Chair: James Le Duc
As many of the previous sessions dealt mainly with BSL-3 labs, this session focused on some of the special issues associated with BSL-4 facilities (see Table 8-1 for a list of operational BSL-4 facilities1). The session examined a number of topics including how many BSL-4 facilities are needed in a region, construction and maintenance costs, biosecurity issues, environmental risks including the potential for large economic impact, training, strategies to manage an individual who becomes infected with a risk group 4 agent, community relations (see Table 8-2 for laboratories communities have prevented from operating at a BSL-4 level), whether existing and planned networks are adequate, and how much and what kinds of ‘surge capacity’ are ideal.
James Le Duc (University of Texas Medical Branch, United States), the session’s chair, opened the session by reminding the participants that risk group 4 agents include the ‘headline viruses’ such as Ebola and Marburg and other causes of viral hemorrhagic fevers and that the lack of vaccines and treatments makes safety and security particularly important. He then introduced the session’s four talks that provided snapshots of BSL-4 operations in different regions of the world and highlighted some of the current issues. The first talk described a network of BSL-4 labs that provides expertise and services in response to outbreaks, often on-site. The second examined the challenges associated with maintaining an aging facility, while the third looked at efforts required to maintain a permanent presence in an isolated region. The final talk addressed the importance of obtaining and maintaining community support. Following the talks, Dr. Le Duc led a discussion that explored many of the issues in greater depth.
Table 8-1 Locations of selected, operational BSL-4 labs.
|Bernard-Nocht-Institute of Tropical Medicine||Hamburg Bernhard Nocht Institute||Hamburg, Germany|
|CDC Special Pathogens Branch||CDC Special Pathogens Branch||Atlanta, GA United States|
|Commonwealth Scientific and Industrial Research Organisation||Australian Animal Health Laboratory||Geelong, Victoria Australia|
|Georgia State University||National B Virus Resource Center||Atlanta, GA United States|
|Health Protection Agency||Centre for Infections||London, England U.K.|
|Health Protection Agency-Centre for Emergency Preparedness and Response||Centre for Emergency Preparedness and Response, Porton Down||Salisbury U.K.|
|Institut Pasteur/Merieux Foundation/National Institute of Health and Medical Research of France (INSERM)||Jean Mérieux BSL-4 Laboratory||Gerland, Lyon France|
|International Center for Medical Research of Franceville (CIRMF)||CIRMF||Libreville, Gabon|
|Laboratory Centre for Disease Control||National Microbiology Laboratory||Winnipeg, Manitoba Canada|
1 It is more difficult to track the number of BSL-3 laboratories worldwide. See pages 15-16 and 26 for more information.
|National Institute for Communicable Diseases||Special Pathogens Unit||Sandringham, Johannesburg South Africa|
|National Institute of Allergy and Infectious Diseases (NIAID)||NIAID Rocky Mountain Lab||Hamilton, MT United States|
|National Institute of Infectious Diseases||Lazzaro Spallanzani Hospital||Rome, Italy|
|Philipps Universität Marburg||Institute for Virology||Marburg, Germany|
|Queensland Health||Queensland Health Forensic and Scientific Services||Brisbane, Queensland Australia|
|Research Institute of Molecular Biology||Vector–Novosibirsk||Novosibirsk, Russia|
|Russian Ministry of Defense||Institute of Microbiology||Kirov, Russia|
|Russian Ministry of Defense||Virological Center of the Institute of Microbiology||Sergiev Possad, Russia|
|Swedish Institute for Communicable Disease Control||Department of Preparedness/Highly Pathogenic Microorganisms||Solna, Sweden|
|Teaching Hospital of Geneva||Teaching Hospital of Geneva||Geneva, Switzerland|
|Texas Biomedical Research Institutea||Texas Biomedical Research Institutea||San Antonio, TX United States|
|United States Army Medical Research Institute for Infectious Diseases (USAMRIID)||USAMRIID||Frederick, MD United States|
|University of Texas Medical Branch||Shope Lab, Galveston National Laboratory||Galveston, TX United States|
|Victorian Infectious Diseases Reference Laboratory||Victorian Infectious Diseases Reference Laboratory||Melbourne, Victoria Australia|
|Westmead Hospital||Centre for Infectious Diseases and Microbiology Laboratory Service (CIDMLS) and The Institute for Clinical Pathology and Medical Research (ICPMR)||Sydney, New South Wales Australia|
a Formerly Southwest Foundation for Biomedical Research
Table 8-2 Laboratories built for BSL-4 work that as of the date of publication community opposition had prevented from operating at a BSL-4 level.
