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RBD Changes Lead to Efficient H5N1 Human Transmission
December 21, 2007
NAMRU staff on site will be able to give us some information, but I guess there's a role for an additional lab to give us a full picture."
The above comment almost certainly indicates samples are being sent to the Skehel lab in London for receptor binding studies. NAMRU-3 has a mobile lab on site as well as a sequencing lab in Cairo. However, the Skehel lab in London can give a full picture by running receptor binding affinity tests to see how changes in the sequence of the receptor binding domain affect affinity for human receptors.
Increased binding to these receptors leads to efficient transmission, which is the final step required for H5N1 to go pandemic. These changes however need not be an all or none situation. Various changes or combinations of changes can produce intermediate effects which lead to more efficient transmission and larger or more frequent clusters.
These types of changes are of concern for the Qinghai strain, because it has already acquired one "human” change that allows for more efficient replication at 33 C, the temperature of a human nose or throat in the winter. This change is present in seasonal flu, which is one of the reason there is more flu in colder months.
Although there is a widely circulated media myth that human to human transmission of H5N1 is rare, but that is simply not true. Most of the transmission involves small clusters of family members which involve infection of the index case by poultry, so these human to human transmissions are not “proven”, but are easily identified by gaps in disease onset dates. However, a cluster alone represents a moré efficient transmission from the original source to a human. For the Qinghai strain, this association with receptor binding domain changes is very tight.
The first reported Qinghai case was in Turkey two years ago. The index case has the receptor binding domain change, S227N. This specific change was predicted because of the endemic H9N2 in the Middle East. In Turkey there were 21 lab confirmed cases and almost all were in a few large clusters and many smaller ones. Only four human H5N1 sequences have been released, and two of the four had S227N. One of the two without S227N was from the sister of the index case, so S227N was almost certainly present in the sibling, but was absent in the virus isolated from the patient, which may have been linked to isolation conditions.
The outbreak in Turkey was followed by an outbreak in Iraq. Only three cases were confirmed, and the first two were a cluster. These sequences had two receptor binding changes, N186S and Q196R. The clusters in Turkey and Iraq were followed by clusters in Azerbaijan. The clusters had another receptor binding domain change, N186K. The following season Egypt had a cluster, and it had two receptor binding domain changes, V223I and M230I. Thus regardless of whether these clusters are “unproven” human to human transmissions, or more efficient transmission to humans, they are associated with receptor binding domain changes.
The outbreak in Pakistan involves at least two clusters. The larger cluster has been sustained for up to six weeks. Therefore it is likely that there are receptor binding domain chages, and samples are ebing sent to London to confirm that these changes result in increased affinity for human receptors.
Although reported human H5N1 cases may have ebbed, the repeated detection of clusters and receptor binding domain changes suggests H5N1 will continue to try new combinations until a pandemic combination emerges.
This season the number of Qinghai H5N1 infections in the fall is at an all time high, which will increase the likelihood of more human infections, more clusters, and more efficient transmission.
Details of disease onset dates and sequences from the clusters would be useful.
Recombinomics Paper at Nature Precedings