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Paradigm Shift Intervention Monitoring
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H1N1 D225E Converted
Although D225G has been reported appended to a D225E background in Europe, the sequence in Japan has C940T, which defines a D225E sub-clade that is largely in the United States and Japan (see list of Genbank sequences here). In addition to the sequences at Genbank, C940T is also in D225E sequences at GISAID, including A/Tennessee/17/2009 and A/Shiga/43/2009. Like the Hong Kong sequence in the list linked above, the Tennessee and Shiga sequences have H274Y, supporting the spread of H274Y in the United States and Japan. Like the position 225 changes, H274Y also jumps from one genetic background to another, but as was seen in the cluster on the train in Vietnam, or the fatal cases at Duke Medical Center, isolates with these newly acquired changes (like D225G and/or H274Y), transmit and create clusters that are linked in time, space, and phylogeny.
This type of clustering is most dramatic in Ukraine, where 33 sequences collected in late October or early November have D225G, D225N, or both on identical or closely related sequences. However, the presence of sequences with wild type receptor binding domain changes indicates sequences with the changes require multiple independent events which are consistent with homologous recombination as was seen during the fixing of H274Y in seasonal H1N1.
These data invalidate the WHO working hypothesis that these changes are spontaneous events generated by recent and repeated copy errors, a paradigm that was thoroughly discounted by the fixing of H274Y.
The clinging of WHO to this outdated paradigm continues to be hazardous to the world’s health.
Moreover, the replacement of D225E, which is widespread in Europe, by D225G raises concerns that D225G/N will become more common in upcoming waves, since Mill Hill has designated H1N1 with D225G as a “low reactor”, and the reduced activity with reference sera directed against D225, signals potential selection of D225G.