Science Publishes The Fouchier Ferret Study

 

BSL-4 Lab Worker - Photo Credit –USAMRIID  

 

# 6398

 

Just over 9 months ago, at the 2011 ESWI Influenza Conference in Malta, Dutch researcher Ron Fouchier described the results of a groundbreaking – and later, ground shaking – experiment he’d conducted with the H5N1 avian flu virus and ferrets.

 

Katherine Harmon’s piece in Scientific American (see SciAm: What Will The Next Influenza Pandemic Look Like?) briefly touched on his work, but it was Debra MacKenzie’s article a week later (see New Scientist: Five Easy Mutations) that really called attention to this experiment.

 

Fouchier was quoted as saying that he’d `mutated the hell’  out of the H5N1 virus in the lab, and then passed it serially through 10 ferrets, during which time it mutated further to become easily transmissible among the lab animals while retaining virulence.

 

Halfway across the world, Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine announced the creation of a comparable H5N1 super flu at roughly the same time.

 

Quietly at first, and then rising to a crescendo, a number of biosecurity experts began to openly question the wisdom of publishing details of (and in some cases, even conducting) these types of experiments.

 

Their concerns included the potential for an accidental lab release of the virus, and the possibility that someone could use this knowledge – if published – to create a bio-weapon.

 

The debate within the scientific community was both lengthy and visceral. A recommendation from the NSABB to redact portions of Fouchier’s study for publication was met with heavy criticism.

 

Those wishing to review that process (some might call it an ordeal) can select this link which will return more than two dozen blog posts on that intense debate.

 

After much discussion, it was decided that both Kawaoka’s and Fouchier’s (revised) studies should be published in full, and six weeks ago, the first paper appeared (see Nature Publishes The Kawaoka H5N1 Study).

 

 

Today the Journal Science publishes the long-awaited Fouchier study in a special section that includes an treasure trove of other H5N1 research-related reports, perspectives, news stories, and even an audio podcast.

 

To great credit to the editors and publishers of Science, all of these articles are being made available – in their entirety – to the public. 

 

 

 

With well over 100 pages of reports and supporting material, there’s a lot here to read and absorb (and a lot of it, particularly for non-scientists – is admittedly tough sledding).

 

Luckily, I’m sure we’ll be hearing a good deal of expert dissection and analysis emerging over the next few days.

 

Under the latest H5N1 news, you’ll find the following offerings:

 

Public at Last, H5N1 Study Offers Insight Into Virus's Possible Path to Pandemic M. Enserink

For Young Scientists, A Wild Ride - M. Enserink

How Much Longer Will Moratorium Last? - D. Malakof

Read all of Science's News coverage of the H5N1 controversy.

A Science Podcast brings us an Interview with Bruce Alberts; Science's Editor-in-Chief.

 

From Fouchier and his team we get the main event; an 8-page, highly technical report on how they created a genetically modified, mammalian-transmissible, version of the H5N1 virus:

 

Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets

Sander Herfst, Eefje J. A. Schrauwen, Martin Linster,
Salin Chutinimitkul, Emmie de Wit, Vincent J. Munster, Erin M. Sorrell, Theo M. Bestebroer, David F. Burke, Derek J. Smith, Guus F. Rimmelzwaan, Albert D. M. E. Osterhaus, Ron A. M. Fouchier

(Excerpt)

Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far
has not acquired the ability to be transmitted by aerosol or respiratory droplet (“airborne transmission”) between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets.

 

 

 

 

Fouchier also includes 34 pages of supporting material.

 

Erasmus Medical Center, where these experiments were conducted, at the same time (2pm ET today)  released a new Bird Flu Research Q&A that responds to several important questions, including:

• What was the purpose of the work?
• What experiments were done?
• What are the main conclusions?
• How does this help public health?

 

 

Along with the publication of Fouchier’s study, we also get a major report from C.A. Russell et al., that looks at the potential for these mutations to occur naturally in the wild.  The report’s pedigree also includes Albert Ostershaus, Ron Fouchier, and Yoshiro Kawaoka.

 

 

The Potential for Respiratory Droplet– Transmissible A/H5N1 Influenza Virus to Evolve in a Mammalian Host

Colin A. Russell, Judith M. Fonville,  AndréE.X.Brown, David F. Burke, David L. Smith, Sarah L. James, Sander Herfst, Sander van Boheemen, Martin Linster, Eefje J. Schrauwen, Leah Katzelnick, Ana Mosterín, Thijs Kuiken, Eileen Maher, Gabriele Neumann, Albert D. M. E.  Osterhaus, Yoshihiro Kawaoka, Ron A.M.Fouchier, Derek J. Smith

ABSTRACT

Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these  substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals.

 

We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.

 

Again, you’ll find copious supplementary information available for this paper as well.

 

Also included in this special section are related commentaries, policy forum papers, and perspectives, including:

 

Statement by Science Editor‐in‐Chief Dr. Bruce Alberts Regarding Publication of H5N1 Avian Influenza Research

 

Regulating the Boundaries of Dual-Use Research - Mark S. Frankel

 

Influenza: Options to Improve Pandemic Preparation -Rino Rappuoli and Philip R. Dormitzer

 

Benefits and Risks of Influenza Research: Lessons Learned - Anthony S. Fauci and Francis S. Collins

 

Evolution, Safety, and Highly Pathogenic Influenza Viruses - Marc Lipsitch, Joshua B. Plotkin, Lone Simonsen, Barry Bloom

 

Securing Medical Research: A Cybersecurity Point of View - B. Schneier

 

 

Like many of you, I’m sure I’ll be spending a good amount of time over the next few days trying to absorb, and understand, this avalanche of new information.

»» Read More

Nature: Bird Flu Research Oversight

 

BSL-4 Lab Worker - Photo Credit –USAMRIID  

# 6342

 

From the journal Nature today, a detailed look by Brendon Maher at how the NSABB examined the Kawaoka and Fouchier H5N1 research papers, and the long, tortuous road towards a final decision on their publication.

