１．Basic information about the BSL-4 facility
Q1-1．What is BioSafety Level (BSL)？
Q1-2．What are the risks associated with pathogens?
Q1-3．Under the Infectious Diseases Control Law, pathogens are classified as “Class I Pathogens, etc.”, “Class II Pathogens, etc.”, and so on. How does this relate to BSL?
Q1-4．Are BSL-4 facilities operational in Japan？
Q1-5．How many BSL-4 facilities are in operation around the world？
Q1-6．What types of BSL-4 laboratories are there other than suit-type (Positive Pressure Suits(PPS))？
Q1-7．What are the advantages of the suit type compared to the glove box type?
Q1-8．Is the BSL-4 facility at Nagasaki University currently in operation？
Q1-9．It seems that the BSL-4 facility is not yet fully operational, but are there any disadvantages due to the delay in its full operation?
Q1-10．What are the plans for using the BSL-4 facility at Nagasaki University？
Q1-11．Please tell me the structure, building area, and total floor area of the BSL-4 facility at Nagasaki University.
Q1-12．I am an ordinary person with no connection to Nagasaki University. Can I visit the BSL-4 facility at Nagasaki University?
２．Procedures related to the Infectious Diseases Control Law (Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases)
Q2-1．What legal procedures are required to conduct research using "Specified Class I Pathogens, etc." at a BSL-4 facility？
Q2-2．What criteria must a BSL-4 facility meet in order to be designated as a “Facility for Possessing Specified Class I Pathogens, etc.”?
Q2-3．What stage is Nagasaki University's BSL-4 facility currently at in the process toward conducting research using "Specified Class I Pathogens, etc."? What step does the university plan to take？
Q2-4．When do you plan to bring in "Specified Class I Pathogens, etc". into the BSL-4 facility？
Q2-5．How are "Specified Class I Pathogens, etc." transported？
３．The necessity of research using BSL-4 facilities
Q3-1．Why is it necessary to conduct research on "Specified Class I Pathogens, etc." such as the Ebola virus？
Q3-2．Ebola won't come to Japan, will it？
Q3-3．If an unknown infectious disease were to emerge, would a BSL-4 facility be necessary to deal with it？
Q3-4．Regarding viruses of unknown infectious diseases, their structures and characteristics are unknown. That means it is difficult to conduct research in advance to prepare for them, isn’t it？
Q3-5．Why do unknown emerging infectious diseases occur？
Q3-6．What are re-emerging infectious diseases? Why do re-emerging infectious diseases occur?
Q3-7．Why do infectious diseases that originate abroad cause pandemics in Japan?
Q3-8．If we utilize the results of BSL-4 research conducted by foreign countries, it may not be necessary to conduct research using BSL-4 facilities in Japan, may it？
４．Research on infectious diseases at Nagasaki University and the National Research Center for the Control and Prevention of Infectious Diseases (CCPID)
Q4-1．Does Nagasaki University have a history of research on infectious diseases and the potential to do so？
Q4-2．Are there any examples of how Nagasaki University's infectious disease research potential has been put to use in the fight against COVID-19？
Q4-3．What kind of research do you plan to conduct once the BSL-4 facility is fully operational？
Q4-4．It says that experiments using BSL-3 or BSL-2 pathogens will be conducted before possession of "Specified Class I Pathogens, etc." but what is the significance of this？
Q4-5．What research are you conducting to quickly detect the emergence of new infectious diseases?
Q4-6．Do you plan to disclose the details of the research conducted at the BSL-4 facility？
Q4-7．Is there any risk of dangerous research will be conducted at the BSL-4 facility？
５．Systems to prevent viruses from leaking from the laboratory
Q5-1．Is there any risk of the viruses in the air in the BSL-4 laboratory leaking out？
Q5-2．I heard that BSL-4 laboratory are highly airtight, and negative pressure is kept in the laboratory. What does negative pressure mean? Also, please tell us about the mechanism that prevents the leakage of pathogens by negative pressure.
Q5-3．Is there any risk that the virus could leak into the environment with wastewater from the BSL-4 laboratory？
Q5-4．Is there any risk that the virus will stick to the experimenter and leak outside？
Q5-5．Is there any risk of infected experimental animals escaping from the BSL-4 facility？
Q5-6．You should have an emergency power supply in case of power outages due to natural disasters, shouldn’t you？
Q5-7．How do you plan to respond if there is suspicion that an experimenter may be infected when he/she conducts experiments using "Specified Class I Pathogens, etc."？
６．Systems to protect experimenters from viruses
Q6-1．Is there any risk of the experimenter getting infected with the virus？
Q6-2．What does “Positive Pressure” mean in the context of the Positive Pressure Suit (PPS)？ Also, please explain how experimenters are protected by the PPS.
