Research on Preparedness for Bioterrorism – Associated Events in Japan: Smallpox Vaccine Preparedness
*Bio-preparedness Research Lab, Department of Tropical Medicine and Parasitology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
**Global Security Research Institute, Keio University, 2-15-45 Mita, Minato-ku, Tokyo 108-8345, Japan
The 2001 anthrax attack in the United States made the deliberate release of biological agents a real issue and forced many countries to improve their bioterrorism preparedness. Smallpox is a threat that requires international preparedness because it spreads from human to human and would be expected to have a high level of lethality. In 2001, Japan restarted the production and stockpiling of a medical countermeasure, the smallpox vaccine LC16m8, which is a cell-cultured, live attenuated smallpox vaccine that was developed in the 1970s in Japan. The Smallpox Vaccine Research Group has continuously worked to characterize LC16m8 genetically, demonstrate the efficacy and safety of the LC16m8 vaccine, reduce the cost of stockpiling through shelf-life extension via the presentation of evidence of its stability in long-term storage, and maintain the quality of the stockpiled vaccine that is available in case of emergency. Maintaining the stockpile and production capacity of “orphan” medical countermeasures has contributed to national security and also to global health. This paper reviews smallpox vaccine preparedness and the surrounding policy issues in Japan as a typical and classic case of biopreparedness research activities and discusses achievements, problems, and future directions.
-  M. Wheelis, L. Rozsa, and M. Dando, “Historical Context and Overview” in: Deadly Cultures, L. Rozsa, M. Wheelis, M. Dando (Eds.), Harvard University Press, Cambridge, pp. 1-8, 2006.
-  J. A. Jernigan, D. S. Stephens et al., “Bioterrorism-Related Inhalational Anthrax: the First 10 cases Reported in the United States,” Emerg. Infect. Dis., Vol.7, pp. 933-944. 2001.
-  World Health Organization, “Declaration of Global Eradication of Smallpox,” Weekly Epidemiological Record, Vol.55, p. 148, 1980.
-  D. A. Henderson, F. Fenner et al., “Smallpox and its Eradication,” World Health Organization, Geneva, 1988.
-  K. Alibek, “Biohazard,” Random House, New York, 1999.
-  D. A. Henderson, T. V. Inglesby et al. for the Working Group on Civilian Biodefense, “Smallpox as a Biological Weapon: Medical and Public Health Management,” JAMA, Vol.281, pp. 2127-2137, 1999.
-  B. Gellman, “4 Nations Thought To Possess Smallpox,” Washington Post, A01, 2002.
available at http://www.washingtonpost.com/ac2/wp-dyn/A5113-2002Nov4 (accessed on May 29, 2009)
-  World Health Organization, “Consensus Document on the Epidemiology of Severe Acute Respiratory Syndrome (SARS),” Rep. WHO/CDS/CSR/GAR/2003.11. 2003.
-  C. W. Dixon, “Smallpox,” J&A Churchill Ltd., London, England, 1962.
-  I. Arita (Ed.), “Research on Stockpile and Usage of Smallpox Vaccine,” Final Report of the Special Research by the Ministry of Health Labour and Welfare, 2005 (in Japanese).
-  B. T. Smith, T. V. Inglesby et al., “Navigating the Storm: Report and Recommendations from the Atlantic Storm Exercise,” Biosecur. Bioterror, Vol.3, pp. 256-267, 2005.
-  I. Arita, “Smallpox Vaccine and its Stockpile in 2005,” Lancet Inf. Dis., Vol.5, pp. 647-652, 2005.
-  World Health Organization, “Smallpox Global Smallpox Vaccine Reserve,” Fifty-eigth world assembly Provisional agenda item 13.6.2005.
-  J. Hart, “The Soviet Biological Weapons Program” in: Deadly Cultures, M. Wheelis, L. Rozsa, M. Dando (Eds.), Harvard University Press, Cambridge, pp. 132-156, 2006.
-  Johns Hopkins Center for Civilian Biodefense, Center for Strategic and International Studies, ANSER, Memorial Institute for the Prevention of Terrorism, “DARK WINTER Bioterrorism Exercise,” June 22-23, 2001.
Available at www.homelandsecurity.org/darkwinter/docs/DARK_WINTER.pdf (accessed on May 29, 2009).
-  F. A. Murphy and B. I. Osburn, “Adventitious Agents and Smallpox Vaccine in Strategic National Stockpile,” Emerg. Infect. Dis., Vol.11, pp. 1086-1089, 2005.
-  A. Baciu, A. P. Anason, K. Stratton, B. Strom (Eds.), “The Smallpox Vaccination Program Public Health in an Age of Terrorism,” The National Academic Press, Washington D.C., 2005.
-  S. Hashizume, H. Yoshizawa et al., “Properties of Attenuated Mutant of Vaccinia Virus, LC16m8, Derived from Lister Strain,” in: Vaccinia Virus as Vectors for Vaccine Antigens, Quinnan GV (Ed.), Elsevier Science Publishing Co Inc., New York, 1985.
