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EXECUTIVE SUMMARY

The last natural case of smallpox occurred in Somalia in 1977, and the remaining research stocks of variola virus, its causative agent, have been restricted officially since 1983 to two containment sites in the United States and Russia. There persists, nonetheless, a concern that unsanctioned stocks of the virus might exist and that variola virus might someday be released in a terrorist act. Because of the lethality of the disease and its ease of transmission, the re-emergence of smallpox would create a major international health crisis.

For this reason, there is worldwide interest in establishing countermeasures to the variola virus, including the development of antiviral drugs. There are currently no FDA-approved antiviral drugs for the treatment or prevention of smallpox or other orthopoxvirus disease. In addition to providing therapy for infected people, the availability of anti-poxvirus therapeutics could decrease the risks associated with existing or future vaccines by providing a treatment for vaccine-associated complications. Moreover, the development of antivirals might deter rogue states and terrorists from releasing variola virus, because of the decreased impact of such an act. Finally, the same or related therapeutic approaches might be useful in treating other poxvirus diseases, such as monkeypox.

To explore ways to encourage the broader academic biology community and the commercial sector to participate in the process of discovering new smallpox antiviral drugs, The National Academies held a brainstorming workshop in Washington, D.C. on June 15-16, 2003. The 30 workshop participants in attendance included several pox virologists and numerous experts in cell biology, biochemistry, and structural biology, as well as representatives from government, the biotechnology industry, and pharmaceutical companies. Following the meeting, The National Academies established the Committee on Transforming Biological Information into New Therapies to prepare a report that describes important scientific questions for research and suggests ways to expedite the discovery of smallpox antiviral drugs. The report has two main parts: I. Scientific Opportunities, and II. Incentives, Logistics, and Policies.



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Discovery of Antivirals Against Smallpox EXECUTIVE SUMMARY The last natural case of smallpox occurred in Somalia in 1977, and the remaining research stocks of variola virus, its causative agent, have been restricted officially since 1983 to two containment sites in the United States and Russia. There persists, nonetheless, a concern that unsanctioned stocks of the virus might exist and that variola virus might someday be released in a terrorist act. Because of the lethality of the disease and its ease of transmission, the re-emergence of smallpox would create a major international health crisis. For this reason, there is worldwide interest in establishing countermeasures to the variola virus, including the development of antiviral drugs. There are currently no FDA-approved antiviral drugs for the treatment or prevention of smallpox or other orthopoxvirus disease. In addition to providing therapy for infected people, the availability of anti-poxvirus therapeutics could decrease the risks associated with existing or future vaccines by providing a treatment for vaccine-associated complications. Moreover, the development of antivirals might deter rogue states and terrorists from releasing variola virus, because of the decreased impact of such an act. Finally, the same or related therapeutic approaches might be useful in treating other poxvirus diseases, such as monkeypox. To explore ways to encourage the broader academic biology community and the commercial sector to participate in the process of discovering new smallpox antiviral drugs, The National Academies held a brainstorming workshop in Washington, D.C. on June 15-16, 2003. The 30 workshop participants in attendance included several pox virologists and numerous experts in cell biology, biochemistry, and structural biology, as well as representatives from government, the biotechnology industry, and pharmaceutical companies. Following the meeting, The National Academies established the Committee on Transforming Biological Information into New Therapies to prepare a report that describes important scientific questions for research and suggests ways to expedite the discovery of smallpox antiviral drugs. The report has two main parts: I. Scientific Opportunities, and II. Incentives, Logistics, and Policies.