Q6-3．How heavy is the Positive Pressure Suit (PPS)？
Q6-4．Why are Positive Pressure Suits (PPS) yellow？
７．Rules and measures for conducting experiments safely
Q7-1．What measures are being taken to minimize the possibility of human error？
Q7-2．What do they do if an experimenter feels unwell during the experiment？
Q7-3．Which unit is responsible for managing the safe use of the BSL-4 facility？
Q7-4．Are there any measures in place with local governments in case of accidents or natural disasters at the BSL-4 facility？
８．Security measures against fraud
Q8-1．How is access to and from the BSL-4 facility controlled？
Q8-2．Is there any risk that the viruses used in the experiments will be stolen or taken away？
Q8-3．What kind of information security measures are in place for the internet at the BSL-4 facility？
１．Basic information about the BSL-4 facility
Q1-1．What is BioSafety Level (BSL)?
A．BSL is an indicator of the strictness of safety management in laboratories and facilities that handle microorganisms and pathogens, based on the Laboratory Biosafety Manual of the World Health Organization (WHO). The BSL of a laboratory that handles a pathogen is determined according to the risk posed by that pathogen. BSL is divided into four levels, with the higher the number, the stricter the safety measures. BSL-1 and BSL-2 are the basic measures for containing pathogens, and BSL-4 is the highest level of safety control. BSL-4 pathogens include Ebolavirus and Lassa virus.
Reference：WHO Laboratory Biosafety Manual, 3rd edition
https://www.who.int/publications/i/item/9241546506
The latest edition of the manual is the 4th edition, but explanations related to BSL is mostly described in the 3rd edition.
Q1-2．What are the risks associated with pathogens?
A．The risk of a pathogen is not evaluated solely based on its virulence. The scope of pathogen risk assessment is influenced by social conditions, such as whether treatment and prevention methods are prepared, whether there is a medical system capable of providing sufficient treatment and vaccinations, the sanitary conditions, and the habitat of animals that transmit infectious diseases. In addition, it is influenced by the health status of people in that society, such as whether they have underlying diseases, their nutritional status, and the presence and degree of various stresses. In conclusion, pathogen risk assessment considers not only the virulence of the pathogen but also the factors mentioned above, and therefore, the risk that a pathogen poses to humans is not universal but varies depending on the specific circumstances in each country.
Q1-3．Under the Infectious Diseases Control Law, pathogens are classified as “Class I Pathogens, etc.”, “Class II Pathogens, etc.”, and so on. How does this relate to BSL?
A．The Infectious Diseases Control Law establishes a management system capable of responding to man-made infections caused by bioterrorism, accidents, etc. The law prohibits the use of “Class I Pathogens, etc.” in principle, based on the risk they pose to the life and health of the public.“Class II Pathogens, etc.” are those that are not as pathogenic as “Class I Pathogens, etc.” but have a significant impact on the life and health of the public. “Class Ⅲ Pathogens, etc.” are not so pathogenic as “Class II Pathogens, etc.” but still may affect the life or health of the public under certain circumstances. We manage “Class Ⅳ Pathogens, etc.” as low risk, as they are not normally considered fatal under Japan's hygiene standards. All “Class I Pathogens, etc.” must be handled in a BSL-4 facility. Most “Class II and Class III Pathogens, etc.” are BSL-3, but some are BSL-2. “Class Ⅳ Pathogens, etc.” include both BSL-3 and BSL-2. Classification into categories Class I to Class Ⅳ is based not only on the safety management of pathogens (i.e., BSL) but also on international trends, the risk of man-made health hazards such as terrorism, the availability of treatment, whether it is fatal, and whether it is transmissible from person to person. Therefore, Class I, II, III, or Ⅳ does not correspond to a specific BSL.
Q1-4．Are BSL-4 facilities operational in Japan?
A．The Murayama Branch of the National Institute of Infectious Diseases (NIID), part of the Japan Institute for Health Security(JIHS), (in Musashimurayama City, Tokyo) has a BSL-4 facility mainly for the diagnosis of infectious diseases. , It was legally designated as a BSL-4 facility (in legal terms, a “Facility for Possessing Specified Class I Pathogens, etc.”) in August 2015 by the Ministry of Health, Labour and Welfare based on the Infectious Diseases Control Law. It was also designated in July 2019 for the import of "Specified Class I Pathogens, etc.". It is currently in operation. It is the only BSL-4 facility that is already in operation.
Q1-5． How many BSL-4 facilities are in operation around the world?
A．There are more than 54 BSL-4 facilities in operation or scheduled to be in operation in over 20 countries around the world*. There are BSL-4 facilities in India, Taiwan, China and South Korea in the Asian region. The United States, Germany, Italy also have BSL-4 facilities, and some of them are located on university campuses. New BSL-4 facilities are currently being planned or constructed around the world. Most of the new BSL-4 facilities that have been built in recent years are suit-type laboratories.
*Virus, Vol. 72, No. 2, pp139-148, 2022
Q1-6．What types of BSL-4 laboratories are there other than suit-type (Positive Pressure Suits(PPS))?