-  M. Yamaguchi, M. Kimura, and M. Hirayama, “Vaccination Research Groups Research Report: Ministry of Health and Welfare Special Research: Postvaccination Side Effects and Research Regarding Treatment of Complications,” Rinsho to Uirusu [Clin. Virus], Vol.3, pp. 269-279, 1975 (in Japanese).
-  J. Kenner, F. Cameron et al., “LC16m8: an Attenuated Smallpox Vaccine,” Vaccine, Vol.24, pp. 7009-7022, 2006.
-  “Terrrorism preparedness,” The Yomiuri Shinbun, Osaka, p. 38, October 16th, 2001 (in Japanese).
-  “50 Bil. Yen Budgeted to Fight Terrorism,” The Daily Yomiuri, Tokyo, section National-1, p. 2, November 10th, 2001.
-  Department of Health Labour and Welfare Public Affairs Office, “Interview Briefing of the Minister of Health, Labour, and Welfare after the Cabinet Meeting,” April 5th, 2004 (in Japanese).
-  Blood and Blood Products Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, “Secure Supply of Smallpox Vaccine and Anti-toxins,” July 11th, 2002.
Available at http://www.mhlw.go.jp/houdou/2002/07/h0711-2.html (in Japanese).
-  “The Bioterrorism Preparedness and Smallpox Vaccine,” The Sankei Shinbun, Tokyo, pp.1, March 1st, 2003 (in Japanese).
-  T. Saito, T. Fujii et al., “Clinical and Immunological Response to Attenuated Tissue-Cultured Smallpox Vaccine LC16m8,” JAMA, 301, pp. 1025-1033, 2009.
-  “Govt Urged to Stockpile Smallpox Vaccine,” The Daily Yomiuri, July 12th, 2005.
Avaliable at http://www.yomiuri.co.jp/dy/national/20050712TDY01004.htm (accessed on July 31st, 2005).
-  World Health Organization Advisory Committee on Variola Virus Research, “Report of the Ninth Meeting,” Geneva, Switzerland, 29-30, November 2007, WHO/HSE/EPR/2008.1.
-  Y. Ohkusa, K. Taniguchi, and I. Okubo, “Prediction of Smallpox Outbreak and Evaluation of Control-Measure Policy in Japan, Using a Mathematical Model,” J. Infect. Chemother., Vol.11, pp. 71-80, 2005.
-  T. Kurata (Ed.), “Research on the Safety of Vaccinia Virus and Vaccination,” Final Report on research funded by Health Sciences Research Grants in the fiscal year 1999, 2000 (in Japanese).
-  M. Morita, K. Suzuki et al., “Recombinant Vaccinia Virus LC16mO or LC16m8 that Expresses Hepatitis B Surface Antigen while Preserving the Attenuation of the Parental Virus Strain,” Vaccine, Vol.5, pp. 65-70, 1987.
-  S. Morikawa, T. Sakiyama et al., “An Attenuated LC16m8 Smallpox Vaccine: Analysis of Full-Genome Sequence and Induction of Immune Protection,” J. Virol., Vol.79, pp. 11873-11891, 2005.
-  M. C. Galmiche, J. Goenaga, R. Wittek, and L. Rindisbacher, “Neutralizing and Protective Antibodies Directed Against Vaccinia Virus Envelope Antigens,” Virology, Vol.254, pp. 71-80, 1999.
-  M. Kidokoro, M. Tashiro, and H. Shida, “Genetically Stable and Fully Effective Smallpox Vaccine Strain Constructed from Highly Attenuated Vaccinia LC16m8,” Proc. Natl. Acad. Sci. USA, pp. 4152-4157, 2005.
-  S. E. Frey, F. K. Newman et al., “Dose-Related Effects of Smallpox Vaccine,” N. Engl. J. Med., Vol.346, pp. 1275-1280, 2002.
-  C. Empig, J. R. Kenner et al., “Highly Attenuated Smallpox Vaccine Protects Rabbits and Mice Against Pathogenic Orthopoxvirus Challenge,” Vaccine, Vol.24, pp. 3686-3694, 2006.
-  H. Yokote, Y. Shinmura et al., “Long-Term Protective Efficacy and Antibody Response Induced by a Single Dose of Attenuated Smallpox Vaccine LC16m8,” American Society for Microbiology Biodefense and Emerging Dieaeses Research Meeting, Baltimore, MD, USA, 2009.
-  C. Empig, K. Higgins et al., “Attenuated Smallpox Vaccine LC16m8 Protects Cynomolgus Monleys from Lethal IV Monkeypox-Zaire Challenge,” American Society for Microbiology Biodefense and Emerging Diseases Research Meeting, Washington, DC, USA, 2006.
