US Civilian Smallpox Preparedness and Response Program, 2003

Article (PDF Available)inClinical Infectious Diseases 46 Suppl 3(s3):S157-67 · April 2008with14 Reads
DOI: 10.1086/524751 · Source: PubMed
Abstract
Variola virus, the cause of smallpox disease, has been deemed a possible bioterrorism agent. Since November 2001, federal, state, and local public health partners implemented activities to prepare for a possible smallpox outbreak. The Centers for Disease Control and Prevention (CDC) produced and delivered training and educational materials for smallpox preparedness in many formats, developed detailed smallpox vaccine information statements about vaccine contraindications and vaccination site care, and established mechanisms to monitor and respond to adverse events after smallpox vaccination. The last included enhancements to the Vaccine Adverse Event Reporting System, a pregnancy registry for inadvertently vaccinated pregnant women, and a Clinician Telephone Information Line to collect reports about adverse events. The civilian responder vaccination program was conducted with rigorous safety procedures, and few historically recognized adverse events were observed. However, myocarditis and/or pericarditis was newly recognized as an adverse event caused by the New York City Board of Health vaccinia vaccine strain. This smallpox preparedness program put into place a number of measures to advance the United States' readiness for a smallpox outbreak that have assisted in preparedness for other threats.

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US Smallpox Preparedness, 2003 CID 2008:46 (Suppl 3) S157
SUPPLEMENT ARTICLE
US Civilian Smallpox Preparedness and Response
Program, 2003
Raymond A. Strikas,
1
Linda J. Neff,
2
Lisa Rotz,
2
Joanne Cono,
2
Donna Knutson,
2
Joseph Henderson,
2
and Walter A. Orenstein
3
1
National Vaccine Program Office, US Department of Health and Human Services, Washington, D.C.; and
2
Centers for Disease Control
and Prevention and
3
Emory University School of Medicine, Atlanta, Georgia
Variola virus, the cause of smallpox disease, has been deemed a possible bioterrorism agent. Since November
2001, federal, state, and local public health partners implemented activities to prepare for a possible smallpox
outbreak. The Centers for Disease Control and Prevention (CDC) produced and delivered training and ed-
ucational materials for smallpox preparedness in many formats, developed detailed smallpox vaccine infor-
mation statements about vaccine contraindications and vaccination site care, and established mechanisms to
monitor and respond to adverse events after smallpox vaccination. The last included enhancements to the
Vaccine Adverse Event Reporting System, a pregnancy registry for inadvertently vaccinated pregnant women,
and a Clinician Telephone Information Line to collect reports about adverse events. The civilian responder
vaccination program was conducted with rigorous safety procedures, and few historically recognized adverse
events were observed. However, myocarditis and/or pericarditis was newly recognized as an adverse event
caused by the New York City Board of Health vaccinia vaccine strain. This smallpox preparedness program
put into place a number of measures to advance the United States’ readiness for a smallpox outbreak that
have assisted in preparedness for other threats.
Variola virus, the cause of smallpox, is a Centers for
Disease Control and Prevention (CDC) category A bio-
terrorism agent [1]. It is an agent of great concern, for
the following reasons: (1) uncertainty exists about
whether all of the variola virus stocks of the former
Union of Soviet Socialist Republics can be accounted
for; (2) the virus can be highly infectious in susceptible
populations (i.e., those unvaccinated or without history
of smallpox disease), which now include most of the
world; and (3) its 30% case fatality rate ranks it as
one of the most deadly infectious agents [2].
The findings and conclusions in this report are those of the authors and do not
necessarily represent the views of the Centers for Disease Control and Prevention
and the National Vaccine Program Office.
Reprints or correspondence: Dr. Raymond A. Strikas, National Vaccine Program
Office, Dept. of Health and Human Services, 200 Independence Ave. SW,
Washington, DC 20201 (Raymond.Strikas@psc.hhs.gov).
Clinical Infectious Diseases 2008;46:S157–67
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4606S3-0002$15.00
DOI: 10.1086/524751
In November 2001, the CDC developed a smallpox
response plan that outlined the major requirements for
a smallpox outbreak response [3]. In October 2002,
the Advisory Committee on Immunization Practices
(ACIP) recommended vaccination of selected public
health and hospital health care emergency response per-
sonnel [4]. The CDC also recommended that state and
local areas receiving federal bioterrorism funds (i.e., the
62 Public Health Emergency Preparedness [PHEP] Co-
operative Agreement grantees, including the 50 US
states, Puerto Rico, the District of Columbia, New York
City, Chicago, Los Angeles, and 7 US territories) take
certain actions. These included preparing and training
personnel to serve as responders in the event of a small-
pox outbreak, improving detection and reporting (sur-
veillance), and putting mechanisms in place to protect
the public.
The most recently employed primary strategy to con-
trol smallpox was surveillance and containment, or ring
vaccination, which has also been recommended by the
CDC and ACIP [3, 4] as the initial response to any
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smallpox outbreak. In addition, the CDC recommended that,
in the event of an outbreak, state and local health departments
develop plans to allow rapid expansion of vaccination efforts
to achieve vaccination of their populations within 10 days, if
needed, as an adjunct to ring vaccination. Ten days was the
period chosen because the incubation period of smallpox was
usually 12–14 days. Therefore, completing vaccination of the
public within 10 days would permit vaccination of most persons
within the incubation period of the first generation of cases,
limit the second generation of cases, and prevent a third gen-
eration of cases.
In December 2002, President George W. Bush announced im-
plementation of a smallpox vaccination program [5]. Two of the
program’s components were vaccination of military personnel
and voluntary vaccination of civilian public health and medical
response teams. The military vaccination program has been de-
scribed elsewhere [6]. The civilian program was authorized by
the Secretary of the Department of Health and Human Services
(DHHS) in a declaration on 23 January 2003, which has been
annually renewed and is now authorized through 23 January
2008 [7]. The CDC was charged with implementing the civilian
preparedness program. The program proposed to train and vac-
cinate 500,000 hospital health care workers and first responders
[8]. In the present article, we describe the implementation of
that civilian smallpox responder vaccination program, also
known as the DHHS Smallpox Preparedness and Response Pro-
gram (DHHS SPRP), beginning in January 2003, and other as-
pects of smallpox preparedness, including training, surveillance,
collaboration with partners, and program evaluation.
