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Evolution and Spread of Fujian H5N1 In China
Recombinomics Commentary

November 3, 2006

The authors believe it is likely that the spread of this new sub-lineage represents a third wave of the H5N1 panzootic. The first wave occurred in early 2004, primarily in Southeast Asia. The second wave started with the outbreak in migratory waterfowls at Qinghai Lake in the spring of 2005 and spread to Europe and Africa. Now this FJ-like sub-lineage is replacing the previously predominant H5N1 strains throughout much of southern China.

“Unless the ministry tell us what's going on and shares viruses on a regular basis, we will be doing diagnostics on strains that are old." Delays in sharing also make it impossible for manufacturers to access the expected efficacy of vaccine candidates under development.

The above comments indicate a review of the history and status of the Fujian H5N1 in southern China is in order.  The strain is characterized by the novel HA cleavage site LRERRRK_R, which, relative to the most common HA cleavage site in Asia, QRERRRKKR, has changed Q to L and dropped a K.  The first isolate with the novel cleavage site, A/duck/Fujian/1734/2005(H5N1) was isolated in April 2005 and deposited at Genbank on June 16, 2005 in association the the July, 2005 publication in Nature.  Fujian spread in China was evident in the human sequences from China (A/Anhui/1/2005, A/Anhui/2/2005, A/Guangxi/1/2005), which were first deposited at Genbank on January 20, 2006.  All human isolates had the novel cleavage site.  Those deposits were also described in a January 6, 2006 report by the Chinese ministry of health. The report included addition human isolates, which all had the novel cleavage site.  Similarly, sequences from multiple poultry outbreaks were compared to the prototype isolate and most were over 98-99% homologous, indicating that the H5N1 in China in early 2006 was primarily the Fujian strain.

Additional sequences from Laos and Malaysia, deposited at Los Alamos in March 2006 also had the novel cleavage site as did wild bird isolates from Hong Kong deposited in June, 2006.  In August WHO came out with pandemic target recommendations, which included the Fujian strain, which was classified as Clade 2 sub-clade 3.

Thus, although the recent PNAS publication provided data on increasing frequency of detection of the Fujian strain in China, as well as the low antibody titers to the Fujian strain, the presence of the Fujian strain in China has not produced major changes in long range migratory birds carrying the Qinghai strain to Russia, Mongolia, India, Afghanistan, Europe, the Middle East or Africa.  Similarly, there has not been an impact on the Indonesian strain of H5N1 in Indonesia.

The sequences of the Fujian strain may impact these strains, but there has been no evidence of the Fujian strain replacing these endemic strains outside of eastern China or Southeast Asia.  However, these is evidence of exchange of genetic information via recombination,  The missing K in the Fujian cleavage site was first reported in H5N1 from a duck being smuggled from Fujian province to Taiwan.  This H5N1 was isolated in December of 2003 and the sequence of all eight gene segments was made public in January 2004.  It had many of the genetic features that were subsequently reported throughout eastern Asia in 2004, including human isolates in Vietnam and Thailand. 

The Fujian strain also has regions of identity found in 1997 isolates from northern China, which were made public last month by the Beijing Genome Institute, including the 20 amino acid deletion in NA,  Additional regions of identity are found in the Qinghai strain as well as the human isolates from Honk Kong patients who became infected while in Fujian province in 2003.  Other regions of identity are found in Indonesian isolates.  These regions of identity highlight the role of recombination in the generation of these strains, but the data do not indicate the Fujian strain is replacing either the Qinghai strain or the Indonesian strain.

Although the Qinghai strain was isolated in May, 2005 at Qinghai Lake in China, there are no reported isolates of the Qinghai strain in eastern China.  The Qinghai strain has a characteristic cleavage site of QGERRRKKR, which was detected in Jiangxi and Hubei provinces, but the Qinghai strain also has PB2 E627K,, which was not in the eastern China isolates.  However, virtually all of the H5N1 HPAI isolates to the west of China, as described above were the Qinghai strain.

Thus, the surveillance in eastern and southern China has not picked up the Qinghai strain until 2006, when the first and only isolate was deposited at Genbank in association with the PNAS publication.  It is closely related to the Qinghai isolates from Qinghai Lake, but the less common polymorphisms are found in east Asian H5N1 instead of the Qinghai isolates to the west.  Thus, there is no evidence that the Fujian strain is replacing the Qinghai strain in southern China because the Qinghai strain has only been detected once in eastern China, and that isolate was from 2006.

Similarly, there is no evidence of the Indonesian strain being replace by either the Qinghai or Fujian strain.  On Bali isolate had the Qinghai cleavage site on an Indonesian genetic background, but there have been no H5H1 isolates outside of southern China and southeast Asia that have had the Fujian cleavage site.

Thus, the Fujian strain may be replacing the H5N1 isolate like the 2003 prototype cleavage site lacking the K, or the original Guangdong goose cleavage site as was seen in the Qinghai strain (QGERRRKKR) or the Indonesian strain in humans (QRESRRKKR), but there is little data to support comments that the presence of the Fujian strain in China was withheld (although sequences have been withheld), or that the Fujian strain is replacing the Qinghai strain, which was recently reported in Russia / Mongolia (in and around Tuva), Afghanistan, and Egypt.  It is also likely that recent H5N1 outbreaks In Kalmayka. Crimea, and Sudan are also the Qinghai strain based on the positive reports this season from the locations west of China..

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