Ferreting out influenza H5N1

6 December 2011

A laboratory in the Netherlands has identified a lethal influenza H5N1 virus strain that is transmitted among ferrets. These findings are under review by the National Science Advisory Board for Biosecurity (NSABB) to ensure that they do not constitute a threat to human health. Meanwhile both the popular and scientific press has been calling this a ‘virus that could change world history’. Even the usually restrained Helen Branswell writes that “…the dangerous virus can mutate to become easily transmissible among ferrets — and perhaps humans…” Should we be frightened?

Details of Ron Fouchier’s experiments are not known because the results have not yet been published. Reports at CIDRAP and Science indicate that Fouchier was attempting to make the H5N1 virus more transmissible in ferrets. This strain of influenza is lethal in birds and humans – there have been over 500 human cases with over 50% mortality. However, the virus is not readily transmitted among humans. The virus is lethal in ferrets but does not transmit among the animals. Fouchier selected a transmissible H5N1 variant by ferret-to-ferret passage. This experiment involves infecting a ferret, harvesting virus from the animal, and infecting another ferret. After ten such passages, the H5N1 variant could spread from one ferret to another by airborne transmission. The two amino acid changes that permit airborne spread among ferrets were identified.

Scientists appear to be responsible for the hype surrounding this experiment. Fouchier called it ‘one of the most dangerous viruses you can make’. Paul Keim, chair of NSABB, ‘can’t think of another pathogenic organism that is as scary as this one’, and Richard Ebright, a molecular biologist at Rutgers University says the experiment should not have been done. Martin Enserink writing in ScienceInsider says that the virus could change world history, and similar proclamations of doom can be found in the popular press.

I cannot fault the press for not having the background to interpret these studies, but scientists should know better than to declare that this is a dangerous virus. First and foremost, ferrets are not humans. Every influenza researcher will say that ferrets are a good model for influenza – they display similar flu-like symptoms, immune responses, and pathological alterations such as elevated temperature, weight loss, and histological changes. But it would be foolish to conclude that ferret influenza is the same as human influenza in all aspects. For example, not all influenza virus strains have the same virulence in humans and ferrets. A good example is the 2009 pandemic H1N1 virus which caused severe infections in some ferret studies, but was relatively mild in humans.

In other words, just because the Fouchier H5N1 virus is transmissible among ferrets does not mean that it will be equally transmissible among humans. The experiment to answer this question cannot be done.

Passage of viruses in a different host is one strategy for reducing the virulence in humans. This concept is explained in this passage from Principles of Virology:

Less virulent (attenuated) viruses can be selected by growth in cells other than those of the normal host, or by propagation at nonphysiological temperatures. Mutants able to propagate better under these selective conditions arise during viral replication. When such mutants are isolated, purified, and subsequently tested for pathogenicity in appropriate models, some may be less pathogenic than their parent.

The possibility that passage of the H5N1 virus in ferrets will attenuate its virulence in humans has been ignored.

In my view, it is highly unlikely that laboratory-modified viruses will be able to cause extensive disease in humans. When humans tinker with viruses, they generally do not know what the virus needs to replicate efficiently, cause disease, and transmit in humans. Consequently, they are likely to introduce changes that attenuate pathogenesis in humans. Nature is far better at producing viruses that can kill – to think that we can duplicate the enormous diversity and selection pressures that occur in the wild is a severe case of scientific hubris.

Another aspect of this story that deserves comment is the review by the NSABB. That body is charged with reviewing experiments that would render a vaccine ineffective; confer resistance to antimicrobial agents; enhance the virulence of a pathogen or make a non-pathogen virulent; increase transmissibility of a pathogen; enable evasion of detection; and enable weaponization of a biological agent or toxin. It is not clear to me how this committee could make some of these conclusions without data from human experiments. Nevertheless, why would the NSABB recommend against publication of Fouchier’s data? Could the sequence of the ferret adapted H5N1 be used for bioterrorism? It seems unlikely: it is not known if the virus would be pathogenic and transmissible in humans. Bioterrorists do not want to carry out an experiment; they want to instill terror. Why use a laboratory modified H5N1 strain when the sequence of the 1918 influenza virus, known to be a lethal and transmissible human virus, is readily available? Ebright calls the 1918 virus “the most effective bioweapons agent now known”.