 

For those who did not follow this story, briefly:

 

In September of 2011, one of the best known flu researchers in the world - Ron Fouchier of Erasmus Medical Centre in Rotterdam - announced at a scientific conference that he’d managed to turn H5N1 into a virulent, and easily transmissible (among ferrets, anyway) pathogen.

 

(You can read about this work in Katherine Harmon’s Sci-Am article and in a follow up to this story in New Scientist: Five Easy Mutations.)

 

Halfway across the world, Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine announced the creation of a comparable H5N1 super flu at roughly the same time.

 

Within weeks biosecurity experts began to question whether scientists should even be tinkering with this particularly lethal flu strain, and whether (or how) those results should be published.

 

The NSABB was tasked with reviewing these projects, and making a recommendation to the United States government.

 

After first recommending that the full studies not be published, the NSABB – under mounting pressure from a number of directions – reconsidered their decision in light of `revised and clarified’ manuscripts from Fouchier, and green-lighted their publication.

 

Brendon Maher explores the process by which these disparate decisions were reached, and the lingering concerns held by many involved in. 

 

This is an important story, and well worth reading in its entirety, so follow the link below:

 

 

Nature | News Feature

Bird-flu research: The biosecurity oversight

The fight over mutant flu has thrown the spotlight on a little-known government body that oversees dual-use research. Some are asking if it was up to the task.

• Brendan Maher

23 May 2012

»» Read More

ScienceInsider: A Flawed Flu Papers Process?

 

 

# 6283

 

 

The `must read’ for today comes from the pen of CIDRAP director and NSABB  board member Michael Osterholm in a letter to the Associate Director for Science Policy at the NIH where he critiques the NSABB’s recent reversal of their previously unanimous decision to block the full publication of Ron Fouchier’s controversial H5N1 ferret studies.

Of the eighteen members who voted again on the issue, twelve recommended publication while six did not.  Osterholm voted in the minority.

 

Jon Cohen writing for Science’s ScienceInsider provides the background, in his report:

 

 

A Flawed Flu Papers Process?

by Jon Cohen on 13 April 2012, 4:26 PM

 

Last month, one-third of the members of the U.S. National Science Advisory Board for Biosecurity (NSABB) disagreed with the group's recommendation to publish in full two studies that describe how to make the bird flu virus transmissible in mammals. Now one of the six dissenters, influenza epidemiologist Michael Osterholm of the University of Minnesota, Twin Cities, has written a sharp critique of the meeting that led to the decision. In a letter sent yesterday to Amy Patterson, an official at the U.S. National Institutes of Health whose office oversees NSABB, Osterholm charged that the meeting was "designed to produce the outcome that occurred."

(Continue . . .)

 

Osterholm’s 7-page letter is available  HERE - and regardless where you stood on the publication of Fouchier’s research - Osterholm calls into serious question many aspects of the NSABB review process that should be of concern to all of us.

Helen Branswell has even more on all of this in her recently updated Canadian Press story:

 

Updated: April 13, 2012 | 6:39 pm

Flu expert slams bird flu panel process

By Helen Branswell The Canadian Press

 

In a world where we can now create `designer’ organisms in the laboratory, the biosecurity issues facing life sciences research are becoming increasingly complex. While the benefits of this kind of work may prove enormous, the risks are not trivial.

 

Despite reassurances from researchers, mistakes, laboratory accidents, and even intentional misuse of these new technologies are always possible.

 

Against this backdrop, public confidence in science and scientists continues to deteriorate (see Science at the Crossroads). Already there is a good deal of public resistance to the use of GM (Genetically Modified) food crops, and bio-engineered organisms, and the anti-vaccine movement continues to thrive.

 

If this type of research is to have a viable future, then it must first engender the public’s trust.

 

And based on their handling of this controversy over the past few months, the scientific community has got a long way to go.

»» Read More

NIH Video: Dual Use Research Of Concern (DURC)

 

NIH Brochure on Dual Use Research

 

# 6264

 

 

Over the past few months an obscure acronym has made it’s way into numerous blogs, news headlines, and even popular usage; DURC -  Dual Use Research of Concern.

 

While it is the current debate over controversial H5N1 transmissibility studies that has prompted its emergence (see The Biosecurity Debate On H5N1 Research), DURC has been a matter of national concern for a number of years.

 

The NIH produced a 7 minute video in 2010 highlighting the concerns of DURC, called Dual Use Research: A dialogue.  Click the link, or the image below to watch.

 

 

 

Last week the  Office of Science Policy at the NIH released a 4 page set of guidelines for DURC (Duel Use Research of Concern) projects designed to beef up oversight and biosecurity of U.S. funded projects.

 

The scope of this new policy is to cover research on the most dangerous of biological organisms, listing;

 

a)  Avian influenza virus (highly pathogenic) 
b)  Bacillus anthracis
c)  Botulinum neurotoxin
d)  Burkholderia mallei
e)  Burkholderia pseudomallei
f)  Ebola virus
g)  Foot-and-mouth disease virus
h)  Francisella tularensis
i)  Marburg virus

j)  Reconstructed 1918 Influenza virus

k)  Rinderpest virus
l)  Toxin-producing strains of Clostridium botulinum
m) Variola major virus
n)  Variola minor virus
o)  Yersinia pestis

 

Specifically any research that seeks to:

 

a)  Enhances the harmful consequences of the agent or toxin; 

b)  Disrupts immunity or the effectiveness of an immunization against the agent or toxin without
clinical or agricultural justification;

c)  Confers to the  agent or toxin resistance to clinically or agriculturally useful prophylactic or
therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies;

d)  Increases the stability, transmissibility, or the ability to disseminate the agent or toxin; 

e)  Alters the host range or tropism of the agent or toxin;  

f)  Enhances the susceptibility of a host population to the agent or toxin; or

g)  Generates or reconstitutes an eradicated or extinct agent or toxin listed in Section (III.1) above.

