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H5N1: Flu transmission work is urgent
Yoshihiro Kawaoka
Nature(2012)doi:10.1038/nature10884Published online 25 January 2012

Yoshihiro Kawaoka explains that research on transmissible avian flu viruses needs to continue if pandemics are to be prevented.

Highly pathogenic avian H5N1 influenza viruses first proved lethal in humans in 1997 in Hong Kong. Since 2003, 578 confirmed infections have resulted in 340 deaths (go.nature.com/epb7ts). Now widespread in parts of southeast Asia and the Middle East, H5N1 viruses have killed or led to the culling of hundreds of millions of birds.

To date, H5N1 viruses have not been transmitted between humans. Some experts have argued that it is impossible. But given the potential consequences of a global outbreak, it is crucial to know whether these viruses can ever become transmissible. Work by my group (accepted by Nature) and an independent study (accepted by Science) led by Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands, suggest that H5N1 viruses have the potential to spread between mammals. As the risks of such research and its publication are debated by the community, I argue that we should pursue transmission studies of highly pathogenic avian influenza viruses with urgency.

To determine whether H5N1 viruses could be transmitted between humans, my team generated viruses that combined the H5 haemagglutinin (HA) gene with the remaining genes from a pandemic 2009 H1N1 influenza virus. Avian H5N1 and human pandemic 2009 viruses readily exchange genes in experimental settings, and those from a human virus may facilitate replication in mammals. Indeed, we identified a mutant H5 HA/2009 virus that spread between infected and uninfected ferrets (used as models to study the transmission of influenza in mammals) in separate cages via respiratory droplets in the air. Thus viruses possessing an H5 HA protein can transmit between mammals.

Our results also show that not all transmissible H5 HA-possessing viruses are lethal. In ferrets, our mutant H5 HA/2009 virus was no more pathogenic than the pandemic 2009 virus — it did not kill any of the infected animals. And, importantly, current vaccines and antiviral compounds are effective against it.



NIBSC/SPL


H5N1 avian influenza virus particles.

Fouchier and his team also generated a transmissible H5 HA-possessing virus — meaning that two independent studies have demonstrated the potential for transmissibility of H5 HA-possessing viruses between ferrets. Their mutant H5 HA virus, generated in the genetic background of an H5N1 virus, did kill infected ferrets.

Some people have argued that the risks of such studies — misuse and accidental release, for example — outweigh the benefits. I counter that H5N1 viruses circulating in nature already pose a threat, because influenza viruses mutate constantly and can cause pandemics with great losses of life. Within the past century, 'Spanish' influenza, which stemmed from a virus of avian origin, killed between 20 million and 50 million people. Because H5N1 mutations that confer transmissibility in mammals may emerge in nature, I believe that it would be irresponsible not to study the underlying mechanisms.

The new work has implications for pandemic preparedness. There is an urgent need to expand development, production and distribution of vaccines against H5 viruses, and to stockpile antiviral compounds. Both studies identify specific mutations in HA that confer transmissibility in ferrets to H5 HA-possessing viruses. A subset of these mutations has been detected in H5N1 viruses circulating in certain countries. It is therefore imperative that these viruses are monitored closely so that eradication efforts and countermeasures (such as vaccine-strain selection) can be focused on them, should they acquire transmissibility.

Consequently, I believe that the benefits of these studies — the knowledge that H5 HA-possessing viruses pose a risk and the ability to monitor them and develop countermeasures — outweigh the risks. High biosafety and security standards can be met. Our experiments were carried out in a high-containment facility by a small group of highly trained individuals who operate under strict procedures to prevent the accidental release of viruses.

However, the US National Science Advisory Board for Biosecurity (NSABB) has recommended that details of both studies (including the mutations that confer transmissibility) should be restricted, and released only to select individuals on a 'need-to-know' basis. I acknowledge the advisory role of the NSABB, but I do not concur with its decision.

