Don’t censor influenza research

Howard Markel, Professor of the history of medicine at the University of Michigan, in the New York Times:

The censorship of influenza research will do little to prevent its misuse by evildoers — and it may well hinder our ability to stop influenza outbreaks, whether natural or otherwise, when they do occur. In this case, censorship is too little, too late. The data generated by one of the research teams was already presented at a conference in Malta in September, where copies of the paper were distributed. But even if the data weren’t already available, the key details could likely be inferred from other information that is already available.

Dr. Markel also agrees that influenza H5N1 virus would not be a good terrorist weapon:

Even if terrorists got their hands on the new data, it’s not certain they could weaponize the virus: no one knows for certain that the virus’s transmissibility and virulence in ferrets means transmissibility and virulence in humans. In any event, the influenza virus, highly variable in its power and spread, is not an optimal terrorist weapon, not least because no one would know for sure if it was unleashed by a terrorist or natural forces.

The implications of the H5N1 story go far beyond ferrets:

In the years since the 9/11 attacks, we’ve witnessed a disturbing trend in the oversight of sensitive science. […] Several prominent scientists, including Donald Kennedy, the former editor of Science, have publicly worried that the federal government is thwarting scientific advancement.

The action by the NSABB has propelled us full-tilt into this controversy. Their incorrect decision to censor the influenza H5N1 data not only will inhibit work on this important virus, but will have far-reaching consequences for scientific research. To this day I cannot understand why the NSABB did not more thoughtfully consider not only the data, but the future of science in coming to their decision.

Thanks to Dr. Markel for writing the Op-Ed I’ve been meaning to put together for a long time.

Related:

The NSABB speaks on influenza H5N1

H5N1 facts, not fear

Moratorium on influenza H5N1 transmission research

Palese: Don’t censor live-saving science

N.Y. Times: H5N1 ferret research should not have been done

Should we fear avian H5N1 influenza?

Ferreting out influenza H5N1

The NSABB speaks on influenza H5N1

The National Science Advisory Board for Biosecurity (NSABB) has published “Adaptations of Avian Flu Virus Are a Cause for Concern”, an explanation of their recommendations with respect to influenza H5N1 research (versions at Science and Nature). It starts with the statement that advances in technology now allow manipulation of microbial genomes in ways that could be misused, leading to global harm. They define dual-use research as “research that could be used for good or bad purposes”.

The authors begin their discussion of influenza H5N1 with the usual incorrect statement about the lethality of the virus:

Highly pathogenic avian influenza A/H5N1 infection of humans has been a serious public health concern since its identification in 1997 in Asia. This virus rarely infects humans, but when it does, it causes severe disease with case fatality rates of 59%.

The reference for this information is a WHO summary of confirmed human cases of H5N1. Both WHO and NSABB ignore the serological evidence for many mild or inapparent H5N1 infections. Omitting these data leads to an overestimation of the virulence of the virus, which has apparently played a large role in the NSABB’s decision.

Next, they engage in extensive speculation:

If influenza A/H5N1 virus acquired the capacity for human-to-human spread and retained its current virulence, we could face an epidemic of substantial proportions.

The virus has been circulating since the 1990s and has not acquired the capacity for human to human spread. This doesn’t mean it never will, but the possibility seems remote. The statement ‘retaining its current virulence’ of course refers to the erroneous 59% case fatality rate. What if the fatality rate is 0.1%, like seasonal influenza?

In discussing influenza H5N1 transmission in ferrets, the NSABB notes the value of the research:

The research teams that performed this work did so in a well-intended effort to discover evolutionary routes by which avian influenza A/H5N1 viruses might adapt to humans. Such knowledge may be valuable for improving the public health response to a looming natural threat.

Many have written that the research should never have been done, and that there are no benefits for human health (New York Times, Tom Inglesby, DA Henderson). Clearly the NSABB believes otherwise.

Next the NSABB describes their consideration of risk assessment of the H5N1 ferret studies. Their conclusion:

We found the potential risk of public harm to be of unusually high magnitude. Because the NSABB found that there was significant potential for harm in fully publishing these results and that the harm exceeded the benefits of publication, we therefore recommended that the work not be fully communicated in an open forum.

But there is no description of how they reached this conclusion. What data did they consider when making this decision? What were the benefits and the potential harms, and how did they weigh them? Apparently we must take the word of the panel that they reached the right decision, even though we cannot know what information they used. To convey their decision in this manner is unacceptable and sends the message that the committee did not consider specific data during their deliberations.

They conclude:

The life sciences have reached a crossroads. The direction we choose and the process by which we arrive at this decision must be undertaken as a community and not relegated to small segments of government, the scientific community, or society.

