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Much Ado About What? The H5N1 Story Gets Murkier Every Day

Posted on by Laurie Garrett

Let’s all take a deep breath, shall we?

As we have repeatedly warned since last November, the man-made H5N1 debate has now widened to include politicians. Flu scientists have displayed extreme hubris in their confidence that they could find an effective balance between the biosecurity risks posed by creation of a mammal-to-mammal transmissible form of bird flu, versus the public health benefits of improved understanding of how that jump in transmission-potential occurs. They have shunned all engagement in the issue by “outsiders” and even tried to exclude the non-influenza biology and public health communities in the ongoing debate.

They have behaved like a special interest cabal. In the latest salvo from defenders of the man-made H5N1 flu research the entire debacle apparently now boils down to irresponsible media. As always happens with cabals that have grown defensive, the “blame the media” strategy becomes the final refuge. One supporter of the man-made H5N1 research went so far last week in Washington as to grab the microphone at a meeting and declare: “It’s lazy and sloppy reporting and I think we should be putting just as much effort to bear on making the journalists behave responsibly,” as various agencies are now exerting to limit potential biosecurity threats from man-made H5N1 viruses.

Perhaps, in order to avoid censorship of full publication of the H5N1 research papers we should now inflict censorship on the mainstream media?

Some scientists have gone so far as to claim that a massive global H5N1 control effort, executed throughout mostly poor countries vigorously since 2005, was entirely needless, as the virus is, they claim, all but harmless. The same researchers, arguing in defense of their personal research, or work that they supported through pass-on grants from the U.S. National Institutes of Health, now insist that what happens in ferrets poorly predicts human risks. So, they say, the man-made virus that kills ferrets will probably be no threat to people.

“If one were going to deduce anything [about] the efficiency of spreading, we would have to conclude that this virus does not spread yet like a pandemic or a seasonal influenza virus,” researcher Ron Fouchier said of his man-made H5N1 last week in Washington.

Moreover, the details of what the flu scientists actually did to H5N1 keep changing. Indeed, Dr. Anthony Fauci, Director of the U.S. National Institute of Allergy and Infectious Diseases, made it clear in his remarks at aFebruary 29 American Society of Microbiology meeting that basic information from Ron Fouchier, of Erasmus University in Rotterdam, and Yoshi Kawaoka of the University of Wisconsin in Madison has strangely morphed over time. The two researchers told the National Scientific Advisory Board on Biosecurity about their work in November, spawning the NSABB December recommendation that details never be published, lest they serve as a cookbook for terrorists or other ne’er-do-wells. But the same scientists gave different information, as well as new data, to the World Health Organization experts’ meeting on February 16-17, prompting an entirely different official response. The WHO group recommended full publication of the scientists’ papers, after a brief period of “education to calm public anxiety,” as WHO’s Dr. Keiji Fukuda explained. Given the discrepancy, Fauci said at the ASM, the NSABB should reconvene, review the newer data and experimental results, and reconsider their recommendation for censorship of publication of the research papers.

The difference between what the NSABB was told and concluded, versus what the WHO gathering – of mostly flu virologists – was told and decided is only one small piece of a mindboggling schism that has emerged in nearly every fundamental aspect of H5N1 threat assessment. Sensenbrenner and his political counterparts all over the world have cause to ask, “What the hell is going on?”

After trying to reconcile comments made by scientists about the research at varying time points over the last few months The New York Times declared on March 3rd that H5N1 is “the Doomsday virus” that merits far more credible investigation:

 “Dr. Fouchier’s new claims are only the latest bizarre twist in a global health debate that badly needs an objective, independent arbiter. The public needs to know whether this virus is a potentially big killer, and if so, how it should be contained. It needs to know what details can be published without giving terrorists a recipe for a biological weapon. And it needs to know that a mechanism will be put in place to assess all the risks and benefits of such research before it is approved — not after a new virus has been created.” 

Let’s step back.

