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Commentary
Widespread H1N1 Low
Reactor G158E In US Raises Concerns
Recombinomics
Commentary 12:01
March 12, 2010
The CDC also tested Bayern/69 and also declared it a "low reactor". However, the recent (October and November) isolates in the US were tested, but not labeled low reactor. Included in the recent sequences with G158E are three isolates from Washington (A/Washington/60/2009, A/Washington/61/2009/ and A/Washington/65/2009). Although all three isolates have G158E, they have different combinations of other polymorphisms, placing them in different sub-clades, signaling recombination..
The most recent isolate, Washington/65 also has E377G. Several other US isolates with G158E have E377K (Texas/65/2009, Idaho/10/2009, Minnesota/18/2009, Arizona/18/2009, Hawaii/29/2009) as well as isolates in Japan (A/Hyogo/1597/2009) and Greece (A/Athens/16606/2009), indicating this sub-clade has spread significantly.
The reason behind the failure of the CDC to classify some of these recent isolates as “low reactors” is unclear. Prior to last week, only two low reactors were reported by the CDC in the US, and both had a change at the adjacent position N159D. Both position map to the same antigenic site and a recent paper on the effectiveness of 1918 anti-sera on the 2009 H1N1 noted that escape mutants also mapped to this antigenic site. However, a recent WHO reported noted that there were differences between labs running antigen characterization tests, and a new universal reference anti-sera had been created using pooled sera from patients, which was available in late 2009. This new reagent may have produce a negative low reactor result because a pooled sera would have a wider range of antibodies, relative to the traditional tests, which use ferret antibodies from experimental animals immunized with the vaccine target.
Since there are approximately 5 amino acid differences between California/7/2009 and the consensus H1N1 sequence, the ferret reference sera may be more sensitive than pooled sera, especially if the sera is from patients infected with H1N1 instead of being vaccinated with California/7. If the sera is from vaccinated patients it is unclear which vaccine was used because there are at least three different sequences in various commercial products. Even within the US the killed vaccine has Q226R, while the live vaccine has D225G. In Europe the adjuvented vaccine has both, but as mixtures with wild type. These differences could affect results, especially for D225G, which Mill Hill designated as a low reactor. In a recent antigenic characterization of an isolate from Ukraine, which had G158E and D225G, the CDC did not classify it as a low reactor, suggesting that the assay being used by the CDC lacks sensitivity.
These differences involving polymorphisms that had been independent mapped to antigenic sites, and have tested as low reactors in earlier assays raise serious concerns about the validity of the recent negative results by the CDC, especially if pooled anti-sera is being used.
Uniform false negatives remain hazardous to the world’s health.
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