1
Introduction

Smallpox is a devastating disease with high case-fatality and transmission rates. It is caused by variola, a large and complex virus from the orthopoxvirus family, which infects only humans. A disease resembling smallpox has been described in many human populations over the last 3,000 years. In 1980, after millennia of suffering and death, variola virus was finally eradicated by a worldwide program of immunization with the related vaccinia virus.

The global eradication of this rampant and devastating disease, stands as the most successful campaign in medical history. Led by a major World Health Organization (WHO) program, it required the cooperation of governments, public health officials, physicians, and untold individuals in almost every country of the world. Once smallpox had been eradicated, all known materials containing variola virus, the responsible pathogen, were consolidated into two international repositories. The WHO Committee on Orthopoxvirus Infections subsequently voted to destroy all variola virus stocks, all stored clinical materials containing variola virus, and all intact variola virus DNA held in the international repositories in June 1999. Since this decision will be reconsidered in May 1999, the Institute of Medicine was asked to assess future scientific needs for live variola virus. This report is intended to serve health policymakers, medical and biological researchers, and the public as an assessment of the potential knowledge and capabilities that would be lost if live variola virus were no longer available for research purposes.



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--> 1 Introduction Smallpox is a devastating disease with high case-fatality and transmission rates. It is caused by variola, a large and complex virus from the orthopoxvirus family, which infects only humans. A disease resembling smallpox has been described in many human populations over the last 3,000 years. In 1980, after millennia of suffering and death, variola virus was finally eradicated by a worldwide program of immunization with the related vaccinia virus. The global eradication of this rampant and devastating disease, stands as the most successful campaign in medical history. Led by a major World Health Organization (WHO) program, it required the cooperation of governments, public health officials, physicians, and untold individuals in almost every country of the world. Once smallpox had been eradicated, all known materials containing variola virus, the responsible pathogen, were consolidated into two international repositories. The WHO Committee on Orthopoxvirus Infections subsequently voted to destroy all variola virus stocks, all stored clinical materials containing variola virus, and all intact variola virus DNA held in the international repositories in June 1999. Since this decision will be reconsidered in May 1999, the Institute of Medicine was asked to assess future scientific needs for live variola virus. This report is intended to serve health policymakers, medical and biological researchers, and the public as an assessment of the potential knowledge and capabilities that would be lost if live variola virus were no longer available for research purposes.

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--> Background Any assessment of the scientific needs for variola virus must include some grasp of the ravages of smallpox and the terrible suffering caused by the disease. The incubation period of smallpox, which can be as short as 7 days or as long as 19 days, is a period of intense activity in terms of viral replication and spread within the body despite the absence of clinical symptoms. The incubation period ends when the patient becomes feverish and ill. The onset of fever is sudden, the patient's temperature usually rising to between 38.5°C and 40.5°C. Other symptoms include severe headache and backache. Vomiting occurs in about half and diarrhea in about 10 percent of cases. The patient frequently exhibits general lethargy and malaise. By the second or third day the temperature falls, and the patient feels somewhat better. At this time the smallpox rash begins to appear. The lesions typically begin as minute red spots on the tongue and palate. Over a period of 24–48 hours, a macular rash appears on the face, then spreads to the trunk and extremities. The lesions progress over a 2-week period to vesicles, pustules, and crusts (scabs). A hemorrhagic and rapidly fatal form of the disease occurs in a minority of patients, Secondary infection of lesions can lead to osteomyelitis and septic arthritis, resulting in bone shortening, flail joints, and gross bone deformities. Scarred lesions or pockmarks remain with those who have survived the disease. Plate 1. Photos from the reverse of the WHO smallpox recognition card showing variola major pustules at their maximum size [1].