A．There are two types of BSL-4 laboratories: glove box type and PPS type. A glove box is a sealed box in which samples are handled by the hand inserted through a rubber glove. The box is also called a Class III cabinet. BSL-4 pathogens are contained within the box in a glove box type laboratory. In a suit-type laboratory, the experimenter wears a high-airtight, PPS and performs the experiment in a worktable (Class II cabinet) with an open front. The laboratory is required to be equipped with a high-airtight structure and a chemical shower for when leaving. The pathogens are contained not only in the Class II cabinet but also in the laboratory itself.
Q1-7．What are the advantages of the suit type compared to the glove box type?
A．A glove box has a very high airtightness, allowing pathogens to be handled only inside the box. It limits the range of pathogen contamination within the inside of the box, making risk control associated with experimental operations easier. On the other hand, only equipment that fits inside the glove box or equipment that can be connected to the glove box can be used in the case of the glove box type. In contrast, the suit type allows you to use experimental equipment in the same way as in a normal laboratory. In addition, the suit type allows you to work with the same degree of freedom as in a normal laboratory. Therefore, the suit-type system enables more diverse and advanced infectious disease research. On the other hand, suit-type systems require more complex equipment specifications, and therefore more advanced maintenance and management techniques, as well as stricter safety management.
Q1-8．Is the BSL-4 facility at Nagasaki University currently in operation?
A．At present, the BSL-4 facility does not possess "Specified Class I Pathogens, etc.". At present, we are in the process of conducting research and development using pathogens of BSL-3 or lower as preparation for research and development using "Specified Class I Pathogens, etc.".
Q1-9．It seems that the BSL-4 facility is not yet fully operational, but are there any disadvantages due to the delay in its full operation?
A．It is impossible to predict when “Specified Class I Pathogens, etc.”, such as Ebolavirus or unknown viruses with high pathogenicity will enter Japan. There is a possibility that a new infectious disease could emerge in Japan, and it is necessary to prepare for such an eventuality. If there is a BSL-4 facility, safe testing can be conducted even if an infectious disease outbreak occurs. Furthermore, we will be able to apply treatments and vaccines for “Specific Class I Pathogens, etc.” developed in BSL-4 facilities to a similar one that has emerged. Without BSL-4 facilities, none of them would be possible, which would be extremely detrimental to Japan's national security.
Q1-10．What are the plans for using the BSL-4 facility at Nagasaki University?
A．We are conducting research to develop diagnostic techniques and therapeutic strategies for infectious diseases caused by BSL-4 pathogens, as well as research to clarify the mechanisms by which diseases occur. Another important objective is to train researchers who will work to control infectious diseases. We also plan to conduct tests on samples from patients suspected of being infected with BSL-4 pathogens in the future.
Q1-11．Please tell me the structure, building area, and total floor area of the BSL-4 facility at Nagasaki University.
A．The structure is reinforced concrete, with some parts made of steel framed reinforced concrete. The building area is about 1,300 square meters, and the total floor area is about 5,100 square meters.
Q1-12．I am an ordinary person with no connection to Nagasaki University. Can I visit the BSL-4 facility at Nagasaki University?
A．The BSL-4 facility has already been designated by the Minister of Health, Labour and Welfare, and strictly managed under national control. Only people who have received training and obtained permission in accordance with the Biosafety and Biosecurity Management Regulation, National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, are permitted to enter the BSL-4 facility. An ordinary person is not allowed to tour the facility. We would appreciate your understanding.
２．Procedures related to the Infectious Diseases Control Law (Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases)
Q2-1．What legal procedures are required to conduct research using "Specified Class I Pathogens, etc." at a BSL-4 facility?
A．It is necessary to be designated as a "Facility for Possessing Specified Class I Pathogens, etc." from the Minister of Health, Labour and Welfare in accordance with the Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases (the Infectious Diseases Control Law) after constructing a BSL-4 facility and conducting equipment verification and trial operations within the facility. After that, research using "Specified Class I Pathogens, etc." can be conducted by obtaining designation from the Minister of Health, Labour and Welfare for importing "Specified Class I Pathogens, etc." from overseas, or approval from the Minister of Health, Labour and Welfare for transferring them from other domestic institutions.
Q2-2．What criteria must a BSL-4 facility meet in order to be designated as a “Facility for Possessing Specified Class I Pathogens, etc.”?
A．The BSL-4 facility at Nagasaki University has already been designated as a “Facility for Possessing Specified Class I Pathogens, etc.” by the Minister of Health, Labour and Welfare on January 24, 2025. In order to receive this designation, it was necessary to meet various standards based on the Infectious Diseases Control Law. The standards in an aspect of hardware include water resistance and airtightness of laboratory walls, floors, ceilings, and so on, and the installation of surveillance cameras to monitor the interior of laboratories at all times. The exhaust and drainage equipment and emergency power supply described in Q&A 5 are also included in these standards. It is also necessary to meet standards regarding how pathogens should be handled within the facility. For example, two or more people must be present when removing or returning pathogens from storage, and eating, smoking, and applying makeup are prohibited in laboratories. The mechanisms to prevent experimental animals from escaping, as mentioned in Q&A 5, and the wearing of Positive Pressure Suits (PPS) in Q&A 6 are also included in these standards.
