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Smallpox and Smallpox Control in the Historical Context

On December 13, 2002, President George W. Bush announced that the United States would begin two programs of smallpox vaccination: a military program, and a voluntary civilian program. The president stated:

We know, however, that the smallpox virus still exists in laboratories, and we believe that regimes hostile to the United States may possess this dangerous virus. To protect our citizens in the aftermath of September the 11th, we are evaluating old threats in a new light. Our government has no information that a smallpox release is imminent. Yet it is prudent to prepare for the possibility that terrorists would kill indiscriminately—who kill indiscriminately would use diseases as a weapon (White House, 2002).

The president’s announcement revived a program of civilian vaccination that the United States discontinued in 1972, after the eradication of naturally occurring smallpox in the Western hemisphere (CDC, 2004).

Smallpox is a highly infectious disease caused by the large and complex variola virus (one of the largest viral genomes known), a member of the family Poxviridae and the genus Orthopoxvirus (WHO, 2001). Although the disease was eradicated over two decades ago and live samples remain in only two known locations, there are concerns that in the wake of the fall of the Soviet Union, samples of the smallpox virus may have fallen in the wrong hands, with the potential of being used as weapons of terror (Henderson et al., 1999). Smallpox virus can be transmitted from person to person, a characteristic that makes it relatively unique among bioterror



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The Smallpox Vaccination Program: Public Health in an Age of Terrorism 1 Smallpox and Smallpox Control in the Historical Context On December 13, 2002, President George W. Bush announced that the United States would begin two programs of smallpox vaccination: a military program, and a voluntary civilian program. The president stated: We know, however, that the smallpox virus still exists in laboratories, and we believe that regimes hostile to the United States may possess this dangerous virus. To protect our citizens in the aftermath of September the 11th, we are evaluating old threats in a new light. Our government has no information that a smallpox release is imminent. Yet it is prudent to prepare for the possibility that terrorists would kill indiscriminately—who kill indiscriminately would use diseases as a weapon (White House, 2002). The president’s announcement revived a program of civilian vaccination that the United States discontinued in 1972, after the eradication of naturally occurring smallpox in the Western hemisphere (CDC, 2004). Smallpox is a highly infectious disease caused by the large and complex variola virus (one of the largest viral genomes known), a member of the family Poxviridae and the genus Orthopoxvirus (WHO, 2001). Although the disease was eradicated over two decades ago and live samples remain in only two known locations, there are concerns that in the wake of the fall of the Soviet Union, samples of the smallpox virus may have fallen in the wrong hands, with the potential of being used as weapons of terror (Henderson et al., 1999). Smallpox virus can be transmitted from person to person, a characteristic that makes it relatively unique among bioterror

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism threats. Given these concerns and recent terror attacks, there has been a surge in interest in the smallpox virus and vaccine and in the history of the disease and its eradication. The potential use of smallpox virus in bioterrorism challenges public health and health care systems in many ways. Smallpox is a disease unfamiliar to most current health care providers, the population of the United States is relatively immunologically naïve since vaccination was discontinued more than thirty years ago, and much of the clinical and epidemiologic data on the virus and the vaccine is decades-old. A BRIEF HISTORY OF SMALLPOX The modern history of smallpox disease begins in the seventeenth century, with detailed records of cases and epidemics, as well as the earliest accounts of variolation, a precursor to contemporary immunization which involved inserting particles obtained from smallpox lesions under the skin or into the nostrils of a person who had never had smallpox. In the late eighteenth century, Edward Jenner discovered that dairy maids who had suffered and recovered from the less serious cowpox were not susceptible to smallpox infection, and he subsequently developed and refined the technique of removing material from a human cowpox lesion and transferring it to another person. Jenner vaccinated his own child as a test case, to give confidence in his technique (Fenner et al., 1988). Jenner published a monograph on the causes and effects of cowpox, in which he speculated about the safety and efficacy of vaccination, the former confirmed by the much milder resulting disease, smaller lesions, and fewer fatalities than variolation, and the latter proven by challenge inoculations with smallpox (Fenner et al., 1988; Radetsky, 1999). Using human sources of cowpox virus presented some technical and medical challenges. Therefore, in 1864, the use of calves as a continuous source of vaccine was expanded from its origins in Italy to the rest of Europe, and then the world (Fenner et al., 1988). Toward the end of the nineteenth century, vaccination became widespread across Europe and the world, and in the 1920s and 1930s, smallpox cases across Europe and North America dropped to a few dozen per year. The Second World War interrupted many public health efforts, including vaccination, and major epidemics again appeared in Asia and Africa. The World Health Organization (WHO) initiated a program of global smallpox eradication at the 11th World Health Assembly meeting in 1958, and revived it at the 18th World Health Assembly meeting in 1965. The Intensified Smallpox Eradication Program was established in 1967, and the invention of the bifurcated needle allowed for improved and efficient immunization against smallpox in the coordinated mass vaccination and surveillance and containment activities (for example, ring vacci-

