Moving beyond metagenomics to find the next pandemic virus

I was asked to write a commentary for the Proceedings of the National Academy of Sciences to accompany an article entitled SARS-like WIV1-CoV poised for human emergence. I’d like to explain why I wrote it and why I spent the last five paragraphs railing against regulating gain-of-function experiments.

Towards the end of 2014 the US government announced a pause of gain-of-function research involving research on influenza virus, SARS virus, and MERS virus that “may be reasonably anticipated to confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route.”

From the start I have opposed the gain-of-function pause. It’s a bad idea fostered by individuals who continue to believe, among other things, that influenza H5N1 virus adapted to transmit by aerosol among ferrets can also infect humans by the same route. Instead of stopping important research, a debate on the merits and risks of gain-of-function experiments should have been conducted while experiments were allowed to proceed.

Towards the end of last year a paper was published a paper on the potential of SARS-virus-like bat coronaviruses to cause human disease. The paper reawakened the debate on the risks and benefits of engineering viruses. Opponents of gain-of-function research began to make incorrect statements about this work. Richard Ebright said that ‘The only impact of this work is the creation, in a lab, of a new, non-natural risk”. Simon Wain-Hobson wrote that a novel virus was created that “grows remarkably well” in human cells; “if the virus escaped, nobody could predict the trajectory”. I have written extensively about why these are other similar statements ignore the value of the work. In my opinion these critics either did not read the paper, or if they did, did not understand it.

Several months later I was asked to write the commentary on a second paper examining the potential of SARS like viruses in bats to cause human disease. I agreed to write it because the science is excellent, the conclusions are important, and it would provide me with another venue for criticizing the gain-of-function pause.

In the PNAS paper, Menachery et al. describe a platform comprising metagenomics data, synthetic virology, transgenic mouse models, and monoclonal antibody therapy to assess the ability of SARS-CoV–like viruses to infect human cells and cause disease in mouse models. The results indicate that a bat SARS-like virus, WIV1-CoV, can infect human cells but is attenuated in mice. Additional changes in the WIV1-CoV genome are likely required to increase the pathogenesis of the virus for mice. The same experimental approaches could be used to examine the potential to infect humans of other animal viruses identified by metagenomics surveys. Unfortunately my commentary is behind a paywall, so for those who cannot read it, I’d like to quote from my final paragraphs on the gain-of-function issue:

The current government pause on these gain-of-function experiments was brought about in part by several vocal critics who feel that the risks of this work outweigh potential benefits. On multiple occasions these individuals have indicated that some of the SARS-CoV work discussed in the Menachery et al. article is of no merit. … These findings provide clear experimental paths for developing monoclonal antibodies and vaccines that could be used should another CoV begin to infect humans. The critics of gain-of-function experiments frequently cite apocalyptic scenarios involving the release of altered viruses and subsequent catastrophic effects on humans. Such statements represent personal opinions that are simply meant to scare the public and push us toward unneeded regulation. Virologists have been manipulating viruses for years—this author was the first to produce, 35 y ago, an infectious DNA clone of an animal virus—and no altered virus has gone on to cause an epidemic in humans. Although there have been recent lapses in high-containment biological facilities, none have resulted in harm, and work has gone on for years in many other facilities without incident. I understand that none of these arguments tell us what will happen in the future, but these are the data that we have to calculate risk, and it appears to be very low. As shown by Menacherry et al. in PNAS, the benefits are considerable.

A major goal of life science research is to improve human health, and prohibiting experiments because they may have some risk is contrary to this goal. Being overly cautious is not without its own risks, as we may not develop the advances needed to not only identify future pandemic viruses and develop methods to prevent and control disease, but to develop a basic understand- ing of pathogenesis that guides prevention. These are just some of the beneficial outcomes that we can predict. There are many examples of how science has progressed in areas that were never anticipated, the so-called serendipity of science. Examples abound, including the discovery of restriction enzymes that helped fuel the biotechnology revolution, and the development of the powerful CRISPR/Cas9 gene-editing technology from its obscure origins as a bacterial defense system.

