The organizers and sponsor opened the workshop on Anticipating Biosecurity Challenges of the Global Expansion of High-containment Biological Laboratories by welcoming the participants and describing the motivations for and objectives of the meeting.
Adel Mahmoud (Princeton University, United States), Chair of the United States National Research Council (NRC) organizing committee for the workshop, reminded the group of the high prevalence of infectious diseases throughout the world. Infectious diseases place great health and economic burdens on society, and the relationship between humans, animals, and microbes is ancient and continually evolving. During the last 30 years, 20-30 new diseases emerged, including AIDS, and dealing with an opponent that greatly outnumbers us will require humankind’s collective intelligence. To that end, he argued that society needs to find new ways to deal with microbes, which necessitates doing research in high-containment labs.
In conducting research to combat infection, Dr. Mahmoud acknowledged that lack of strict adherence to laboratory practices can also result in the spread of disease. Nonetheless, he stressed that in discussing the need for safe and secure labs, the group should not forget that society does need labs. He also recognized that in some cases the results of an experiment, such as the often-cited work where the introduction of a cytokine into a virus caused mice to lose resistance to mousepox (Jackson et al., 2001), are unpredictable. With that in mind, Dr. Mahmoud argued that we must choose between either stopping science or doing science responsibly, and he strongly advocated for the latter. He also cautioned that while we may need improved or new standards to protect scientists, the community, and the environment, we should avoid being unnecessarily restrictive and keep in mind that humanity is served by the new tools and discoveries produced by science.
Then, Şevket Ruacan (Koç University and Turkish Academy of Sciences) welcomed the group to Turkey; explained that biosafety, biosecurity, and responsible science are a priority for both Turkey and world; and provided some background information about the Turkish Academy of Sciences (TÜBA).1 He noted that TÜBA, which was founded in 1993 and currently includes about 130 members, was a founding member of both the InterAcademy Panel and the InterAcademy Medical Panel. As a reflection of Turkey’s geography, TÜBA is also a member of both the Association of Academies of Sciences in Asia and the All European Academies.
Next, Sumi Paranjape (United States Department of State Biosecurity Engagement Program) thanked the attendees for traveling to the meeting and thanked the United States National Research Council for their efforts in organizing the workshop. She observed that it was an important and timely meeting and an opportunity to synthesize lessons learned from prior experience and to suggest strategies for moving forward. She then introduced the three main priorities of the United States State Department’s Biosecurity Engagement Program (BEP): (1) improving biosafety and biosecurity, (2) enhancing disease surveillance, and (3) supporting research and development in these areas.2
After reiterating the importance of international high-containment lab capacity, she mentioned that the United States government is discussing ways to help satisfy that need. The report of this workshop will inform that discussion. While the United States government has put
effort and resources into building facilities, she contended that creative solutions are also needed to help meet health and veterinary needs and to improve lab sustainability. As an example, she cited the growing interest in using molecular diagnostics instead of culture-based assays for some tests.
PART 1: THE FUNCTION OF HIGH-CONTAINMENT LABS AND FACTORS ENCOURAGING AND CONSTRAINING THE CREATION OF NEW LABS
Chair: Katsuhisa Furukawa
Katsuhisa Furukawa (Rebuild Japan Initiative, Japan) opened the session by relating that the March 11, 2011 earthquake off the Pacific coast of Tohoku and the resulting tsunami is the worst natural disaster his country has experienced in the last 1,000 years, and that even though the resulting nuclear power crisis at the Fukushima nuclear plant was caused by an exceedingly rare combination of events, the public blamed the government and the power companies for their lack of preparation. He cautioned the audience that if a similar incident were to occur at a biological laboratory, they should not expect their failure to be met with public forgiveness.
Dr. Furukawa continued that in view of the number of labs being built or expanding, it is particularly important to think about the responsibility of the scientific community, the potential for both accidental and malicious breaches, and what is required to be safe. He explained that the first two talks in the session would provide examples of some of the many ways different countries may choose to approach biosafety and biosecurity using regulations, improved training, and investments in technology. He expressed his hope that in the course of the discussions participants would report on the options their countries were using.
To end the introduction, he explained that the third talk would provide some background on the scale of containment laboratory capacity expansion as well as some of the factors underlying this growth. He then reiterated his hope that in the discussions participants would add additional information about their countries and regions.