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism nation, described in Chapter 2) that followed (IOM, 1999; Radetsky, 1999). The combined extraordinary efforts of health care and public health workers from across the world led to the eradication of smallpox, officially acknowledged by the WHO in 1980 (Barquet, 1997). The last endemic case of smallpox in the world occurred in 1977 in Somalia. Since that time, the virus has ceased to exist in the wild, with official repositories for live variola virus remaining only at two secure locations in Atlanta, Georgia, in the United States, and in Novosibirsk, Russia. Subsequently, the WHO Committee on Orthopoxvirus Infections planned a coordinated destruction of all existing stocks of smallpox virus, all stored clinical material containing virus, and all intact virus DNA in June 1999. However, by the late 1990s, the scientific and public health communities had found both scientific and civil defense reasons for retaining the stocks of live virus. In 1998, an Institute of Medicine committee was convened “to assess the scientific and medical information that might be lost were live variola virus no longer available for research purposes” (IOM, 1999). The Assessment of Future Scientific Needs for Variola Virus found that “much scientific information, particularly concerning the human immune system, could be learned through experimentation with live variola virus,” but “the most compelling need for long-term retention of live variola virus is for the development of antiviral agents or novel vaccines to protect against a reemergence of smallpox due to accidental or intentional release of variola virus” (IOM, 1999). After international dialogue on the fate of the known smallpox virus stocks, the WHO did not proceed with the planned destruction of the virus but resolved to temporarily retain variola stocks for future use in specific scientific endeavors and in research activities related to the preventing and responding to bioterrorism. Variola research accomplishments and outcomes would be reviewed periodically (WHO, 2002, 2003). UNDERSTANDING THE DISEASE The last endemic case of smallpox in the United States was in 1949, and vaccination of the general public in this country ended in 1972 (DHHS, 2003). The reintroduction of civilian smallpox vaccination in 2003 called on the public health and health care communities to recall and prepare to fight a mostly forgotten microbe. Variola virus is a specifically human pathogen, and there are no known animal reservoirs for the disease (Fenner et al., 1988). There are two types of the disease: variola major and variola minor. The latter has been found to cause a much milder form of the disease, with a fatality rate of 1 percent, compared to the 30 percent rate of variola major (Henderson et al., 1999). Five clinical types of variola major have been identified: the ordinary type,

