Executive Summary

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. In 1980, after millennia of suffering and death, smallpox was formally declared eradicated as the result of an intense worldwide program of inoculation with vaccinia virus.

Because scientific research on live variola virus has been restricted to maximum containment facilities in two international repositories, few research efforts have been undertaken using the live virus since eradication. During that time, scientific knowledge about the molecular pathogenesis of viral infections has become considerably more sophisticated. Variola virus is the only uniquely human orthopoxvirus, and exhibits a complex and well-tuned adaptation to exploit and circumvent the human immune system. Research using variola therefore offers the potential to contribute to mankind's knowledge of the human body's uniquely evolved system of defense against infection.

Scope

In preparation for international deliberations concerning whether to destroy all known variola virus stocks, stored clinical materials containing live variola virus, and variola virus intact genome DNA held in the two international repositories, this committee was asked to assess future scientific needs for live variola virus. The committee's charge was restricted to that assessment. It did not include consideration of risks that may be associated with retention of the existing stocks, and no attempt was made to determine whether the scientific needs identified by the committee outweigh these risks. Furthermore, the



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--> Executive Summary 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. In 1980, after millennia of suffering and death, smallpox was formally declared eradicated as the result of an intense worldwide program of inoculation with vaccinia virus. Because scientific research on live variola virus has been restricted to maximum containment facilities in two international repositories, few research efforts have been undertaken using the live virus since eradication. During that time, scientific knowledge about the molecular pathogenesis of viral infections has become considerably more sophisticated. Variola virus is the only uniquely human orthopoxvirus, and exhibits a complex and well-tuned adaptation to exploit and circumvent the human immune system. Research using variola therefore offers the potential to contribute to mankind's knowledge of the human body's uniquely evolved system of defense against infection. Scope In preparation for international deliberations concerning whether to destroy all known variola virus stocks, stored clinical materials containing live variola virus, and variola virus intact genome DNA held in the two international repositories, this committee was asked to assess future scientific needs for live variola virus. The committee's charge was restricted to that assessment. It did not include consideration of risks that may be associated with retention of the existing stocks, and no attempt was made to determine whether the scientific needs identified by the committee outweigh these risks. Furthermore, the

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--> committee did not address the likelihood that the funds and other resources needed to pursue this research, including facilities with suitable biological containment provisions, would be available. It must also be recognized that predicting the future is impossible, and while the committee has done its best to provide an assessment of future scientific needs for live variola virus, the unfolding of actual needs and opportunities is likely to depend on the emergence of unforeseeable technical developments, experimental tools, and model systems. For these reasons, the committee expresses its findings and conclusions below in conditional form: If particular knowledge or capability were to be pursued, would the associated research require live variola virus? Scientific Needs for Live and Replication-Defective Variola Virus The committee first notes a need associated with the short-term use of variola virus stocks. Genomic sequencing and limited study of variola surface proteins derived from geographically dispersed specimens is an essential foundation for important future work. Such research could be carried out now, and could require a delay in the destruction of known stocks, but would not necessitate their indefinite retention. Although some insight into variation might be obtained by restriction fragment length polymorphism comparison of variola genes amplified by polymerase chain reaction, the precise nature of individual gene variation and resultant impact on the protein product(s) requires more detailed sequencing. Given that the current policy is to destroy the stocks of variola virus in 1999, this need is urgent. The committee identified six areas of research related to the potential scientific needs for live variola virus, replication-defective variola virus, and gene segments of variola virus. 1. The most compelling reason for long-term retention of live variola virus stocks is their essential role in the identification and development of antiviral agents for use in anticipation of a large outbreak of smallpox. It must be emphasized that if the search for antiviral agents with activity against live variola virus were to be continued, additional public resources would be needed. There is currently no effective antiviral for the treatment or prevention of variola. Only vaccination can reduce the severity of the disease, and only if

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--> administered within 4 days of exposure. The possibility of obtaining misleading results with surrogate viruses means that candidate antiviral agents must be tested against several clinical isolates of variola. Since smallpox has been eradicated, cell culture assays using live variola provide the only pre-outbreak opportunity to evaluate quantitatively the ability to block infection of (or replication within) human cells. 2. Adequate stocks of smallpox vaccine must be maintained if research is to be conducted on variola virus or if maintenance of a smallpox vaccination program is required. Live variola virus would be necessary if certain approaches to the development of novel types of smallpox vaccine were pursued. Supplies of vaccinia vaccine in the United States have dwindled and may be deteriorating. In addition, vaccinia vaccine, which is used for smallpox immunization, is a live virus and cannot be used safely with immunocompromised individuals. This latter concern suggests a need for novel vaccines. Vaccines derived from tissue culture could be compared with the standard vaccine by evaluation in human subjects and by laboratory assays. Live variola virus would be required only for testing of novel vaccine development strategies using materials other than live vaccinia virus. 3. If further development of procedures for the environmental detection of variola virus or for diagnostic purposes were to be pursued, more extensive knowledge of the genome variability, predicted protein sequences, virion surface structure, and functionality of variola virus from widely dispersed geographic sources would be needed. Evaluation of the specificity and sensitivity of detection methods for variola virus and other orthopoxviruses would require increased knowledge regarding the DNA sequence not only of variola virus from multiple geographic locations, but also of other orthopoxviruses, especially monkeypox. 4. The existence of animal models would greatly assist the development and testing of antiviral agents and vaccines, as well as studies of variola pathogenesis. Such a program could be carried out only with live variola virus. The current absence of suitable animal models for variola virus does not mean that such models cannot be developed in the future, given advances in reconstituting certain experimental animals with human genes. There is no way of anticipating, however, when such a model system might become available.

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--> 5. Live or replication-defective variola virus would be needed if studies of variola pathogenesis were to be undertaken to provide information about the response of the human immune system. The specific spatial and temporal patterns of variola virus gene expression must be deciphered in the context of infection at the level of cells, organs, and animal models. Studies of these phenomena could provide information on how the virus manipulates the human immune response in order to spread, on the mechanisms of cell death, and on other aspects of variola infection. 6. Variola virus proteins have potential as reagents in studies of human immunology. Live variola virus would be needed for this purpose only until sufficient variola isolates had been cloned and sequenced. Variola virus could serve as a resource for the discovery of human-specific reagents, such as cytokine inhibitors, anti-inflammatory proteins, and regulators of apoptosis. Overall Conclusions 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. In addition, much scientific information, particularly concerning the human immune system, could be learned through experimentation with live variola virus.