The Laboratory Bio-Safety Backlash Continues

Credit CDC

 

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The groundswell of concern over controversial `gain of function’ laboratory experiments, and recent high-profile lapses in biosecurity at the nation’s top labs, continues to grow with a scathing editorial appearing yesterday in the Annals of Internal Medicine penned by Deputy Editor Deborah Cotton, MD, MPH.

 

While much of the editorial is behind a pay wall, you can find a readable scan of the first page at the link below.  Fortunately, Medscape Medical News  published a detailed summary, and interview with the author, yesterday (more on that after you return).

 

Editorials | 29 July 2014

Biocontainment Laboratories: Addressing the Terror Within 

Deborah Cotton, MD, MPH, Deputy Editor

Ann Intern Med. Published online 29 July 2014 doi:10.7326/M14-1668

Recently revealed safety lapses in U.S. government facilities that work with deadly pathogens suggest that, despite efforts to protect us from bioterrorism as well as naturally occurring infectious diseases, there is another grave bioterror threat: the risk emanating from biocontainment laboratories themselves. This commentary discusses possible factors contributing to the safety lapses and strategies to prevent future incidents.

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The following lengthy report from Medscape provides more detail on the above editorial, along with comments from the author, and additional input from by Nancy Kingsbury, PhD, of the Government Accountability Office and  by Richard H. Ebright, PhD, professor of chemistry and chemical biology at Rutgers University  (see House Subcommittee Hearing on Biosafety  for their recent testimony). .

 

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

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Beyond suspension of work pending a a safety overhaul, experts are calling for a dramatic scale back in the number of BSL-3 and BSL-4 labs in the county that are allowed to work on the most dangerous pathogens.  Currently, there isn’t even a good count on the number of BSL-3 labs in operation, and there is no one single regulatory agency in charge of monitoring their operations.

 

While we continue to get bland assurances from researchers that their work is both safe and essential (“We’re scientists . . . trust us” )  we are also hearing from others – like the Director of the CDC - that there  remains an insufficient `culture of safety’ among research scientists.  

 

We are also seeing reports  that the number of laboratory `incidents’ may be far higher than is reported.

 

While many researchers will be justifiably dismayed by the draconian recommendations made in the above editorial, and I doubt that we’ll see anything close to the reduction in BSL-3 labs they are calling for, it is obvious that serious changes are needed.  

 

For the past ten years – spurred on in part by national security concerns – there’s been an `anything goes’ attitude when it comes to biomedical research.  Since the 9/11 attack, the number of BSL-4 labs in the United States has jumped from 2 to 14, and the number of BSL-3 labs has grown from around 400 to over 1400 (although the exact number is murky).

 

Although BSL-3 and BSL-4 labs are essential parts of national security, biomedical research, and the testing of pathogens - the more of them that are in operation - the better the chance of a seeing a serious accident.

 

How many are too many, will be one of the major decisions facing regulators.

 

Given the money, power, and prestige at stake, I don’t expect to see many BSL-3 labs voluntarily sacrifice themselves on the altar of public safety.  So we should expect more than a little resistance to any reductions.

 

For more on this growing debate, you may wish to revisit:

 

Scientists For Science: GOF Research `Essential’ & Can be Done `Safely’

Updating The Cambridge Working Group

ECDC Comment On Gain Of Function Research

CDC: Press Conference Transcript, Audio & Timelines For Lab Incidents

Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential

Lipsitch & Galvani: GOF Research Concerns

Lipsitch & Galvani: GOF Research Concerns

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

# 8648

 

In September it will have been three years since Dutch Virologist and flu researcher Dr. Ron Fouchier announced, at the 2011 ESWI Influenza Conference in Malta, that he’d created a `more transmissible’ form of the H5N1 virus (see Debra MacKenzie’s New Scientist: Five Easy Mutations).

 

At roughly the same time we saw a similar announcement from Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine, that together set alarm bells ringing in the world of biosecurity.

 

While the media furor (see New York Times An Engineered Doomsday) has since quieted, the debate over the wisdom and safety of conducting certain types of Gain of Function (GOF) experiments – designed to enhance the transmissibility, virulence, or host range of potentially deadly microorganisms - has not gone away.

