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H5N1 Confirmed On South Korean Farm
Recombinomics Commentary
November 25 2006

South Korea said on Saturday a poultry farm was hit by bird flu, saying it found the H5N1 strain of avian influenza in the country's first outbreak in three years of the virus that is potentially fatal for humans.

The agriculture ministry said earlier this week it suspected that a highly virulent strain of bird flu killed 6,000 chickens at a farm in the southwest part of the country that lies on a path for migratory birds.

"It is the H5N1 strain," the agriculture ministry official said by telephone of test results. It was too early to say whether the strain found at the farm was highly pathogenic, he added.

The virus' virulence could be known later on Saturday, he said.

The above confirmation of H5N1 in the southwest part of Korea leaves little doubt that it is highly pathogenic H5N1, which can easily be deduced by the rapid death of about 1/2 of the chicken population at the index farm.  This diagnosis can be confirmed by either sequencing HA cleavage site, or running a 10 day pathogenicity test, involving the infection of 10 experimental chickens with the virus.  However, since H5N1 generally kills all 10 choices in 1-2 days, the 10 day test can be ended as soon as all 10 chickens are dead.

The HA cleavage site sequences is more important, because it not only determines pathogenicity, but it also correlates well with the strain of H5N1, which is rapidly evolving in Asia.  The original HPAI H5N1 cleavage site in Asia was QRERRRKKR, which was first reported for a 1996 goose in Guangdong.  That is the sequence of the Clade 1 human H5N1 described in 2004 in Vietnam and Thailand.  However, H5N1 has evolved into multiple versions of H5N1, and these versions can be approximated by simply looking at the cleavage site.

In humans, the three Clade 2 sub-clades are easily distinguished by the HA cleavage site and each defines a strain that has been selected as a vaccine target by The WHO. Sub-clade 1 is the human Indonesian strain, which has a cleavages site of QRESRRKKR. Sub-clade 2 is Qinghai strain, which has the cleavage site of QGERRRKKR.  Sub-clade 3 is the Fujian strain in China, which has the cleavage site of LRERRRK_R. 

The sub-clades represent the human cases reported to date from Indonesia, China, and all human cases west of China.  The have many H5N1 variations on these themes, but the reported human cases targeted by pandemic vaccines targeting isolates with the four major HA cleavage sites described above.

The recent PNAS paper on the spread of the Fujian strain in southern China included comments indicating that the Fujian strain may represent a 3rd wave of H5N1.  However, the only data supporting such a conclusion was the failure to report more than one Qinghai isolate in the 2005 and 2006 isolates collected primarily from feces of birds in live markets in southeastern China. 

However, the Qinghai strain is widespread in wild birds and has been detected in over 700 samples of H5N1 in Europe.  It is the only HPAI strain reported for Europe, the Middle East, or Africa.  To date there has been only one Qinghai isolate reported for eastern Asia, so the failure to detect the Qinghai strain in southern China says more about the surveillance and ability of the Qinghai strain to displace endemic strains in China and southeast Asian, than the persistence of the Qinghai strain in other countries, including wild birds which can migrate to South Korea.

The H5N1 isolated at Qinghai Lake in China in 2005 had regions of identity with H5N1 from Shantou in Guangdong Province, as well as South Korea/Japan isolates from 2003/2004.  Therefore, it is likely that a new H5N1 outbreak in South Korea, particularly at this time of the year, will be the Qinghai strain, although the cleavage site of the only public sequence from South Korea, A/duck/Korea/EAS1/03, is QREKR_KKR may have generated a recombinant cleavage site, such as the reported bird HA cleavage site in the Sudan, which is a recombinant between Qinghai QGERRRKKR, and tree sparrow QREGRRKKR cleavage site sequences, to give QGEGRRKKR. 

Thus, the key question for the South Korea isolate is the HA cleavage site, which will not only confirm that it is HPAI, but will also provide the first clue on its relations ton the various H5N1 strains in the area, which can be used to trace origins.

The tracing of the origin is clearer when full sequences on all eight gene segments is released, which should be completed in a matter of days after the H5N1 is isolated.

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