|Boston University||National Emerging Infectious Diseases Laboratories||Boston, MA United States|
|Central Public Health Laboratory||Central Public Health Laboratory||Etobicoke Ontario, Canada|
|Institute of Physical and Chemical Research (RIKEN)||RIKEN||Kanto, Tokyo Japan|
|National Institute of Infectious Diseases (NIID)||NIID||Tokyo, Japan|
From the Detection of BSL-4 Pathogens to the Development of Preventive and Curative Strategies
Gary Kobinger (Public Health Agency of Canada, Canada) described the structure and goals of the Emerging and Dangerous Pathogens Laboratory Network (EDPLN).
EDPLN, as Dr. Kobinger explained, resulted from informal consultations in Libreville, Gabon, in March 2008 and at World Health Organization (WHO) Headquarters in Geneva in February 2009. EDPLN is a network of BSL-4 and BSL-3 human and veterinary laboratories able and willing to share their knowledge, biological materials, reagents, protocols, and experimental results in real time to detect, diagnose, and control novel disease threats (e.g., Ebola, Marburg, SARS, Nipah, etc.). Currently, EDPLN contains 25 laboratories in 18 countries and 6 WHO regions and has infrastructure such as portable glove-box labs that can be rapidly deployed to outbreaks sites anywhere in the world using standard commercial crates suitable for air transport.
The EDPLN network has a number of goals:
• Support diagnostic functions for laboratory response to global epidemic threats of new, emerging, and dangerous pathogens;
• Build capacity and transfer technology for safe and appropriate diagnostics to regional networks and countries in zones of emergence to enhance outbreak detection and management; and
• Provide surge capacity in response to epidemic activity.
He noted that EDPLN has working groups for laboratory outbreak response, assay and reagent development, technology transfer and training, international engagement, and applied research. Biosafety, biosecurity, and shipment of dangerous goods are issues of concern to the international engagement group. He added that in addition to sharing reagents for ELISA-based (enzyme-linked immunosorbent assay) detection of various pathogens in primates, EDPLN also develops post-exposure treatment options for Ebola virus and other agents. Dr. Kobinger ultimately hopes to develop treatments for use both in the lab for post-exposure prophylaxis and in the field to treat naturally infected individuals.
Dr. Kobinger noted that EDPLN is just one element in the WHO-coordinated Global Outbreak Alert and Response Network (GOARN) that also includes clinical networks, mathematical modeling groups, and infection control networks. The overall GOARN approach includes social mobilization, health education, risk communication, case management, safe funerals, death audits, infection control, environment and vector control, logistics, security, communications, epidemiological investigation, and surveillance. He explained that WHO created this multidisciplinary approach for emerging, infectious disease outbreak control to help the affected population and countries take appropriate measures to interrupt the spread of disease and ensure the safety of both the population at risk and the international partners assisting in the outbreak response. Additionally, GOARN also works to ensure that our understanding of new diseases progresses in a manner that will increase global preparedness.
Requirements for and Challenges Associated with BSL-4 Laboratories
Greg Smith (Australian Animal Health Laboratory, Australia) talked about the Australian Animal Health Laboratory (AAHL) and the challenges associated with maintaining and upgrading an aging facility and the lab’s biosecurity and public relations efforts.
Dr. Smith started by introducing AAHL, which is located in Geelong, Australia. The lab opened in 1985, cost $200 million to build in 1985 Australian dollars, and would cost $650-700 million Australian dollars to replace today. The facility has 15,000 m2 of lab space including 2,900 m2 of BSL-3 space (28 rooms) and 100 m2 of BSL-4 space. The AAHL also has two BSL-4 animal rooms, one of which can hold up to six horses, and 955 m2 of animal biosafety level (ABSL)-3 space. The facility is available to scientists across Australia and globally and has government, academic, and commercial clients.
AAHL’s staff includes 60 full-time engineers and has annual maintenance and running costs of $6.8 million. He added that the lab just completed a $25 million engineering upgrade that focused on control and monitoring and that changing standards will require additional significant investment. Additionally, the lab would like to add 127 m2 of ABSL-4 space as well as additional BSL-4 space. He noted that the scientific mission requires continuous operation during refurbishment and expansion, which greatly increases construction costs.