Banning certain types of potentially risky experiments is short sighted and impedes the potential of science to improve human health. Rather than banning experiments, such as those described by Menachery et al., measures should be put in place to allow their safe conduct. In this way science’s full benefits for society can be realized, unfettered by artificial boundaries.

1977 H1N1 influenza virus is not relevant to the gain of function debate

The individuals who believe that certain types of gain-of-function experiments should not be done because they are too dangerous (including Lipsitch, Osterholm, Wain-Hobson,) cite the 1977 influenza virus H1N1 strain as an example of a laboratory accident that has led to a global epidemic. A new analysis shows that the reappearance of the 1997 H1N1 virus has little relevance to the gain-of-function debate.

Human influenza viruses of the H3N2 subtype were circulating in May of 1977 when H1N1 viruses were identified in China and then Russia. These viruses spread globally and continue to circulate to this day. The results of serological tests and genetic analysis indicated that these viruses were very similar to viruses of the same subtype which circulated in 1950 (I was in the Palese laboratory in 1977 when these finding emerged). Three hypotheses were suggested to explain the re-emergence of the H1N1 virus: a laboratory accident, deliberate release, or a vaccine trial.

Rozo and Gronvall have re-examined the available evidence for the origin of the 1977 H1N1 virus. While there is ample documentation of the extensive work done during the 1970s in the Soviet Union on biological weapons, there is no evidence that Biopreparat had attempted to weaponize influenza virus. The release of the 1977 H1N1 virus from a biological weapons program is therefore considered unlikely.

It is more likely that the 1977 H1N1 virus was released during testing of influenza virus vaccines. Many such trials were ongoing in the USSR and China during the 1960s-70s. C.M. Chu, a Chinese virologist, told Peter Palese that the H1N1 strain was in fact used in challenge studies of thousands of military recruits, an event which could have initiated the outbreak.

The hypothesis that the 1977 H1N1 virus accidentally escaped from a research laboratory is formally possible, but there are even less data to support this contention. Shortly after this virus emerged, WHO discounted the possibility of a laboratory accident, based on investigations of Soviet and Chinese laboratories. Furthermore, the H1N1 virus was isolated at nearly the same time in three distant areas of China, making release from a single laboratory unlikely.

It is of interest that with the onset of the gain-of-function debate, which began in 2011 with the adaptation of influenza H5N1 virus to aerosol transmission among ferrets, the ‘laboratory accident’ scenario for the emergence of the 1977 strain has been increasingly used as an example of why certain types of experiments are ‘too dangerous’ to be done (See graph, upper left). For example, Wain-Hobson says that ‘1977 H1N1 represented an accidental reintroduction of an old vaccine strain pre-1957, probably from a Russian research lab’. Furmanski writes that ‘The virus may have escaped from a lab attempting to prepare an attenuated H1N1 vaccine’. In the debate on gain-of-function experiments, the laboratory escape hypothesis is prominently featured in public presentations.

The use of an unproven hypothesis to support the view that some research is too dangerous to do is another example of how those opposed to gain-of-function research bend the truth to advance their position. I have previously explained how Lipsitch incorrectly represented the results of the H5N1 ferret transmission studies. We should not be surprised at this tactic. After all, Lipsitch originally called for a debate on the gain-of-function issue, then shortly thereafter declared that the moratorium should be permanent.

Rozo and Gronvall conclude that the use of the 1977 influenza epidemic as a cautionary tale is wrong, because it is more likely that it was the result of a vaccine trial and not a single laboratory accident:

While the events that led to the 1977 influenza epidemic cannot preclude a future consequential accident stemming from the laboratory, it remains likely that to this date, there has been no real-world example of a laboratory accident that has led to a global epidemic.

TWiV 321: aTRIP and a pause

On episode #321 of the science show This Week in Virology, Paul Duprex joins the TWiV team to discuss the current moratorium on viral research to alter transmission, range and resistance, infectivity and immunity, and pathogenesis.