I’ve covered both sides of this debate previously, in:

Laurie Garrett On Biosecurity Reforms

H7N9: Reigniting The `Gain Of Function’ Research Debate 

Nature: H5N1 viral-engineering dangers will not go away

Morens & Taubenberger - Influenza Viruses: Breaking All the Rules

mbio Science Should Be in the Public Domain

Last September we looked at a presentation by Dr. Marc Lipsitch on the the risks of these types of experiments, while last December (see The Call For Urgent Talks On `GOF’ Research Projects), we saw a a letter – signed by 56 scientists – and published both in SciAm and the journal Nature - calling for `urgent talks’ over the future course of GOF research on influenza viruses, and other pathogens.

 

Yesterday Dr. Lipsitch - Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health – along with Yale's Alison Galvani, published an opinion piece in PLoS Medicine  on the risks involved in experimenting on potential pandemic pathogens (PPPs).

 

Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens

Marc Lipsitch mail, Alison P. Galvani

Published: May 20, 2014  DOI: 10.1371/journal.pmed.1001646

Summary Points

• “Gain of function” experiments involving the creation and manipulation of novel potential pandemic pathogens (PPPs) deserve ethical scrutiny regarding the acceptability of the risks of accidental or deliberate release and global spread.
• The Nuremberg Code, a seminal statement of clinical research ethics, mandates that experiments that pose a risk to human life should be undertaken only if they provide humanitarian benefits that sufficiently offset the risks and if these benefits are unachievable by safer means.
• A novel PPP research program of moderate size would pose substantial risks to human life, even optimistically assuming a low probability that a pandemic would ensue from a laboratory accident.
• Alternative approaches would not only be safer but would also be more effective at improving surveillance and vaccine design, the two purported benefits of gain-of-function experiments to create novel, mammalian-transmissible influenza strains.
• A rigorous, quantitative, impartial risk–benefit assessment should precede further novel PPP experimentation. In the case of influenza, we anticipate that such a risk assessment will show that the risks are unjustifiable. Given the risk of a global pandemic posed by such experiments, this risk assessment should be part of a broader international discussion involving multiple stakeholders and not dominated by those with an interest in performing or funding such research.

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Although you’ll want to read the whole article, the Harvard School of Public Health has published a press release with a summation of their findings.  A few excerpts follow:

 

Experiments using virulent avian flu strains pose risk of accidental release

Research in mammals that aims to prevent future influenza pandemics raises ethical, public health concerns

Boston, MA — Experiments creating dangerous flu strains that are transmissible between mammals pose too great a risk to human life from potential release, according to an editorial by researchers from Harvard School of Public Health (HSPH) and Yale School of Public Health. The researchers are calling for greater scrutiny of experiments that make virulent influenza strains transmissible, and for future studies on flu transmission to use safer and more effective alternative approaches.

<SNIP>

The authors call for the U.S. government and other funders to conduct a comprehensive risk-benefit analysis before backing further PPP studies. They estimate that if 10 high-containment laboratories in the United States were running such experiments for a decade, there would be a nearly 20% risk of at least one laboratory-acquired flu infection with the potential to spread. In countries operating under less-stringent conditions than the United States, the risk is much greater.

If a PPP were released, it could lead to widespread human-to-human transmission of a highly virulent virus. It is believed that the H1N1 flu strain that caused a pandemic in 1977 and continued to circulate for 20 years was accidently released from a lab in Russia or China.

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While accidents in well regulated Bio-level 4 labs are rare, they are not unheard of.  And many researchers doing GOF studies only have access to Bio-level 3 or 3+ labs, where safety standards are not as rigorous. Last November, in BMC Medicine: Containing Laboratory Escape Of Pandemic Viruses, we looked at a report that found the risks of seeing an accidental release from one of these labs is far from zero.

 

They calculated a .3% chance of release from any given lab each year, which works out to be roughly one every 100 years of lab operation.  With hundreds of of BSL-3 and BSL-4 labs around the world, the odds of seeing an accident in any given year somewhere in the world go up substantially.

 

Between 2003 and 2009, US government laboratories had 395 incidents that involved the potential release of select agents, according to this report from CIDRAP NEWS.  While only 7 related infections were reported, this does add weight to the concerns being expressed by GOF research critics.  

While there is often a tendency of the public (and the press) to overreact to new fields of scientific research  – imagining the worst possible outcome – over the past three years we’ve seen a growing number of sober, rational, and highly skilled scientists who see a genuine and unacceptable risk in certain types of GOF research, and are concerned enough to take an unpopular  position in academia.

 

Something that ought to give us serious pause, regardless of how we might feel about the benefits that this type of research might someday yield. 