This is precisely why the decision to redact publication should not have been made by the NSABB or any small group of individuals. I agree that this is an ‘Asilomar moment’, a time when scientists must meet to decide what types of microbial research should be regulated. This should be a discussion among a large group of scientists, not bioterrorism policy analysts.

I understand the need to regulate certain types of experiments on microbes. But when I balance the benefits and risks of the H5N1 ferret transmission experiments, it does not make sense to stamp them as dual use and restrict publication of the results. Let publication proceed and then decide how to decide on how to move forward.

H5N1 facts, not fear

Peter Palese and Taia Wang have written a compelling article that uses scientific facts to address the controversy over publication of research involving transmission of avian influenza H5N1 in ferrets. In response to calls in the media to destroy the viruses, curtail the research, and protect the public from frightening research, they write that “fear needs to be put to rest with solid science and not speculation”.

The authors begin with the facts: they indicate that the object of ferret-to-ferret passage of avian H5N1 influenza virus was to determine whether sustainable aerosol transmission could be achieved in this animal model. The finding that transmission in ferrets is conferred by a small number of mutations emphasizes the need for continued surveillance of H5 viruses and development of vaccines and antivirals.

Are these studies relevant to humans?

Ferrets are quite susceptible to infection with influenza viruses. However, it is not clear that all virus strains that replicate in and transmit between ferrets necessarily do so in humans. Ferrets are also more likely than humans to have disseminated, multiorgan influenza disease including neurological sequelae….one cannot directly extrapolate from the data to make predictions about humans.

Under the heading ‘fear’, they address the heart of this controversy, the notion that the fatality rate for human H5 infections is greater than 50%:

…in order for a case to be confirmed by WHO, a person must have an acute, febrile respiratory illness with known H5 exposure in the 7 days preceding and have molecular confirmation of H5 infection by a WHO approved laboratory. This definition does not allow for asymptomatic infections and essentially requires that a person actively seek medical help at a hospital that is equipped to draw samples and ship them to an approved laboratory….it seems unlikely that even a small fraction of the total number of infected cases has been accounted for under the WHO surveillance system.

They also review seroevidence in humans for H5 infections:

Of the 10 largest studies of which we are aware…eight report rates ranging from 0.2% to 5.6%….even if only a low percentage of the rural population is asymptomatically/subclinically infected, the case fatality rate that is offered by the WHO – and that is driving this controversy – is likely orders of magnitude too high.

The authors believe that selection of these papers for redaction by the National Science Advisory Board for Biosecurity appears arbitrary, considering what has been published on influenza in the past:

In 2005, the complete sequences for the 1918 pandemic influenza virus were published…in 2006, both Science and Nature published reports of specific mutations that enable the H5 viral hemagglutinin to bind human, rather than avian tissues. In 2012, a report from the CDC that bears striking resemblance, in principle, to the works by Fouchier and Kawaoka was already published in Virology: it describes mutations in an H5N1 virus that confer airborne transmissibility between ferrets.

Finally the address the question: Could the data from these two papers realistically be used to generate an H5N1 biologic weapon?

The answer is simply no.

Everyone should read this article, including anyone who is concerned about the safety of the H5N1 experiments; biosecurity analysts who do not seem to understand the underlying science; and science writers who propagate misinformation about the virus.

Live chat: Should science be censored?

Science magazine is conducting a live chat about research that produced H5N1 influenza strains that are more easily transmissible between ferrets. Among the topics to be addressed will be the benefits and risks of the H5N1 transmissibility studies and whether they should be published in full; and should experiments that could help aspiring bioterrorists be more tightly regulated.

The guests will be epidemiologist and NSABB member Michael Osterholm, PhD, MPH, Director of the Center for Infectious Disease Research and Policy (CIDRAP), and influenza virologist Andrew Pekosz, PhD, Associate Professor in the Department of Microbiology and Immunology, Johns Hopkins University.

The live chat begins at 3 p.m. EST on Thursday, 12 January. You can join the chat here on virology blog (below) or at the Science website. Questions may be entered in the comment box below before the chat starts.

 

Avian H5N1 influenza and biosecurity on Science Friday

Science FridayI will be on NPR’s Science Friday this afternoon (6 January, 2 PM EST) to discuss the H5N1-NSABB story. You can listen live, or download the recording which will be available later.

I written three posts (one, two, three) about the ferret H5N1 experiments and why the NSABB should not prevent the publication of these data.

