TWiV 291: Ft. Collins abuzz with virologists

Vincent, Rich, and Kathy and their guests Clodagh and Ron recorded episode #291 of the science show This Week in Virology at the 33rd annual meeting of the American Society for Virology at Colorado State University in Ft. Collins, Colorado.

You can find TWiV #291 at www.microbe.tv/twiv.

TWiV 287: A potentially pandemic podcast

On episode #287 of the science show This Week in Virology, Matt Frieman updates the TWiV team on MERS-coronavirus, and joins in a discussion of whether we should further regulate research on potentially pandemic pathogens.

You can find TWiV #287 at www.microbe.tv/twiv.

Fouchier vs the Dutch government on influenza H5N1 research

ferretFrom Martin Enserink at ScienceInsider:

Virologist Ron Fouchier has suffered a loss in a legal battle with the Dutch government over the publication of his controversial H5N1 influenza research. On Friday, a Dutch district court ruled that the government was right to ask Fouchier to obtain an export license before sending two hotly debated papers out for publication.

Readers of this blog will remember the furor sparked by Fouchier’s experiments in 2011 in which he developed an avian influenza H5N1 isolate that could transmit among ferrets by aerosol. When Fouchier was ready to publish the results, the Dutch government required that Fouchier apply for an export license. In so doing they were applying EU regulations that are designed to prevent the spread of biological weapons.

Fouchier applied for and was granted an export license on 27 April 2012. Fouchier’s employer, Erasmus Medical Center, appealed the decision to require an export license for this type of work. It is this appeal that was recently denied by a Dutch district court.

Fouchier rightfully claims that such EU regulations put him at a disadvantage compared with other groups. For example, Kawaoka’s findings on aerosol-transmitted avian influenza H5N1 virus in ferrets were not subject to EU export rules and were published ahead of Fouchier’s paper. I can understand Fouchier’s position; science is very competitive and being the first to publish is a coveted position. I am not sure that this is an issue worth bringing to the courts: even though Fouchier published after Kawaoka, most virologists credit the observations to both laboratories. The Dutch government should recognize that its scientists must be internationally competitive and expedite such future requests.

In my view, there is a larger issue at stake here: what constitutes research that requires an export license? I would argue that the avian influenza H5N1 virus that Fouchier produced is not a biological weapon. Remember that while this virus could transmit among caged ferrets by aerosol, it was markedly attenuated. In other words, gaining the ability to transmit by aerosol came at a fitness cost that reduced the virulence of the virus in ferrets. Such a virus is not a biological weapon, and should not have been subject to EU export requirements.

I do not know who in the Dutch government reviews such export license requests, but hopefully the next time Fouchier or any other virologist applies, there will be knowledgeable virologists involved in making the correct decision.

Further defense of the Chinese H1N1 – H5N1 study

Robert Herriman of The Global Dispatch interviewed me this week on the H1N1 – H5N1 reassortant study that has been in the headlines:

There was much written concerning the research published earlier this month in Science, where researchers from China’s Harbin Veterinary Research Institute reported creating an  avian H5N1 (highly pathogenic) and pandemic 2009 H1N1 (easily transmissible) hybrid, that according to them, achieved airborne spread between guinea pigs.

Read the rest of the article at The Global Dispatch.

Ferreting out the truth on Science Sunday Hangout on Air

I joined Buddhini SamarasingheScott Lewis, Tommy Leung, and William McEwan for a discussion of the avian influenza H5N1 virus transmission experiments done in ferrets.

 

Going viral at Studio 360

Studio 360 with Kurt Andersen is a radio show co-produced by Public Radio International and WNYC. The show for the week of 8 March 2013 is called ‘Going Viral‘ and includes seven segments entitled ‘Viruses at the movies’, ‘Does your zombie have rabies’, and ‘Playing against the virus’. They did speak with one virologist for a segment called ‘Reconstructing viruses‘.

To record this segment of Studio 360 I traveled down to the WNYC studios on Varick Street in New York. I sat in a glass-walled, silent room with headphones and before a large microphone. I spoke with the show’s host, Kurt Andersen, who was in a studio somewhere in Los Angeles. The sound quality was excellent and our conversation was wide-ranging, including a discussion on synthetic viruses, avian influenza H5N1, dual-use research, bioterrorism, and zombies. We spoke for 30 minutes but only a bit of that ended up being released. I think that a five minute discussion of science is far less than optimal – I favor long-form science discussions which can truly inform the listener.