-  M. Saijo, Y. Ami et al. , “LC16m8, a Highly Attenuated Vaccinia Virus Vaccine Lacking Expression of the Membrane protein B5R, Protects Monkeys from Monkeypox,” J. Virol., Vol.80, pp. 5179-5188, 2006.
-  M. Saijo, Y. Ami et al. “Long-term Protection of Nonhuman Primates from Monkeypox with a Highly Attenuated Vaccinica Vaccine, LC16m8,” The 12th Annual Meeting of the Japanese Society for Vaccinology, Kumamoto, Japan, 2008 (in Japanese).
-  Y. Shinmura, T. Sasaki et al., “Investigation into the Protection Mechanisms of Attenuated Smallpox Vaccine LC16m8,” American Society for Microbiology Biodefense and Emerging Diseases Research Meeting, Washington D.C., USA, 2007.
-  M. Saijo, Y. Ami et al., “Post-Exposure Vaccination with a Highly Attenuated Vaccinia Vaccine, LC16m8, for Protection of Nonhuman Primates from Monkeypox,” 13th International Congress on Infectious Diseases, Kuala Lumpul, Malaysia, 2008.
-  S. Hashizume, M. Morita et al., “Intracerebral Inoculation of Monkeys with Several Vaccinia Strains: an Approach to the Comparison of Different Strains,” Proceedings of the International Symposium on Smallpox Vaccine, Symposium Series Innmunobiological Standard, Bilthoven, pp. 325-331, 1972.
-  M. Morita, Y. Aoyama et al. “Comparative Studies of Several Vaccinia Virus Strains by Intrathalamic Inoculation into Cynomolgus Monkeys,” Arch. Virol., Vol.53, pp. 197-208, 1977.
-  S. Hashizume, “Development of the Attenuated Smallpox Vaccine, LC16m8, Produced by Cell Culture,” Modern Media, pp. 28-33, 2004 (in Japanese).
-  H. Yokote, Y. Shinmura et al., “Safety and Efficacy Study of Attenuated Smallpox Vaccine LC16m8 in Animals,” American Soceity for Microbiology Biodefense and Emerging Diseaese Research Meating, Washington D.C., USA, 2006.
-  J. D. Grabenstein and W. Winkenwerder, Jr., “US Military Smallpox Vaccination Program Experience,” JAMA, Vol.289, pp. 3278-3282, 2003.
-  J. S. Halsell, J. R. Riddle et al., “Myopericarditis Following Smallpox Vaccination among Vaccinia-Naive US Military Personnel,” JAMA, pp. 3283-3289, 2003.
-  M. K. Arness, R. E. Eckart et al., “Myopericarditis Following Smallpox Vaccination,” Am. J. Epidemiol., Vol.289, pp. 642-651, 2004.
-  K. Ohkuma (Ed.), “Research on the Improvement of the Quality and Productivity of Live-Attenuated Virus Vaccines,” Final Report on research funded by the Health Labour Sciences Research Grants from FY2006 to FY2008, 2009 (in Japanese).
-  Y. Shinmura, T. Nagai et al., “Investigation of Risk Evaluation Animal Model for Severe Skin Complications Caused by Live Vaccines,” The 55th Annual Meeting of The Japanese Society for Virology, Sapporo, Japan, 2007 (in Japanese).
-  Y. Shinmura and H, Yokote, “Safety Evaluation of Attenuated Smallpox Vaccine LC16m8 in Animals,” Sci. Rep. Chemo-Sero-Therap. Res. Inst., pp. 50-60, 2007.
-  V. Hochstein-Mintzel, T. Hanichen et al., “An Attenuated Strain of Vaccinia Virus (MVA). Successful Intramuscular Immunization against Vaccinia and Variola (author’s transl),” Zentralbl Bakteriol [Orig. A], Vol.230, pp. 283-297, 1975.
-  J. S. Kennedy and R. N. Greenberg, “IMVAMUNE: Modified Vaccinia Ankara Strain as an Attenuated Smallpox Vaccine,” Expert Rev. Vaccines, Vol.8, pp. 13-24, 2009.
-  Tuberculosis and Infectious Diseases Control Division, Ministry of Health, Labor and Welfare in Japan, “Guideline for Smallpox,” 5th edition, 2004 (in Japanese).
-  Infectious Disease Subcommittee in the Health Science Advisory Board in the Ministry of Health, Labour and Welfare, “Report by the Special Committee for Pandemic Preparedness,” 2002.
Available at http://www.mhlw.go.jp/topics/2002/05/tp0531-2a.html#3-2 (accessed on 20th May, 2009) (in Japanese).
-  H. Kondo (Ed.), “Research on Building a Health Crisis Management System Using International Collaborative Networks,” Final Report on research funded by Health Labour Sciences Research Grants for FY2008, 2009 (in Japanese).
-  D. B. Di Giulio and P. B. Eckburg, “Human Monkeypox: an Emerging Zoonosis,” Lancet Infect. Dis., Vol.4, pp. 15-25, 2004.