Suspend Work, Close Most High-Level Biosafety Labs, Experts Say

Janis C. Kelly

July 29, 2014

( UPDATED July 29, 2014 ) Management of US government bioterrorism research facilities is so lax that work in biosafety level (BSL) 4 laboratories (which house deadly organisms for which there are no effective treatments or vaccines) should be suspended pending a complete safety overhaul, Annals of Internal Medicine deputy editor Deborah Cotton, MD, MPH, writes in an editorial published online July 28 in the journal.

The editorial was in part a response to a July 11 Centers for Disease Prevention and Control (CDC) report on an incident in which staff at the CDC Bioterrorism Rapid Response and Advanced Technology laboratory (BRRAT) in Atlanta, Georgia, failed to follow correct protocols to inactivate samples of anthrax. According to the report, the staff then transferred the samples to 2 other CDC laboratories (the Bacterial Special Pathogens Branch laboratory and the Biotechnology Core Facility Branch laboratory), where again CDC staff did not follow protocols to ensure the anthrax specimens were inactive and safe for use in the less-secure facilities. As a result of the missteps, 80 people were potentially exposed to and at risk for infection from aerosolized anthrax bacteria.

Among the problems highlighted in Dr. Cotton's editorial and at a July 16 Congressional hearing are that nobody knows how many BSL-3 laboratories there are (for organisms that can cause potentially lethal but treatable disease after inhalation, such as plague and tuberculosis). In addition, documented safety failures at CDC and US Department of Agriculture (USDA) laboratories now stretch back more than 10 years, and the recent anthrax exposure incident greatly resembled another anthrax exposure in 2004, after which new safety practices were supposed to have been adopted. Also, there is no coherent national policy for monitoring what is in the laboratories, which leads to dangerous "legacy" specimens left over from discontinued projects, such as the samples of live smallpox virus from 1954 that were discovered on July 1 in cold storage in the middle of the National Institutes of Health (NIH) campus by a surprised staffer who was preparing a US Food and Drug Administration laboratory for relocation. The 327 vials in that trove also included organisms that can cause plague, dengue fever, influenza, spotted fever, and Q fever.

"My point is that the dangers recently reported from within these labs appear greater than any danger that has been reported to be directed toward the labs from outside," Dr. Cotton told Medscape Medical News. "We need biocontainment labs to do both biodefense research and research on emerging infectious diseases. However, we need to stop the proliferation of these labs and better monitor and regulate the ones that already exist. Most importantly, we have to focus on human behaviors in the labs as much as on technology in order to ensure safety."

Dr. Cotton's editorial followed blistering testimony delivered at a July 16 hearing of the US House of Representatives Committee on Energy and Commerce Subcommittee on Oversight and Inspections by Nancy Kingsbury, PhD, managing director for applied research and methods of the Government Accountability Office, Washington, DC, and by Richard H. Ebright, PhD, professor of chemistry and chemical biology at Rutgers University and laboratory director of the Waksman Institute of Microbiology, Piscataway Township, New Jersey.

Dr. Kingsbury summarized the chaotic state of oversight of high-containment laboratories: "No federal entity is responsible for strategic planning and oversight of high-containment laboratories. Since the 1990s, the number of high-containment laboratories has risen; however, the expansion of high-containment laboratories was not based on a government-wide coordinated strategy. Instead, the expansion was based on the perceptions of individual agencies about the capacity required for their individual missions and the high-containment laboratory activities needed to meet those missions, as well as the availability of congressionally approved funding." Dr. Kingsbury said.

Dr. Cotton echoed that point, noting that increased funding for "biodefense" projects after the September 11, 2001, terror attacks led to an increase from 2 to 14 operational or planned BSL-4 laboratories and from about 400 to more than 1400 BSL-3 laboratories.

"Building BSL-4 laboratories promised status and extraordinary long-term grant support for universities, which may have made them less than objective about the suitability of their campuses for such research. A BSL-4 laboratory was built at the University of Texas Medical Branch at Galveston, in an island city historically ravaged by hurricanes and protected only by a seawall," Dr. Cotton writes.

Dr. Cotton recommends limiting the number of BSL-3 and BSL-4 laboratories "to ensure their safety."

Dr. Kingsbury also testified that the 2014 CDC anthrax incident resembled an incident in 2004 in which workers at Children's Hospital Oakland Research Institute in California "unknowingly received and used a suspension from a contract laboratory that likely contained viable [Bacillus] anthracis organisms, although the pathogen was supposed to have been inactivated." The subsequent CDC investigation led to recommendations that supposedly inactivated suspensions of B anthracis be cultured at both the preparing laboratory and the receiving laboratory to ensure sterility before being used in research.

Following that protocol would have prevented the June 2014 anthrax incident. Furthermore, the presence of active anthrax was discovered entirely by chance. The CDC BRRAT laboratory used a nonstandard sterility testing procedure with an incubation time of 24 hours, rather than 48 hours. At 24 hours, the samples were considered sterile, and on June 6 they were shipped off to the other laboratories for use in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, a method for rapid bacterial species identification that is explicitly limited to use with inactivated organisms.

Dr. Kingsbury said that according to CDC officials, after the anthrax samples were sent from BRRAT to the 2 other laboratories, the sterility test samples "were left in the incubation chamber rather than destroyed, as would normally occur, because of technical problems with the autoclave that would have been used for destruction."

