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2
Overview of Smallpox and
Its Surveillance and Control
S
mallpox, the disease caused by the variola virus, is characterized by
fever; headache; back pain; vomiting; and, most distinctly, a papular,
and later vesicular, rash. Smallpox has a lengthy incubation period
that averages 12–14 days, during which time the infected person is non-
contagious. Within 2–3 days of the sudden onset of fever and other symp-
toms, skin lesions begin to appear on the face, hands, arms, and legs, and
eventually the trunk. Lesions erupt first on mucosal surfaces, including the
mouth and nasal cavities, where they ulcerate and shed the virus in respi-
ratory secretions (see Figure 2-1). Smallpox is most contagious during the
febrile period and early stages of the rash, but remains transmissible until
the resulting scabs have fallen off (Breman and Henderson, 2002).
Smallpox was originally considered a single disease. However, it was
subsequently subdivided into two clinical types, caused by closely related
variants of the variola virus: “classical” or variola major, and variola minor
or alastrim. The former had a higher case fatality rate of around 30 percent,
while the latter was less severe, with only about 1 percent of cases resulting
in death (Henderson and Fenner, 2001).
EPIDEMIOLOgy
Smallpox is uniquely a human disease, and variola virus has no other
known host or reservoir species. Historically, the virus was transmitted pri-
marily through aerosolization of respiratory secretions, as well as by direct
contact with skin lesions or exposure to contaminated bedding or clothing.
For variola major, transmission occurred mainly to close contacts because
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0
FIgURE 2-1 Clinical manifestations and pathogenesis of smallpox and the immune response. Reprinted with permission from
(Breman and Henderson, 2002) and (Strano, 1976). Copyright © 2002 Massachusetts Medical Society. All rights reserved. Other
images provided by WHO, NIH, the American Registry of Pathology.
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OVERVIEW OF SMALLPOX
the severity of the disease rendered most victims bed-ridden shortly after
the onset of illness. Variola minor, with its milder presentation, could be
transmitted much more widely because of patients’ mobility and remained
endemic in some parts of the world even after variola major had been
eliminated (Fenner et al., 1998).
Smallpox epidemics occurred in cycles that varied from annually to
every few years. The periodicity depended largely on the number of sus-
ceptible individuals in the community, which was heavily influenced by
the prevalence of prior infection and by vaccination levels (Fenner et al.,
1998). As smallpox vaccination coverage increased, the size and frequency
of outbreaks decreased (Fenner et al., 1998).
Smallpox was endemic in almost all parts of the world until the mid-
twentieth century. Vaccination campaigns had eliminated the disease from
nearly all of Europe, Australia, and New Zealand by the early 1950s and
from the American continents a decade later. The last case of smallpox in
the United States occurred in 1949. Global eradication efforts accelerated
in the mid-1960s, and areas of endemicity rapidly diminished in Asia and
Africa. As noted in Chapter 1, the last known naturally transmitted case
of smallpox occurred in 1977 in Somalia, while the last known case of the
disease was due to a laboratory-associated accident in England the follow-
ing year. WHO declared smallpox eradicated in May 1980. This achieve-
ment has not yet been repeated with any other human pathogen. Table 2-1
summarizes the timeline for smallpox eradication.
SURVEILLANCE AND CONTROL
The 2001 anthrax attacks in the United States reminded the world
that a biological agent could be used as a weapon of terror and made the
research agenda for high-consequence pathogens such as variola a national
priority (Lane et al., 2001). Even though naturally occurring smallpox has
been eradicated (Henderson, 1987), the risk of smallpox resulting from a
deliberate or accidental release of the agent remains (Mahalingam et al.,
2004).
