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trH3N2 Transmission Raises Pandemic Concerns
Recombinomics Commentary 19:20
February 5, 2011

One case of human infection with a novel influenza A virus was reported by the Pennsylvania Department of Health. The patient was infected with a swine origin influenza A (H3N2) virus. The patient reported contact with pigs in the week preceding symptom onset on September 6, 2010, did not require hospitalization, and has since fully recovered. Initial testing of the specimen indicated a seasonal influenza A (H3N2) virus and the specimen was submitted to CDC as a routine surveillance sample.
The delay from onset to detection occurred because attempts to culture the virus were unsuccessful. RT-PCR testing confirmed swine-origin influenza A (H3N2). Six other human infections with swine origin influenza A (H3N2) viruses have been identified in the United States during 2009 through 2010, including one other case from Pennsylvania in week 44 of 2010.

The above comments from the week 4 FluView report raise concerns that trH3N2 is transmitting human to human (H2H) at a level markedly higher that the reported cases mentioned above.  In November, 2010 WHO issued a pager alert describing two novel influenza isolates identified in the United States.  Both were H3N2 triple reasortants (trH3N2) and were of concern because two such isolates identified over a short time frame was unusual.  The first human trH3N2 in the United States was in Kansas in the summer of 2009.  Prior to the alert there had been three trH3N2 cases (in Kansas and Iowa in 2009 and in Minnesota in 2010), so two cases in the fall of 2010 raised concerns.  The latest report from the CDC indicates there were at least three cases in this time frame, and two of the three were from Pennsylvania.

The above comments confirm that trH3N2 sequences are recognized by current H3 sub-typing reagents, which was expected because the H3 and N2 in swine trH3N2 have a human origin.  However, the genes trace back to the mid-1990’s and have been evolving is swine, so there has been significant genetic drift, which could lead to an “unsubtypable” designation if the clinical sample is compromised.  Others, like the sample above would simply type as seasonal H3N2, and the swine origin would not be obvious in the absence of more detailed testing, such as antigenic characterization tests, where isolates would register as “low reactors”, or by sequencing, where the relatedness to seasonal H3N2 from the 1990’s would be clear.

Thus, detection of trH3N2 requires more testing than a simple influenza A test or human sub-typing, raising concerns that the number of trH3N2 isolates may be markedly higher than the seven cases reported to date.  Moreover, the Kansas sequence, as well as all four 2010 sequences have PB1 E618D.  This marker is of concern because it is in virtually all pH1N1 sequences and is not in any swine trH3N2 sequences, suggesting it represents an adaptation to a human host, and signals H2H transmission.  Several of the trH3N2 cases do not have a history of contact with swine.  Moreover, for cases with swine contact, there has been no demonstration that the swine were H3N2 infected or that H3N2 sequences in the contact swine were closely related to the human trH3N2. 

Moreover, as noted, there have been no reports of PB1 E618D in any swine trH3N2, even though it is in 5 of the 6 human trH3N2 sequences.
Therefore more information on additional samples under investigation as well as an explanation for the large number of “unsubtypable” cases in Pennsylvania, which have been noted in weekly reports in 2010 and 2011, would be useful.

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