The primary justification for the NSABB's recommendation is that publication of our data “could enable replication of the experiments by those who would seek to do harm” (go.nature.com/nywkdy). But redacting our papers will not eliminate that possibility — there is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus.

The mechanism that the US government proposes for releasing data would also be unwieldy. Thousands of applications to access the research are likely to be filed, and potential background checks would create a huge administrative burden. We cannot afford to lose time if we are to combat emerging pandemic threats. Even if an efficient process can be established, it would be difficult to enforce continued confidentiality in the scientific community.

By contrast, wide data dissemination will attract researchers from other areas to contribute to the field. This is crucial, because new ideas are needed to answer some of the most urgent questions. For example, the specific mutations that we identified suggest that influenza transmission is more complex than anticipated and involves not only the receptor-binding properties of HA, but other biological and physical properties.

The redaction of our manuscript, intended to contain risk, will make it harder for legitimate scientists to get this information while failing to provide a barrier to those who would do harm. To find better solutions to dual-use concerns, the international community should convene to discuss how to minimize risk while supporting scientific discovery. Flu investigators (including me) have agreed to a 60-day moratorium on avian flu transmission research (go.nature.com/ttivj5) because of the current controversy. But our work remains urgent — we cannot give up.

http://www.nature.com/nature/journal/va ... 10884.html

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The use of H5 on a H1N1pdm09 background raises serious concerns regarding the H1N1pdm09 sequences in PB1 and PB2 is H5N1 isolates from Egypt.

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H1N1pdm09 in H5N1 in Egypt described here

viewtopic.php?f=5&t=7850&start=50

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TORONTO — A scientist at the centre of a raging controversy over bird flu transmission studies has broken his silence, in the process revealing information about his study that has not been made public previously.

In a commentary in the journal Nature, flu virologist Yoshihiro Kawaoka argued the work he and other high level influenza scientists do to try to puzzle out why some flu viruses spread in humans while others don't is too important to be shelved.

"Our work remains urgent -- we cannot give it up," wrote Kawaoka, who up until now has made no comment on the controversy that is pitting flu scientists against the community of biosecurity experts, some of whom insist no further transmission studies on the dangerous H5N1 flu virus should be undertaken.

In his commentary, Kawaoka revealed that his laboratory at the University of Wisconsin-Madison made a hybrid virus, fusing the hemagglutinin protein (the H in a flu virus's name) from H5N1 onto the human H1N1 virus that caused the 2009 pandemic.

The H1N1 virus spreads easily among people but H5N1 currently does not.

They found the viruses came together readily, and spread easily among ferrets kept in separate cages. Ferrets are considered the best animal model for predicting how a flu virus will act in humans and that type of study is meant to replicate the conditions under which flu viruses transmit among humans.

But while it was highly transmissible, the mutant virus did not kill the ferrets, Kawaoka reported. In fact, it was no more pathogenic to the animals than the 2009 H1N1 virus, he said.

"Our results ... show that not all transmissible H5 HA-possessing viruses are lethal," he wrote. HA is the short form for hemagglutinin used by flu scientists.

Nature, which plans to publish Kawaoka's paper, acknowledged it had given him dispensation to release information about this work. Normally journals will not publish studies if the findings have already been reported elsewhere, including in the mainstream media.

Spokeswoman Rachel Twinn said Nature decided it was in the public interest to allow Kawaoka to share details of his findings at this time.

Kawaoka -- who also has an appointment at the University of Tokyo -- runs one of two labs caught up in this roiling controversy. The other is run by Dutch virologist Ron Fouchier of Erasmus Medical Centre in Rotterdam.

Fouchier has been front and centre in this debate. And before now, much more was known about his work because he reported on it at an influenza conference in Malta in the fall. (Journals' pre-publication bans don't apply to presentations made to scientific conferences.)

Fouchier's team forced evolution of an H5N1 virus in ferrets, getting it to the point where it easily transmitted among the animals.

It was a full H5N1 virus -- it was not a hybrid -- and it was fatal to at least some of the animals. His paper is to be published in Science.

