Canada this month announced that any research on mammalian-transmissible strains of the H5N1 avian flu virus in the country’s labs would need to be done at the strictest level of biocontainment, biosafety level 4 (BSL-4). It’s the first country to issue a biosafety rating following the creation of such H5N1 strains in two recent controversial studies (see Nature News Special: Mutant Flu).
The question of which biosafety rating is appropriate for research on the new strains was highlighted as crucial by an expert meeting convened in Geneva last week by the World Health Organization (WHO). The new, modified H5N1 strains are held at Erasmus Medical Center in Rotterdam, the Netherlands, and at the University of Wisconsin-Madison, in two BSL-3-enhanced facilities (the second highest biocontainment level), and the WHO described these as “well-established research facilities with high security and high safety“. But it also recommended that regulators “urgently” review the biosafety and biosecurity conditions under which further research on such strains is conducted, and that until that’s done, the strains should stay where they are and not be shared with other labs.
In biosafety assessment, pathogens are classified in terms of their ‘risk group’ (RG) on a scale of 1–4, where 4 is the highest, on the basis of an assessment of the relative threat they pose to people. They are also classified in terms of the biological containment levels needed, again on a scale of 1–4. What can be a bit confusing is that although required biocontainment levels for various research on a pathogen largely mirror the risk-group rating, they don’t necessarily equate with it. Some types of research may be permitted at a lower biocontainment level than their risk group, if it’s assessed that the research can be done safely with less-restrictive precautions. As the WHO explains, biocontainment level designations are “based on a composite of the design features, construction, containment facilities, equipment, practices and operational procedures required for working with agents from the various risk groups”.
Barry Bloom, a researcher and former dean at the Harvard School of Public Health in Boston, Massachusetts, also emphasizes the importance of training. “Security in handling dangerous pathogens is, in my view, less a function of the physical containment facilities than the training, experience and competence of the scientists working with them,” he says.
Some flu researchers are concerned that work on mammalian-transmissible H5N1 viruses will be severely hampered if it is restricted to BSL-4 laboratories, because BSL-4 conditions are much more constraining than BSL-3 labs, and because there are only a few dozen BSL-4 labs worldwide. Other experts feel that such high containment is essential, given the risk that any escape of the viruses could cause a H5N1 pandemic (see Fears grow over lab-bred flu.)
Whatever biocontainment levels are eventually decided as appropriate by the relevant authorities, many researchers are concerned about the proliferation of such mammalian-transmissible avian flu strains: as more labs work on them, the risk of release — accidental or intentional — goes up. Bloom says that he hopes that the number of labs allowed to work on them “would be limited, transparently identified, and monitored for safety under the aegis of an international body such as WHO”.
Declan Butler asked Sandra Fry, director-general of the Public Health Agency of Canada’s Pathogen Regulation Directorate, and Marianne Heisz, head of the directorate’s Office of Biosafety Programs and Planning, how the agency reached its decision to classify work on the new lab strains as requiring BSL-4 (note that Canada uses the term ‘CL’ in place of BSL) facilities.
Read the Q&A under the fold.
What prompted Canada to review the biosafety level of the new flu viruses and give them the highest RG4/BSL-4 rating?
The Public Health Agency of Canada (PHAC) is the national authority for human pathogen oversight, and administers and enforces the Human Pathogens Importation Regulations and the Human Pathogens and Toxins Act, which require any person in Canada importing or working with human pathogens to follow national biosafety requirements, specifically, the Laboratory Biosafety Guidelines. PHAC routinely reviews the scientific literature and conducts risk assessments on human pathogens, and assessments of new or emerging pathogens that result in new or altered biosafety requirements for working with that pathogen lead to the issuing of a Biosafety Advisory. Communicating the outcome of the risk assessment through a biosafety advisory raises awareness among PHAC’s regulated parties of the containment level requirements for biosafety and biocontainment for these specific viruses. Transmissible forms of the highly lethal H5N1 virus clearly meet the definition of an RG4 human pathogen, and should thus be handled under CL4.
How did you weigh up what was an appropriate biosafety rating?
The Human Pathogens and Toxins Act states that RG3 human pathogens pose a high risk to the health of individuals and low risk to public health. RG4 human pathogens are pathogens that pose a high risk to the health of individuals and a high risk to public health. These pathogens are likely to cause serious disease in a human and there are generally no effective treatments or preventative measures available. The risk of spread of disease caused by RG4 human pathogens is high.
PHAC completed a risk assessment on the H5N1 viruses that were engineered in the Netherlands and the United States taking into account their transmissibility in ferrets, which involved careful consideration of specific pathogen characteristics including pathogenicity, route of infection, and communicability. Although the H5N1 virus circulating in nature poses a serious risk to human health, human-to-human transmission of H5N1 occurs inefficiently, and this limited transmissibility has restricted the spread of H5N1 and is the main factor that distinguishes this pathogen as Risk-Group 3. By modifying H5N1 to be efficiently transmissible, including via aerosols, the risk to public health would increase vastly, as every primary infection could potentially lead to multiple secondary infections.
