china

Recombinomics Commentary 16:45
January 23, 2012

"A man died in southern China on Sunday from the H5N1 bird flu virus, the Health Ministry reported. It was China’s second such death in less than a month.

On Sunday, Chinese censors generally blocked Internet users from reading reports of the latest death."

The above comments describe censorship of news on the H5N1 case (39M) from Guiyang, Guizhou who had no reported contact with poultry, suggesting that the case would be linked to clade 2.3.2.1 as seen in the recent case from Shenzhen, who also had no reported contact with poultry.  The sequences from the Shenzhen case, A/Guangdong-Shenzhen/1/2011, were released less than a week after collection, and the HA sequence had a number of receptor binding domain changes.  The two changes reported in the Gharbia cluster, V223I and M230I, were present, as expected.  However, the sequence also had S227R as well asQ196K, raising concerns that the combination of changes could be approaching the five changes reported in the paper censored by Science. 

That paper described five changes on two genes and four of the five changes have already been found in published sequences.  One of those changes is PB1 E627K, which was not in the Shenzhen clade 2.3.2.1, but was present in the most recent H5N1 sequence from cases in Cambodia, where all 8 of the cases in 2011 have died, as has the only case in 2012.  That case also had S227N, which is likely to be one of the HA changes in the aerosol version of H5N1 that transmits in ferrets.

The co-circulation of the above changes raises concerns that new combinations may be generated by recombination, leading to enhanced transmission, which may or may not match the changes described in the censored paper at Science.

It is unclear if the censorship of news on the most recent case will impact release of sequences from the Guizhou case.  Similarly, Indonesia quickly released sequences from the Bali cluster, which also had receptor binding domain changes.  That cluster was followed by a cluster from North Jakarta. And sequences from that cluster have not been released, raising concerns that the censorship of the papers and nature and Science will have a chilling effect on transparency and lead to more hidden sequences, as it becomes increasingly clear that H5N1 currently in circulation is very close to efficient transmission.

The natural versions pose a far greater hazard than some unnamed rogue state or terrorist who are said to benefit from the release of the five changes describe in the Science paper.  Since it is already known that 4 of 5 changes are already in circulation in a published sequence, the creation of a transmissible H5N1 is a trivial task, although the value of such bioweapon is far from clear, since influenza cannot be controlled, and effects on rogue nations would be significant.

Thus, the censorship by Nature and Science continues to endanger the world’s health, and the lack of understanding of influenza evolution by the NSABB is glaring.  Therefore replacement of the current board with one more knowledgeable about influenza evolution should be actively pursued.

Recombinomics Commentary 16:30
January 4, 2012

" In order to investigate the escape process and to enable predictions of escape, we serially passaged influenza A H5N1 virus in vitro 100 times under immune pressure. The generated escape viruses were characterized phenotypically and in detail by full genome deep sequencing. Mutations already found in natural isolates were detected, evidencing the in vivo relevance of the in vitro induced amino acid substitutions".
 
The above comments are from an upcoming publication, “Highly Pathogenic Avian Influenza Subtype H5N1 escaping neutralization: more than HA variation” which describe the identification of escape mutants which are present as a minor species in the original sample.  P198S was identified in a swan clade 2.2 (Qinghai strain) isolate from Germany, A/cygnus cygnus/Germany/R65/2006, using this approach, and it was also in a clade 2.2 swan isolate from Russia, A/Cygnus olor/Caspian Sea/2006, confirming it was in circulation in clade 2.2 in Europe in 2006.

P198S was in the recently released sequence from the fatal case in Shenzhen, China, A/Guangdong-Shenzhen/1/2011, which had a large number of HA changes, including the adjacent change Q196K, which is in clade 2.2 isolates in Egypt, Germany, and Kuwait (see list here).

The Shenzhen sequence is clade 2.3.2.1 (Fujian strain) also has another receptor binding domain change, S227R, but was generated via novel coding that was distinct from S227R in clade 2.3.2.1 in Hokkaido and Fukushima.  The coding found in the Shenzhen sequence is found in H5 sequences from wild birds.

H5N1 is frequently found in wild birds in Hong Kong at this time of year, due to migration patterns.  In 2008  clade 2.3.2 was found Japan, South Korea, and Primorsky (southeastern Russia) in poultry and wild birds, which create expansion concerns.  Clade 2.3.2 was subsequently identified in Mongolia, followed by Romania, matching the wild bird path that brought clade 2.2 to Europe, the Middle east, and Africa.

The movement of clade 2.3 into the clade 2.2 flyway created an environment for co-infections and recombination, leading to the acquisition of clade 2.2 polymorphisms in poultry and wild birds in Europe, the Middle East, and Africa.

These interactions lead to rapid evolution as seen in the large number of HA changes in the fatal case in Shenzhen, China.

Recombinomics Commentary 21:20
January 1, 2012 CDC experts found that the patients infected with the virus is 2.3.2.1 sublines highly pathogenic avian influenza virus to humans is highly pathogenic…..

the results show that virus is adamantane class of drugs are more sensitive but resistance to Tamiflu, the role of drugs still under study
 
The above translation indicates the H5N1 from the fatal case In Shenzhen, China is clade 2.3.2.1, which is common in wild birds.  Between December and February, Hong Kong typically finds clade 2.3.2.1 in wild birds.  A clade 2.3.2.1 case was identified in Hubei last year, and WHO has selected that isolate, A/Hubei/1/2010 as a pandemic vaccine target.  Last November an H5N1 case was also identified in Hong Kong, A/Hong Kong/6841/2010).  Both isolates are in the phylogenetic tree in figure 3 in the WHO vaccine update.  As seen in the top 100 matches for the Hubei isolate (here) or the Hong Kong isolate (here), wild bird isolate are closely related, although the Hong Kong isolate is closer to sequences from Laos.