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism the modified type, variola sine eruptione, flat type, and hemorrhagic type (Fenner et al., 1988). Before the eradication of the variola virus, ordinary type smallpox accounted for approximately 90 percent of cases in unvaccinated individuals and 70 percent in previously vaccinated individuals whose immunity had weakened over time (CDC, 2002b). The variola virus spreads relatively slowly (Fenner et al., 1988). Its transmission generally occurs through aerosols or respiratory-droplet nuclei that settle on the nasal or oropharyngeal mucosal membranes or on the alveoli of the lungs, and also (though less frequently) through infected bedding or clothing. The disease is less infectious than measles or influenza, requiring considerable exposure to an infected person, such as that found in the household or in the health care setting (Breman and Henderson, 2002; Henderson et al., 1999). Furthermore, a person infected with smallpox is not infectious during the incubation stage of the disease, which may range from 7 to 17 days (19 days has also been reported), with a mean of 10-12 days (Breman and Henderson, 2002; Fenner et al., 1988; Henderson et al., 1999; IOM, 1999). Although this stage is free of observable symptoms, it is a period of intense viral replication and spread to internal organs. The disease’s prodromal (initial symptoms) stage, which lasts 2 to 4 days, is characterized by the sudden onset of severe headache, backache, and fever, sometimes vomiting, and less frequently, diarrhea (Breman and Henderson, 2002; CDC, 2002a). Individuals in the prodromal stage may be contagious. The prodromal stage is followed by eruption into a rash with lesions on the skin and lesions of the oral mucosa, which shed large amounts of the virus. The early rash stage is followed by the progression of the lesions simultaneously from macules, to papules, which become vesicles, then pustules, and finally, crusts or scabs (CDC, 2002a). Individuals remain infectious, though less so, until the last scab has separated from the skin, 3 to 4 weeks after the onset of the rash (CDC, 2003e). Smallpox infection leads to a generally distinctive rash. However, smallpox has not been part of the diagnostic experience of most currently practicing health care providers, and smallpox disease could be confused with certain drug reactions and other diseases (such as chickenpox) or skin conditions. The smallpox rash may be distinguished by its centrifugal distribution—lesions are found in greater concentration at the extremities, on the face, hands, and feet, but as the disease progresses, they generally cover the entire body—and the fact that all pustules in a given area develop and progress at the same time rather than in crops (Fenner et al., 1988). Definitive diagnosis can be confirmed in the laboratory; the shape of the variola virus is different from that of varicella-zoster, the cause of chicken pox, and a polymerase-chain-reaction assay is the definitive method for identifying variola virus (Breman and Henderson, 2002).

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism Controlling and Eradicating Smallpox The smallpox virus, while a formidable historic threat to health, was eradicated as a result of characteristics of the smallpox virus, the disease, and the vaccine. These characteristics include: a highly effective and very stable vaccine, a noninfectious incubation stage and a disabling prodromal stage that limited the mobility of infected individuals, a distinctive rash that made smallpox cases readily identifiable and helped to facilitate limiting the spread of the disease, and the fact that humans are the only known reservoir for variola virus (IOM, 1999). At the time smallpox was endemic in much of the world, smallpox vaccination proved to be highly effective in preventing smallpox infection, and in the rare cases where symptoms of the disease occurred, they were milder, and the disease was far less likely to be fatal. In addition to vaccination’s prophylactic value, there is historic evidence that administering the vaccine within three days of a suspected exposure to smallpox virus can prevent the onset of the disease or significantly lessen its severity (Breman and Henderson, 2002; Lane and Goldstein, 2003). Although the smallpox vaccine is very effective, it was its use in conjunction with surveillance and containment that ultimately brought the disease under control and culminated in the eradication of the disease (Fenner et al., 1988). Vaccine Efficacy Experience documented during the global smallpox eradication campaign has shown that smallpox vaccine is highly effective, but its efficacy has not been measured with precision in controlled studies (CDC, 2003a). The Dryvax® vaccine (used in the vaccination campaign begun in 2003) was used successfully to eradicate smallpox in West and Central Africa and other areas during the global campaign. The scar showing previous vaccination signified that an individual was protected against smallpox, and in household contact studies, there was a 90 percent reduction in smallpox among contacts with a vaccine scar, compared to those without (CDC, 2003a). The need for vaccination disappeared along with the disease itself. By 2002, some Americans had not been vaccinated against smallpox in over three decades, and the remainder had never been vaccinated. It is unclear what level of vaccine-induced immunity remains in previously vaccinated Americans; past evidence on the efficacy and durability of protection provided by vaccination is limited (Henderson, 1988). According to one estimate, fewer than 20 percent of persons vaccinated before 1972 retain immunologic protection (CIDRAP and IDSA, 2004). Other twentieth-century data show that vaccinated individuals have a high level of protection for up

