Origin of the H5N1 storm

10 July 2012

ferretI still wonder why the influenza virus H5N1 ferret transmission studies generated such fear and misunderstanding among the public, the press, and even some scientists. I still cannot fully explain what transpired, but now that the papers have been published some new clues have emerged.

In my opinion, the main catalyst of the storm was the article Scientists brace for media storm around controversial flu studies by Martin Enserink. It began with the inflammatory statement ‘Locked up in the bowels of the medical faculty building here and accessible to only a handful of scientists lies a man-made flu virus that could change world history if it were ever set free’. Fouchier said that he created ‘probably one of the most dangerous viruses you can make’. Members of the NSABB were quoted as saying ‘I can’t think of another pathogenic organism that is as scary as this one’, and ‘This work should never have been done’.

This article presented a one-sided view because only Fouchier or NSABB members were quoted. I don’t understand why Fouchier made some of the statements that he did; perhaps he was quoted out of context. The NSABB members were on the way to restricting publication of the paper, so their views were clear. What Enserink did not do – what he should have done – was to speak with other virologists. This he could not do because the manuscript describing the work had not been made public. He violated a main tenet of journalism, to present both sides of the story.

With the publication of the Fouchier and Kawaoka papers, it became immediately apparent that all of the inflammatory statements in the Enserink article are wrong. For example, after 10 passages in ferrets, an altered H5N1 virus does transmit in the air among ferrets, but inefficiently and without killing the animals. Hardly one of the most dangerous viruses you can make.

To be fair, Enserink was not the first to report these findings. Fouchier presented the results of his H5N1 ferret transmission studies at a meeting in Malta in September 2011. A week later, New Scientist published an article on the findings entitled Five easy mutations to make bird flu a lethal pandemic. In the first paragraph, the author writes ‘…five mutations in just two genes have allowed the virus to spread between mammals in the lab. What’s more, the virus is just as lethal despite the mutations.’ A few paragraphs later: ‘The tenth round of ferrets shed an H5N1 strain that spread to ferrets in separate cages – and killed them.’ Both the title and these statements are all wrong. Fouchier’s published paper does not prove that five mutations are sufficient for aerosol transmission among ferrets, and the virus does not kill ferrets when it is transmitted through the air.  Also problematic is Fouchier quoted as saying that ‘The virus is transmitted as efficiently as seasonal flu’. Given the published data, and his comments at an ASM Biodefense Meeting in February 2012, I do not understand this statement.

It is easy to see how the misinformation in these two articles ignited the fear. Their stories were repeated by countless other publications without verifying whether or not they were correct, amplifying the false conclusions and spreading misinformation even further. Those of us who pointed out inconsistencies were dismissed as risk-takers. Even the New York Times - without ever having seen the data – declared that the experiments should not have been done and the virus stocks should be destroyed.

A comparison of the original Fouchier manuscript with the version recently published in Science provides additional insight (I do not have the original version of the Kawaoka paper).  The first version of the manuscript was submitted to Science and reviewed by the NSABB, whose members recommended that it should be published in redacted form. Fouchier and colleagues then submitted a revised version which was reviewed by the NSABB, who then decided that the entire paper could be published.

Curiously, the titles of the paper are different. The original: Aerosol transmission of avian influenza H5N1 virus. The published version: Airborne transmission of influenza A/H5N1 virus between ferrets. The first is clearly ‘scarier’.

Another big difference between the two manuscripts is the length. A research article in Science is typically brief: it begins with a paragraph or two of background information, then delves right into the results. This is how the original Fouchier manuscript was constructed. In contrast, it is not until page five of the published version do we reach the data: the previous pages are filled with background material reminiscent of a review article. Included is information on the basic biology of influenza viruses, the functions of individual proteins, virulence, why the authors decided to do these studies, what is known to control host range and transmission, and the containment procedures that were undertaken. It is an impressive amount of background information, none of which was present in the original version.  The additional material does help to put the experiments in their proper context.

I found two examples of changes in the wording that I feel could make substantive changes in reader perceptions of the results.