METHODS
The CDC smallpox response plan has been revised since 2001,
with particular attention paid to disease surveillance. In ad-
dition, the CDC developed guidelines for large-scale vaccina-
tion, including supporting materials [9]. In 2002, the PHEP
grantees developed their own postevent, or postoutbreak, re-
sponse plans, as well as pre-event vaccination plans. Beginning
in 2003, the CDC and its federal, state, and local partners,
particularly state and local health departments, worked to fur-
ther improve smallpox preparedness in a number of ways, de-
scribed below.
Preparing Responders
Clinician education. Training and education materials for
smallpox preparedness were produced and delivered in many
formats. These materials covered smallpox disease history, dif-
ferential diagnosis, vaccine storage and handling, vaccination,
vaccine adverse events, and response plans to a smallpox out-
break. The formats included in-person courses held for federal,
state, and local public health staff, satellite television broadcasts,
CD-ROMs, videotapes, Web-based educational programs, and
print materials.
Vaccination screening and vaccination. The CDC devel-
oped detailed information materials, including a smallpox vac-
cine information statement with a number of supplements
about reactions after vaccination, vaccination site care, and
contraindications to vaccination (including eczema, atopic der-
matitis, immunosuppression, and pregnancy) [10]. These ma-
terials also included explanations of the role of vaccinia immune
globulin (VIG) and cidofovir in treating adverse events after
vaccination, as well as an information sheet for contacts of
vaccinated persons [10]. A screening worksheet was also de-
veloped for potential vaccinees, enabling each to systematically
review his or her own health status and that of his or her
contacts to identify contraindications to vaccination. To ensure
that potential vaccinees were well aware of requirements for
vaccination and postvaccination care before vaccination, each
completed a medical history and consent form, and, after vac-
cination, each received a postvaccination follow-up sheet. For
health care workers, postvaccination site care included the use
of gauze covered by a semipermeable dressing and a layer of
clothing while engaged in patient care. In addition, daily vac-
cination site inspections, with dressing changes (as necessary),
were recommended until the vaccination scab fell off [4]. Fol-
lowing reports of ischemic heart disease after smallpox vacci-
nation, the CDC and ACIP revised their recommendations for
vaccination to exclude persons with known heart disease and/
or 3 risk factors for ischemic heart disease [11].
The vaccine used in the program was Dryvax (Wyeth), the
vaccinia (smallpox) vaccine currently licensed in the United
States. It is a lyophilized, live virus preparation of infectious
vaccinia virus. It was prepared from calf lymph with a seed
virus derived from the New York City Board of Health
(NYCBOH) strain of vaccinia virus and has a minimum con-
centration of 10
8
pock-forming units/mL [12]. Two to 3 punc-
tures are recommended for primary vaccination, and 15 punc-
tures are recommended for revaccination. If no trace of blood
is visible after vaccination, an additional 3 insertions are rec-
ommended, by use of the same bifurcated needle without rein-
serting the needle into the vaccine vial. If no evidence of vaccine
take is apparent after 7 days, the person may be vaccinated
again [4].
PHEP grantees identified public health and hospital health
care response teams for smallpox vaccination. Public health
teams included nursing, medical, epidemiologic, laboratory,
and vaccinator personnel. Hospital health care teams included
emergency department staff, intensive-care staff, general med-
ical staff, primary-care house staff (i.e., medical, pediatric, and
family physicians), medical subspecialists, infection control
professionals, respiratory therapists, radiology technicians, se-
curity personnel, and housekeeping staff.
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The CDC developed a vaccination administration reporting
system for state and local health department use (known as
the Pre-Event Vaccination System [PVS]), which permitted
rapid reporting of vaccination data from states to the CDC.
The PVS provided the country with the capability to not only
report pre-event vaccination but also prepare for emergency
vaccine administration in the event of a national response. The
system included a secure Web-based reporting system. Because
some states had their own established administration systems,
a secure data-exchange system, including exchange specifica-
tions, was provided. By either Web-based reporting or data
exchange, states were able to provide daily vaccination admin-
istration information to the CDC. The capability of the PVS
has been refined, and it has become part of the CDC’s Coun-
termeasure Response Administration (CRA) system. The CRA
system expands significantly on the capacities of the PVS for
national, state, and local use. The CRA system advances func-
tionality that ensures that individuals receive recommended
countermeasures and tracks and manages multiple vaccination
types, pharmaceutical prophylaxis courses and treatments, iso-
lation and quarantine, and other interventions [13]. The CRA
system is one tool public health partners may choose to manage
countermeasure and response administration activities within
their jurisdictions.
Section 304 of the Homeland Security Act, passed by Con-
gress in November 2002, included provisions that offered lia-
bility protection to vaccinated response team personnel, vac-
cinators, and employers [14]. In April 2003, the Smallpox
Emergency Personnel Protection Act was passed. It established
the Smallpox Vaccine Injury Compensation Program, a no-
fault program to provide benefits and/or compensation to cer-
tain individuals; these individuals include health care workers
and emergency responders injured as the result of the admin-
istration of smallpox countermeasures, including the smallpox
vaccine [7]. The Smallpox Emergency Personnel Protection Act
also provides benefits and/or compensation to certain individ-
uals who are injured as a result of accidental vaccinia inocu-
lation through contact. The table of injuries included in its
provisions was published on 27 August 2003. Additional in-
formation about the program and extension can be found at
http://www.hrsa.gov/smallpoxinjury/ and http://www.hrsa
.gov/smallpoxinjury/frn012907.htm.
