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PB1 E618D in pH1N1 and Human H3N2 Triple Reassortant KS13
Recombinomics Commentary 17:50
November 13, 2010

The recent WHO pager alert has raised concerns that swine H3N2 triple reassortants in humans may pose a pandemic threat.  The pager alert was followed by CDC comments in the week 44 FluView, as well as an update of swine H3N2 in humans.  The reports described two recent examples, a 7 month old child from Wisconsin and an adult (46M) from Pennsylvania.  The report of two novel H3N2 examples in a weekly report is without precedence.  The two latest cases bring the total in the United States to five.  All five cases developed in 2009 and 2010, after the emergence of the pandemic H1N1, which also involved triple reassortants.

The latest CDC report noted that all  five case had a very loose association with swine, but only two of the five cases had “direct contact” with “live swine”.  None of the descriptions of these cases noted symptomatic swine, or the isolation of H3N2 from any swine with temporal or spatial linkage to the five cases.

The emergence of all five cases after the 2009 H1N1 pandemic has raised concerns that genetic changes that allowed for sustained human transmission of swine H1N1, would be acquired by swine H3N2 leading to increased transmission in humans.

Although pandemic H1N1 is clearly linked to swine, the H1N1 genes have a number of unique changes that may have facilitated sustained transmission in humans.  Prior to the 2009, there were reports of 11 cases of H1N1 triple reassortants in humans in the United States, suggesting that these cases represented partial adaptation to sustained human transmission.

One of the polymorphisms found in virtually all pandemic H1N1 sequences is PB1 E618D.  Although PB1 in triple reassortants traces to seasonal H3N2 from the mid-90’s, the human sequences generally do not have E618D, although it is present in A/South Australia/11/2000(H3N2).  However, the PB1 in triple reassortants forms a complex with two other polymerase genes which have an avian origin and one protein encoded by the PB1 gene segment is truncated. Therefore unique combinations may be required for this complex to contribute toward sustained human transmission.

Only one set of H3N2 sequences from a human triple reassortant has been made public.  Full sequences for all 8 gene segments from A/Kansas/13/2009 were deposited by the CDC at GISAID in February, 2010.  It was collected on July 27, 2009 by the Kansas Department of Health and Environment, who had issued a press release on the H3N2 infection of a child at the Riley County fair in late July, 2009.  However, the characterization sheet at GISAID indicated the above isolate came from an adult (22M).  Regardless of the age of the patient, the sequences are clearly an H3N2 triple reassortant, and the PB1 sequence has E618D.

Sequences from the other reported cases have not been released, but the CDC has said that sequences from all five reported cases, including Kansas, were “similar”.  However “some differences” were found, but none were named.  Similarly no phylogenetic analysis has been reported and the precise level of identity between genes of the isolates has not been stated.
All of the above can be quickly generated by the raw sequence data, which has been withheld, even though the case in Iowa was reported in January, 2010 and the case in Minnesota was reported in May, 2010.  Moreover, the sequences from the two recent cases had to be generated to classify the infections as caused by triple reassortants that were similar to the prior cases.

Therefore the CDC should make all five sets of sequences public immediately, so the relationship between these sequences can be independently determined by the scientific community.

The time for comments on “similar’ sequences with “some changes” has passed. 

The scientific community eagerly awaits the release of the underlying sequence data.

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