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H1N1 D225G and D225N in Moldova Patient
Recombinomics Commentary 14:20
January 10, 2010

Mill Hill has placed a series of H1N1 sequences on deposit at GISAID including more recent sequences from Ukraine.  Two of the sequences were from lung washes and both had mixtures of position 225 changes including D225G and D225N.  Included in the series of HA sequences were 8 of 18 samples from Moldova which had changes at position 225. Seven of the eight had D225E, but one, A/Moldova/G-152/2009, had the changes seen in Ukraine, D225G and D225N in the same patient.  Demographic information was not included for the Oct 23 collection, but the first reported fatality (50M) in Moldova was Oct 24.  Moreover, all sequences from Ukraine with D225G, D225N, or both, appear to be from fatal cases, which is also true for Russia.  Thus, the detection of these two changes in the same patients is cause for concern.

The two changes were initially seen in a fatal infection of a patient in Utah, which was followed by two fatal infections in San Luis Potosi and a severe or fatal infection in Stockholm.  In the latest series of published sequences, this combination of both changes in the same sample was extended to two locations in Ukraine (Kyiv and Chenihiv), supporting the spread of these two changes and an increased complexity created when both changes are in the same patient.

Although some have claimed that these changes are "spontaneous" and do not spread, the cluster of examples in and around Ukraine clearly demonstrates a pattern of spread, and  the combination of both changes in multiple patients also essentially eliminates coincidental random errors.

The increasing frequency of sequences with both changes raises concerns that the changes will offer an immunological escape.  Earlier, Mill Hill noted that the tested Lviv sample was a "low reactor", link the acquisition of D225G to immunological escape, which is also supported by increasing antigenic complexity at that position, with reports of D225G, D225N, D225A, and D224E co-circulating.

The recent end of wave 2 throughout the northern hemisphere creates an opportunity for these co-circulating changes to emerge.  Seasonal influenza A (H1N1 and H3N2) have all but disappeared from the United States and Europe, setting the stage for emergence of competing pandemic H1N1 variants.  In addition to the change at position 225, Q226R is also being reported at higher frequencies in the region, creating multiple opportunities for new combinations via homologous recombination, as was seen in the fixing of H274Y in seasonal H1N1 during the 2008/2009 season.

The latest changes in position 225 further increase concerns of the emergence of pandemic H1N1 dominated by such changes, which are associated with severe and fatal outcomes.

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