United States Biosafety Experiences During the Last Two Decades: Lessons and Achievements
The first speaker in this session was Peter Palese (Mount Sinai School of Medicine, United States), who described the United States requirements for biosafety and biosecurity from the point of view of a working scientist.
Dr. Palese works with negative strand RNA viruses, including influenza, measles, Newcastle disease, and Ebola. His lab relies on the 5th edition of the manual “Biosafety in Microbiological and Biomedical Laboratories” (BMBL) (United States HHS, 2009), which is considered the “biosafety bible,” as well as the Centers for Disease Control and Prevention (CDC) website3 for biosafety guidance. To decide on the risk level of an experiment and what precautions are appropriate, he consults the United States National Institutes of Health (NIH) guidelines on risk groups4 and proposed biosafety levels, evaluates proposed lab procedures, including the quantity of the organism to be used in the work, and considers the staff involved.
4 NIH Guidelines for Research Involving Recombinant DNA Molecules (Appendix B). Available at: http://oba.od.nih.gov/oba/rac/Guidelines/NIH_Guidelines.htm. Accessed September 14, 2011.
He also seeks permission from his local Institutional Biosafety Committee (IBC) to conduct the experiment.
About five years ago, the 1918 influenza virus, which he helped reconstruct (Tumpey et al., 2005), was added to the United States Select Agents list, which controls the possession, use, and transfer of the hazardous pathogens classified as Select Agents in the United States. To accommodate the new requirements imposed by Select Agent classification of the 1918 flu virus, he asked the NIH to pay for a BSL 3+ facility that would allow him to continue his work. The NIH agreed and built the lab on the 17th floor of a building in New York City next to Central Park. He indicated that there have been no incidents and no objections voiced in either the community or facility, demonstrating that it is possible to put containment labs in urban settings.
Working in the new facility, his research group used animal tests to show that the 2009 H1N1 influenza vaccine is 100 percent effective against the 1918 virus, the most virulent influenza strain known. Given that research has recently shown that the current H1N1 vaccine provides some cross protection against the 1918 flu, the 1918 strain should no longer be as effective as a bioterrorism agent (Medina et al., 2010).
To emphasize the real dangers inherent in biological laboratories, Dr. Palese reminded the audience that over 5,000 people have suffered from laboratory-acquired infections (LAIs) since 1930, and nearly 200 have died (Pike, 1979; Harding and Byers, 2000). While the numbers of LAIs have decreased in recent years and the organisms responsible for the bulk of these infections have changed, laboratory work has not become risk-free.
Dr. Palese finished his presentation by sharing a quote5 that argues that unnecessary regulation is in itself a threat to good science and stated that he agrees with a recent United States National Research Council report that argues for a healthy balance in regulations (NRC, 2009e).
Russian Biosafety Experiences During the Last Two Decades: Lessons and Achievements
Sergey Netesov (Novosibirsk State University, Russia) described Russian successes in disease control, current health threats, and steps Russia is taking to improve biosafety and biosecurity.
Dr. Netesov relayed to the group that over the years, Russia has successfully controlled a number of diseases within its borders. The country virtually eradicated plague in the 1930s through the creation of an approach that combined research with surveillance and the eradication of large rodents. Russia had also eradicated smallpox nationally by the end of the 1930s. Later, Russia manufactured polio vaccine and implemented a successful polio vaccination strategy. The country has also controlled measles, mumps, and tick-borne encephalitis.
Dr. Netesov then acknowledged that some new diseases including respiratory diseases, tuberculosis, AIDS, hepatitis C, Crimean-Congo hemorrhagic fever (CCHF), Lyme disease, Yersiniosis, hemorrhagic fever with renal syndrome (HFRS), and West Nile virus fever currently require more attention from the Russian public health system. Additionally, a number of cases of dengue fever, malaria, and other diseases are imported into Russia annually.
He noted that Russia’s successes in disease control have not been without cost. Some researchers working on Venezuelan equine encephalitis, HFRS, CCHF, Machupo, Dhori, vesicular stomatitis virus, and Kyasanur Forest disease in Russia between 1950 and 1990
5 “Biological science provides our primary, continuing defense against diseases, natural or man-made, with knowledge that can be translated into effective countermeasures such as vaccines and new therapies. Any regulation that unnecessarily hinders this research is a real and unnecessary threat to our health, our economy, and our national security” (Franz et al., 2009).