I’m a bit dismayed that Science Friday tweeted about this event earlier today saying “Today, 2-3p ET we’ll talk about the placebo effect. Then, we’ll tackle the debate over research into making influenza more deadly.” I had hoped for a less sensational, and scientifically accurate description from a well-respected science program.

Making influenza virus more deadly is not what this research was about. The over-hyping of the entire H5N1 story (both by scientists and the press) is what has got us into this situation in the first place. On Science Friday I hope to focus on the science which does not support restricting publication of the H5N1 ferret results.

Update: Here is a recording of this SciFri episode (27 MB mp3).

I thought it was interesting that Dr. Henderson discounted the possibility that there is widespread H5N1 seropositivity in rural Asian populations. His reason was that, among all the H5N1 infections, no seropositivity has been observed in their contacts. This would be expected as the H5N1 viruses are known not to be transmitted among humans! Where we would expect to see wide seropositivity is among workers who have frequent contact with poultry, not in the contacts of those who have been infected with the virus.

Dr. Henderson also stated that the experiment done in the Fouchier lab was ‘a little more than passage from ferrets to ferrets’. What he alluded to are the mutations introduced into the starting H5N1 virus to allow it to bind sialic acid receptors found in the mammalian respiratory tract. These types of modifications are widely known in the virology community and could easily be done before passaging the virus in ferrets.

Should we fear avian H5N1 influenza?

influenza virus

The only thing we have to fear is fear itself – Franklin D. Roosevelt

Why is there such widespread fear of avian H5N1 influenza virus?

Why did Paul Keim, chair of the National Science Advisory Board for Biosecurity (NSABB) say “I can’t think of another pathogenic organism that is as scary as this one”.  What lead Donald McNeil, writing about H5N1 in the New York Times, to conclude that “In its natural form, it is known to have infected only about 600 people since its discovery in 1997, but it killed more than half of them.”

McNeil’s statement is incorrect. Yet it summarizes why Paul Keim, the NSABB, and many others fear the virus.

The problem is that we cannot say with any certainty that the virus has infected only about 600 people. What we do know is that among the 600 seriously ill individuals infected with influenza H5N1 who are admitted to hospital, over half of them die.

To know the fatality rate of avian H5N1 influenza virus in humans, we need to divide the number of fatalities by the number of infections. We do not know that last number – but there are hints that it could be quite large. In a recent study of rural Thai villagers, sera from 800 individuals were collected and analyzed for antibodies against several avian influenza viruses, including H5N1, by hemagglutination-inhibition and neutralization assays. The results indicate that 73 participants (9.1%) had antibody titers against one of two different H5N1 strains. The authors conclude that ‘people in rural central Thailand may have experienced subclinical avian influenza virus infections’. A subclinical infection is one without apparent signs of illness.

If 9% of the rural Asian population has been subclinically infected with avian H5N1 influenza virus strains, it would dramatically change our view of the pathogenicity of the virus. Extensive serological studies must be done to determine the extent of human infection with avian H5N1 influenza viruses.

Until we know how many individuals are infected with avian influenza H5N1, we must refrain from making dire conclusions about the pathogenicity of the virus. Doing so has only lead us down a dangerous path of fearing that H5N1 influenza virus might be used as a weapon of bioterrorism, and restricting the publication of scientific papers on the virus.

Update. A meta-analysis reveals that about 1.3% of over 8,500 study participants had serological evidence of infection with influenza H5N1 (Palese, personal communication).

Khuntirat, B., Yoon, I., Blair, P., Krueger, W., Chittaganpitch, M., Putnam, S., Supawat, K., Gibbons, R., Pattamadilok, S., Sawanpanyalert, P., Heil, G., Friary, J., Capuano, A., & Gray, G. (2011). Evidence for Subclinical Avian Influenza Virus Infections Among Rural Thai Villagers Clinical Infectious Diseases, 53 (8) DOI: 10.1093/cid/cir525

TWiV 164: Six steps forward, four steps back

xmrvHosts: Vincent RacanielloRich Condit, and Alan Dove

Vincent, Alan, and Rich review ten compelling virology stories of 2011.

Please help us by taking our listener survey.

