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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. REFERENCES Aitichou, M., S. Javorschi, and M. S. Ibrahim. 2005. Two-color multiplex assay for the iden- tification of orthopox viruses with real-time LUX-PCR. Molecular & Cellular Probes 19(5):323–328. Artenstein, A. W. 2008. New generation smallpox vaccines: A review of preclinical and clinical data. Reviews in Medical Virology 18(4):217–231. Bolken, T. C., and D. E. Hruby. 2008. Discovery and development of antiviral drugs for bio- defense: Experience of a small biotechnology company. Antiviral Research 77(1):1–5. Breman, J. G., and D. A. Henderson. 2002. Diagnosis and management of smallpox. New England Journal of Medicine 346(17):1300–1308.

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