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Commentary
H1N1
Ferret Failure Raises Pandemic Concerns
Recombinomics
Commentary 12:17
October 22, 2010
The above comments cite ferret data in Table 2 to claim that the variant H1N1 is not antigenically distinct from the vaccine virus, A/California/7/2009, but the table also includes seasonal H1N1 which indicates seasonal H1N1 is not antigenically distinct from A/California/7/2009, indicating the assay lacks sensitivity.
Pandemic H1N1 originates from swine and is clearly distinct from seasonal H1N1. These differences allowed pandemic H1N1 to rapidly spread through a younger human population, which would have high levels of antibody to seasonal H1N1. Similarly, the elderly population was protected from pandemic H1n1 because of antibodies generated against seasonal H1N1 in circulation decades earlier.
Thus, the use of data in Table 2 to claim a lack of antigenic distinction between the variant pandemic H1N1 strain and the vaccine prototype as a predictor of vaccine success has no scientific basis.
CORRECTION: Table 2 does not contain seasonal H1N1 targets. A/BRISBANE/2013/2009 is a pandemic H1N1 isolate. The July 1, 2009 collection date listed as 1/7/2009 was mistakenly read as January 7, 2009 leading to the assumption that it was a seasonal H1N1 isolate collect prior to the earliest pandemic H1N1 collection date. Similarly, A/Illinois/9/2007 was assumed to be seasonal H1N1 because of the collection date, but is in fact a swine sequence isolated from a human in 2007. Although this sequence does not appear to be public, it is likely to be similar to other swine sequences in humans in 2007 like A/Ohio/1/2007, which is swine, but easily distinguished from pandemic H1N1. Thus, although all targets in Table 2 have a swine origin, the 2 fold or less titer difference between A/Illinois/9/2007 and all isolates except A/Lviv/N6/2009 highlights the lack of sensitivity in the assay and the low probability of identifying vaccine failure in the pandemic H1N1 variant.
The table clearly shows the limitations in the ferret antisera for identifying most antigenic changes that generate vaccine failure. However, the table does demonstrate that A/Lviv/N6/2009 is a clear low reactor, as indicated previously by Mill Hill. The non-synonymous HA change in A/Lviv/N6/2009 is D225G, which raises serious pandemic concerns since D225G is tightly linked to targeting of human lung and fatal outcomes.
The linkage of D225G to low reactors was confounded by a series of characterization sheets released by the CDC, including an isolate of A/Lviv/N6/2009 which had D225G as well as G158E. Both changes have been found in low reactors, yet the characterization sheet released by the CDC at GISAID did not note that A/Lviv/N6/2009 was a low reactor. Similarly, other sequences with D225G were also listed as A/California/7-like, with no low reactor designation. CDC designations of low reactors was limited to position 159 changes, even though an earlier isolate from Germany, which had G158E, was designated by the CDC as a low reactor. This lack of consistency between isolates characterized by the CDC is similar to failures to distinguish seasonal H1N1 sub-clades by ferret antisera.
In spite of these clear shortcomings in ferret antisera to identify clinically relevant differences between H1N1 clades and sub-clades, this abysmal assay is used to justify the lack of vaccine target updates. Consequently, the 2009 target, A/California/7/2009 was used for the 2010 target for the southern hemisphere, the 2010/2011 target for the northern hemisphere, and the 2011 target for the southern hemisphere.
In addition to the failure to identify new vaccine targets, the fatally flawed assay is used to ignore the low reactor values linked to D225G, which could generate catastrophic outcomes if D225G is selected due to its linkage to immunological escape from vaccines targeting A/California/7 with wild type 225D. The assays shows an 8 fold reduction in titer when California/7 antisera is tested on A/Lviv/N6/2009, which has D225G.
The failures continue to be hazardous to the world’s health.
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