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Frequent Low Reactors in H1N1 S188T Sub-clade In Japan

Recombinomics Commentary 22:50
May 3, 2011

NIID released 33 HA sequences, which were largely from 2011. All 33 sequences had S188T, once again demonstrating the dominance of that sub-clade in early 2011 throughout the northern hemisphere.

However, these sequences frequently had changes at positions 156, 157, 158, 159 (1, 3, 5, 1 respectively) which are within the antigenic site most commonly linked to low reactors (the 5 coded for G158E). Moreover, all 10 changes were mixtures with wild type, allowing for rapid dominance of the "low reactor" genotype within the patient, if subjected to selection pressure.  Thus, these “low reactors” may be more dangerous, since the wild type component reduces the likelihood that the isolates would register as low reactors, leading to a gross underestimate of the true level of low reactors in circulation.
This gross under-estimate can be affected further through lab manipulation of isolates and anti-sera used in the antigenic characterization tests used to identify low reactors.  Results generated by the CDC have produced intra-lab and inter-lab inconsistencies.  Inter-lab differences were discussed at the recent vaccine selection meeting regarding the higher number of low reactors identified by Mill Hill.  The CDC claimed that the low reactors were identified because of the cell line used, and suggested that Mill Hill change cell lines to identity fewer low reactors, which is a recurring CDC theme. 

Other WHO regional centers like NIID in Japan also has identified increasing numbers changes associated with low reactors as indicated above, yet the CDC argues for use of a cell line that is less sensitive for detection of such changes.

These low numbers are seen in data produced by the CDC.  Last season the CDC only identified 6 low reactors in the United States out of 1847 tested and all six had a change at position 159.  This year the CDC has identified an even lower frequency (1 out of 490 tested) even though the above sub-clade is now dominant throughout the northern hemisphere, including the United States.

This denial of low reactors is consistent with similar positions on the linkage of D225G or D225N changes with severe and fatal cases, as well as the decision to designate isolates with H274Y below 50% as Tamiflu sensitive.

The pattern of discounting important changes associated with immunological escape, increased virulence, or anti-viral resistance continues to be hazardous to the world’s health, which has been exacerbated by the decision to leave the H1N1 unchanged once again (in spite of compelling reports on vaccine breakthroughs) and to discount the clinical significance of D225N detected at high frequency in the Chihuahua sub-clade, which has generated a WHO pandemic alert.

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