Because of its characteristic rash, surveillance for smallpox was straight-
forward when natural disease was present in the world. Today, by contrast,
physicians lack familiarity with smallpox and may be unable to diagnose
it (Breman and Henderson, 2002; Woods et al., 2004). WHO considers a
single verified case of smallpox to be a public health emergency of interna-
tional concern, and under the 2005 revisions of the International Health
Regulations, reporting of such a case to WHO is obligatory. A diagnosis of
smallpox must be confirmed by laboratory testing. Whereas transmission
was historically limited primarily to close contacts, most people now alive
have no natural or vaccine-induced immunity to the disease, and society is
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LIVE VARIOLA VIRUS
TABLE 2-1 Timeline for Smallpox Eradication
Date Location Event
430 BC Survivors of smallpox called upon to care for the afflicted
(as survivors were immune)
Unknown Variolation, or inoculation, practiced in Africa, India, and
China
1721 Europe and Variolation method introduced
North America
1744 Japan Variolation method introduced
1798 England Edward Jenner first to discover a vaccine using cowpox
1909 Guinea First time an experimental dried vaccine was used
1949 Michigan State Freeze-drying invented
Laboratories
1949 United States Last case of smallpox
1950s Western Eradication program started in western hemisphere by
Hemisphere Pan American Sanitary Organization
1954 Lister Institute in Freeze-dried vaccine produced for commercial use
England
1958 USSR suggests a global eradication program to WHA
1966 WHA decides to intensify the eradication program
1967 Intensified plan for eradication is launched by WHO
1977 Somalia Last naturally occurring case in the world
1978 United Kingdom Last two cases in the world, laboratory acquired
1979 Global eradication certified by a group of scientists
1980 Global Eradication and previous certification endorsed by WHA
highly mobile; therefore, transmission dynamics today may be considerably
different from those seen in the past.
One key to implementing effective disease control strategies for a patho-
gen such as variola is prompt and accurate detection, either directly by
identifying the biological agent or indirectly by methods that demonstrate
the host’s response to the suspected pathogen (Fraser et al., 2004). Since
1999, technological advances have yielded laboratory methods that permit
the analysis of clinical specimens for orthopoxvirus nucleic acid (Loparev
et al., 2001; Nitsche et al., 2004; Olson et al., 2004; Wenli et al., 2004;
Aitichou et al., 2005; Shchelkunov et al., 2005; Fitzgibbon et al., 2006;
Li et al., 2007; Sulaiman et al., 2008) or orthopoxvirus-specific proteins
or antibodies (Karem et al., 2005; Huelseweh et al., 2006; Davies et al.,
2007). CDC has distributed validated variola clinical diagnostics through
the Laboratory Response Network (LRN), and assays for environmental
detection exist (CDC, 2008).
In response to the detection of variola, three options exist for control-
ling any resulting outbreak of disease: isolation and quarantine, vaccina-
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OVERVIEW OF SMALLPOX
tion, and administration of antiviral drugs. CDC has specific procedures in
place for containment of the disease should it be diagnosed, including use
of isolation and quarantine, identification and vaccination of close contacts,
and vaccination of those not directly exposed. Similar protocols exist else-
where in the world.
The last decade has seen considerable efforts to develop next-generation
smallpox vaccines, and progress has been made in the development and
licensure of live attenuated vaccinia-based vaccines utilizing modern pro-
duction techniques (Monath et al., 2004; Vollmar et al., 2006; Wiser et
al., 2007; Artenstein, 2008; Greenberg and Kennedy, 2008). In addition,
contemporary experience has been acquired with vaccinating large popu-
lations of individuals, including military personnel (CIDRAP, 2008) and
volunteer first responders and laboratory workers (Casey et al., 2005). This
experience has yielded new data on the safety profile and adverse effects
associated with vaccination in a largely immunologically naïve population
(Fulginiti et al., 2003; Grabenstein and Winkenwerder, 2003; Halsell et al.,
2003; Talbot et al., 2003; Greenberg et al., 2004; Wollenberg and Engler,
2004; Malone, 2007; Kroger et al., 2008; Reif et al., 2008), as well as on
the nature of the host’s response (Hammarlund et al., 2003a,b; Kennedy et
al., 2004; Kim et al., 2006, 2007; Kan et al., 2007; Gassmann et al., 2008;
Grosenbach et al., 2008). Progress has also been made in the development
of drugs for treatment and postexposure prophylaxis of smallpox (Yang et
al., 2005; Sliva and Schnierle, 2007; Bolken and Hruby, 2008; Nalca et al.,
2008; Tse-Dinh, 2008; Painter et al., 2008).
Despite the research that has been accomplished since 1999, capability
gaps for smallpox control remain. These include the development and licen-
sure of rapid field diagnostics that are specific for variola or for antibodies
induced by variola infection, further assessment and licensure of antivirals
for the treatment of smallpox, and a licensed smallpox vaccine with a more
favorable safety profile.
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