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Commentary
CDC Comments Raise
H1N1
D225G/N Surveillance Concerns
Recombinomics
Commentary 15:46
March 8, 2010
"I think additional work needs to be done before we conclude that there is a causal relationship," she said.
The above comments by the CDC on the significant correlation between D225G and D225N with severe and fatal cases in Norway reflects the current position of CDC and WHO, even after overwhelming numbers have been made public in Ukraine. In Norway, 8/27 fatal cases had D225G and 1/27 had D225N, but the 33% rate of D225G/N in fatal cases in Norway was dwarfed by the detection of D225G/N in 73% (27/37) of autopsy lung samples in Ukraine. Like Norway, which failed to find D225G in mild cases, the Ukraine sequences with D225G/N were almost exclusively limited to fatal cases.
After the initial release of HA sequences which indicatd D225G was limited to the four fatal cases in the first nine sequences from western Ukraine, Mill Hill released sequences from 12 Dniprpetrovsk isolates grown on mammalian cells and only one had D225G (as a mixture with wild type). Another 6 isolates from Cherkasy grown in eggs had a wild type receptor binding domain (RBD), indicating that D225G/N was rarely detected in milder cases. Virus from lung autopsy samples also contained D225G/N when grown on mammalian cells. Only one sample that had a mixture of D225G with wild type based on direct sequencing lacked D225G in the sequence from the mammalian cell isolate.
Thus, the Mill Hill data demonstrated that almost all D225G/N positive samples were from fatal cases, and the RBD changes could be found in direct sequencing, as well as in isolates grown on mammalian cells. In contrast, direct sequencing, or growth on mammalian cells or eggs rarely found D225G (one sample) when milder cases were tested.
Although the positive samples in Ukraine are clearly not linked to lab growth of virus, detection of lower levels of D225G may require selection via grown in eggs, which have gal 2,3 receptors, which is also true for human lung. Early isolates from mild cases in the United States had D225G when grown in eggs, but not when sequences were direct or from virus grown in mammalian cells. As indicated in CDC remarks on the number of cases with D225G, samples with D225G limited to egg isolates are not included in CDC totals. Other labs have followed suit and use of various mammalian cells are increasing, limiting detection of these lower levels of D225G.
The Norway and Ukraine data clearly demonstrate the linkage of D225G to severe and fatal cases, and the worldwide levels of D225G/N are a high priority surveillance target. In 1918/1919, 40% of sequences from fatal lung samples had D225G, including the only 1919 sample.
The above comments by the CDC, which were made after the Ukraine sequences have been made public, raises serious concerns about current surveillance approaches, which includes a trend away from creation of egg isolates, which may be the most sensitive method for detection of D225G.
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