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Commentary
Genetic
Linkage of Human trH1N1 trH1N2 trH3N2
Recombinomics
Commentary 22:05
December 1, 2010
1 patient (9%) attended a fair but did not visit areas where pigs were exhibited.
The above comments describe one of the 11 patients in the United States with confirmed infection by trH1N1 or trH1N2 as described in the New England Journal of Medicine report in 2009, following the start of the 2009 pandemic. The paper focused on linkage between these patients and swine, although some, like the patient above did not have a direct link. However, the paper only provided sequence data for 5 of the 11 patients in the form of accession numbers for HA sequences. The sequences from the above patient, who attended a fair in Illinois in August, 2007, and the other patients in the report, as well as recent trH3N2 sequences were recently released by the CDC at GISAID. These sequences raised serious questions about the widely held assumption that the human cases of swine triple reassortant infections are due to direct infection via swine contact.
Peer reviewed papers, such as the NEJM paper require authors to provide sufficient detail to allow for independent reproduction and analysis. The NEJM paper is a good example of why such requirements include the release of underlying sequence data at the time of publication.
Two of the five HA sequences cited in the paper were from exhibitors at the 2007 Huron county fair. Both sequences were identical and match sequences from swine at the fair (which were release in association with other papers on the swine sequences. However, the sequences from the above patient were withheld, even though the HA sequences were an exact match with the Ohio sequences. The identity between sequences from attendees at a fair in Illinois as well as a fair in Ohio support a human to human transmission chain, rather than the identical virus passing from swine to humans at two distinct locations.
The very close relationship between the sequences from the Illinois and Ohio fairs was extended in the full sequences which demonstrated that all eight gene segments from Illinois and Ohio matched. Moreover, a trH1N2 patient from Michigan was also described in the paper, and the internal genes from that isolate were also closely related to the sequences from Ohio and Illinois. Thus, all four patients with infections in the summer of 2007 had closely related genes even though the linkage to swine was via ongoing fairs in three different states, Ohio, Illinois, and Michigan. These similarities would raise serious questions about a swine to human mechanism for transmission of these trH1N1 and trH1N2 sequences.
Moreover, the first reported trH3N2 infection in the US was linked to a 2009 fair at Riley, Kansas. Sequences from this patient were released in early 2010 and the internal genes were closely related to the four sets of human sequences from 2007. That relationship was obscured by the withholding of the earlier sequences. The Kansas infection was followed by trH3N2 infections in Iowa in 2009 and Minnesota, Wisconsin, and Pennsylvania in 2010. The two most recent cases led to a pager alert and a CDC update in the week 44 Fluview and supplemental report. Those reports also suggested that the trH3N2 were due to transmission from swine to humans, which was not supported by the sequence data which was withheld until those reports were released.
The sequences were released in the following week and demonstrated a closely relationship between four of the five trH3N2 with each other as well as the trH1N1 and trH1N2 sequences, further supporting transmission within the human population. Moreover, the two most recent sequences, which were the subject of the pager alert and from unlinked individuals from Wisconsin and Pennsylvania who were infected six weeks apart.
Although the swine sequence database is small, it has significantly increased in the year following the 2009 pandemic, which also involved trH1N1, but the lineage was distinct from the sequences described above. However, the above sequences do cluster in phylogenetic analysis of North American swine sequences, indicating the sequences represent isolates with an increased affinity for human hosts and raise serious questions about the emphasis of the NEJM paper as well as the CDC updates on triple reassortant infections in humans.
The genetic linkages between human trH1N1, trH1N2, and trH3N2 dictate an increased surveillance of human and swine infections coupled with rapid release of associated sequences for all eight gene segments.
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