(Gaidamovich et al., 2000) suffered LAIs. More recently, in May 2004, an experienced technician who worked at the State Research Center of Virology and Biotechnology (Vector Institute) pricked herself with a syringe needle containing blood from a guinea pig infected with Ebola virus (Akinfeeva et al., 2005) and, in spite of extensive treatment, she died. This incident, he said, illustrates the need for even experienced workers to receive regular refresher training.
Dr. Netesov argued that biosafety and biosecurity should be enhanced not only due to the large number of non-intentional laboratory accidents in the world (>5,400 during the last 70 years), but also because of the larger consequences from the much smaller number (<50) of unintentional release accidents at industrial biotech plants and the even smaller number of instances of bioterrorism in the world (<5). To that end, he reported that Russia’s leading universities are developing and offering new courses in biosafety, biosecurity, and bioethics, many of which are described in the country overview for Russia (Appendix E4). He feels that these subjects should be taught according to modern international recommendations, should include the history of bioethics, and should cover the Biological and Toxin Weapons Convention (BWC). In particular, he would like bioethics courses to educate students about the social responsibility of researchers working in dual-use research fields.
Containment Labs: Who Wants Them, Who Funds Them, and Why
Jennifer Gaudioso (Sandia National Laboratories, United States) described the recent expansion in the number of high biological containment labs worldwide as well as some of the factors motivating lab construction.
Dr. Gaudioso explained that her talk was based on public information that Sandia National Laboratories (SNL) gathered and acknowledged that workshop participants might find omissions. She elaborated that international information is always difficult to obtain; the United States picture is also incomplete, in part because labs that do not work with Select Agents are not required to register or report their activities to any central authority. She also explained that many labs do not describe themselves with a particular World Health Organization (WHO) biosafety level, and the terms BSL-3 and BSL-4 encompass a range of capabilities.
Caveats notwithstanding, she reported that the United States has experienced tremendous growth in the number of containment labs. According to the United States Government Accountability Office, the number of BSL-3 labs increased from 415 in 2004 to 1362 in 2008, and the number of entities with BSL-3 labs increased from 150 to 242 during the same time period6 (United States GAO, 2009 and Appendix E9). In 1998, which was prior to the creation of the Laboratory Response Network (LRN), only 12 states had public health labs with BSL-3 space; by 2007, 46 had BSL-3 labs.7 Overall, the LRN contained 120 labs with BSL-3 capabilities in 2005 and that number had grown to 150 by 20113 including federal, state, and local public health laboratories; military labs; food testing labs; veterinary labs; and even some international labs (e.g., Canada, U.K., and Australia).
She then described similar growth worldwide, citing as examples BSL-3 labs that have recently been built or are being built in Bangladesh, India, Indonesia, China, Brazil, and Mexico. She also noted India’s and China’s interest in increasing their BSL-4 capacity. The World Bank is currently funding 43 labs.
Dr. Gaudioso then provided a number of reasons for building a lab:
• Management of an existing lab may want to improve safety.
6 Numbers are for BSL-3 labs registered with the United States CDC Division of Select Agents and Toxins.
• A university may want to attract external funding.
• A country may want to increase national prestige, promote growth in the biotechnology sector, or support the government’s desire to combat effectively endemic or emerging infectious diseases.
• A region may decide that existing labs are farther away than samples can realistically be transported.
On the most fundamental level, she indicated that scientific or diagnostic needs typically motivate lab construction. For example, the Stop TB Partnership recommended one BSL-3 lab for every 500,000-1 million people,8 which would necessitate 6,800-13,000 labs worldwide for tuberculosis (TB) diagnostics alone. More recently, however, the Stop TB Partnership and WHO are promoting molecular diagnostics that require fewer safety precautions as an alternative to culture-based tests.9 The advantage of molecular diagnostics is that these methods generally do not necessitate working in a BSL-3 facility. However, the disadvantage is that they may require difficult-to-obtain reagents and offer less flexibility than traditional, culture-based tests.
