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Human H5N1 Bird Flu in China Raise Pandemic Concerns

Recombinomics Commentary
April 3, 2006

China has released three human H5N1 bird flu sequences.  These sequences are similar to each other and most closely related to a duck isolate in Fujian Province.  However, these isolates are quite distinct from other H5N1 sequences in China and elsewhere.  Consequently, the pandemic vaccine in clinical trails around the world and the new vaccine target from Indonesia that was recently selected by the United States will not offer significant protection against these newly released sequences from China.  Moreover, the vaccines under development will also offer little protection against the Qinghai strain which is linked to recent human outbreaks in Turkey, Iraq, Egypt, and Azaerbaijan.

Thus, at this time there are four distinct H5N1's causing fatal human infections which will likely require custom pandemic vaccines.  Thus, as H5N1 evolves, the distance between vaccines under development and new versions of H5N1 cause human infections is increasing.  In 2004 human cases in Vietnam and Thailand were linked to a similar H5N1.  Last year Indonesia and China reported human cases and the recent release of sequence data clearly shows that the H5N1 in humans in Indonesia is quite distinct from H5N1 infecting humans in China and all three versions are distinct from the Qinghai strain of H5N1 causing human infections in the Middle East and Africa.

The spread of human H5N1 cases has also been associated with changes in the receptor binding domain.  The first reports were identified in 2003 isolates from a Hong Kong family that had visited Fujian province.  The H5N1 isolated from the patients contained S227N.  This change was subsequently found in human isolate(s) in Vietnam and most recently in the index case in Turkey.

One of the isolates from China has a change at the adjacent position, Q226R.  Unlike the S227N change, Q226R has not been linked to increased affinity for human receptors, although Q226L is the change in human H3 HA that has been linked to increased affinity.  Another change, G228S has been predicted for Europe due to recombination between Qinghai H5N1 and European swine H1N1.

In addition to these changes within the receptor binding domain, changes near the receptor binding domain, (P185S, N186S, R193K) have been recently reported in Iraq and China.  These changes in and around the receptor binding domain are cause for concern because donor sequences are frequently found in flu from birds and the H5N1 host and geographical ranges are rapidly expanding.

The number of changes is also not know because many of the recent human isolates have been sequestered in a private WHO database.  The human H5N1 sequences from Iraq, Indonesia, and China have been released in the past few weeks.  However, human sequences from Turkey, Azerbaijan., Egypt and additional sequences from China and Indonesia have not been released, so additional polymorphisms linked to the receptor binding domain may have already entered the reservoir of human H5N1 infections.

H5N1 is clearly rapidly evolving via recombination, as efforts to address these genetic changes continue to lag.

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