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Appendix C.2

Defense Threat Reduction Agency

The Defense Threat Reduction Agency (DTRA) began to expand bioengagement with Russian institutions in 1997. Initially, the focus was on eight pilot research projects, developed with the assistance of the U.S. National Academy of Sciences. These pilot projects were sited at the State Research Center for Virology and Biotechnology Vector (Koltsovo) and State Research Center for Applied Microbiology (Obolensk). A joint U.S.-Russian conference in Kirov during the development of the pilot projects broadened subsequent Russian participation in collaborative activities to include a number of other research institutions as well. At the outset, most of the Russian institutions were components of Biopreparat, a research-industrial complex, which was in the process of redirecting activities that had supported the Soviet-era biological defense program to civilian-oriented activities.

As of 2000, DTRA had committed more than $30 million to bilateral biology-related engagement activities. By 2011, the total commitment had increased to $71.2 million, although the annual commitments had steadily declined to about $1.5 million in 2011. Overall, about 9 percent of DTRA’s global bioengagement program has been focused on Russia despite the much larger percentages in the early years. The activities supported in Russia have been primarily (a) research projects to characterize especially dangerous pathogens and to prevent and develop therapies for infections (see below) and (b) upgrades of security and safety conditions at selected Russian institutions, which handle large quantities of dangerous pathogens. Such upgrades have included consolidation of pathogens in secure areas, construction of fences around facilities, improved security at entry portals into laboratory complexes, and safety precautions within laboratories. While DTRA was interested for a number of years in working with Russian insti-



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Appendix C.2 Defense Threat Reduction Agency The Defense Threat Reduction Agency (DTRA) began to expand bioengage- ment with Russian institutions in 1997. Initially, the focus was on eight pilot research projects, developed with the assistance of the U.S. National Academy of Sciences. These pilot projects were sited at the State Research Center for Virol- ogy and Biotechnology Vector (Koltsovo) and State Research Center for Applied Microbiology (Obolensk). A joint U.S.-Russian conference in Kirov during the development of the pilot projects broadened subsequent Russian participation in collaborative activities to include a number of other research institutions as well. At the outset, most of the Russian institutions were components of Biopreparat, a research-industrial complex, which was in the process of redirecting activities that had supported the Soviet-era biological defense program to civilian-oriented activities. As of 2000, DTRA had committed more than $30 million to bilateral biol- ogy-related engagement activities. By 2011, the total commitment had increased to $71.2 million, although the annual commitments had steadily declined to about $1.5 million in 2011. Overall, about 9 percent of DTRA’s global bioengage- ment program has been focused on Russia despite the much larger percentages in the early years. The activities supported in Russia have been primarily (a) research projects to characterize especially dangerous pathogens and to prevent and develop therapies for infections (see below) and (b) upgrades of security and safety conditions at selected Russian institutions, which handle large quantities of dangerous pathogens. Such upgrades have included consolidation of pathogens in secure areas, construction of fences around facilities, improved security at entry portals into laboratory complexes, and safety precautions within laboratories. While DTRA was interested for a number of years in working with Russian insti- 143

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144 APPENDIX C.2 tutions to upgrade disease surveillance systems in Russian (the TADR program), this activity was not undertaken due to difficulties in reaching agreement on the details of proposals for cooperation. By 2010, DTRA had shifted its emphasis to support of linkages of (a) U.S. universities and other institutions with (b) Russian universities and institutes. Recent projects have supported joint research to address topics such as the following: • Mapping of the microbial biosphere. • Relationship of plant pathogens and zoonotic pathogens. • Understanding of persistent relationships between humans and pathogens. • New applications of synthetic biology. • Host response to infectious diseases. Engagement over many years has benefited many scientists and institutions on both sides of the ocean. As to biosecurity/biosafety upgrades, visitors to Rus- sian institutions that have participated in cooperative efforts have almost always commented positively on the much improved approaches to ensuring the security and safety throughout the institutions. As to research projects that have been fully implemented, U.S. partners give high marks to their Russian colleagues who have served as the project managers in various universities and institutes. The American participants have been generally pleased with opportunities to benefit from the work of Russian researchers, who have quickly mastered new techniques and produced results of considerable interest to the international sci- entific community. DTRA has committed to continuing engagement with Russian organizations through pursuit of shared scientific interests, recognizing that key Russian minis- tries do not consider the Department of Defense a legitimate partner in address- ing civilian biological concerns. DTRA plans to support activities of other U.S. organizations that are more acceptable partners. DTRA considers the following reasons as important motivation for U.S.-Russian engagement: • Russia and U.S. cooperation in combating infectious diseases and poten- tial bioterrorist acts sends a message of warning to potential terrorist groups. • Transparency in research advances global progress toward dealing with infectious diseases and builds trust among countries. DTRA has articulated the following characteristics of its future approaches: • Engagement is to be based on cutting-edge research that responds to key scientific questions.

