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2012 H3N2v Evolution Raises Pandemic Concerns
Recombinomics Commentary 14:15
April 13, 2012

CDC has confirmed this virus is very similar to the 12 H3N2v viruses that infected 12 people in the United States in the latter half of 2011.

Although the CDC has not released the sequence of the 2012 case from Utah (F <5), the above comments strongly suggest that the isolate has a constellation of genes that matches human isolates from 2011, which provides additional evidence that this H3N2v, which includes the H1N1pdm09 M gene, is circulating in humans in the United States.

Although seasonal H3N2 peaks in January or February, this high frequency limits detection of H3N2v in these months because the seasonal H3N2 is more efficiently transmitted in humans, and is more easily detected by PCR tests that target seasonal H3N2 gene sequences.  H3N2v is detected via cross reactivity with H3 from seasonal H3N2 or NP from H1N1pdm09, which creates weaker signals and inconclusive/negative results.  Lower RNA levels have produced an H3 positive and NP negative, which is commonly designated as seasonal H3N2.  However, positives in the off season, or those from cases with a swine exposure, are frequently sent to the CDC for further analysis, which leads to the detection of H3N2v via sequencing.  This testing protocol creates the illusion that the cases are due to the exposure to H3N2v in swine, when in fact the detection is due to more rigorous testing (which is linked to reports of swine exposure).

These testing protocols lead to a division of H3N2v season into calendar years, with most detection in the latter part of the year.  These “seasons” are also associated with more dramatic changes in flu genes at the beginning of the new season, for which the first isolates in the 2012 season is the above isolate from Utah.  However, the above CDC comments suggests the differences between the 2012 isolates an those from 2011 is limited, raising additional concerns that the current H3N2 has adapted to human transmission.

The evolution of H3N2v extends well beyond the acquisition of an H1N1pdm11 M gene.  The first US was in the summer of 2009 and had internal genes that evolved from H1N1v (12 cases in the US between 2005 and 2009).  The internal genes were closely related to the sequences from the Hudson County Fair in 2007, which was linked to the isolate of H1N1v from an exhibitor and her father (A/Ohio/01/2007 and A/Ohio/02/2007), but was also associated with 26 attendees with ILI.  Moreover,, the first US H3N2v isolate, A/Kansas/13/2009, had PB1 E618D, which was not present in prior swine isolates, but was present in H1N1pdm09.

This PB1 (with E618D) was present in all 6 H3N2v cases in 2010 (as well as the H1N2v cases in 2011).  It subsequently appeared in swine isolates, but phylogenetic analysis indicated the swine sequences evolved from the human isolates. In the 2010 human isolates most of the genes in most of cases were from the same lineage, although only two cases, A/Wisconsin12/2010 and A/Pennsylvania/40/2010, matched each other in all 8 genes.

Five of these eight genes (PB2, PA, HA, NP, NS) were also present in the 2011 human cases which acquired the other three genes (PB1, NA, MP) from an H1N2 swine isolate such as one from Ohio (A/swine/Ohio/FAH10-1/2010).  Although the PB1 was an earlier version, which had not acquired E618D from H1N1pdm09, the MP gene segment was from H1N1pdm09.  This new constellation was present in all of the first 10 H3N2v human cases in 2011, signaling a major adaptation to human transmission, which was supported by the absence of this lineage in reported swine sequences (limited to two September isolates, A/swine/NY/A01104005/2011 and A/swine/Iowa/A01202640/2011).

However, the final two sequences from 2011 human cases were from a cluster in West Virginia which had swapped the N2 gene from swine H1N2 sequences for an N2 from swine H3N2, raising concerns that this adaptation led to more efficient transmission because influenza like illness (ILI) was reported in 23 contacts of the West Virginia index case, A/West Virginia/06/2011, including A/West Virginia/07/2011.

The CDC has not released the sequences from the Utah case, so it is unclear if it has the N2 gene from the lineage in the first 10 2011 human cases, or the lineage seen in the West Virginia cluster.  However, the CDC description indicates the Utah isolate has an H1N1pdm09 M gene and is very closely related to the 2011 human cases, suggesting the 2012 sequences has not dramatically evolved away from the 2011 cases, raising concerns that the number of 2012 cases will be markedly higher than the 12 cases reported in 2011.

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