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Human and Swine H3N2v Sub-clade Discordance
Recombinomics Commentary 16:30
August 8, 2012

The USDA has released additional series of swine sequences which contained another match (based on sequences from HA, NA. and MP) with the human cases from 2011 and 2012.  The new match, was from a February 15 collection and increased the number of swine isolates which matched to 28.  Recent human sequences (released at GISAID by the CDC) from Hawaii, Indiana, and Ohio has increased the number of sets of public H3N2v human sequences.  All 48 isolates are chronically listed below, with location annotation added to the human isolates and bolding of the novel sub-clade, which emerged in late 2011 in the human cases and is present in all 2012 human cases, but is only found twice in the swine isolates.  This discordance seriously discounts the role of swine in the spread of the two sub-clades found in humans in 2011 and 2012 and raises concerns that the recent increase in human and swine clusters is associated with humans infecting swine.

The evolution and adaptation to humans of this sub-clade is supported by sequence data which includes the earlier human cases.  The first H3N2v cases in the United States was in 2009 in Kansas (A/Kansas/13/2009) in an isolate that had much in common with the H1N1v isolated from a 2007 outbreak at the Heron County Fair in Ohio.  Prior to the 2009 pandemic there were 13 reported human cases of triple reassortants, which began in 2005.  12 of the 13 were H1N1v, but only one outbreak had two confirmed cases, which was at the Ohio fair were A/Ohio/01/2007 and A/Ohio/02/2007.  This outbreak was of concern because of the two confirmed cases (a presenter and her father), 26 attendees had influenza-like illness (ILI) which is unusual in Ohio in August.

The six internal genes of the first H3N2v human isolate in the United States were closely related to the sequences from the 2007 Ohio cases (which also match infected swine at the 2007 fair), but they also had a PB1 change, E618D, which was in all H1N1pdm09 sequences (from human or swine), but not present in swine (other than swine infected with H1N1pdm09).  This novel PB1 was also in all six human H3N2v cases in 2011 (as well as the H1N2v case in 2011, which was the only human isolate in 2011 without an H1N1pdm09 M gene).  E618D was not found in swine until the fall of 2010.  Thus, the appearance in humans prior to swine raised concerns that the acquisition of E618D was associated with human adaptation, since it was in all H1N1pdm09 cases.  Moreover, all six of the human cases in 2010 were closely related in most of the genes, and some genes, like PB1 with E618D were in all six human isolates from 2010.

In 2011 a new H3N2 sub-clade appeared in human cases.  It had 5 genes (PB2, PA, HA, NP, NS) from the consensus constellation of the 2010 human cases.  However, the other three genes match swine H1N2 sequences.  The PB1 was also similar to the sequences from the 2007 Ohio fair (and did not have E618D), but the MP gene matched H1N1pdm09, and the NA was distinct from the NA in most of the 2010 isolates.  This constellation was present in the first 10 human cases in 2011 and all 10 isolates had the same constellation, which included the MP gene matching H1N1pdm09.

A novel sub-clade appeared in late 2011.  It matched the earlier sub-clade in 7 of the 8 gene segments, but the N2 matched a lineage circulating in H3N2 swine.  Like the N2 from H1N2 swine, it was from seasonal H3N2 from 2003, but had evolved in swine so the two N2 sequences were easily distinguished.  As seen in the lists below, the first 10 human cases were one sub-clade, which the next ten, including all 2012 isolates were the novel sub-claded (bolded in lists).

The distribution of the novel sub-clade is quite different.  It is not found in any swine isolate collected prior to the human cases in West Virginia, and is only in two of the 28 sequences.  Thus, although the 2012 H3N2v swine matches are dominated by the earlier human sub-clade, there were no matching human cases in 2012.

The last human case was in the cluster at the Iowa day care center, where three cases were confirmed (index case and two classmates) while the brother and father of the index case were symptomatic (but not tested).  It the Iowa cluster there was no swine exposure or contact and the sequences were virtually identical, supporting human to human transmission.  Thus, although the earlier sub-clade could infect and transmit between humans, and was present in swine in late 2011 and throughout 2012, include four June isolates from Ohio, there have been no reported human cases since November 14, 2011.

Instead, the ten most recent isolates, beginning with the West Virginia day care center on November 21, 2011 have been the novel sub-clade and most of the isolates have been linked to large cluster.

In West Virginia only two cases were confirmed, but the collections were more than two weeks apart, indicating the index case did not infect her classmate.  An epidemiological investigation identified 70 contacts, of which 23 were symptomatic as described in the alert from the California Department of Health to counties throughout the state.  Similarly, the large cluster in West Virginia led to a CDC alert to all fifty states. 

