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Commentary
D225G/N
H1N1 Clustering Raises Concerns
Recombinomics Commentary 14:17
January 27, 2010
The above comments, from Friday’s WER, are a restatement of the December 28 WHO announcement on D225G, which were similar comments by the ECDC, which was also on December 28.
However, sequences from Ukraine had already been made public, and those sequences clearly demonstrated temporal and geographic clustering. The initial series was published by Mill Hill, a WHO regional center. 10 HA sequences were released. Nine were from western Ukraine and were the same clade, and D225G was found in the four fatal cases. All western Ukraine samples were collected on Oct 27-28 and the four fatal sequences signal clustering. These sequences were public a day after WHO announced that there were no significant genetic changes in the Ukraine sequences. However, the clustering I fatal cases was obvious, which prompted Norway to look at samples and they found 3 examples of D225G. Two were fatal and the third was severe, leading to Norway issuing an alert, which was followed by a WHO announcement on the “Norway” mutation (which was called insignificant two days earlier when found in Ukraine.
The fatal Ukraine sequences also included a rare marker on one of the sequences. This marker was only found in two pandemic H1N1 sequences at Genbank, and both were from New York and had D225N, providing a genetic link between D225G and D225N. This linkage was strengthened by two fatal Ukraine sequences released by the CDC, another WHO regional center, who found D225N in the two samples. In addition, the CDC released a partial PB2 sequences on five isolates (which included three of the mild cases in the Mill Hill release) and all five had F340N, adding further confirmation that the sequences from western Ukraine were all from the same clade.
The association between D225G and D225N was further established by addition sequences from lung samples in an around Kiev, which had both D225G and D225N in samples from the same patients. Thus, prior to the December 28 comments by WHO and ECDC, there was clear clustering in time and space of D225G/N in Ukraine.
The Ukraine clustering was expanded by additional sequences from neighboring countries. When Mill Hill released the two fatal Ukraine cases with D225G/N, they also released a sequence from Moldova which also had D225G and D225N from a sample collected within a day of the first reported H1N1 fatality in Moldova. In addition, multiple labs in Russia were releasing sequences from fatal cases with D225G/N, including sequences from the same clade and collected at the same time (November), increasing the number of sequences which were collected at the same time and in the same general area. These sequences were released at the end of 2009 and beginning of 2010, well in advance of Friday’s WER, which did not include updates in concepts of cases.
More sequences from Ukraine were released on Monday. 28 HA sequences from autopsy lung had 21 examples of D225G/N. 11 of the 21 had both D225G and D225N and the recent data brought the number of cases with D225G/N in Ukraine to 30, and 29 were from fatal cases.
Thus, the absence of clustering cited above is false, but the Ukraine is not the only area where D225G is clustering in time and space. Sequences released from the fatal outbreak at Duke Medical Center were released. These sequences had also been generated by the CDC, and followed a December 2 announcement on the death cluster. The three fatal cases were part of a cluster of 4 patients who were Tamiflu resistant. The sequences from those patients showed that all had a rare polymorphism, supporting patient to patient transmission, and three of the sequences with these markers also had D225G/N. Since these samples were collected in October and announced December 2, the transmission data was also available to the authors of the December 28 WHO report.
The North Carolina cluster involved a different clade and was at different location, but it was the movement of these polymorphisms from genetic background to genetic background that led to the prediction that the Ukraine sequences would have D225G/N.
This movement from one genetic background to another had been documented in the oseltamivir resistances cases in H1N1 seasonal flu. H274Y had jumped from one genetic background to another in patients who were not taking Tamiflu. This jumping was a product of hitchhiking and homologous recombination.. Additional polymorphisms from clade 2C jumped to clade 2B which led to the fixing of H274Y in seasonal flu. These data thoroughly discounted the WHO mantra on “random mutations” by the same excuse was used to claim that the D225G and D225N in Ukraine was spontaneous and did not transmit, which has also been thoroughly discounted by the recent data from Ukraine and North Carolina.
Thus, the reliance on “random mutations” to explain data that is clearly not generated by random mutations continues to be hazardous to the world’s health.
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