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Fixing PB2 E627K In Pandemic H1N1

Recombinomics Commentary 02:16
March 17, 2010

They added that the clinical and epidemiological significance of the mutation is unclear and that experimental infection of ferrets with the H1N1 virus containing the mutation did not suggest increased shedding, virulence, or transmissibility.

Shaw said nothing stood out about the Dutch patients—the mutation didn't appear to give the virus a transmission advantage. If the mutation described by the Indian researchers turns out to be the E627K in PB2 mutation, "it's an interesting observation, but probably irrelevant clinically," he said.

The above comments further support the interpretation that the PB2 change in three patients in India is E627K.  The above comments rely upon negative ferret data to suggest the change has no clinical relevance, even though all human seasonal flu since 1918 has E627K, indicating it offers significant selective advantage for multiple human sero-types and clades including pandemic H1N1 from 1918.

The CDC also cited negative ferret data to downplay the significance of D225G even though 2 of 5 isolates from fatal cases in 1918/1919 have D225G and 27/37 fatal lung samples in Ukraine have D225G/N and virtually all samples positive for D225G/N in Ukraine and several other countries are from fatal or severe cases.

The use of animal models which fail to replicate natural history to refute natural history is rather bizarre, but is used again and again by the CDC and WHO consultants to offer assurances and set policy, which continues to be hazardous to the world’s health.

Pandemic H1N1 is a swine virus adapting to a human host.  All prior seasonal flu’s have had E627K, so the acquisition of the same change by pandemic H1N1 is not a surprise.  Last spring, when E627K was found in an isolate from Shanghai or last fall when E627K was found in two Dutch patients, there was little selection pressure, which is also true for the experimental ferrets. 

Now that the second wave has ended, much of the target population has some immunity, so there will be a selection pressure for H1N1 that can evade the human immune response, and E627K may pair up with one or more additional adaptations to human hosts.  The finding that three patients already have this change may indicate that such a pairing has already happened.  Therefore, the spread of E627K is expected, as is the fixing of E627K, ferret experiments notwithstanding although the ferret data did show a decline in the 1918 virus when E627K was changed to E627.

Full sequences from these patients as well as the earlier cases in The Netherlands would be useful.

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