Surveillance for adverse events after vaccination. The
CDC established a number of mechanisms to both monitor
and respond to adverse events after smallpox vaccination.Com-
mon reactions were assessed by a survey, performed by
Northern California Kaiser Permanente, of 825 vaccinees from
7 states at 10 and 21 days after vaccination [15]. The Vaccine
Adverse Event Reporting System (VAERS) was enhanced to
allow for more-rapid (within several days of the report) sum-
mary reporting. Sixty percent of PHEP grantees (37 of 62)
conducted active surveillance among vaccinees 28 days after
vaccination [16]. The active system was implemented on 24
January 2003. In addition, the CDC established the Hospital
Smallpox Vaccination Monitoring System, a voluntary, Web-
based application developed to assist hospitals or other facilities
in real-time monitoring and tracking of health care workers
who received smallpox vaccine [17]. This program enrolled 246
health care facilities in 38 states. A pregnancy registry was de-
veloped to monitor women who were inadvertently vaccinated
while pregnant or who became pregnant shortly after vacci-
nation [18]. The CDC developed a Clinician Information Tele-
phone Line to rapidly respond to clinicians’ concerns about
possible adverse events and to send out VIG and/or cidofovir
promptly if indicated, with instructions for their use under an
Investigational New Drug protocol. Finally, the CDC and the
Department of Defense jointly created an independent small-
pox vaccine safety working group from the ACIP and the
Armed Forces Epidemiology Board (AFEB) membership and
outside experts on vaccinia and smallpox. This working group
was charged with oversight responsibility for the safety of both
the civilian and military vaccination programs [19]. The goal
of these measures was to limit adverse events to frequencies
lower than those historically observed: (1) inadvertent inocu-
lation (529.2 cases/million primary vaccinations), (2) gener-
alized vaccinia (241.5 cases/million primary vaccinations), (3)
eczema vaccinatum (38.5 cases/million primary vaccinations),
(4) progressive vaccinia (1.5 cases/million primary vaccina-
tions), and (5) postvaccinial encephalitis (12.3 cases/million
primary vaccinations). Death also had occurred in 1 per mil-
lion primary vaccinations, usually as a result of progressive
vaccinia, postvaccinial encephalitis, or severe eczema vaccina-
tum [20].
Detection and Reporting
The CDC developed a clinical rash illness algorithm that fa-
cilitates rapid assessment and reporting of any person pre-
senting with a febrile rash illness for the likelihood of smallpox
versus other similar rash illnesses, most commonly varicella
[21]. In 1999, the CDC, in coordination with other partners,
such as the Association of Public Health Laboratories and the
Federal Bureau of Investigation, developed the Laboratory Re-
sponse Network (LRN), a network of sentinel and reference
hospital and state and local public health laboratories. The LRN
included 120 reference laboratories as of December 2003 [22,
23]. Currently, there are
1160 member laboratories, and the
network continues to be an integral part of the public health
system for assessing febrile rash illness. The purpose of the LRN
now includes running a network of laboratories that can re-
spond to biological and chemical terrorism and other public
health emergencies. The LRN has also grown in the variety of
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its member laboratories; it now includes state and local public
health, veterinary, military, and international laboratories [23].
Protection of the Public from Smallpox
Since the fall of 2000, the federal government has worked to
ensure an adequate smallpox vaccine supply for the entire pop-
ulation of the United States. This has been accomplished by
evaluating the smallpox vaccine Dryvax at dilutions of 1:5 and
1:10, to assess how much the previous supply could be ex-
tended, and by contracting with Acambis for the development
and production of a new tissue culture vaccine using the
NYCBOH vaccinia virus strain [24, 25]. In addition, following
the CDC’s guidance, beginning in October 2002, PHEP grantees
have developed contingency plans for rapid vaccination of their
respective populations in the event of a smallpox outbreak [26].
Collaboration with Partners
From the outset of expanded smallpox preparedness activities in
November 2001, the CDC has worked with a variety of partners.
Within the federal government, these included the US Food and
Drug Administration and the National Institutes of Health on
vaccine development, licensure, and production issues; the
Health Resources Services Administration on hospital prepar-
edness; and the Departments of Defense and Veterans Affairs on
vaccination programs. At the state and local level, these included
health departments and their representative organizations, no-
tably the Association of State and Territorial Health Officials, the
National Association of County and City Health Officials, the
Council of State and Territorial Epidemiologists, and the Asso-
ciation of Public Health Laboratories.
Program Evaluation
The Institute of Medicine (IOM), following a request from the
CDC, convened the Committee on Smallpox Vaccine Program
Implementation. The IOM committee met 5 times in open
session between December 2002 and March 2004 and issued 6
letter reports, as well as a final summary report [27].
The CDC has conducted a number of evaluations of the
smallpox preparedness program. These included evaluation of
individuals’ and hospitals’ reasons for participation or non-
participation [28–30], individual states’ rates of vaccine take,
utility of the information systems used, and long-term follow-
up of selected individuals with adverse events after vaccination,
with particular emphasis on myocarditis, pericarditis, and other
possibly related syndromes [31]. Beginning in 2004, the CDC
also submitted target capabilities and measures to the PHEP
grantees to guide their assessment of state and local programs
in enhancing their overall preparedness to manage responses
to all hazards, including smallpox [32]. In the fall of 2005,
PHEP grantees were required to assess their capacity to im-
plement mass prophylaxis, including mass vaccination. PHEP
grantees were expected to meet the critical task of ensuring
that smallpox or other vaccines can be administered appro-
priately [33]. In the case of smallpox, this assessment included
vaccine administered to all known or suspected contacts of cases
within 3 days and, if indicated, to the entire jurisdiction within
10 days.
RESULTS
Preparing Responders
Clinician education. In 2003, in-person training courses
were attended by 3676 persons. Three special training sessions
on smallpox vaccination methods were attended by 318 per-
sons, who, in turn, reported having trained an additional
15,349 persons by December 2003. In 2003, 7 comprehensive
satellite television courses were broadcast. Online registration
data for these courses indicate that there were at least 69,830
live viewers. Smallpox preparedness was also included in gen-
eral CDC immunization updates televised in 2004 and 2005.
