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Summary S mallpox was a devastating disease that decimated human popula- tions for centuries, and its eradication in 1980 was a monumental achievement for the global health community. Since then the remain- ing known stocks of its causative agent, variola virus, a member of the Orthopoxvirus genus, have been contained in two World Health Organiza- tion (WHO)–approved repositories—in the United States at the Centers for Disease Control and Prevention in Atlanta, Georgia; and in Russia at the Research Institute for Viral Preparations in Moscow, transferred in 1994 to the State Centre for Research of Virology and Biotechnology (VECTOR) in Novosibirsk. In 1999, the World Health Assembly (WHA) debated the issue of destroying these remaining stocks. Arguments were presented on the need to retain the live virus for use in additional important research, and the decision to destroy the virus was deferred until this research could be completed. In that same year, the Institute of Medicine (IOM) convened a consensus committee to explore scientific needs for the live virus. The IOM committee reached a number of conclusions, focused in particular on the need to develop medical countermeasures for smallpox and the role of the live virus in meeting this need (see Box S-1). Ten years have passed since that committee conducted its analysis, and the scientific, political, and regulatory environments have changed. Technological advances have led to breakthroughs in drug development and genomic analysis. The 2001 anthrax attacks in the United States dem- onstrated the feasibility of using a biological agent as a weapon of terror and the need for better detection and control methods for such threats. 

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 LIVE VARIOLA VIRUS BOX S-1 Conclusions from the 1999 Institute of Medicine Report 1. 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. 2. 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. 3. 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. 4. If further development of procedures for the environmental detection of variola virus or for diagnostic purposes were to be pursued, more extensive knowl- edge of the genome variability, predicted protein sequences, virion surface structure, and functionality of variola virus from widely dispersed geographic sources would be needed. 5. The existence of animal models would greatly assist the development and test- ing of antiviral agents and vaccines, as well as studies of variola pathogenesis. Such a program could be carried out only with live variola virus. 6. 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. 7. Variola virus proteins have potential as reagents in studies of human immu- nology. Live variola virus would be needed for this purpose only until sufficient variola isolates had been cloned and sequenced. SOURCE: IOM, 1999, pp. 82–85. As a result, licensing requirements for medical countermeasures for use in such circumstances have become more comprehensive. In this new climate, the IOM was once again tasked to consider scientific needs for live variola virus. With the body of knowledge that has accumulated in the past 10 years has come new insight into the fundamental biology of variola. In particular, understanding of the virus’s unique adaptation to its sole host—humans— has implications for learning more about the human host response to viral infection. A deeper understanding of the life cycle of variola and its ability to subvert immune defense has provided, and will continue to provide,

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 SUMMARY potential novel targets for antiviral and vaccine design. Genomic advances have led to the sequencing of at least 48 geographically diverse isolates of variola, as well as the theoretical potential for resynthesis of whole genomes, broadening the knowledge base on all orthopoxviruses and setting the stage for the possible development of surrogates for live variola virus in research. And finally, increased attention to the threat of bioweapons of terror has led to further refinement of the regulatory pathway to approved use and licensure of medical countermeasures. The current IOM committee was charged with revisiting the question of scientific needs for live variola virus; like its predecessor, this committee was not asked to consider the issue of retention versus destruction of the existing stocks of the virus. In addressing its charge (see Box S-2), the com- mittee made a concerted effort to perform a comprehensive assessment that encompassed research in both the United States and the rest of the world. BOX S-2 Charge to the Committee An ad hoc committee of the Institute of Medicine shall conduct a study on the continued use of live variola virus stocks for research and public health purposes. In follow-on to the IOM’s 1999 report, Assessment of Future Scientific Needs for Live Variola Virus, an IOM committee will perform a comprehensive evaluation of the research and development work recommended in that report and completed to date, and consider what unmet needs still exist that require the use of live variola virus. The conclusions and recommendations will inform policy discussions in the United States and within the world community regarding the continued need to retain the official stocks of live variola virus for research purposes, and would provide a major review of completed, ongoing and planned research activities that should be undertaken. The committee shall specifically consider and offer recommendations perti- nent to the utility of live variola virus in addressing potential unmet requirements including: • Advanced development through licensure and post-licensure of antivirals for use in treatment of variola virus infections. • Advanced development through licensure and post-licensure of new, safe and effective vaccine(s). • Development through licensure and post-licensure of less-reactogenic vaccines. • Development of approved protein-based diagnostics which can be used in field situations or diagnostics which have sources of error distinct from those of nucleic acid-based diagnostics. • Improved pathogenesis data to drive therapeutic discovery.

