The AIDS pandemic

Origin of HIV

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TWiV 217: I just flu in and my arms are shot

On episode #217 of the science show This Week in Virology, Vincent, Alan, Rich, and Dickson review influenza vaccines.

You can find TWiV #217 at www.microbe.tv/twiv.

Headline writers: Please take a virology course

Yesterday Denise Grady wrote in the New York Times about the end of the moratorium on influenza H5N1 virus research. The story headline read:

Research to resume on modified, deadlier bird flu

The Minneapolis Star Tribune reprinted Ms. Grady’s story with the following headline:

Studies will resume on deadly modified flu virus

Where do these headlines come from, outer space? The H5N1 viruses produced by Kawaoka and Fouchier, which transmit by aerosol among ferrets, are far less virulent than the parental H5N1 virus! Furthermore, the moratorium applied to all research on H5N1 virus, not just that related to these transmission experiments.

If most of the public obtains their virology information from the popular press, it is no wonder that much of the public distrusts these H5N1 experiments.

Yesterday I taught the first lecture of the 2013 version of my virology course (details forthcoming).  I told the students that one reason I want to teach virology is to enable them to understand why headlines like these are wrong.

Maybe some of my students will one day write the headlines and get them right.

End of moratorium on influenza H5N1 research

In early 2012 influenza virus researchers around the world decided to stop working on highly pathogenic avian influenza H5N1 virus. This decision came after work from the Fouchier and Kawaoka laboratories revealed the isolation of influenza H5N1 strains that can be passed among ferrets by aerosol. The moratorium on influenza H5N1 virus research has now been lifted, as described in a letter from influenza virologists to Science and Nature.

Lifting the embargo on H5N1 research is an important step forward for understanding what regulates influenza transmission. In my view it was an ill-conceived move, done to quell the growing concern over the adaptation of influenza H5N1 virus to aerosol transmission in ferrets. We now know that these viruses are not lethal for ferrets, and much of the outrage expressed about this work was misguided. In my view the moratorium has accomplished little other than delaying the conduct of important virology research.

According to the influenza virus researchers who signed on to the moratorium, its purpose was to:

…provide time to explain the public-health benefits of this work, to describe the measures in place to minimize pos- sible risks, and to enable organizations and governments around the world to review their policies (for example on biosafety, biosecurity, oversight, and communication) regarding these experiments.

An important consideration is the level of containment that will be required for studying influenza H5N1 transmission. WHO has released recommendations on risk control measures for H5N1 research, and individual countries will decided how to proceed. The US has not yet made a decision on the level of containment needed for H5N1 virus transmission research. Influenza virologists who participated in the moratorium have their own view:

We consider biosafety level 3 conditions with the considerable enhancements (BSL-3+) outlined in the referenced publications (11–13) as appropriate for this type of work, but recognize that some countries may require BSL-4 conditions in ac- cordance with applicable standards (such as Canada).

Their last statement forms the crux of the issue on H5N1 transmission research:

We fully acknowledge that this research—as with any work on infectious agents—is not without risks. However, because the risk exists in nature that an H5N1 virus capable of transmission in mammals may emerge, the benefits of this work outweigh the risks.

TWiV 211: Viruses r us

On episode #211 of the science show This Week in Virology, the TWiV four discuss an mRNA-based influenza vaccine, and a phage tubulin that forms a filamentous array in the host cell that is needed for positioning viral DNA.

You can find TWiV #211 at www.microbe.tv/twiv.

TWiV 201: Rabid about viruses

On episode #201 of the science show This Week in Virology, Vincent, Alan, Rich, Dickson, and Kathy answer reader email about rabies, xenotransplantation, poliovirus, Ph.D. programs, mosquitoes, and much more.

You can find TWiV #201 at www.microbe.tv/twiv.

TWiV 198: Pox has got a squeeze-box, seals are gonna sneeze all night

On episode #198 of the science show This Week in Virology, Vincent, Alan, Rich, and Kathy review fatal avian influenza virus in harbor seals, and poxvirus deployment of genomic accordions to counter antiviral defenses.

There once was a virus named pox
Whose genome contained a squeeze-box
When placed under pressure
It expanded its measure
Overcoming the new cellular blocks

You can find TWiV #198 at www.microbe.tv/twiv.

Don’t panic, Ebolavirus is not heading for you

An outbreak of Ebola hemorrhagic fever that began in early July 2012 has involved at least 36 individuals and 16 deaths. So far the disease has been confined to a rural region west of Kampala, the capital of Uganda. The subject of Richard Preston’s scary The Hot Zone, Ebolavirus is newsworthy because it can be highly lethal and inspires scenarios of pandemics. An examination of the virus and the disease should temper our fear of this pathogen.

[read the rest of my article at TakePart]

Origin of the H5N1 storm

ferretI still wonder why the influenza virus H5N1 ferret transmission studies generated such fear and misunderstanding among the public, the press, and even some scientists. I still cannot fully explain what transpired, but now that the papers have been published some new clues have emerged.

In my opinion, the main catalyst of the storm was the article Scientists brace for media storm around controversial flu studies by Martin Enserink. It began with the inflammatory statement ‘Locked up in the bowels of the medical faculty building here and accessible to only a handful of scientists lies a man-made flu virus that could change world history if it were ever set free’. Fouchier said that he created ‘probably one of the most dangerous viruses you can make’. Members of the NSABB were quoted as saying ‘I can’t think of another pathogenic organism that is as scary as this one’, and ‘This work should never have been done’.