No one can guarantee that Fouchier’s virus would not be lethal and transmissible in humans. But the same could be said about any number of laboratory modified viruses, none of which have attracted the attention of the NSABB or the press. When dealing with viruses, both caution and restraint are necessary qualities.

This article is based on the conversation with Rich Condit and Alan Dove on TWiV 159 and 160.

  • colm

    Luckily, there’s evidence that the 2009 pandemic vaccine confers resistance to 1918 infection, at least in mice. See:
    Immunization with 1976 swine H1N1- or 2009 pandemic H1N1-inactivated vaccines protects mice from a lethal 1918 influenza infection.
    Easterbrook JD, Kash JC, Sheng ZM, Qi L, Gao J, Kilbourne ED, Eichelberger MC, Taubenberger JK.
    Viral
    Pathogenesis and Evolution Section, Laboratory of Infectious Diseases,
    National Institutes of Allergy and Infectious Diseases, National
    Institutes of Health, Bethesda, MD 20892-3203, USA.

  • colm

    Also,
    Pandemic 2009 H1N1 vaccine protects against 1918 Spanish influenza virus.
    Medina RA, Manicassamy B, Stertz S, Seibert CW, Hai R, Belshe RB, Frey SE, Basler CF, Palese P, García-Sastre A.
    Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

  • http://www.virology.ws profvrr

    Correct, more on that here: http://www.virology.ws/2010/02/11/protection-against-2009-influenza-h1n1-by-immunization-with-1918-like-and-classical-swine-viruses/. Plus there is evidence that oldsters were more immune to 2009 H1N1: http://www.virology.ws/2009/11/02/why-being-older-is-a-good-defense-against-2009-h1n1-influenza-virus/

  • Stephen Braigen

    “In other words, just because the Fouchier H5N1 virus is transmissible among ferrets does not mean that it will be equally tranmissible among ferrets. ” Do you mean “equally transmissible among humans.”?

  • http://www.virology.ws profvrr

    An unfortunate typo…too quick to hit ‘publish’. Thanks, it’s been fixed.

  • Helen Branswell

    I said “perhaps in people” in my lead precisely because I didn’t want to readers to make the assumption that transmissibility in ferrets automatically means  transmissibility in humans. I appreciate being called “usually restrained,” but I don’t think I broke that pattern in my reporting on this story. 
    Cheers,

    Helen 

  • Stephen Braigen

    Much thanks for writing this up, by the way, I held roughly the same overall opinion (it should probably be published) – though it hadn’t occurred to me that we really don’t know how virulent this variant may be in humans. 

    I’ve been having discussions with friends regarding this to try to understand as many angles of the story as possible, as well as other discussions with a few individuals with more fervent opinions that this work should not have been done. Your commentary has already been quite helpful in all of these interactions.

  • Stephen Braigen

    Much thanks for writing this up, by the way, I held roughly the same overall opinion (it should probably be published) – though it hadn’t occurred to me that we really don’t know how virulent this variant may be in humans. 

    I’ve been having discussions with friends regarding this to try to understand as many angles of the story as possible, as well as other discussions with a few individuals with more fervent opinions that this work should not have been done. Your commentary has already been quite helpful in all of these interactions.

  • Chris

    All of which prompts further questions.

    SV40 proved cancerous in several animals, but most vacinees dodged that bullet – thankfully, after Beatrice Eddy got locked in a closet, and Michael Carbonne later ran out of friends at Bethesda.   It is easy now to argue there was no bullet for the most humans to dodge and perhaps neither should have talked to the press.  Yet if the truth turned out differently, who else at NIH was big enough to handle it?

    The press (lay and medical) is what it is, FBOW depending on your purpose.  The verdict on XMRV as a “contaminant” conveniently suggested something inert – which just also happened to have a preference for primate organs and multiple lab tissue types.  ‘Quite the little monster.  Whether it could cause human illness, there’s probably not a monkey left to tell us.  

