S212 • CID 2008:46 (Suppl 3) • Thomas et al.
S U P P L E M E N T A R T I C L E
A Review of the Smallpox Vaccine Adverse Events
Active Surveillance System
Tracy N. Thomas,1,2Susan Reef,1Linda Neff,1Mercedes M. Sniadack,1,3and Gina T. Mootrey1
1National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia;
3Logistics Health, La Crosse, Wisconsin
2Constella Group, Durham, North Carolina; and
In response to concern about smallpox possibly being used as a biological weapon, the President of the United
States launched the National Smallpox Pre-Event Vaccination Program on 13 December 2002. Given safety
concerns, identifying potentially serious adverse events (SAEs) was an essential tool of the program.Tomonitor
for SAEs, both enhanced passive surveillance and active surveillance systems were used. The enhanced passive
system was built, in part, on the existing Vaccine Adverse Event Reporting System; the active system was
implemented 24 January 2003. During January 2003–May 2005, the active system detected only 1 SAE in
addition to those reported through the enhanced passive system. Furthermore, the active system was not
universally used by states. With the enhancements to passive surveillance, the performanceofenhancedpassive
surveillance was comparable to that of active surveillance. However, an active surveillance system may be
important when there is no enhanced passive surveillance system available.
The 11 September 2001 terrorist attacks in the United
the possible use of biological agents. The risk of small-
pox as a bioterrorism agent is unknown. Its potential
release presents unique clinical and epidemiological
challenges: the disease has been absent for 12 decades,
the discontinuation of routine immunizations has re-
sulted in a significant proportion of the US population
being without immunity, and deliberately introduced
smallpox may transmit differently than naturally oc-
curring smallpox . On 13 December 2002, President
George W. Bush announced the launching of the US
National Smallpox Pre-Event Vaccination Program in
an effort to improve readiness for and response to a
biological agent release.
The Centers for Disease Control and Prevention
(CDC), in collaboration with state and local health de-
The findings and conclusions in this report are those of the authors and do not
necessarily represent the views of the funding agency.
Reprints or correspondence: Dr. Susan Reef, Div. of Viral Diseases, Centers for
Disease Control and Prevention, 1600 Clifton Rd. NE, MS E-05, Atlanta, GA 30333
Clinical Infectious Diseases2008;46:S212–20
? 2008 by the Infectious Diseases Society of America. All rights reserved.
partments, developed and implemented the smallpox
vaccination program for civilian public health and
health care response team members. The known risks
of the vaccine, the potentially unknown risks of vaccine
administration to a population older than that previ-
ously vaccinated for smallpox in the United States, and
uncertainty regarding whether the population at risk
for developing an adverse event would have a profile
similar to those of groups identified in the past added
extra dimensions of urgency to monitoring the safety
of the smallpox vaccine compared with that of other
vaccines [2–9]. The existing mechanism for monitoring
the safety of vaccines is the Vaccine Adverse Event Re-
porting System (VAERS). VAERS, jointly administered
by the CDC and the US Food andDrugAdministration,
receives spontaneous reports of suspected vaccine ad-
verse events after administration of any US licensed
vaccine . To improve the monitoring of adverse
events after smallpox vaccination, the CDC formed a
Clinical Team and a Cardiac Team to improve case
investigation, thus enhancing the surveillance system.
This enhanced surveillance system provided additional
follow-up of potentially serious reports submitted
The CDC requested that the Institute of Medicine
(IOM), an independent body that advises the govern-
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Smallpox Active Surveillance • CID 2008:46 (Suppl 3) • S213
(PVS), and Clinical and Cardiac Team Databases (CCTDs). PVS is a Web-based vaccine administration support database that managed pre-event
smallpox vaccinations. CCTDs are smallpox databases developed through the enhanced surveillance of the Vaccine Adverse Event Reporting System
(VAERS). AE, adverse event; CDC, Centers for Disease Control and Prevention; FDA, US Food and Drug Administration.
Schematic flow of information among the Smallpox Vaccine Adverse Events Active Surveillance (SVAEAS), Pre-Event Vaccination System
ment on public health issues, provide guidance on imple-
menting the smallpox vaccination program. The IOM’s initial
report, issued 24 January 2003, addressed safety and the moni-
toring of vaccine adverse events . The IOM acknowledgedthe
CDC’s efforts to monitor serious adverse events (SAEs) after
vaccination through the existing passive surveillance system.
However, the IOM suggested that reliance on a passive system
may not capture all SAEs. The dependence on vaccinees and
health care providers to submit reports and the unknown ac-
the possibility of underestimating the incidence of SAEs .
The IOM recommended the addition of an active surveillance
system intended to confirm the response of every vaccinee to
the vaccine and to allow for the gathering of data, primarily on
rare SAEs and secondarily on common adverse events . On
was developed and implemented.
We used the CDC evaluation guidelines to assess SVAEAS
as a public health surveillance system . We compared the
frequency of SAEs detected by the active surveillance system
with that detected by the enhanced passive system. Here, we
describe SVAEAS, analyze its attributes, and discuss factorsthat
had an impact on the performance of the system.
and Clinical and Cardiac Team Databases (CCTDs) were used
to review the SVAEAS system. CDC guidelines for evaluating
public health surveillance systems were also used .
A survey administered to the state and
local health departments on 22 April 2003 collected infor-
mation on utilization of and experiences with the active sur-
veillance system. The survey was sent to 62 health depart-
ments, including those of the 50 states, the District of
Columbia, 3 cities (New York City, Chicago, and Los Angeles),
1 commonwealth (Puerto Rico), and 7 territories (Virgin Is-
lands, American Samoa, Micronesia, Guam, Marshall Islands,
Northern Mariana Islands, and Palau), henceforth referred to
PVS, VAERS, and CCTDs.
gram resources and databases that contributed to the overall
data collection of smallpox vaccinations included the PVS,
VAERS, and CCTDs (figure 1). The PVS database functioned
The network of smallpox pro-
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S220 • CID 2008:46 (Suppl 3) • Thomas et al.
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