In the abstract of the original manuscript, the authors wrote:

The virus acquired the ability to transmit via aerosols or respiratory droplets while remaining highly pathogenic to ferrets.

In the revised manuscript, this sentence has been changed:

None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses.

The second version better represents the data. The first version is incorrect as stated because the virus is virulent only when inoculated intratracheally into ferrets, not after transmission by aerosols.

A second example occurs during discussion of the response of ferrets to infection with mutant H5N1 virus. In the original manuscript the authors note that after intransal inoculation, the animals have signs of disease but did not die. However, after intratracheal inoculation with the virus, all six ferrets died. Their conclusion:

 These data are similar as described previously for A/H5N1wildtype and thus do not point to reduced virulence (italics mine).

In the revised manuscript this sentence has been modified:

These data are similar to those described previously for A/H5N1wildtype in ferrets. Thus, although the airborne-transmissible virus is lethal to ferrets upon intratracheal inoculation at high doses, the virus was not lethal after airborne transmission.

The first version is misleading because it does not clearly state that virulence was assessed by intratracheal inoculation.

For the most part the same data are presented in the two versions of the manuscripts. A virologist would not draw different conclusions from the two manuscripts despite the longer introduction and the two modifications noted above. I remain puzzled as to why the first manuscript raised such a furor. I cannot believe that it was simply a consequence of overzealous writers and a few scientific overstatements.

Although the Kawaoka and Fouchier papers have been published, the effect of the H5N1 storm will linger for a long time. The moratorium on H5N1 transmission research continues, meaning that important questions cannot be answered. On 29 March 2012 the United States government issued its Policy for Oversight of Life Sciences Dual Use Research of Concern (pdf).  According to this new policy, seven different types of ongoing or proposed research (including transmission studies) on 15 different pathogens (including highly pathogenic avian influenza viruses) must now be reviewed by a committee for risk assessment and if the development of mitigation plans. Once the work is in progress, no deviations from proposed experiments are permitted without further review. I understand from a number of virologists that this policy has had a chilling effect on avian influenza virus research. As a consequence, this area of investigation is likely to substantially contract, depriving us of potentially important findings that could be useful in limiting influenza and other viral diseases.

We are in this position because access to the Fouchier and Kawaoka papers was restricted, and few could actually read them to understand exactly what was done. I can’t think of a better reason for unrestricted publication of scientific findings.

  • Alan Dove

    It’s easy to blame the reporters, and I agree that in a perfect world Enserink et al. would have interviewed more sources for their original reports. But we do not inhabit a perfect world. When the researcher who conducted a study describes the work as scary and dangerous, and multiple well-regarded experts who have seen the paper also describe it that way, it’s reasonable for a reporter on deadline to presume that he’s probed a representative sampling of the truth. In this case, I think blame rests squarely on the shoulders of the scientists themselves, not “the media.” Because the manuscript was unpublished (and in fact classified at the point when these stories were written), reporters had to rely on the opinions of those who’d seen the data. Science journalists do make mistakes, but here it was the scientists who screwed the pooch.

    We’ll never know why NSABB members misunderstood and Fouchier apparently misrepresented the study. I suspect that Fouchier wanted to draw attention to his work by pointing out how dangerous H5N1 might be, without understanding how his statements would sound to the public. He may also have chosen his words poorly when being interviewed in English. The NSABB conducted its deliberations in a marathon of conference calls. That type of intensive, closed discussion often yields bad policy, especially when the group includes strong personalities who can dominate the debate and force an artificial consensus.

  • josh

    I admit, I jumped on the band-wagon saying how dangerous this was, thinking how all these ferrets were killed off after aerosol transmission.  Vincent, your commentary and the nice job done by Robert Roos summarizing the passaging (see below) is quite informative.

    http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/jun2112fouchier.html

    Enough about that, I’m really wanting to see what comes of this EV-71 virus in Malaysia.  I didn’t think this type of enterovirus caused severe damage to the lungs as being reported.  Very interested to see the genome sequence of this dangerous thing.

