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WHO Silence on D225G Immune Escape Raises Concerns
Recombinomics Commentary 13:18
November 27, 2009

The recent upgrade of the characterization sheet for A/Lviv/N6/2009 to "low reactor" status has created significant pandemic concern.  The change affects receptor binding specificity and allows the virus to bind alpha 2,3 targets which are on the lung, and also affects the antigenic site.  However, early data on the development of the attenuated vaccine target indicated that there was no difference between the response to wild type and D225G.  These differences have not been explained, although the testing of the candidate vaccine target would be on the cold adapted background, while the testing that produced the "low reactor" designation would be on the D225G on its natural swine H1N1 background.  Initial investigations were carried out by Mill Hill, but then the CDC in Atlanta was also involved, possibly to confirm the "low reactor" results.

However, WHO has not issued any updates on this development.  They have said that the D225G change in Ukraine was "not significant" even though it was in four of four fatal cases and now has been designated a low reactor.  The only indication is at the GISAID database, which is public, but requires membership and is password protected.  This designation has serious implications because there is direct and circumstantial evidence that D225G is circulating as a mixture, and immune responses that fail to target D225G can shift the ratio in favor of D225G, which could lead to a significant rise in severe and fatal cases.

It was the rise in severe and fatal cases that led Norway to closely examine cases there, and D225G was found in three cases (2 fatal and 1 severe).  However, release of sequences from Norway identified a fourth case, where D225G was identified as a mixture with wild type.  Moreover this mixture was the earliest sub-clade in Norway that matched the sub-clade in Ukraine.  This sub-clade was isolated prior to the first reported fatal cases in Norway, which was also the same sub-clade, although D225G was not present in the sequence from a throat swab from that patient.

The failure of the WHO or CDC to comment on the low reactor status of the Ukraine sequences from fatal patients is also cause for concern.  More detail on this designation, and vaccine plans to address this issue, would be useful.

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