She also noted that political competition or a lack of trust between countries can motivate lab construction. She recounted how during the 2009 H1N1 influenza outbreak wealthy, vaccine-producing countries did not deliver on their promises to share vaccines with low-income countries until scientists reduced the recommended number of doses for adults from two to one and the pandemic strain proved less virulent than initially feared. Such experiences reinforce lack of trust.
In spite of the attractiveness and utility of containment labs, she pointed out that some countries and institutions are choosing not to build their own. For example, while SNL and its sister lab, Los Alamos National Lab (LANL), both consider biology a priority, LANL decided to build a BSL-3 lab and SNL did not because SNL did not consider Select Agent work a priority and thought a BSL-3 lab was too expensive. Although the LANL lab was built seven years ago, it is still not functional. Without a BSL-3, SNL found strategic partners, invested in molecular techniques including sequencing, and was able to play a role in the Amerithrax investigation.10
During the discussion, several participants shared stories of how containment labs had helped their country characterize and control disease outbreaks. A few indicated that when diagnostics are needed during a crisis and an appropriate laboratory is not available, the work is by necessity done using the facilities that are available. These participants argued that this risk should be weighed against the risk of having an additional facility housing pathogens. Others offered additional reasons for building labs or elaborated on those that had been presented:
• Due to intellectual property concerns, some countries do not want to share biological materials, such as those that could be used to make vaccines, and hence prefer to build their own lab and do the research and development work within their own borders.
8TB Diagnostics and Laboratory Services: Information Note. Available at: http://www.stoptb.org/assets/documents/global/tbfriends/laboratory%20info%20note%20GF%20R%2011.pdf. Accessed August 29, 2011.
9World Health Organization. Tuberculosis Diagnostics Xpert MTB/RIF Test: WHO Endorsement and Recommendations. Available at: http://www.who.int/tb/features_archive/factsheet_xpert_may2011update.pdf. Accessed August 29, 2011.
10 LANL also participated in the Amerithrax investigation. NRC, 2011a; pp. 100-102.
• Private companies may build BSL-3 labs to help them win government contracts, even if the labs themselves lose money.
• In addition to promoting human health, labs can also contribute to animal and plant health.
An opinion frequently expressed was that all countries should have access to containment labs, and it was pointed out that the WHO International Health Regulations (IHR) (2005) require States Parties to have the capacity to analyze samples either domestically or through a collaborative agreement (WHO, 2008). One person noted that some countries may not want their own BSL-4 lab, but would like to be able to use one if the need arose. Many argued, however, that the difficulty of transporting samples, both from regulatory and logistical points-of-view, effectively requires most countries that want laboratory access to build their own lab (the numerous conversations about transportation issues that occurred during the workshop are summarized in Chapter 6). Another individual acknowledged the merits of a regional approach, but felt that the rights of countries to act autonomously and take whatever actions they deemed necessary to protect their citizens from disease took precedence.
PART 2: THE CURRENT STATUS AND OPPORTUNITIES FOR THE FUTURE
Chair: Anwar Nasim
Anwar Nasim (Ministerial Standing Committee on Scientific and Technological Cooperation [COMSTECH], Pakistan) chaired this session, which was intended to describe the challenges that currently operating labs are encountering, summarize the current discussions on this topic, and conjecture about future trends. The first talk described the current situation in Africa as an example of the types of difficulties being encountered worldwide and examined the increasing role of biosafety organizations in bringing attention to laboratories and catalyzing change. The second talk described challenges commonly encountered in Southeast Asia and questioned whether the current trend of developing countries adopting energy and technology intensive laboratory design standards from the West will continue.
Laboratory Capacity, Biosafety, and Biosecurity in Africa: Gaps, Goals, Needs, and Progress
Willy Tonui (African Biological Safety Association [AfBSA], Kenya) described the current status of African labs, common challenges in the region, and the roles of AfBSA and the International Federation of Biosafety Associations (IFBA) in promoting change.
Dr. Tonui opened by explaining that the concepts of biosafety and especially biosecurity are still in their formative stages in most institutions in Africa. However, biotechnology, particularly work on genetically modified organisms, has raised public awareness about biosafety in the context of GMOs. Many African countries are signatories of the Cartagena Protocol on Biosafety and have created biosafety laws to ensure compliance. African countries are also building biosecurity awareness through their membership in the Biological and Toxin Weapons Convention (BWC) and implementation of United Nations Security Council Resolution 1540.