To Congressman Sensenbrenner and other political leaders concerned about the potential for an influenza pandemic: In September 2011, when Fouchier first presented his now infamous man-made H5N1 revelations at a small scientific meeting in Malta, the consensus view of the deadly bird flu virus could be summarized as: 

  • H5N1 first emerged in southern China sometime in the 1990s, and garnered global attention in 1997 when it raged through Hong Kong, sickening 18 people, killing six of them, and forcing destruction of the entire poultry population of the region. Fukuda told author Alan Sipress. “It looks like young people dying from something new. So it really brought us back to 1918,” and the great flu pandemic.
  • Blood tests of farmers, healthcare workers and the poultry-control workers found only nine individuals that had antibodies to H5N1 without having been sick. It seemed that a new virus was in the world, rarely capable of infecting human beings but fatal for about one out of five people that caught H5N1 infection. Two leaders of the Hong Kong anti-flu effort were Drs. Margaret Chan and Keiji Fukuda: Today, Chan is Director-General of the WHO and Fukuda is Assistant D-G in charge of pandemic responses.
  • Hong Kong’s control measures paid off: H5N1 was not again detected until 2003, when outbreaks in Thailand in commercial poultry farms signaled its return. The virus had mutated since 1997; it underwent two subsequent rounds of mutation in 2004 and 2005, vastly increasing the range of bird species H5N1 could infect, and the geographic distance of its spread. By the end of 2005 the virus could be found in birds from southernmost Indonesia, north thru Asia into Siberia, west to the European Atlantic coast, and south again to equatorial Africa.
  • Since 2005 the virus has resurfaced every year with devastating impact on birds, killing up to 100% of some species that were infected. In some countries H5N1 is endemic, including Indonesia, China, Egypt, Nigeria. Despite enormously difficult and costly control efforts, culling hundreds of millions of birds, obliterating small farming businesses, vaccinating chicken flocks from Papua New Guinea to Istanbul, H5N1 keeps returning, mutating, and defying human eradication efforts.
  • About 60 percent of people sickened by the virus have died. In Indonesia the percentage is much higher – more than 85%. In Egypt, much lower at about a third. If the virus ever managed to be human-to-human transmissible, it would pose an apocalyptic threat to humanity.
  • There was evidence of a few cases of person-to-person transmission of H5N1 within households and hospitals, but by far the majority of detected cases got infected after handling an ailing bird or consuming bird products.
  • In lieu of testing H5N1 effects on human beings – which is clearly unethical – the best experimental substitute is the ferret, a weasel-like mammal. The receptors located on respiratory tract cells in the throat, nostrils and lungs of ferrets are very similar to those in human beings. Prior research on the animals showed that bird flus needed to mutate in fewer than six ways to become humanly transmissible: The exact mutations necessary had been identified individually by various research teams.

The NSABB, citing the high virulence and lethality of H5N1, recoiled at deliberate manufacture of a virus capable of transmitting between mammals. Were such viruses to escape their laboratory confines, or were malevolent individuals to copy the Fouchier or Kawaoka efforts for nefarious purposes, the results could be catastrophic. So, NSABB concluded, the “how-to” details of the experiments should never be published.

In order to reverse the NSABB fiat Fouchier, his financial supporters at Mt. Sinai School of Medicine in New York (chiefly Dr. Peter Palese, whose lab passed NIH research money onto Dutch scientist Fouchier), and a coterie of their supporters set out to dispel all the assumptions that lend credence to the notion of unique H5N1 danger. First, they argued that the ferret is a lousy research model: transmission and death in the ferret has nothing to do with human outcomes (or almost nothing, or impossible to extrapolate).

Cong. Sensenbrenner, we wonder:

  • If that is so, why did Fouchier and Kawaoka use ferrets at all?
  • Why, in justifying their experiments, do they argue that the ferret studies provide clear guidance for public health leaders regarding what they should watch out for and make vaccines against?
  • Why have American taxpayers been asked to fund ferret influenza research for well over a decade?
  • Should you, Cong. Sensenbrenner, justifiably question whether any further U.S. taxpayer funds should be spent working with ferrets?