It is estimated that 9248 persons viewed these latter 2 pro-
grams. Videotape and CD-ROM versions of the satellite
broadcasts were distributed to an additional 172,085 individ-
uals and organizations. Web-based educational programs and
materials have been accessed by
11.7 million persons. Begin-
ning in February 2003, the CDC and its state health depart-
ment partners mailed an information packet on smallpox dis-
ease and differential diagnosis to all physicians in the United
States. The CDC also published guidance for clinicians, re-
garding the evaluation and treatment of patients with com-
plications from smallpox vaccination [34], and guidance pro-
viding uniform criteria used for surveillance case definition
and classification for these previously recognized adverse re-
actions during the DHHS SPRP [35].
Vaccination screening and vaccination. Through 31 De-
cember 2003, 38,783 civilian personnel from all 50 states re-
ceived licensed smallpox vaccine as part of state and local small-
pox preparedness programs (table 1). Of those vaccinated for
whom complete data were available (38,518), 16,608 were hos-
pital health care staff, 12,722 were public health response team
personnel, and 9188 were defined as other personnel (most of
whose occupations were listed as “other health care”). At least
2992 of these other personnel were first responders, such as
law enforcement personnel, fire fighters, and emergency med-
ical technicians. The median age of vaccinees was 48 years, with
80% 40 years of age. Sixty-three percent of vaccinees were
women. Too few vaccinees reported racial and ethnic categories
to allow meaningful analysis. The number vaccinated per state
ranged from 19 in Nevada to 4599 in Texas. The vaccination
take rates were 93% in primary vaccinees and 93.5% in revac-
cinees. At least 1 employee was vaccinated in each of 1854 acute
care hospitals (37% of all US acute care hospitals identified by
PHEP grantees). Subsequent to 2003, vaccination of response
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Table 1. Demographic characteristics of US civilian smallpox
vaccinees, 24 January–31 December 2003.
Characteristic Value
Age, years
Mean (SD) 47 (9.48)
Median (range) 48 (17–95)
Sex, no. (%)
Female 24,721 (63.7)
Male 14,062 (36.3)
Vaccination status, no. (%)
Primary vaccinee 8914 (23.0)
Revaccinee 29,315 (75.6)
Unknown 554 (1.4)
NOTE. for whom complete data are available.N p 38,783
team members has continued, although in much lower
numbers.
The CDC continues to provide licensed smallpox vaccine,
available on request, to state public health authorities for vac-
cination of designated smallpox response teams, as outlined in
the supplemental recommendations of the ACIP and the
Healthcare Infection Control Practices Advisory Committee for
using smallpox vaccine in a pre-event vaccination program [4].
This is in coordination with the state smallpox response plans.
In addition, the Biologics License Application for intravenous
VIG produced by the Cangene Corporation was approved by
the US Food and Drug Administration on 2 May 2005. VIG
is the recommended agent of choice for treating certain adverse
events after smallpox vaccination, including eczema vaccinatum
and progressive vaccinia [12]. Physicians seeking consultation
on an adverse event were, and are, advised to first notify their
state health department. If further consultation is required or
VIG is recommended, the physician or state health department
should contact the CDC Director’s Emergency Operation Cen-
ter at 770-488-7100. A CDC smallpox vaccine subject matter
expert will provide in-depth consultation and facilitate VIG
release as appropriate. As with other vaccine adverse events,
smallpox vaccine adverse events should also be formally re-
ported through VAERS.
Surveillance for adverse events after vaccination. Active
surveillance data for 17,316 vaccinees collected 28 days after
vaccination indicated that 81 vaccinees (0.47%) acknowledged
having contraindications that were not discovered before vac-
cination [16]. Common adverse events were reported from the
Northern California Kaiser Permanente 10- and 21-day survey
[15]. Severe symptoms, such that vaccinees were unable to
perform usual activities, occurred in 6.2% at 10 days and in
4.0% at 21 days. Of the 601 vaccinees surveyed at 21 days after
vaccination, 73 (12.5%) reported having missed work for any
reason, and 53 (8.8%) reported having missed work because
of illness or pain ascribed to the vaccination [15]. In addition,
the Hospital Smallpox Vaccination Monitoring System received
reports from 57 facilities that provided complete data on 759
vaccinees, and
!2% of scheduled workdays were lost because
of adverse events in the 4 weeks after smallpox vaccination
([17] and Deva Joseph, CDC, personal communication, 30 De-
cember 2003).
Through 31 December 2003, there were 857 adverse events
in civilian vaccinees reported to VAERS [36, 37] (tables 2 and
3). Of these, 107 (12.5%) were categorized as serious, defined
as resulting in death, hospitalization, prolongation of an ex-
isting hospital stay, and/or permanent disability. Three deaths
were reported, including 2 women, 55 and 57 years of age, who
had myocardial infarctions (MIs) 1 and 4 days after vaccination,
and 1 man, 45 years of age, who died of an MI 69 days after
vaccination. No cases of eczema vaccinatum, progressive vac-
cinia, or transfer of vaccinia virus to contacts of vaccinees were
reported. Only 1 case of postvaccinial encephalitis was reported.
The rates of these adverse events were similar to, or lower than,
those historically reported [20] (table 2). Of the 8163 women
of childbearing age vaccinated during the civilian program in
2003, 10 (0.12%) were discovered, after vaccination, to have
become pregnant shortly before or after vaccination, and they
were enrolled in the National Smallpox Vaccine in Pregnancy
Registry ([18] and CDC, unpublished data). One additional
woman vaccinated in the DHHS SPRP was enrolled after 2003.
As of September 2006, pregnancy outcome data were available
for 376 women vaccinated in both civilian and military pro-
grams. Most (77%) were vaccinated near the time of concep-
tion, before results of a standard pregnancy test would have
been positive. To date, outcome evaluations have not revealed
higher-than-expected rates of pregnancy loss (11.9%), preterm
birth (10.7%), or birth defects (2.8%), compared with those
in healthy referent populations [38–42]. No cases of fetal vac-
cinia have been identified. Of the 11 women enrolled from the
DHHS SPRP, 7 delivered at term, 3 had pregnancy loss, and 1
was lost to follow-up and was not reported in the overall reg-
istry results. The Smallpox Vaccine in Pregnancy Registry con-
tinues to actively enroll women and to follow infant and early
childhood health outcomes [18].