    Which CDC is content with, I’m sure.   As readers of Mr. Tuller’s essay (Thank You) might finally grasp, if CDC still won’t study CFS as an organic illness, and continues to drag in correcting costly falsehoods it perpetrated, who in our federal health establishment can be trusted about anything?  

    Regarding “bioterrorists,” hey, it’s Earth – why so limit your thinking?  The Japanese in Manchuria loved their anthrax experiments, from raining bio-shrapnel on strapped-down POWs to feeding laced chocolates to Chinese kids.   Ken Abilek didn’t exactly work out of a garage either.  1918 wasn’t enough for any of these perversely sick minds needing toys of their own, backed by their governments directly or by blind eye.  

    I’d trust the ferrets more any day.  Bring on the next meteor.

  • Michael Mathison

    Thanks very much for this Vincent – an excellent dose of
    reason. On a related matter, I’ve been wondering for a while (from a layman’s
    perspective) about the often quoted 50% mortality for H5N1 in humans – which is
    presumably much of the foundation for its deep scariness. Is it not possible
    that H5N1 could actually be a virus with severe (and thus highly visible)
    outcomes for only a small subgroup of the population but that might actually cause
    only mild or even asymptomatic outcomes in everyone else? In other words, do we
    really know how many people have been exposed to and/or infected with this thus
    far apparently rare (in humans) virus? Given that these infections are sporadic
    and (almost) always associated with contact with birds, do we have good reason
    to assume that we are *not* missing quite a lot of transmissions of H5N1 from
    birds to humans that resulted in either mild or even asymptomatic outcomes?
    Presumably testing for H5N1 is only performed on presentation of very ill
    people and their immediate contacts, so, perhaps naively, should we not be
    surprised to find that a large proportion of all the people who have so far ever
    been confirmed with H5N1 were indeed very unwell or died? Maybe the answer to
    my question is that we would have expected the background influenza
    testing/typing (in countries where human H5N1 has been reported) to have picked
    up on mild infections if they were present?

  • Neeltje1984

    Hi Vincent, thanks for publishing a more restraint opinion on this research. Personally, I really don’t understand the bioterrorism threat. Surely, a weapon that would infect a large proportion of humanity with no known reason for selectivity, no vaccine against it and a 50-60% mortality rate would be an incredibly stupid weapon? Chances are that a large part of the terrorist’s families will die, plus nobody is able to control it. Better off picking something which stays local…

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  • gsgs

    and I hope the 1918 virus is not easily available, you can’t yet
    make a virus just from the sequences.

    But the Fouchier-experiment can be redone , whether published
    or not.

    Strange that it took 14 years to figure this out,
    given all the concern in those years.
    Now things have calmed down.
    Imagine we had read about that experiment in 2006 …

  • gsgs

    >Ferreting out influenza H5N1
    >6 December 2011
    >A laboratory
    >in the Netherlands has identified a lethal influenza H5N1 virus
    >strain that is transmitted among ferrets. These findings are under
    >review by the National Science Advisory Board for Biosecurity
    >(NSABB) to ensure that they do not constitute a threat to human
    >health. Meanwhile both the popular and scientific press has been
    >calling this a “virus that could change world history”. Even

    and half of mankind could die. But how likely ? “Noone knows …”

    >the usually restrained Helen Branswell writes that “… the dangerous
    >virus can mutate to become easily transmissible among ferrets
    >” -  and perhaps humans…” Should we be frightened?

    yes, but how much ?

