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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.
at Nature Precedings