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Similarities In CDC and Fouchier H5N1 Transmission Papers
Recombinomics Commentary 12:00
February 23, 2012

A reverse genetics virus with HA of EG06-196R/226L/228S, the N2 neuraminidase from a human seasonal H3N2 virus, A/Brisbane/10/2007, and 6 internal genes from a clade 1 H5N1 virus, VN04, known to replicate efficiently in ferrets (Maines et al., 2011), was generated and evaluated in the ferret transmission model. As shown in Table 2, both direct contact ferrets that were housed in the same cage with inoculated ferrets became infected, as evidenced by virus shedding and seroconversion results. In addition, viral shedding was also detected in one of two ferrets housed in adjacent cages and exposed only via respiratory droplets.

The above comments are from the CDC paper, “In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity", published online on November 5, 2011 in the journal Virology.  As noted above, the three receptor binding domain changes included the two most noted changes in H5N1 transmission discussions, Q226L and G228S, along with Q196R which was present in H5N1 clusters in Iraq and described in previous studies by Kawaoa.  These changes were placed on a clade 2.2 H5 (A/egret/Egypt/1162/2006) which was pl aced on a genetic background using human N2 (A/Brisbane/10/2007) 6 H5N1 clade 1 genes (A/Vietnam/1203/2004), which includes PB2 E627K.  This combination led to H5N1 transmission in ferrets via respiratory droplets as stated above.

Thus, the “recipe” for H5N1 was published in full in a scientific journal which could be accessed by anyone with an internet connection.  It provided full detail on the changes, which have been described in detail previously.  Moreover, it used well known isolates which had been sequenced and were publicly available at Genbank or GISAID.

Thus, after the details were published describing the US CDC H5N1 transmission results, the US NSABB requested papers submitted to Nature and Science be delayed and censored.  Ironically, the CDC paper was more of a recipe for a bioterrorist because it cobbled together a virus that was unlikely to be created in nature because clade 2.2 is now largely limited to Egypt, clade 1 has never been reported outside of southeast Asia, and the assembled virus included a human N2 gene so technically the transmitting H5N1 was really H5N2. 

In contrast, the Fouchier paper, which is delayed at Science, started with changes present in the CDC published paper.  It had the two most publicized RBD changes, Q226L and G228S, in HA, as well as the most publicized polymerase change, PB2 E627K.  The Fouchier paper placed these three well known changes on an Indonesia clade 2.1 genetic background, which also achieved ferret transmission, while maintaining lethality.  Passage in ferrets led to the selection of two additional well known changes, and these two changes are of interest to the scientific community, but of little interest to a bioterrorists, since passage in ferrets is a well known technique which would select the two additional changes.

The Kawaoka paper also used a combination that was more likely to be generated via natural selection because he used a clade H5 from Hanoi (almost certainly A/Vietnam/HN31604/2009) which was placed on an H1N1pdm09 genetic background (A/California/04/2009).  It is unclear if he also created Q227L and G228L, but it is well known that H1N1pdm09 PB2 can substitute for H5N1 PB2 with E627K to produce efficient human transmission, and H1N1pdm09 is widespread in humans, swine, and turkeys which provide natural opportunities for the creation of an H5 reassortant with a composition that matches the H5N1 used by Kawaoka in his paper in Nature.

Thus, the two delayed papers demonstrate that a subset of the changes used in the published CDC paper, which were on a clade 2.2 H5 from Egypt, could be placed on a clade 2.1 H5 from Indonesia to create droplet transmission in ferrets, which can also be achieved using a clade H5 from Vietnam (on an H1N1pdm09 background).

Therefore, the NSABB request to redact detail in the Fouchier and Kawaoka papers had no scientific basis, and was appropriately rejected by the scientific community familiar with the detail.  The papers at Nature and Science should be published immediately, and the NSABB should get a new board that is more knowledgeable about H5N1 evolution and reasons why a transmitting H5N1 would not be a good choice as a weapon of mass destruction.

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