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Commentary
H1N1
Low Reactors Raise Vaccine Selection Concerns
Recombinomics
Commentary 12:01
February 19, 2010
Vaccines containing influenza A/Brisbane/10/2007 (H3N2)-like antigen stimulated anti-HA antibodies of similar geometric mean HI titres, that were lower to recent isolates than to the vaccine virus (average reductions: children, 67%; adolescents, 53%, young adults, 57%; the elderly, 66%).
The above comments from the WHO report on the selection of the 2010/2011 vaccine target describe data generated by low reactors, which are identied by ferret antisera directed against the pandemic H1N1 or the prior seasonal H3N2 target. Reductions in activity using sera from patients were similar in both cases. However, for H3N2 the target was changed, while for pandemic H1N1 it was not.
This difference was due in part to the frequency of detection of low reactors. For H3N2 the number of positives was small, but most were classified as low reactors. In contrast, for pandemic H1N1 number of low reactors was low, but this frequency was dependent on the reference anti-sera.
In the US, the latest CDC report cites two low reactors. It is likely that the two low reactors were A/South Carolina/18/2009 and A/Utah/20/2009, which have been characterized as low reactors. These isolates have four or five non-synonymous changes, including N159D, which is present in both sequences (as well as WSN/33) raising concerns that this change may present problems, like a recent report of severe H1N1 in a vaccinated patient in Wyoming. However, the number of sequences with N159D is low, so the effect on public health remains to be determined.
Of much greater concern are changes at position 225, most notabley D225G and D225N, which have been found on multiple genetic backgrounds and are associated with fatal cases. Moreover, D225E has been found at high frequencies in western Europe, which has raised concerns that similar increases in frequencies of D225G and D225N would produce a dramatic increase in frequencies of severe and fatal cases.
These concerns have been increased by antigenic characterization data by Mill Hill on one of the Ukraine isolates with D225G. It was classified as a low reactor, raising concerns that the low activity with the anti-sera directed against the California/7 target would signal selection for D225G. However the CDC failed to find four-fold reductions in titer when they tested an isolate with the same HA sequence, raising concerns that some assays would fail to detect the reductions seen by Mill Hill. WHO has acknowledged inter-lab differences, which are likely linked to use of different anti-sera, so a reference sera from pooled human collections has been created.
However, the data from Mill Hill coupled with increasing numbers of sequences with D225G and D225N, raised concerns because the vast majority of isolates were from fatal cases. Moreover these increases were from collections in 2009 and more recent sequences may have D225G/N with additional changes, leading to further reductions in titers.
The WHO report failed to directly address these low reactor examples, and concerns that the vaccine targets selected for 2010/2011 will produce limited activity against emerging sequences with D225G and D225N.
More information on the testing of samples with D225G and D225N would be useful.
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