H1N1 Tamiflu Resistance Vax Evasion
Recombinomics Commentary 22:36
October 2, 2008

Recently released HA and NA sequences and phylograms define the recent emergence and evolution of oseltamivir (Tamiflu) resistance in H1N1.  The presence of H274Y in influenza from hosts in the absence of oseltamivir began with H5N1 in wild birds in 2005, followed by various H1N1 sub-clades in patients.  Initial isolates were clade 2C (Hong Kong/2562) in the 2005/2006 season in China, followed by clade 1 (New Caledonia/20) in 2006/2007 in the United States, followed by clade 2B (Brisbane/59) in the United States, which then led to a dominant clade 2B sub-clade which accounted for most cases in the United States and Europe (supported by recently released sequences from France and Luxembourg).  Recent data demonstrates the spread of this sub-clade into the Southern Hemisphere and the frequency of H274Y in H1N1 is now approaching 100% in many countries.

However, recent sequence data out of South Africa and Hong Kong raises concerns of rapid evolution which will evade the new H1N1 vaccine being introduced into the northern hemisphere, which is directed against Brisbane/59 (clade 2B).  The vax evasion is taking multiple forms.  Last season clade 2A (Solomon Island/3) was targeted, but clade 2A was no longer in circulation.  It had been replaced by clade 2B and 2C.  Although initial testing demonstrated significant cross reactivity between the three clade 2 sub-clades, the activity was linked to growth of targets in chicken eggs,  When Brisbane/59 was grown in mammalian cells, there were significant antigenic differences between the three sub-clades, consistent with phylogenetic analysis.

Although the new H1N1 vaccine now targets clade 2B, the recent sequences from South Africa had a cluster of changes surrounding the receptor binding domain at position190 (H3 numbering).  These changes are being facilitated by recombination.  The two changes on the 3’ side of the cluster are found in H1N1 isolates from the 1940’s, while the change at the 5’ end of the cluster is rare, but now has appeared in recent clade 2B isolates in South Africa and the Seychelles, but has also been found in clade 2C in Hong Kong.

In addition to rapid change in clade 2B, the three recently released clade 2C sequences from Hong Kong also have H274Y.  In two of the isolates, the H274Y is on a 2C NA, while the other is on the NA background that matches the dominant clade 2B sequence.

Thus the vax evasion is linked to rapid changes clade 2B and well as movement of clade 2B sequences to clade 2C, which is not targeted by the new vaccine.  Thus the presence of H274Y on all three recent clade 2C sequences from Hong Kong raises concerns that the fixing of H274Y into clade 2B, may also be spreading to clade 2C, which is not targeted by the current vaccine in the northern hemisphere, or the one being produced for the southern hemisphere in 2009.  thus, the vaccine continues to chase H1N1 evolution in clade 2B and 2C, where the level of H274Y continues to rise.

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