  • Virginiajim

    I like this conclusion about transparency,  but don’t know if it has universal application nor what, if any, other conditions should apply, such as responsibility.  It’s interesting that just as biology is undergoing a revolution, so is our ability to communicate. Even if we are responsible, as conditions change we need knowledge about what hazards are developing, how to recognize them and how best to quickly distribute information about their identification and containment.

  • http://www.virology.ws profvrr

    Josh, EV71 is known to be lethal: 240 dead so far this year in China. Why the Cambodian lethality surprises is not clear to me. Perhaps the children who end up in hospital are have mutations in immune response genes that predispose them to severe illness – which is what I think is happening to those who die of H5N1 infection.

  • http://www.virology.ws profvrr

    I don’t just blame the writers, I do think Fouchier is at fault as well. Unfortunately we will never know what he said to Enserink; how much of the hype did Enserink craft on his own? Perhaps this was one story that should not have been written. After all, being published in Science, it carried a lot of credibility, which is why it caused the echo effect (to use your term). And you won’t deny that the people he interviewed – NSABB members – all were ‘on board’ (another phrase of yours). If Enserink had spoken to Palese, Garcia-Sastre, Krug, Lamb, hell, even me, he would have received mitigating comments. Hell, I wrote mitigating comments right here without having seen the manuscript! It was just common sense. But Enserink did not, and therefore did the wrong thing. He must bear some of the blame.

  • josh

    Your right I researched it some more, and you talked about it in 2010 on TWiV….fascinating virus. It is so diverse in sequence, pin-pointing the lethal vs. non-lethal strains is quite a chore. Elegantly simple (being monopartitie) there is some great work that could still be done in the context of an infectious clone and mutants.

  • gsgs

    but it is obvious that you, Palese and presumably also Garcia-Sastre, Krug, Lamb,
    are at the lower end of the H5N1-threat-painting spectrum of flu-researchers.
    A more balanced journalist would have chosen a better average.
     
    E.g. from the list of the 39 who signed the research moratorium in Jan.Fouchier, García-Sastre, Kawaoka, Barclay, Bouvier, Brown, Capua, Chen, Compans,  Couch, Cox, Doherty, Donis, Feldmann, Guan, Katz, Klenk, Kobinger, Liu, Liu, Lowen,  Mettenleiter, Osterhaus, Palese, Peiris, Perez, Richt, Schultz-Cherry, Steel, Subbarao, Swayne, Takimoto, Tashiro, Taubenberger, Thomas, Tripp, Tumpey, Webby, Webster
     
    what would they have said ? What do they say now ?
    How does that compare with what you write here ?

  • http://www.psandman.com/ Jody Lanard M.D.

    Given what the Erasmus Medical Center website said (and still says) about Fouchier’s study, we don’t really have to obsess about whether the good science reporters quoted Fouchier accurately, or in context, etc. His own institution posted even more hyperbolic statements  than the reporters did, and the context is clear. All of the following Erasmus Medical Center statements, posted in both English and Dutch, went uncorrected for months. All but one are still posted as of today. 

    Here are quotes from the November 28 2011 Erasmus Medical Center press release,  dated 6 days after Enserink’s interview with Fouchier, and still posted as of today July 11 2012:

    http://bit.ly/HazZFt

    [Title] 
    Avian influenza could evolve into dangerous human virus

    [First sentence] 
    Erasmus MC researchers have discovered that the H5N1 influenza virus (bird flu) could develop into a dangerous virus that can spread among humans.

    [Other excerpts, with a direct quote from Fouchier]
    Of the 600 people who have to date been infected with the H5N1 virus worldwide, 60 per cent have died. 

    Scientists worldwide have been concerned with the question whether the virus could change into a virus that can spread among humans. “We have discovered that this is indeed possible, and more easily than previously thought”, says Ron Fouchier, researcher at Erasmus MC. “In the laboratory, it was possible to change H5N1 into an aerosol transmissible virus that can easily be rapidly spread through the air. This process could also take place in a natural setting.”[End of excerpts from press release]

    And here is the extremely hyperbolic, inaccurate, and misleading  first sentence from the Erasmus Medical Center FAQ about the study, which was posted from the end of November 2011 until about the time the Fouchier paper was published. I last accessed and took a screen shot of it on May 16 2012. At: http://psandman.com/articles/Fouchier.htm  

    [First sentence]
    Erasmus MC researchers have discovered that the avian influenza virus spreads more easily among humans than previously thought.[End of excerpt from FAQ]

  • guest

    Many real flu scientists (Palese et al.) had/have very distinct opinions from those offered by the NSABB folks (none of whom are real flu scientists).  This does not in any way mean that the opinions of Palese et al. are less likely to be correct.  In fact, those are the folks who know flu data/history/the virus better than anyone else.

