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D225G In Fatal Chihuahua H1N1 Index Case
Recombinomics Commentary 18:30
August 17, 2011

The CDC has released another series of 2011 H1N1 sequences.  Included was A/Mexico/2058/2011 from a 36M collected on March 15, 2011.  The age, gender, and collection date match an earlier case which was associated with another sequence, A/Mexico/DRE1945/2011.  However, it is unclear why sequences from the same patient would be given different numbers.  The March 15 was a week earlier than subsequent collections, strongly suggesting that Mexico/2058 and Mexico/DRE1945 are from the first confirmed cases in Chihuahua from the Chihuahua sub-clade.

The sequences from the National Labs contained D225N, which was stated in the title of the associated characterization sheet, “Detection of D222N substitution in Pandemic Influenza A (H1N1) Virus in Chihuahua, Mexico”.  The CDC sequence was from an egg isolate, and was closely related to the earlier sequence, but had D225G, raising concerns that the frequency of D225G is grossly under-reported because most isolates are from MDCK cells which select against D225G.

The sequence from the lab in Mexico was direct and from a sample from the upper respiratory tract and was not reported as a mixture.  Similarly, the CDC sequence was from an egg isolate, and also not reported as a mixture, although the age, gender, and collection date indicate both sequences were from the first confirmed case, which was fatal and from the partner of another fatal case, who had similar symptoms, but isolation attempts failed.  The linkage of these two fatal cases, as well as additional severe and fatal cases from the same traffic patrol office led to a WHO pandemic alert.

The time delay, and egg isolation raises concerns that there are many more sequences from Chihuahua with D225G and D225N, which would provide more linkage to severe and fatal H1N1 cases, as indicated in multiple anecdotal reports.  Similarly, the detection of D225G in an egg isolate raises concerns that the H1N1 sequence database in general grossly underestimates the frequency of D225G and D225N in severe and fatal cases since most sequences are from isolates grown in mammalian MDCK cells.

The changes in positions 225 and 226, as well as positions 156-159 are important because they are associated with immunological escape, as well as targeting of human lung.  Both human lung and chicken embryos in eggs, are rich in gal 2,3 receptors.

The heavy use of MDCK would also produce a gross undercount in low reactors, which led to the recent recommendation to leave all three vaccine targets unchanged in spite of record high fatality rates in pneumonia and influenza (P&I) patients.  These concerns are likely linked to the recent sequences for new vaccine targets.  The latest, A/Victoria/502/2010, was just released by the WHO regional center in Australia.  Like the new pandemic H1N1 target released by the CDC, it has Q226R.  The initial egg isolate from this patient had D225G, while an MDCK isolate was wild type at positions 225 and 226.  These new vaccine target raise concerns that the current vaccine in use in the southern hemisphere, as well as the vaccine shipping for the 2011/2012 season in the northern hemisphere, will have limited utility.

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