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Paradigm Shift Intervention Monitoring
Sequences Signal Human Transmission
Swine-origin triple reassortant Influenza A (H3N2) viruses have been circulating among North American swine herds since the late 1990's. Human infections with these viruses are detected sporadically, and cases usually occur following direct or indirect contact with pigs.
The above comments are from today’s (week 41) CDC FluView, which highlights the rapid generation and release of sequences from this case (8M). The confirmation was two days after Maine tests, and a full set of sequences were made public (at GISAID) the following day (and made available at Genbank 2 days later).
However, the CDC has not addressed the significance of the 2011 trH3N2 sequences, which provide compelling data for human to human transmission. Instead the CDC recites its standard comment on triple reassortants, and ignores the fact that all five isolates from 2011 have the same constellation of genes, which goes beyond the more general composition of 7 gene segments from trH3N2 cases and an M gene segment from pandemic H1N1.
The human trH3N2 sequences, release on November, 2010 had obvious clustering, which increased as additional cases were identified. WHO issued a page alert on two of these cases, A/Wisconsin/12/2010 and A/Pennsylvania/14/2010 and offer assurance of o transmission based largely on significant differences in the sequences from these two isolates. However, when those assurances were presented, another Pennsylvania case, A/Pennsylvania/40/2010 (PA/40/10), was being analyzed. That patient developed symptoms less than a week prior to the Wisconsin case, but the PA/40/10, was initially designated seasonal H3N2 and was reported to be trH3N2 in 2011, five months after infection, and the sequence was virtually identical to the Wisconsin case.
Moreover, just after the pager alert another case was identified in Minnesota, A/Minnesota/11/2010, and most of the gene segments, including H3, were closely related to the Wisconsin and Pennsylvania cases. In addition, the daughter of the Minnesota was subsequently trH3N2 confirmed (serologically), increasing the number of confirmed trH3N2 cases infected between September and November 2010 to five, and four of the five had gene segments, including H3 that were closely related, signaling human adaptation.
This adaptation was significantly increased in the 2010 isolates. The early release MMWR report by the CDC described the first two cases, A/Indiana/08/2011 and A/Pennsylvania/09/2011, and noted that both had an M gene from pandemic H1N1. Again assurances were offered based on sequences differences because although both isolates had the same constellation of genes, the Pennsylvania isolate was a drift variant and a few of the genes had evolved further from the 2010 sequence than the Indiana isolate. However, two additional cases were identified in Pennsylvania (A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011) which were virtually identical to each other as well as the Indiana case. Thus, these three cases not only had the same constellation of genes, but the sequences of all 8 gene gene segments were virtually identical, even though infections in Indiana and Pennsylvania were a month apart and not link epidemiologically, supporting human to human (H2H) transmission.
The H2H transmission was further supported by the Maine sequence, A/Maine/06/2011, which had the same constellation of genes as seen in the four earlier 2011 cases, but evolution from the 010 sequences was slightly different. The Maine genes branched off the 2010 sequences earlier, and consequently were more closely related to several of the 2010 gene than the IN/PA cases even though the ME case was infected more recently.
This earlier divergence indicates human trH3N2 infections have more heterogeneity than seen in the five sets of sequences released, and this earlier divergence highlights the significance of the lack of the detection of this constellation in swine isolates, which has not been reported in any swine, including a high number of 2011 isolates collect as recently as July, 2011.
This, the identity in the overall constellation of flu genes in all five 2011 human cases and its absence in all swine cases signals H2H transmission, as does the acquisition of the M gene segments from pandemic H1N1, and the close relationship to the 2010 human trH3N2 sequences.
In contrast to the public data supporting human to human transmission, the CDC focuses of linkage to direct or indirect swine exposure based largely on selective testing of patients with a swine linkage for trH3N2. To date the CDC has released H3N2 sequences from 15 US cases collected since July 2011, and 5 of the 15 cases have been trH3N2.
This high frequency, coupled with the sequence identities in these five cases, indicates the number of trH3N2 cases in the US is orders or magnitude higher than the five cases reported to date, and PCR test kits for swine H3 should be distributed to all state labs as soon as possible.