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United States Selects Indonesian H5N1 for Pandemic Vaccine

Recombinomics Commentary

March 11, 2006

The selection of a new pandemic vaccine candidate by the United States is not a surprise.  When initial results of the first candidate vaccine was announced, it was clear that H5N1 was evolving away from that target, which was a 2004 isolate from Vietnam.  The Qinghai version of H5N1 was spreading rapidly in Russia, Kazakhstan, and Mongolia, and further spread was anticipated.

However, an Indonesian strain has been selected as the next target. It is unlikely that a vaccine against an Indonesian isolate would offer significant protection for the Qinghai H5N1 strain of bird flu.

However, the specific examples an not publicly known.  No human sequences from Indonesia have been made public.  Similarly, no human isolates from China, Turkey, or Iran have been released to the public..  H5N1 is clearly evolving rapidly, suggesting several pandemic vaccines will be required because of the increasing number of genetically diverse strains that are causing fatal human infections.

In 2004 confirmed human cases were limited to Vietnam and Thailand and human isolates were closely related.  Therefore a single vaccine would offer similar protection for H5N1 in Vietnam and Thailand.

However, in 2005 human cases were reported for Cambodia, Indonesia, and China.  Although the Cambodian isolates were closely related to isolates from Vietnam and Thailand, Indonesian H5N1 isolates from poultry were distinct, as were isolates from poultry in China.  There is also evidence that the Indonesian human sequences are different than the poultry sequences, especially in the HA cleavage site.  Recent reports indicated that the cleavage site in a cat sequence from Indonesia matched the cleavage site in isolates from humans, but was distinct from the poultry isolates. 

These differences bare a striking similarity to PB2 E627K.  Prior to Qinghai Lake, all PB2 E627K isolates in H5N1 were in mammals.  In the field, they were in humans, wild and domestic cats.  At Qinghai Lake, all bird isolates did have E627K and all related sequences have had it since Qinghai Lake.

The same type of selection process may be happening in the HA cleavage site.  However, there are no human sequences available from Indonesia or China for compaision.

Although WHO and consultants maintain that these small changes are due to random mutation, the evidence for recombination is overwhelming.  The recent release of sequences from the 1970's and 80's clearly shows the movement of polymorphisms from North America to Asia via recombination. 

The database for H5N1 sequences and other serotypes should be greatly expanded to identity donor sequences.  The S227N sequence was generated via recombination with H9N2 donor sequences and the predicted G228S change also involves donor sequences from another serotype (H1N1 in European swine).

The existing database should be expanded with recent H5 isolates from Canada.  The serotypes included H5N1, H5N2, H5N3, H5N9.  These isolates will contain additional donor sequences for additional recombinations.  The recent H5N1 Qinghai related sequences from Europe, the Middle East, Africa, and southern Asia should also be made available immediately..  The sequence contain important donor sequences that fuel H5N1 recombination and evolution.  A more complete database of donor sequences will generate appropriate recombinant sequences for vaccine development.


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