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The 2011 H3N2pdm11 Pandemic Puzzle
Recombinomics Commentary 19:30
November 29, 2011

WHO trying to hit the sweet spot in responding to puzzling new flu virus

The spread of an odd new flu virus that has been jumping from pigs to people in parts of the United States has the World Health Organization gearing up its response planning, a senior official of the agency says.

The above title and introduction are from a Helen Branswell piece on WHO preparations for the 2011 trH3N2 pandemic.  The virus itself is not puzzling (or odd).  In the US this trH3N2 was first reported in a Riley County fair attendee (12M) and the full sequence, A/Kansas/13/2009 was published at GISAIID followed by an EID report and release at Genbank.

Subsequent release of sequences from the human cases in 2009 and 2010 (A/Iowa/16/2009, A/Minnesota/09/2010, A/Wisconsin/12/2010, A/Pennsylvania/14/2010, and A/Minnesota/11/2010 led to a prediction of the trH3N2 pandemic on December 17,2010 and that prediction was reinforced by each announcement of trH3N2 cases in 2011,.

The large Iowa cluster, in the absence of swine exposure, was expected as was the WHO response.  Similarly, the naming of the novel trH3N2 is also straightforward.  The triple reassortant that cases the 2009 pandemic is named H1N1pdm09 (representing the H1N1 serotype and the year of the pandemic) and the novel trH3N2 causing the 2011 pandemic should be called H3N2pdm11.

The real puzzle is the media’s description of H3N2pdm11 as a virus “jumping from pigs to people” or use of the CDC name for the virus S-OtrH3N2, which ignores the pandemic and directs attention to the Swine-Origin of the H3N2 triple reassortant, to reinforce the CDC narrative on “swine exposure”, which is and has been destroyed by the sequences of the human trH3N2 cases, including H3N2pdm11.

The story behind the evolution and emergence of H3N2pdm11 came into focus when the WHO issued a pager alert on two trH3N2 cases in Illinois and Pennsylvania, a year ago in early November, 2010.  Prior to the alert there had been three reported trH3N2 cases in the US, beginning in 2009.  The triple reassortants were of interest because the 2009 pandemic was due to a triple reassortant and there had been 13 cases reported in the US, other than H1N1pdm09.  Eleven of these case were described in a 2009 publication in the New England Journal of Medicine, which had emphasized “swine contact” but did not include the release of the sequences for the cases, which is odd for peer reviewed articles, because such articles are supposed to have sufficient data for replication and confirmation by other scientists, which includes release of sequences in papers where the sequences are key for the interpretation of the key points in the paper, which was clearly the case for a paper entitled “Triple-Reassortant Swine Influenza A (H1) in humans in the United States, 2005-2009.

The WHO pager altert create serious concerns, especially in eastern Europe, but the CDC offered assurances in its week 44 FluView which noted that the sequences from the isolates from the two cases (A/Wisconsin/12/2010 and A/Pennsylvania/14/2010)  were distinct, isolated 6 weeks apart, and did not signal human transmission.  These comments were in contrast to the first two confirmed cases in the US linked to the 2009 pandemic.  These sequences matched even though the two cases in southern California were more than 100 miles apart, had no contact with swine or each other, and were not epidemiologically linked.  This set of circumstances in 2009 signaled the start of a pandemic because swine triple reassortants in humans were rarely reported, and the absence of a link between the two confirmed cases indicated the linkage between the two sequences was based on a large number of unreported human cases.

Thus, while the CDC offered assurances on sequence differences between the cases in the pager alert, they did acknowledge similarities between all five trH3N2 cases, which could not be independently analyzed, because only the sequences from the first trH3N2 were available (at GISAID).  Moreover, the sequences from the prior human triple reassortant cases in the NEJM publication were also withheld.  A few sequences such as the HA sequences from two cases in Ohio, A/Ohio/01/2007 and A/Ohio/02/2007, were public but solving the puzzle of the trH3N2 was difficult because the CDC was holding and hiding most of the pieces.

The H1 from the two Ohio cases could be compared to H3 from the only trH3N2 case because they were different sero-types.  The cases were triple reassortants because of the internal genes, which could be compared, but not directly because of the failure of the CDC to release the sequences.  The Ohio sequences were of interest because they were from the only two cases in the trH1 cases from the same location, the Huron County fair.  These cases were of interest, because in addition to the isolation of trH1N1 from the fair presenter (10F) and her father (36M), two dozen attendees had ILI, which is unusual for Ohio in August, and suggested that the virus had sped well beyond the two confirmed cases.
However, phylogenetic analysis involving the internal genes of the two trH1n1 cases at the Ohio fair and the trH3N2 case at the Kansas fair, because trH1N1 was isolated from swine at the Ohio fair (A/swine/OH/511445/2007 and A/swine/Ohio/24366/2007), and full sequences from these swine, as well as more recent swine identified through enhanced surveillance due to the 2009 pandemic and its swine origin.  The surveillance failed to find matches for H1N1pdm09 in swine isolates from samples collected prior to the pandemic, but such sequences were frequently identified in the US and throughout the world because H1N1pdm09 was spread throughout the world via human to human transmission, and then swine populations worldwide were seeded via human to swine transmissions.  In addition, other SOIVs (Swine Origin Influenza Viruses) were isolates in the US, including the Huron fair isolates provided a background for phylogenetic analysis, and it was known that the Huron swine sequences exactly matched the two human cases, allowing for analysis between the human sequences at the fair and the trH3N2 cases from Kansas.