Q2-3．What stage is Nagasaki University's BSL-4 facility currently at in the process toward conducting research using "Specified Class I Pathogens, etc."? What step does the university plan to take?
A．On January 24, 2025, the BSL-4 facility was designated by the Minister of Health, Labour and Welfare as a "Facility for Possessing Specified Class I Pathogens, etc." in accordance with the Infectious Diseases Control Law. This means that the facility has been recognized as meeting the standards for possessing "Specified Class I Pathogens, etc."(Lassa virus, Ebolaviruses, Marburg virus, Crimean-Congo hemorrhagic fever virus, and South American hemorrhagic fever viruses).
The figure below shows the four steps involved in conducting research using "Specified Class I Pathogens, etc." at a BSL-4 facility. With this designation, we have now advanced to Step 3.
Currently, we are at Step 3, which means that we do not yet possess any “Specified Class I Pathogens, etc.” but BSL-4 facilities are already under national supervision in accordance with the Infectious Diseases Control Law. In order to conduct research using “Specified Class I Pathogens, etc.” we must obtain ministerial designation for import or ministerial approval for domestic transfer from the Ministry of Health, Labour and Welfare, and then proceed to Step 4 in the above diagram. We are currently conducting research using low-pathogenic pathogens, while preparing to proceed to Step 4.
Q2-4．When do you plan to bring in "Specified Class I Pathogens, etc." into the BSL-4 facility?
A．It is supposed to take a considerable amount of time to be able to actually transport "Specified Class I Pathogens, etc." into the facility. Before the transport, we need coordination with the institution which already holds and manages "Specified Class I Pathogens, etc." and arrangements for transportation. It is also necessary to obtain designation or approval from the Minister of Health, Labour and Welfare for transportation. The timing of the delivery and the specific kinds of pathogens etc., cannot be forementioned.
Q2-5．How are "Specified Class I Pathogens, etc." transported?
A．When transporting "Specified Class I Pathogens, etc." the transport must be entrusted to a transport company with the necessary expertise and technology. The pathogens must be carried out under the supervision of the Public Safety Commission, in accordance with the Infectious Diseases Control Law.
３．The necessity of research using BSL-4 facilities
Q3-1．Why is it necessary to conduct research on ”Specified Class I Pathogens, etc.” such as the Ebolavirus?
A．When we consider the expansion of areas where infectious diseases are prevalent due to climate change as well as the increase in international mobility due to the growth of international exchange, we believe that it is extremely important to respond to infectious diseases that are prevalent around the world to ensure the safety and reassurance of our country. The 2014-16 Ebola outbreak in West Africa spread to Europe and the United States. Marburg Virus Disease was first discovered in Germany. Crimean-Congo hemorrhagic fever has also occurred in Europe. There has been one case of a person returning to Japan who developed Lassa fever. Therefore, these should not simply be dismissed as endemic diseases of remote areas of Africa. It would not be surprising if these infectious diseases were to enter Japan at any time in the future.
Research on ”Specified Class I Pathogens, etc.” may be applicable to other infectious disease control measures. For example, the development of therapeutic drugs and vaccines for Ebola hemorrhagic fever was immediately put to use in the outbreak of COVID-19 that began in late 2019. This has been a significant help in the fight against the COVID-19 pandemic.
Specifically, Remdesivir, a drug developed for Ebola, has been shown to be a very effective antiviral drug against COVID-19 (as long as it is administered early). Establishment of new modalities has also contributed to the rapid development and practical application of COVID-19 vaccines.
As mentioned above, research into the Ebolavirus and other Class I pathogens is also expected to be of great use in the fight against other infectious diseases. Thus, we believe it is important to conduct research into "Specified Class I Pathogens, etc." in a BSL-4 facility.
Q3-2．Ebolavirus won't come to Japan, will it?
A．An big outbreak of Ebola virus disease occurred in West Africa from 2014 to 2016. During this outbreak, several imported cases of Ebola virus disease were reported in countries such as the United Kingdom and the United States, resulting in actual cases of healthcare-associated secondary infection at hospitals in those countries. In Japan, several people who had traveled to West Africa at that time developed fever symptoms after returning home and were admitted to specialized medical institutions. They underwent genetic testing (PCR test) for Ebola virus disease at the Murayama Branch of the National Institute of Infectious Diseases (NIID) (reorganized as Japan Institute for Health Security in April 2025). In this case all the PCR results were negative. However, when Ebola virus disease spreads overseas again in the future, there is still a possibility that people who travel to affected areas and return to Japan may be infected. That being the case, there is no guarantee that Ebola virus disease will not occur in Japan.
Q3-3．If an unknown infectious disease were to emerge, would a BSL-4 facility be necessary to deal with it?