He then addressed the lab’s biosecurity features. In addition to employing a microbiology security staff of 10, the building, which is surrounded by a perimeter fence, has infrared cameras and was designed using the box within a box principle. Doors have dual access controls and cyberlocks that record identity of each person who attempts access along with the time and date. AAHL has a dedicated training lab and uses structured competency based training during which all routine and emergency procedures are practiced. The Australian Security Intelligence Organization clears all AAHL staff with security access. Local regulations prohibit residents from keeping cloven-hoofed animals within 5 km of the laboratory, and AAHL staff may not live on farms.
AAHL formed a Medical Advisory Committee (MAC) about 15 years ago following a Newcastle incident to manage any individual who might become infected while working in the facility. The MAC includes the State Chief Health Officer, the State Chief Veterinary Officer, a local general practitioner, and an infectious disease physician. All incidents are referred to the MAC, which can put people in home quarantine or admit them to an infectious diseases ward. The MAC is aware of all pathogens and reagents in use at AAHL.
Dr. Smith observed that the facility’s long record of safe operation has led to strong community support. To help maintain that support, he explained that AAHL employs a dedicated public relations officer who facilitates media coverage and actively engages with the community. Activities include school programs and tours for key state and federal politicians. While community support is strong, he admitted that it is not unconditional: Although the lab was built for foot and mouth disease (FMD) diagnosis and vaccine production, FMD virus has never been placed in the lab due to opposition from farmers and ranchers.
Potential and Constraints Associated with Developing an Advanced Laboratory in a Challenging Technical and Social Environment
Jean-Paul Gonzalez (The International Centre of Medical Research of Franceville, Gabon [CIRMF]) talked about the special challenges that accompany the unique location of CIRMF.
Dr. Gonzalez started by reminding the audience that his facility, which contains a glove box BSL-4 lab, is located in the middle of a tropical rainforest and that Libreville, the nearest city, is 3 hours away by small plane or 12 hours by car or train. He described how the lab’s location, which is critical for its mission, makes communications, scientific exchanges, and supply and equipment delivery difficult. Field stations, for example, rely on satellite dishes for communications, and the facility’s isolation requires them to generate their own liquid nitrogen, make their own dry ice, and maintain two generators to ensure uninterrupted power for their -80°C freezers. In addition to the difficulty of finding technical and scientific personnel in such a small country, all visitors and researchers require on-site accommodations. Furthermore, the low standards of local products make maintenance a challenge.
CIRMF does not, however, rely on its isolation for security. The BSL-4 lab is separated from the other buildings and has electric fences and a guard on duty at all times. For additional control, only three people know the code to the BSL-4 freezer.
Dr. Gonzalez attributed the facility’s success to relatively secure funding; local, regional, and international partners; and national political stability. He ended by pointing to the
approximately 700 peer-reviewed papers the facility has produced over the last 30 years as evidence of the scientific return on investments in CIMRF.
The High-containment Laboratory of the National Institute of Infectious Diseases, Tokyo, Japan: Activities, Circumstances, and Future Challenges
Masayuki Saijo (National Institute of Infectious Diseases, Japan) talked about the importance of community support in operating a BSL-4 laboratory.
He opened by explaining that the National Institute of Infectious Diseases (NIID) constructed a glove box BSL-4 facility in its Murayama annex in the early 1980s, but the lab, which is expensive to maintain, has never been used as a BSL-4 due to local opposition. In an effort to increase community support, NIID periodically gives seminars on infectious diseases to community residents and has established a safety committee that includes members of the local municipalities.
In addition to community opposition, Dr. Saijo explained that NIID’s situation is also complicated by the Japanese Infectious Diseases Control Law, which restricts importation, possession, transportation, and transfer of many agents including Ebola virus, Marburg virus, Crimean-Congo hemorrhagic fever (CCHF) virus, Lassa virus, South American hemorrhagic fever viruses, and Yersinia pestis.
Dr. Saijo argued that NIID, in collaboration with key partners, has an important role to play in the world, and to fulfill that role it must operate as a BSL-4. Specifically, operating the facility as a BSL-4 laboratory would better allow NIID to prepare for possible outbreaks of hemorrhagic fever and other emerging infections in both Japan and other parts of the world. Dr. Saijo recognizes that fulfilling what he views as the NIID’s mission will require mutual understanding between NIID and the community about safety and operational risks and will also require mutual collaboration between NIID; the Ministry of Health, Labor, and Welfare of Japan; and the Ministry of Education, Culture, Science, and Technology.
