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Commentary
Norway H1N1 D225G/N
Publication Refutes WHO Position
Recombinomics
Commentary 16:24
March 4, 2010
The above comments from a recent report on position 225 (222 in H1 numbering) changes in clinical samples from Norway, flatly refute WHO comments indicating the changes were not significant or not even worth mentioning when found in a death cluster involving transmitting H1N1 at Duke Medical Center.
D225G/N received increased attention in association with an H1N1 outbreak in Ukraine. Young, previously healthy, adults were dying with a high rate with a hemorrhagic component and the rapid destruction of the lungs. There has been earlier evidence of D225G and D225N linked to.fatal cases, including the detection of D225G in 2 of 5 HA sequences from the 1918/1919 pandemic. Moreover, in 2009 there was evidence of D225G and D225N jumping from one genetic background to another. Thus, the detection of these two changes in the fatal cases in Ukraine was predicted.
However, just prior to the release of initial sequences by Mill Hill, the WHO put up a Ukraine update on Nov 17 stating that no significant changes had been found in the sequences from Ukraine patients, but the next day 10 HA sequences were released and D225G was found in all four fatal cases. Five other sequences from milder cases infected with the same sub-clade strongly suggested the linkage to fatal cases was significant.
The sequence data led to the examination of earlier sequences generated in several countries, including Norway. An alert was issued when Norway found 3 sequences with D225G, which were from two fatal cases and one severe case, which was the first severe cases reported in Norway.
The Norway announcement was followed by a Nov 20 briefing note from WHO, again stating a lack of current evidence linking D225G to an increase in severe or fatal cases.
The Nov statement from WHO was followed by a Dec 2 announcement of transmitting Tamiflu resistance (H274) at a medical center in the UK and the US. The US cluster was at Duke Medical center and 3 of the 4 patients died. The presence of D225G and D225N in that cluster was not disclosed, even though the cluster led to the prediction that D225G/N would be involved.
The WHO then issued a Dec 28 preliminary report on D225G, which claimed that D225G was spontaneous and due to copy errors. The evidence supporting this assertion was based on a lack of clusters in time and space, as well as a lack of linkage to a specific sub-clade.
However, that report was followed by the release of sequences from Ukraine with D225G in the same sub-clade. In Ukraine the sequences were collected over a 2-3 week time frame. There were 37 lung samples from fatal cases and 27 had D225G, D225N, or both (11 samples had both).
The Ukraine sequences formed branches that included sequences with receptor binding domains that were wild type, had D225G, or had D225N. This pattern of different sequences on the same branch, or the same change on multiple branches has led to an explanation of spontaneous mutation. However, the presence of D225G and D225N in the same sample, as well as the high frequency of these changes leads to a much higher likelihood that the movement of the changes from background to background is based on recombination.
These combinations are also found in the Duke cluster, where all four patients were on the same ward and had the same series of markers. However, in spite of this clustering in time and space as well as identical genetic backbones, D225G was found in one patient (in two collections) and D225N was in another, once again supporting acquisition by recombination, as well as transmission, with sporadic detection.
The Norway study also found a statistically significant association of D225G and D225N with severe and fatal cases. They also found D225G on multiple genetic backbones, providing additional support by acquisition by recombination.
The Norway data, as well as sequences from Ukraine, Russia, the United States and other countries show clear clustering and decisively refute WHO claims of lack of significance as well as spontaneous appearances due to copy errors.
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