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Paradigm Shift Intervention Monitoring
for trH3N2 Pandemic
The WHO wants to be ready to make recommendations and issue guidance to countries if the need arises — though Fukuda stressed at this point it is far from certain there will be that need.
"We're very aware that we don't want to over-play or under-play. We're trying to get that right," says Fukuda, a leading influenza expert.
"(We're) trying to make sure that we're ready to move quickly, if we have to move quickly, but also trying not to raise alarm bells."
The desire to be prepared without raising alarm is a legacy of the 2009 H1N1 pandemic. The WHO was heavily criticized in Europe for declaring that event a pandemic when the outbreak turned out to be far milder than originally feared.
But what exactly the agency — and the world — might need to prepare for now is very unclear. With the public relations problems of the 2009 outbreak fresh in the minds of health officials, no one is using the "p" word these days.
Yet in some respects the parallels to 2009 are striking.
The above comments are from the response to the WHO pager alert (in blue), issued almost exactly one year ago, and the latest media report (in red) of current WHO pandemic plans.
The alert issued in November, 2010 cited two trH3N2 isolates (A/Wisconsin/12/2010 and A/Pennsylvania/14/2010), but WHO and the CDC were probably aware of a third case (A/Pennsylvania/40/2010) who developed symptoms less than a week prior to the Wisconsin case (cited as an Illinois cases in the alert).
If the WHO and CDC didn’t know about the second Pennsylvania case when the alert was issued, within days they knew of that case, as well as a case from Minnesota (A/Minnesota/11/2010) and symptomatic contacts. When the CDC released the sequences from these cases, there was clear cause for concern, as seen in slide 7 from the CDC (Nancy Cox) presentation in February, 2011 (at the FDA vaccine advisory committee meeting).
The H3 sequences from cases in Wisconsin, Pennsylvania, and Minnesota were clustering, indicating the H3 for all three cases were remarkably similar and distinct from trH3N2 swine isolates. Moreover, the sequences from the Wisconsin case and the Pennsylvania case that was not mentioned in the alert, were virtually identical, creating striking parallels between the trH3N2 data and the initial cases in southern California at the start of the H1N1 pandemic in 2009.
However, the absence of the sequences from the second case allowed the CDC to offer assurances that there was no human transmission because of sequence differences between the two cases in the alert, which were isolated 6 weeks apart. The announcement of the second case in Pennsylvania was delayed until February 5, because the case was initially classified as seasonal H3N2, but sequence data showed that the case was clearly trH3N2. That sequence was used in slides 7 and 8 in the CDC February 25, 2011 presentation, but the sequence was not released until Sunday, April 17, 2011 at GISAID without comment.
As seen in slides 7 and 8, the PA/40/2010 sequence was virtually identical to WI/12/2010 and this identity extended to all 8 gene segments. Moreover the two cases developed symptoms within a week of each other, even though they were not epidemiologically linked. Thus, the only significant difference between the trH3N2 matches in 2010 and the trH1N1 matches in 2009 was the claim of “swine exposure” for the trH3N2 cases.
However, this “exposure” was listed in the CDC slide as a “visit to a local animal fair”. Since the Wisconsin case was only seven months old at the time, the extent of “contact” was likely limited, and no trH3N2 was reported at any of the swine at the fair. Similarly, the Pennsylvania case (3F) was only 3 years of age, and swine contact at the fair was also likely limited, and no trH3N2 matching the human cases has been reported from either state. Similarly, the other case from Pennsylvania (PA/14/2010) had no reported exposure to swine, although he lived in a rural area (and closely related sequences to this case were subsequently identified in Pennsylvania swine).
Thus, the red flag raised over a year ago in the WHO pager alert signaled the start of a series of events which left little doubt that the trH3N2 had begun in 2010, and gained significant speed in 2011. In week 21 of 2011 trH3N2 was lab confirmed (serologically) in the daughter of the Minnesota case and her lack of swine exposure led to the CDC concession that the case represented limited human to human transmission.
This concession was made again for the first 2011 trH3N2 case (A/Indiana/08/2011), who also had no swine contact. However, the caretaker of the patient had swine exposure, so the case was said to have “indirect swine exposure” even though the caretaker and swine were asymptomatic and not trH3N2 was identified in either case.
Similarly, the first 2011 case from Pennsylvania (A/Pennsylvania/09/2010) also visited an agricultural fair (Washington county) but no symptomatic swine was identified at the fair, which included the market hogs exhibited by the second Pennsylvania case. The third case also visited the fair and a friend who exhibited swine, but there was no evidence that any of the three cases were infected by trH3N2 in swine at the fair, and the sequences from the 2nd and 3rd Pennsylvania case (A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011) were virtually identical to the Indiana case.
Thus, the matches between cases that were not epidemiologically linked as seen in late 2010, was repeated in the initial cases in 2011, although this sequence had evolved from the 2010 sequences by acquiring an NA gene matching the other Pennsylvania case (PA/14/2010) and an M gene segment from 2011.
This constellation and lineage has now been found in all 2011 human cases, including the Iowa cluster, which had no swine contact and involved three confirmed cases and two symptomatic family members of the index case.
Thus, the “swine exposure’ link, which generated the more advanced testing at the CDC required to confirm trH3N2, was absent from the Iowa cluster, leaving little doubt that the novel trH3N2 was spreading in humans and was orders of magnitude higher than the ten confirmed cases from four states (Indiana, Pennsylvania, Maine, Iowa) as well as one novel trH3N2 swine isolate from New York, A/swine/NY/A01104005/2011.
Consequently, WHO is planning for the trH3N2 pandemic, without using the “P” word.