The grave risk of lab-created potentially pandemic pathogens

In 2012, researchers in the Netherlands and the United States shocked the establishment by publishing studies on making avian influenza contagious through the air among mammals. The work of professors Ron Fouchier and Yoshihiro Kawaoka renewed the debate over whether potential pandemic virus research is too dangerous to conduct.

It wasn’t the first time that researchers had raised the risks of a pandemic through their work in the lab. In a 2005 article in Science, a US Centers for Disease Control researcher, Terrence Tumpey, and his co-authors described how they resurrected the 1918 pandemic influenza that killed some 50 million people. They said the purpose of resurrecting the virus was to “study the properties associated with its extraordinary virulence,” which are important to know. And they confirmed just how dangerous a pathogen it was: “The coordinated expression of the 1918 virus genes most certainly confers the unique high-virulence phenotype observed with this pandemic virus.”

Before Tumpey and his colleagues reconstructed the 1918 strain, the virus had been hard to find. In 1951, for example, Johan Hultin went to a remote Alaskan village to obtain samples from the bodies of pandemic victims preserved in Arctic permafrost. But without the techniques of modern molecular biology, he could not resurrect the virus. In the lab, Tumpey and his colleagues created a threat that had essentially passed from Earth.

Several experts have weighed in on the dangers that a community release of the 1918 virus would pose, but perhaps the most persuasive is Donald A. Henderson, the epidemiologist credited with eradicating smallpox through a ring vaccination strategy. “The potential implications of an infected lab worker–and spread beyond the lab–are terrifying,”

After Fouchier and Kawaoka published their work, the debate over creating pathogenic threats for the purpose of study led the US government to implement a moratorium on funding of so-called “gain-of-function” research. That temporary pause has since been lifted, and many facilities are creating and researching avian and human potentially pandemic viruses. The debate over the risks of this research continues.

Back in 2012, when Fouchier and his co-authors wrote their paper, highly pathogenic avian influenza or H5N1 was known to transmit from one sick person to another only rarely. The virus “can cause morbidity and mortality in humans but thus far has not acquired the ability to be transmitted by aerosol or respiratory droplet (`airborne transmission’) between humans,” they wrote. If it were able to readily transmit through the air, however, it would become much more threatening, the authors reasoned: “Avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals … and therefore constitute a risk for human pandemic influenza.”

Arguing that avian influenzas might naturally evolve to become a dangerous airborne threat to humans and that therefore scientists needed to show proof of that potential, Fouchier and his colleagues justified creating the very thing they feared: a pandemic-capable pathogen.

H5N1 was not efficiently spread through the air before Fouchier and Kawaoka’s research; they created a version that was.

In his Letter to the Editor of the journal mBIO, Fouchier argued for the extreme safety of his facility. I agree with Fouchier that his lab is “mechanically” very safe.

Experiments were conducted in closed biosafety cabinets, and lab workers wore special personal protective equipment that covered them completely. Fouchier’s argument was that even if a pathogen escaped the biosafety cabinet where workers access the inside wearing rubber gloves, workers would still be protected because of their personal protective equipment.

But he missed the point about overall the biosafety of his lab. The problem with his argument is that there were activities involving infected animals that took place outside the biosafety cabinet, opening up the possibility that a worker could be infected and quarantined. For example, workers would have had to transport animals around the facility, deal with carcasses, decontaminate bedding, and so on. The quarantine area was likely to be inside the facility itself.

In his letter, Fouchier did not take into account the many types of human error that could lead to worker exposure. If the exposed worker acquired an undetected or unreported laboratory-acquired infection, by definition a release into the community would have occurred when the worker left the facility at the end of the workday. This is the sort of incident that could seed a pandemic

Turning now to Kawaoka’s facility:

In his 2012 paper, Kawaoka and his coauthors noted that “ferrets have human-like … receptors in their lungs.” This is why they’re often used as models for humans, especially for pathogens that infect through the lungs. The authors also note that “H5N1 viruses with pandemic potential, including avian–human reassortant viruses as tested here, may emerge.” Both Fouchier and Kawaoka recognized that the mammalian airborne transmissible H5N1 avian influenza viruses they made could cause a pandemic in humans.

I learned through a Freedom of Information Act request I submitted to the National Institutes of Health’s Office of Science Policy that the office harshly criticized Kawaoka’s facility after learning of sometimes appalling biosafety conditions in there. After an accident, for example, facility officials sent a worker who had been potentially infected with a pandemic influenza virus to quarantine at home.

Facilities that use recombinant DNA must report incidents and accidents to the agency’s Office of Science Policy. The quotes below are directly from the Kawaoka facility official reporting to the office and the office’s reply.