You can find TWiV #321 at www.microbe.tv/twiv.

End of moratorium on influenza H5N1 research

In early 2012 influenza virus researchers around the world decided to stop working on highly pathogenic avian influenza H5N1 virus. This decision came after work from the Fouchier and Kawaoka laboratories revealed the isolation of influenza H5N1 strains that can be passed among ferrets by aerosol. The moratorium on influenza H5N1 virus research has now been lifted, as described in a letter from influenza virologists to Science and Nature.

Lifting the embargo on H5N1 research is an important step forward for understanding what regulates influenza transmission. In my view it was an ill-conceived move, done to quell the growing concern over the adaptation of influenza H5N1 virus to aerosol transmission in ferrets. We now know that these viruses are not lethal for ferrets, and much of the outrage expressed about this work was misguided. In my view the moratorium has accomplished little other than delaying the conduct of important virology research.

According to the influenza virus researchers who signed on to the moratorium, its purpose was to:

…provide time to explain the public-health benefits of this work, to describe the measures in place to minimize pos- sible risks, and to enable organizations and governments around the world to review their policies (for example on biosafety, biosecurity, oversight, and communication) regarding these experiments.

An important consideration is the level of containment that will be required for studying influenza H5N1 transmission. WHO has released recommendations on risk control measures for H5N1 research, and individual countries will decided how to proceed. The US has not yet made a decision on the level of containment needed for H5N1 virus transmission research. Influenza virologists who participated in the moratorium have their own view:

We consider biosafety level 3 conditions with the considerable enhancements (BSL-3+) outlined in the referenced publications (11–13) as appropriate for this type of work, but recognize that some countries may require BSL-4 conditions in ac- cordance with applicable standards (such as Canada).

Their last statement forms the crux of the issue on H5N1 transmission research:

We fully acknowledge that this research—as with any work on infectious agents—is not without risks. However, because the risk exists in nature that an H5N1 virus capable of transmission in mammals may emerge, the benefits of this work outweigh the risks.

Moratorium on influenza H5N1 transmission research

In letters to Science and Nature, the authors of the controversial avian H5N1 influenza virus transmission experiments in ferrets, together with other influenza virologists, have agreed to a 60 day moratorium on transmission research:

…we have agreed on a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. In addition, no experiments with live H5N1 or H5 HA reassortant viruses already shown to be transmissible in ferrets will be conducted during this time.

They write that research will continue on assessing the “transmissibility of H5N1 influenza viruses that emerge in nature and pose a continuing threat to human health”.

This research is being halted because of the concerns that ferret-transmissible H5N1 viruses may escape from laboratories. They argue that the finding in two laboratories that viruses with a hemagglutinin (HA) protein from highly pathogenic avian H5N1 influenza viruses can become transmissible in ferrets advances our understanding of influenza transmission. Nevertheless,

We recognize that we and the rest of the scientific community need to clearly explain the benefits of this important research and the measures taken to minimize its possible risks. We propose to do so in an international forum in which the scientific community comes together to discuss and debate these issues.

I agree in principle with this decision, because the argument over this research has become increasingly polarized in recent weeks, with a distressing demarcation between those who believe the work should proceed, and those who feel it should not be done. A dialogue to identify the crucial issues and develop plans to address them, while continuing this important line of research, is certainly welcome.

I am curious to see who will participate in the proposed dialogue. I do hope it will be a balanced forum: a fair mix of microbiologists, especially those working on influenza virus, and those interested in biosecurity. As I have said before, scientists will listen to the policy analysts, but the latter must also understand the science.

Update: Alan Dove has written an honest analysis of the moratorium announcement.

Related:

Palese: Don’t censor live-saving science
N.Y. Times: H5N1 ferret research should not have been done
Should we fear avian H5N1 influenza?
A bad day for science
Ferreting out influenza H5N1