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 LIVE VARIOLA VIRUS It considered both practical and theoretical research while making no judg- ment on the infrastructure for or financial feasibility of either. In formulating its conclusions and recommendations, the committee drew a distinction between those uses for live variola virus which are important and essential and those which are useful but not essential. The committee considered the development of medical countermeasures against this deadly pathogen—including therapeutics, vaccines, and diagnostic tools—to be an important and essential need because of the potential for an accidental or deliberate release. CONCLUSIONS The committee evaluated the scientific need for live variola virus in four areas: development of therapeutics, development of vaccines, genomic analysis, and discovery research. The committee’s conclusions in each of these areas are presented below and summarized in Table S-1. Development of Therapeutics Currently, no therapeutic to treat smallpox infection exists. The previ- ous IOM committee determined that the development of therapeutics was the most immediate need requiring retention of the live variola virus stocks. Since then, a number of candidate drugs have been developed, one of which has been approved for compassionate use. Work still remains on the full development and licensure of these drugs, as well as on the discovery and development of other therapeutics with different targets and adverse effect profiles. In addition, research into other therapies, such as those that enhance or modulate immune response, could result in alternative or adjunctive treatments for smallpox. Finally, based on experience with other pathogens, the threat of drug resistance remains a real possibility, and drug TABLE S-1 Overview of Essential Versus Useful Scientific Needs for Live Variola Virus Need Requires Use of Live Virus Does Not Require Live Virus • Development of therapeutics • Development of first- and second- Essential and assessment of resistance generation vaccines that produce a take • Development of vaccines that • Development of methods for detection do not manifest a take and diagnosis • Functional genomics-based • Variola genome sequence analysis Useful research • Discovery research

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 SUMMARY designs and regimens that could reduce the emergence of resistance need to be investigated. The committee concludes that, for both scientific and regulatory reasons, the final developmental stages leading to licensure of small- pox therapeutics cannot occur without the use of live variola virus. Furthermore, although the regulatory environment may change, the scientific reasons will remain. Therapeutic agents need to be evaluated against a representative panel of variola strains to reduce the possibility that some strains might be naturally resistant. Development of Vaccines Thirty years after the eradication of smallpox, a majority of the world’s population is no longer immune to the disease. Despite the known effec- tiveness of currently licensed smallpox vaccines, the small risk of adverse events contraindicates their use in specific subpopulations, such as the immunocompromised. In response, research into less reactogenic and safer vaccines has been conducted, resulting in the licensure of a second- generation vaccinia vaccine. Research is also continuing on third-generation vaccines, which have the potential to protect vulnerable populations. How- ever, second-generation vaccines use the same strain of vaccinia virus as the first-generation vaccines; validation with live variola virus has not been necessary; and efficacy can be assessed through the manifestation of “take”—a cutaneous lesion that forms at the site of inoculation. Non- replicating and subunit third-generation vaccines do not present a take; therefore, an estimate of their potential efficacy requires vaccination and challenge with live variola virus in animal models, as well as testing of the immune responses of human vaccine recipients with methods that show activity against the live virus. The committee concludes that the current development and licen- sure pathway for first- and second-generation vaccinia vaccines that produce a “take” does not require use of the live variola virus. Use of the live virus will be necessary, however, for the develop- ment and licensure of any vaccine that does not manifest such a cutaneous lesion at the site of inoculation. Development of Methods for Detection and Diagnosis Contemporary nucleic acid-based methods for viral detection have been shown to identify variola virus genes directly, and multiplex polymerase chain reaction (PCR) assays differentiate variola from other poxviruses