 

 

For more on DURC, the NSABB, and the Office of Biotechnology Activities, you may wish to visit the following links.

Brochure on Dual Use Research

Video on Dual Use Research

International Meetings

NSABB FAQs

Summary of NSABB Reports and Activities

Responsible Communication of Life Sciences Research with Dual Use Potential

Global Status of Strategies for Addressing the Intersection of Science and Security

Roundtable at the ASM Biodefense and Emerging Diseases Research meeting

»» Read More

Webcast: Royal Society Meeting on H5N1 Research

 

Note: Due to this Symposium my blogging over the next couple of days will probably be light.

# 6258

 

Tomorrow (Apr 3rd) and the following day (Apr 4th), The Royal Society, London will host a 2 day international symposium on the `practice and policy of H5N1 research’.

 

Attending will be some of the biggest names in influenza research - including Ron Fouchier and Yoshihiro Kawaoka – whose H5N1 research papers got the green light by the NSABB for publication last Friday.

 

Other recognizable names include (but are not limited to) Robert Webster, Malik Pieris, Dr. Paul Keim, Michael Osterholm, Thomas Inglesby, Dr Philip Campbell, Dr. Bruce Alberts, Laurie Garrett, David Brown, Professor Peter Doherty, and Arthur Caplan.

 

 

The good news is that this two day session will be live streamed on the web. 

 

Note: Broadcast times listed are for local London Time.  So adjust for your time zone accordingly.

 

 

For details, including a list of sessions and participants, follow the link below.

 

H5N1 research: biosafety, biosecurity and bioethics

9:00 am on Tuesday 03 April 2012 – 6:00 pm on Wednesday 04 April 2012

 

 

 

For details on how to watch live, visit the following link:

 

H5N1 research: biosafety, biosecurity and bioethics

An international symposium

Tuesday 03 April 2012 - Wednesday 04 April 2012
at The Royal Society, London

Organised by the Royal Society in partnership with the Academy of Medical Sciences and the Foundation for Vaccine Research with support from the American Society for Microbiology, the Bill & Melinda Gates Foundation, Fondation Mérieux, the German National Academy of Sciences Leopoldina, Institut Pasteur, and the Society for General Microbiology.

 

Webcast requires Windows Media Player and a 500k or better broadband connection. Test your connection speed here. For best results use Internet Explorer and 1024X768 or higher resolution. Latest Windows Media Player download here. MAC users: if the video does not play, please ensure you have the appropriate media player or flip4mac. If you are still having problems with a MAC try this test and this live link.

 

 

Since I will be away from my computer for part of the day tomorrow and will miss some of these broadcasts, I am hoping that these videos will appear on the Royal Society TV website within a few days.

»» Read More

The Scientist: Deliberating H5N1 Research

 

 

# 6256

 

The decision on Friday by the NSABB to clear the way for the publication of the Fouchier and Kawaoka research papers has not lessened the debate over the risks and benefits of DURC (Duel Use Research of Concern).

 

Today The Scientist published an extended debate over the appropriateness of this type of research, soliciting opinions on three different questions from a variety of experts.

The questions being:

 

QUESTION 1: To Research or Not to Research?

QUESTION 2: To Publish or Not to Publish?

QUESTION 3: How to Regulate?

 

Responding to these issues are Rob Carlson, Peter Doherty, Richard H. Ebright ,David L. Heymann, Michael J. Imperiale, Yoshihiro Kawaoka, Lynn Klotz,Randall Murch, Daniel Perez,John Steinbruner, and Ed Sylvester.

 

Follow the link below to read:

 

 

Deliberating Over Danger

 

The creation of H5N1 bird flu strains that are transmissible between mammals has thrown the scientific community into a heated debate about whether such research should be allowed and how it should be regulated.

April 1, 2012

»» Read More

NSABB Clears H5N1 Studies For Publication

 

# 6254

 

 

From Helen Branswell this evening, a report that the NSABB – after reviewing new data submitted by flu researcher Ron Fouchier – has cleared the way for the publication of both his, and Yoshihiro Kawaoka’s work on ferret transmissible H5N1.

 

The vote to publish Karaoka’s paper was unanimous, while the vote for Fourchier’s was 12 to 6.

 

The NSABB serves in an advisory capacity only, and it will be up to the United States government to either accept or reject their recommendations.

 

 

Follow the link below for the story by Helen Branswell.

 

US biosecurity panel clears publication path for controversial bird flu studies

By Helen Branswell, The Canadian Press |   

 

For more on what the future of U.S. government sponsored life sciences research will look like, you may wish to revisit yesterday’s blog on U.S. Issues New DURC Oversight Rules.

»» Read More

U.S. Issues New DURC Oversight Rules

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

# 6252

 

 

While the current H5N1 research row has centered around the publication of two specific research projects (see NSABB To Re-examine H5N1 Research Risks), the bigger issues at play involve how we oversee (and fund) future life sciences research in order to avoid future controversies.

 

To that end, today the Office of Science Policy at the NIH released a 4 page set of guidelines for DURC (Duel Use Research of Concern) projects, and ordered a review of all current life sciences projects.

