Saturday, November 07, 2009

withheld ukraine sequences raise pandemic concerns

Recombinomics | Right now we know that many clinical specimens and viruses have been sent to one of the WHO collaborating centres for further study. We don't know the results of those studies, and it will probably take a couple of days for the full analysis of those viruses to be available. But in the meantime, what we do not have is any evidence of viruses there or anywhere else as showing any big mutations. I raise this point because I have seen in some media reports that there are reports that WHO or other groups are saying that there are mutations and I want to point out that these are rumours and factually, untrue.

The above comments from Keiji Kukuda offer some general comments on the Ukrainian H1N1 sequences at Mill Hill in London. He specifically says WHO doesn't see any "big" mutations in the samples being sequenced, which would refer to reassortment or Tamiflu resistance. However, the changes seen in Ukraine do not require "big" mutations. Small mutations, such as SNP can have profound effects for a virus like pandemic H1N1.

That virus normally circulates in swine, and has recently jumped to humans. It already has many characteristics with the 1918 pandemic strain. Both are swine H1N1 that jumped to humans. Such species jumpers can increase efficiencies with small changes. One good example is position 627 in the PB2 gene. That position comes in two forms. When there is glutamic acid (E) at that position, the PB2 enzyme copies the viral genetic material most efficiently at 41 C, the body temperature of a bird. However, if that position has a lysine (K), the enzyme is most active at 33 C, the temperature of a human nose in the winter. The swine H1N1 has an E, which may be why it goes well in lung, which is 37 C and closer to the optimal replication temperature of 41C. However, a single change that produced the most efficient replication at 37C would lead to even higher levels in the lungs, which could lead to frequent cytokine storms, like those in 1918, instead of the less frequent level seen in Ukraine.

However, the rapid spread of H1N1 in Ukraine (see map), coupled with the high frequency of hemorrhagic pneumonia raise concerns that a small change is leading to a more virulent virus. Similarly, the rapid spread of the virus could also be affected by a small change in another gene, such as HA, which controls entry of the virus to cells and influences tissue tropism.

Mill Hill has acknowledged that they have at least 15 H1N1 positive samples from Ukraine, which would identify a Ukranian specific change. The delay in the announcement of sequence results raises concerns that such changes have been detected, and such changes are undergoing further analysis.

The number of cases in Ukraine continues to expand. The number of patients with H1N1 symptoms is now approaching 1 million. Cases have been increasing at almost 200,000 per day, so it is likely that tomorrow's report will have over 1 million cases. This rapid spread increases concern that the 15 sequences at Mill Hill contain one or more of these small changes, which has led to a delay in the announcement of sequence results.

More detail on the sequences at Mill Hill is overdue. The rapid spread of H1N1 in Ukraine demands rapid sequence results. Continued delay will only increase concerns.