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CDC Hopes and Dreams On 2011 trH3N2 Evolution
Recombinomics Commentary 17:30
October 24, 2011

The acquisition of the M gene likely occurred as a result of swine being co–infected with the swine influenza A (H3N2) virus and the human 2009 H1N1 virus.

The above comments are from the latest CDC “Have You Heard” which discusses the most recently reported trH3N2 cases (8M), A/Maine/06/2011.  This isolate increases the overwhelming evidence for the transmission of trH3N2 in humans, yet the CDC continues to cite swine involvement, which is not supported by data.

The sequence data provides compelling evidence for human transmission, and the evidence was initially made public in November, 2010 when the CDC released the sequence data on trH3N2 cases. The sequences were released just after the WHO issued a pager alter on two trH3N2 patients and the sequences (A/Wisconsin/12/2010 and A/Pennsylvania/14/2010) raised concerns. Many of the internal genes from cases were clustering phylogenetically, signaling adaptation to humans. However, the CDC put out its first “Have You Heard” on trH3N2, which suggested the two cases did not represent human transmission because of differences between the two sets of sequences.

Shortly after these assurances were given, another case was reported.  This case was in Minnesota and the sequences, A/Minnesota/11/2010, were closely related to the Wisconsin case, providing more evidence for human transmission.  This sequence data was strengthened by 2011 reports on additional 2010 cases.

The first data set came from the report of a second Pennsylvania case, A/Pennsylvania/40/2010, who developed symptoms less than a week prior to the Wisconsin case.  However, the sample was initially classified as seasonal H3N2, and additional analysis / reporting was delayed because of technical difficulties in growing the virus.  In week 4 of 2011 the case was reported as another trH3N2 case, and the sequence was closely related to the Wisconsin case, demonstrating clear clustering of sequences from human trH3N2.

The concern that this clustering signaled human transmission was confirmed in week 21, when the daughter of the Minnesota case was confirmed to have also been trH3N2 infected, even though she had no swine contract.  The CDC then acknowledged limited human transmission (additional family members were also symptomatic, but trH3N2 confirmations were reported as “inconclusive), and selected the isolate from the father as a pandemic H3N2 vaccine target.

However, the sequence data for human transmission was significantly strengthened, when sequences from the first 2011 trH3N2 case (2M), A/Indiana/08/2011, were released at GISAID without comment, other than a note mentioning the presence of an M gene segment from pandemic H1N1 (H1N1pdm09). The acquisition of the M gene was a concern because an independent reported cited the M gene as being critical for the jump of H1N1pdm09 from swine to humans.  Therefore, this acquisition could drive the jump of trH3N2 from swine to humans.  The sequences of the other genes also increased concerns.  5 gene segments (PB2, PA, HA, NP, NS) including H3 matched the most common 2010 human trH3N2 sequences, while the NA was closely related to the second Pennsylvania isolate (PA/14/2010) and the PB1 was related to two other human cases, A/Ohio/01/2007 and A/Ohio/02/2007, linked to the Huron County outbreak.  This, all seven of the trH3N2 gene segments matched prior human isolates, adding to the evidence of human adaptation.

The release of the Indiana sequence was followed by an early release MMWR which described the Indiana case (2M) as well as a 2011 case (2F), A/Pennsylvania/09/2011, who was from Schuylkill County in eastern Pennsylvania, but attended the Washington County agricultural fair in western Pennsylvania.  The Indiana case had no swine contact, but his caretaker contact with swine was cited as a potential trH3N2 source leading to limited human to human contact.  However, the caretaker and associated swine were asymptomatic, so no true link was established.  Similarly, the Schuylkill resident attended an agricultural fair, but no symptomatic swine was identified.  The MMWR also cited sequence differences between the Indiana and Pennsylvania cases, suggesting the infections did not come from a common source.  However, both sets of sequences had the same constellation of genes, including the M gene from H1N1pdm09, as well as matches for all 7 trH3N2 gene segments.

The early release MMWR was followed by another “Have You Heard” which described two addition cases (both 9F), A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011, which had the identical set of gene segments.  These three cases from the same county fair represented the largest number of trH3N2 isolates from a single location.  However, the investigation, which the CDC characterized as “intensive”, failed to identify a source for any of the 2011 cases.

The release of the sequences from the 2011 trH3N2 cases in Pennsylvania strongly supported human transmission.  Although the sequences from PA/09/2011 signaled a different source, the sequences from the other two cases, PA/10/2011 and PA/11/2011, were virtually identical to each other as well as IN/08/2011, even though the Indiana case was a month earlier and at a location 100’s of miles away.  The sequence identity between these three cases, which were not epidemiologically linked, strongly supported sustained transmission, and the identical constellation of genes in the third Pennsylvania case strong supported human adaptation.

The support was increased with the report of the 5th trH3N2 case (8M), A/Maine/06/2011, which also had the M gene from H1N1pdm09.  The sequences confirmed that the identical constellation of genes was involved, although several gene segments began evolving away from the 2010 human trH3N2 sequences at an earlier data, strongly suggesting that this novel trH3N2 represented a new human contagion, and represented sustained transmission.

The CDC has denied sustained transmission based on epidemiological data, which was generated using the same approach that failed to identify a source for any of the 5 2011 trH3N2 cases.  The linkage to swine was based solely on the pseudo linkages, which led to trH3N2 testing, which is only done by the CDC and is limited to samples received, which are flagged due to pseudo linkage to swine, including the Indiana case which had no direct linkage, and the other four cases who had attended fairs where asymptomatic swine were exhibited.

However, no symptomatic swine have been identified at these fairs, and no swine have been identified with the constellation of genes found in all five human cases from three states (Indiana, Pennsylvania, and Maine).

Thus, in spite of this lack of any real data linking human trH3N2 to trH3N2 infected swine, the CDC continues to statements such as the one quoted above, which are based on hopes and dreams, and lack any real data.

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