A．In the event of an outbreak of an unknown infectious disease, the properties of the pathogen are unknown in the early stages. Thus, the risk of handling the pathogen in the laboratory is assessed based on the characteristics of the pathogen, the situation (transmissibility, severity, etc.) of the infectious disease in the community and the characteristics of similar pathogens. As a result, if it is determined that the highest level of safety management is necessary to ensure the containment in the laboratory and the safety of workers, it will be necessary to handle the unknown pathogen in a BSL-4 facility. Therefore, BSL-4 facilities are also necessary for dealing with unknown infectious diseases (sometimes referred to as “Disease-X”) that may arise in the future.
Q3-4．Regarding viruses of unknown infectious diseases, their structures and characteristics are unknown. That means it is difficult to conduct research in advance to prepare for them, isn’t it?
A．First, some viruses have a history of repeatedly attacking humans. For example, influenza viruses caused pandemics such as the Spanish flu (1918-1920), Asian flu (1957-1958), and Hong Kong flu (1968-1969), resulting in a large number of infections. Regarding coronaviruses, SARS (Severe Acute Respiratory Syndrome, 2002-2003) and MERS (Middle East Respiratory Syndrome, 2012-, outbreak in South Korea in 2015) have occurred, and COVID-19 has caused a pandemic since 2019, resulting in numerous deaths worldwide, a fact that is still fresh in our memories. With regard to these viruses, there is a high possibility that new types will re-emerge as emerging infectious diseases, so it is extremely important to conduct research on the occurrence trends of infectious diseases on a regular basis. In addition, if an unknown virus is discovered, recent technological advances have made it possible to quickly determine the genome sequence of the virus using new genome sequencing equipment. Therefore, even though it is impossible to completely predict emerging infectious diseases, conducting preparatory research under various assumptions will enable us to quickly establish infection control measures by making adjustments based on the assumed cases when an unknown virus actually appears.
Q3-5．Why do unknown emerging infectious diseases occur？
A．Many emerging infectious diseases are zoonotic, originating in wild animals. In the process of developing civilization, humans have destroyed the natural environment at the same time. For example, in the process of increasing food production to feed the growing global population, people are destroying forests and clearing land for agriculture, thereby encroaching on previously untouched natural areas and domesticating wild animals, which is leading to increased contact with wildlife. New zoonotic diseases emerge when humans and livestock come into contact with wild animals carrying pathogens. In addition, illegal trade in poached wild animals and the movement of infected people and livestock to other locations can spread the infection to new areas. In this way, pathogens that coexist with wild animals are crossing species barriers and infecting humans, spreading as emerging infectious diseases.
Q3-6．What are re-emerging infectious diseases? Why do re-emerging infectious diseases occur?
A．A re-emerging infectious disease is one that was once prevalent but is no longer considered a public health problem, yet has reappeared with a large number of new cases. One representative example in Japan is measles, which was prevalent among people in their teens and twenties in 2007 and 2008. In the past, it was common for children to contract measles and acquire immunity naturally. However, with the increase in measles vaccination rates, fewer people are infected naturally. Those who received one dose of the vaccine during infancy gain additional immunity through exposure to the virus※ during measles outbreaks. Thus, each individual’s immunity to the measles virus becomes weakened with age if the measles outbreak disappears. In 2007 and 2008, it was believed that there was a significant number of people in their teens and twenties who had never been vaccinated against measles, or who had not acquired sufficient immunity from or had weakened immunity after only one vaccination during infancy, resulting in a decline in herd immunity. It’s supposed that measles became prevalent due to the above circumstances. Therefore, additional vaccinations were administered intensively to first-year junior high school students and third-year high school students to strengthen the immunity of the group, and as a result, the outbreak was brought to an end. Currently, herd immunity is maintained through two vaccinations, one at age 1 and the other before entering elementary school. As mentioned above, there is a risk of reemerging infectious diseases in societies where herd immunity has declined.
※：In most cases, symptoms do not appear.
Reference：Ministry of Health, Labour and Welfare’s website on measles
https://www.mhlw.go.jp/seisakunitsuite/bunya/kenkou_iryou/kenkou/kekkaku-kansenshou/measles/index.html
Q3-7．Why do infectious diseases that originate abroad cause pandemics in Japan?
A．With globalization, economics, culture, politics, and other aspects are becoming interconnected beyond national and regional boundaries, while transportation is developing and the movement of people and goods is getting increasingly intense. In addition, the world's population has increased rapidly since the 19th century, leading to more densely populated societies. As a result, infectious diseases that would have once been considered endemic to small areas and would have wiped out only those areas are now spreading rapidly from person to person and across countries, spreading around the world in no time. When people, goods, and animals (such as birds and mosquitoes) move from one country or region to another along with pathogens, and these pathogens spread from person to person in crowded environments, this can easily cause a pandemic.
Q3-8．If we utilize the results of BSL-4 research conducted by foreign countries, it may not be necessary to conduct research using BSL-4 facilities in Japan, may it?