In the DHHS SPRP, 21 cases of myocarditis and/or pericar-
ditis (hereafter referred to as “myo/pericarditis”) were reported
during this period, of which 16 were classified as suspect and
5 were classified as probable [43]. Three vaccinees, who had
not received a diagnosis of myo/pericarditis previously, were
reported to have dilated cardiomyopathy after vaccination [43].
In addition, within 30 days after vaccination, 4 vaccinees re-
ported angina pectoris (angina), and 6 reported an MI [44].
Although the point estimates for rates of both angina and MI
were greater than predicted in this population, the differences
were not statistically significant (i.e., the rates were within the
95% predicted intervals) [44]. After 28 March 2003, persons
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Table 2. Selected adverse events associated with smallpox vaccination in the civilian Smallpox Prepar-
edness and Response Program, by type—United States, 24 January–31 December 2003.
Adverse event Suspected
a
Probable
b
Confirmed
c
Total
Eczema vaccinatum 0 (0) 0 (0) 0 (0) 0 (0)
Fetal vaccinia 0 (0) 0 (0) 0 (0) 0 (0)
Generalized vaccinia 2 (51.6) 0 (0) 1 (25.8) 3 (77.3)
Inadvertent inoculation, nonocular 11 (283.6) 0 (0) 9 (232.1) 20 (515.7)
Ocular vaccinia 1 (25.8) 0 (0) 2 (51.6) 3 (77.3)
Progressive vaccinia 0 (0) 0 (0) 0 (0) 0 (0)
Erythema multiforme major (Stevens-Johnson syndrome) 0 (0) 0 (0) 0 (0) 0 (0)
Myocarditis and/or pericarditis 16 (412.6) 5 (128.9) 0 (0) 21 (541.5)
Postvaccinial encephalitis or encephalomyelitis 1 (25.8) 0 (0) 0 (0) 1 (25.8)
Pyogenic infection of vaccination site 0 (0) 0 (0) 0 (0) 0 (0)
NOTE. Data are no. of cases (rate per million vaccinated persons) and include those under investigation or completed as of
31 December 2003; nos. and classifications of adverse events are updated regularly in Morbidity and Mortality Weekly Report as
more information becomes available.
a
Events are classified as “suspected” if they have clinical features compatible with the diagnosis but either further investigation
is required or additional investigation of the case did not provide supporting evidence for the diagnosis and did not identify an
alternative diagnosis.
b
Events are classified as “probable” if possible alternative etiologies are investigated and supportive information is found.
c
The first 6 events listed are classified as “confirmed” if virologic test results are positive. The last 4 events are classified as
“confirmed” on the basis of diagnostic testing (e.g., histopathological testing); confirmation of events thought to be immunologically
mediated (i.e., erythema multiforme, myocarditis and/or pericarditis, postvaccinial encephalitis, or encephalomyelitis) does not
establish causality.
Table 3. Number of cases of other adverse events reported after
smallpox vaccination among civilians, by severity—United
States, 24 January–31 December 2003.
Other adverse events No.
Serious
a
97
Nonserious
b
712
NOTE. Cases are those under investigation or completed as of 31 De-
cember 2003; nos. and classifications of adverse events are updated regularly
in Morbidity and Mortality Weekly Report as more information becomes
available.
a
Includes events that result in hospitalization, permanent disability, life-
threatening illness, or death. These events are temporally associated with
vaccination but are not necessarily causally associated with vaccination.
b
Includes expected self-limited response to smallpox vaccination (e.g., fa-
tigue, headache, pruritis, local reaction at vaccination site, regional lymphade-
nopathy, lymphangitis, fever myalgia and chills, and nausea); additional events
are temporally associated with smallpox vaccination but are not necessarily
causally associated with vaccination.
with cardiac risk factors or known heart disease were deferred
from vaccination; since that time, no ischemic cardiac events
have been reported [36]. The ACIP-AFEB Smallpox Vaccine
Safety Working Group concluded that insufficient evidence was
available to reject or accept a causal relationship between small-
pox vaccination and ischemic heart disease events [19].
Between its inception on 28 January 2003 and 31 December
2003, the CDC’s Clinician Information Line received 3569
smallpox vaccine-related calls, of which 263 (7.4%) were re-
ferred to CDC staff. None of the patients discussed in these
calls required VIG or cidofovir to treat an adverse reaction to
smallpox vaccine. Only 1 civilian received VIG during this pe-
riod. She developed ocular vaccinia after contact with a military
vaccinee [45]. No cidofovir was released under an Investiga-
tional New Drug protocol.
It is important to compare these results from the DHHS
SPRP with those from the Department of Defense. As of 17
May 2007, the Department of Defense has reported vaccinating
11.2 million operational forces and health care workers [46].
Most adverse events reported occurred at rates below historical
rates. One hundred forty cases of myo/pericarditis developed
after smallpox vaccination. Another 16 cases of ischemic heart
disease (such as heart attacks, atherosclerosis, or angina) oc-
curred within 6 weeks after smallpox vaccination. This number
of ischemic heart disease cases is reported as similar to what
normally occurs among unvaccinated military personnel of
similar age. Among 27,700 smallpox-vaccinated health care
workers, there were no cases of transmission of vaccinia from
worker to patient. However, 61 cases (36 laboratory confirmed)
of contact transfer of vaccinia virus have occurred after vac-
cination of military personnel, principally to spouses and adult
intimate contacts. One case of eczema vaccinatum occurred,
but no cases of progressive vaccinia occurred [47]. The total
number of treatments with VIG given to military personnel or
their contacts has been 6: 1 patient with burns, 1 patient with
eczema vaccinatum, 1 contact transmission, 2 patients with
ocular vaccinia, and 1 unconfirmed contact transmission.