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APPENDIX C.2 145 • Partnerships will engage leading U.S. scientists who will attract broad interest in collaborations. • Science and scientific outcomes will drive bilateral dialogues and activities. • Partnerships are in and of themselves a threat-reduction metric since they build mutual confidence and serve as verification mechanisms. • New business models will be developed that are consistent with the needs of DTRA. DTRA, working with Russian partners, developed the following metrics in 2008, which at times can be helpful in assessing biosafety and biosecurity efforts: • Enhance capabilities to prevent theft. o Regulations o Biosafety guidelines o Facility plans o Biosafety and security standards o Biosafety and security upgrades at institutes o Biosecurity event notification o Biosafety event notification • Enhance capabilities to detect events o Sharing of data on especially dangerous pathogens o Reporting laboratory results to responsible officials o Providing human-related reports to WHO o Providing animal-related reports to OIE o Sharing of case data o Reporting epidemiological data o Reporting laboratory results o Personal health data reported to WHO o Animal diseases reported to OIE o Investigations of incidents involving especially dangerous pathogens o Appropriate sample collection o Capabilities to diagnose especially dangerous pathogens o characterization of plant pathogens Strain o Appropriate sample transportation • Sustainability o Testing of trainee test results • Miscellaneous o Credible research results o Contribution to efforts of international scientific community o Biosafety guidelines

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146 APPENDIX C.2 DTRA-SPONSORED RESEARCH PROJECTS IN RUSSIA Genome of Monkeypox Virus (ISTC #884-2p) State Research Center of Virol- ogy and Biotechnology Vector, Koltsovo Project Agreement Date: 10/8/99 Projected End Date: 10/8/01 Cost: $362,880 Key Findings: A long-range PCR approach was used to construct clones for the complete genomes of different strains of pox viruses, including variola, to do comparative sequencing that establishes relationships among various viral forms. The work established that monkeypox is less related to variola than are other pox viruses, suggesting that the origin of the monkeypox disease is not related to smallpox. Development of Liposomal Forms of IgAs for Prophylaxis and Treatment of Y. pestis (ISTC #1515) State Research Center for Highly Pure Biopreparations, St. Petersburg Project Agreement Date: 08/01/02 Projected End Date: 10/31/05 Budget: $657,251 Key Findings: Protection is provided to mice by aerosolized liposomal- delivered IgA antibodies directed towards the F1 antigen before challenge with 104 Y. pestis. No protection was observed if the aerosol was delivered after challenge. Design of Experimental Aerosol DNA-vaccine Preparation against Hanta- viral Infection (ISTC #1813) Research Center for Toxicology and Hygienic Regulation of Biopreparations, Serpukhov Project Agreement Date: 06/01/01 Projected End Date: 07/31/05 Budget: $599,000 Key Findings: Genes from small and medium segments of the hantaviral genome were cloned into plasmids. These plasmids were complexed with polyethylenimine (PEI) and delivered to mice in an aerosol form. Antibodies to the plasmid encoded antigens were measured. It was found that antibody

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APPENDIX C.2 147 production was best against antigens from the medium segment and that the efficiency depended upon the presence of immunomodulators. Genetic Identification of Crimean-Congo Hemorrhagic Fever (CCHF) Virus Isolates Circulating in Countries of the Region (ISTC #1291.2) State Research Center of Virology and Biotechnology Vector, Koltsovo Project Agreement Date: 08/01/00 Projected End Date: 10/31/05 Budget: $604,645 Key Findings: A unique variable section in the genome encoded by the L-segment of CCHF was explored as a possible marker for geographically distinct isolates of the virus. The variable region was studied in 16 different isolates. The variable segment was found to encode a region between the main structural sequences involving the RNA-dependent RNA polymerase. Studying the Role of Yersinia pestis Lipopolysaccharides Structural Organi- zation in the Development of Immune Preparations (ISTC#1197) Zelinsky Institute of Organic Chemistry, Moscow Project Agreement Date: 04/01/01 Projected End Date: 09/30/05 Budget: $943,408 Key Findings: This project has made major contributions to the understand- ing of the structures of lipopolysaccharide (LPS) structures and their bio- logical activities. The work was the first to describe temperature dependent structural alterations in LPS structure that correlate with the bacterium’s life in the insect vector and mammalian host. The investigators have developed a comprehensive data base on LPS and other glycostructure from the world- wide literature on this topic (http://www.glyco.ac.ru/bcsdb/start.shtml). Immunofiltration and Immunoenzyme Express Diagnostic Test Kits for Determination of Infectious Diseases (ISTC #1233.2) Research Center for Molecular Diagnostics and Therapy, Moscow Project Agreement Date: 03/01/00 Projected End Date: 08/31/05 Budget: $972,354