Although these alerts failed to result in any detected cases during the peak of the 2011/2012 flu season, the first H3N2 case in 2012 was identified in Utah in March, followed by a case in Hawaii in July.

However, the subsequent July cases were also linked to large clusters.  The four confirmed cases in LaPorte represented the largest confirmed cluster to date,  However, in addition to the four isolates listed below the Indian State Department of Health (ISDH) has reported a fifth confirmed cases, and more than a dozen people linked to the LaPorte County Fair were symptomatic.  Similarly, the isolate from the Jackson County Fair was from a county where symptomatic cases were noted in the 6 weeks prior to the fair.  Moreover, three additional confirmed Jackson County cases have beeb reported by the ISDH.

The Ohio case listed below is also from a large cluster from the Butler County fair, where there are 14 confirmed cases and more than two dozen symptomatic cases.  In addition to the large human clusters at these fairs associated swine have also been H3N2v confirmed indicating H3N2v is passing between humans and swine, which could be moving from swine to human or human to swine as noted in recent comments from the CDC and other agencies.

Thus, the novel sub-clade, first detected in the West Virginia cluster, which was not linked to swine contact or exposure, has been associated were large clusters of human cases (confirmed or suspect) and swine in the recent clusters linked to county fairs.  However, this novel cluster was not commonly deyected in swine prior to the recent outbreaks, and the ealier sub-clade has been frequently detected in swine in 2012, but no human cases have been report.

This discordance signals human adaptation and transmission of the novel sub-clade, which is now linked to large clusters involving humans and swine.

Human Isolates
A/Indiana/08/2011                  07/27/11   Caretaker had swine contact
A/Pennsylvania/09/2011        08/20/11   Washington County Fair
A/Pennsylvania/11/2011        08/25/11   Washington County Fair
A/Pennsylvania/10/2011        08/26/11   Washington County Fair
A/Maine/06/2011                    10/10/11   Fryeburg Fair
A/Maine/07/2011                    10/24/11   Fryeburg Fair
A/Indiana/10/2011                  10/22/11   Veterinarian
A/Iowa/07/2011                       11/14/11   Day Care Center
A/Iowa/08/2011                       11/14/11   Day Care Center
A/Iowa/09/2011                       11/14/11   Day Care Center
A/West Virginia/06/2011      11/21/11   Day Care Center
A/West Virginia/07/2011      12/07/11   Day Care Center
A/Utah/10/2012                       03/29/12  Processing plant
A/Hawaii/03/2012                   07/12/12  Farmer
A/Indiana/06/2012                  07/16/12  LaPorte County Fair
A/Indiana/07/2012                  07/16/12  LaPorte County Fair
A/Indiana/08/2012                  07/16/12  LaPorte County Fair
A/Indiana/09/2012                  07/16/12  LaPorte County Fair
A/Indiana/12/2012                  07/27/12  Jackson County Fair
A/Ohio/13/2012                       07/27/12  Butler County Fair
Swine Isolates
A/swine/Iowa/A01202529/2011                       08/22/11
A/swine/Iowa/A01202530/2011                       08/22/11
A/swine/Iowa/A01202573/2011                       09/07/11
A/swine/NY/A01104005/2011                          09/13/11 
A/swine/Iowa/A01202878/2011                       09/17/11
A/swine/Iowa/A01202879/2011                       09/17/11
A/swine/Indiana/A01202621/2011                   09/28/11
A/swine/Iowa/A01202639/2011                       09/30/11
A/swine/Iowa/A01202640/2011                       09/30/11
A/swine/Illinois/A00857138a/2011                  10/20/11
A/swine/Illinois/A00857138b/2011                  10/20/11
A/swine/Illinois/A00857300/2011                     11/28/11 
A/swine/Illinois/A01202978/2011                     12/16/11
A/swine/Illinois/A00857304a/2012                   01/05/12 
A/swine/Illinois/A00857304b/2012                   01/05/12
A/swine/Ohio/A01203186/2012                        01/24/12
A/swine/North Carolina/A01203272/2012   02/13/12
A/swine/Illinois/A00857318a/2012                   02/23/12
A/swine/Texas/A01104013/2012                      02/15/12
A/swine/Indiana/A01203372/2012                    04/03/12
A/swine/Iowa/A01203503/2012                         05/09/12
A/swine/Indiana/A01203509/2012                  05/09/12
A/swine/Indiana/A01203521/2012                     05/15/12
A/swine/Indiana/A01203522/2012                     05/15/12
A/swine/Ohio/1/2012                                                 06/12
A/swine/Ohio/6/2012                                                 06/12
A/swine/Ohio/7/2012                                                 06/12
A/swine/Ohio/9/2012                                                 06/12

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