    >Details
    >of Ron Fouchier’s experiments are not known because the results
    >have not yet been published. Reports at CIDRAP and Science indicate
    >that Fouchier was attempting to make the H5N1 virus more transmissible
    >in ferrets. This strain of influenza is lethal in birds and humans
    >- there have been over 500 human cases with over 50% mortality.
    > However, the virus is not readily transmitted among humans. The
    >virus is lethal in ferrets but does not transmit among the animals.
    > Fouchier selected a transmissible H5N1 variant by ferret-to-ferret
    >passage. This experiment involves infecting a ferret, harvesting
    >virus from the animal, and infecting another ferret. After ten
    >such passages, the H5N1 variant could spread from one ferret to
    >another by airborne transmission. The two amino acid changes that
    >permit airborne spread among ferrets were identified.

    just 2 aa in the whole genome ? Frightening. I remember, in 2005(?) we had the
    much cited study that suggested 10 mutations were needed to distinguish
    the 1918 virus from avian ones and that H5N1 already is getting some of those

    >Scientists
    >appear to be responsible for the hype surrounding this experiment.

    too much “hype” or too few, who knows. Compare with 2005f

    > Fouchier called it “one of the most dangerous viruses you can
    >make”. Paul Keim, chair of NSABB, “can’t think of another
    >pathogenic organism that is as scary as this one”, and Richard
    >Ebright, a molecular biologist at Rutgers University says the
    >experiment should not have been done. Martin Enserink writing
    >in ScienceInsider says that the virus could change world history,
    > and similar proclamations of doom can be found in the popular
    >press.

    the problem is the typical use of words “can”,”could”,”may”,…
    here, instead of giving probability estimates.
    Now, you say “does not mean”,”not guaranteed” …which is even
    less informative. Then you say “highly unlikely” , but even 1%
    would be highly frightening …

    >I cannot fault the press for not having the background
    >to interpret these studies,

    and I think this is because of the lack of clear words from scientist,
    i.e. subjective probability estimates.
    And the hesitation and non-insistence of the press to ask for those.

    > but scientists should know better
    >than to declare that this is a dangerous virus.

    you mean, it is not ??? You should know better …

    > First and foremost,
    > ferrets are not humans. Every influenza researcher will say that
    >ferrets are a good model for influenza – they display similar
    >flu-like symptoms, immune responses, and pathological alterations
    >such as elevated temperature, weight loss, and histological changes.
    > But it would be foolish to conclude that ferret influenza is
    >the same as human influenza in all aspects. For example, not all
    >influenza virus strains have the same virulence in humans and
    >ferrets. A good example is the 2009 pandemic H1N1 virus which
    >caused severe infections in some ferret studies, but was relatively
    >mild in humans.
    >In other words, just because the Fouchier H5N1
    >virus is transmissible among ferrets does not mean that it will
    >be equally transmissible among humans.

    right. And below you write:
    ” No one can guarantee that Fouchier’s
    virus would not be lethal and transmissible in humans. ”
    So it’s undecided either way. But it’s a clear indication that the
    chances are not bad (IMO > 20%) that the same few or other mutations
    would make it equally or better transmissable in humans.
    And yes, that would not yet give a pandemic … but maybe 10%
    that it would ? Give your estimate !

    > The experiment to answer
    >this question cannot be done.

    It can and it was. E.g. in USA 1918:
    Roseman,M.J.,Keegan,W.J.,Goldberger,J,and Lake,G.C.:
    Experiments upon volunteers …
    Maybe it is being done in China. And you needn’t necessarily
    risk human health, some questions can be ansered in simulations
    or cell cultures. Animal experiments can answer further questions.
    And I think it’s worth to be figured out. How much should be
    published – that’s another question

    >Passage of viruses in a different
    >host is one strategy for reducing the virulence in humans. This
    >concept is explained in this passage from Principles of Virology:
    >Less virulent (attenuated) viruses can be selected by growth
    >in cells other than those of the normal host, or by propagation
    >at nonphysiological temperatures. Mutants able to propagate better
    >under these selective conditions arise during viral replication.
    > When such mutants are isolated, purified, and subsequently tested
    >for pathogenicity in appropriate models, some may be less pathogenic
    >than their parent.
    >The possibility that passage of the H5N1 virus
    >in ferrets will attenuate its virulence in humans has been ignored.

    it did not happen in the ferrets. It did not happen in chicken and
    mice experiments with H5N1. It did not happen in humans (well,
    the current H5N1 in Egypt is less deadly, but not Indonesia,China,..)
    It’s possible but not very likely IMO (In my view, it is highly unlikely that laboratory-modified viruses
    >will be able to cause extensive disease in humans.

    now, this is strage. Who else thinks this ?
    There are lots of examples. Maybe we should run all viruses through a lab
    to make them less dangerous …

    >When humans tinker with viruses, they generally do not know what the virus
    >needs to replicate efficiently, cause disease, and transmit in
    >humans. Consequently, they are likely to introduce changes that
    >attenuate pathogenesis in humans.