But before Science and Nature could publish the works, a panel of biosecurity experts urged the U.S. government to ask the journals not to publish the full works, saying to do so would be to print recipes for potential bioterror weapons.

The journals and the scientists have grudgingly agreed. But the flu community and some others in the science world have objected to the decision, saying to hold back the full details of the studies will impede science that needs to be done.

In the hopes of creating room for a compromise, last week 39 leading flu scientists -- including Kawaoka and Fouchier -- announced they would observe a voluntary 60-day moratorium (from Jan. 20) on H5N1 transmission studies. The idea was to give the global community time to sort through the troubling issues the work raises.

The World Health Organization, which has been asked to help mediate the problem, has said it will convene a meeting of technical experts in Geneva in mid February, probably Feb. 16-17.

The WHO's point person on the issue, Dr. Keiji Fukuda, has said the meeting will be small, involving fewer than 50 people. The scientists who did the studies as well as scientists from WHO's network of flu laboratories will be invited to attend.

A representative of the U.S. biosecurity panel -- the National Science Advisory Board on Biosecurity -- will also be invited to attend, Fukuda has said.

In his commentary, Kawaoka argued that trying to disseminate the full details of his and Fouchier's work on a need-to-know basis -- the U.S. proposal -- will be unworkable.

And he said redacting the studies won't eliminate the possibility that the information will become public.

"There is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus," he warned.



Read more: http://www.ctv.ca/CTVNews/Health/201201 ... z1kV4SAXhR

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Commentary

http://www.recombinomics.com/News/01251 ... pdm09.html

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Scientist Says Danger of Flu Strain He Created Is LimitedBy DONALD G. McNEIL Jr.
Published: January 25, 2012
A Wisconsin virology team that created a more contagious form of bird flu did not produce a highly lethal superflu, as a Dutch team famously and controversially did last year, according to the leader of the Wisconsin team.

Scientists to Pause Research on Deadly Strain of Bird Flu (January 21, 2012) Dr. Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo said in a commentary published online by Nature magazine that his team’s virus had infected ferrets through the air, but did not kill any of them. Ferrets catch flu just as humans do. Also, he said, “current vaccines and antiviral compounds are effective against it.”

By contrast, a virus created by Ron Fouchier of Erasmus Medical Center in the Netherlands had both the high lethality of the H5N1 avian flu and the ability to transmit easily among ferrets, touching off fears that his virus could cause a devastating epidemic in people.

However, a flu expert who serves on an American scientific advisory panel that looked at both Dr. Fouchier’s work and Dr. Kawaoka’s said the panel still believes key details should be censored from both papers before they are published to keep terrorists or rogue scientists from being to replicate the work, since the gene-manipulation techniques and intermediate mutations are as potentially dangerous as the end products.

Some scientists believe that Dr. Fouchier created what is potentially the most lethal virus in history — a flu that would transmit through a sneeze and kill more than 50 percent of those who caught it. That has led to calls for restrictions. Some — including the editorial board of The New York Times — have argued that the virus stocks should be destroyed; others want the virus restricted to a small number of laboratories with the highest biosecurity levels.

Some scientists, including Dr. Fouchier, argue that the fear of his virus is exaggerated. What works in ferrets does not always work in humans, they argue, and the true lethality of avian H5N1 is unknown because there have been fewer than 600 confirmed human cases and many milder ones might exist.

The debate about Dr. Kawaoka’s work is likely to be less heated since what he produced is less dangerous.

In his commentary for Nature, published online on Wednesday, Dr. Kawaoka said his team took the hemagglutinin gene from the avian H5N1 — which produces the “spike” that allows it to attach to receptors on cells in the human nose — and attached it to the other seven genes of the virus that caused the H1N1 “swine flu” pandemic in 2009.

That virus — once called “a real mutt” by a top virologist — was a novel mixture of genes from flus previously found in humans, birds, North American pigs and Eurasian pigs. It spread easily through humans but — despite having caused panic when it filled emergency rooms in Mexico City, where it was first noticed — ultimately turned out to be less lethal than most seasonal flus.