Many labs in the region are BSL-1 facilities, although research institutions often have BSL-2 labs and some have BSL-3 facilities. The Kenya Medical Research Institute, for example, has five BSL-3 labs. Enhanced BSL-3 facilities exist at the Naval Medical Research Unit No. 3 in Cairo, Egypt and the University of Nairobi. Africa has two BSL-4 facilities: the International
Center for Medical Research of Franceville in Gabon and the National Institute for Communicable Diseases in South Africa.
Dr. Tonui reported that many laboratories in African countries suffer from a number of common problems: poor spill management, inappropriate waste disposal, poor post-exposure management, minimal recording mechanisms for tracking safety errors and laboratory-acquired infections (LAIs), inadequate availability or use of personal protective equipment, poor use and maintenance of biosafety equipment, and no mandatory immunizations for lab workers (e.g., tuberculosis, hepatitis B, and typhoid fever). Additionally, there are few high-quality biosafety training programs, and the region lacks technical expertise and the budgetary resources to maintain containment labs. Most institutions do not designate a safety officer, safety guidelines are frequently not available, and policies and standard operating procedures (SOPs) are often not available or not followed. Most countries have little regulation due to a lack of both resources and awareness among top-level officials.
Dr. Tonui explained that AfBSA,11 which he helped found in 2007, is a professional association that promotes biosafety and biosecurity in the African region and is working to address a number of issues. AfBSA currently sees opportunities to promote international partnerships, to work with governments to develop biosafety and biosecurity standards, to enhance collaboration and networking among laboratories, to help African laboratories implement risk assessment principles, and to design and implement biosafety training programs. Several African countries have formed or are forming their own national biosafety organizations to pursue similar goals within their borders.
AfBSA is one of many national and regional biosafety associations that belong to IFBA,12 a not-for-profit, non-governmental organization (NGO) that works with national and international public and animal health authorities and international agencies (e.g., the World Health Organization [WHO], the World Organisation for Animal Health [OIE], the Food and Agriculture Organization of the United Nations [FAO]) to enhance biosafety, biosecurity, and biocontainment laboratory capacity within the greater framework of strengthening health systems. In addition to member organizations, IFBA also has observer organizations such as the Griffin Foundation, the United States Biosecurity Engagement Program (BEP), and the International Council for the Life Sciences (ICLS). IFBA programs include helping members to develop national biosafety guidelines and policies; adapt international best practices (i.e., the WHO Laboratory Biosafety Manual) to local needs and conditions; design, equip, and operate diagnostic laboratories to safely handle and contain infectious diseases; and establish and support regional biosafety training centers, train-the-trainer programs, and twinning and mentoring programs.
Dr. Tonui, who is a co-chair of IFBA, concluded by noting that IFBA and the Elizabeth R. Griffin Foundation designated 2011 as the “Year of Building International Biosafety Communities.”
Current Thinking and Trends Ahead
Teck-Mean Chua (Asia-Pacific Biosafety Association [A-PBA], Malaysia) described the technology-intensive nature of today’s high-containment laboratory facilities. He hypothesized that in the future, scientists, engineers, and regulators will work together more closely to assess accurately their needs and options to create more sustainable, less energy-intensive labs that provide the desired containment.
12 International Federation of Biosafety Associations. Available at: http://www.internationalbiosafety.org/english/index.asp. Accessed August 29, 2011.
Dr. Chua reminded the participants that disease outbreaks, whether from bioterrorism or naturally occurring emerging or re-emerging diseases, do not respect national boundaries and are a global problem. Thus, even though people work in different environments and cultures, everyone faces many of the same issues and threats and no one is safe unless their neighbors are.
He pointed out that developed countries had a head start on biosafety and biosecurity and have led with regulations, standards, and guidelines that call for complex, technology-intensive facilities. Hallmarks of high-containment facility designs in developed countries include double door entries, directional airflow, negative pressure gradients, single pass air, many air changes per hour, autoclaves, 24/7 operation, and multiple safety redundancies.
Dr. Chua then explained that countries that do not have their own guidelines often adopt the guidelines of another country. For example, the United States guidelines described in “Biosafety in Microbiological and Biomedical Laboratories” (BMBL) (United States HHS, 2009) are commonly used world-wide both to allow labs to apply for United States research funding and because biosafety professionals helping with a foreign project often import their own practices. WHO’s Laboratory Biosafety Manual (LBM) (WHO, 2004), whose guidelines are less comprehensive than the BMBL, is another popular choice for countries without their own guidelines.