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--> Smallpox is readily transmitted, with each patient typically infecting three or four others who have been in close contact [1]. Besides the characteristic eruptions, some patients have generalized collapse with failure of multiple organs during the initial stages of fever. However, patients are not infectious until the focal eruptions appear in the throat and on the skin. A disease resembling smallpox was described as early as 1122 B.C. in China and is referred to in ancient Sanskrit texts of India. The Pharaoh Ramses V apparently died of smallpox in 1157 B.C. The disease spread from Japan and Korea and reached Europe in 710 A.D., and was transferred to America by Hernando Cortez in 1520; 3.5 million Aztecs died in the next 2 years. In cries of 18th-century Europe, smallpox reached plague proportions. Five reigning European monarchs died from smallpox during the 18th century [2, 3]. From the time it was first recognized until about the end of the 19th century, smallpox was regarded as a uniformly severe disease associated with a high case-fatality rate. However, starting about 1900 a less severe form of smallpox (variola minor) was recognized, exhibiting case-fatality rates of 1 percent or less in unvaccinated persons. During the first half of the 20th century, all outbreaks of smallpox in Asia and most of those in Africa were due to variola major, with case-fatality rates of 20 percent or more, while variola minor with case-fatality rates of I percent or less was endemic in some countries of Europe and North and South America. After the global smallpox eradication program was begun by WHO in 1959, more careful examination revealed some outbreaks in central and eastern Africa and in Indonesia with case-fatality rates of between 5 and 15 percent, but with clinical characteristics indistinguishable from those of variola major [1]. Although eradication of smallpox was established as a goal of WHO in 1959, preoccupation with malaria on the part of WHO and many member countries resulted in a relative lack of interest in smallpox until 1967, when the Intensified Smallpox Eradication Program was established. A strategic plan was developed, involving first mass vaccination, and then surveillance and containment of outbreaks [1]. The eradication of smallpox constituted, in principle, a straightforward disease control activity. An easily administered vaccine provided long-term protection. The presence of smallpox could be readily determined because of its distinctive rash. Only patients with a rash transmitted the infection to others, and then only to persons with whom they were in close contact. Because about 2 weeks elapsed before the infected person could transmit the disease to others, epidemics did not spread rapidly. Little more was required than to isolate the patient and vaccinate his or her close contacts. Nevertheless, global eradication of smallpox was a complex and difficult task that in the end required the cooperation of all countries. Famine, flood, epidemic cholera, and civil war all disrupted smallpox eradication efforts. Ultimately, a massive effort that effectively surveyed every household in countries where smallpox remained endemic was

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--> required to identify remaining cases and reduce the incidence of smallpox. The last naturally occurring case occurred on October 26, 1977, in Somalia, and in 1980 the World Health Assembly declared that smallpox had been eradicated [1]. Contemporary Context A smallpox outbreak today would present unique epidemiological and clinical features. Because smallpox vaccination ceased following eradication, an outbreak would occur in a population with little immunity, and therefore would differ substantially from other 20th-century outbreaks of the disease. An outbreak today in a highly mobile and susceptible population would likely spread widely before being recognized and before appropriate countermeasures could be put in place. In addition, existing smallpox vaccines are not safe for use by individuals with compromised immune systems. Such individuals include those with AIDS (which emerged after smallpox was eradicated), those taking drugs designed to suppress rejection of organ transplants, and those being treated for cancer, all of whose numbers have grown tremendously. Finally, aerosolized variola virus is considered a serious threat as a biological weapon. Testimony before a committee of the U.S. Congress, for example, alleged that scientists in the former Soviet Union experimented with variola virus as a biological weapon on a large scale [4]. The possibility of a smallpox outbreak poses particular ethical and policy dilemmas regarding the retention of live variola virus stocks. Whether continued existence of such stocks would produce human benefits and reduce potential harm depends, in part, on whether the known stocks in the two tightly controlled international repositories are in fact the only remaining samples. While there are many potential medical advances that could derive from studies using live variola virus, the risks of maintaining and working with the virus (ranging from release due to laboratory accidents to acquisition and use by terrorists) may outweigh the benefits. Moreover, assessment of the benefits and risks of destroying or maintaining virus stocks may depend on regional and cultural factors. For example, a country that has suffered recent outbreaks of smallpox may make a different assessment than a nation that has been relatively free of smallpox during this century. There are also ethical concerns about the intentional destruction of a species, although many would have no ethical qualms about eradicating such a virulent pathogen if doing so were in the best interest of mankind.

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--> Scope The committee was charged with assessing, from a careful and balanced perspective, the potential scientific and medical information that would be lost were live variola virus no longer available. The committee was not asked to make a recommendation about destruction or retention of smallpox stocks, and such a determination involves information beyond the purview of the committee. It is important to recognize that the findings and conclusions about future needs for live variola virus presented in this report fit into a larger, complex policy and ethical debate. The committee assembled to conduct this assessment has experience with smallpox cases and expertise in viral genetics, molecular biology, immunology, pathogenesis, epidemiology, ethics, antivirals, vaccines, and diagnosis. The committee includes members experienced with poxviruses and a range of other viruses; the chair and two other members observed or treated smallpox patients during field assignments in South Asia. The committee members were selected for their collective ability to provide a broad and balanced perspective on the issues to be addressed. The committee recognizes that articulation of future scientific needs for live variola virus implies that funds and other resources, including facilities with suitable biological containment provisions, would have to be available to pursue such research. The committee was not, however, able to conduct an assessment of the likelihood of such future support. For this reason, and other reasons discussed more fully in Chapter 12, the committee's findings and conclusions are expressed conditionally: If particular knowledge or capability were to be pursued, would the associated research require live variola virus? Moreover, although the committee did not directly address biological warfare as such, it did consider medical and scientific issues that would likely arise if this pathogen were used as a weapon. We believe the scientific questions likely to be directed to scientists with regard to use of the virus for biological warfare are included in the research-oriented issues encompassed by the committee's charge. Scientific Needs for Variola Virus Because scientific research on live variola virus must be conducted in maximum containment facilities, few such efforts have been undertaken in the United States in the past 20 years. There are very few suitable laboratories worldwide, and only two in the United States that would be available for this research. Since smallpox was eradicated, however, understanding of the molecular pathogenesis of viral infections has become considerably more sophisticated. The poxviruses constitute a large, distinctive family of DNA viruses that infect insects, birds, humans, and other mammals. Variola virus is the only

