
[48]. Among DHHS vaccinees, the proportion of men among
identified myo/pericarditis cases was similar to the proportion
of men among all vaccinees, and primary vaccinees were underrepresented among myo/pericarditis cases [49].
Smallpox Vaccine Safety Oversight Report • CID 2008:46 (Suppl 3) • S265
In addition to myocarditis reported among NSVP vaccinees,
Acambis reported 3 symptomatic and 5 asymptomatic cases of
suspect and probable myo/pericarditis from a vaccine trial of
a tissue culture–derived vaccinia vaccine, ACAM2000, compared with the calf-lymph vaccine Dryvax. The cases were identified in both ACAM2000 and Dryvax vaccinees among 1162
primary vaccinees, for a rate of 6.9 per 1000 [71]. This rate,
identified through prospective testing of all vaccinees, was ∼50
times higher than that observed in the military program in
which cases were identified when symptomatic vaccinees presented for medical evaluation [52]. No cases of myocarditis
were observed in 1819 previously vaccinated subjects who received ACAM2000 or Dryvax (T. Monath and N. KanesaThasan, Acambis, personal communication) [71]. The observation of inflammatory cardiac disease in primary vaccinees
given a tissue culture–derived vaccinia vaccine supports the
hypothesis that these inflammatory events are related to the
vaccinia virus rather than to other components in the vaccine
formulation [71]. The onset of symptoms of cardiac disease
clustered coincident with peak viral replication at the vaccination site (at 7–14 days) and presumably with peak-associated
inflammatory response. Vaccinia virus was not isolated from
or identified by PCR or immunohistochemical studies of tissue
from myocardial biopsies [48, 49, 51, 53]. Intermediate-term
follow-up of identified myocarditis cases suggest recovery
among recognized cases [50, 52]. The capture of incident cases
of myo/pericarditis is incomplete, and the duration of observation too short to be able to reach definitive conclusions about
long-term effects.
DCM. DCM was observed in 7 previously healthy subjects.
The recognition of this rare event some months after vaccination in a relatively older population (median age, 39 and
54.5 years for DoD and DHHS DCM cases, respectively, compared with median ages of 26 and 48 years for all DoD and
DHHS vaccinees, respectively) makes it difficult to determine
the relationship, if any, to vaccination. There are no accurate
population-based data on the expected occurrence of DCM.
This experience remains insufficient to favor or reject a causal
association. However, biological mechanisms can be postulated
to support a hypothesized etiologic association. DCM and myocarditis may be linked to both direct infection and autoimmune
processes in mouse models. A subclinical inflammatory event
in humans could be hypothesized to be a precursor of DCM
[41, 42, 72–75]. No myo/pericarditis cases after smallpox vaccination have been recognized to progress to DCM. DHHS
myo/pericarditis cases were actively followed for ∼1 year after
recognition, and DoD cases for 2 years (duration of follow-up
for more recently identified cases may be !24 months at the
time of this report). Further evaluation, including epidemiological data assessing the frequency of DCM in smallpox vacS266 • CID 2008:46 (Suppl 3) • Neff et al.
cinees compared with the baseline among unvaccinated persons, are needed.
Ischemic events. Reports of ischemic cardiac events and
deaths in individuals who had cardiac risk conditions were
received within 3 months after implementation of smallpox
vaccination [53]. This experience was similar to that of the
1976 National Influenza Program, when several heart attacks
on 1 day in the same city among influenza vaccinees triggered
media reports that shook public confidence [76]. Objective
analysis showed that the deaths corresponded to the expected
background death rate among unvaccinated people.
Military data indicated that smallpox-vaccinated and unvaccinated personnel developed ischemic events at comparable
rates. The DoD smallpox vaccinee population, although young
on average, included 180,000 vaccinees ⭓40 years of age. An
epidemiological analysis of observed numbers of incident ischemic cardiac events occurring within 3 weeks after vaccination
among persons vaccinated between 24 January 2003 and 22
August 2003, compared with estimates of expected numbers of
incident cardiac events in a similar population, did not support
an increase [53, 54]. Although the 5 acute myocardial infarctions and 2 myocardial infarction–associated deaths observed
among NSVP vaccinees within 3 weeks after vaccination at that
time point exceeded the point estimates of 2 and 1, respectively,
both observations remained within the 95% predictive interval
for these events [53, 54]. Further, the 2 observed incident angina cases were below the expected count of 10 [53, 54]. Because
these data do not support but cannot refute a causal relationship between vaccination and ischemic cardiac events, the SVS
WG concurs with the CDC, DoD, and ACIP recommendations
that persons with ⭓3 cardiac risk factors be deferred from
vaccination in a preoutbreak setting [54].
CONCLUSIONS
The 2002–2004 federal smallpox vaccination programs confirmed that education and screening can reduce the risk of
serious adverse events from smallpox vaccination. Education
and screening reduced but did not eliminate inadvertent vaccination of pregnant women. Nonetheless, fetal vaccinia is a
rare event that was not identified as a result of this vaccination
program.
