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H1N1 G158E and D225G Low Reactors Recombine in Italy
Recombinomics Commentary 08:33
February 22, 2010

Sequence analysis of pandemic A(H1N1)2009 viruses indicated that they were genetically homogeneous.  A small number of viruses showed reductions in their reactivity with some ferret antisera (raised against a panel of representative viruses including the vaccine virus) in HI assays.

The above comments from the WHO report on the selection of 2010/2011 targets acknowledge the detection of low reactors but provide little detail.  Recently released sequences at GISAID by the CDC and Mill Hill identify a series of low reactors which include changes at three consecutive positions (157-159).  In each case the wild type amino acid is replaced with an acidic amino acid (K157E, G158E, N159D) raising concerns that a single nucleotide change at any one of three positions in this region creates a low reactor.  Those concerns are increased by reports that a single nucleotide change in the receptor binding domain creates D225G, which has also been designated a low reactor.

Moreover, recombination allows for these two changes to combine and produce a sequence with two low reactor changes.  This has been described for a sequence from Russia, which is in the same clade as the sequences from Ukraine with D225G/N.  Thus,
A/Salekhard/01/2009, has both G158E and D225G.

A similar scenario has evolved in Italy.  One sequence,
A/Roma/ISS1941/2009, had C940T as well as T717A, which are frequently found together in D225E sequences.  However, the sequence then acquired G715A, converting the D225E to D225G.  Now that converted sequence has acquired G158E, creating a new sequence with two polymorphisms linked to low reactors, and in both cases low reactors have been reported with only G158E or D225G.  However, this combination is on a genetic background that is distinct from the Russian subclade.  Thus, G158E has paired up with D225G on a background frequently found in eastern Europe, as well as D225G on a background frequently found in western Europe.

This jumping of critical polymorphisms from background to background via recombination creates opportunities for dramatic increases in genetic drift away from the vaccine target.

The recent WHO decision to leave the H1N1 vaccine target unchanged, even though low reactors with G158E and D225G have been reported raises serious doubts about WHO’s expert’s ability to understand how H1N1 evolves, and how that evolution can rapidly destroy the efficacy of the vaccine recommended for the 2010/2011 season.

This falure to understand influenza evolution at the most basic level, continues to be hazardous to the world's health.

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