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Discovery of Antivirals Against Smallpox In Part I of its report, the committee illustrates the complex structure, genome, and replication cycle of poxviruses (in particular of orthopoxviruses). Several enzymes made by orthopoxviruses are possible targets for antiviral drugs, among them several important in viral replication. The ideal viral enzyme target would be structurally and mechanistically peculiar to poxviruses. In this regard, the enzymes listed in Table 3 of the full report are promising candidates. Of those enzymes, the atomic structures of only two, the topoisomerase 1 and the poly(A) polymerase stimulatory subunit, have been thus far determined. The committee goes on to describe six subjects of poxvirus research particularly ripe for investigation. These include: the mechanism of entry into host cells; compartmentalization and intracellular organization of replication, transcription, and translation; viral manipulation of host-cell membrane traffic; viral subversion and exploitation of host-cell signaling pathways; viral exploitation of motor proteins for movement within a cell and for propulsion toward another cell; and, mechanisms of host-range restriction in vitro and in vivo. These subjects overlap, but the list gives some indication of the array of specialized biological expertise that could be brought to bear on poxvirus biology in order to expand our understanding of the infectious process and lead to novel antiviral strategies. Another research focus that could yield therapeutically important information is the study of the viral and cellular determinants of the host response. As is the case with many other viruses, little is known with certainty about the molecular details of protective immunity against variola viruses or other poxviruses. Consequently, research is needed on all aspects of the innate and acquired immune response. This research requires that animal models be further developed--another area in need of study. The study of the immune response to variola virus could also be enhanced by greater knowledge of the variola proteome. Because only the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia and the Vektor Institute in Novosibirsk, Russia are permitted to work with the virus and its complete genome, a coordinated international effort of those two centers with other groups working on smaller parts of the genome would be an important contribution to the field. In the committee’s view, the poxviruses offer a rich opportunity for investigation, and developing an antiviral drug against smallpox is an achievable goal. The challenge is to expedite that development by mobilizing scientific expertise in the academic and industrial research communities, and coordinating their efforts with the roles played by federal agencies involved in poxvirus research, including the National Institutes of Health (NIH), the US Army Medical Research Institute on Infectious Disease (USAMRIID), the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA)—the latter having the ultimate authority to approve a drug for use.

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Discovery of Antivirals Against Smallpox In the case of an antiviral against smallpox, which cannot be ethically tested in humans, facilitating a route to FDA approval means clarifying the requirements for demonstrating a drug's efficacy in animal models (the Animal Efficacy Rule). Part II of the report discusses the incentives, logistics, and polices related to strengthening the academic and industrial base of investigators working on poxviruses. The following recommendations from Part I and II of the report summarize our suggestions for engaging academe and industry in the drug discovery process, speeding the process of uncovering critical biological information about poxviruses, and smoothing the path of drug development and production. Recommendations 1. Pharmaceutical and biotechnology company engagement. a. We propose an immediate focus on currently identifiable therapeutic targets that are essential enzymes of poxviruses (see Table 3 in body of the report). To gain the participation of major companies, we suggest the following program: i. Direct contact between senior government officials and leaders of major pharmaceutical and biotechnology companies to initiate and encourage participation; ii. Targeted solicitation of proposals to carry out the screening of chemical libraries beginning with currently identifiable targets and elaboration of an early lead discovery phase, followed by federal support of preclinical development for those companies that present the most promising discovery-phase data; iii. Support of full clinical development of the best pre-clinical candidates through negotiated guarantees of purchase contingent on meeting predetermined product specifications; b. Successful engagement of industry through the process just outlined will require the following: i. High-level planning and oversight of the process, by the advisory panel proposed in Recommendation 6; ii. New procedures for rapid, insightful review, including participation of individuals with extensive experience in drug discovery and development; iii. Addressing the issue of indemnification, through legislation to limit liability of companies that develop smallpox antivirals under this program. iv. Consortium arrangements that permit companies to share information and thereby reduce risks. c. Therapeutics against smallpox will need to be licensed under the FDA’s Animal Efficacy Rule. To promote sound application of this rule, NIH, USAMRIID, the CDC and the scientific community at large should engage in research on appropriate animal models for poxvirus infections and on the kinds of studies needed to show efficacy of antiviral drugs. The FDA itself should also receive sufficient funding to supports its own