 

For those unfamiliar with the lexicon of biomedical research, DURC in this new policy is defined as:

 

. . . life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security

 

The scope of this new policy is to cover research on the most dangerous of biological organisms, listing;

 

a)  Avian influenza virus (highly pathogenic) 
b)  Bacillus anthracis
c)  Botulinum neurotoxin
d)  Burkholderia mallei
e)  Burkholderia pseudomallei
f)  Ebola virus
g)  Foot-and-mouth disease virus
h)  Francisella tularensis
i)  Marburg virus

j)  Reconstructed 1918 Influenza virus

k)  Rinderpest virus
l)  Toxin-producing strains of Clostridium botulinum
m) Variola major virus
n)  Variola minor virus
o)  Yersinia pestis

Specifically any research that seeks to:

 

a)  Enhances the harmful consequences of the agent or toxin; 

b)  Disrupts immunity or the effectiveness of an immunization against the agent or toxin without
clinical or agricultural justification;

c)  Confers to the  agent or toxin resistance to clinically or agriculturally useful prophylactic or
therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies;

d)  Increases the stability, transmissibility, or the ability to disseminate the agent or toxin; 

e)  Alters the host range or tropism of the agent or toxin;  

f)  Enhances the susceptibility of a host population to the agent or toxin; or

g)  Generates or reconstitutes an eradicated or extinct agent or toxin listed in Section (III.1) above.

 

 

While this new policy does not automatically halt or defund research found to meet the DURC definition, it does require greater agency oversight and an assessment of the risks and benefits of any research, along with the development of appropriate risk and safety measures.

 

As far as `teeth’ in this new policy, if perceived risks cannot be satisfactorily mitigated Federal Agencies may request voluntary redaction of scientific papers, may move to `classify’ the research, or may withhold or terminate financial support.

 

Agencies that conduct or fund life sciences research are instructed to perform a review to identify any projects that meet the DURC definition, and if found, to:

 

 

c)  Assess the risks and benefits of such projects, including how research methodologies may
generate risks and/or whether open access to the knowledge, information, products, or technologies  generates risk.

d)  Based on the risk assessment, in collaboration with the institution or researcher, develop a risk
mitigation plan to apply any necessary and appropriate risk mitigation measures.  In addition:

• i)  For DURC that is proposed and not yet funded, departments and agencies will assess
  whether to incorporate risk mitigation measures in the grant, contract, or agreement.

• ii)  For currently funded DURC, funding departments and agencies will consider modifying the grant, contract, or agreement to incorporate risk mitigation measures. If such modifications are not possible or desirable, departments and agencies will seek voluntary implementation of mitigation measures by the institution. 

 

 

You can access the full policy on the Office of Biotechnology Activity’s News Page:

 

Now Available:

US Government Issues Policy on Oversight of Life Science Dual Use Resarch of Concern:

The purpose of this Policy is to establish regular review of United States Government funded or conducted research with certain high-consequence pathogens and toxins for its potential to be dual use research of concern (DURC) in order to: (a) mitigate risks where appropriate; and (b) collect information needed to inform the development of an updated policy, as needed, for the oversight of DURC. The fundamental aim of this oversight is to preserve the benefits of life sciences research while minimizing the risk of misuse of the knowledge, information, products, or technologies provided by such research.

(March 29, 2012)

 

 

And just as I was finishing this post up, I saw that Lisa Schnirring at CIDRAP NEWS has an excellent overview of this new policy.   Read it at:

 

US debuts life sciences dual-use research policy

Lisa Schnirring Staff Writer

 

It will be interesting to see how this new policy is received by scientists working in the life sciences field.

»» Read More

NSABB To Re-examine H5N1 Research Risks

 

# 6249

 

 

Today and tomorrow the NSABB (National Science Advisory Board for Biosecurity) will reconvene to re-examine the issues surrounding the publication of controversial H5N1 research that produced a ferret-transmissible strain of bird flu.

 

Last September, Ron Fouchier from the Netherlands (and almost simultaneously Professor Yoshihiro Kawaoka from Wisconsin) announced success in creating enhanced strains of the avian flu virus in the laboratory, which subsequently unleashed a firestorm of controversy.

 

For some background, see Katherine Harmon’s Sci-Am article , New Scientist: Five Easy Mutations, & NPR: Bio-Terrorism Concerns Over Bird Flu Research.

 

Over the ensuing six months we’ve seen a steady stream of opinion pieces from both sides of this debate (see H5N1 Research: A Plethora Of Positions), including side forays into the lethality of the H5N1 virus (see The Great CFR Divide).

 

This week we’ve seen the release of additional dueling commentaries, three of which Lisa Schnirring of CIDRAP NEWS  highlighted last night in her article:

 

Scientists volley ahead of more dual-use H5N1 debate

Lisa Schnirring Staff Writer

Mar 28, 2012 (CIDRAP News) – As researchers from both sides of the debate over two controversial H5N1 studies weighed in yesterday on full publication versus a more cautionary approach, two US journals said they are developing policies to address any future such instances.

(Continue . . .)

 

 

The NSABB serves strictly in an advisory role, and any policy decisions must come from the United States government. Nonetheless, all eyes will be on the NSABB as they consider this issue.

 

And I can think of no one better than Helen Branswell  of the Canadian Press to preview this meeting for us:

 

Biosecurity panel reconvenes to reexamine controversial bird flu studies

3-28-12 6:31 PM EDT  By Helen Branswell

A bid from some quarters in the U.S. to resolve the ongoing controversy over two unpublished bird flu studies will begin to play out over the next two days as government biosecurity advisers reconvene to reconsider the issue.

 

The National Science Advisory Board for Biosecurity will meet Thursday and Friday in Washington, D.C., to go over revised versions of the two studies and hear about the work from their principal authors, noted flu virologists Ron Fouchier of Erasmus Medical Centre in Rotterdam, the Netherlands, and Yoshihiro Kawaoka of the University of Wisconsin-Madison.

(Continue . . . )

»» Read More

mBio: The H5N1 Biosafety Level Debate

 

UPDATED: mBio has published4 editorial/commentary pieces on the H5N1 research debate.  I’ve posted the links at the bottom of this blog post.

 

 

 

# 6197

 

 

Later today mBio will publish a pair of opposing views on what level of  laboratory biosecurity (BSL-3 or BSL-4) should be required in order to work on the H5N1 virus.

 

While there are many differences in procedures between them, in the broadest definition under BSL-3 it is the pathogen that is kept isolated, and worked on in specially designed negative airflow biological safety cabinets (BSC). Lab personnel wear fairly standard PPEs (Personal Protective Equipment) in BSL-3 labs.

