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The WHO Surprise on D225G / D225N H1N1 Fatalities
Recombinomics Commentary 17:48
December 29, 2009

After considering the current available virological, epidemiological and clinical findings and following discussions on an earlier draft with WHO and its European-based Collaborating Centre ECDC has come to a preliminary formulation namely that the G222D/N variants exist in a small proportion of sporadic severe, as well as mild cases of 2009 pandemic
influenza A(H1N1) infection and that these represents natural variation of the virus with no special association with severity of the disease course. As such and while they do not transmit they should have a minimal impact on public health and pandemic response. Current data suggests that the cases involving variant viruses in different parts of the world are unrelated and the underlying mutation events probably occurred independently from each other in the infected individuals as a consequence of the natural variability of influenza viruses and their inability to correct random coding
errors. However because of that inherent variability and ability to surprise the 2009 A(H1N1) will need on-going combined virological, epidemiological and clinical surveillance and study.

The above comments in the latest ECDC report confirm attempts by WHO consultants to explain the strong association of D225G and D225N (aka D222G and D222N) with fatal and severe H1N1 cases as "random coding errors" even though the WHO regional lab in Mill Hill found D225G in four of four fatal cases, while the WHO region lab in Atlanta (CDC) found D225N in two of two additional cases, which were almost certain fatal cases also. 

D225G and D225N are rare and have been reported in about 1% of H1N1 HA sequences, yet they have a 100% case fatality rate in sequences from Ukraine.  This 100% CFR was matched in several additional countries, including two D225G and two D225N sequences in Brazil (Sao Paulo), as well as two D225G sequences in France and three recent sequences (1 D225G and 2 D225N) in Mexico.  Moreover, recent sequences with mixed signals for both D225G and D225N have been found in 1 fatal case in the US (Utah), 2 fatal cases in Mexico (San Luis Potosi) and one severe case in Sweden (Stockholm).  Similarly, Denmark, who filed a formal notification when three examples were identified and two were fatal while the third was severe, has a high rate.

Although there were a few mild cases with D225G in the US at the start of the pandemic last spring, including the vaccine target California/7, mild cases are common at the start of a pandemic because there is little immunity in the target population, and infections and symptoms can be caused by low viral loads which are effectively contained by a weak host response.  The association of D225G and D225N is severe and fatal cases since the summer has been remarkable, especially since the vast majority of pandemic H1N1 infections are mild and resolve without treatment.  In contrast, nearly 100% of recent cases with D225G, D225N, or both have been fatal or severe.

In Ukraine five isolates from patients who recovered had a wild type receptor binding domain, while six patients who were infected by the same sub-clade had either D225G in the four known fatal cases or D225N in the two likely fatal cases.  This rate of 100% of six patients is not associated with six independent random errors in six patients, who died in the same general area at the same time, and only affects the position 225 codon. 

This "random mutation" paradigm constantly produces "surprises", for which the above "experts" readily acknowledge on a very regular basis.  They were surprised and baffled by H274Y Tamiflu resistance in patients infected with seasonal H1N1, and will again be surprised and baffled by the same result in pandemic H1N1.

WHO's reliance on consultants who try to use random mutation to explain these examples of 100% case fatality rates in multiple countries is cause for increasing concern.

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