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Media Myth On CDC H5N1 Transmission
Recombinomics Commentary 19:15
May 3, 2012

while our paper was under review, one study14 reported that a virus with a mutant H5 HA and a neuraminidase (NA) of a human virus in the H5N1 virus background caused respiratory droplet transmission in one of two contact ferrets.

Several groups had previously reported that mutations to the binding site could make the virus switch its preference from bird to human cells. Indeed, on 5 November 2011, while NSABB was debating the wisdom of publishing the Kawaoka and Fouchier papers in full, a report appeared online in Virology that identified two such mutations. But the mutations alone still didn't make the virus transmissible between ferrets through respiratory droplets.

The above comments are from the Kawaoka Nature paper (in blue) and Science comments on the paper (in red).  The Science comments are grossly misleading and suggest that the published study in Virology did not lead to transmission via droplets, which is false.  The published Nature paper reveals significant similarities between the published (November 5, 2011) Virology paper and the recently released Nature paper (as well as the Ron Fouchier Science paper, which has still not been made public).

Media reports on the initial NSABB request to censor or the Nature and Science papers began in mid-November, after the CDC paper was published in Virology.  The Virology paper gave a complete recipe for the creation of an H5 reassortant that transmitted in ferrets, which is the topic of the Nature paper.  However, the Nature and Science papers extended the studies by selecting variants generated  via passage in ferrets, which the CDC paper did not.

The CDC paper started with a 2006 egret isolate, A/egret/Egypt/1162/2006, (clade 2.2) from Egypt and added two receptor binding domain changes, Q226L and G228S which were present in H2 and H3 pandemics and have been widely cited as changes that would alter the H5 receptor binding specificity.  The CDC used a receptor binding assay to identify Q196R, which in combination with the above two changes led to a shift the exclusive binding to 2.6 gal (mammalian upper respiratory tract) receptors.  These three changes, on a clade 1 background (A/Vietnam/1203/2004), which also had a seasonal N2, produced droplet transmission in ferrets..

The Nature paper used an H5 from the same clade I isolate, A/Vietnam/1203/2004 (not a clade 2.3.4 isolate from Vietnam, as guessed based on recent publications by Kawaoka, which was placed on an H1N1pdm09 genetic background. 

Like the Virology paper, various changes were screened in a receptor binding domain assay, and the H5 was modified with N224K and Q226L based on a shift to exclusive binding to 2,6 gal receptors.  Passage in ferrets led to partial droplet transmission (similar to the Virology result) and the recovered H5 had acquired N158D, which was already present on the egret isolate.  Further passage in ferrets led to the identification of the fourth H5 change, T318I, which increased transmission frequencies.  Thus, the Virology paper was virtually identical to the Kawaoka result prior to further passage in ferrets.

Although the Fouchier paper in Science has not been published, media reports indicate the Fouchier study was remarkably similar to the two published studies described above.  Fouchier used a clade 2.1 H5 from Indonesia (A/Indonesia/5/2005), which used the same two changes used in the Virology study (Q226L and G228S).  PB2 E627K was also added, which was also done in the Virology study because the clade 1 background also has E627K.
Like the Nature paper, efficient transmission was achieved through passage in ferrets, which led to the acquisition of two additional H5 changes.  One of those changes is almost certainly a change like N158D which eliminates the glycosylation site, since the Indonesian isolate also has N at position 158 and T at position 160, and Fouchier has noted similarities in acquired changes due to ferret passage described in the Nature and Science studies.

Thus, the publication of the Nature papers confirms the lack of any scientific basis for the initial NSABB request, which was unanimously approved even though a transmission recipe had already been published in Virology, and the published recipe was very similar to the Nature and Science studies.  Moreover, the NSABB subsequently unanimously voted to withdraw request with regard to the Nature paper, yet six members still voted to censor the Science paper, even though the recipe (three changes on a clade 2.1 background) were well known and influenza selection via ferret passage was initially described in the 1930’s and has been described and refined many times since, including the published Virology and Nature papers.

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