Click the arrow above to play, or right-click to download TWiV 164 (60 MB .mp3, 99 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Ten virology stories of 2011:

  1. XMRV, CFS, and prostate cancer (TWiV 119, 123, 136, 150)
  2. Influenza H5N1, ferrets, and the NSABB (TWiV 159)
  3. The Panic Virus (TWiV 117)
  4. Polio eradication (TWiV 127, 149)
  5. Viral oncotherapy (TWiV 124, 131, 142, 156)
  6. Hepatitis C virus (TWiV 130, 137, 141)
  7. Zinc finger nuclease and HIV therapy (TWiV 144)
  8. Bacteria help viruses (TWiV 154)
  9. Human papillomaviruses (TWiV 126)
  10. Combating dengue with Wolbachia (TWiV 115, 147)

Links for this episode:

Weekly Science Picks

Rich – Fundamentals of Molecular Virology by Nicholas H. Acheson
AlanFetch, with Ruff Ruffman
Vincent – Year end reviews at Rule of 6ix and Contagions

Listener Pick of the Week

GarrenTrillion-frame-per-second video
Judi – iBioMagazine
Ricardo –
Brain Picking’s 11 best science books of 2011

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

A bad day for science

The virologists who carried out the contentious experiments on influenza H5N1 transmission in ferrets have agreed to remove certain details from their manuscript, according to ScienceInsider:

Two groups of scientists who carried out highly controversial studies with the avian influenza virus H5N1 have reluctantly agreed to strike certain details from manuscripts describing their work after having been asked to do so by a U.S. biosecurity council. The as-yet unpublished papers, which are under review at Nature and Science, will be changed to minimize the risks that they could be misused by would-be bioterrorists.

Apparently a second manuscript on similarly sensitive material, submitted to Nature, has been studied by the NASBB and its details will also be redacted. Members of both scientific groups disagree with the decision.

The article hints that details of the experiments may be made available to influenza virologists ‘with a legitimate interest in knowing them’. Who will decide what constitutes a legitimate interest? And what if a virologist, or another scientist who does not work on influenza virus, has an idea for an experiment and would like the details? Will they be denied because they are not card-carrying influenza virologists? Science often works in unusual ways, and one of them is that difficult problems are often solved by individuals from different areas of research.

I agree with Albert Osterhaus, who noted that this debate could have been held in 2005 when the complete genome sequence of the 1918 pandemic influenza virus strain was released. That H1N1 strain is known to be lethal and transmitted efficiently among humans. In contrast, it is not known if the ferret-passaged influenza H5N1 virus would be transmitted in people and cause disease.

This is a bad day for virology, and for science in general. The decision by the NSABB sets a precedent for censoring future experimental results whose wide dissemination would benefit, not harm, humanity.

Update: A member of the NSABB has written about the committee’s thoughts on this issue. See comments below.

Ferreting out influenza H5N1

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

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

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

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

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

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

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

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

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

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

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

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

Should smallpox virus be destroyed?

smallpox virusAfter the eradication of smallpox in 1980, the World Health Organization called for destruction of known remaining stocks of the virus. The United States and Russia, which hold the known stocks of smallpox virus, have not destroyed their stocks. The WHO met in January 2011 to debate the future of smallpox, and a committee will issue a final recommendation sometime this year. For further information on this topic, there is an editorial in Vaccine entitled “Why not destroy remaining smallpox virus stocks“, and a WHO review on smallpox research.

During TWiV #124, I was surprised to learn that the remaining stocks of smallpox are not just a few tubes of virus, but a substantial strain collection. Here is a transcript of the relevant portion of the podcast, beginning at 1:13:00, where Rich Condit and Grant McFadden discuss the nature of smallpox virus stocks:

Rich Condit: One thing that people don’t fully appreciate is that we are not just talking about one strain of virus, we are talking about a repository of hundreds, at least, strains collected over time, and globally…not all of them have been studied, not all of them have been sequenced. And so there is an incredibly rich repository of information about virus virulence, pathogenesis, evolution, etc, that has not been tapped.

Grant McFadden: Yes, and in fact it’s very hard to tap some of those things right now with our current technologies, and one of the big unknown issues is what will the technologies be like in the future, might some of those things be tappable in the future.

With this information in mind, please take the poll below and register your position on the fate of smallpox virus.

Update: An analyst at the Center for Biosecurity of UPMC alerted me to a commentary by DA Henderson, the architect of smallpox eradication, entitled “Smallpox Virus Destruction and the Implications of a New Vaccine”. According to the analyst, Dr. Henderson “raises a number of the questions that have yet to be considered in the literature, but are absolutely essential to formulating well informed policy, particularly regarding the cost of developing and stockpiling vaccines against smallpox.”

Update 2: The WHO has voted to keep the remaining stocks of smallpox virus. They will revisit the issue in 2014 and in the meantime only permit completion of ongoing studies of the virus. Notice in the article the author writes “a committee of world leaders decided to keep, for now, the world’s two remaining vials of the deadly disease smallpox”. As Rich and Grant discuss above, the remaining stocks comprise hundreds of vials of the virus.