This analysis was described in a November 14 commentary, which noted the striking similarities between internal genes from A/Kansas/13/2009 and the swine isolates from the fair (representing A/Ohio/01/2007 and A/Ohio/02/2007).  These similarities raised concerns that the human trH3N2 cases were adapting to humans, which was also supported by the detection of PB1 E618D in the trH3N2 human sequence and virtually all H1N1pdm09 sequences, suggesting acquisition via recombination.

This analysis was followed by the CDC’s November 18 release of all of the sequences (at GISAID) from the human triple reassortant cases, which largely consisted of full sequences for all 8 gene segments and confirmed that the human trH3N2 sequences were beginning to cluster and PB1 E618D was in four of the five human cases signaling an emerging pandemic.

The release of sequences was followed by the announcement of another trH3N2 case, A/Minnesota/11/2010 leading to the December 17, 2010  prediction of a trH3N2 pandemic, which was followed by the release of the sequences from that cases, which showed that most of the genes matched most of the 2010 cases, including E618D, increasing the evidence for adaptation to humans.

The first confirmed trH3N2 case in 2011 was from 2010 isolate that was initially designated as seasonal H3N2, highlighting the technical challenges of distinguishing seasonal H3N2 from trH3N2.  This case developed symptoms on September 6, 2010 days prior to the case from Wisconsin, indicating two trH3N2 cases were in Pennsylvania when WHO issued its pager alert. 

The sequences from the second case in Pennsylvania, A/Pennsylvania/40/2010, were quietly released on Sunday, April 17 and the CDC has yet to comment on the match with A/Wisconsin/12/2010 for all eight gene segments, which had striking similarities with the first two confirmed cases in the 2009 pandemic.  These cases were collected from patients who developed symptoms within days of each other, matched in all eight gene segments, and were not linked epidemiologically, indicating many undetected human cases were transmitting this trH3N2, which had E618D, which was in all human cases other than A/Iowa/16/2009.

Human to human transmission was lab confirmed when the daughter of the index case from Minnesota was serologically confirmed to be trH3N2 infected.  The daughter had no swine exposure, supporting infection by her father, or other symptomatic family members who tested as “inconclusive” strongly suggesting that A/Minnesota/11/2010 had infected multiple family members beyond the two confirmed cases.

The first reported trH3N2 case due to an infection in 2011 was from a child (2M) in Indiana.  The sequence, A/Indiana/08/2011 was released at GISAID without comment, although the M gene from H1N1pdm09 was noted.  The full sequence showed that it had evolved from the dominant human trH3N2 sequences from 2010 with matches for 5 of the 8 gene segments (PB2, PA, HA, NP, Ns) including H3.  The N2 matches one of the Pennsylvania isolates. A/Pennsylvania/14/2011, while the PB1 matches an earlier version more closely related to the two Huron fair isolates (A/Ohio/01/2007 and A/Ohio/02/2007) which don’t have E618D, which is in H1N1pnd09, but does have the H1N1 M gene.  This, this constellation represents a human contagion, with all eight gene segments matching recent human isolates.

The release of these sequences was followed by an early release MMWR, describing the Indiana case and a case from Pennsylvania.  Like the daughter of the Minnesota index case, the Indiana case had no swine exposure (although the CDC cited “indirect exposure” because the child’s caretaker had a swine exposure, but the caretaker and swine were asymptomatic.  The Pennsylvania case (2F) had visited an agricultural fair in western Pennsylvania (Washington County fair) and also was infected with a trH3n2 with an M gene from H1N1pdm09.  However, once again the CDC offered assurances on human transmission by noting sequence differences between the Indiana and Pennsylvania sequences, but the Pennsylvania sequences had not been released.

The MMWR was followed by a CDC “Have You Heard?” which described two more cases from the Washington County fair, setting a record for the largest number of confirmed cases from a single event.  These cases also had an M gene from H1N1pdm09.

These announcements were then followed by the release of the sequences from the cases at the fair, which again voided the CDC assurances.  There were sequences differences between the first Pennsylvania case, A/Pennsylvania/09/2011, and the sequence from Indiana, but the other two cases (A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011) matched each other and Indiana, once again duplicating the relationships seen in the sequences between the first to cases in the 2009 pandemic, leaving little doubt that the 2011 trH3N2 sequences should be designated H3N2pdm11 acknowledging widespread transmission in humans in the US, which would spread worldwide.

The matches between sequences in Pennsylvania and Indiana were then extended to Maine, when one case, A/Maine/06/2011 was then followed by two more cases, A/Maine/07/2011 and A/Indiana/10/2011) all of which were in October.

The coupe de grace was awarded to the cluster in Iowa, which involved three confirmed cases (A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011) and two symptomatic family members (brother and father) of the index case, all of which lacked swine exposure.

Thus, the trH3N2 virus, including H3N2pdm11 was not a puzzle and the pandemic clearly began months ago.  Only one example of H3N2pdm11 in swine has been reported (a Sept 13 collection from a pig in New York,
A/swine/NY/A01104005/2011, and the November 22, “Have You Heard”? claiming reported case of H3N2pdm11 in swine in “several states” may signal detection in one of more states in the Midwest, as suggested by a Nancy Cox quote indicating detection of H3N2pdm11 in “pigs in the US Midwest”.  However, the details on the detection in pigs in the Midwest have not been published, so the similarity with the human cases, or date of sample collection remain unknown, and at this stage are rather moot.

Thus, the main puzzle at this time centers on media reports which still claim that H3N2pdm11 has been jumping from pigs to people, as well as the lack of H3N2 sequences from children under 10 who have been infected since July, 2011. 

Currently there are only 12 such sets of public sequences, and 9 of the 12 are H3N2pdm11.

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