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Ukraine H1N1 Sequence Changes Raise Concerns
Recombinomics Commentary 13:17
November 17, 2009

Preliminary tests reveal no significant changes in the pandemic (H1N1) 2009 virus based on investigations of samples taken from patients in Ukraine. Analyses are being performed by two WHO influenza collaborating centres as part of the global influenza surveillance network.
Preliminary genetic sequencing shows that the virus is similar to the virus used for production of the pandemic influenza vaccine, reconfirming the vaccine's efficacy at this time.

A total of 34 samples were analysed independently by the WHO Collaborating Centre for Reference and Research on Influenza, Mill Hill in London, UK, and the WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza in Atlanta, Georgia, USA.

The above WHO comments from the latest update on sequences from isolates from Ukraine (see map) raised additional concerns.  Earlier comments indicated that there were no "large changes", which simply meant that there was no significant reassortment with other influenza viruses, such as seasonal flu, and the constellation of genes was unchanged (5 swine, 1 human, and 2 avian). 

However, the comments did not rule out small changes, such as receptor binding domain changes seen in other swine H1N1 isolates such as D225E, D225N, and D225G.  The latter two changes were of concern because they had recently been isolated from Sao Paulo fatal cases, and three of the four isolates with D225N or D225G were found in lung samples, which were of conern because of reports of total destruction of lungs in Ukraine..

The recent comments from WHO stating that sequences are "similar" to other sequences does not rule out receptor binding domain changes, and such changes were not denied, as was done previously with H5N1 sequences from patients in Pakistan, which again raises concerns that the sequences from Ukraine do have receptor binding domain changes.

Such changes could affect transmission or tropism and could also affect the vaccine reactivity.  The involvement of the CDC in Atlanta, as well as Mill Hill in London suggests the isolates were tested against the current vaccine, which would again suggest that there were sequence differences, but that the differences did not significantly reduce titers against reference anti-sera. 

However, the involvement of the CDC would also raise questions about antiviral resistance which would be addressed in biological testing, which would be more sensitive that sequencing, which would be more prone to miss minor populations.  The antiviral concerns have been also increased, due in part to the recent announcement of a cluster of H274Y patients in Scotland.

It has now been over two weeks since samples were sent to WHO collaborative center(s) and full sequences have been generated.  The absence of any statement on the presence or absence of receptor binding domain changes continues to raise concerns that such changes are present in the Ukraine sequences and these sequences affect transmission or tropism.

Release of the sequences is long overdue and such a release would end speculation about the significance of such changes.

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