1. Highly containment laboratory in the National Institute of Infectious Diseases, Tokyo, Japan: activities, circumstances, and future challenges Masayuki Saijo, M.D., Ph. D Department of Virology 1, National Institute of Infectious Diseases

2. Current situation of BSL-4 facilities in NIID Glove box-type BSL-4 facility was constructed and installed in the NIID (Murayama annex) in early 1980’s. Role of the Special Pathogens Laboratory in Dept Virol 1, NIID –Basic science for viral hemorrhagic fevers and other emerging virus infections –Quality Control of Smallpox vaccine –Preparedness for the risk of viral The BSL-4 facility has not yet operated as BSL-4 facility but as BSL- 3 laboratories. –Opposition by the residents and local municipality to the operation of the facility as BSL-4

3. Japanese Infectious Control Law Ebolavirus, Marburg virus, Crimean-Congo hemorrhagic fever virus, Lassa virus, South American hemorrhagic fever viruses, Variola virus, and Yersinia pestis are defined as BSL-4 pathogens in the JIDC law. The law restricts importation, possession, transportation, transfer and sterilization. Furthermore, the law tightened the control of animal importation.

4. Research Activities in Highly Containment Laboratory Development of diagnostic systems for Hemorrhagic fever viruses (Ebola, Marburg, CCHF, Lassa, etc) -mission Monkeypox virus infections –Pathogenesis, diagnostics, immunology SARS –Diagnostics, Vaccine development, Animal model development, and Pathogenesis Efficacy assessment of a newly developed highly pathogenic avian influenza vaccine using nonhuman primate models Efficacy assessment of a highly attenuated smallpox vaccine, LC16m8, using nonhuman primate models –Induction of protective efficacy, Post-exposure vaccination, long-term efficacy

5. Recombinant NP-based diagnosis of CCHF Tang Q, et al. A patient with Crimean-Congo hemorrhagic fever diagnosed with recombinant nucleoprotein-based antibody detection systems. Clin Diag Lab Immunol 10:489-491, 2003

6. Clinical course Patient: 28-year old shepherd in the Xinjiang Uygur Autonomous Region in 2001 Symptoms ： fever, unconsciousness, hemorrhage (nostril, gingiva, rectum) Laboratory findings ： anemia (Hb 10.0 g/dl), thrombocytopenia (8.4  10 10 /L), elevated transaminases (ALT, AST, LDH;173, 216, 268 U/L), hyperbilirubinamia, hypoalbuminamia

7. Virological test results on CCHF virus infection Days from onset 159 (Days) RT-PCR (nested)+-- Ag-capture ELISA0.3810.0070.000 (OD 405 ) IgG-ELISA (1:100)0.0750.9241.882 (OD 405 ) (1:400)0.0310.4860.972 IgM-capture ELISA (OD 405 ) (1:100)0.0202.6922.711 (1:400)0.0401.6062.001 200 300 159NC

8. International collaborations US CDC (Atlanta, GA) –Ebola, Marburg, Smallpox (vaccine study) INSERM (Lyon, France) –Lassa, Marburg China CDC (Beijing, China) –Crimean-Congo hemorrhagic fever RITM (Manila, the Philippines) –Reston Ebolavirus University of Maiduguri (Maiduguri, Nigeria) –Hemorrhagic fevers University of Ghana (Acura, Ghana) –Hemorrhagic fevers

9. Future challenges -key player- Need to operate the facility as BSL-4 laboratory in order to prepare the possible outbreak of highly pathogenic hemorrhagic fever virus infections and other novel emerging infections not only in Japan, but also in the other part of the world. Need to play an important role to combat the highly pathogenic infections in collaboration with the key partners in the world.

10. Future challenges -operation- Requirement of mutual understandings on the safety and operation risks between the NIID and communities. Requirement of mutual collaboration to the operation of BSL-4 facilities between NIID and the Ministry of Health, Labor, and Welfare of Japan.

11. Action plans Mutual understanding –Periodical seminars on infections diseases to the residents in communities –Establishment of Safety committee between the local municipalities and the NIID –Others Mutual collaboration –Between the NIID and MHLW –Between the NIID and Ministry of Education, Culture, Science, and Technology –Between the NIID and Academics