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Detail On Fouchier H5N1 Transmission Paper
Recombinomics Commentary 17:30
February 22, 2012

Ron Fouchier and colleagues at the Erasmus Medical Centre in Rotterdam, the Netherlands, created transmissible H5N1 by putting two mutations into the HA surface protein of an H5N1 virus, and one into its polymerase enzyme, before exposing ferrets to it. It spontaneously acquired two more significant mutations, and remained lethal.

The above comments strongly suggest that the H5N1 that transmitted in ferrets began with two receptor binding domain changes, Q226L and G228S, as well as PB2 E627K.  Passage in ferrets selected two more changes with S227N and Q196R at the top of the list of likely acquisitions, based on a CDC publication in Virology, "In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity"..

The CDC paper looked at quasi-species in A/Vietnam/1203/2004, which had a number of receptor binding domain changes, including S227N and Q196R which synergized with each other.  However, Q196R, when combined with two receptor binding domain changes seen in prior pandemics, Q225L and G228S, produced a dramatic change in receptor binding, favoring 2,6 receptors which are present at high levels in human (and other mammal) upper respiratory tracts.  This combination led to detectable H5N1 in the upper respiratory tract of ferrets.  However, to achieve efficient transmission, the above construct was placed on a clade 2.2 H5 background, A/egret/Egypt/1162/2006, and 6 H5N1 genes from A/Vietnam/1203/2004, which contained PB2 E627K (which was also in the clade 2.2 isolate from Egypt, and the N1 was replaced with an N2 from seasonal H3N2 (A/Brisbane/10/2007).  This construct transmitted in ferrets.

Thus, the Fouchier result demonstrated that the requirement for a clade 2.2 genetic background, as well as a seasonal N2 could be eliminated by two changes on H5 when clade 2.1 from Indonesia was used, indicating the creation of a transmitting H5N1 was easier than changes noted in the CDC paper.

Similarly, the Kawaoka paper showed that H1N1pdm09 genes could substitute for the human N2 and the PB1 E627K.

The results confirm that H5N1 transmission requires a minimal number of changes, and reproduction of the results described in the Science and Nature papers can be easily achieved with the public information described above.

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