A．The inability to conduct BSL-4 research in Japan means that the country cannot develop vaccines and antiviral drugs against BSL-4 pathogens on its own. When a novel pathogen emerges, research for diagnosis, treatment, and prevention can be safely conducted by using a BSL-4 facility until its virulence and transmissibility are well understood. In the future, when infectious diseases caused by these pathogens become pandemic worldwide, there is no guarantee that vaccines and antiviral drugs will be supplied smoothly from other countries, which could threaten the health of the Japanese people and place a significant economic burden on the country. From a security perspective, we believe it is necessary to conduct research using BSL-4 facilities in Japan. Infectious diseases caused by BSL-4 pathogens primarily occur in developing countries, but it is difficult for these countries to address them on their own. Infectious disease control is a global issue, and as a member of the international community, Japan is expected to contribute to the development of diagnostic, therapeutic, and preventive measures. Such international contributions also help protect our own country from infectious diseases emerging around the world.
４．Research on infectious diseases at Nagasaki University and the National Research Center for the Control and Prevention of Infectious Diseases (CCPID)
Q4-1．Does Nagasaki University have a history of research on infectious diseases and the potential to do so?
A．Nagasaki has functioned as an international city open to the world since the Edo period. On the other hand, they were also the first to suffer the effects of the emerging infectious diseases of the time, such as cholera, measles, smallpox and influenza, which were brought to Japan from overseas via Dejima, the artificial island in Nagasaki used as a trading post. The Nagasaki Igaku Denshusho (later changed to the Kojima Yojosho and now the Nagasaki University School of Medicine), which was the modern Western-style hospital and medical school, was founded in 1857. The treatment and prevention of infectious diseases such as cholera formed an important part of its educational and medical activities. This infectious disease research has now been taken over by the Nagasaki University School of Medicine and the Nagasaki University Institute of Tropical Medicine. In this way, we believe that Nagasaki University has the potential and many years of accumulated experience in research and education in diagnosis, treatment and prevention methods, making it a base for infectious disease research not only in Japan but also around the world.
Q4-2．Are there any examples of how Nagasaki University's infectious disease research potential has been put to use in the fight against COVID-19?
A．Nagasaki University has promptly developed a rapid testing system for COVID-19 using the fluorescence LAMP method, a gene amplification technique. This testing system can detect the CCPID-19 genes from patients in a short time. The device used in this system is lightweight, compact, and easy to use, so it can be used not only in a building of medical institutions but also can be carried to areas where infection is spreading. Since this testing system was developed early in the pandemic, it was possible to quickly test all passengers on the cruise ship “Costa Atlantica” when it arrived at Nagasaki Port. Consequently, the outbreak on the ship was brought under control without any deaths.
Q4-3．What kind of research do you plan to conduct once the BSL-4 facility is fully operational?
A．We are aiming at making progress in research and development into highly lethal infectious diseases and emerging infectious diseases that are not being researched on a global scale, and also creating world-leading results in research into "Specified Class I Pathogens, etc." For this goal, we plan to conduct research into the analysis of the mechanisms of infection and onset of diseases such as Ebola hemorrhagic fever and Crimean-Congo hemorrhagic fever, the development of therapeutic drugs and vaccines, and responses to unknown infectious diseases that may emerge in the future. Until "Specified Class I Pathogens, etc." are introduced and the BSL-4 facility begins fully operational, we will conduct preparatory experiments using BSL-3 or BSL-2 pathogens for the above research.
Through the above research, we also plan to train personnel who can handle "Specified Class I Pathogens, etc.". Specifically, we aim to establish a systematic education and training program for the first time in Japan for researchers and those involved in the maintenance and management of facilities who will use the Positive Pressure Suit (PPS)-type BSL-4 facility. Then we will train personnel with extensive knowledge and experience in the safe handling of "Specified Class I Pathogens, etc.".
Q4-4．It says that experiments using BSL-3 or BSL-2 pathogens will be conducted before possession of "Specified Class I Pathogens, etc." but what is the significance of this?
A．The BSL-3 or lower pathogens used in the experiments here are similar in nature to BSL-4 viruses. For example, they have similar characteristics in terms of how they invade cells, how they multiply, and how the human immune system is involved in this process. In addition, the process of analyzing BSL-3 or lower pathogens also serves to familiarize researchers with the use of equipment and procedures. Starting with experiments using BSL-3 or BSL-2 pathogens is extremely important as a preparation before handling BSL-4 pathogens.
Q4-5．What research are you conducting to quickly detect the emergence of new infectious diseases?
A．Currently, most of the emerging viral infectious diseases that are problematic in Japan and around the world are zoonotic diseases. Those diseases have spread from wild animals to humans. Such infections occur in regions where there is frequent contact between wild animals and humans, such as Asia, Africa, and South America. In this regard, Nagasaki University has research stations for infectious diseases in Asia, Africa, and South America, which is a major advantage in conducting research.
Among wild animals, bats, for example, are considered to be natural hosts for many emerging viruses. At CCPID, we capture bats in Africa and comprehensively analyze the genome sequences of viruses present in their bodies. We are investigating the possibility of the emergence of a new infectious disease called Disease X by checking whether viruses similar to existing viruses (i.e., viral genes) that are pathogenic to humans or viruses that proliferate in human-derived cultured cells exist. Other research institutes affiliated with Nagasaki University are conducting similar research on bats at the aforementioned research station in Asia (i.e., Vietnam).