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148 APPENDIX C.2 Key Findings: Presentation was made of a simple, fast, sensitive, and universal immunoassay method for detection of a broad range of infectious diseases, including diseases caused by agents with defense applications. The basis of this novel concept was microfiltration, using micro-column flow immunoassays using analytical markers of different types and nature as reporters. In the course of this project, novel monoclonal antibodies against unique epitopes biological warfare agents were developed, as well as a sensi- tive method of detecting uniform magnetic microspheres. A Sampler for Detection and Express-Identification of Airborne Microorgan- isms and Implications for Counterterrorism (ISTC #1487) Research Center for Toxicology and Hygienic Regulation of Biopreparations, Serpukhov Project Agreement Date: 07/01/00 Projected End Date: 03/31/06 Budget: $680,000 Key Findings: A unique sampler capable of collection and preservation of the viability of biological organisms from the air was designed, fabricated, and tested. The collector is based on a cyclone collector technology applied to a portable, personalized collector. Comparative testing of these devices has been carried out in the United States, and the results have proven the superiority of the design. DTRA’s Visiting Scientist program has contributed significantly to the design and testing of these devices. Various detection technologies can also be adapted for use with the collectors. Search for Antivirals for Treating and Prevention of Orthopoxviral Infec- tions Including Smallpox (ISTC #1989) State Research Center of Virology and Biotechnology Vector, Koltsovo Project Agreement Date: 3/01/01 Project End Date: 3/13/03 Buidget: $1,433,374 (co-funded with Department of Health and Human Services) Key Findings: Utilization of the extensive chemistry capabilities in Russia and the coupling of this technology with the unique testing facilities at Vector have resulted in the identification of a collection of new compounds that show antiviral activities when tested against pox viruses. These compounds are being evaluated in the United States against variola viruses. A movie of an expedition into Northern Siberia to collect smallpox samples from the

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APPENDIX C.2 149 bodies of people suspected of death from smallpox was developed. Such expeditions have resulted in a number of samples that contained DNA, but no viable viruses. Combinatorial Antibody Libraries of Orthopoxviruses (ISTC #1638) State Research Center of Virology and Biotechnology Vector, Koltsovo Project Agreement Date: 9/05/01 Project End Date: 9/05/03 Budget: $217,296 (co-funded with Department of Health and Human Services) Key Findings: Project resulted in a new phage display combinatorial library derived from the lymphocytes of an individual vaccinated with vaccinia virus. The new library contained phage, which showed different reactivities to vaccinia, cowpox, and ectromelia viruses. These antibodies were thus species-specific. Neutralization tests were carried out with these antibodies, and they were shown to be positive. In addition, these antibodies are active in western blots allowing the identification of specific targets for these phage displayed humanized antibodies. Conservation of Genetic Material and Study of Genomic Structure of Dif- ferent Variola Virus Strains (ISTC #1987) State Research Center of Virology and Biotechnology Vector, Koltsovo Project Agreement Date: 3/01/01 Project End Date: 6/13/03 Cost: $1,336,913 (co-funded with Department of Health and Human Services)    Key Findings: This project has made major contributions to understanding the interrelationships of different pox viruses. The eradication of smallpox as a disease of concern has left the medical community with the question as to whether this virus could reemerge from another pox virus. Also, ques- tions about the recent appearance of monkey pox virus as a potential human disease has added to this concern. Comparative sequence studies performed by Vector and Centers for Disease Control scientists have shown that the large number of sequence differences between variola and monkey pox suggest that emergence of a smallpox-type disease from monkey pox is not likely. Variola is, in fact, more closely related to other pox viruses, such as camel pox.

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150 APPENDIX C.2 Magnetometric Immunosensor for Multi-Pathogen Continuous Monitoring (ISTC #2129) Research Center for Molecular Diagnostics and Therapy, Moscow, and Institute of Physics, Moscow Medical Academy Project Agreement Date: 08/01/05 Projected End Date: 07/31/2007 Budget: $496,906 Key Findings: This project developed a magnetometric immunosensor for detection of three pathogens and one toxin: B. anthracis, Y. pestis, F. tularen- sis and Clostridium botulinum toxin A. This detection system is portable and has increased sensitivity and speed over conventional detection techniques. The system has been field tested for environmental sampling. Upgrade of the Security and Safety Systems to Protect Biological Material at the All-Russian Research Institute of Phytopathology (ISTC #2685) All- Russia Scientific Research Institute for Phytopathology (VNIIF), Russian Acad- emy of Agricultural Sciences Project Agreement Date: 09/01/04 Projected End Date: 06/30/13 Budget: $2,929,404.91 Key Findings: This project has made major contributions in providing a safer and more secure working environment for VNIIF scientists, research- ers, and visitors, ensuring that phytopathogens and the specialists who work with them are properly protected, along with protection of the environment. The research aspect of this project has contributed to determinations of the pathogenic and toxic properties of collection strains of fungi responsible for barley and wheat Root Rot, Snow Mold, and Fusarium Head Blight, which could negatively impact Russia’s food and agriculture industries. NOTE: Other DOD components such as DARPA, have also supported bioen- gagement. Information provided by DTRA and ISTC, February 2012.