You can listen to my segment below or over at the Studio 360 website.

Proposed US policy on dual use research of concern

The US Office of Science and Technology Policy recently released proposed guidelines for maximizing the benefits and minimizing misuse of life sciences research. The measures establish oversight responsibilities for universities and other institutions that receive Federal funding:

Specifically, such institutions would be required to review their current life sciences research involving those pathogens or toxins deemed to be the most dangerous or most amenable to misuse, and then work with the researchers and funding agencies to develop appropriate risk mitigation plans.

This adds to a previously announced internal policy to identify DURC research and institute risk-reducing mitigation plans.

OSTP has requested comments on the proposed policy from researchers, institutions, consumers, security experts, and other stakeholders. The proposed policy can be found at this location (pdf), and instructions on how to submit comments can be found in the Federal Register.

Here is the gist of the proposal. It pertains to you if you get Federal money to work on the following organisms or toxins:

  1. Avian influenza virus (highly pathogenic)
  2. Bacillus anthracis
  3. Botulinum neurotoxin
  4. Burkholderia mallei
  5. Burkholderia pseudomallei
  6. Ebola virus
  7. Foot-and-mouth disease virus
  8. Francisella tularensis
  9. Marburg virus
  10. Reconstructed 1918 Influenza virus
  11. Rinderpest virus
  12. Toxin-producing strains of Clostridium botulinum
  13. Variola major virus
  14. Variola minor virus
  15. Yersinia pestis

And if your research might have the following consequences:

  1. Enhances the harmful consequences of the agent or toxin
  2. Disrupts immunity or the effectiveness of an immunization against the agent or toxin without clinical and/or agricultural justification
  3. Confers to the agent or toxin resistance to clinically and/or agriculturally useful prophylactic or therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies
  4. Increases the stability, transmissibility, or the ability to disseminate the agent or toxin
  5. Alters the host range or tropism of the agent or toxin
  6. Enhances the susceptibility of a host population to the agent or toxin
  7. Generates or reconstitutes an eradicated or extinct agent or toxin listed above

If any of this applies to you, it is necessary for you and your institution to develop and implement a risk mitigation plan which must be approved by the funding agency.

If any of this applies to you, but you do not receive Federal funds for the research, you are strongly encouraged to carry out similar oversight procedures.

Harvard University: Great virology, bad science writing

Harvard virologyHarvard University is home to some of the world’s finest virologists. But apparently they do not communicate with the writers at Harvard Magazine, where a botched story on the avian H5N1 influenza virus has just been published.

The problems begin with the first paragraph:

But when Dutch researchers recently created an even more deadly strain of the virus in a laboratory for research purposes, they stirred grave concerns about what would happen if it escaped into the outside world.

Readers of virology blog will know by now that the Dutch researchers did not make an ‘even more deadly strain of the virus’ – they made one that could be transmitted by aerosol, but which had lost its lethality.

The title of the article, ‘The Deadliest Virus’, presumably refers to the H5N1 virus that transmits by aerosol among ferrets. This title is simply wrong, because the virus is not deadly to ferrets.

The first paragraph also contains an equally egregious statement by epidemiologist Marc Lipsitch:

If you make a strain that’s highly transmissible between humans, as the Dutch team did, it could be disastrous if it ever escaped the lab.

Dr. Lipsitch seems to be saying that the Dutch group created an H5N1 virus that transmits among humans. As far as I know, ferrets are not humans.

The article is accompanied by a photograph of two scientists working in BSL4 suits. The legend reads:

The modified H5N1 virus could infect a billion people if it escaped a biocontainment lab like the Canadian facility shown above.

And later Lipsitch is quoted as saying:

It could infect millions of people in the United States, and very likely more than a billion people globally, like most successful flu strains do. This might be one of the worst viruses—perhaps the worst virus—in existence right now because it has both transmissibility and high virulence.

For Lipsitch to say that the virus is both transmissible and of high virulence in humans is a misrepresentation of the Dutch group’s findings. He seems to be making up numbers and scenarios.