In an e-mail message, Dr. Kawaoka said that there were some mutations in the hemagglutinin gene he got from avian H5N1, but that he “could not comment on the specifics.”

A vaccine created to protect humans against infection with avian H5N1 virus also worked against his version of the virus, he said.

Asked if it was possible that his virus could be passed around among laboratories for further work while Dr. Fouchier’s virus ought to be more highly restricted, he said, “That judgment has to be made in discussions with the international scientific community.”

After reading Dr. Kawaoka’s commentary, Dr. Fouchier said it appeared that Dr. Kawaoka’s virus was less lethal than the one he created, although he reiterated that he did not think what he had created was as dangerous as it had been portrayed.

But, he said, “I have not seen Kawaoka’s data, so I would not know the details of his study.”

Richard H. Ebright, a chemistry professor and bioweapons expert at Rutgers University who has long opposed unrestricted research into making flu viruses more lethal, said his impression was that Dr. Kawaoka’s virus was less lethal than Dr. Fouchier’s, but that if the only vaccine against it was an experimental H5N1 vaccine that is not widely stockpiled, “it still has significant pandemic potential.”

Even if the virus is safe enough to be studied in laboratories with only medium-high biosecurity levels, he said, “this virus will not be the endpoint — the first experiment that will be done with it will be an effort to enhance its lethality.”

That process, he argued, should not go forward without national or international review.

“These are decisions that cannot be left to the individual investigators,” he said.

Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota and a member of the National Science Advisory Board for Biosecurity, said the panel still wants the details of Dr. Kawaoka’s work censored as it does those of Dr. Fouchier.

“We have concerns both about the organisms and about how you manufacture them,” he said.

http://www.nytimes.com/2012/01/26/healt ... ss&emc=rss

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A mutant bird flu virus created in a laboratory by University of Wisconsin-Madison virologist Yoshihiro Kawaoka did not kill any of the infected ferrets involved in the research, and current vaccines and antiviral compounds were effective against it, Kawaoka disclosed in a commentary published Wednesday in the journal Nature.

The discovery that the bird flu virus, scientifically known as H5N1, could potentially be transmitted between mammals has led to fears of both accidental release and misuse of the research. Scientists involved in the research agreed last week to halt their research for 60 days, until an international forum can be held to discuss it.

The virulence of the virus Kawaoka's team of researchers created in a lab has not been publicly disclosed until now, and Kawaoka has not previously spoken about the details of his latest work because his research manuscript has not yet been published. It is typical not to discuss findings until research is peer reviewed and published.

In his commentary in the journal that plans to publish his research, Kawaoka says that H5N1 viruses circulating in nature may already pose a threat because influenza viruses constantly mutate and can cause pandemics.

A subset of the specific HA mutations identified by Kawaoka's research team, and by another independent team of Dutch scientists, has already been detected in H5N1 viruses circulating in certain countries, according to Kawaoka. It is therefore imperative, Kawaoka argues, that these viruses are monitored closely so that eradication efforts and countermeasures can be focused on them if they should acquire transmissibility.

"In response to scare stories about the H5N1 virus, (Kawaoka) flags that the work also revealed that not all transmissible H5 HA-possessing viruses are lethal," said a Nature news release advancing the commentary.

"In fact, his team showed that, in ferrets, the mutant H5 HA virus was no more deadly than the pandemic 2009 virus. Importantly, Kawaoka’s mutant virus did not kill any of the infected animals, and current vaccines and antiviral compounds were effective against it."

Kawaoka and his colleagues generated viruses that combined the H5 haemagglutinin (HA) gene from bird flu with genes from a pandemic 2009 H1N1 swine flu virus, demonstrating that this mutant virus could spread from infected to uninfected ferrets via respiratory droplets in the air.

Kawaoka argues in his commentary that research into deadly pathogenic viruses must continue if pandemics are to be prevented.