“A needlestick occurred in the ABSL3+ laboratory while the researcher was attempting to collect tissue culture supernatant. … A decision was made to home quarantine the individual because the route of exposure (needlestick) was not expected to place the researcher at high risk for infection and this influenza strain, which contained the HA gene from H5N1, was determined not to be a mammalian-transmissible strain. … [T]he University determined that the researcher should be placed under quarantine at his home. … The researcher’s family was subsequently escorted to a hotel room for the duration of the researcher’s quarantine. To date, the researcher has not shown any signs or symptoms of illness.”

Also, a spill of avian H5N1 occurred in the facility, which was documented elsewhere in the office’s response.

The office delivered a critical response to Kawaoka facility’s reporting official:

“We detailed our concerns regarding the University’s lack of a dedicated quarantine facility to house individuals who have experienced a high-risk exposure to mammalian-transmissible strains of HPAl [highly pathogenic avian influenza] H5N1. … Regarding the spill, the researcher was described as having two to three inches of exposed skin between where his tyvek suit ended and his shoe covers began.  While it was reported that none of the spilled material landed on the researcher’s bare skin, we made it clear in our letter that having bare skin in the ABSL3+ laboratory was unacceptable under the containment requirements for this research specified in the NIH Guidelines.”

Not having a dedicated quarantine facility for a lab handling dangerous pathogens is clearly a big omission, and having bare skin in a biosafety level (BSL)-3+ laboratory is clearly a serious violation of common safety rules.

According to the facility official who corresponded with the Office of Science Policy, the virus strain in the needlestick incident was not a mammalian airborne transmissible H5N1 avian influenza. But a needlestick with this deadly virus could have theoretically infected researchers. If the strain were airborne transmissible, quarantining in a home (maybe an apartment?) would have placed neighbors at risk.

In an example of a simple error in the Kawaoka facility, someone forgot to turn off a faucet and flooded several labs in the facility. In one lab that was flooded, resurrected 1918 H1N1 pandemic flu virus was present. Again, a facility official reported this incident to the government:

“An incident in which there was a back-up of the effluent decontamination system in the high-containment suite at the Influenza Research Institute at the University of Wisconsin. The effluent decontamination system (EDS) which handles all the effluent from the three high containment suites … [was] shut down resulting in water backup in the BSL- 3Ag suite and, to a lesser extent, the ABSL-3 suite. The situation was primarily caused by a staff member’s failure to turn off the sink faucet in the BSL-3 suite resulting in an inability of the EDS system to handle the volume being generated. A secondary cause was the failure of a high-water level alarm linked to the EDS to be sent to the appropriate maintenance staff (as was supposed to happen). Work conducted in one room involves 1918 H1N1 viruses both wild type and mutant made by reverse genetics.”

I have calculated key numbers that demonstrate the high likelihood of release into the community from at least one of the 14 facilities that now create airborne-transmissible potential pandemic viruses and made estimates of the probability that a release will seed a pandemic with potentially millions of fatalities. The 14 facilities work with both avian and human pandemic influenza viruses.

These numbers provide the rationale for my grave concern that the probability of a pandemic caused by a lab incident or accident is much too high. The likelihood of at least one release into the community from a lab for an estimated five years of research creating and researching mammalian airborne transmissible H5N1 avian influenza and human flu viruses is 15.8 percent, by my calculations. A conservative estimate that a community release will seed a pandemic is 15 percent. Therefore, the probability that a lab release into the community will seed a pandemic is 2.5 percent, a worryingly high figure.

Human error can lead to incidents or accidents that release a deadly virus into the community. According to my research, data from two sources show that human error was the cause of 73.5 percent and 79.3 percent of incidents leading to potential exposures in BSL-3 labs. These percentages come from an analysis of years of incident data from the Federal Select Agent Program and the Office of Science Policy. We can’t be sure how virulent or airborne-transmissible in humans mammalian airborne transmissible H5N1 avian influenza virus would be if released into the community. The best-case scenario is that the virus would soon die out with little to no sickness and no fatalities. But that is a scenario no one can guarantee.

Just the possibility of a pandemic dictates that we must proceed with the utmost caution. Put another way: The precautionary principle should apply.[1]

I dislike invoking the precautionary principle because it often stands in the way of testing promising ideas. But in the case here, where a pandemic could result, I feel it is fitting.

The most prudent course of action is to impose a moratorium on this mammalian airborne transmissible avian influenza research. This moratorium is not meant to apply to other gain-of-function research, as every proposal must be evaluated on its merits and risks.

[1] See The precautionary principle – PubMed (nih.gov): “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause-and-effect relationships are not fully established scientifically.”