Vaccinated health care workers provided direct patient care
to immunocompromised persons during the period of shedding of vaccinia virus from the vaccination site. A strict regimen
for site care and monitoring in the health care setting prevented
nosocomial contact transmission and should be followed.
The increased risk of smallpox vaccination–associated inflammatory cardiac events was an important unanticipated
event. Although vaccinees who developed inflammatory cardiac
disease observed during this experience have largely recovered,
concern remains that disease in some vaccinees could progress
to DCM. These cardiac observations deserve further study.
Observations to date do not support but cannot refute an
etiologic relationship between smallpox vaccination and ischemic cardiac events. Because ischemic cardiac events may be
related to cardiac inflammation in persons with underlying
ischemic disease, in the pre-event setting, it is advisable to
withhold vaccination from those who have cardiac risk factors.
The risk-benefit ratio that supports this recommendation
would reverse for people potentially exposed to smallpox virus.
Finally, this program has occurred in the absence of smallpox
infection. Were smallpox virus to be reintroduced, the criteria
for deferral would decrease substantially so that screening programs would be modified and streamlined. This experience has
defined a safe and effective approach to modern pre-event
smallpox vaccination of those at risk of exposure in the event
of variola reintroduction.
DHHS SMALLPOX VACCINE SAFETY TEAM
Ex officio representatives to the SVS WG. US Food and Drug
Administration: Karen Goldenthal and Ann Ward McMahon;
Health Resources and Services Administration: Vito Caserta
and Carol Konchan; and CDC: Linda Quick and Louisa
Chapman.
CDC Smallpox Vaccine Adverse Events Response and Monitoring Activity. Executive Team: Gina Mootrey, Eric Mast,
Herschel Lawson, and Mary McCauley; Cardiac Team: Martha
Roper, Christine Robin Curtis, Patricia Galloway, Beth Hibbs,
Paige Hightower, Nidhi Jain, Nancy Levine, Mona Marin,
Jacqueline Miller, Juliette Morgan, Pedro Moro, Rich Schieber,
Margarita Sniadack, and David Swerdlow; Clinical Team: Francisco Averhoff, Christine Casey, Rosaline Dhara, Kristina Ernst,
Kirsten Ernst, Kathleen Fullerton, Michael Deming, Daniel
Fishbein, Lamar Hasbrouck, James Heffelfinger, Barbara Herwaldt, Andrew Kroger, Anne Moore, Juliette Morgan, Monica
Parise, Meredith Reynolds, Scott Santibanez, James Sejvar,
Bruce Tierney, Thomas Török, Claudia Vellozzi, Charles Vitek,
and Xiaojun Wen; State Team: Susan Reef, Eduard Eduardo,
Masa Tanaka, John McGowan, Danice Eaton, Carol Knowles,
Kathleen McDuffie, Jennifer Cleveland, Jami Fraze, Elizabeth
Bolyard, Lynne Sehulster, Philip Baptiste, Ceil Threat, Fred Ingram, and Tracy Thomas; Surveillance Team: Sara Critchley,
Hayley Hughes, John Iskander, Joyce Goff, Madeline Sutton,
Phuc Nguyen-Dinh, Roumiana Boneva, Roseanne English, and
John Copeland; Pre-Event Vaccination System: David Walker
and Kimp Walton; CDC Pregnancy Registry: Joe Mulinare,
Karen Broder, Kristen Kenyan, Susan Goldstein, Sheryl Lyss,
and Jane Seward; Statistical Team: Robert Pollard and John
Copeland; and Smallpox and Vaccinia Consultant: J. Michael
Lane.
DOD SMALLPOX VACCINE SAFETY TEAM
Ex officio representatives to the SVS WG. AFEB: Severine
Bennett, Roger L. Gibson, and James R. Riddle.
Smallpox Vaccine Safety Monitoring and Response.
Brooke Army Medical Center: David P. Dooley, Eric A. Shry,
Robert E. Eckart, Sean P. Javaheri, and William Nauschuetz;
Darnall Army Community Hospital: Cory Costello and Raul
Palacios; Elmendorf Air Force Base: Michael Tankersley and J.
L. Adkins; Landstuhl Army Regional Medical Center: George
W. Christopher, David G. Heath, Sidney R. Hinds, Michael G.
Bryan, and Kevin M. Kumke; Madigan Army Medical Center:
Peter Napolitano, Mary P. Fairchok, L. C. Raynor, Vinaya A.