Kawaoka suggests, after reviewing many factors, that pursuing studies of highly pathogenic viruses must be done with urgency.

Kawaoka also argues that U.S. National Science Advisory Board for Biosecurity recommendations to leave key details out of his paper, and a paper the Dutch research team submitted to the journal Science, will not eliminate the possibility of experiments being replicated by those who want to do harm.

In reality, he says, there is already enough information publicly available to allow someone to make a transmissible H5HA-possessing virus. He also suggests that mechanisms proposed by the U.S. government, in which researchers will submit individual applications to access results, will create a “huge administrative burden” which may cause delays in combating emerging pandemic threats.

Kawaoka concludes that leaving key details out of his research manuscript, intended to contain risk, may in fact make it harder for legitimate scientists to get information, while failing to prevent it getting into the hands of those who wish to do harm. He instead suggests that the international community should focus on how to minimize risk while supporting scientific discovery.

http://www.jsonline.com/blogs/news/138054408.html

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In the heated debate about two labs that engineered a variant of the deadly H5N1 avian flu virus that for the first time easily transmits between mammals, one critical voice has been missing: Yoshihiro Kawaoka. But today, Kawaoka speaks his mind in a Nature commentary and in a detailed response to questions from ScienceInsider.

A virologist at the University of Tokyo and the University of Wisconsin, Madison, Kawaoka led one of the studies that has sparked alarm around the world that these lab creations might escape or give ideas to bioterrorists. In a commentary published online by Nature today, he offers intriguing details about his study, a report of which has been accepted by the journal but remains unpublished. Kawaoka also discusses his thoughts about the recommendation from the U.S. government's National Science Advisory Board for Biosecurity (NSABB) that Nature and Science, which has accepted but not published a paper by the second lab that did these studies, redact key portions of the experiments to prevent the widespread dissemination of the recipe for a potential bioweapon.


As Kawaoka explains, his experiment differs in several keys ways from one led by the lab of Ron Fouchier at Erasmus MC in Rotterdam, the Netherlands. Both teams did their experiments in ferrets, a favorite laboratory model for studying transmission of influenza viruses as they mimic viral spread in humans. Until now, H5N1 has never efficiently transmitted between humans or ferrets, although it decimates flocks of chickens and often kills the mammals it infects. Fouchier, who has discussed his work at scientific meetings and with the media, concocted a transmissible H5N1 in ferrets by both manipulating viral genes and repeatedly passaging the virus through the animals to help it adapt to that host. This virus was highly lethal.

Kawaoka, in contrast, stitched the hemagglutinin gene from the avian virus—the H5—into a H1N1 virus that easily spreads between humans and caused the relatively mild 2009 pandemic. His mutant, like Fouchier's, readily transmitted between ferrets housed in different cages, but it was not lethal. "And, importantly, current vaccines and antiviral compounds are effective against it," writes Kawaoka in his commentary.

Although Kawaoka joined Fouchier and others last week in signing an agreement to suspend studies for 60 days on H5N1 viruses that can transmit in mammals, he emphasizes in both his commentary and to ScienceInsider that he strongly disagrees with efforts to limit this work and its full publication. "As the risks of such research and its publication are debated by the community, I argue that we should pursue transmission studies of highly pathogenic avian influenza viruses with urgency," he writes in Nature. "Because H5N1 mutations that confer transmissibility in mammals may emerge in nature, I believe that it would be irresponsible not to study the underlying mechanisms."

Kawaoka emphasizes that the benefits of conducting and fully publishing this work outweigh the perceived risks. He contends that "there is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus," highly trained researchers have conducted the work under stringent biosafety standards, the findings can help inform surveillance efforts, and the proposed mechanisms for restricting access to the data are "unwieldy." He further stresses that the work may well attract other investigators to help answer critical questions. He notes, for example, his lab's surprising finding that the mutations connected to transmission do not simply involve the way influenza's hemagglutinin protein binds to cellular receptors, as many researchers assume. "The redaction of our manuscript, intended to contain risk, will make it harder for legitimate scientists to get this information while failing to provide a barrier to those who would do harm," he writes.