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism to 5 years, and some level of immunity, while diminishing over time, may persist for up to 10 years, and perhaps even longer (CDC, 2001; Cohen, 2001; WHO, 2001; Eichner, 2003). Current research is still in its early stages and takes place in the absence of actual smallpox disease, relying instead on three surrogate measures of immunity: neutralizing antibody, cellular immunity, and skin reactions. There is some evidence that significant immunity may be maintained beyond five to ten years after vaccination. Crotty and colleagues (2003) found that smallpox-vaccine–specific memory B cells may persist for longer than 50 years after immunization. Also, Hammarlund and colleagues (2003) found that more than 90 percent of volunteers vaccinated 25-75 years ago exhibited stable levels of vaccinia-specific antibody, and persisting, though diminishing antiviral T-cell response. There is little agreement whether these findings can be interpreted to mean that individuals vaccinated before 1972 would have any significant level of protection against smallpox (Roos, 2003). Additional research is needed to shed more light on this complex matter. Smallpox Vaccine and Vaccination Dryvax vaccine is a highly stable, live-virus vaccine containing the vaccinia virus, another orthopoxvirus. Vaccinia’s origins are unclear, as it differs from Jenner’s “variolae vaccinae,” but vaccinia has been widely studied, and much of what is known about orthopox viruses was first learned from this species (Fenner et al., 1988). Immunization with vaccinia-based vaccines involves inoculation of the skin using a bifurcated needle that holds a dose of the vaccine (a small drop) in its fork, and that is first used to release the liquid on the skin and then, held perpendicular to the skin, to rapidly and vigorously puncture the skin in an area of about 5 mm diameter, making a trace of blood appear (CDC, 2003c).1 Reaction to the vaccine, or “vaccine take,” can be evaluated based on the appearance of the skin lesion that develops after vaccination. There are two types of reactions: major and equivocal. A major reaction, proof of successful vaccination, consists of “a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which might be a scab or an ulcer” (CDC, 2003d). The size of lesions peaks between days 8 and 12, and the infection is sometimes accompanied by mild fever and malaise. Three weeks after vaccination, the scab falls off, leaving a small 1   CDC recommended 15 punctures for secondary vaccinees and 3 punctures for primary vaccinees (CDC, 2003c).

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism pitted scar (IOM, 1999). Any type of reaction that is not a major reaction is considered equivocal and indicates that revaccination is necessary. In 1999, the Working Group on Civilian Biodefense, an expert panel convened by the Center for Civilian Biodefense Studies at Johns Hopkins University (now the Center for Biosecurity at the University of Pittsburgh Medical Center) acknowledged that a deliberate release of smallpox virus was in the realm of possibility and that such an event would require widespread vaccination (Henderson et al., 1999). However, until the fall of 2001, smallpox vaccine had FDA approval only for use in a very small group of laboratory workers, and a limited supply of smallpox vaccine existed under the control of the Centers for Disease Control and Prevention (CDC), containing the New York City Board of Health (NYCBH) vaccinia virus strain grown on scarified calves, and produced by Wyeth laboratories under the trade name Dryvax (Henderson et al., 1999). The policy changes that revived civilian smallpox vaccination and vaccine research, development, and production in the United States are discussed in Chapter 2. The Vaccine Supplies Available in the United States At the time the military and civilian smallpox vaccination programs began in late 2002 and early 2003, respectively, the federal government had access to two stores of smallpox vaccine: 15 million doses of Dryvax in government storage since 1982, and 70-90 million doses of Aventis Pasteur vaccine available from the company (Lueck, 2002; Roos, 2002; CDC, 2003b). Both vaccines were derived from the NYCBH strain of vaccinia virus, but Dryax was stored frozen in dry form, while the Aventis vaccine was stored frozen as a liquid. A clinical trial of Dryvax conducted by the National Institute of Allergy and Infectious Disease (NIAID) showed that the vaccine was viable and could be diluted fivefold and even tenfold and retain its efficacy, as shown by high “take” rates (Fauci, 2003; Frey et al., 2002; NIH, 2002). A later dilution study of Aventis Pasteur (also derived from the NYCBH strain) vaccine showed similarly high vaccination success rates among the three dilution groups (Talbot et al., 2004). Diluting existing vaccine and efforts to develop new vaccines provided assurance that enough vaccine would soon be available to protect all Americans in case of an attack with smallpox virus. In 2002, changes to the diluent used for Dryvax required that the vaccine be relicensed by the Food and Drug Administration (FDA). On October 25, 2002, FDA approved a new 100-dose kit for Dryvax that included a new supply of diluent (to be mixed with the dried vaccine before it is administered) and bifurcated needles for vaccine administration (FDA, 2004). Each available lot would be approved separately. At the time civilian