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Discovery of Antivirals Against Smallpox work on these issues, so that the criteria for licensing smallpox antivirals can be established as early as possible. 2. Focused, short-term basic research. Rapid progress toward deeper understanding of poxvirus biology will result from active collaborations between academic laboratories already engaged in poxvirus research and those with specific biologic or technologic expertise. NIH should support established investigators, nationally and internationally, to work with pox virologists on well defined, short-term projects, in which technology and personnel are exchanged, and also on longer-term, co-investigator initiated collaborations. The structural biology of poxvirus proteins, the cell biology of poxvirus infection, and the interaction between poxviruses and the host immune system are three areas in which such collaborations should be encouraged. Establishing the credibility of animal models for variola infection is also a high priority. 3. Recruiting and training a new cohort of young investigators. Long-term progress will require “new blood”, and research initiatives should be designed with this point in mind. a. NIH should attract new talent into poxvirology, by granting one- to two-year fellowships that permit students and postdoctoral scientists to move between laboratories with complementary expertise and by awarding additional institutional training grants in viral pathogenesis. b. NIH should support one or more laboratory courses in poxvirus research at sites such as Cold Spring Harbor, New York or Woods Hole, Massachusetts. c. A high-profile fellowship (NIH Fellow in Viral Pathogenesis) should be established to support the most outstanding students during postdoctoral studies and their first few years of faculty research. 4. Centralized resources. The NIH, with the collaboration of the CDC, should establish repositories and databanks. Large libraries of chemical compounds will be particularly useful for academic investigators who have the experience and facilities to undertake large-scale screening. NIH and the CDC should also create an accessible central mechanism for facilitating WHO and CDC approvals and for coordinating access to the use of national laboratory facilities. The Research Centers of Excellence being established by NIAID’s Biodefense Program can provide mechanisms for responding to some of these needs. 5. WHO restrictions. The NIH and the CDC should encourage WHO to re-evaluate its prohibition of certain manipulations of variola virus that would greatly facilitate novel screening methods—for example, the introduction of reporter genes into variola virus and the use of variola virus

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Discovery of Antivirals Against Smallpox genes in other vectors. Mechanisms should be developed for undertaking such studies in the CDC poxvirus research laboratories. The CDC should also explore with WHO whether other qualified laboratories under its control might be deemed part of its site and otherwise take measures to ensure the continuing, vigorous function of its poxvirus research effort. 6. Implementation. In view of the importance of including expert scientific guidance throughout the steps recommended in this report, a high-level advisory and oversight panel, analogous to the AIDS Vaccine Research Working Group, should be created immediately, reporting to the heads of the NIH, the CDC, and any other federal agencies involved in this effort. Membership on this committee should represent experience in drug discovery and development, poxvirus expertise at the highest level, and international efforts in smallpox antiviral research. Its first, urgent task will be to establish a specific timeline for drug discovery and development, including prioritization of currently feasible targets and approaches. A second important task will be to work out a blueprint for an effective international effort (see Recommendation 7). 7. International participation. The prospect of an intentional release of the variola virus is a global concern. Research on bioweapon countermeasures should therefore involve broad international collaborations. There should be no undue restrictions on the participation of non-US citizens in work at US laboratories, and grant and contract funding should extend, where appropriate for support of the best science, to laboratories outside the United States. Conclusion There is little available information about the likelihood that undeclared smallpox stocks exist, and thus it is difficult to assess the degree of risk of deliberate release. The consequences of such a release would be extremely grave, however, and the pursuit of safe therapeutics could mitigate the adverse effects of infection and would provide a strong deterrent to intentional release. Effective development of such deterrents will require a deeper understanding of the biology of poxviruses and of how they interact with their hosts. Scientists in academia, government, and the commercial sector have important roles to play in uncovering that understanding and translating it into new therapies.