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--> uniquely human orthopoxvirus. The only other poxvirus specific to humans is molluscum contagiosum, which causes a rather benign self-limiting skin disease, usually found in children, and does not spread to other parts of the body. Molluscum contagiosum virus is a significant problem only for individuals whose immune systems are compromised. Thus, variola virus interacts with humans in a unique way that cannot be mimicked by other poxviruses. This uniqueness, along with the virus' complex and well-tuned adaptation to the human immune system, suggests a potential for contributing to mankind's knowledge of that system and its defense against infection. The vertebrate body is an excellent breeding ground for viruses and, by virtue of millions of years of co-evolution, provides conditions that promote virus replication, survival, and transmission. The immune system's response to infecting pathogens is based on a recognition of general molecular patterns in the pathogen or in infected cells. The study of host-virus interactions can illuminate this essential functioning of the immune system [5]. Few would argue the importance of developing new strategies for obtaining knowledge of the human immune system and of mechanisms for modulating human immune responses. More than 50 different viral gene products that modulate the immune system, many from unrelated viruses, have been identified, and it is certain that more will be found. While many of these modulators have similar immune system targets, they show little if any structural similarity [5]. Much remains to be learned from studies of virus-host interactions, and it is likely that those insights could be used to devise better therapies. And because variola virus is human-specific and exhibits unique interactions duplicated by no other known pathogen, studies of variola are likely to provide singular insights. The variola virus genome is large enough to contain approximately 200 genes, about half of which are devoted to essential functions needed for viral replication and half to interactions with the host. Little is known about how poxviruses enter cells or how cellular receptors interact with the virus. After entry into the cell, virus gene expression, necessary for replication of the viral DNA, begins. Although these processes have not been examined in specific studies using variola virus, they can confidently be predicted because of the extensive similarity between the variola and vaccinia viruses. The genomes of both variola and vaccinia have been sequenced and are 95 percent identical [6]. The genes involved in DNA replication, gene expression, and assembly of new virions are located mainly in the center of the DNA genome. Studies from many laboratories with different strains of poxviruses have shown that the genes involved in virus-host interactions are located near the ends [7, 8]. It is there that most of the differences among the genomes of the poxviruses are found—in those regions determining the interactions with the immune system of the host. Investigations of these interactions are likely to provide fundamental insights into human biology and the functioning of the human immune system. Studies of other viruses provide extensive support for this belief [5]. One notable exam-

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--> ple is the wholly unexpected finding that proteins within the endoplasmic reticulum can be targeted for destruction and transported into the cytoplasm by virus-encoded gene products [9]. Smallpox was eradicated before the development of many modem techniques of microbiology. As these tools emerged, they were generally applied to studies of pathogens posing current health threats. Partly as a result of the successful eradication of smallpox, therefore, modem analytical techniques have not been applied to enhance understanding of the pathogenesis of variola virus in the human host. Modern microbiology offers a variety of exploratory tools applicable at different scales, ranging from individual proteins to the entire genome. An assessment of future scientific needs for live variola virus must consider the knowledge that could potentially be derived from the application of these new capabilities, as well as the live variola virus. It also is necessary to consider knowledge that would be greatly facilitated by experiments with variola virus in cell culture, as well as the potential knowledge to be gained from experiments using live variola virus in animal model systems. And given the extensive similarity among the poxvirus genomes, one must consider the extent to which studies with live variola could be supplanted by studies of other poxviruses. Finally, while the eradication of smallpox was an unequaled public health success, the termination of widespread smallpox vaccination means that virtually the entire global population would now be susceptible should a smallpox outbreak occur. This vulnerability increases the importance of knowledge about variola virus, its pathogenesis, and antiviral strategies that can be employed against it. Organization of this Report Part II of this report reviews basic knowledge about the pathogen that causes smallpox (Chapter 2), the major features of the disease (Chapter 3), and its spread and strategies for controlling outbreaks (Chapter 4). This part concludes with a brief review of the handling of variola virus stocks following the eradication of smallpox and of research on the virus in the United States (Chapter 5). Part III reviews the scientific needs for variola virus in six areas: the development of antiviral agents (Chapter 6), the development of vaccines (Chapter 7), detection and diagnosis (Chapter 8), bioinformatics (Chapter 9), understanding of the biology of variola virus (Chapter 10), and research on the expressed protein products of variola (Chapter 11). Part IV presents a brief summary and the committee's overall findings and conclusions (Chapter 12). The report ends with a glossary of specialized terms used in the report and brief biographies of the committee members and staff.

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