They then took on the very lethality of H5N1, arguing that by pooling all studies ever conducted on human outbreaks of the disease in a statistical survey (known as a metanalysis), Palese concluded that no more than 2 percent of human H5N1 cases are lethal in people; perhaps only 1%. Far from being the most dangerous microbe on Earth, they insist, H5N1 has infected thousands of people harmlessly. It’s a wimp. According to the WHO, as of March 5, 2012 the virus has since 2003 sickened 592 people, killing 349 of them, or 57%. If Palese were correct, there ought to be more than half a million people in the world with H5N1 antibodies in their blood, indicating they were harmlessly infected with the virus.

Congressman Sensenbrenner, this leads us to ask: 

  • If H5N1 offers only a 1% chance of killing an infected human, should Sensenbrenner and other political leaders question why we are spending billions of dollars annually supporting overseas animal control efforts, pharmaceutical research for novel vaccines and treatments, and basic influenza research?
  • In 2002 the NIH research budget for all influenza work was $17 million. Since H5N1 reemerged in 2003 the NIH has spent $1.9 billion, some of it directed to Fouchier, Palese, Kawaoka and several of the scientists now decrying the NSABB decision: Should Sensenbrenner and other politicians now cut off that money on the grounds that H5N1 is not dangerous and therefore poses no unique threat to the American people?
  • By 2009 USAID was spending nearly $1 billion/year helping poor countries find H5N1 and stop outbreaks – should that all now be cut? Congress has already cut the Centers for Disease Prevention to the bone, and shaved 50,000 public health jobs from states and cities in the U.S.: Should we now conclude it is safe to eliminate the entire biosecurity/influenza budget?

In November Fouchier told Science magazine that the virus he’d made is “probably one of the most dangerous viruses you can make.” When he presented the work in Malta two months earlier he shrugged and told the audience, “I did a very stupid thing.”

But last week at the ASM meeting Fouchier disclosed further details regarding his mutant virus, arguing that it really wasn’t a very dangerous microbe, after all. The notion that it would be capable of causing a pandemic was, “far-fetched” Fouchier insisted. For the first time he publicly stated that his virus – which bears 5 single nucleotide mutations, three of which were engineered into it, the other two of which arose through passage of the microbe through successive ferrets – doesn’t kill animals unless it is manually stuffed down their throats. If animals sneezed or coughed at one another, the infection was passed, but it never proved lethal. His key slide:

“It is absolutely clear that H5N1 is deadly for chickens,” Fouchier told the ASM gathering. “You inoculate a chicken the chicken will drop dead. But in mammals this is certainly not the case. It we infect ferrets for instance with very, very high doses…and put it straight down into the lungs of the animals – yes, the animals will drop dead. And they will do so by about day 3. But if we infect ferrets or other mammals by an intranasal route the animals generally do not get sick at all. They might get a little bit of flu, but they certainly do not drop dead…The mutant virus only causes disease in 1 out of 8 animals if we [intranasally] inoculate at this very high dose. But if we now look after aerosol transmission we actually see no severe disease at all.”

Fouchier concluded: “It is certainly not lethal if ferrets start coughing and sneezing to each other.”

This is in striking contrast to what Fouchier told Science reporter Martin Enserink on 23 November 2011, who wrote in ScienceInsider:

In a 17th floor office in the same building, virologist Ron Fouchier of Erasmus Medical Center calmly explains why his team created what he says is "probably one of the most dangerous viruses you can make"—and why he wants to publish a paper describing how they did it. Fouchier is also bracing for a media storm. After he talked to ScienceInsider yesterday, he had an appointment with an institutional press officer to chart a communication strategy.

Perhaps the striking changes on Fouchier’s tone have something to do with advice from that communications team.

For the first time Fouchier revealed in last week’s ASM meeting that most – perhaps all? – of the genetic changes made in the Indonesian flu strain, turning it into a mammalian infector were directly manipulated. Or – and his remarks were quite confusing on this point – he has done a separate round of experiments in whichhe made the five mutations directly, not via passaging of infections through generations of ferrets, as was originally explained.

