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S188T Low Reactors In European H1N1
Recombinomics Commentary 02:30
March 31, 2011

Mill Hill has released 32 HA sequences (at GISAID) from H1N1 isolates largely collected from patients in Europe between late December 2010 and February 2011.  27 of the sequences had S188T, while another had S186P, consistent will earlier reports demonstrating the dominance of the sub-clade containing S188T.  However, 18 of the sequences (56% of total), also had a change a positions 56-59 (2, 3, 10, 3 respectively) signaling “low reactor” status.  These changes, in addition to S188T, strongly suggested that H1N1 was rapidly evolving away from immunological responses direct to wild type sequences or the 2009 or 2009/2010 H1N1 vaccine target (A/California/7/2009).  However, 17 of the 18 changes were present as mixtures (quasi-species) which may be modulated by isolation techniques.  The high level of low reactor sequences as mixtures was also seen in recent sequences from Germany.

Moreover, there were also 7 changes at positions 225 and 226 (D225G, D225N, Q226R) in the latest sequences, signaling additional evolution at key positions in the receptor binding domain.

Multiple assays and labs have shown that these changes can lead to increased growth in cells with gal 2,3 receptors such as chicken embryos in eggs or human lung.  Thus, the high frequencies reported in the recent isolates may be present in collections made by other labs which use mammalian cells to isolate virus for sequencing.

Recent reports indicated that WHO affiliated labs do not report H274Y mixtures (Tamiflu resistance) when mixtures represent less than 50% of the signal.  It is unclear if this under-reporting for H274Y extends to the mixed signals for the markers described above.

The increased evolution of the recent sequences in Europe may play a role in the emerging H1N1 in Mexico and Venezuela.  H274Y would lead to poor responses to Tamiflu treatment, and additional changes may target the patient’s lung, producing a poor prognosis.

Recent sequences from the United States have not been released by the CDC.  H3N2 and influenza B sequences from 2011 were released last week, but the last release for H1N1 sequences was February 2, 2011, and most of those sequences were collected prior to 2011.

The latest data from Europe raises concerns that the rapidly evolving H1N1 will lead to vaccine failures and rapid spread of novel sub-clade, such as the recently reported activity in Mexico and Venezuela.

Release of sequences from the United States, Mexico, and Venezuela is overdue.

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