This article presented a one-sided view because only Fouchier or NSABB members were quoted. I don’t understand why Fouchier made some of the statements that he did; perhaps he was quoted out of context. The NSABB members were on the way to restricting publication of the paper, so their views were clear. What Enserink did not do – what he should have done – was to speak with other virologists. This he could not do because the manuscript describing the work had not been made public. He violated a main tenet of journalism, to present both sides of the story.

With the publication of the Fouchier and Kawaoka papers, it became immediately apparent that all of the inflammatory statements in the Enserink article are wrong. For example, after 10 passages in ferrets, an altered H5N1 virus does transmit in the air among ferrets, but inefficiently and without killing the animals. Hardly one of the most dangerous viruses you can make.

To be fair, Enserink was not the first to report these findings. Fouchier presented the results of his H5N1 ferret transmission studies at a meeting in Malta in September 2011. A week later, New Scientist published an article on the findings entitled Five easy mutations to make bird flu a lethal pandemic. In the first paragraph, the author writes ‘…five mutations in just two genes have allowed the virus to spread between mammals in the lab. What’s more, the virus is just as lethal despite the mutations.’ A few paragraphs later: ‘The tenth round of ferrets shed an H5N1 strain that spread to ferrets in separate cages – and killed them.’ Both the title and these statements are all wrong. Fouchier’s published paper does not prove that five mutations are sufficient for aerosol transmission among ferrets, and the virus does not kill ferrets when it is transmitted through the air.  Also problematic is Fouchier quoted as saying that ‘The virus is transmitted as efficiently as seasonal flu’. Given the published data, and his comments at an ASM Biodefense Meeting in February 2012, I do not understand this statement.

It is easy to see how the misinformation in these two articles ignited the fear. Their stories were repeated by countless other publications without verifying whether or not they were correct, amplifying the false conclusions and spreading misinformation even further. Those of us who pointed out inconsistencies were dismissed as risk-takers. Even the New York Times without ever having seen the data – declared that the experiments should not have been done and the virus stocks should be destroyed.

A comparison of the original Fouchier manuscript with the version recently published in Science provides additional insight (I do not have the original version of the Kawaoka paper).  The first version of the manuscript was submitted to Science and reviewed by the NSABB, whose members recommended that it should be published in redacted form. Fouchier and colleagues then submitted a revised version which was reviewed by the NSABB, who then decided that the entire paper could be published.

Curiously, the titles of the paper are different. The original: Aerosol transmission of avian influenza H5N1 virus. The published version: Airborne transmission of influenza A/H5N1 virus between ferrets. The first is clearly ‘scarier’.

Another big difference between the two manuscripts is the length. A research article in Science is typically brief: it begins with a paragraph or two of background information, then delves right into the results. This is how the original Fouchier manuscript was constructed. In contrast, it is not until page five of the published version do we reach the data: the previous pages are filled with background material reminiscent of a review article. Included is information on the basic biology of influenza viruses, the functions of individual proteins, virulence, why the authors decided to do these studies, what is known to control host range and transmission, and the containment procedures that were undertaken. It is an impressive amount of background information, none of which was present in the original version.  The additional material does help to put the experiments in their proper context.

I found two examples of changes in the wording that I feel could make substantive changes in reader perceptions of the results.

In the abstract of the original manuscript, the authors wrote:

The virus acquired the ability to transmit via aerosols or respiratory droplets while remaining highly pathogenic to ferrets.

In the revised manuscript, this sentence has been changed:

None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses.

The second version better represents the data. The first version is incorrect as stated because the virus is virulent only when inoculated intratracheally into ferrets, not after transmission by aerosols.

A second example occurs during discussion of the response of ferrets to infection with mutant H5N1 virus. In the original manuscript the authors note that after intransal inoculation, the animals have signs of disease but did not die. However, after intratracheal inoculation with the virus, all six ferrets died. Their conclusion:

 These data are similar as described previously for A/H5N1wildtype and thus do not point to reduced virulence (italics mine).

In the revised manuscript this sentence has been modified:

These data are similar to those described previously for A/H5N1wildtype in ferrets. Thus, although the airborne-transmissible virus is lethal to ferrets upon intratracheal inoculation at high doses, the virus was not lethal after airborne transmission.

The first version is misleading because it does not clearly state that virulence was assessed by intratracheal inoculation.

For the most part the same data are presented in the two versions of the manuscripts. A virologist would not draw different conclusions from the two manuscripts despite the longer introduction and the two modifications noted above. I remain puzzled as to why the first manuscript raised such a furor. I cannot believe that it was simply a consequence of overzealous writers and a few scientific overstatements.

Although the Kawaoka and Fouchier papers have been published, the effect of the H5N1 storm will linger for a long time. The moratorium on H5N1 transmission research continues, meaning that important questions cannot be answered. On 29 March 2012 the United States government issued its Policy for Oversight of Life Sciences Dual Use Research of Concern (pdf).  According to this new policy, seven different types of ongoing or proposed research (including transmission studies) on 15 different pathogens (including highly pathogenic avian influenza viruses) must now be reviewed by a committee for risk assessment and if the development of mitigation plans. Once the work is in progress, no deviations from proposed experiments are permitted without further review. I understand from a number of virologists that this policy has had a chilling effect on avian influenza virus research. As a consequence, this area of investigation is likely to substantially contract, depriving us of potentially important findings that could be useful in limiting influenza and other viral diseases.

We are in this position because access to the Fouchier and Kawaoka papers was restricted, and few could actually read them to understand exactly what was done. I can’t think of a better reason for unrestricted publication of scientific findings.

TWiV 190: The second ferret of the Apocalypse

On episode #190 of the science show This Week in Virology, Vincent, Alan, and Kathy review selection of influenza H5N1 viruses that can transmit among ferrets by aerosol.

You can find TWiV #190 at www.microbe.tv/twiv.