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 LIVE VARIOLA VIRUS and unrelated viruses, such as varicella-zoster virus, that may cause similar clinical signs. Protein-based assays have not been pursued as extensively as PCR assays; however, these assays can be tested using variola proteins made in expression vectors. Limited information has been published about the performance of any methods for environmental sampling to detect variola. The primary barrier to development of these methods is a lack of develop- ment incentives and of a market for products that would allow rapid field detection and diagnosis. The committee concludes that live variola virus is not required for further development of detection and diagnostic methods. Virus mate- rials such as DNA and proteins would suffice for this purpose. genomic Analysis Progress in sequencing variola strains has revealed some of the genetic variability of variola—in particular, similarities and differences among genes in various regions—although much genetic information remains to be discovered. In addition, the biological consequences of sequence differences have not been well explored. Beyond the genome, analysis of functional pathways and expressed proteins would yield even deeper understanding. The committee concludes that live variola virus is not needed for variola genome sequence analysis, as long as specimens contain- ing viral DNA of adequate quantity and quality are available. Live variola virus would be needed for functional genomics-based experimental approaches. Discovery Research Variola virus can be useful for understanding human physiology and immunology because it has the capacity to overwhelm the host in a way that few viral pathogens do. Through studies in nonhuman primates, some progress has been made in understanding how variola virus modulates the functions of host cells for its benefit and how infection with the virus progresses in the host. While there is no immediate need for this type of research, it could result in knowledge that might one day lead to the dis- covery of new drugs or vaccines. In particular, better understanding of the genomic variability among variola strains, of the differences and similari- ties among orthopoxviruses, and of the host response to variola (and other orthopoxvirus) infection could elucidate how best to enhance the ability to counter a smallpox outbreak or infection.

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 SUMMARY The committee concludes that discovery research to gain greater understanding of human physiology and immunology, while not essential, would require use of the live variola virus and might ultimately support efforts to discover and evaluate therapeutics and vaccines. Further, research with live variola virus and research with variola proteins could lead to discoveries with broader implications for human health. RECOMMENDATIONS In the context of the above conclusions, the committee recognizes addi- tional research that would enhance understanding of variola virus. Gaps remain in knowledge about the virus and its interaction with its host that could be critical in identifying potential targets for drug and vaccine dis- covery. In particular, better understanding of the diversity and variability of variola strains would result in more refined diagnostics and more effec- tive therapeutics. Genome sequencing could close existing knowledge gaps by illuminating differences in molecular mechanisms of infection and response. The committee recommends that WHO authorize the complete genome sequencing of all remaining variola strains, with the aim of understanding the patterns and extent of sequence variation and the relationships of these patterns to disease severity. This activity would be carried out at CDC, and ideally at VECTOR as well. Similarly, a better understanding of variola pathogenesis would enhance the development of therapeutics and vaccines. Because smallpox is no longer naturally occurring, the closest approximation to human infection would involve a nonhuman primate. A more precise nonhuman primate model is essential for correct characterization of the efficacy of new therapeutics and vaccines. It is important to optimize approaches to infecting nonhuman primates so as to best recapitulate variola pathogenesis as it occurs in the human host, for example, by testing aerosol or intratracheal delivery as well as intravenous inoculation. The committee recommends that a comprehensive evaluation of the work done to date on the nonhuman primate model of variola pathogenesis be undertaken by CDC, in conjunction with an expert panel knowledgeable about poxviruses and animal models of viral infection. The objective would be to identify ways in which the predictive value of the model for testing therapeutics and vaccines might be improved.

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 LIVE VARIOLA VIRUS Finally, functional genomic tools, which are used to evaluate interac- tions between a replicating virus and the host cell, should be applied using a few representative variola strains in a number of representative differenti- ated human cell types. The purpose of this research would be to identify novel targets for therapeutics and to design third-generation vaccines. The committee recommends that WHO explore the use of func- tional genomics approaches to improve understanding of variola pathogenesis and advance the development of novel strategies for therapeutic intervention. REFERENCE IOM (Institute of Medicine). 1999. Assessment of future scientific needs for live variola virus. Washington, DC: National Academy Press.