 

With enhanced BSL-4 security, the focus is on isolating and protecting lab workers from the pathogen, and so they must all wear fully contained BSL-4 `space suits’, and decontaminate before leaving the work area.

 

BSL-4 labs work on the most dangerous pathogens that pose a particularly high risk of infection, such as Marburg, Ebola, Lassa fever, CCHF, and smallpox.

 

BSL-4 labs are far more expensive to build and maintain than BSL-3 facilities, and there are not nearly as many of them around the world.

 

Which presents a dilemma.  If you restrict work on the H5N1 virus to only BSL-4 labs, that would exclude many universities (and even entire countries) from being able to conduct research on the virus.

 

You may recall that early in February Canada restricted H5N1 research to BSL-4 facilities (see  Canada Issues Biosafety Advisory For H5N1 Research).

 

Although the mBio articles won’t be published for a few more hours, we’ve got a press release with some of the details and a preview by Helen Branswell.

First stop, the press release from the American Society for Microbiology

 

New H5N1 viruses: How to balance risk of escape with benefits of research?

In the controversy surrounding the newly developed strains of avian H5N1 flu viruses, scientists and policy makers are struggling with one question in particular: what level of biosafety is best for studying these potentially lethal strains of influenza? In a pair of commentaries, researchers from the Mount Sinai School of Medicine in New York and the University of Michigan argue their different views of how to safely handle H5N1 flu viruses. The commentaries will be published in mBio®, the online open-access journal of the American Society for Microbiology, on Tuesday, March 6.

 

This fall, the U.S. National Science Advisory Board for Biosecurity (NSABB) set off a debate when it asked the authors of two recent H5N1 research studies and the scientific journals that planned to publish them to withhold crucial details of the research in the interest of biosecurity. The researchers had taken H5N1, a virus that cannot easily transmit from human to human, and developed strains of the virus that can transmit easily between ferrets, which are a common model for human influenza.

 

These H5N1 strains and others like them that might be developed in the future could pose a grave threat to human life, but researchers and others argue that studying these H5N1 strains could help bolster preparedness efforts and vaccine development to help fend off a potential H5N1 pandemic. How can we balance the need to protect human life from the accidental escape of an H5N1 strain with the need to continue research that might prevent a naturally occurring outbreak? Which biosafety level (BSL) is right for the H5N1 virus?

 

In the commentaries appearing in mBio, two experts offer opposing views of the appropriate level of security for dealing with H5N1 viruses. The authors agree that, with a reported case fatality rate that could be as high as 50% or more, H5N1 could create a pandemic of disastrous proportions, but they differ in their opinions of how to strike a balance between biosecurity and potentially life-saving research.

(Continue . . . )

 

Next up, from the Canadian Press, a preview from Helen Branswell.

 

The Canadian Press - ONLINE EDITION

Future work on lab-made bird flu viruses should be done in most secure labs

By: Helen Branswell, The Canadian Press

Posted: 03/6/2012 3:02 AM TORONTO - Future work on mutated bird flu viruses should only take place in laboratories with the highest level of biosafety, suggests a new commentary on the controversy over two studies that led to the creation of these viruses.

 

But an opposing view argues that to restrict work on the viruses to so-called BSL4 labs would not leave the world safer, but would impede the quest to find out how flu viruses that normally infect birds can adapt to infect people.

(Continue . . .)

 

Both opinion pieces should be online at 10am EST, March 6th, and available at this link.

 

Mammalian-Transmissible H5N1 Virus: Containment Level and Case Fatality Ratio

Arturo Casadevall and Thomas Shenk

doi:10.1128/mBio.00054-12

 

Working Safely with H5N1 Viruses

Adolfo García-Sastre

doi:10.1128/mBio.00049-12

 

Biosafety Considerations of Mammalian-Transmissible H5N1 Influenza

Michael J. Imperiale and Michael G. Hanna III

doi:10.1128/mBio.00043-12

 

Ferret-Transmissible Influenza A(H5N1) Virus: Let Us Err on the Side of Caution

Lisa N. Murillo

doi:10.1128/mBio.00037-12

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Science Magazine: NSABB Members React To Fouchier Statement

 

 

# 6193

 

 

In the wake of the surprise announcement by Ron Fouchier earlier this week that the H5N1 virus he created is less lethal, and less transmissible than widely believed (see ASM BioDefense Meeting Video Now Online), we get reaction from a number of NSABB board members at the suggestion they take another look at his study.

 

Very much worth reading.

 

 

NSABB Members React to Request for Second Look at H5N1 Flu Studies

by Jon Cohen and David Malakoff on 2 March 2012,

Members of a U.S. government biosecurity advisory board are offering a range of reactions to the news that they are being asked to take a second look at two controversial flu studies. Some have not previously spoken publicly about the issue, which has sparked a global debate about biosecurity versus scientific freedom. And several say they are skeptical that the new review will reverse their opposition to fully publishing the methods and results of the two experiments.

(Continue . . .)

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CIDRAP News: NSABB May Revisit H5N1 Research

 

 

# 6184

 

Robert Roos, News editor for CIDRAP News, has a detailed report on today’s ASM Biodefense panel discussion (see ASM BioDefense Meeting Video Now Online).

 

With new data presented by Ron Fouchier at this meeting, the NSABB may take another look at these studies.

 

 

With new data, NSABB may revisit H5N1 studies

Robert Roos News Editor

Feb 29, 2012 (CIDRAP News) – The mutant H5N1 virus generated in one of two controversial studies was less lethal and contagious than has been generally understood, and the US government's biosecurity advisory committee will be asked to examine new and clarified data from the study, scientists and government officials revealed today.

(Continue . . . )

 

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ASM BioDefense Meeting Video Now Online

 

 

# 6182

 

This morning’s ASM BioDefense panel discussion of the NSABB’s call to redact portions of two H5N1 research papers is now online, and available to all.