On June 13, a BRRAT laboratory scientist "observed unexpected growth on the anthrax sterility plate, possibly indicating that the sample was still infectious" and reported that discovery, triggering the immediate recovery of samples from the BSL-3 laboratories and several days of effort to identify any staff members who might have been exposed to live anthrax spores.

According to Dr. Kingsbury, the failure to implement safety protocols recommended after the 2004 anthrax incident points to a need for a national strategy to plan and oversee laboratories working with highly infectious pathogens.

Dr. Ebright agreed with Dr. Kingsbury on the need for a national strategy regarding such facilities and further recommended that oversight authority be removed from the CDC and the USDA.

"Regulatory responsibility for biosafety and biosecurity of US select-agent laboratories should be reassigned from the CDC and the USDA to an independent entity (an entity that neither conducts nor funds select-agent research)," Dr. Ebright said. A "select" agent is a biological agent or toxin that poses a severe threat to public health, animal or plant health, or animal or plant products and is regulated by specific rules for possession, use, and transfer. Dr. Ebright noted that at this time, the CDC and USDA not only regulate safety for select-agent work but also fund and perform select-age studies, creating "clear conflict of interest."

Dr. Ebright told Medscape Medical News that there is increasing support in Congress for this kind of restructuring. "Arguments that have not gotten traction in the past are getting traction now," he said.

Dr. Ebright also agreed with Dr. Cotton that many of the BSL-3 and BSL-4 laboratories should be closed.

"I recommend restricting federal funding for select-agent (bioweapons-agent) high-level biocontainment facilities to the following subset of already-constructed, already-operational, federally sponsored facilities: 2 NIH BSL-3/BSL-4 integrated research facilities, 2 NIH BSL-3/BSL-4 national biocontainment laboratories, 12 NIH BSL-3 regional biocontainment laboratories, 1 NIH BSL-3 main campus facility (Bethesda, MD), 1 CDC BSL-3/BSL-4 facility (Atlanta, GA), 1 CDC BSL-3 facility (Ft. Collins, CO), 1 Department of Defense BSL-3/BSL-4 facility (Ft. Detrick, MD), 1 Department of Homeland Security BSL-3/BSL-4 facility (Ft. Detrick, MD), and 1 USDA BSL-3/BSL-4 facility (Plum Island, NY, with upgrade)," Dr. Ebright said.

Dr. Ebright also recommends ending all federal support for the construction and operation of other government, academic, foundation, or corporate select-agent high-level biocontainment facilities. "This would yield 22 US institutions, all government-operated, with select-agent high-level biocontainment facilities, as compared to the current approximately 450 US government, academic, foundation, and corporate institutions with select-agent high-level biocontainment facilities. Assuming an average 2 to 4 distinct select-agent high-level biocontainment laboratories per institution, this would yield approximately 40 to 90 US select-agent high-level biocontainment laboratories, as compared to the current approximately 1500 US select-agent high-level biocontainment laboratories," he said.

In addition to the resignation of Michael Ferrell, PhD, head of the BRRAT since 2009, the CDC has taken steps to prevent a recurrence of the June anthrax exposure incident. These include closing the BRRAT laboratory, reviewing protocols for inactivation and transfer of virulent pathogens, establishing a CDC-wide single point of accountability for laboratory safety, establishing an external advisory committee for laboratory safety, and setting up an "incident command structure" to deal with future internal incidents.

Dr. Cotton said that those responses are good first steps but do not address the key issues: how many of these laboratories are needed and how adequate oversight and regulation can be achieved.

Donald A. Henderson, MD, MPH, professor of medicine and public health, University of Pittsburgh, Pennsylvania, told Medscape Medical News, "From my perspective as an epidemiologist, and one with particular concern about health security, I would agree with Dr. Cotton that 1400 BSL-3 and 14 BSL-4 laboratories is far beyond practical or presumptive needs, and that a serious review of national and international needs and threats is very much in order. There is no question but that there are organisms that represent a very real threat and must be handled responsibly, [and] that specially designed and operated laboratories are required for a number of organisms. However, the concern about ultrasecure measures can be overdone in this arena, as in others. We have to recognize that there is no way to achieve 100% security and that every step taken as we move toward ultrasecure measures becomes logarithmically more expensive and can make laboratory research less attractive. Difficult as it may be, a balance has to be struck between the ideal and what is affordable and practical. It seems to me that a fundamental need is for effective administrative oversight."

Dr. Henderson said that CDC Director Thomas R. Frieden, MD, MPH, has publicly recognized the problems at the CDC and is taking active steps to rectify serious deficiencies. "Suspending all research at BSL-4 facilities is not an action I would want to contemplate," Dr. Henderson said.

Dr. Henderson also raised questions about the proposal to move oversight of biocontainment labs to an independent body. "CDC staff, in particular, have played an important role in effecting these changes, as I have witnessed. Whereas one might wish a fully independent group to oversee compliance, I fail to see where one might find needed and current professional personnel who were detached from ongoing concerns and implementation," he said.

The CDC did not respond to Medscape Medical News requests for comment.

Dr. Cotton, Dr. Ebright, and Dr. Kingsbury have disclosed no relevant financial relationships.

Ann Intern Med. Published online July 28, 2014. Abstract

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