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10 Conclusions and Recommendations T hirty years have passed since WHO declared smallpox eradicated. Since then, programs for universal vaccination against smallpox have ceased worldwide, yielding a growing population of immuno- logically naïve individuals; U.S. and international regulatory requirements for licensure of antiviral drugs and vaccines have become better defined; and technological advances in molecular biology have generated sophisti- cated tools for research and development, many of which have been applied to improving knowledge about variola virus. Given that an accidental or deliberate release of variola virus could have devastating results worldwide, current global public health preparedness efforts address the potential threat of a smallpox outbreak. WHO considers any confirmed case of smallpox to be a public health emergency of international concern, and the U.S. government classifies this pathogen as a select agent. This committee was not asked to consider whether live variola virus stocks should be retained or destroyed or to address the potential for a smallpox outbreak. Nevertheless, these issues underlie global deliberations about smallpox, and the development and availability of adequate medical countermeasures against one of the most virulent and dangerous pathogens remains a strategic international goal. Variola is a unique and highly adapted pathogen that has established a close and obligate relationship with the human species, its only natural host. While not immediately essential, research that advances understand- ing of the biology of the human species and its responses to life-threatening microbial challenges could be highly beneficial. Such research could provide fundamental insights into human physiology and immunology that would 

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 LIVE VARIOLA VIRUS be relevant for biomedical research, leading to new therapies and preven- tive measures. Capabilities in DNA synthesis, sequence error correction, and assembly of custom-designed long DNA molecules have grown exponentially over the past decade. It is now technically feasible to chemically synthesize and assemble a complete variola genome in the laboratory, although the subse- quent steps necessary for production of intact, replication-competent virions are likely to be challenging. It is uncertain that variola virions generated from synthetic variola genomes would be virulent for humans, and if so to what degree. However, fully virulent synthetic variola virus is a distinct pos- sibility. This disconcerting reality should be acknowledged because it has major implications for the risks associated with unregulated possession and genetic manipulation of variola virus. These advances also offer potential benefits for the future development of variola countermeasures. In this contemporary context, some research with live variola virus remains essential for public health preparedness, some would be useful for this purpose, and some would have significant scientific merit as biomedical research without an immediate connection to preparedness. All research with live variola virus requires rigorous scientific evaluation before being undertaken, proper laboratory safeguards to protect those working with the virus and the public, and a significant investment in public health infrastructure and research capacity. Research to develop and improve diagnostics and preventive and therapeutic countermeasures against small- pox must also be undertaken with specific attention to regulatory concerns. While the scientific pathway for development of these diagnostics and countermeasures may offer a spectrum of options, from ideal to practical, the absence of human infection presents special challenges for regulatory approval. Regulatory agencies must evaluate new interventions that are of potential but unproven value for the prevention and treatment of smallpox and establish appropriate contingency protocols for their use in the event of an accidental or intentional release. These interventions may also warrant evaluation against nonvariola poxvirus infections, such as disseminated vaccinia or monkeypox disease, under conditions that make standard clini- cal trials difficult or impossible to accomplish. CONCLUSIONS This committee, like its predecessor in 1999, did not consider the risk assessment or financial resources required to undertake necessary or useful research, as these issues were beyond its scope. In addition, since decision making can be based only on information in hand, the committee recog- nizes that future technological advances or policy considerations based on assessment of the risk of an accidental or intentional release of variola

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 CONCLUSIONS AND RECOMMENDATIONS virus could alter the scientific landscape. With these caveats, the committee offers the following conclusions, which are based on its evaluation of cur- rent scientific capabilities and are meant to address the question of whether live variola virus would be needed should the recommended research be undertaken. Development of Therapeutics The discovery of antiviral drugs and alternative therapeutic agents effective against smallpox and their advanced development through licen- sure and postlicensure is vital. Such agents are needed for the medical man- agement of variola infection, a critical element in preparedness for a rapid response to an outbreak. Antiviral agents with good oral bioavailability that are effective for prophylaxis as well as treatment are important for containing the spread of smallpox in an immunologically naïve population. Having more than one licensed therapeutic utilizing multiple mechanisms of action is desirable because of the potential for the emergence of drug resistance and unanticipated adverse effects. Even if multiple licensed drugs were available, there would be gaps in information regarding their safety in special populations, such as children or pregnant women. If an appropri- ate clinical context is available, such as a monkeypox outbreak or cases of eczema vaccinatum, candidate drugs should be assessed in these groups. The development of licensed therapeutics is a long-term effort. Over the last decade, substantial progress has been made in the development of antiviral drugs with potential efficacy against smallpox using surrogate orthopoxviruses. Live variola virus has been used to measure the activity of lead candidate drugs in vitro and in nonhuman primate models. Additional studies are needed to develop useful drugs and immunobiologics through discovery efforts aimed at identifying variola-specific targets. This under- taking will require a better understanding of variola-specific proteins and their functions in cultured cells and of how these gene products contribute to the pathogenesis of smallpox disease in suitable animal models. 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.