 

In a bit of a surprise, Erasmus University researcher Ron Fouchier characterized the results of his experiments somewhat differently than we’ve seen in the past.

 

While the mutated virus could be spread via the aerosol route between ferrets, Fouchier reassured, "Our data suggests this virus spreads very poorly."

 

Fouchier also downplayed the pathogenicity of virus, stating that ferrets infected this way only suffered mild illness (it required direct deep-lung inoculation to produce death/severe illness).

 

“It is not highly lethal if ferrets start coughing and sneezing to one another”, he said.

One must note that when the news was `all bad’ about the transmission and pathogenicity of this mutated virus, many scientists were quick to caution us that “ferrets aren’t a perfect model for how the virus will act in humans’.

 

Which means that the reduced pathogenicity and transmissibility in ferrets described by Fouchier today may not necessarily translate to how the virus would act in a human host.

 

 

The 70 minute video may now be viewed at THIS LINK.

 

Very much worth watching.

 

Featuring: 

Michael T. Osterholm, Ph.D., MPH  NSABB/CIDRAP

Anthony S. Fauci, M.D  (NIAID)

Bruce Alberts, Ph.D. Editor-in-Chief of Science

Ron A.M. Fouchier, Ph.D.    H5N1 Researcher

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Webcast: Discussion Of NSABB’s H5N1 Recommendations

 

 

# 6181

 

My thanks to Helen Branswell for tweeting this event.

 

Set you alarm clocks accordingly, as tomorrow morning (Wednesday, February 29th) the ASM Biodefense and Emerging Diseases Research Meeting will provide a live webcast of an hour-long discussion over the NSABB’s recommendations to redact portions of two H5N1 research papers.

 

Featuring: 

Michael T. Osterholm, Ph.D., MPH  NSABB/CIDRAP 

Anthony S. Fauci, M.D  (NIAID)

Bruce Alberts, Ph.D. Editor-in-Chief of Science

Ron A.M. Fouchier, Ph.D.    H5N1 Researcher

Live Stream Details
Date: Wednesday, February 29, 2012
Time: 7:15 a.m. - 8:15 a.m. EST
Link:

If you are unable to watch the live feed, a video should be posted by 1:00pm.

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mBio: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

Photo Credit – CDC PHIL

 

 

# 6172

 

As I mentioned yesterday in Science: Peter Palese On The CFR of H5N1, not everyone agrees with his analysis of H5N1 seroprevalence studies, which he believes supports the idea that `millions’ of people have already been infected by the virus, and that the true fatality rate (CFR) is far lower than advertised.

 

Today, a counter argument (an added bonus, this is an open access paper) appears in mBio, authored by CIDRAP director Michael T. Osterholm and Nick Kelley.

 

(Fair disclosure: I’m acquainted with both Mike and Nick, and was invited to be presenter at a CIDRAP pandemic conference back in 2009).

 

The paper is called:

 

Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

Michael T. Osterholm Nicholas S. Kelley

Abstract

Two recently submitted (but as yet unpublished) studies describe success in creating mutant isolates of H5N1 influenza A virus that can be transmitted via the respiratory route between ferrets; concern has been raised regarding human-to-human transmissibility of these or similar laboratory-generated influenza viruses.

 

Furthermore, the potential release of methods used in these studies has engendered a great deal of controversy around publishing potential dual-use data and also has served as a catalyst for debates around the true case-fatality rate of H5N1 influenza and the capability of influenza vaccines and antivirals to impact any future unintentional or intentional release of H5N1 virus.

 

In this report, we review available seroepidemiology data for H5N1 infection and discuss how case-finding strategies may influence the overall case-fatality rate reported by the WHO.

We also provide information supporting the position that if an H5N1 influenza pandemic occurred, available medical countermeasures would have limited impact on the associated morbidity and mortality.

 

I would encourage you to read the entire article, where the authors dissect some of the methods used in existing seroprevalence studies.

 

It is quite a detailed analysis, and worthy of your full consideration.

 

After excluding some of the seroprevalence studies that utilized an extremely low antibody titer threshold (in some studies, set as low as ≥1:10), the author’s conclude that:

 

The available seroepidemiologic data for human H5N1 infection support the current WHO-reported case-fatality rates of 30% to 80%

 

The go on to say that:

 

In fact, if H5N1 virus does become a pandemic virus, the virulence (as measured by the case-fatality rate) could decrease 10- to 20-fold from what is currently documented and the virus would still generate a more severe pandemic than the 1918 pandemic, where the overall case-fatality rate was probably about 2%.

 

Given the global population and the current dynamics of population movement around the world, an H5N1 pandemic, even with a relatively low case-fatality rate, would be a truly catastrophic event.

 

I’ve reproduced their summary below.

 

SUMMARY

In summary, we believe that the debate about the case-fatality rate of H5N1 influenza in humans and the suggested important role of currently available antivirals and vaccines in mitigating an H5N1 pandemic are without merit.

 

Furthermore, we do not believe that continued focus on these issues helps to address how best to manage research involving influenza viruses, such as H5N1, that are transmissible between mammals and have the potential to be highly virulent in humans.

 

Future discussions specific to the current controversy need to resolve critical questions such as how we safely conduct H5N1 virus transmission studies in mammals, how we share critical methods and results with those who have a need to know, and how we ensure that laboratory-generated H5N1 viruses do not escape controlled environments.

 

Resolution of these issues with regard to H5N1 influenza viruses has the potential to serve as a template for similar situations involved existing or emergent pathogens. It is our belief that the current controversy provides a valuable opportunity for scientists and public policy experts to work together in creating this road map for the future.

 

Notes

Dr. Osterholm is a member of the National Science Advisory Board for Biosecurity. His views expressed here do not represent the official policy or scientific conclusions of the NSABB.

