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8
REQUIREMENTS FOR AND CHALLENGES ASSOCIATED WITH BSL-4
LABS (PLENARY SESSION)
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.
Institution Laboratory Location
Bernard-Nocht-Institute of Tropical Hamburg Bernhard Nocht Institute Hamburg, Germany
Medicine
CDC Special Pathogens Branch CDC Special Pathogens Branch Atlanta, GA United
States
Commonwealth Scientific and Industrial Australian Animal Health Laboratory Geelong, Victoria
Research Organisation 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 Centre for Emergency Preparedness and Salisbury U.K.
Emergency Preparedness and Response Response, Porton Down
Institut Pasteur/Merieux Jean Mérieux BSL-4 Laboratory Gerland, Lyon
Foundation/National Institute of Health France
and Medical Research of France
(INSERM)
International Center for Medical Research CIRMF Libreville, Gabon
of Franceville (CIRMF)
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.
81
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82 Biosecurity Challenges
National Institute for Communicable Special Pathogens Unit Sandringham,
Diseases Johannesburg
South Africa
National Institute of Allergy and Infectious NIAID Rocky Mountain Lab Hamilton, MT
Diseases (NIAID) 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 Brisbane,
Services 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 Sergiev Possad,
Microbiology Russia
Swedish Institute for Communicable Department of Preparedness/Highly Solna, Sweden
Disease Control Pathogenic Microorganisms
Teaching Hospital of Geneva Teaching Hospital of Geneva Geneva,
Switzerland
a a
Texas Biomedical Research Institute Texas Biomedical Research Institute San Antonio, TX
United States
United States Army Medical Research USAMRIID Frederick, MD
Institute for Infectious Diseases United States
(USAMRIID)
University of Texas Medical Branch Shope Lab, Galveston National Laboratory Galveston, TX
United States
Victorian Infectious Diseases Reference Victorian Infectious Diseases Reference Melbourne, Victoria
Laboratory Laboratory Australia
Westmead Hospital Centre for Infectious Diseases and Sydney, New South
Microbiology Laboratory Service (CIDMLS) Wales Australia
and The Institute for Clinical Pathology and
Medical Research (ICPMR)
SOURCE: Committee
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.
Institution Laboratory Location
Boston University National Emerging Infectious Diseases Boston, MA United
Laboratories States
Central Public Health Laboratory Central Public Health Laboratory Etobicoke Ontario,
Canada
Institute of Physical and Chemical RIKEN Kanto, Tokyo Japan
Research (RIKEN)
National Institute of Infectious Diseases NIID Tokyo, Japan
(NIID)
SOURCE: Committee
PLENARY PRESENTATIONS
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).
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Requirements and Challenges- BSL-4 Labs
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.
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84 Biosecurity Challenges
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
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Requirements and Challenges- BSL-4 Labs
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.
DISCUSSION
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
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86 Biosecurity Challenges
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.
Personnel Reliability
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
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Requirements and Challenges- BSL-4 Labs
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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