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism vaccination began, 6.7 million doses of the undiluted Dryvax vaccine were approved for distribution as a licensed vaccine: 1 million doses for use in the military vaccination program, and the remaining 5.7 million doses for the Department of Health and Human Services to be used for smallpox preparedness vaccination activities. New vaccine then under production was not expected to be available as a licensed product until 2004, but in the event of a smallpox release, the government planned to use available vaccine under Investigational New Drug protocol for mass vaccination. In September 2000, CDC awarded Acambis Inc. a contract for a stockpile of 40 million doses of smallpox vaccine, and the contract was later increased to 54 million doses (DHHS, 2001). In November 2001, a second contract was awarded by DHHS to Acambis in partnership with Baxter Healthcare Corporation to produce an additional 155 million doses of vaccine for the U.S. government (DHHS, 2001). Although the Acambis vaccines, ACAM1000 and ACAM2000, are also derived from the NYCBH strain, they are grown in two types of cell culture rather than on the skin of a calf (Dryvax) (FDA, 2004). The Department of Defense is also supporting the clinical development of a cell culture vaccine by DynPort Corporation (PRNewswire, 2002). Vaccine Safety Vaccination is an effective public health tool in cases where the known risks of the vaccine are weighed against the known benefits of the vaccine and the risk of disease. Smallpox vaccination is known to cause generally mild symptoms and only rarely has resulted in more severe infection or death. Given the remarkable severity of smallpox disease, and the high effectiveness of the vaccine, the risk-benefit ratio was very clear while the disease was endemic. Historic objections to vaccination were made on moral or philosophical grounds and not on the basis of vaccine safety. It had always been known that smallpox vaccine was not innocuous, and as smallpox cases dropped to zero in industrialized nations, the adverse outcomes related to vaccination became more worrying. The case-fatality rate for smallpox vaccines in 1968 was one per one million primary vaccinations, and children had higher rates (number of events per million primary vaccinees) of severe vaccine-related complications when compared with primary vaccinees age 20 and older (Breman and Henderson, 2002). This was part of the reason the United States halted vaccination of the general public in 1972. At the end of the century, analysis of the risks posed by the vaccine could only be assessed in the context of a disease presenting no cases, leading to a significantly different risk-benefit balance. Vaccine safety findings must also be viewed in the context of differ-

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism ences between the experience of developing nations and that of developed nations. The reaction rate of vaccinees in developing countries may be confounded by malnutrition, co-infections, and other factors. Furthermore, experience with smallpox vaccine in the United States was largely in infants, and adequate surveillance among adults may have been lacking. Specific events, such as the New York smallpox outbreak in 1947 provide some evidence about vaccinating adults. Four main complications may be associated with vaccination; three complications are in the form of skin eruptions (eczema vaccinatum, progressive vaccinia, and generalized vaccinia) and a fourth, and the most serious, is postvaccinial encephalitis (CIDRAP and IDSA, 2004). Two studies conducted in 1968, a national study and a 10 state study of these complications, provide somewhat different estimates of vaccine adverse event rates, reflecting differences in methods and case definitions (for example, the case definition of generalized vaccinia). In the national survey, 14 million people were vaccinated, leading to a total of 9 deaths, 11 cases of progressive vaccinia, 74 cases of eczema vaccinatum, 143 cases of generalized vaccinia, and 16 cases of encephalitis (WHO, 2001). Based on such historic data, 1,000 per million primary vaccinees would experience severe adverse events, and 14 to 52 individuals per million primary vaccinees would experience life-threatening reactions to the vaccine (i.e., eczema vaccinatum, progressive vaccinia, and postvaccinal encephalitis), and 1 or 2 people would die (CDC, 2003g). Although recent smallpox vaccination has been associated with adverse events affecting the heart (discussed in Chapter 3), studies of death certificates of vaccine-associated deaths were conducted in 1959-1966 and in 1968 did not find deaths associated with cardiac complications (CDC, 2003f). The vaccine’s side effects are known to include malaise and fever that could interfere with a person’s ability to work, therefore raising questions about the need for time off, with implications for the workforce and for staff scheduling. In the dilution study of Aventis Pasteur vaccine, 25 percent of volunteers missed regularly scheduled duties due to vaccine-related symptoms (Talbot et al., 2004). Because of those safety concerns and the changed risk-benefit balance in the face of the limited number of cases of disease, the United States ceased general vaccination in 1972, several years before smallpox was officially declared eradicated. After the terrorist attacks of 2001, the safety of the vaccine came into focus as one of the most significant factors in decision-making (see below). Smallpox vaccination plans included vaccinia immune globulin (available in very limited quantity in 2002) and cidofovir as first- and second-line therapies, respectively, for treatment of serious vaccine-related complications (CIDRAP and IDSA, 2004; CDC, 2003h).