Although NIID has been unable to operate as a BSL-4 lab, Dr. Saijo gave examples of how the facility is still working to combat emerging and exotic infectious diseases by developing diagnostic tests and vaccines, often in collaboration with international partners. Organisms of interest include the CCHF virus, for which NIID developed a recombinant nucleoprotein-based antibody detection system; avian influenza virus, for which they have been testing vaccines using nonhuman primates; and severe acute respiratory syndrome (SARS) coronavirus, for which they are developing diagnostics, vaccines, and animal models. NIID is also engaged in an efficacy assessment of a highly attenuated smallpox vaccine, LC16m8, using nonhuman primate models.
During the discussion, participants focused on three main topics:
Community Relations and the Power of Perceived Risks
Participants reported a wide range of reactions to local labs from pride to apathy to intense opposition. Support sometimes stemmed from the associated jobs, and opposition was normally due to fear of accidental or intentional releases. Furthermore, many felt that perceived rather than real risks were the primary drivers of negative community reactions.
The need to distinguish real and perceived risks was mentioned in many discussions, including the one in this session. For example, numerous people noted that pregnant lab workers often quit working in containment laboratories out of fear for themselves and their unborn child, but participants did not agree on whether that fear was justified. (Many felt it was
not.) Another example was whether regulations should be changed to permit recirculation of HEPA-filtered air from the containment laboratory into non-laboratory parts of a building, which could decrease heating and cooling costs. Several people felt the rule existed mainly because office workers did not feel comfortable breathing lab air and that no real risk was present, particularly if filters were tested annually as required. Others considered recirculation unacceptably risky regardless, indicating that some HEPA filters have poor integrity and that while some of the energy used in heating or cooling the air could be recovered, the air itself should not be. In contrast, recirculation of HEPA-filtered air (both from biological safety cabinets [BSCs] and from the lab itself) is currently permitted to a BSL-3 lab, which many people felt was acceptable due to the additional precautions in place and, possibly, more permissive attitudes among lab workers. Several people indicated that often evidence to accurately characterize and assess risks is not available.
Many also felt that perceived risks had a large impact on regulations and enforcement for both BSL-3 and BSL-4 labs. Someone suggested that liability concerns and society’s current aversion to risks have made regulators increasingly conservative and that it was far easier for regulators to say ‘no’ than to understand the real risks. Others expressed a need to educate regulators and felt that caution was a reasonable response to a lack of understanding. One person recommended that inspectors have lab experience and that evidence be collected to serve as a basis for writing sensible regulations. Another pointed out the difficulty in writing regulations or training inspectors in places with only a small number of facilities.
Various participants offered a number of suggestions for improving and maintaining community support. Ideas included educating locals about infectious diseases, particularly those diseases that are endemic to their location, and approaching communities that are comfortable with and support existing labs, rather than communities with no laboratory experience, when new BSL-4 space is needed. One person reported success with having the organization’s top leadership engage with the community and answer questions before plans were finalized and before money was spent.
Current BSL-4 Needs
Many people felt that the world had sufficient BSL-4 diagnostic capacity but needed more BSL-4 research space. As threats can arise from anywhere, some felt that the diagnostic capacity could, however, be more widely distributed. Participants were divided concerning the comparable merits of a small number of larger, more economical labs and a larger number of small labs closer to potential endemic sites or existing centers of excellence. Several participants also noted that few BSL-4 labs can work with large animals and that in addition to direct concerns about animal health, livestock and companion species often serve as reservoirs for pathogens (e.g., cattle harbor Crimean-Congo hemorrhagic fever [CCHF] virus) and that the entire human-livestock interface is very important for biosecurity. Additionally, several people pointed to fieldwork with risk group 4 organisms as another area that could benefit from improved safety and security.
The group had a number of thoughts about how to increase personnel reliability and to guard against threats from those working in containment laboratories (insider threats). Ideas included increasing trust among scientists and technicians working within containment facilities, enhancing transparency regarding the work being undertaken, monitoring how well those working within biocontainment facilities adhere to protocols, requiring accurate record keeping, and allowing people to opt-out of containment lab work when under personal stress or otherwise unable to fully concentrate on a particular day with few questions asked. Many indicated that
the facility director had a critical responsibility to set the overall atmosphere and that a director should know and establish relationships with every scientist in a lab. Thoughts on the values of psychological screenings were mixed and concerns were raised about the value and utility of existing testing tools. Some, including a few who expressed skepticism about the accuracy of the tests, felt that given the high costs of even a single accident, not using all possible tools could be considered irresponsible. One person, however, indicated that denying someone the right to work on the basis of a psychological test would be considered a human rights violation in some countries.
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