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H3N2v NA N234D In LaPorte and Butler County Clusters
Recombinomics Commentary 11:30
August 21, 2012

The recently released CDC sequences from H3N2v cases in Indiana and Ohio raises additional concerns of human adaptation and an increase in transmission.  All of the Indiana and Ohio isolates match the novel H3N2 sub-clade first reported in the West Virginia cluster at a Mineral County day care center.  The sub-clade swapped out an N2 gene that has a lineage common in H1N2 swine and replaced it with a lineage found in H3N2 swine.

This novel sub-clade raised initial concerns because the index case (A/West Virginia/06/2011) and confirmed contact (A/West Virginia/07/2011) had no swine exposure, and the disease onset dates signaled additional transmission at the daycare center.  Initial data from an epidemiological studied identified ILI (influenza-like illness) in 23 of the 70 contacts of the index case, leading to a series of warnings by the CDC in late 2011 and early 2012.

These warnings however did not lead to any reported H3N2v during the peak of the 2011/2012 flu season, once again highlighting surveillance issues regarding detection of variants during the flu season.  The first human H3N2v cases identified in March 29, 2012 collection from a Utah case (A/Utah/10/2012) confirming the onward spread of this sub-clade, which was confirmed by sequences from July isolates from cases in Hawaii, Indiana, and Ohio.

The initial sequences from Indiana were from four cases at the LaPorte County fair.  All four sets of sequences (A/Indiana/06/2012, A/Indiana/07/2012, A/Indiana/08/2012,  A/Indiana/09/2012) were identical and included a newly acquired N2 change, N234D (N2 numbering), which abolished the glycosylation site.  This change was not present in the earlier human H3N2v cases, or the July Indiana sequence from the Jackson County Fair, A/Indiana/12/2012. However, it was in the first July isolate from Ohio, which was from the Butler County Fair, A/Ohio/13/2012.

The CDC release 10 additional sets of sequences from four cases in Indiana and 6 cases from Ohio.  All of the additional Ohio sequences were closely related to the first sequence, suggesting all were from the Butler County Fair and all had N234D.  In contrast the four additional cases from Indiana formed two additional distinct clusters.  Two (A/Indiana/13/2012, A/Indiana/17/2012) were similar but distinct from the Jackson County sequence, while the other two were closely related to each other (A/Indiana/15/2012 and A/Indiana/19/2012) but distinct from the other Jackson County cluster.  These patterns suggest that the five Indiana isolates that are not from LaPorte are from Jackson County and adjacent Jennings County.  However, none of the Indiana sequences which are distinct from the LaPorte sequence have N234D.

The LaPorte cluster included at least 5 confirmed cases, but the number of symptomatic cases was markedly highly, signaling efficient human transmission at the fair.  Similarly, there were 14 confirmed cases linked to the Butler County Fair, and the number of confirmed Butler County sequences has increased to 17, which also signaled increased human transmission.

The finding of N234D in all of the LaPorte County, Indiana (located in northwestern Indiana) and Butler County, Ohio (located in southwestern Ohio) raises concerns that this NA change is present in additional large clusters in Indiana (Monroe and Washington Counties) as well as Ohio (Gallia and Champaign Counties).

The loss of a glycosylation site in the NA gene has parallels with the loss of a glycosylation site in the HA gene in H5N1 transmission studies. N158D was identified in transmission studies by Kawaoka, which used H5 clade 1 from Vietnam and Fouchier, which used clade 2.1 from Indonesia.  This loss of the glycosylation site was also seen in the Donis transmission which used clade 2.2 from Egypt, which already had lost the glycosylation site.

Thus, the loss of a glycosylation site in the NA gene in two large H3N2v clusters in Indiana and Ohio raise concerns that this change will be found in additional clusters linked to the novel sub-clade that was first identified in West Virginia in late 2011 and has been found in all human H3N2v sequences from 2012.

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