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G158E and D225G Low Reactors Recombine in Russia
The above comments from the WHO report on the selection of 2010/2011 vaccine targets acknowledge the detection of low reactors but provide little detail. Recently released sequences at GISAID by the CDC and Mill Hill provide some specifics. Both detail isolates from Germany that have N158E as the only non-synonymous HA change, and both isolates are designated as low reactors. The linkage of low reactor status to a single nucleotide change raises concerns that such low reactors will become increasingly common, as the human target population develops more immunity to H1N1. Mill Hill has also reported that another single nucleotide change, which produces D225G, also generates a low reactor designation.
The linkage of immunological escape to these small changes also allows for combining these designators by recombination, which has happened in Russia. The recently released sequence, A/Salekhard/01/2009, from lung tissue has both low reactor polymorphisms, N158E and D225G. Since each of these changes lowers the titer by at least four fold, the combination may produce an additive effect which reduces the titer by at least 16 fold, which would require titers of 640 against the wild type sequence to produce borderline protection offered by a titer of 40 to sequences with both polymorphisms. Thus, the additive effect would lead to widespread vaccine failure.
The presence of sequences (also seen in Italy) with both changes, would raise serious questions about the WHO decision to leave the vaccine target unchanged through 2011, when low reactors with both changes were identified in 2009, well in advance of the selection committee meeting.
California/7 was a controversial original selection because it was a mixture and not well represented in subsequent sequences. The current vaccine target, X-181A, has five amino acid differences with the consensus sequence, setting the stage for rapid progression to a low reactor status.
The combination of two low reactor polymorphism, N158E and D225G in the same HA sequence is cause for concern.