Q4-6．Do you plan to disclose the details of the research conducted at the BSL-4 facility?
A．In accordance with the “Biosafety and Biosecurity Management Regulation, National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University” etc., the date and month when work using “Specified Class I Pathogens, etc." was conducted, as well as the content of the research and work (excluding confidential information), will be disclosed at Regional Liaison Council, etc. In addition, research outcomes will be disseminated through academic publications and journals.
Q4-7．Is there any risk of dangerous research will be conducted at the BSL-4 facility?
A．The contents of experiments conducted at the BSL-4 facility are confirmed as follows. Firstly the Research Unit will review the research plans prepared by researchers at the National Research Center for the Control and Prevention of Infectious Diseases (CCPID) to determine whether the experiments are appropriate. Secondly the Biorisk Management Unit will then review the plans from a safety perspective, and the university's Biorisk Management Committee will conduct a further review. Finally, the president of the university, who is legally responsible for the possession of pathogens, will make the final decision on whether the experiments can proceed. We believe that there is no risk of dangerous research being approved, as it is necessary to go through the strict procedures within the university.
５．Systems to prevent viruses from leaking from the laboratory
Q5-1．Is there any risk of the viruses in the air in the BSL-4 laboratory leaking out?
A．BSL-4 facilities have a structure in which a sealed BSL-4 laboratory is installed inside a building. The laboratory is kept at a lower pressure than the outside. Thus the air inside the laboratory does not flow out to the outside. Exhaust air from the laboratory is discharged outside after being filtered through double high-efficiency (HEPA; High Efficiency Particulate Air) filters to remove even the finest particles.
Q5-2．I heard that BSL-4 laboratory are highly airtight, and negative pressure is kept in the laboratory. What does negative pressure mean? Also, please tell us about the mechanism that prevents the leakage of pathogens by negative pressure.
A．Negative pressure means that the air pressure inside the laboratory is lower (i.e. negative) than the air pressure outside the laboratory. The laboratory is built with thick concrete walls and has a special sealing process, etc., so it has extremely high airtightness and prevents the air inside the laboratory from leaking outside. In addition, the ventilation system in the laboratory ensures that the air inside is constantly replaced with clean air, and the exhaust air from the laboratory is cleaned by a HEPA filter before being discharged. This prevents any pathogens, which may be contained in the air in the laboratory, from leaking out of the laboratory.
Q5-3．Is there any risk that the virus could leak into the environment with wastewater from the BSL-4 laboratory?
A．At BSL-4 facilities, all wastewater from the laboratory area is first sterilized by high-pressure steam, and then chemically disinfected with a chemical agent. This process completely sterilize (kills) any viruses contained in the wastewater.
Q5-4．Is there any risk that the virus will stick to the experimenter and leak outside?
A．When the experimenter leaves the laboratory, they decontaminate their laboratory suit (Positive Pressure Suits(PPS)) with a shower of disinfectant. At this stage, even if any viruses are on the suit, they will be sterilized (killed).
Q5-5．Is there any risk of infected experimental animals escaping from the BSL-4 facility?
A．Experimental animals are kept in individually ventilated cages. Furthermore, it is necessary to pass through several rooms to get from the animal room to the exit of the laboratory area. The doors at the front and back of the several rooms are designed not to open at the same time. Thus, multiple systems are in place to prevent the escape of animals.
Q5-6．You should have an emergency power supply in case of power outages due to natural disasters, shouldn’t you?
A．Emergency power supply has been installed in BSL-4 facilities in preparation for power outages due to natural disasters, including flooding. It has a capacity that can maintain the facilities' pathogen containment equipment normally. It is also redundant so that it can operate even if one unit fails.
Q5-7．How do you plan to respond if there is suspicion that an experimenter may be infected when he/she conducts experiments using ”Specified Class I Pathogens, etc.”?
A．If there is suspicion that an experimenter has been infected during an experiment, emergency measures will be taken and the experimenter will be examined at Nagasaki University Hospital. Until the results of the examination are available, the patient will be immediately isolated in a facility capable of accommodating patients with Class I Infectious Diseases and undergo testing (the experimenter will be isolated until it is confirmed that they are not infected). Nagasaki University Hospital, a Designated Medical Institution for Class I Infectious Diseases, currently has beds available for patients with Class I Infectious Diseases. In addition, we conduct drills and other training based on the “Biosafety and Biosecurity Management Regulation, National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University“ to confirm the above response measures.
６．Systems to protect experimenters from viruses
Q6-1．Is there any risk of the experimenter getting infected with the virus?
A．During experiments, the experimenter wears Positive Pressure Suits(PPS) (experimental suits), so they are completely isolated from the environment inside the laboratory. In addition, there are rules in place in the laboratory, such as not using sharp instruments as much as possible, to ensure the safety of the experimenters. Measures have been taken to ensure that the risk of infection to the experimenter is as low as possible, both in terms of equipment and in terms of work rules.
