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Fujian H5 Media Myth On Human Risk
Recombinomics Commentary
April 23, 2015 14:45

"H5N2 along with H5N8 and H5N1 viruses do pose a risk to poultry and the poultry sector in all states now," Dr. Nancy Cox, an influenza expert who not too long ago retired from the Centers for Disease Manage and Prevention, mentioned by way of email. "Though there have not been any human instances triggered by the introduction of these viruses into the U.S. by wild migratory birds, it is possible that there will be an isolated human case or two as time passes and more humans come in close make contact with infected birds.

"One thing experts agree on is that this particular virus is not a threat to people. Two other strains of avian influenza — H5N1 and H7N9 — can infect people.

The above comments (in red) from an April 5 media report acknowledge the potential of all three Fujian H5 serotypes in North America (H5N1, H5N2, and H5N8), which are clade, to cause human cases because the Fujian clade (2.3) has been killing humans (as H5N1) since 2005, when it was identified in Fujian Province in China.

This potential has been known because the biological and pathological characteristics of influenza are largely driven by the H, which is also used to name the clade (or strain). 

H5N1 concerns began in to increase in late 2003 when children in northern Vietnam were dying.  They were influenza A positive but were not infected with season flu.  H5N1 was identified and it quickly spread throughout eastern Asia.  In 2005 there were four major clades / sub-clades (clade 1 in southeast Asia, clade 2.1 in Indonesia, clade 2.2 in wild birds at Qinghai Lake, clade 2.3 in southern China, which was initially identified in Fujian Province).  By the end of 2005 all four of these strains had infected humans.

As the clades evolve, they are further divided with additional numerical extensions.  The two major Fujian sub-clades were 2.3.2 which was found in wild birds in eastern China, and clade 2.3.4 causing the human cases in China in 2005. 

Clade 2.3.2 was most commonly found in wild birds which were identified in and around Hong Kong at the beginning of a calendar year.  However, in the spring of 2008 it had migrated to South Korea where is caused a major poultry outbreak.  The military was used to cull the infected farms and one soldier (culler) developed severe flu symptoms and was hospitalized.  He was H5 PCR confirmed, signaling infection with clade 2.3.2.  However, South Korea could not confirm the N1, so the case was not reported, in part because in 2008 all current and prior human cases were 2.3.4, so South Korea claimed that the only Fujian sub-clade that could infect humans was 2.3.4.  The following year the first human clade 2.3.2 case was confirmed in China.

Fujian clade 2.3.4 continued to evolve, which gave rise to clades,,, and  All four of these sub-clades have caused human cases, but prior to 2014 all human Fujian clade 2.3.4 cases were H5N1.  However, in 2008 Fujian 2.3.4 began to swap the N gene to produce a number for Fujian clade 2.3.4 serotypes, including H5N6 and H5N8. 

In 2014 the first human H5N6 case was confirmed (in Sichuan Province) followed by cases in late 2014 (Guangdong Province) and early 2015 (Yunnan Province).  All three human cases were clade, the same subclade as the H5N8 that caused a major poultry outbreak in South Korea in early 2014.

The H5N8 in South Korea in early 2014 gave rise to the H5N8 that spread to Europe in late 2014, as well as North America, although the North American version was most closely related to a crane isolate from Japan identified in late 2014.  The H5N8 in North America swapped out three of the Asian flu genes for low path North American wild bird flu genes to produce H5N2, and an independent event swapped out 4 Asian flu genes to produce H5N1.  However, all three versions in North America had the Fujian clade H5, so all were high path for poultry and were capable of infecting humans as Fujian H5 has done since 2005.

The effect of the Fujian H5 is easily seen in poultry, where high pathogenicity correlates with a polybasic cleavage which allows the virus to attack multiple organs in poultry leading to rapid death.  This pathogenicity can be quantified experimentally by a pathogenicity test.  Ten experimental chickens are infected and monitored for 10 days.  Each chicken gets a score from 0 (no evidence of disease) to 3 (dead) for each day.  The lowest score of 0 would be given if all 10 chickens remained symptom free for all 10 days, while the highest score of 3.0 would be obtained if all 10 chickens died within 24 hours.

When Fujian H5N2 cause the outbreak in Fraser Valley in December, 2014, Canada did a pathogenicity test on initial isolates and obtained a score of 2.96 to 2.98, well above the 1.2 threshold for a high path designation, and close to the highest possible score, showing that the presence of the three wild bird low path gene segments, including N2, had little impact of the pathological effect of H5N2 on the experimental chickens.  Similarly, the test on the H5N2 from the first confirmation in Ontario produced a score of 2.97.

Additional indications on the ability of the Fujian H5N8 or derivatives to infect humans comes from receptor binding domain studies, which showed that the H5N8 from the 2014 outbreak in South Korea could bind to mammalian (gal 2,6) receptors.  Moreover, antibodies to H5 were found in dogs in South Korea in early 2014 and more recently H5 was PCR confirmed in dogs in South Korea confirming the ability of the avian H5N8 to jump to mammals.

These mammalian indicators may be linked to the loss of the glycosylation site at position 158 (H3 numbering).  In H5N1 gain of function studies, modified H5N1 was passaged in ferrets to identify H5 changes linked to the ability to transmit ferret to ferret via aerosol.  Two such studies using clade 1 or clade 2.1 found that abolition of the position 158 glycosylation site (via N158D in clade 1 or T160A in clade 2.1) was the first adaptation for air borne transmission. 

The Fujian H5 in the H5N8 in South Korea as well as all three serotypes in North America have T160A, signaling mammalian adaptation.

Thus, human cases due to the H5N8, H5N2, and H5N1 in North America are expected, as quoted above in red.  However, in the CDC USDA presser, human transmission was cited as low, and media reports such as the above quote (in blue) suggested that human cases were unlikely. 

However, as the number of outbreaks increase, the number of human exposures and strain on safe culling increases, leading to an increase in the likelihood of human cases, CDC assurances or media interpretations notwithstanding. 

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