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Widespread S246N Tamiflu Resistance Clusters Raise Concerns
Recombinomics Commentary 20:15
June 13, 2011

The recent report on “moderate” Tamiflu and Relenza resistance (6 and 3 fold reductions in efficiencies) linked to S246N has raised concerns that this genetic change will become widespread and the modest reduction in efficiencies will lead to an increase in changes that have more severe consequences, such as H274Y, which reduces Tamiflu effectiveness by 600 fold, and syngergizes with S246N to generate 6000 fold reductions. 

There are concerns that similar synergies will be seen in isolates with S246N and changes at position 222 (I222R or I222K) which reduce Relena effectiveness rendering the two major neuraminidase inhibitors useless.

The paper noted the increasing levels of S246N in Singapore and Australia due to rapid clonal expansion.  However, the paper included a phyogentic tree showing S246N on multiple H1N1 backgrounds, signaling expansion via recombination, which appended S246N onto multiple gentic backgrounds.

However, a close examination of these additional cases, most of which were from 2009 or 2010, also formed small clusters, signaling additional clonal expansion and an absence of a selection penalty.  Two identical sequences with S246N (A/Jiangxi-Donghu/SWL131/2010 and A/Jiangxi-Donghu/SWL157/2010) were collected a week apart from the same province in China.  Similarly three other sequences which matched each other (A/Athens/INS342/2009, CY062875 A/Athens/INS161/2009, A/Athens/INS350/2009) were collected days apart from three patients in Athens).  In other clusters the sequences were closely related to each other including three isolates from the United States (A/North Carolina/03/2010, A/North Carolina/05/2010, A/Minnesota/02/2010) or two isolates from eastern Europe (A/Croatia/18576-1/2010 and A/Slovenia/234/2011).  Thus, each cluster represents an independent introduction of S246N via recombination), and the clustering in time and space presents clonal expansion of each introduction.  These clusters are smaller than those reported for Singapore and Australia in part because in 2009 and 2010 there was little immunity in those under the age of 60 so novel sub-clades did not dominate. 

In the 2010/2011 new and larger sub-clades began to appear such as the S188T and S186P sub-clade that were large and widespread.  Another sub-clade with changes near the larger receptor binding domain, which had R208K and I219V in addition to D100N and V252L began to expand in Sweden, Iraq, and Iran in late 2010, early 2011.  More evolved versions of this sub-clade were seen in large numbers in Italy (Milan and Pavia) and these sequences were very closely related to the sequences in Singapore and Australia.  Most of the sequences from Italy did not include NA, so the presence or absence of S246N could not be determined for most public isolates, but S246N was not in the few NA sequences published.  However, the large number of sequences from this sub-clade indicated it could spread rapidly, which happened in Singapore and Australia after S246N was acquired.

Thus, the prior history of small clusters in 2009 and 2010 on multiple genetic backgrounds, coupled with the rapid spread in Australia and Singapore after S246N was acquired raises concerns that S246N will be common in the current flu season beginning in the southern hemisphere, and this change will lead to significant clinical consequences involving additional resistance changes including H274Y and I222R/K.

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