Forty-three patients with possible generalized vaccinia were re-
ported, all of whom were treated primarily as outpatients. Eight
deaths due to disease after vaccination have been reviewed; 1
after an acute lupus-like illness may have been caused by vac-
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US Smallpox Preparedness, 2003 CID 2008:46 (Suppl 3) S163
cination, on the basis of review by 2 independent panels of
civilian physicians. Additional information on this case is avail-
able at http://www.smallpox.mil/event/panelreport.asp. An-
other case involved the sudden death of a 26-year-old soldier
given smallpox and influenza vaccines 16 days earlier; in this
case, evidence of parvovirus B19 was found in his heart tissue.
The other deaths involved the following diagnoses (1 each,
except as noted): myocardial infarction, atherosclerotic coro-
nary vascular disease (2), pulmonary embolism, heat injury,
and benzodiazepine overdose. These deaths were judged to be
unrelated to vaccination, on the basis of individual factors such
as preexisting disease, incidence among unvaccinated people,
and lack of physical evidence to implicate a vaccine [46].
Detection and Reporting
The CDC clinical rash illness algorithm has been widely dis-
seminated and was included in the mailing to US physicians
in 2003. From January 2002 through 31 December 2003, the
CDC received 36 reports about patients suspected to have
smallpox. All of these were categorized as low [32] or mod-
erate [4] risk for smallpox. Twenty-four of the patients had
laboratory specimens collected and evaluated to assist in the
diagnosis, and the remainder had a clinical diagnosis only.
Varicella infection accounted for 16 (47%) of the cases, and
no one had smallpox [48]. A prospective, multicenter study
examined the performance of this algorithm for patients with
an acute, generalized vesicular or pustular rash (AGVPR) ad-
mitted to emergency departments and inpatient units of 12
acute-care hospitals in 6 states. Of 26,747 patients (3.5% of
all admissions) with rash-like conditions screened, 89 (1.2
patients per 10,000 admissions) had an AGVPR. Physicians
or study staff classified none of 73 enrolled patients as being
at high risk for smallpox; 72 (99%) were classified as being
at low risk, and 1 was classified as being at moderate risk.
The discharge diagnosis for 55 (75%) of these 73 participants
was varicella illness [21].
As of June 2007, 83 LRN laboratories can perform rapid
assays to support the rash illness testing algorithm for varicella,
vaccinia, and orthopoxvirus, which can be used in combination
to rule out variola (smallpox) virus infection. A number of
these same laboratories have the facilities and trained personnel
needed to perform variola virus–specific testing. All LRN ref-
erence laboratories (
1160) have the contact information needed
to quickly refer suspect specimens to the closest LRN laboratory
if their laboratory is unable to perform variola virus–specific
testing.
Protection of the Public from Smallpox
Enough smallpox vaccine is presently available to vaccinate the
entire US population. In addition to the Dryvax smallpox vac-
cine currently being used in both the military and civilian re-
sponder vaccination programs, 85 million doses of stored
vaccine were discovered by Aventis Pasteur. This latter vaccine
has also been shown to be immunogenic if diluted 1:5. Acam-
bis, under its contract with the US government, has delivered
192.5 million doses into the Strategic National Stockpile. The
vaccine was approved by the US Food and Drug Administration
on 31 August 2007 [25].
The CDC issued guidance in its smallpox response plan for
large-scale use of smallpox vaccine, with estimated resource
requirements to vaccinate 1 million people in 10 days [26]. An
October 2003 survey by the Association of State and Territorial
Health Officials indicated that 30 (60%) of 50 states responding
to the survey reported that they could vaccinate their popu-
lations against smallpox in 10 days [49]. Reporting in response
to the 2005 PHEP guidance for smallpox mass vaccination
capability has been incomplete, and further assessments are
under way. However, all states were funded and tasked to en-
hance mass vaccination capability in preparation for an influ-
enza pandemic [50]. In 2007, 80% of PHEP grantees reported
capability for mass vaccination in the setting of an influenza
pandemic, including adequate staffing, clinic locations, security,
vaccine storage, and monitoring of adverse events (CDC, un-
published data).
To address mass vaccination capability, grantees continue to
(1) train public health responders in smallpox vaccination roles,
(2) work with local health departments to ensure that all have
a smallpox response plan, (3) conduct exercises of state and
local smallpox response plans, and (4) improve smallpox vac-
cination electronic tracking systems. For example, the North
Carolina Division of Public Health has developed and pro-
moted an algorithm for smallpox mass vaccination clinics and
has established standing orders for smallpox vaccine for use in
local health departments. In addition, they have provided small-
pox vaccination refresher certification courses for medical vol-
unteers as needed, conducted training and drills with Public
Health Regional Surveillance Teams on rapid case-tracing
methodology using handheld PC technology, and maintained
up-to-date information on their cache of smallpox vaccine.
The New York City Department of Health and Mental Hy-
giene (NYC DOHMH) has maintained surveillance for sus-
pected smallpox cases by maintaining awareness among health
care providers who need to report patients with suspicious
rashes. In addition, it has developed protocols and provided
staff training and patient simulation drills at all hospital emer-
gency departments and primary care clinics, regarding appro-
priate triage of patients presenting with fever and rash symp-
toms. The NYC DOHMH has continued to conduct smallpox
vaccination technique training, and, as of June 2007, a total of
1021 individuals from hospitals, New York City agencies, and
the NYC DOHMH has received smallpox vaccination training.
At least 5 clinical staff members from 57 New York City hos-
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S164 CID 2008:46 (Suppl 3) Strikas et al.
pitals have received training. An additional 13 hospitals have
1–4 staff members trained. As of 31 October 2005,
1291,400
vaccine doses have been released to state health departments
for the civilian smallpox responder program. Much of the un-
used vaccine is in storage in the states and offers an additional
state preparedness measure, since the vaccine could be used to
begin vaccinations in response to a public health threat in-
volving smallpox until additional vaccine can be delivered from
the Strategic National Stockpile.