For many developing countries, however, Dr. Chua called for a greater focus on the fundamentals of biosafety because many of their facilities for handling infectious agents were built more than 10 or 20 years ago and incorporate limited biosafety measures. A recent survey13 by FAO and A-PBA of BSL-2 and BSL-3 labs in seven countries in the Asia-Pacific region, for example, indicated that many labs are below an acceptable level of functionality for their BSL level. The survey noted that often HEPA filters lack the dampers necessary for maintenance, biological safety cabinets (BSCs) are uncertified and usually powered off, and unreliable electrical power is not backed up with generators. Overall, about 30% of the Class II BSCs tested were poorly designed or dysfunctional and failed, and many BSL-3 facilities were either designed incorrectly or being operated incorrectly.
Dr. Chua argued that future goals should not simply be about closing gaps between developed and developing countries but about providing practical, sustainable solutions for effective biocontainment in countries with limited resources. Additionally, he speculated that the effects of global warming and higher energy costs will create a demand for a “green technology approach” towards the design and operation of high-containment facilities and that threats of bioterrorism and emerging and re-emerging diseases will continue to drive the integration of national communities into a global biosafety community.
Dr. Chua pointed to the BSL-3 airflow requirements described in the LBM as an area where greener approaches might be useful. For example, as HEPA-filtered air that is already conditioned can be recirculated into a lab, perhaps it could also be used in other areas of the building. Furthermore, he urged people to consider whether it might be possible to create a ‘sleep mode’ for a lab with reduced airflow. Given the expense involved in high numbers of air changes per hour, he also proposed examining the issue to determine conditions when a lower number of air changes would be acceptable. Also, as not all BSL-3 labs house the same scientific activities and face the same biorisks, he suggested that creating a spectrum of BSL-3 types, rather than the current one-size-fits all solution, might provide the required containment with simpler, less-expensive, easier-to-maintain facilities.
Rather than simply taking the developed world approach of focusing on engineering and equipment, Dr. Chua advised balancing engineering controls with scientific and management controls. Scientific controls include risk assessments of the work to be undertaken, proper
13 Dr. Pawin Padungtod (FAO Regional Office for Asia and the Pacific) and Dr. Robert A. Heckert (Robert Heckert Consulting, LLC) were co-authors on the study.
SOPs, and the employment of well-trained scientists and technicians. Management controls include policies, administrative support, and funding availability. He made the analogy that a BSL-3 lab is like a car—while engineering and maintenance are critical, safe operation also requires a trained driver and prudent traffic laws.
Dr. Chua concluded by noting that developing countries may be the weakest link in the chain of control in biosecurity against the misuse of biological agents to inflict harm.
During the discussion, a number of participants commented on common laboratory usage and funding patterns. Several mentioned that BSL-3 and BSL-4 labs, particularly diagnostic labs, are (1) typically used at that level only a small fraction of the time and (2) often do not have sufficient capacity to handle the required workload during an outbreak. A few individuals gave examples of BSL-2 labs adopting BSL-3 procedures to provide needed surge capacity during times of high demand. One mentioned that research labs can supplement the local public health system during outbreaks and indicated this is most effective when an institution’s director regularly makes and communicates an inventory of available resources and capabilities. Others observed that funding is often tied to demand and that labs often lose resources during periods without a disease outbreak. A few indicated that labs could perform research during times of low diagnostic demand in order to maintain readiness, but noted that research funds are not always available. Several suggested that guidelines from developed country or international organizations should offer more guidance on creating scalable capacity.
A number of individuals speculated on whether the number of containment labs will continue growing at its current pace. A few hypothesized that the increasing availability of molecular diagnostic methods, which have the potential to replace culture-based tests, will reduce the demand for new BSL-3 and BSL-4 labs, while others felt that the pace would continue or increase with every country or institute wanting their own lab. One conjectured that the factors driving capacity have changed; where previously labs were desired simply to diagnose dangerous pathogens, increasing travel and difficulty in containing diseases within national borders has increased the demand for cures, which requires research.
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