  • gsgs

    taking the average of the expert opinions is the bestthat we can do, what else ?Whould you think that by following the debate and getting informed you can come up with a more qualifiedestimate than the average of experts ?
    That would mean you are better than them …

  • guest

     I just mean that we should look at who the “experts” are before we take their opinions into consideration.  There are no flu experts within the NSABB…  If you average the opinions of flu experts on this topic, I think you will find that there is not a huge spectrum of different opinions (one or two outliers, sure).

    Another well done piece on this topic:

    http://www.nature.com/nature/journal/v486/n7403/full/nature11170.html

  • Martin Enserink

    Vincent,

     

    I share your interest in the minutiae of the H5N1 debate, but I
    think your criticism of my story is off-target and unfair.

     

    You speculate that I quoted Ron Fouchier out
    of context when he said that he had created “probably one of the most dangerous
    viruses you can make.” I did not. Fouchier was referring to the
    ferret-transmissible H5N1 virus produced in his lab. He also confirmed that the
    message in the earlier New Scientist story
    that you mention–and that of another one in Scientific American–were basically accurate, and he did not
    indicate that either story hyped the threat.

     

    If Fouchier believed that I misquoted him or
    that my story was over the top, he never let me know; on the contrary, he wrote
    me that it was a “nice story”. When I asked him whether he regretted the
    “most-dangerous-virus” quote, at a press briefing in London more than three months after the story
    ran, he said he did not.

     

    Your claim that I only presented one side of
    the issue is inaccurate. Fouchier wanted his study published; when I wrote my
    story, the NSABB had already delayed publication and was very close to
    recommending that the paper not be published without major redactions. In other
    words, Fouchier and my two sources at the NSABB were on opposite sides of the
    most important issue.

     

    Of course, it would have added to the story
    if other virologists had discussed the dangers of the virus; I would have
    gladly included reassuring comments from informed influenza experts. But very
    few people knew the actual data at that point, so at best they could have
    offered speculations.

     

    There were compelling reasons to report that
    the virus was dangerous. I had talked to three sources who knew the paper:
    Fouchier himself and the two NSABB members, both well-respected scientists who
    had studied and debated the paper for many weeks. While their policy views may
    have differed, they corroborated each other on the dangers of the virus. Any
    good journalist would have reported those opinions and used a pithy quote to
    illustrate them. The lethality didn’t surface as an issue until much later.

     

    The first sentence of my piece indeed was
    dramatic; as journalists, we like to draw people into a story. That said, the
    vast majority of the influenza scientists I have talked to over the past decade
    have said that an H5N1 pandemic could cause disease and death on a large scale
    if it occurred. It’s one of the key reasons the H5N1 transmissibility studies
    were commissioned by NIH in the first place.

     

    Finally, it’s easy in hindsight to blame
    reporters for not talking to all the right people or not getting everything
    exactly right. But this story was intensively researched. I was the first to report
    Yoshihiro Kawaoka’s involvement in the H5N1 debate and tried very hard to get
    him to comment. I contacted many other scientists, biosafety and biosecurity
    experts, university officials, regulators and representatives of NIH and WHO. I
    think the result was a solid and balanced news story.

     

    It was not the last word on the risks of the
    virus, or on anything else for that matter. That’s how journalism works. If we had
    to wait until we got the story 100% right, we’d never write anything at all.

