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trH3N2 Pigs To People Media Myth
Recombinomics Commentary 19:00
November 5, 2011

The U.S. Centers for Disease Control is reporting two new cases of a flu virus that has been sporadically jumping from pigs to people.

The new cases, in Maine and Indiana, bring to seven the number of cases seen in the United States since July.

Most of the people who have been infected had close contact with pigs and the two latest cases are no exception.

The above comments extend the media myth that the swine “exposure” signals jumps of trH3N2 from “pigs to people”.  The CDC has not present any direct evidence of these jumps, even though the initial cases in Indiana and Pennsylvania were 2-3 months ago and investigated “intensively” according to CDC comments.

The sequence data clearly raises serious questions about the above “media” interpretation because all seven of the 2011 trH3N2 have the same unique constellation of genes, which has never been reported in swine. Similarly, the last time three or more human triple reassortants with the same constellation of genes were reported was at the start of the 2009 H1N1 pandemic.  Thus, the sequence data, as well as small clusters of cases, has led to a very noticeable change in CDC comments on human transmission in the past year.  Last year, right after the WHO pager alert, the CDC stated there was no human to human (H2H) transmission of trH3N2.  The cluster of cases in Minnesota led to a change to limited H2H, with no sustained transmission, which was repeated after the lack of a swine exposure for the first Indiana case was reported, which was the first case with the trH3N2 novel constellation. Now after the number of cases has increased to seven, the CDC only cites a lack of evidence of sustained transmission in the states of the two most recent cases, because the sequence data leaves little doubt that a new trH3N2 human contagion has appeared.

The failure of media report(er)s to grasp these significant changes is linked in part to the series of updates prepared for the media under the CDC’s “Have You Heard?” (HYH) category.  Many of the statements have been voided by clear sequence data, but the voiding is not announced directly.  Instead the effect of the sequence data is seen in the evolution of CDC statements on H2H transmission.  Therefore, a review of evolution and emergence of trH3N2 using the associated “Have You Heard?” reports may be useful.

The CDC page of SOIV (swine origin influenza virus) in humans describes triple reassortants which were first reported in humans in 2005.  However, all triple reassortants prior to the 2009 H1N1 pandemic were H1, while all after the pandemic were H3N2.  There were two cases in 2009 (A/Kansas/13/2009 and A/Iowa/16/2009) and one in the spring of 2010 (A/Minnesota/09/2010), but the increases in the fall of 2010 attracted attention and generated the first trH3N2 HYH which came out on November 12, 2010, after the WHO put out a pager alert on two trH3N2 cases which had been reported for Illinois and Pennsylvania.  The alert caused considerable alarm in Europe, but the HYH noted that the symptoms for the two cases began 6 weeks apart, and although both were trH3N2 cases with similarities to the three earlier cases, sequence differences indicated they were not linked and did not signal human transmission.

At that time, the only public trH3N2 sequences were front the initial case, who had been affect at a fair near Fort Riley, Kansas.  Since all sequences from all 8 gene segments had been released, they could be compared to other public sequences, and matches with swine sequences from another fair, the Huron County Fair in Ohio in August, 2007.  Those sequences were of interest because HA sequences from two human cases, a presenter (9F) and her father (32M), A/Ohio/01/2007 and A/Ohio/02/2007) were available, and two dozen fair attendees had reported flu-like symptoms, which was unusual for August in Ohio.   Although not confirmed, the large number of cases suggested that the trH1N1 was efficiently transmitting in humans.  The other gene segments from these cases were not public, but the swine sequences from the fair were complete, and phylogenetic analysis revealed clustering between the multiple internal genes from the trH1N1 Ohio swine, and the human case from Kansas.

The ability to monitor the evolution of human trH3n2 cases changed dramatically when the CDC released the sequences on the earlier trH1N1 and trH1N2 cases, as well as the 2009 and 2010 trH3N2 sequences.  There was clear clustering indicating many of the internal trH3n2 genes had evolved from the trH1N1 genes from the Huron County fair (and the two sets of human sequence from the fair matched each other and the swine sequences from the fair).

The sequence story became clearer when a Minnesota case was announce in the December 17 HYH, and the associated sequences were announced, indicating that the trH3N2 cases were clustering and six of the eight genes from the Minnesota case were closely related to the Illinois case described in the page alert, which was designated A/Wisconsin/12/2010 because the Illinois case was reported by Wisconsin. Moreover, the December HYH also indicated the contacts of the Minnesota case were under investigation.

The trH3N2 evolution however, became much clearer and more alarming when the additional trH3N2 cases were reported in 2011.  The first case was from Pennsylvania, but was a case who had developed symptoms on September 06, prior to the Illinois case described in the page alert.  However, reporting of this case had been delayed for 5 months because it was initially reported as seasonal H3N2, and there were technical difficulties isolating the virus for antigen characterization and sequencing.  Thus, when the WHO issued its pager alert there were three trH3N2 cases, and two of them developed symptoms within 6 days of each other, rather than the 6 weeks reported in the November HYH.
Five weeks later, the sequences from this case were released, at GISAID on Sunday, April 17.  There was no HYH issued and the CDC has not discussed the sequences, which were alarming because they were virtually identical to the Illinois case.  Thus, the assurances in the first HYH that the cases were distinct and from cases isolated 6 weeks apart, ignored the second Pennsylvania case, A/Pennsylvania/40/2010, who developed symptoms 6 days prior to the Illinois case, A/Wisconsin/12/2010, raising serious human transmission concerns.

