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Commentary
Evolution of a
Novel Human
H3N2v Sub-clade
Recombinomics
Commentary 12:55
July 31, 2012
The above comments are from the CDC page on H3N2v cases. It was created to tally H3N2v cases which have the H1N1pdm09 M gene, which was confirmed almost a year ago on a July case. Samples were collected on July 24 and July 27 and sequencing confirmed the novel constellation. However, the first H3N2v case in the United States was three years ago in a case linked to the Riley County Fair in Kansas (A/Kansas/13/2009), and the most recent reported cases in 2011 were linked to a Mineral County day care center, where two confirmed cases were identified (A/West Virginia/06/2011 and A/West Virginia/07/2011), and the N2 gene segment represented a distinct lineage (found in H3N2 swine). All subsequent human sequences reported to date have been this novel sub-clade, including the two sequences from the LaPorte County Fair in Indiana.
The first H3N2v case in the United States was reported after the start of the 2009 pandemic. Prior to the pandemic there had been 13 reported cases in the United States, and the only outbreak with two confirmed cases was in 2007 at the Heron County Fair in Ohio. Like the recent outbreak in Indiana, the confirmed cases had contact with swine (cases were a presenter and her father – A/Ohio/01/2007 and A/Ohio/02/2007).
The sequences from the two human cases were identical and matched H1N1v sequences from swine at the fair. In addition to the two confirmed cases, 26 fair attendees were symptomatic, but not tested. Flu-like symptoms in August in Ohio are uncommon, suggesting most or all of the symptomatic attendees were also infected with the H1N1v.
Although the first H3N2v case had an H3 which traced back to seasonal H3N2 circulating in the mid-1990’s and anN2 linking back to seasonal H3N2 from 2003, the internal genes were closely related to the sequences from the 2007 Heron County Fair. However, the PB1 in A/Kansas/13/2009 had acquired E618D, which was in all human and swine H1N1pdm09 sequences, but not present in swine sequences (other than H1N1pdm09). The first reported swine case was reported more than a year later, in the fall of 2010.
In addition to the first H3N2v case in 2009, E618D was present in all six human H3N2v PB1 sequence in 2010. Similarly, most of the other genes were present in most of the 2010 cases, but two of the cases, A/Wisconsin/12/2010 and A/Pennsylvania/40/2010 match each other in all 8 gene segments.
In 2011, the first case, A/Indiana/08/2011 had five gene segments (PB2, PA, HA, NP, NS) which matched the above two 2010 sequences, while the other three genes (PB1, NA. MP) matched 2010 sequences from H1N2 Ohio swine (A/swine/Ohio/FAH10-1/2010 as well as NA and MP from many additional H1N2 isolates for which only HA, NA and MP sequences were released). The PB1 was closely related to the Heron County Fair sequence, but did not have E618D. However, the MP was from H1N1pdm09, while the N2 was from a lineage common to H1N2 swine, but also traced back to seasonal H3N2 from 2003.
The constellation in Indiana/08/2011 was also present in the next 9 human cases (from Pennsylvania, Maine, Indiana, and Iowa). The common constellation in all 10 cases, including an H1N1pdm09 M gene led to the creation of the CDC H3N2v website.
However, the final two reported cases in 2011 represented a novel sub-clade, which replaced the N2 found in H1N2v swine with an N2 found in H3N2v swine. This novel sub-clade has also been seen in all three human sequences from 2012 (and presumably in the two additional cases from LaPorte as well as the 12 sequences from swine at the fair (which are in addition to the two earlier 2012 swine sequences with this novel constellation.
Although the MMWR on the West Virginia outbreak noted the gap between disease onset dates for the two confirmed cases and noted that additional contacts with the index case were symptomatic, the extent of the spread was not revealed. The two confirmed cases had no swine contact, but a CDC report distributed to all fifty states noted that 23 of 70 contacts with the index case were symptomatic, indicating the novel constellation was efficiently transmitting in humans.
Concerns regarding human adaptation were increased when the sequence from the first human case (A/Utah/10/2012) were released and matched the West Virginia cases. Although the case had swine contact at a family owned slaughter house, no symptomatic swine were reported and exposure was over a week prior to disease onset, casting doubt on the role of swine in the infection.
In contrast, the LaPorte County Fair outbreak in Indiana had symptomatic swine, and 12 of 12 swine were H3N2v positive (and testing included asymptomatic swine). The H3N2v testing supported efficient spread through the swine at the fair, and four presenters or family members were H3N2v confirmed, representing the largest number of confirmed H3N2v cases reported to date. However, comments from attendees indicated the number of symptomatic attendees was significantly higher than the four confirmed cases, and raised concerns that the H3N2v also transmitted efficiently in humans. The first two confirmed cases (13F and 11F) were from separate families, and at least two sisters of one of the cases (11F), as well as 3 swine, were symptomatic. Similarly, another attendee noted symptoms in four family members as well as additional adult cases, suggesting the demographics for the symptomatic cases in Indiana were different than the earlier cases which were almost exclusively in children under the age of 8.
The changing demographic parameters and the large number of symptomatic cases linked to the West Virginia and Indiana outbreaks raises concerns that H3N2v adaptation is increasing the efficiency of human transmission.
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