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Transmission of Novel D225G in Norway and Sweden
Recombinomics Commentary 12:57
December 2, 2009

Recently released HA sequences from Norway and Sweden at Genbank and GISAID have D225G and support the spread of the polymorphism, but raise additional questions about the true frequency of the change.  Although D225G was present as a mixture in one of the first swine H1N1 isolates, A/California/7/2009, which is the source of the current vaccine, only about 1% of published HA sequences have D225G.  Since D225G can grow in cells with alpha 2,3 receptors, which include lung cells, the detection of D225G may be tissue specific and detection in the upper respiratory tract, which is dominated by cells expressing 2,6 receptors, may be limited.

The two recent sequences represent isolates from each anatomical area.  In Norway, the sample is from a Danish truck driver who was the first reported fatal cases of H1N1 and the HA sequence, A/Norway/3206-3/2009,  was from post mortem lung.  In Sweden, the isolate A/Stockholm/48/2009 was from a nasopharyngeal swab from a recovered case.  However, both sequences contained tandem polymorphisms usually associated with D225G or D225E.  This tandem set of polymorphisms is also found in two earlier isolates from Spain (A/Catalonia/NS2001/2009 and A/Catalonia/NS2008/2009).  The presence of the rare coding of D225G in four unrelated cases suggests D225G is widespread, but detection is usually associated with infected tissue samples, so the low frequency is largely linked to frequent collection of nasopharyngeal samples from milder cases.

This distribution is most evident in the sequences from Ukraine, which had 10 HA sequences from 10 cases. 9 of the10 were from western Ukraine and belonged to the same sub-clade.  However, D225G was not in the 5 nasopharyngeal washes from survivors, but was in four of four tissue samples (3 from lung) from fatal cases.

This differential detection suggests that D225G is transmitting as a mixture.  In addition to California/7, other isolates have given mixed signals at position 225 (coding for D225G and D225E). 

This situation is analogous the upcoming paper on detection of Tamiflu resistance (H274Y) in a San Francisco traveler who was not taking Tamiflu. The patient was identified at the entry point to Hong Kong and the sequence containing H274Y was published.  However, the upcoming paper indicates that the H274Y was present as a mixture.  In the sequence from the virus grown in MDCK cells, the consensus was H274Y, but the tracing showed a small signal for the wild type sequence for codon 274. Cloning from the original tissue sample showed that the H274Y and wild type sequences were present in almost equal amounts.  The mixture also explains the rapid appearance of H274Y in patients treated with Tamiflu, supporting the silent spread of the polymorphism.

The same is true for D225G, which is likely transmitting in at a frequency that is much higher than the reported 1%.  Moreover, as the viral load increases, the likelihood of the minor population with D225G establishing itself at high levels in the lung increases, leading to more hospitalizations and deaths.

Therefore, a more aggressive campaign of testing lower respiratory tract samples, especially at autopsy, would be useful.  Currently, the vast majority of sequences are from the upper respiratory tract, producing a false reading on virus causing the more serious disease.

In addition, the Ukraine sample with D225G was classified as a "low reactor", raising concern that natural immunity to wild type H1N1, as well as immunity generated by the killed vaccine, which does not have D225G, will lead to high ratios of D225G to wild type, leading to more serious disease.

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