Q6-2．What does “Positive Pressure” mean in the context of the Positive Pressure Suit (PPS)? Also, please explain how experimenters are protected by the PPS.
A．”Positive Pressure” means that the air pressure inside the Positive Pressure Suit (PPS) is higher (＝positive) than the air pressure outside the PPS. PPS has an airtight construction with no leaks and protects the experimenter from pathogens by physically isolating them from the laboratory environment. The positive pressure means that even if there is a leak at the surface of the PPS, the air in the laboratory will be pushed out so that it does not enter the inside of the PPS. This allows experimenters to carry out their activities without coming into contact with pathogens in the laboratory air.
Q6-3．How heavy is the Positive Pressure Suit (PPS)?
A．The PPS weighs about 7 kg (varies depending on size).
Q6-4．Why are Positive Pressure Suits (PPS) yellow?
A．In experiments, there are cases where you may handle culture fluid (red) or blood that contains viruses, etc. If any of these fluids containing viruses get on PPS, it is necessary to be able to see them easily. The color of PPS is yellow, as it is a color with relatively high contrast to the color of these fluids.
７．Rules and measures for conducting experiments safely
Q7-1．What measures are being taken to minimize the possibility of human error?
A．Nagasaki University allows access to the BSL-4 laboratory to those who have fulfilled the conditions stipulated in the safety management regulations, such as by attending training courses. In addition, when conducting experiments in a BSL-4 laboratory, there are rules that require at least two people to be present at all times to check each other's actions, and that the experiment time is limited to six hours per day to prevent excessive fatigue. This ensures to prevent human error. Furthermore, we aim to prevent human error by preparing and regularly reviewing safe procedures for work in the laboratory, and by conducting regular training.
Q7-2．What do they do if an experimenter feels unwell during the experiment ?
A．When entering the BSL-4 laboratory, multiple experimenters enter together to support each other's experiments. Staff constantly monitor the inside of the laboratory with surveillance cameras and other equipment. Thus, they can respond immediately when an experimenter feels unwell. The experimenters also conduct emergency response training in preparation for such cases. In addition, we are prepared for emergencies, such as conducting transport training in collaboration with Nagasaki University Hospital, which is a designated medical institution for Class I Infectious Diseases within the same university. Then staff who enter and exit BSL-4 facilities are going to take AED training and cardiopulmonary resuscitation courses.
Q7-3．Which unit is responsible for managing the safe use of the BSL-4 facility?
A．It is managed by the Biorisk Management Unit of the National Research Center for the Control and Prevention of Infectious Diseases (CCPID) at Nagasaki University. The Unit manages the safe use of the BSL-4 facility from both a biosafety (protecting people and the environment from pathogens) and biosecurity (protecting pathogens from theft and misuse) perspective. In addition, strict regulations based on the Infectious Diseases Control Law have been established regarding the possession and use of pathogens, covering both facilities and equipment (hardware) and their use (software). The Unit inspects and records whether facilities are being used in accordance with these guidelines and the management status of facilities. The Unit works to improve and strengthen measures while undergoing regular audits conducted by the national government and the university, thereby striving to establish a safety foundation for conducting experiments.
Q7-4．Are there any measures in place with local governments in case of accidents or natural disasters at the BSL-4 facility?
A．Nagasaki University will work closely with Nagasaki City, Nagasaki Prefecture, and other relevant organizations to ensure safety and security in the event of an accident or natural disaster at the BSL-4 facility. Specifically, based on the “Regional Disaster Prevention Plan, Nagasaki City” and the “Biosafety and Biosecurity Management Regulation, National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University” We have established a reporting and communication system and response manuals in cooperation with Nagasaki City and other entities, and conducted regular disaster prevention drills with Nagasaki City, the fire department, and other entities, as well as drills with the police and other entities.
８．Security measures against fraud
Q8-1．How is access to and from the BSL-4 facility controlled?
A．Access to and from BSL-4 facilities is strictly controlled. The facility has a multi-layered personal authentication system, including security cards, and is also equipped with surveillance cameras and an access control system. Thus only authorized personnel are allowed to enter.
Q8-2．Is there any risk that the viruses used in the experiments will be stolen or taken away?
A．Only those who have been registered and approved in advance are allowed to enter the building according to the rules for the BSL-4 facility. Furthermore, access to and from the BSL-4 laboratory is strictly controlled (as mentioned in the previous Q). Multiple researchers work at the same time, and they monitor each other when handling the virus. The situation inside and outside the laboratory is constantly monitored by surveillance cameras, etc. In addition, we plan to conduct regular training with the police in case of suspicious person, etc.
Q8-3．What kind of information security measures are in place for the internet at the BSL-4 facility?
A．The network within the BSL-4 facility uses a closed network system that is separate from the internet and is only accessible within the building. In addition, there are strict restrictions on bringing electronic devices into the facility.