Collaboration with Partners
The CDC held regular conference calls with state and local
public health departments and health care provider partners to
review program implementation issues, pending policy changes,
and program progress. These occurred 3 times per week ini-
tially, then once per week through 2003 and as necessary.
Program Evaluation
The IOM Committee on Smallpox Vaccine Program Imple-
mentation reports addressed all facets of the vaccination pro-
gram, including vaccination screening materials and processes,
surveillance for adverse events, and information systems. The
active surveillance system for adverse events was implemented
following this committee’s recommendation [16]. The com-
mittee concluded that they were uncertain whether prepared-
ness for a smallpox outbreak had been enhanced [27]. Their
major concerns included the lack of a clear definition of pre-
paredness; an apparent primary focus on numbers of persons
vaccinated; poor communication to health care workers and
potential responders, as well as to the public, about the goals
of the program; and lack of information about how perfor-
mance indicators for states were being developed and imple-
mented [27].
The CDC, in addition to conducting program evaluation of
training, vaccination, adverse-events monitoring, and rash ill-
ness surveillance described above, conducted surveys of health
care workers, first responders, and program coordinators in
hospitals and local health departments. These surveys assessed
predictors of smallpox vaccination and nonvaccination. Health
departments had higher vaccination rates than hospitals, as did
facilities that invited
!10 employees to be vaccinated [29]. The
leading reason for vaccination was preparation for participation
in a smallpox response team [30]. Leading reasons for non-
vaccination were the belief that the risk of smallpox was not
high enough to warrant the risks of vaccination and concern
about vaccine adverse events [28, 30]. Hispanic, black, and
Asian individuals were significantly more likely than white in-
dividuals to be somewhat or very concerned about vaccine
adverse events [28].
DISCUSSION
We believe that the smallpox preparedness program with the
accomplishments outlined in this article has strengthened pre-
paredness and the public health infrastructure. The clinician
education component of the program reached out to all public
health departments and to all physicians and nurses in the
United States. The program also included the first effort at
large-scale organized civilian smallpox vaccination since 1971.
Although the number of persons vaccinated was small in com-
parison with the initial proposed target, the infrastructure de-
veloped to support the vaccination effort, such as plans, ed-
ucational materials, adverse-events surveillance systems, and
vaccination monitoring, was substantial. This infrastructure
laid the groundwork for subsequent preparedness activities,
such as those for pandemic influenza preparedness [51].
The small numbers of vaccinations in comparison with the
larger numbers projected by state and local health departments
in their initial plans likely reflect the voluntary nature of the
program, concerns about adverse events after vaccination, and,
possibly, the fact that standard provisions for compensation for
illness from those adverse events were not put in place until
after the program began [27]. Uncertainty about the likelihood
of a smallpox outbreak has also been cited as a reason for
limited vaccination uptake [28, 30]. Both the DHHS SPRP and
Department of Defense vaccination programs have been con-
ducted with rigorous safety measures and have resulted in rates
of adverse events similar to or lower than those historically
observed. In the DHHS SPRP, there were no reports of contact
transmission of vaccinia virus. However, both in this program
and in the military, myo/pericarditis was newly recognized as
an adverse event caused by the NYCBOH vaccinia vaccine
strain, with probable cases occurring at the rate of 116–541
cases/1,000,000 vaccinees.
The rates of successful vaccination (take rates) of 93%–93.5%
documented among civilian vaccinees were slightly lower than
that reported among military vaccinees, 95%. These differences
may have been attributable to very conservative take readings
in the civilian program. In August 2003, the CDC issued revised
guidance to improve take readings and assessment of immunity
after vaccination [52].
The relatively few inquiries to the CDC about febrile patients
with rash illnesses that might be smallpox suggested that wide-
spread dissemination of the rash illness algorithm has been
successful in assisting clinicians and public health staff in eval-
uating such patients at the local level. Alternatively, it may be
that physicians did not seriously consider smallpox in the dif-
ferential diagnosis of potentially compatible clinical illnesses.
In collaboration with external partners, the CDC established
performance indicators for the PHEP grantees in 2005, in-
cluding many relevant to smallpox preparedness [33]. These
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US Smallpox Preparedness, 2003 CID 2008:46 (Suppl 3) S165
indicators had 4 goals, corresponding to 4 phases of public
health emergencies: (1) pre-event planning and infrastructure
development, including the development of emergency plans,
formalizing of networks and mutual collaborativerelationships,
workforce development, and vulnerability assessment; (2) sys-
tems for early detection and reporting of illnesses related to
biological, chemical, and radiological agents, to recognize op-
portunities for early intervention; (3) response and contain-
ment, including the marshalling of resources and systems for
the escalation of public health capacity during an emergency;
and (4) recovery, including mental health services, remediation
of community risk, and incorporating lessons learned into
emergency plans and procedures. These indicators address 2 of
the concerns of the IOM committee, in that general prepar-
edness for urgent health threats has been addressed, beyond
the narrow focus of preparedness for a smallpox outbreak, and
that performance indicators are in place and utilized.
The purposes of the indicators were to (1) define and es-
tablish a fundamental level of preparedness against which
grantees can measure their progress; (2) help the CDC identify
technical assistance needs for the grantees; (3) serve as the
foundation for future evaluations of grantee preparedness
programs; (4) help the CDC develop milestones, targets, and
standards to be used in future CDC guidance; and (5) help
quantify the resources—human and fiscal—necessary to be
fully prepared at the local, state, and federal levels. To date,
assessments of implementation have been incomplete, but
more are under way.
These indicators were derived from the concentrated effort
in the smallpox program and facilitated the evolution of current
thinking about general preparedness for responding to all pub-
lic health emergencies attributed to all hazards. Many of the
specific program and policy efforts during the DHHS SPRP
initiative were successful in leading to an improved public
health response to emergencies such as the severe acute respi-
ratory syndrome and monkeypox outbreaks [27, 53]. The ca-
pacity to move vaccine into communities and build up the
infrastructure to conduct mass campaigns is a major strategy
for containment of the transmission of many biological threats
to health, including pandemic influenza [54]. By maintaining
and exercising emergency response plans for smallpox, the pub-
lic health community has improved the local capacity to re-
spond to infectious disease threats.
