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H5N1 RBD Changes Raise Pandemic Concerns

Recombinomics Commentary
December 21, 2007

Rainford declined to predict today how soon confirmatory testing in the eight cases, which were identified in preliminary tests by Pakistan's national lab, will be completed. He said some samples from the patients would be sent to London for analysis.

"I hope we'll get some early results but question whether we'll have lab results that are what we need," he said. "We've got, hopefully, samples arriving in London sometime over the weekend that will provide a better environment to assess what we've got."

The above comments strongly suggest that receptor binding domain changes have been found in sequences from patients in Pakistan.  In the past, frequent clusters were reported in infected patients in Turkey, Iraq, Azerbaijan, and Egypt.  In every case, the clusters were associated with changes in the receptor binding domain (RBD).  These changes increase the affinity of H5N1 for mammalian cells, which is the key change required fro H5N1 to generate a pandemic with an unprecedented case fatality rate.

Currently the case fatality rate for H5N1 varies, but two of the countries with the highest rate were Azerbaijan and Iraq.  Reported cases in these two countries were almost exclusively clusters involving human to human transmission.  The involvement of the Qinghai strain in such clusters is cause for concern because one human acquisition, PB2 E627K, has become fixed in this sub-clade.  This change allows H5N1 to replicate faster at lower temperature (33 C).  All seasonal flu isolates have E627K, which may be one of the reasons why seasonal flu is seasonal.

H5N1 has already evolved so it efficiently replicates in mammals, including humans.  However, transmission is lower than seasonal flu, which is likely linked to receptor binding domain specificities. Recent work, including the Skehel lab in London, has shown that several changes in H5N1 can increase affinity for 2.6 gal linkages found in the upper respiratory tract in humans.

These changes were common in the clusters in the Middle East in 2006.  Last year the number of reported human cases in the region was limited to Egypt.  The largest cluster in Egypt had two changes in or near the receptor binding domain, V223I and M230I.  All patients with M230I died.

The association of receptor binding domain changes with human to human transmission in patients in the Middle East raises questions about the receptor binding domain in Pakistan, where the clusters described in media reports includes transmission which may have lasted fro 6 weeks.  Changes in the receptor binding domain of H5N1 associated wthe that cluster would not be a surprise.

The above comments on shipment of samples to London suggest the samples will be used in receptor binding domain studies in the Skehel lab at Mill Hill.

The WHO has delayed release of a situation update for Pakistan.  The outbreak began on October 25 and positives were confirmed last Saturday In Pakistan, but no situation update has been published.  The above comments suggest that there will be additional delays in the release of the update, which again suggests receptor binding domain changes have been seen in sequences from cluster members.

A situation update, with the disease onset dates of the confirmed patients and the relationships of the patients to each other, and receptor binding domain changes in H5N1 sequences would be useful.

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