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H1N1 Tamiflu Resistance (H274Y) Spikes In Delaware

Recombinomics Commentary 13:45
May 11, 2011

Continued laboratory testing of flu cases at the request of the Centers for Disease Control and Prevention (CDC) confirms four additional Delaware cases of antiviral-resistant influenza for the 2010 – 2011 flu season. This brings the total number of resistant flu cases to 10.
- a 2-month-old boy from Sussex County, briefly hospitalized.
- a 7-year-old girl from Sussex County, did not require hospitalization.
- a 45-year-old woman from Sussex County, who died Feb. 24. This was the second flu death of the 2010-2011 flu season, and was announced Feb. 25
- a 28-year-old man from New Castle County, briefly hospitalized.
A form of influenza that cannot be successfully treated with common medicines was identified in eight more people in Delaware, public health officials reported Tuesday.
Those new discoveries -- which included four new cases identified Tuesday afternoon -- bring the total number of antiviral-resistant flu cases during the 2010-2011 flu season in Delaware to 14.

The above comments are from a May 9 Delaware Health and Social Services press release followed by a media report indicating four additional cases were discovered yesterday, raising the Delaware total to 14.
The CDC recently released US H1N1 sequences from 2011, which included the first four cases from Delaware, as well as four cases from Maryland.  Seven of the eight isolates are the S188T sub-clade, which is dominant in the US in 2011. 

However, the eighth case, A/Maryland/04/2011, is the Chihuahua sub-clade.  The first three cases from Delaware also had A189T, which is one of the key changes found in the Chihuahua sub-clade, signaling recombination between the co-circulating sub-clades.  Two additional sequences from Virginia had S188T and A189T, but were not reported to have H274Y.  However, WHO collaborating labs have agreed to classify isolates as Tamiflu sensitive if the mixtures have more than 50% of signal as wild type, so it is unclear if H274Y was detected in Virginia also (as a mixture).

In addition, the fourth case from Delaware, A/Delaware/08/2011, was virtually identical to A/Maryland/06/2011, providing additional evidence for transmission in the area, as well as H274Y jumps between various genetic backgrounds (two S188T backgrounds, as well as Chihuahua with A189T).

The 8 announced cases in Delaware this week have striking parallels with seasonal H1N1 in the 2007/2008 season, when transmitting Tamiflu resistance was reported in multiple countries, but was highest in northern Europe.  The H1N1 vaccine target Solomon Island/03/2006 was mismatched with Brisbane/59/2007, but the CDC used a non-discriminating ferret anti-serum to classify Brisbane/59 isolates as Solomon Island-like.  The target was changed the following year to Brisbane/59, but the H1N1 in the 2008/2009 season had acquired A193T as well as a least one change at positions 187, 189, or 196 via recombination with co-circulating H1N1 sequences.
The current H1N1 in the United States is dominated by sub-clades with S186P, S188T, or A189T.  The first three Delaware sequences had S188T and A189T, but are classified as California/07/2009 by another ferret anti-sera that fails to classify isolates with the key changes as low reactors (although one sequence with S186P and S188T was designated a low reactor).

Thus, the rapid increase in the number of H274Y cases in Delaware, including jumps from genetic background to background, coupled with the acquisition of RBD changes around position 190, and the failure to classify these changes isolates as low reactors while defending a mismatched vaccine target, has striking parallels with the fixing of H274Y in seasonal H1N1.

Release of recent Delaware sequences with H274Y (and similar sequences from Maryland and Virginia) would be useful.

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