Fouchier, who has been in close contact with Kawaoka during this controversy, welcomed his colleague going public with his thoughts about the issues. "I think it is a very powerful statement about the factual benefits of this type of work that by far outweigh the theoretical risks," says Fouchier. "By following the NSABB advice, the world will not get any safer, it may actually get less safe."

In an e-mail response to questions submitted by ScienceInsider, Kawaoka explains that he has not spoken out until now in part because of his discussions with Nature. "The journal advised me to avoid talking to the media until the paper was published," he wrote. "Without being able to describe our findings, I cannot address fully the issues the media want to discuss." He said he decided to break his silence because of the decision to delay publication of his study. "I felt that now, especially with publication of the statement that we would pause the transmission studies, it was time to comment," he said.

Kawaoka appeared unruffled by assertions that this type of research itself is irresponsible and should never have been conducted. "Actually, I don't let this type of criticism bother me," he wrote. "I acknowledge the public anxiety about research with highly pathogenic avian influenza. But, despite what the headlines say, I know our research has the potential to provide significant public health benefits."

In Japan, which unlike the United States has had several outbreaks of H5N1 in birds, "not much" controversy has surrounded this study, he said, as "the public has concerns about a genuine risk that exists in nature rather than a potential risk by bioterrorism." He added that "people wonder why we are pausing the research—they think it is important that we continue."

Kawaoka agreed to the 60-day moratorium because he hoped it would lead to a more thoughtful discussion about the issues. "I realized the controversy about these experiments had provoked a very serious situation and that discussions about regulating and publishing our research were taking place without the input of scientists," he said. "And we were losing the support of the public, those who we meant to benefit from our findings."

He said he is confident that 60 days is enough time to resolve many of the issues raised by the work. "We should be able to find solutions if people are willing to listen to one another and make decisions based on data, not fear," he concluded.

http://news.sciencemag.org/scienceinsid ... -h5n1.html

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Pandemic 2009 H1N1 virus gives wings to avian flu

25 Jan 2012 | 18:17 GMT | Posted by Declan Butler | Category: Biology & Biotechnology, Health and medicine, Policy, Swine flu


Has the 2009 H1N1 flu pandemic increased the risk that the H5N1 avian flu virus could evolve to create a human pandemic?

That’s a possibility raised by the work of Yoshihiro Kawaoka of the University of Wisconsin, Madison, the main conclusions of which — but not the details — are revealed in a Comment article in Nature today. His team created a virus that has the H5 haemagglutinin (HA) surface protein from the H5N1 virus, with all the remaining genes coming from the 2009 pandemic H1N1 virus. The resulting virus proved to be highly transmissible in ferrets, and is therefore likely to have the same behaviour in other mammals, including humans.

What’s intriguing is that before the 2009 pandemic, several research groups had tried the same experiment, using the garden-variety seasonal H1N1 flu, but without success. The difference is that the 2009 pandemic H1N1 virus, which is a triple reassortant of pig, avian and human viruses, contains the triple reassortant gene (TRIG) cassette, which is believed to make it far easier for a flu virus to swap genes with those from other species. This suggests that H5N1 may find it much easier to reassort with pandemic 2009 H1N1 virus circulating in the wild to create a pandemic virus, whereas it had coexisted with seasonal flu since 1997 without evolving into a pandemic strain, explains Bruno Lina, a virologist and flu researcher at the CNRS, France’s basic-research agency, who works at the University of Claude Bernard Lyon-1.