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism Surveillance and Containment Although vaccination was responsible for the dramatic drop in smallpox deaths during the first decades of the twentieth century, its success was at least in part due to the use of vaccination in conjunction with public health strategies of surveillance and containment. Even compared to mass vaccination, surveillance and containment are thought to have provided the more effective means of controlling the spread of smallpox disease (Fenner et al., 1988). Epidemiologic study of the spread of smallpox in Pakistan and Bangladesh in the 1960s demonstrated that the disease was not widely disseminated, but occurred in clusters, transmitted through close personal contact (Fenner et al., 1988). To cope most effectively with this type of disease distribution, smallpox eradication teams emphasized the identification of cases and the containment of outbreaks, a strategy termed surveillance and containment. A critical component of this strategy was the program known as ring vaccination. When a smallpox case was identified, all immediate contacts and their households were identified and vaccinated (ACIP, 2002). Any individuals who then developed a fever were isolated. In this way, an initial case was effectively surrounded with (or ringed by) vaccinated individuals, virtually stopping transmission to others in the population (CIDRAP and IDSA, 2004). Historic evidence also suggests that surveillance and containment worked well not only in populations with a high level of immunity, but also in areas where population immunity was relatively low (e.g., due to lack of vaccination) (IOM, 1999). Contemporary Circumstances A smallpox release in today’s world would present new clinical and epidemiologic challenges. For example, a significant proportion of the population in the United States (most individuals born after 1972) has never been vaccinated against smallpox. This means that there is little or no herd immunity, and previously identified patterns of disease spread may not apply (Gani and Leach, 2001). Furthermore, the current population includes more very elderly people and individuals with immune systems impaired due to chemotherapy, preparation for organ transplantation, or HIV infection. Vaccination strategies that were successful in the past might be less successful in the contemporary context. Ring vaccination that was an effective means of controlling disease transmission among developing country populations that may have been significantly less mobile may not work for today’s highly mobile populations. There are further concerns about ways in which the deliberate introduction of smallpox virus could differ from

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism naturally occurring smallpox (for example, multiple points of simultaneous introduction or repeated attacks) (Fauci, 2002). There has also been speculation about the existence of weaponized smallpox, a pathogen with some different characteristics from naturally-occurring Variola virus, including potentially less protection afforded by existing vaccine. Although epidemiologic data about smallpox disease is substantial, one of the difficulties of relying on historic data to assess smallpox infectivity is the fact that these data were collected in a context of significant population immunity. As smallpox vaccination was discontinued, successive generations of children were born and grew to adulthood without vaccination, gradually decreasing the immunity of the population. This means that whereas past findings showed that an initial case of smallpox could infect at most 5 others, a case caused by a contemporary deliberate release of the disease could potentially infect more, perhaps as many as 10 additional persons (WHO, 2001). Concluding Observations Smallpox disease has been unknown for over two decades. Routine immunization has been discontinued for many years, new generations of clinicians have little knowledge of the disease, and the United States population is characterized by significant numbers of people with weakened immune systems (e.g., due to cancer chemotherapy, HIV infection). As the nation’s public health and health care systems contemplated the possibility of a deliberate release of smallpox virus by terrorists, these factors were reasons for concern, subjects of research, and considerations for vaccination plans and other types of preparedness activities. REFERENCES ACIP (Advisory Committee on Immunization Practices). 2002. Record of the Meeting of the Advisory Committee on Immunization Practices, June 19-20, 2002. Centers for Disease Control and Prevention, National Immunization Program, Atlanta, GA. Barquet NDP. 1997. Smallpox: the triumph over the most terrible of the ministers of death. Annals of Internal Medicine 127:635-642. Breman JG, Henderson DA. 2002. Diagnosis and management of smallpox. New England Journal of Medicine 346(17):1300-1308. CDC (Centers for Disease Control and Prevention). 2001. Vaccinia (Smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. Morbidity and Mortality Weekly Report 50(RR-10):1-25. CDC. 2002a. Smallpox Fact Sheet: Smallpox Disease Overview. [Online] Available at http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp. Accessed September 13, 2004. CDC. 2002b. Smallpox Response Plan and Guidelines (Version 3.0). [Online] Available at http://www.bt.cdc.gov/agent/smallpox/response-plan/. Accessed January 9, 2003.