 

 

NOTE: Since this was an open access paper I was able to incorporate more of it into today’s blog than I could with yesterday’s Palese paper.

 

 

I suspect this debate will rage, unresolved, until we get more and better data.

 

Hopefully, we’ll get that data from well mounted and standardized seroprevalence studies, and not from the butcher’s bill from the next pandemic.

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WHO Releases List Of Participants At H5N1 Meeting In Geneva

 

# 6148

 

Today the World Health Organization released the names of the 22 scientists invited to participate in the first technical consultation on H5N1 research currently being held in Geneva.

Reading like a WHO’s Who of global influenza specialists, this august group of scientists will meet behind closed doors over the next two days to discuss the fate of two research papers by Fouchier and Kawaoka that detail how they created a transmissible (in ferrets) strain of H5N1 in the lab.

 

 

Technical consultation on H5N1 research issues

WHO Headquarters, Geneva
16-17 February 2012

List of participants

Professor Tjandra Y. Aditama
Director-General of Disease Control and Environmental Health, Ministry of Health
Indonesia

Dr Philip Campbell
Editor-in-Chief Nature
United Kingdom

Dr Nancy Cox
Director, WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention
United States of America

Dr Anthony Fauci
Director, National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH)
United States of America

Professor Ron Fouchier
Institute of Virology, Erasmus Medical Center
Netherlands

Professor Didier Houssin
President, French Evaluation Agency for Research and Higher Education (AERES)
France

Dr Barbara Jasny
Deputy Editor for Commentary, Science/AAAS
United States of America

Dr Yoshihiro Kawaoka
Influenza Research Institute, University of Wisconsin
United States of America

Dr Paul Keim
Acting Chair, National Science Advisory Board for Biosecurity (NSABB), Division Director, Pathogen Genomics, Northern Arizona University
United States of America

Professor Anne Kelso
Director, WHO Collaborating Centre for Reference and Research on Influenza
Australia

Dr Willem Luytjes
National Institute for Public Health and the Environment (RIVM)
The Netherlands

Dr Le Thi Quynh Mai
Head of Virology Department, National Institute of Hygiene and Epidemiology (NIHE)
Viet Nam

Dr John McCauley
Director, WHO Collaborating Centre for Reference and Research on Influenza, National Institute for Medical Research
United Kingdom

Professor A.D.M.E. Osterhaus
Head, Institute of Virology, Erasmus Medical Center
Netherlands

Dr Malik Peiris
WHO H5 Reference Laboratory, Department of Microbiology, University of Hong Kong
Hong Kong Special Administrative Region of China

Dr Vivi Setiawaty
Head of Virology, National Institute of Health Research and Development (NIHRD)
Indonesia

Dr Yuelong Shu
Director, WHO Collaborating Centre for Reference and Research on Influenza, Chinese Center for Disease Control and Prevention
China

Professor Jerome Singh
Head of Ethics and Health Law, Nelson R. Mandela School of Medicine
South Africa

Dr Masato Tashiro
Director, WHO Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases
Japan

Dr Trihono
Director General, National Institute of Health Research and Development (NIHRD)
Indonesia

Dr Philip Van Dalen
Cluster Coordinator, Infectious Diseases, Ministry of Health, Welfare and Sport
Netherlands

Dr Richard Webby (not present 16 February 2012)
Director, WHO Collaborating Centre for Studies on the Ecology of Influenza in Animals, St. Jude Children's Research Hospital
United States of America

»» Read More

Video: NYAS H5N1 Debate

 

 

# 6128

 

 

Last week (Feb 2nd) the New York Academy of Sciences hosted a 2-hour debate over H5N1 `dual use’ research.

 

The discussion – called  Dual Use Research: H5N1 Influenza Virus and Beyond – was moderated by famed epidemiologist and virus hunter Professor Ian Lipkin, who among his many accomplishments is Director, Center for Infection & Immunity, and John Snow Professor of Epidemiology at Columbia.

The panel members consisted of:

• Arturo Casadevall, MD, PhD, Albert Einstein College of Medicine, and member, NSABB;
• Laurie Garrett, PhD, Council on Foreign Relations;
• Barbara R. Jasny, PhD, Science;
• Veronique Kiermer, PhD, Nature Publishing Group;
• Michael T. Osterholm, PhD, MPH, Center for Infectious Disease Research and Policy, University of Minnesota, and member, NSABB;
• Peter Palese, PhD, Mount Sinai School of Medicine;
• Vincent Racaniello, PhD, Columbia University;
• Alan S. Ruldolph, PhD, Defense Threat Reduction Agency.

 

The result was a lively, sometimes heated debate.

 

Today, the NYAS has posted video of that debate (in 2 parts) on their website.

 

"Dual Use Research: H5N1 Influenza Virus and Beyond" Panel Sparks Lively Debate

 

 

A hat tip to Vincent Racaniello  & Laurie Garrett for tweeting the announcement.

»» Read More

H5N1 Research: A Plethora Of Positions

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

# 6123

 

While historically politics, religion, or sporting contests can be counted on as being the most divisive of subjects, over the past few months we’ve seen rise to a different bitter line of debate;

 

Under what circumstances should potentially dangerous life or bioscience research be conducted and/or published?

Although it has been simmering in the background for years, this issue came to the forefront several months ago when Ron Fouchier announced at a scientific conference in Malta that he’d successfully `mutated the hell’ out of the H5N1 virus and turned it into a highly transmissible (and still lethal) virus in ferrets.

 

At the same time, in a different lab half a world away, virologist Yoshihiro Kawaoka accomplished very nearly the same feat, albeit without the high lethality seen in Fouchier’s ferrets.

 

In November alarm bells were raised by bio-terrorism experts, who warned that this information in the wrong hands could be catastrophic (see NPR: Bio-Terrorism Concerns Over Bird Flu Research).

Last December, the NSABB - after reviewing the papers from both of these projects - recommended unanimously that key details on how they were conducted be redacted from the publically available journals. 