The study by Kawaoka’s team, which has been accepted for publication by Nature, is one of two studies that have succeeded in creating H5N1 strains capable of transmitting between ferrets. The other, by a team led by Ron Fouchier of Erasmus Medical Center in Rotterdam, the Netherlands, has been submitted to Science. The papers have been at the centre of controversy since 20 December, when the United States government — acting on advice from the US National Science Advisory Board for Biosecurity (NSABB) — asked both journals to publish only the main conclusions of the two flu studies, but not to reveal details. Insights from the research might help to improve pandemic preparedness in the future, but some are concerned that the publication of such work would amplify the risk of an accidental, or intentional, release of the virus that could spark a human pandemic. Flu researchers working on such studies last week declared a 60-day voluntary pause to allow governments and other bodies “time to find the best solutions for opportunities and challenges that stem from the work” (see ‘Pause on avian flu transmission studies‘).

Kawaoka and Fouchier succeeded in creating the transmissible virus in completely different ways. Fouchier used mutation, taking a H5N1 virus and then mutating it until it became transmissible. He initially introduced three mutations, using a technique called reverse genetics, but the resulting virus was not transmissible, so he then took that virus and passaged it through multiple ferrets, a procedure that is known to allow viruses to adapt to their host. The result was a virus with just five mutations, which were enough to make it highly transmissible.

Kawaoka instead used reassortment, which occurs in the wild. He took an HA protein from H5N1 and inserted it into a virus made of up genes from the pandemic 2009 H1N1. The flu virus has eight genes. Two code for the surface proteins HA and neuraminidase (NA), and six code for internal proteins. The eight genes are on separate segments, which means that when two different flu viruses infect the same host, they can swap genes and create new viruses in a process known as reassortment. An H1N1 human and H5N1 avian virus, for example, would generate a new virus that has most of the genes from the human virus, making it transmissible in humans, but an avian haemagglutinin and/or neuraminidase. A largely human virus carrying an H5, to which humans have no previous exposure of immunity, could cause a pandemic if it retained the transmissibility of the human virus, and the lethality of H5N1.

Fouchier’s virus was lethal in ferrets, whereas Kawaoka’s was “no more pathogenic than the pandemic 2009 virus”, and killed none of the animals. A reassortant that occurred in the the wild might have different pathogenicities. But two independent groups have now shown that H5N1 can transmit in ferrets, and so such human-transmissible viruses could potentially arise naturally in avian and other animal populations. What controls the exchange of genes between viruses is poorly understood, says Lina, who himself failed in the past to create highly transmissible reassortants of H5N1 and seasonal H1N1. Triple-reassortant viruses that have this TRIG cassette, of six highly conserved internal genes, seem capable of capturing various HA and NA genes from multiple species, he says. “The pandemic 2009 H1N1 virus has a flexibility of function which makes it capable of associating at the molecular level with virus and gene segments from pig, bird and humans.”

The 2009 pandemic H1N1 is circulating in humans in countries such as Indonesia, China and Egypt, where H5N1 cases in human continue to occur. Co-infection of a person with both viruses would give them opportunities to reassort. Pandemic H1N1 also infects pigs, from which it originally emerged, which could provide further opportunities for reassortment. This emphasizes the need for better surveillance to detect human cases of H5N1 infection.

Monitoring of human cases could also help to prevent flu viruses acquiring human transmissibility. There has been some evidence of limited human-to-human transmission of H5N1 in clusters of human cases, and a virus that passes along even a small chain of human hosts has opportunities to adapt to its host, just as H5N1 did in Fouchier’s ferrets.

But as a news article in this week’s edition of Nature shows (see ‘Caution urged for mutant flu work‘), surveillance of H5N1 in birds worldwide is patchy, particularly in poorer countries, where the virus is prevalent. It is also largely geared towards simply detecting and monitoring outbreaks, and few of the viral samples collected are ever sequenced, with just 160 H5N1 isolates submitted to the GenBank database last year. Moreover, if H5N1 surveillance in birds is poor, the situation is far worse in pigs, where there is virtually no systematic surveillance, even in richer countries. H5N1 infections in pigs are uncommon and cause only mild illness, creating little economic incentive to monitor them — GenBank contains partial sequences from just 24 pig H5N1 isolates in total.

http://blogs.nature.com/news/2012/01/pa ... n-flu.html

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Open the debate on flu research
Discussions over H5N1 studies must be international and transparent, says Anthony Fauci.