These concerns increase when the second confirmed trH3N2 case for 2011 was described in a June 23 MMWR influenza summary report indicating several contacts of the Minnesota case were symptomatic and one, the daughter of the index case, had been serologically trH3N2 confirmed.  Since the daughter had no swine contact, the CDC acknowledged that this cluster represented this first lab confirmation of trH3N2 human to human transmission.  Moreover, testing of other contacts was “inconclusive” suggesting other symptomatic contacts had also been infected with A/Minnesota/11/2010, which proved the H3 and N2 for a pandemic trH3N2 vaccine.  However, no HYH was issued for this cluster (reported 6 months after the fact), and a link to the MMWR reporting the cluster is conspicuously absent from the CDC web page on SOIV cases in humans since 2005.

Thus, four of the five confirmed cases had closely related sequences for most of the gene segments, including H3 (A/Pennsylvania/40/2010, A/Wisconsin/12/2010, A/Minnesota/11/20101, and the daughter of the Minnesota index case), demonstrating human adaptation of this emerging trH3N2 contagion.

This emergence was clearer when the CDC released sequences from the first trH3N2 case that was due to an infection in 2011, A/Indiana/08/2011.  These sequences identified multiple reassortment events.  Five of the genes (PB2, PA, HA, NP, NS) had evolved from the dominant 2011 sequences, including H3.  The NA gene matched the other Pennsylvania isolate, A/Pennsylvania/14/2010.  Thus, the H3 and N2 traced back to two human isolates from Pennsylvania, A/Pennsylvania/40/2010 and A/Pennsylvania/14/2010.  The PB1 gene was the same linage, but was more closely related to the earlier sequence in the two isolates from the Huron fair, A/Ohio/02/2007 and A/Ohio/02/2007).  Of most interest however was the M gene, which was from H1N1pdm09.  Thus, all 8 gene segments were from human lineages that included the H1N1pdmo9 M gene which was critical from the jump of H1N1pdm from swine to humans.

The release of the Indiana sequences was followed by an early release MMWR (released a week ahead of its scheduled publication date), which included the case from Indiana as well as a case (2F) from Pennsylvania.  The Pennsylvania sequence wasn’t released, but like the Indiana case, it had an M gene from H1N1pdm09.  However, the CDC again noted sequence differences to between the two isolates, indication the two infections were not due to a common source. Like the daughter of the Minnesota index case, the Indiana case (2M), had no swine exposure, leading the CDC to acknowledge another example of H2H transmission, based on the assumption that the child was affected by his caretaker, who had swine contact (although the caretaker and associated swine were asymptomatic and no SOIV infections in the caretaker or swine has been reported).  In spite of the acknowledged H2H transmission in Minnesota and Indiana, the CDC issued a request for samples from cases with a swine exposure.

The early release MMWR was quickly followed by a September 6 HYH, which announced two more cases from Pennsylvania which also had the H1N1 M gene.  These cases all had a swine “exposure” via attendance at the Washington County fair, but like the Indiana case, no symptomatic swine were reported and no SOIV infections have been reported in any swine at the fair.  The three confirmed cases from the same location were the largest reported cluster to date for trH3N2 (or any triple reassortant other than H1N1pdm09).

The September HYH was followed by release of the Pennsylvania sequences, which again voided the assurances given by the CDC (in the early release MMWR).  Although the sequences from the first Pennsylvania case (2F), A/Pennsylvania/09/2011, were a drift variant (same constellation but with some accelerated evolution indicating a separate source), the sequences from the two subsequent cases (both 9F), A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011) were virtually identical to each other and the Indiana sequence signaling widespread human transmission.

This widespread human transmission was supported by the release of the next trH3N2 case (8M) in October from Maine, A/Maine/06/2011.  This was another drift variant and increased the number of human cases with this novel constellation to 5, which was not seen in any swine sequences including those as recent as July, 2011.  The Maine case also led to an October 21 HYH.

This release was followed by release of sequences from two more cases from samples collected two days apart.  The Indiana case (59M) had sequences, A/Indiana/10/2011 (initially reported as A/Indiana/11/2011), similar to the Maine case, but the polymerase genes were closer to the earlier Indiana and Pennsylvania cases. The Maine case (8M) was represented by short sequences from HA, NP, MP, NS, (A/Maine/07/2011) but these were closely related to the earlier sequences from Maine.  The cases led to a November 4 HYH.

Thus, the sequence analysis leaves little doubt that the novel trH3N2 has jumped to humans in 2011.  In 2010 the human isolates began to cluster phylogenetically, with most isolates sharing most genes.  In 2011 the 2010 isolates gave rise to the 2011 novel constellation, including the M gene from H1N1pdm09.  This constellation has never been reported in swine, although eventually it will jump from human to swine and be confirmed.

The swine “exposure” has yet to yield any examples of SOIV infected swine (and of course no such swine with this constellation).  The swine linkage is more associated with prioritizing / testing of such cases both by surveillance sites, as well as selection of samples for submission to the CDC, since states cannot directly confirm trH3N2.  The designation of “unable to subtype” such as influenza A positive H3/H1 negative or inconclusive, may facilitate shipment to the CDC, but prioritizing/testing/reporting issues drive the public data, as does a request for samples from patients with a swine exposure, as was done in the early release MMWR.

The heavy emphasis on swine exposure by the CDC and state labs has created the media myth of trH3N2 jumps from swine to humans, as indicated in the initial quotes.

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