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The Smallpox Vaccination Program: Public Health in an Age of Terrorism CDC. 2003a. Course: “Smallpox: Disease, Prevention, and Intervention.” Module 5: Smallpox Vaccine Overview. CDC. 2003b. Questions and Answers: Smallpox Vaccination Program Implementation. [Online] Available at http://www.bt.cdc.gov/agent/smallpox/vaccination/vaccination-program-qa.asp. Accessed March 10, 2003. CDC. 2003c. Smallpox Fact Sheet—Information for Clinicians: Smallpox Vaccination Method. CDC. 2003d. Smallpox Vaccination Status and Procedures—Guidelines for Grantees Using Licensed Undiluted Wyeth Dryvax Vaccine. CDC. 2003e. Smallpox Response Plan and Guidelines. Executive Summary. (Updated). CDC. 2003f. Cardiac adverse events following smallpox vaccination—United States, 2003. Morbidity and Mortality Weekly Report 52(12):248-250. CDC. 2003g. Smallpox Fact Sheet: Side Effects of Smallpox Vaccination. [Online] Available at http://www.bt.cdc.gov/agent/smallpox/vaccination/reactions-vacc-public.asp. Accessed September 7, 2004. CDC. 2003h. Smallpox vaccination and adverse reactions: guidance for clinicians. Morbidity and Mortality Weekly Report Dispatch 52:1-29. CDC. 2004. Smallpox Fact Sheet: Vaccine Overview. [Online] Available at http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp. Accessed January 26, 2005. CIDRAP (Center for Infectious Disease Research and Policy) and IDSA (Infectious Disease Society of America). 2004. Smallpox: Current, Comprehensive Information on Pathogenesis, Microbiology, Epidemiology, Diagnosis, Treatment, and Prophylaxis. [Online] Available at http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/biofacts/smllpx-summary.html. Accessed August 2004. Cohen J. 2001. Smallpox vaccinations: how much protection remains? Science 294(5544):985. Crotty S, Felgner P, Davies H, Glidewell J, Villarreal L, Ahmed R. 2003. Cutting edge: long-term B cell memory in humans after smallpox vaccination. Journal of Immunology 171(10):4969-4973. DHHS (Department of Health and Human Services). 2001. News Release: HHS Awards $428 Million Contract to Produce Smallpox Vaccine. Acambis/Baxter Will Produce 155 million Doses by End of 2002. [Online] Available at http://www.hhs.gov/news/press/2001pres/20011128.html. Accessed January 26, 2005. DHHS. 2003. FAQs About Smallpox: The Disease and the Vaccine. [Online] Available at http://www.smallpox.gov/QuestionsAnswers.html. Accessed August 1, 2004. Eichner M. 2003. Analysis of historical data suggests long-lasting protective effects of smallpox vaccination. American Journal of Epidemiology 158:717-723. Fauci A. 2003. NIH’s Role in Implementing a Smallpox Vaccination Program. Testimony before the Senate Committee on Appropriations: Subcommittee on Labor, HHS, Education and Related Agencies, January 30, 2003. Fauci AS. 2002. Smallpox vaccination policy—the need for dialogue. New England Journal of Medicine 346(17):1319-1320. FDA (Food and Drug Administration). 2004. Smallpox Vaccines: Questions and Answers. [Online] Available at http://www.fda.gov/cber/vaccine/smallpox.htm#lic. Accessed November 14, 2004. Fenner F, Henderson D, Arita A, Jezek Z, Ladnyi I. 1988. Smallpox and Its Eradication. Geneva: World Health Organization. Frey SE, Couch RB, Tacket CO, Treanor JJ, Wolff M, Newman FK, Atmar RL, Edelman R, Nolan CM, Belshe RB. 2002. Clinical Responses to Undiluted and Diluted Smallpox Vaccine. New England Journal of Medicine 346(17):1265-1274. Gani R, Leach S. 2001. Transmission potential of smallpox in contemporary populations. Nature 414(6865):748-751.

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