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Fixing H1N1 Tamiflu Resistance
Recombinomics Commentary 17:32
September 29, 2008

The recently released phylogenetic HA and NA trees from recent H1N1 isolates raise concerns that oseltamivir (Tamiflu) resistance (H274Y) is becoming fixed in H1N1 seasonal flu.  The recent sequences include isolates from Africa and South America, which are largely evolving versions of the dominant Brisbane/59 (clade 2B) sub-clade with H274Y.  However, there is also evidence of additional independent introductions, indicating Tamiflu resistance is evolving through two mechanisms.  One involves evolution of the dominant sub-clade, while he other involves movement of H274Y from the dominant sub-clade, to other clade 2B sub-clades, raising concerns that H274Y will soon be fixed in H1N1.

Evidence for fixing comes from the 100% incidence in H1N1 in South Africa and Australia.  However, the additional isolates indicate that the frequency of H274Y H1N1 continues to climb, suggesting the change offers a selective advantage.  This advantage may create even higher frequencies in the upcoming season because of earlier mismatches with the H1N1 vaccines used last season, and the evolution of H1N1 I the previous season.

The recent HA sequences from Seychelles have the same non-synonymous changes seen in isolates from South Africa, raising concerns that the effectiveness of the Brisbane/59 vaccine that is being introduced this season will have limited utility.  Last season the H1N1 target was Solomon Island/3 (clade 2A), which was no longer in circulation.  Although various reports characterized the clade 2B isolates as Solomon Island like, this designation was largely dependent on poor reference vaccines which cross reacted with virus grown in eggs, but the same virus grown in mammalian cells had limited cross reactivity.  Thus, the clade 2A and clade 2B isolates could be readily distinguished via phylogenetic analysis as well as antigenic analysis, which led to a change in the H1N1 vaccine target this season (to clade 2B from clade 2A).

However, the mismatch last season facilitated the expansion of Brisbane/59-like isolates, including those with H274Y.  This dramatic increase in the H1N1 genetic reservoir with H274Y, which creates concern that the frequency of H274Y will continue to increase as H1N1 continues to evolve.

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