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Paradigm Shift Intervention Monitoring
Chronology of 2010 trH3N2
Reported cases of Human Infection with Swine Origin Influenza A (H3N2)
Cs Age Onset Swine Exposure Strain Designation
1 Child July, 09 Visit local animal fair A/Kansas/13/2009
2 Child Sept, 09 No reported exposure A/Iowa/16/2009
3 Child May, 10 Visit live animal market A/Minnesota/09/2010
4 Child Sept, 10 Visit local animal fair A/Wisconsin/12/2010
5 Adult Oct, 10 No direct exposure A/Pennsylvania/14/2010
6 Child Sept, 10 Visit local animal fair A/Pennsylvania/40/2010
7 Adult Nov, 10 Visited live animal market A/Minnesota/11/2010
The above data are from the CDC’s (Nancy Cox) presentation at the Feb, 2011 FDA meeting of the advisory committee on vaccine selection. The data summarizes the “swine exposure” for the first 7 trH3N2 cases. The 8th case was the daughter of the Minnesota index case (#7), who was lab confirmed (serologically) as trH3N2 infected, but no virus was isolated. However, she had no swine contact and was assumed to have been trH3N2 infected by her father. Therefore, the sequence for the 8th confirmed case would be closely related to A/Minnesota/11/2010. Moreover, additional family members were symptomatic and testing was “inconclusive”, suggesting the number of cases matching Minnesota/11/2010 was greater than the two lab confirmed cases.
Thus, the list above clearly shows that the “swine exposure” of the first 8 trH3N2 fell well shy of the “close contact” cited by ProMED for the 2011 trH3N2 cases, which evolved from the above cases and acquired an H1N1pdm09 M gene, which was “critical” for the H1N1pdm09 jump from swine to humans.
The trH3N2 evolution and adaptation can be seen in the HA and NA phylogenetic trees of the trH3N2 human cases (in red) compared to swine trH3N2 cases. In the HA tree, four of the five 2010 human trH3N2 map together at the top of the tree(and since one of the cluster sequences is from the Minnesota index case, five of the six 2010 human trH3n2 HA sequences map together. The exception is A/Pennsylvania/14/2010 (PA/14), which has an HA and NA which map on separate branches. Thus, the HA and NA trees shows that most of the genes of most of the 2010 human isolates map together (and this clustering of human sequences extends to the other six gene segments) signaling adaptation to humans.
The 2011 sequences extends this clustering because the HA sequences match the five clustered 2010 HA sequences, while the NA sequence matches PA/14 (as well as the internal genes), other than the M gene. Thus, all eight of the gene segments in the 2011 cases were in 2010 cases, and all seven of the human cases, as well as the recent New York swine sequence, match each other in all eight gene segments.
However, in addition to defining “swine exposure” and demonstrating the clustering (adaptation) of the human trH3N2 HA and NA sequences, the order of the over cases is curious.
The 6th case (A/Pennsylvania/40/2010) is list out of chronological order, in part because it was initially classified as seasonal H3N2, and reporting of the designation of trH3N2 in February, 2011, and the release of the sequence in March, 2011 were delayed due to technical issues related to isolation of the virus. However, sequences can be generated by direct sequencing of the clinical sample, and as seen in the second 2011 case from Maine, low abundant RNA samples can rapidly yield partial sequences which conclusively demonstrate that isolates are trH3N2.
The WHO pager alert was issued in November, just prior to the identification of the Minnesota index case (and subsequent cluster). The alert was for two cases, A/Wisconsin/12/2010 and A/Pennsylvania/14/2010, and assurance were given for a lack of human transmission because of sequences differences between these isolates, as seen in the HA and NA phylogenetic trees cited above. However, the listing of the second Pennsylvania case (PA/40) as case #6 and ahead of the November case #7 raises the distinct possibility that when the WHO page alert was issued, the CDC and Who knew that PA/40 was a trH3N2 case, which was from a patient who developed symptoms 6 days prior to WI/12, and as seen in the phylogenetic trees, the HA and NA sequences of WI/12 and PA/40 were closely related (and this close relationship extended to the other six gene segments), voiding the CDC assurances that there was no evidence of human transmission because of the time gap between disease onset, as well as significant sequence differences.
Thus, regardless of when the CDC knew that PA/40 was a trH3N2 that was virtually identical to WI/12, or how many contacts in the Minnesota cluster were infected with MN/11, the emergence of the 2011 trH3N2 cases from the human 2010 trH3N2 cases, and the identities between all seven 2011 trH3N2 cases is clear as is the clear support for human transmission, CDC parsed announcements of swine exposure , media claims of 2011 trH3N2 jumping from pigs to people, and ProMED claims of “close contact” between swine and cases, notwithstanding.