Acknowledgments
We thank Curtis Allen, Larry Anderson, John Becher, Stephen Bice, Erin
Burns, Denise Cardo, Christine Casey, Louisa Chapman, Robert Chen,
Marty Cicchinelli, Inger Damon, Scott Deitchman, La Mar Hasbrouck,
Wendy Heaps, James Heffelfinger, Sonja Hutchins, John Iskander, Denise
Jackson, Vickie Kipreos, Monina Klevens, Glen Koops, Andrew Kroger,
John Loonsk, Randy Louchart, Boris Lushniak, Mary Thomas Mackay,
Harold Margolis, Mehran Massoudi, Eric Mast, McCauley, Dennis Mc-
Dowell, Gina Mootrey, Juliette Morgan, Tim Morris, Rick Nelson, Glen
Nowak, Claudia Parvanta, Todd Piester, Linda Quick, Mary Rackson, Susan
Reef, Russell Regnery, Lance Rodewald, Von Roebuck, Martha Roper, Mi-
chael Sage, Charles Schable, Jane Seward, Kristine Sheedy, Diane Simpson,
Natalie Smith, Lynne Steele, David Swerdlow, Thomas Torok, Gary Ur-
quhart, Claudia Vellozzi, Charles Vitek, David Walker, Sabrina Walton,
Xiao-Jun Wen, Melinda Wharton, and Mark Winarsky; state adverse event
coordinators, state bioterrorism coordinators, and state immunization pro-
gram managers; and partners at the Association of State and Territorial
Health Officials, the National Association of County and City Health Of-
ficials, the Association of Public Health Laboratories, and the Council of
State and Territorial Epidemiologists.
Supplement sponsorship. This article was published as part of a sup-
plement entitled “Posteradication Vaccination against Smallpox,” spon-
sored 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 Pre-
vention and Emergency Response, CDC.
Potential conflicts of interest. All authors: no conflicts.
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by guest on December 7, 2015http://cid.oxfordjournals.org/Downloaded from
    • "In addition, their assumptions regarding the control strategies implemented (for instance, vaccination of susceptible individuals ) are not suitable in the case of smallpox. In particular, any vaccination campaign against smallpox should take place within 10 days because the incubation period of smallpox is usually 12–14 days (Strikas et al., 2008). Other weak aspects, besides the poor description of epidemiological characteristics, of these studies are the lack of adherence to smallpox control guidelines published by national or international organisations worldwide, the absence of robust control scenarios and their assessment and, finally, their limited applicability. "
    [Show abstract] [Hide abstract] ABSTRACT: Effective control of an infectious disease outbreak calls not only for a rapid response but also for the establishment of an emergency supply chain. During the control effort, huge amounts of medical supplies should be distributed from central warehouses to local points of dispensing. In this paper, the case where a large-scale deliberate smallpox attack occurs is considered. For changes in various baseline assumptions (possible delays in response actions, limited response capacities, etc.), the logistical requirements and subsequently the flow of materials for implementing a regional mass vaccination campaign are assessed. For capturing the disease's dynamics, a transmission mathematical model is used. In addition, a linear programming model for optimally distributing a predetermined vaccine stockpile to several affected subpopulations is also used. A numerical example is finally presented illustrating the methodology proposed. The proposed methodology could serve as a sound operational planning tool for health-care personnel as well as medical decision-makers.
    Full-text · Article · Jan 2016
    • "Nevertheless , the last decades have encountered a renewed scientific interest in the use of vaccinia virus. The resurgence of biomedical science employing vaccinia virus or related orthopoxviruses has taken two divergent routes: 1) as a biosecurity concern, identified by the National Institutes of Health/Department of Defense as Category A biosecurity concerns (NIAID, 2014), particularly after the events of September 11, 2001 (Strikas et al., 2008 ), and 2) as a research model because of the beneficial capabilities as recombinant vectors for disease prevention or therapeutics. These include applications for other human orthopoxvirus infections, various infectious diseases including hemorrhagic fever viruses and HIV, and cancer immunotherapy (Moss, 2011; Walsh & Dolin, 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: The vaccinia virus vaccine was effectively used during the 19th and 20th centuries to eradicate smallpox. Over the last decade, vaccinia virus and derived recombinant vectors have been increasingly used in biomedical research, in preclinical animal studies, as well as in clinical trials. While laboratories engineer and test orthopoxvirus vaccine vectors against infectious diseases and tumors, or develop countermeasures against inadvertent or bioterrorist-intended release of poxviruses, laboratory workers handling non-highly attenuated viruses are at risk of potential occupational exposure. This article describes an employee’s percutaneous exposure to a recombinant non-highly attenuated vaccinia virus with subsequent infection. Lessons learned from the incident investigation set the basis for improved work practices, refinements in the medical surveillance plan, and proactive measures to preclude recurrence.
    Article · Apr 2015
    • "of research related to OPV posed another concern and vaccination of laboratory workers is nowadays highly recommended in science centers of the USA and Europe [6] [7] [8]. "
    [Show abstract] [Hide abstract] ABSTRACT: Extensive use of Vaccinia virus (VACV) in research has led to associated accidental human exposure in laboratories worldwide. In spite of the social and economic relevance of Bovine Vaccinia outbreaks in Brazil, national data concerning laboratory workers handling these infectious agents are relatively scarce. Therefore, a serological survey was conducted in a Brazilian laboratory to evaluate staff exposure to orthopoxviruses (OPVs). Information concerning direct work with OPVs, vaccination status and laboratory accidents was collected and correlated to serology results. This study presents an opportunity for discussion of routine procedures involving OPVs in laboratories and their intrinsic risks. Aspects of the live attenuated smallpox vaccine are also discussed.
    Full-text · Article · Aug 2013
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