And that has unleashed a firestorm of controversy.

 

You can find a nice recap of all of this by Debra MacKenzie in this morning’s edition of New Scientist (Doomsday flu decision time: The story so far).

 

Later this month, in a closed-door meeting in Geneva, a small, select group of scientists will gather to discuss this controversy.  The hope is they will forward some recommendations on how to proceed for consideration by the greater international scientific community.

 

In the meantime, the media is filled with diverse opinions on this subject.

 

One of the more extreme views comes this morning via John Horgan writing for Scientific American.  He gives his list of available options, and finds all of them lacking. He proposes that the `least bad’ option is:

 

Let’s Ban Research That Makes the Bird-Flu Virus and Other Pathogens Deadlier

By John Horgan | February 6, 2012 | 

 

 

While at the far end of the spectrum in this debate, Horgan echoes many of the same sentiments as Tom Inglesby, Director of the Center for Biosecurity at the University of Pittsburgh Medical Center.

 

In a letter to the Editor of the New York Times, Inglesby recently argued:

 

The potential benefits of the research do not justify the potential dangers, so the research should be discontinued. While in almost all circumstances basic research should be fully disseminated in the science community, in this case the results should not be published in a way that allows them to be replicated by others. If allowed to continue, the research should be performed only in pursuit of concrete, urgent goals under international approval and the greatest possible safety conditions.

TOM INGLESBY
Baltimore, Jan. 24, 2012

 

 

The Director of Australia's National Centre for Biosecurity, Professor Ian Ramshaw, warned in an article yesterday in The Canberra Times that potentially dangerous H5N1 research is being conducted in labs with insufficient biosecurity measures, and even states that these mutated viruses should not have been created to begin with.

 

 

Killer bug in the system

BY PHILLIP THOMSON

05 Feb, 2012 01:00 AM

THE CANBERRA scientist who argued against details of a new strain of potentially apocalyptic bird flu being published has warned of inadequate security at the lab where the virus was developed and says the virus should not have been developed at all.

(Continue . . . )

 

A bit ironic, as Professor Ramshaw gained considerable notoriety a decade ago when he and his research team published details on how they created a new, and highly pathogenic form of mousepox.

 

Comparatively speaking, the above views make the recommendations of the NSABB appear almost centrist, as they only called for the redaction of key elements from two scientific papers, not for a ban into this type of research.

 

Surprisingly, an opinion published last week by none other than Robert G. Webster, considered to be one of the world’s foremost authorities on influenza, got very little mention in the press.

 

 

Mammalian-Transmissible H5N1 Influenza: the Dilemma of Dual-Use Research

1. Robert G. Webster

 

While conceding that the details of how these two H5N1 experiments were conducted will likely leak out at some point, he nonetheless believes the details on how to create a transmissible H5N1 virus should not be published.

 

Webster believes this type of research must continue, but also worries that the lower biosecurity level labs (BSL-3) may not have adequate safety measures for containing H5N1.

 

He has a lot more to say, so by all means follow this link to read it in its entirety.

 

 

Last week, in an apparent response to the BSL-3 / BSL-4 debate, the Public Health Agency of Canada issued a Biosafety Advisory for working with transmissible strains of the H5N1 virus, relegating such work to their highest containment (CL-4) labs.

 

On the other end of the spectrum are researchers and scientists who believe that concerns over the biosafety aspects of these experiments are overblown, and that work on these viruses must continue and the results should be published in their entirety.

 

Virologist and blogger Professor Vincent Racaniello  argues strenuously for this position in his recent mBio article:

 

 

Science Should Be in the Public Domain

Vincent R. Racaniello 

Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA

ABSTRACT

Variants of avian influenza H5N1 virus that are transmitted by the airborne route among ferrets have been identified. The National Science Advisory Board for Biosecurity has advised against publication of the details of the methods used to obtain these viruses and the amino acid changes that lead to transmission in ferrets. This decision is not based on sound scientific principles and risks setting a precedent that will make it easier to put in place highly restrictive regulations on scientific research and publication.

(Continue . . . )

 

And similarly, noted microbiologist Peter Palese, in an opinion piece recently published in PNAS – argued:

 

H5N1 influenza viruses: Facts, not fear

 

Peter Palese  2. Taia T. Wang

Abstract

The ongoing controversy over publication of two studies involving the transmission in ferrets of H5N1 (H5) subtype influenza viruses and the recommendations of the National Science Advisory Board for Biosecurity to redact key details in the manuscripts call for an examination of relevant scientific facts. In addition, there are calls in the media to destroy the viruses, curtail future research in this area, and protect the public from such “frightening” research efforts. Fear needs to be put to rest with solid science and not speculation.

(Continue . . . )

 

As a non-scientist, I must rely on the opinions and judgments of scientists I trust.

 

Here, that proves exceedingly difficult, as the range of opinion from people I highly respect covers the gamut – from preserving the ideals of scientific and intellectual freedom . . .  to an outright ban on conducting this type of research.

 

In this issue we have an honest disagreement among experts, and all sides have at least some solid ground to stand on.  And no matter how diverse, I believe these opinions to be heartfelt and sincere.

We are on the cusp of a new era of life sciences, where scientists can manipulate and even create life forms in the laboratory. Although the potential for good that this research offers is immense, there is also the possibility of serious mishap as well.

 

While we are focused today on the fate of two H5N1 research papers, the real problem runs far deeper;

 

Our failure to anticipate and deal with the numerous ethical and practical issues that these new bioengineering sciences presents.

 

The Fouchier and Kawaoka papers have merely brought this issue to a head.

 

Whether these papers end up published in their entirety or not, the bigger issue is that the international scientific community must come up with a consensus over rules and guidelines for life sciences research. 

 

Otherwise, these bitter debates will form an ongoing rift between scientists, and over time, further erode the public’s confidence in the scientific establishment.

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