     

  • CV

    Interesting article and interesting conclusions about transparency.  But your criticism of Enserink is way off base.  His rebuttal below speaks for itself but I’d also point out that the commentor in his story that said “this work should never have been done” was attributed to Richard Ebright.  Ebright is not an NSABB member, which further demonstrates that Enserink found an additional outside commenter.  It also points out an error in your criticism that Enserink where you state he only quoted Fouchier or members of the NSABB.  The article may have is flaws but saying he violated a major tenet of journalism is akin to accusing a scientist of academic fraud.  It shouldn’t be thrown around lightly.

  • gsgs

    journalists should ask the experts for their probability
    estimates (numbers) that these bad things may happen.
    Instead they use words to describe the thread
    which are confusing to the people. (and lengthy)

  • gsgs

    the outliers are found here in this thread ?
    ahh, Morens,Taubenberger. Reminds me to an earlier paper
    by Morens,Fauci,Taubenberger about the H5N1-thread which
    we discussed in the forums as the “ode to uncertainety”

  • http://www.virology.ws profvrr

    From Martin’s comments (thank you), and also those of Jody, and others who have emailed me privately, it seems that the article accurately reflected Fouchier’s comments. 

    However, my other criticisms of the article are still valid. The article was about the danger of Fouchier’s ferret adapted virus – for which Enserink only spoke with NSABB members, aside from Fouchier. He should have spoken with other virologists. Enough of them had seen the presentation at Malta and could have had mitigating comments. Others could speak intelligently about the likelihood of the ferret-passaged virus of causing disease in humans. As it stands, the article was one-sided in presenting a fearsome outcome. Because it was published in Science, it garnered respect and was repeated subsequently many times.

    I understand that this is all clear in hindsight – but the article might have been far more cautious had others been consulted. Either present a more balanced view, or don’t publish it at all. 

  • Elizabeth Hart

    A media release published in Australia today announces:  “New Australian research showing that poultry
    vaccines have recombined to produce more virulent viruses has prompted the
    Australian Pesticides and Veterinary Medicines Authority (APVMA) to examine
    regulatory controls over the approval and use of veterinary vaccines.”

    Ref: “Agvet regulator responds to chicken vaccine concerns”. APVMA 13
    July 2012: http://www.apvma.gov.au/news_media/media_releases/2012/mr2012-04.php

    According to a report on Australia’s ABC News, the scientists involved
    in the research “say the findings are not only important for vaccines in
    chickens, but also for any vaccine which might be able to multiply – including those
    used in humans…Dr Joanne Devlin, a lecturer in Veterinary Public
    Health-Epidemiology at the Asia-Pacific Centre for Animal Health, says the
    deaths were caused when two vaccines used to treat the virus combined. “These
    new strains were formed by recombination from the different vaccine strains and
    that they were actually more virulent than the vaccine strains that gave rise
    to them,” she said. “This is something we’ve never…seen before in the
    field.” Live vaccines, where a weaker version of the virus is introduced
    to allow the immune system to build up its own defences, are quite commonly
    used for animals and humans, and include polio, measles, mumps, rubella,
    chicken pox and rabies.”

    Ref: “Chicken vaccines combine to create deadly virus”. ABC News, 13
    July 2012: http://www.abc.net.au/news/2012-07-13/chicken-vaccines-combine-to-create-deadly-virus/4127804

    The paper regarding this research has been published today in the
    journal Science.  The paper is titled “Attenuated
    Vaccines Can Recombine to Form Virulent Field Viruses”, authored by Sang-Won
    Lee et al.  Given the possible
    implications of this research, including relevance to the H5N1 controversy, it
    is surprising that this paper is currently not free access.

    This example of poultry vaccines recombining to produce more virulent
    viruses brings to mind “The Law of Unintended Consequences”, i.e. consequences
    of action that were not anticipated, which could be perverse effects that
    result in the opposite of what was intended.

    Ref: http://university-discoveries.com/the-law-of-unintended-consequences

    I think this highlights the care that should be taken in vaccination
    practice, across the variety of vaccines, e.g. live, inactivated, subunit,
    toxoid, conjugate, DNA or recombinant vector. 
    There is always the possibility of unintended consequences, over the
    short or long term, which is why what David Sackett calls the “unsuspecting
    healthy”(1) must learn to be vigilant and questioning about any medical
    interventions pressed upon them by the pharmaceutical industry and governments.