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 LIVE VARIOLA VIRUS Development of Vaccines The availability and strategic deployment of an effective vaccine enabled the eradication of smallpox. Despite the occurrence of adverse reactions, enough people worldwide were vaccinated and developed immunity suffi- cient to interrupt transmission. Today, the majority of the world’s popula- tion is unvaccinated, placing them at risk of life-threatening disease in the case of a smallpox outbreak. Should an outbreak of smallpox occur, scaling up immunization programs with the traditional vaccines could be expected to be effective again. However, vaccine safety would be of particular con- cern for the substantial number of immunocompromised individuals and other vulnerable populations. Since the 1999 IOM report was issued, traditional vaccines such as Dryvax and the Lister/Elstree vaccine, which were manufactured by being grown in animals, have been augmented by the production and licensure of second-generation vaccines using modern tissue culture techniques. For first- and second-generation vaccines, successful vaccination is manifested by a “take”—formation of a lesion at the site of inoculation. This method cannot be used for evaluation of third-generation vaccines, and immuno- logic correlates of protection cannot be defined in the absence of circulating variola virus. Evidence that would support likely efficacy can be obtained only in animal model studies using variola virus. It should be emphasized that populations for whom the use of first- and second-generation vaccines would be contraindicated would need to rely on safer third-generation vac- cines in the event of an outbreak. Some consideration should be given to methods that could accelerate the pathway to licensure (or at least approved use) in these populations. 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 PCR assays differentiate variola from other poxviruses and unrelated viruses, such as varicella-zoster virus, that may cause similar clinical signs. Since tissues contain inhibitors that may reduce the sensitivity and specificity of nucleic acid-based methods, the development of these assays is enhanced by the

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 CONCLUSIONS AND RECOMMENDATIONS availability of stored clinical materials and specimens from nonhuman pri- mates infected with variola virus, but these materials and specimens are not essential. Whether these methods have been tested with a representative set of phylogenetically and genetically diverse smallpox isolates is an important question, but further testing, if needed, does not require the growth of the live virus from existing stocks. Protein-based assays have not been pursued as extensively as PCR methods; however, these methods 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, but again such assessments do not require live variola virus. Licensing of these methods can also proceed without experiments using live virus. The primary barrier to development of these methods is a lack of development incentives and of a market for products that would allow rapid field detec- tion and diagnosis. The committee concludes that live variola virus is not required for further development of detection and diagnostic methods. Virus materials such as DNA and proteins would suffice for this purpose. genomic Analysis The past decade has seen advances in genome sequencing and functional genomics capabilities. As a result, significant progress has been made in acquiring new variola genome sequence data and in furthering understand- ing of the evolution of variola. This work has revealed significant sequence variability among variola strains, some of which is likely to be associated with virulence. The observed genetic differences between variola and other orthopoxviruses must be responsible for the specificity of variola virus for the human host. Variola genomic sequence data may enhance efforts to develop therapeutics and vaccines that are predicted to be active against the breadth of available variola strains. Despite the progress in sequencing variola strains, much remains to be learned about the extent of variola’s genetic variability. In addition, the biological consequences of sequence dif- ferences for replication in particular cell types important to pathogenesis and to host range specificity and virulence are unknown. Today, sequenc- ing of the genomes of all remaining variola strains to completion would be relatively straightforward and inexpensive.

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 LIVE VARIOLA VIRUS 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. However, current methods for studying variola in vitro and in vivo are inadequate or have not been fully exploited for the expeditious discovery of novel interventions, both for smallpox and for other diseases, that might result from a better understanding of how this pathogen takes over human cells and subverts the immune response. Further research is needed to develop improved animal models that can recapitulate key aspects of the human disease and to understand virus–cell interactions in human target cells relevant to pathogenesis and immune response. 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 Gaps remain in understanding of variola virus and its interaction with its human host that could be critical in identifying potential targets for the discovery of therapeutics and vaccines. In particular, better understanding of the diversity and variability of variola strains would result in more effec- tive therapeutics and vaccines, as well as more refined diagnostics. Genome sequencing could close existing knowledge gaps by illuminating differences among strains in molecular mechanisms of infection and response.

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 CONCLUSIONS AND RECOMMENDATIONS 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. Finally, functional genomics 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.

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