BMC Medicine: Containing Laboratory Escape Of Pandemic Viruses

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

# 8017

 

While nobody really knows how the H1N1 influenza virus – absent in the human population for 20 years – managed to spark a pseudo-pandemic in 1977,  many researchers suspect it escaped a lab in either Russia or China in the mid-1970s.  Genetically, it was very similar to a strain that had circulated 2 decades earlier, something that would be difficult to occur in the wild, but might well  be explained had the virus been stored in a lab freezer (see EID Journal article Influenza Pandemics of the 20th Century Edwin D. Kilbourne).

 

The evidence is only circumstantial, so we may never know the truth of the matter.

 

With the rise of `Gain of Function’  (GOF) research – which aims to enhance the virulence, host range, or transmissibility of dangerous pathogens so that we may better understand their pandemic potential – biosecurity experts have warned that an accident at a BSL-3 or BSL-4 lab could have global ramifications (see mBio: The H5N1 Biosafety Level Debate).

 

While most researchers involved in this sort of work call the risks both manageable, and negligible, the truth is - lab accidents have occurred in the past, and despite very strict bio-safety rules and procedures, they are likely to happen again in the future. 

 

In 2009, the United States GAO issued a 104 page report (HIGH-CONTAINMENT LABORATORIES : National Strategy for Oversight Is Needed ) that looked at four high-profile biosecurity breeches {see below), and examined the risks of future lab accidents.

 

• Alleged insider misuse of a select agent and laboratory;
• Texas A&M University’s (TAMU) failure to report to CDC exposures to select agents in 2006
• Power outages at CDC’s high-containment laboratories in 2007 and 2008
• The release of foot-and-mouth disease virus in 2007 at the Pirbright facility in the U.K.

 

The GAO described the risks going forward (bolding mine):

 

Four highly publicized incidents in high-containment laboratories,  as well as evidence in scientific literature, demonstrate that (1) while laboratory accidents are rare, they do occur, primarily due to human error or systems (management and technical operations) failure, including the failure of safety equipment and procedures, (2) insiders can pose a risk, and (3) it is difficult to control inventories of biological agents with currently available technologies. Taken as a whole, these incidents demonstrate failures of systems and procedures meant to maintain biosafety and biosecurity in high-containment laboratories. For example, they revealed the failure to comply with regulatory requirements, safety measures that were not commensurate with the level of risk to public health posed by laboratory workers and pathogens in the laboratories, and the failure to fund ongoing facility maintenance and monitor the operational effectiveness of laboratory physical infrastructure.

 

 

At one of the most secure BSL-4 facilities in the world – USAMRIID (U.S. Army Medical Research Institute of Infectious Diseases) - their safety record is exceedingly good  . . .  but it is not perfect.  This (bolding mine) from their website:

 

In order to properly assess safety performance over time, USAMRIID compares the number of incidents to the number of times employees entered BSL-3 and BSL-4 laboratories in a given year.  It is important to note that in every incident from 2010-2012, no symptoms were reported and there were no signs of illness.

For instance, in 2012, USAMRIID had 20,402 entries into BSL-3 laboratories. During that time, there were 9 safety incidents within those laboratories; 2 were Potential Biological Exposures (PBE).  A PBE means that some risk of exposure to infectious agents and/or toxins may have occurred, resulting in Occupational Health staff placing the personnel involved on precautionary medical surveillance.  No illness or disease occurred in either case. The 2012 incident rate for BSL-3 laboratories was 0.044 percent.

Looking at BSL-4 laboratories, USAMRIID had 9,154 entries during 2012, with a total of 30 incidents including 6 Potential Biological Exposures (PBE).  A PBE means that some risk of exposure to infectious agents and/or toxins may have occurred, resulting in Occupational Health staff placing the personnel involved on precautionary medical surveillance.  In every case, no illness or disease occurred.  The 2012 incident rate for BSL-4 laboratories was 0.328 percent.

 

In 2011 CIDRAP NEWS published a report called:

 

Report: 395 mishaps at US labs risked releasing select agents

By Robert Roos

Sep 28, 2011 (CIDRAP News) – US government laboratories had 395 incidents that involved the potential release of select agents between 2003 and 2009, though only seven related infections were reported, according to a new National Research Council (NRC) report.