Perhaps Dr. Lipsitch does not know that ferret studies are not predictive of how viruses will behave in humans. With so many virologists at Harvard, the writer could have checked Dr. Lipsitch’s statements. But he did not, and the result looks as foolish as the New York Times.

Comment on H5N1 lethality in humans

In a brief letter to Biosecurity and Bioterrorism, Alan Zelicoff notes a problem with serosurveys for influenza H5N1 infection:

…peak titers after H5N1 infection occur at about 4 to 6 weeks postinfection and may drop by as much as 32-fold over the course of a year, probably decreasing the sensitivity of serologic testing for past asymptomatic infections. Micro-neutralization testing may be more sensitive.

He cites a serological survey carried out on poultry workers in South Korea, in which 9 of 2,500 subjects were found to have antibodies to H5N1 virus, in the absence of illness. These seropositive individuals carried antibodies that neutralize H5N1 virus infectivity. Assays for antibodies that block infection may be more specific for infection than hemagglutination-based assays. His conclusion:

One can anticipate additional serological surveys that will better inform public health practitioners of the threat to humans from circulating H5N1 clades….morbidity from novel influenza strains does not equate with an impending pandemic, let alone one with high mortality. It would appear likely that a systematic, prospective cohort study is in order to adequately capture the frequency of asymptomatic infection.

Human infections with influenza H5N1 virus: How many?

The lethality of avian influenza H5N1 infections in humans has been a matter of extensive debate. The >50% case fatality rate established by WHO is high, but the lethality of the virus might be lower if there are many infections accompanied by mild or no disease. One way to answer this question is to determine how many individuals carry antibodies to the virus in populations that are at risk for infection. A number of such studies have been done, and some have concluded that the results imply a low but substantial level of infection (even less than one percent of millions of people is a lot of infections). The conclusion of a new meta-analysis of H5N1 serosurveys is that most of the studies are flawed, and that the frequency of H5 infections appears to be low.

Twenty-nine different H5N1 serological studies were included in this meta-analysis. None of these are particularly satisfactory according to the authors:

None of the 29 serostudies included what we would consider to be optimal, blinded unexposed controls in their published methodologies, i.e., including in the serology runs blinded samples from individuals with essentially no chance of H5N1 infection. Serological assays can easily produce misleading results, especially when paired sera are not available.

Some of the problems identified in the serological surveys include the possibility that many H5N1 positive sera are the result of false positives, that is, cross reaction with antigens from other influenza virus strains. In addition, many studies utilized H5N1 strains that are no longer circulating.

It is clear that most of the H5N1 serosurveys have not been done as well as they should have been. The authors conclude that “it is essential that future serological studies adhere to WHO criteria and include unexposed control groups in their laboratory assays to limit the likelihood of misinterpreting false positive results.”

Let’s not forget that a completely different way of assessing H5N1 infection – by looking for virus-specific T cells – has been reported. The results provide further evidence for subclinical H5N1 infection and are not subject to the caveats noted here for antibody surveys.

I come away from this meta-analysis with an uneasy sense that the authors are not being sufficiently objective, and that they firmly believe that there are no mild or asymptomatic H5N1 infections. One reason is the authors’ use of ‘only’ to describe their findings. For example: “Of studies that used WHO criteria, only [italics mine] 4 found any seropositive results to clades/genotypes of H5N1 that are currently circulating”. The use of ‘only’ in this context implies a judgement, rather than an objective statement of fact. Furthermore, despite the authors stated problems with all H5N1 serosurveys, they nonetheless conclude that there is little evidence for asymptomatic H5N1 infection. If the studies are flawed, how can this conclusion be drawn?

My concern about the authors’ objectivity is further heightened by the fact that they are members of the Center for Biosecurity at the University of Pittsburgh. These are individuals whose job it is to find dangerous viruses that could be used as weapons. On the front page of the website for the Center for Biosecurity is a summary of the meta-analyis article which concludes that “In the article, Assessment of Serosurveys for H5N1, Eric Toner and colleagues discuss their extensive review of past studies and conclude that there is little evidence to suggest that the 60% rate is too high.”

I would argue that if the H5N1 serosurveys are flawed, then do them properly; it is incorrect to simply assume that the H5N1 virus is as lethal as WHO suggests. The World Health Organization should call for and coordinate a study that satisfies criteria established by virologists and epidemiologists for a robust analysis of human H5N1 exposure.