PHAC decided that, based on the severe impact on human health, high risk to public health, and uncertainty about the availability of effective preventative and therapeutic measures, the engineered H5N1 viruses should be rated as RG4 viruses.
One of the criteria in designating a pathogen as requiring BSL-4 facilities is that effective drugs and vaccines are not available. How do you apply that criterion to these new flu strains, given that although some H5N1 vaccines and drugs do exist, in practice there wouldn’t be remotely near enough of them should the virus escape from the lab and spread in the community?
The availability of effective preventative or therapeutic measures is a factor considered when conducting a pathogen-risk assessment. Although H5N1 vaccines have been developed, the research in question involves the deliberate modification of H5N1, and we have not yet determined how effective existing vaccines would be against the modified viruses. In considering the potential impact of a release of transmissible H5N1 into circulation, the availability of effective medical intervention and the capacity of the health-care response system will need to be determined. PHAC considered these and other factors, and they weighed into the conclusion that this pathogen is to be worked at in CL 4.
Did you consult with researchers, and what was their opinion?
Several experts in the field of biosafety were consulted in the development of the engineered H5N1 viruses Biosafety Advisory. As part of our standard Biosafety Advisory development process, the risk assessment is conducted in collaboration with researchers at the PHAC National Microbiology Laboratory (NML), and with our colleagues from the Canadian Food Inspection Agency (CFIA) for expertise on the animal pathogen component. Additional rigour was added by consulting with public-health experts through the Canadian Public Health Laboratory Network (CPHLN). There was general agreement that transmissible H5N1 should be handled at the highest level of containment.
The two studies that created these strains used ‘BSL-3-enhanced‘ labs, and some researchers say that this is adequate. What particular aspects of BSL-4 containment do you feel are most important with respect to ensuring the safety of these viruses?
In Canada the assigned levels of containment of human pathogens range from CL1 to CL4, with no ‘enhanced’ designations. Facilities meeting the ‘BSL-3-enhanced’ design generally include features that the Canadian Food Inspection Agency requires for CL3 containment of animal pathogens such as avian H5N1. These features include requirements such as the laboratory being the primary containment barrier, to name just one.
CL4/BSL-4 containment is the maximum level of containment available, and the features addressing protection against the potential for airborne transmission of the engineered virus to lab personnel, the environment and general public are key. CL4 ensures maximum containment through the complete sealing of the containment zone, isolation of personnel from the pathogen through the use of positive pressure suits, double-HEPA (high-efficiency particulate air) filtration of exhausted air, HEPA filtration of supply air, and decontamination of all effluents. This type of containment provides the maximum protection for laboratory personnel who handle the pathogen as well as the maximum protection to contain the pathogen from release into the environment. This level of containment was considered the appropriate containment level based on the extensive risk assessment done for this pathogen.
Did you consider biosecurity aspects in your assessment as well as biosafety?
As biosecurity is a subset of biosafety, the crucial aspects of biosecurity are always taken into account when completing our biosafety risk assessments and subsequent biosafety advisories. The specific requirements for CL4 include secure access to the CL4 lab and supporting facility and stringent controls on pathogen inventories, storage and access, to name just a few.
Did you liaise with the United States and other governments or the WHO on your assignment of RG/BSL level, and is there any emerging consensus?
As part of our Biosafety Advisory development process, our colleagues at the CDC and the WHO were contacted to determine their organizations’ intentions with respect to a given emerging pathogen. At the time of consultation, both organizations had not made the determination as to whether or not to develop a biosafety advisory.
How does the PHAC track lab-safety incidents? Do you have a list of all accidents or incidents in recent years at BSL-3 and BSL-4 facilities?
Under national regulations, the PHAC has a mechanism in place that captures the reporting of biosafety accidents or incidents for high-security CL4 facilities. For CL3 facilities, persons importing risk-group 3 human pathogens are required under the Laboratory Biosafety Guidelines to report biosafety accidents or incidents to their institutions. At present, there is no mandatory reporting requirement to inform PHAC, although voluntary reporting is a practice that the PHAC encourages.
The reporting and tracking of biosafety incidents or accidents in all Canadian labs is now being developed for all levels of containment under the development of the PHAC’s new Human Pathogen and Toxins Regulations through a stakeholder-consultation approach. The PHAC is now comparing international-reporting mechanisms to improve its monitoring programme and to influence evidence-based biosafety interventions both domestically and globally.
WHO Laboratory Biosafety Manual (2004)
WHO Biorisk management: Laboratory biosecurity guidance (2006)
Biosecurity Challenges of the Global Expansion of High Containment Biological Laboratories
Protecting the Frontline in Biodefense Research: The Special Immunizations Program
Responsible Research with Biological Select Agents and Toxins
GAO: High-Containment Laboratories: National Strategy for Oversight Is Needed