    OK, maybe you meant that most changes are bad for the virus
    statistically. But those are being filtered out.
    The changes that survive can as well make it more dangerous,
    spread to other organs than the original.

    >Nature is far better at producing
    >viruses that can kill –

    nature has no interest to kill. The virus wants to replicate,
    but killing is usually a disadvantage here.
    In fact influenza mainly evolves in mallards and there it is most often
    not much pathogenic. When it jumps to other species, that is “accidental”
    and may cause severe disease, but the virus doesn’t benefit and after
    years,decades,centuries of evolution in those species it usually
    becomes less virulent.

    >to think that we can duplicate the enormous
    >diversity and selection pressures that occur in the wild is a
    >severe case of scientific hubris.

    they were quite successful. Apparently nature didn’t yet find
    those 2 or 5 mutations.

    >Another aspect of this story
    >that deserves comment is the review by the NSABB. That body is
    >charged with reviewing experiments that would render a vaccine
    >ineffective; confer resistance to antimicrobial agents; enhance
    >the virulence of a pathogen or make a non-pathogen virulent; increase
    >transmissibility of a pathogen; enable evasion of detection; and
    >enable weaponization of a biological agent or toxin. It is not
    >clear to me how this committee could make some of these conclusions
    >without data from human experiments. Nevertheless, why would the
    >NSABB recommend against publication of Fouchier’s data? Could
    >the sequence of the ferret adapted H5N1 be used for bioterrorism?
    >It seems unlikely: it is not known if the virus would be pathogenic
    >and transmissible in humans.

    “unlikely” could just only be Bioterrorists do not want to carry
    >out an experiment; they want to instill terror.

    all terrorism is experiment. They never know whether it works
    as planned.

    >Why use a laboratory
    >modified H5N1 strain when the sequence of the 1918 influenza virus,
    > known to be a lethal and transmissible human virus, is readily
    >available?

    is it ? Is it still dangerous to humans ?
    H5N1 is another HA, so pandemic potential, while for H1 we have some immunity.
    H5N1 is also much more deadly.

    >Ebright calls the 1918 virus “the most effective
    >bioweapons agent now known”.
    >No one can guarantee that Fouchier’s
    >virus would not be lethal and transmissible in humans. But the
    >same could be said about any number of laboratory modified viruses,

    the same = “No one can guarantee”.

    > none of which have attracted the attention of the NSABB or the
    >press. When dealing with viruses, both caution and restraint are
    >necessary qualities.

    But only influenza does these pandemics.
    And H5 is a candidate

    >This article is based on the conversation
    >with Rich Condit and Alan Dove on TWiV 159 and 160.

    

  • http://www.virology.ws profvrr

    Writing ‘perhaps in people’ is not clear enough for most people. In my view that statement should not have been in the first sentence of the article, but reserved for later when it could be fully explained.

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  • Ed

    We have known about this virus since 1997. The first of many papers that
    showed a successful protection by a vaccine candidate against HPAI H5N1
    in a mammlian system appeared less than a year later due to concerns
    about the pandemic potential of the virus: Protection against a lethal
    avian influenza A virus in a mammalian system. Riberdy JM, Flynn KJ,
    Stech J, Webster RG, Altman JD, Doherty PC. J Virol. 1999
    Feb;73(2):1453-9.
    The same year saw successful vaccine candidates in ferrets published.
    My
    point is, even if the virus the Fouchier and Kawaoka groups created
    were a threat we already have many vaccine candidates for it that could
    be put into production. I wonder if there is a expt. in either paper
    showing protection by such a vaccine.

    “The only thing we have to fear, is fear itself.”

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