Both of the human isolates from 2010 had receptor binding domain changes V223I, D225G, M230I, which are common in wild bird sequences in eastern Asia, and were also in the Gharbya cluster in Egypt in 2006.

The 2010 cases in China were wild type at positions 274 (275) and 294 in NA and therefore susceptible to Tamiflu (oseltamivir).

Although the translation suggests the latest case is wild type at HA positions 226 and 228, but changes at positions 223, 225, and 230 raise concerns that more efficient transmission can be achieved by changes at additional positions. 

Release of the sequences from the Shenzhen cases, as well as those that led to airborne transmission in ferrets would be useful.

A man in southern China died of bird flu on Saturday, a week after being admitted to hospital, although he apparently had not been in contact with poultry. It has been the country’s first deadly case in more than a year, state media reported.

AP - A Chinese bus driver who tested positive for the H5N1 bird flu virus died Saturday in a city bordering Hong Kong, health officials said, in the country’s first reported case of the disease in humans in 18 months.

The man surnamed Chen died in the wealthy southern city of Shenzhen, provincial health officials said. Shenzhen is separated by a small river from Hong Kong, where thousands of birds have been slaughtered after two were confirmed to have the virus last week.

During the month prior to his fever, Chen, 39, apparently had no direct contact with poultry and did not travel out of Shenzhen, a metropolis of 10 million people.

H5N1 rarely infects humans and usually only those who come into close contact with diseased poultry. But among those infected, nearly 60 percent die, and scientists are closely watching the virus for any signs it is becoming more easily transmissible from human to human.

Chen developed a fever on Dec. 21 and was hospitalized on Dec. 25, city and provincial authorities said in a statement. Health Ministry experts confirmed on Saturday that he was infected with H5N1, the provincial health department said.

The Guangdong health department also said 120 people who had close contact with Chen have not developed any abnormal symptoms.

The Ministry of Health has informed the World Health Organization about the case, local authorities said.

WHO says globally there have been 336 human deaths from 573 confirmed bird flu cases since 2003. Of these, 40 cases were in China, 26 of which were fatal.

Chen’s death comes a week after two dead birds tested positive for the virus in Hong Kong.

More than 19,000 birds at a Hong Kong market were slaughtered and imports and sales of live poultry were banned for three weeks after a chicken carcass tested positive for H5N1. Lab tests later confirmed that an Oriental magpie robin found dead on Dec. 17 was also infected.

China’s last reported human case of H5N1 was in June 2010. A pregnant 22-year-old woman from central Hubei province died after being exposed to sick and dead poultry.

http://www.france24.com/en/20111231-bird-flu-kills-china-H5N1-health-poultry

Recombinomics Commentary 22:45
December 30, 2011  A CHP spokesman said the patient was a 39-year-old man living in Shenzhen. He developed symptoms on December 21 and was admitted to a hospital on December 25 because of severe pneumonia. He is now in critical condition. The man had no travel history or contact with poultry before the onset of symptoms.

The above comments describe a confirmed H5N1 case in critical condition in Shenzhen, which is in Guangdong province and adjacent to Hong Kong and Fujian Province.  The absence of poultry contact heightens concerns on human transmission which can be most effective addressed by the sequences of the H5N1.

Sequence data has been of note lately because of recent experiments which achieved airborne transmission through the introduction of five changes in two genes as well as selection via passage in ferrets.  Publication of this critical information is long overdue.

The timing of this controversy with the above case and location is of note.  The first cases of H5N1 in humans were in Hong Kong in 1997, and one of the key pieces of information centered on the role of PB2 E627K, which has been researched by one of the labs that generated airborne H5N1, which almost certainly involves PB2 E627K as one of the changes.

Hong Kong was also the center of two additional outbreaks.  One began in Guangdong province in late 2002 and then spread internationally from the Metropole Hotel in Hong Kong by an infected physician who had treated Guangdong cases and came to Hong Kong for a wedding.  He infected those on the 9th floor when he vomited outside his room (911) and guest and visitors to the ninth floor the spread the mystery virus to Hong Kong, Singapore, Hanoi, and Toronto.  An international team of investigators identified the SARS coronovirus as the etiological agent and published sequences at their websites, which led to the rapid development of diagnostic test to monitor the spread.

In early 2003 there was a smaller by instructive cluster of H5N1 in a Hong Kong fanily who travel to Fujian province.  The daughter died in China, while the father and sone returned to Hong Kong where H5N1 was isolated from each.  The father also died but the son survived and both sets of sequences were identical and had the HA receptor binding domain change S227N, which is aother likely change leading to enhanced transmission.  Other adjacent changes are already circulating in clade 2.3.2 in the area.  These changes, V223I and M230I are also of concern, as are changes at positions 226 and 228, all of which are well known and are additional candidate, as are changes flanking positiin190.  These changes are also well known and studied by the labs who achieved the efficient transmission in ferrets.

On a somewhat related note, the movie Contagion also involved an infectious agent that jumped species in Guangdong province and the isolates were stored in liquid nitrogen adjacent to SARS CoV and H1N1pdm09, which are well know pathogens which have been sequenced thousands of times.

Thus, the release of the sequences from the above patient, as well as key changes associated with airborne H5N1 should be released or published immediately.