British reporter Debora MacKenzie of New Scientist is one of the most careful science journalists I know. She was in the audience in Malta in September, and heard Fouchier’s presentation last week in Washington. Sheconcludes: “What's going on is the continued dispute about whether the work can be published…Fouchierpresented the new information at the Washington meeting. Nothing in his talk contradicts the story I heard in Malta, although it may refute some of the more hysterical interpretations of it. You just have to listen carefully.”

In September in Malta Fouchier said all his animals died when exposed airborne to the mutant virus. And that is true. But what he didn’t say in Malta, but did say in Washington, is that the “airborne” exposure was manually stuffing virus right down the animals’ throats. They did not die when passively exposed to the air or sneezes from another infected animal.

I first realized something was strange on February 20th when I saw a report on ABC News – the only TV coverage to date in which Fouchier allowed cameras inside his lab. In the report Fouchier said 100% of his animals got infected, and 100% died. I was startled – if true, this was a significantly more dangerous microbe not only than what he had described in Malta, but more terrifying than any virus every found on Earth. I reached out immediately to ABC News and begged them to get back to Fouchier for clarification. They did, and ABC Producer Bruno Roeber spoke with Fouchier. On February 23 Roeber sent back word that Fouchier agreedthat he had spoken of 100% ferret death, “But he now says that while the ferrets died it was not when they caught the virus via aerosol ‘Only upon ‘high dose intratracheal challenge, we see death.’ This is a distinction her never made in conversation with [correspondent] Jeffrey or me. In fact, we never heard about intratracheal challenge in any conversation with him.”

Measuring the shedding of virus from infected animals – a common way to determine an animal’s likelihood or spreading disease – Fouchier conceded that the original wild Indonesian H5N1 caused more ferret shedding than his mutated strain did. I live tweeted this key set of points as follow (hash marks and such removed) from the ASM meeting:

  • Compared 2 Indonesian viruses, one wild H5N1, one changed thru reverse genetics, 3 mutations made. Ferrets in cages.
  • Wild H5N1 not spread ferret- to -ferret between cages. Mutant form -- spread to 3 of 4 ferrets via sneezing. Repassage it:
  • On repassage get 100% spread betwn ferrets via sneezing. "Now know which mutations necess. 4 transm. between ferrets"
  • Amt virus shed by infected ferrets MUCH lower with H5N1 compared to 2009 H1N1 flu. Airborne spread NOT kill ferrets
  • Ferrets only die from mutant H5N1 if virus admin'ed into trachea in high dose. Aerosol exposure causes mild flu
  • Insists mutant H5N1 not dangerous "very few humans would develop severe disease" Should work continue? "Yes"
  • Fouchier: blames the media for "misperceptions" and "distortions". Need to publish in full to clear up what really happened

The CDC flu team used the methods is seems Fouchier deployed but reached opposite conclusions regarding pandemic potential – or the opposite of what Fouchier originally said about pandemic potential.

Congressman Sensenbrenner, we have many times warned that the stakes in this debate go far beyond whether or not Drs. Fouchier and Kawaoka should publish full details regarding their experiments. At this point we have no choice but to support full disclosure, simply to find out the truth, as the spin and experimental sagas keep changing.

But political pressure should now be applied to ensure that this debate gets out of the clutches of the flu cabal, and that decisions reached by government authorities – in the US, Scandinavia, Netherlands, EU and the rest of the world – not simply deal with the H5N1 virus. As we have noted in past articles and blogs since November, biology is in the midst of a spectacular revolution. Fantastic things are happening with synthetic and DIY biology – most of it absolutely thrilling and worthy of strong support. But it also poses possibilities that go well beyond the comparatively crude scientific methods apparently deployed by Fouchier and Kawaoka – creating risks that policies forged in this flu atmosphere must manage to address.

So, Congressman Sensenbrenner, take a deep breath. And keep asking questions. This entire mess has only just entered Phase Two: bargaining. Phase Three will bring hard ball negotiations and, we hope, solutions.

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