The accidents, including animal bites, needle sticks, and other mishaps, are mentioned briefly in an NRC report on the plans for a risk assessment for an Army biodefense lab to be built at Ft. Detrick in Frederick, Md.

"The Centers for Disease Control and Prevention (CDC) reports 395 cases of potential release events at national laboratories working with select agents," the report says.

"Seven LAIs [laboratory-acquired infections] were reported to CDC; four infections involved Brucella melitensis, two involved Francisella tularensis, and one involved an unspecified Coccidioides species," it continues. "CDC plans to publish an analysis of these events." The report does not list the outcomes of the infections.

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All of which serves as prelude to a report that was published yesterday in BMC Medicine, that models the ability of a research lab to detect and contain a potentially dangerous biosecurity breech, once it has occurred.

 

Containing the accidental laboratory escape of potential pandemic influenza viruses

Stefano Merler, Marco Ajelli, Laura Fumanelli and Alessandro Vespignani

BMC Medicine 2013, 11:252  doi:10.1186/1741-7015-11-252

Published: 28 November 2013

Abstract (provisional)

Background

The recent work on the modified H5N1 has stirred an intense debate on the risk associated with the accidental release from biosafety laboratory of potential pandemic pathogens. Here, we assess the risk that the accidental escape of a novel transmissible influenza strain would not be contained in the local community.

Methods

We develop here a detailed agent-based model that specifically considers laboratory workers and their contacts in microsimulations of the epidemic onset. We consider the following non-pharmaceutical interventions: isolation of the laboratory, laboratory workers' household quarantine, contact tracing of cases and subsequent household quarantine of identified secondary cases, and school and workplace closure both preventive and reactive.

Results

Model simulations suggest that there is a non-negligible probability (5% to 15%), strongly dependent on reproduction number and probability of developing clinical symptoms, that the escape event is not detected at all. We find that the containment depends on the timely implementation of non-pharmaceutical interventions and contact tracing and it may be effective (>90% probability per event) only for pathogens with moderate transmissibility (reproductive number no larger than R0 = 1.5). Containment depends on population density and structure as well, with a probability of giving rise to a global event that is three to five times lower in rural areas.

Conclusions

Results suggest that controllability of escape events is not guaranteed and, given the rapid increase of biosafety laboratories worldwide, this poses a serious threat to human health. Our findings may be relevant to policy makers when designing adequate preparedness plans and may have important implications for determining the location of new biosafety laboratories worldwide.

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From a press release via Northeastern University, we get additional background on this research.  Follow the link to read it in its entirety, as I’ve only included an excerpt:

 

The potential pandemic

November 28, 2013 by Angela Herring

(EXCERPT)

The results of the sim­u­la­tion sug­gest a 5–15 per­cent chance that an acci­dental escape would not be detected, espe­cially in the case of very trans­mis­sible viruses and those where symp­toms are not imme­di­ately spotted. In addi­tion, they found that con­tain­ment would depend on the struc­ture and den­sity of the local pop­u­la­tion sur­rounding a facility.

 

“Most BSL labs are in big urban areas,” Vespig­nani explained. “In those areas we show that the prob­a­bility of not con­taining the out­break is three to five times larger than what it would be in iso­lated areas.”

 

While the prob­a­bility of acci­dental release is extremely low—there’s only 0.3 per­cent chance of a virus escaping one of these labs each year—even a single event can trans­late into a vast public health emer­gency, said Ste­fano Merler, one of the researchers who is based at the Kessler Foun­da­tion. More­over, the number of BSL3 and 4 lab­o­ra­to­ries is increasing, cre­ating a greater com­bined risk the world over.

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While there are only a few dozen BSL-4 labs around the world, there are literally thousands of BSL-3 capable labs. Admittedly, few are conducting GOF research, but even the release of an un-enhanced pathogen could potentially produce a huge impact.

 

Although many researchers can justifiably point out their lab’s exemplary safety record, the standards set and met in labs around the world can vary substantially.  And even the finest biosecurity methods can be thwarted by deliberate `bad acts’ by staff.  

 

Whether researchers doing this sort of research like to admit it it, the risks of seeing an accidental release from one of these labs is far from zero. While a .3% chance of release from any given lab works out to be roughly one every 100 years, with hundreds of of BSL-3 and BSL-4 labs around the world, the odds of seeing an accident in any given year somewhere in the world go up substantially.

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And if today’s BMC Medicine study is correct, containment – particularly of a high R0 pathogen (highly infectious) – is far from guaranteed.