    There are some very alarming things happening in the vaccination
    industry, not the least of which is the US NIH funding research into making the
    H5N1 flu virus more transmissible.  (Also, in relation to the H5N1 controversy, my open letter to the NSABB re the political and ethical implications for lethal virus development provides some background: http://users.on.net/~peter.hart/Open_Letter_to_Paul_Keim_NSABB_31_Jan_2012.pdf  I am continuing to follow this matter with interest.)

    It seems to me there is a lot of fear-mongering, and ‘over-vaccination’
    of both humans and animals being promoted by pharmaceutical companies, and their
    supporters in the human and veterinary medicine establishment, including the World
    Health Organisation and Centers for Disease Control.  It’s about time the spotlight was thrown onto
    the exploitation of the “unsuspecting healthy”. 
    Who can we trust to do that?  The
    mainstream media needs to do more to expose this problem and warn the public.

    Ref. 1: Sackett, David L. The arrogance of preventive medicine. CMAJ
    August 20, 2002 Vol. 167 No. 4

  • Daniel Lee

    Virology is considered to be a subfield of microbiology or of medicine, by Daniel@ccie exam

  • Elizabeth Hart

    Further to my previous post, this article is interesting: “DNA vaccines and future of disease control”, The Poultry Site, 18 July 2012: http://www.thepoultrysite.com/poultrynews/26292/dna-vaccines-and-future-of-disease-control

    Here’s a quote:  
    “Bird diseases are also a target for DNA vaccines. With 55Bn chickens produced worldwide in 2010 (ref 2), there is huge market potential for new avenues that can keep poultry free of disease, and without some of the problems associated with conventional approaches. For instance, by just six weeks of age the average chicken has received between five and eight vaccinations; by 18 weeks this can be more than 12 live attenuated vaccines boosted with several inactivated shots to improve antibody levels in hens and offspring. So there is concern that intensive use of vaccines could be driving certain pathogens, notably Marek’s disease herpesvirus (MDV) and infectious bursal disease virus (IBDV), to become more virulent (ref 3).”

    I think this information about poultry vaccines is very relevant to general discussion about vaccination.

    PS: I listened to the audio of discussion on TWiV 191: “When two rights make a wrong” re recombination among attenuated herpesvirus vaccines leading to pathogenic viruses.  I was relieved that at least one of the virologists participating in the discussion took the matter seriously.  I wasn’t impressed with the flippant attitude of one of the participants…

  • Pingback: Contagions Round-up 24: The Links of Summer « Contagions()

  • Pingback: Social Capitalist Reform &raquo Mutant Bird flu strain reported.()

  • http://profile.yahoo.com/DGLEJBMBN2OXFAE356FFXDBJBU Elizabeth

    Research into potentially lethal pathogens appears to have blossomed in an over-the-top response to bioterrorism attacks in the US in 2001.(1,2) Perhaps this research has the potential to do more harm than good? I suggest we need critical analysis of what is going on, and who is really benefiting from the empire-building and enormous sums being spent in this area?

    Recently I took the opportunity to register my opposition to lab-engineering of potentially lethal pathogens. My submission to the Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (HHS) can be accessed via this link: http://bit.ly/U9nq4f

    My open letter re the political and ethical implications of lethal virus development, addressed to Paul Keim of the US National Science Advisory Board for Biosecurity (NSABB), can be accessed via this link: http://bit.ly/AfyAtQ

    Elizabeth Hart

    References:
    1. Erika Check Hayden. The price of protection. Nature. Vol. 477, 9 September 2011, pp 150-152: http://www.nature.com/news/2011/110907/full/477150a.html
    2. Erika Check Hayden. Pentagon rethinks bioterror effort. Nature. Vol. 477, 22 September 2011, pp 380-381: http://www.nature.com/news/2011/110920/full/477380a.html

  • Pingback: Fouchier vs the Dutch government on influenza H5N1 research()

  • Pingback: Public Health United | Viruses gone viral: difficulties in virus research communication()