Declan Butler 25 January 2012

As director of the US National Institute of Allergy and Infectious Diseases, Anthony Fauci oversees much of the flu research in the United States.

Insights from research that has created strains of the H5N1 avian flu virus that are highly transmissible in mammals might help to improve pandemic preparedness in the future. But concerns have been raised that the publication of such work would amplify the risk of an accidental, or intentional, release of the virus that could spark a human pandemic. Flu researchers working on such studies last week declared a 60-day voluntary pause to allow governments and other bodies “time to find the best solutions for opportunities and challenges that stem from the work" (see 'Pause on avian flu transmission studies').

Anthony Fauci is the director of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, which funds much of flu research, including such H5N1 transmission studies. He tells Nature about his hopes for a meeting to be hosted by the World Health Organization in Geneva, Switzerland, next month, at which flu experts will come together to consider the many thorny issues raised by such research, and how best it might safely proceed. It as part of an ongoing international effort to establish a framework for global oversight of research that increases the transmissibility of the H5N1 virus, and the data it generates.

The research community seems to be deeply split on the relative risks and benefits of flu research. How will this meeting help?
The degree of polarization in the scientific community is unprecedented, and that has motivated me to push very, very hard for transparent, open discussion of these issues. We need to get people in the same room discussing the pros and cons rather than having duelling soundbites. That doesn't help anybody.

There have been understandable concerns that the discussion so far has been behind closed doors, and is being dominated by the United States. I have been very uncomfortable with that perception, so I have been pushing to hold this international forum. The US government really does not want to, and should not, totally drive a debate that involves global health and international issues, scientists and laboratories.

Some researchers have suggested that such research on the H5N1 virus might let scientists scan flu viruses in animal populations for these mutations conferring mammalian transmissibility and get early warning of, or avert, a pandemic. But is that realistic?
How would one translate knowledge of mutations into a practical capability to spot their evolution, when there is very limited surveillance, we have few sequences of animal H5N1 virus isolates and it takes a really long time to get them? That is a problem, but it doesn't necessarily negate the potential importance of such knowledge, should we get the ability, perhaps through specialised centres, that could do much more extensive sequencing of sample viruses from outbreak areas.

These are exactly the types of conversations that I hope will take place at foras in the coming months, including that next month. I think that one of the indirect, almost unintended, benefits of the controversy over this research is that it is getting people to focus on the weaknesses of how we are currently addressing the H5N1 threat. Proving that the virus can become highly transmissible may mean that we will start taking seriously the failings and gaps in our surveillance capability.

Are we in danger of paying too much attention to just the sets of mutations highlighted by the recent research, when there are many others to worry about?
Having a menu of mutations that many studies indicate are usually associated with some increase in transmissibility is important knowledge to have. But it's true that if you focus in only a narrow way on those, you may miss the mutation that is really important. I use the metaphor that the bullet that kills you is the one you don't hear. But that doesn't rule out the fact that knowing about these mutations may be helpful.

Are there any areas where you would say there is an immediate public-health benefit that can be had from this research?
I think any immediate benefit would have been a benefit in terms of surveillance, but you make the point that from a logistics standpoint that would be difficult, so I would say that in a perfect world the immediate benefit would be in surveillance, but in the world we live in that will be difficult to do.

If there were major, immediate, public-health benefits to this research, higher risks might be acceptable. But if any potential benefits are years down the line, shouldn't we take our time to get regulation of this right?
I totally agree with you, and that's why I am very much in favour of the pause in such research. What is the rush? As I pointed out in a commentary that I wrote for The Washington Post, there are potential advantages to having the information from this research, but my positive inclination for these types of studies, is more in expanding the envelope of understanding of the interface between animal and human influenza, and the biological context in which species adaptability and transmissibility occurs.
Journal name:
Nature
DOI:
doi:10.1038/nature.2012.9896
http://www.nature.com/news/open-the-deb ... rch-1.9896

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