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H5N1 Expands Geographical Reach and Genetic Diversity in 2005

Recombinomics Commentary

December 31, 2005

In 2005 H5N1 dramatically expanded its geographical reach and genetic diversity.  In 2004 H5N1 exploded across eastern and southeastern Asia including reported human cases in Vietnam and Thailand.  In 2005 new outbreaks in Vietnam were reported in the north and south, but the case fatality rate in the north was markedly lower than the south and the size and frequency of familial clusters was increased.

In the south the case fatality rate approached 100% and spread into neighboring Cambodia.  The H5N1 in the north had acquired a new HA cleavage site that had been circulating in eastern China and Japan in 2004.  However, this new cleavage site was found on the genetic background classified as clade 1 of the Z genotype, although the cleavage site had previously been limited to clade 2, supporting a mechanism of genetic recombination.

In May, WHO considered raising the pandemic phase from 3 because of the larger familial clusters and evidence of genetic change, especially in the H5N1 from the north.  PCR and northern blot data indicated H5N1 was detected in a large number of serum samples, signaling more efficient human-to-human transmission.

At the same time H5N1 was discovered in long range migratory birds at Qinghai Lake.  Although the H5N1 identified was unique, many of the genetic markers form HPAI H5N1 in eastern Asia were present.  However polymorphisms from Europe were also found, signaling again that H5N1 was evolving via recombination.  Moreover, all of the isolates had the PB2 E627K polymorphism which had not previously been reported for avian H5N1 isolates.  The polymorphism was in all human isolates of serotype H1, H2, and H3.  This human polymorphism was associated with an increased ability to replicate at a mammalian body temperature and was also linked to increased virulence in mammals.

Transport and transmission of these novel sequences were confirmed by sequence data from H5N1 isolated near Chany Lake in Novoisibirsk, Russia.  This outbreak represented the first reported cases of HPAI H5N1 in Russia.  Similar outbreaks were then reported for the first time in neighboring Kazakshtan and Mongolia.

H5N1 was then reported for the first time in humans in Indonesia.  The human cases in Indonesia frequently formed familial clusters.  Increased efficiency of transmission was also identified in visitors to the Jakarta Zoo.  Although these cases were mild, the increased infections demonstrated that H5N1 could be transmitted by casual contact with H5N1 infect birds at the zoo.  Media reports indicated at least two versions of H5N1 were circulating in Indonesia.

This fall H5N1 migrated into Europe.  Outbreaks were reported for the first time Turkey, Romania, Croatia, European Russia, Ukraine, and the Volga Delta.  The HA cleavage site of these isolates were identical to the GERRRKKR identified at Qinghai Lake, Chany Lake, and Erhel Lake, providing additional evidence for transmission and transportation by long range migratory birds.

Similar transportation of H5N1 was reported in China as outbreaks were reported for northeastern and northwestern China.  The outbreaks were subsequently linked to human cases which were reported for the first time in China.  The reported human cases quickly expanded to six provinces in eastern China.  The origin of the most recent case remains a mystery, although widespread human-to-human transmission of H5N1 in Fujian Province has been suspected following the export of H5N1 from Fujian Province to Hong Kong visitors in 2003.

Increased genetic diversity has been signaled by novel HA cleavage sites in Mongolia and Hunan Province in China.  Moreover, the RERRRKKR cleavage site commonly found in eastern Asia has been detected on a wild bird genetic background in the Ukraine.

Most recently, four children with bird flu symptoms have been hospitalized in Turkey, where new H5N1 outbreaks have been reported.

In summary H5N1 has dramatically expanded its geographical range in 2005, setting the stage for a worldwide presence in 2006.  Recombination has dramatically increased the genetic complexity of H5N1 and the number of strains capable of causing human infections has also dramatically expanded in 2005.

The peak H5N1 season begins in early 2006 as do seasonal flu infections.  Recombination has increased the H5N1 gene pool and new sequences bring new challenges.  Increased human-to-human transmission efficiency is expected in 2006 as the looming H5N1 pandemic looms larger.


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