Garde, Vance M. Rothmeyer, and Steven D. Mahlen; Military
Vaccine Agency: John D. Grabenstein, Gaston M. Randolph,
Jr., Steven P. Jones, Jeffrey S. Halsell, Charles H. Hoke, Kenneth
Hoffman, Marc L. Caouette, Patrick Garman, Paula Doulaveris,
Ronald Harris, Eric Sones, David Beauchene, and Allison
Christ; National Naval Medical Center, Bethesda: Sybil A. Tasker, G. A. Schnepf, and Joyce A. Lapa; Naval Health Research
Center: Margaret Ryan, Shirley Chow, Ava Conlin, Brian Pierce,
Cheryl Rudy-Goodness, Victor Stiegman, Jennifer Strickler, and
Timothy S. Wells; Naval Hospital Portsmouth: Suzanne S. Love,
Robin Rogers, Denise Chernitzer, Teresa Riddick, and Anne
Morse; Tripler Army Medical Center: Andrew C. Whelen,
Glenn Wasserman, C. A. Bell, and Susan L. Fraser; US Air Force
Surgeon General’s Office: R. Dana Bradshaw, Mylene T. Huynh,
Kelly Woodward, and Linda Bonnel; US Army Center for
Health Promotion and Preventive Medicine: Mark V. Rubertone, John F. Brundage, Jenny C. Lay, Thomas F. Bateson, Arthur R. Baker, Mark K. Arness, Marilyn K. Null, and Roxanne
D. Smith; US Army Medical Research and Materiel Command:
Timothy P. Endy, Ellen Boudreau, Patricia Petitt, Sandra M.
Escolas, and David R. Shoemaker; US Army Surgeon General’s
Office: Jeffrey D. Gunzenhauser, Paula K. Underwood, and
Benedict Diniega; US Central Command: Geoffrey Hobika,
Douglas G. Smith, Kevin L. Pehr, J. A. Lees, and Larry J. Godfrey; US Coast Guard: Sharon L. Ludwig and Mark Tedesco;
Walter Reed Army Medical Center: Renata J. M. Engler, Limone
C. Collins, Jr., Robert LaButta, Scott A. Norton, Lisa A. Black,
Thomas J. White, K. Scott Bower, William P. Madigan, Laurie
L. Duran, J. Edwin Atwood, Dmitri C. Cassimatis, Marina N.
Vernalis, Gary L. Fillmore, Thomas P. Ward, E. J. Dudenhoefer,
G. K. Berry, Felisa S. Lewis, Tara King, Bryan L. Martin, Michael
R. Nelson, David W. Craft, Dallas C. Hack, Joyce N. Hershey,
Praxes Belandres, Jeannette Williams, and Mary Minor; Wilford
Hall Air Force Medical Center: John Dice, Caroline C. DeWitt,
David Hrncir, Pam Garwood, Catherine Skerrett, and Sandra
Johnson; Womack Army Medical Center: Jeff Kingsbury, Ava
Huchun, Mercedes Payne, Beth Stanfield, Marian Gordon,
Jeanie Kim, Carolyn Robinson, and Howard Oaks; and other
military treatment facilities: Brian R. Guerdan, Roland B. CaSmallpox Vaccine Safety Oversight Report • CID 2008:46 (Suppl 3) • S267
biad, T. W. Barkdoll, H. E. Caraviello, Naomi Aronson, Peter
E. Linz, Kenneth W. Schor, Kylee V. Sutherlin, and Susan Bailey.
Acknowledgments
Background surveillance data for cardiovascular outcomes were provided
by the National Heart, Lung, and Blood Institute and by the Atherosclerosis
Risk in Communities, Framingham Offspring, and Coronary Artery Risk
Development in Young Adults studies. The Advisory Committee on Immunization Practices and the Armed Forces Epidemiological Board joint
Smallpox Vaccine Safety Working Group expresses appreciation for the
conscientious work and remarkable spirit of collaboration among all parties
who supported our work, including entities of the National Academy of
Sciences, the US Department of Defense (DoD), and the US Department
of Health and Human Services (DHHS); pharmaceutical industry colleagues (Wyeth and Acambis); civilian and military health care providers;
state, territorial, county, city, and local health department professionals;
response team and research study volunteers; and others. Particular appreciation is expressed to the members of the DoD and DHHS Smallpox
Vaccine Safety Teams, whose monitoring efforts provided the basis for our
review.
Financial support. US Department of Health and Human Services;
US Department of Defense.
Supplement sponsorship. This article was published as part of a supplement entitled “Posteradication Vaccination against Smallpox,” sponsored by the National Center for Immunization and Respiratory Diseases,
Coordinating Center for Infectious Diseases, Centers for Disease Control
and Prevention (CDC), and by the Coordinating Office for Terrorism Prevention and Emergency Response, CDC.
Potential conflicts of interest. J.N. serves on the Data and Safety Monitoring Board for Acambis. T.M. serves on the Data and Safety Monitoring
Board for VaxGen. G.P. served as principle investigator for a smallpox
clinical study sponsored by Acambis and serves on the scientific advisory
board for Dynport. All other authors: no conflicts.
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