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Emergence of a Novel Human H3N2v Sub-clade
Recombinomics Commentary 23:55
July 28, 2012

Four people tested positive for influenza A (H3N2) variant virus.* Genetic testing confirmed that the viruses found in humans and those found in swine are nearly identical, and both have the M gene from the pandemic H1N1 virus. These cases bring the total number of detected infections with the H3N2v virus containing the pandemic M gene in the United States since 2011 to 17.

The above comments from the CDC’s  July 26 “Have You Heard” describe the largest outbreak of confirmed H3N2v cases reported to date.  Yesterday the CDC released a full set of sequences from two of the four confirmed cases, A/Indiana/07/2012 and A/Indiana/09/2012, which were identical and signaled the emergence of a novel sub-clade, which was initially seen in 2011 at a Mineral County day care center in West Virginia, where two cases were confirmed (A/West Virginia/06/2011 and A/West Virginia/07/2011) and 22 additional contacts had influenza-like illness, but were not tested.

Although the sequences were similar to the first 10 confirmed cases in 2011, including an H1N1pdm09 M gene, the N2 sequence was from an H3N2 lineage circulating in swine instead of the N2 circulating in H1N2 swine.  All other gene segments matched the lineage of the earlier 2011 cases.  The novel constellation present in West Virginia was also in the first confirmed cases in 2012, A/Utah/10/2012, but the latest outbreak, at the LaPorte County Fair in Indiana, confirms that the novel constellation has become dominant in humans.

This constellation, with matching lineages, was first seen in swine in a North Carolina isolate, A/swine/North Carolina/A01203272/2012, identified in a February 13, 2012 collection (based on HA, NA, and MP sequences).  The same sub-clade was then found in Indiana in a May 9, 2012 collection, A/swine/Indiana/A01203509/2012 (also based on HA, NA, MP sequences).

The CDC has a website on human H3N2v cases, which is focused on the 17 cases noted above (which include the latest four cases from Indiana), which have been isolated since July, 2011 and have an H1N1pdm09 M gene.  However, the CDC has not acknowledged the N2 difference in the 7 most recent cases.

Six of the seven confirmed cases were from large clusters where the number of symptomatic cases exceeded the confirmed cases.  The outbreak in West Virginia led to a CDC alert and conference call to all 50 states in December, 2011.  However, detection of H3N2v is largely limited to the off season, so the first case was in Utah in March.  The latest cluster confirms the emergence of the novel sub-clade and raises concerns that sub-clade is producing a higher viral load.

Initial CDC sequences generally come from direct sequencing of the clinical sample.  The samples are then used to isolate clones which can be expanded in cell culture.  The success for obtaining clones is somewhat dependent on the viral load present in the collection.  Sequences from clones from the West Virginia and Utah have not been reported.  However, the full sequences from all eight gene segments for two of the LaPorte isolates were from clones, signaling a higher viral load.

The investigation of the LaPorte County fair is ongoing, and the number of symptomatic cases has not been cited.  However, postings from fair attendees and local media reports have described 9 symptomatic children, including at least two who recovered in 24 hours and did not seek medical attention, suggesting dozens of the fair attendees were infected because flu-like symptoms are uncommon in Indiana in July and the reported cases had contact with symptomatic swine or siblings.

Moreover, all 12 fair swine tested were H3N2v positive (including asymptomatic swine) and initial sequence data indicated the 12 sets of swine sequences were closely related to the human sequences.

Thus, the latest sequences from the CDC clearly indicate this novel sub-clade has emerged in humans and is in the 7 most recent human cases as well as the 12 most recent swine cases.

The large size of the outbreaks in West Virginia and Indiana raises concerns that the number of 2012 confirmed human H3N2v cases will significantly exceed the 12 cases reported in 2011.

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