Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as human vaccines

[Giuseppe Michieli]

From World Health Organization (http://www.who.int/entity/csr/diseas...te20080214.pdf)
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[HenryN]

http://www.who.int/csr/disease/avian...te20080214.pdf

Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as human vaccines
February 2008

[Aeolus]

Is a recommendation this specific normal or are they showing their hand?

[HenryN]

Originally Posted by Aeolus

Is a recommendation this specific normal or are they showing their hand?

They are showing a losing hand. H5N1 in Egypt has the vaccine selectors beat by a long shot.

[AlaskaDenise]

Are the recommendations be based partly on unpublished sequences?

.

[HenryN]

Originally Posted by AlaskaDenise

Are the recommendations be based partly on unpublished sequences?

.

No, the sequences are published, but the selection is significantly lagging. I will be doing a series of commentaries.

[HenryN]

Commentary

http://www.recombinomics.com/News/03...cine_2008.html

[AlaskaDenise]

Originally Posted by niman

Commentary

http://www.recombinomics.com/News/03...cine_2008.html

Commentary

H5N1 Evolution Outpaces Pandemic Vaccine Selection

Recombinomics Commentary 03:58
March 4, 2008

WHO has published its latest update on “Antigenic and genetic characteristics of H5N1 virus and candidate vaccine viruses developed for potential use as human vaccines." Although it is dated February, 2008, it is already clearly out of date. H5N1 is rapidly evolving as evidenced by 8 vaccine targets already approved (in red in the phylogenetic tree in Figure 1 on page 5), the four targets developed and waiting approval (in blue) and the three selected for development (in green). The tree in this year's report is more complex than the tree from a year and a half ago.

However, in the rapidly evolving clade 2.2 which was been reported in approximately 50 countries west of China, the selections are significantly lagging H5N1 evolution. The approved isolates are from 2005 and include one of the original Qinghai isolates from China in the spring of 2005, an isolate from Mongolia in the summer of 2005, and an isolate from Turkey in the fall of 2005. These three were followed by an isolate from India in the winter of 2006, which is awaiting approval. Although Europe reported little activity in late 2006, early 2007, clade 2.2 was rapidly evolving in Egypt as well as at Uvs Lake in Mongolia in the summer of 2006.

These new and improved versions of H5N1 were easily seen a year ago at the beginning of 2007. The Uvs Lake version appeared in Kuwait in February 2007. Although it was clade 2.2.3, like the Indian isolate, it had evolved markedly, as represented on the tree by isolates from Kuwait and Krasnodar. This evolved version of clade 2.2.3 has now spread throughout Europe, as seen in the recently released sequences from the Czech Republic, Germany, Romania, Saudi Arabia, and Ukraine (as well as reported but unpublished isolates from England, Poland and northeastern Germany). All of these have significantly evolved away from the Indian isolate awaiting approval.

Similarly, the evolution in Egypt has been extensive. Consequently, the tree has five 2007 isolates from Egypt, representing three major branches. One of these five has been selected for vaccine development. The selected isolate is from a mild case in Aswan that had the Mongolian cleavage site. However, the diversity in Egypt a year ago is under-represented on the tree. There are no isolates representing the Gharbiya cluster, which has two receptor binding domain changes, including M230I, which was only detected in fatal cases. Similarly, other sequences from a year ago, including other Gharbiya sequences are also not represented in the published tree.

Thus, the current report has not kept pace with samples collected a year ago. The recent samples from Egypt are significantly more evolved than the sequences represented in the published tree or the early 2007 sequences not represented.

The evolution of H5N1 in India and Bangladesh is not public, and may represent significant additional heterogeneity.

The phylogenetic tree in the latest report is clearly dated, and the vaccine targets are lagging further because of production and approval issues.

H5N1 obviously knows how to evolve more rapidly than the WHO vaccine selection committee.


.

[AlaskaDenise]

....targets are lagging further because of production and approval issues.

What is that timeline? What should it be to keep pace with viral changes?

.

[tropical]

"The phylogenetic tree in the latest report is clearly dated, and the vaccine targets are lagging further because of production and approval issues.
H5N1 obviously knows how to evolve more rapidly than the WHO vaccine selection committee."

The same slow process used for seasonal flu vaccine selection, probably.

[Giuseppe Michieli]

The complete PDF text (with tables) is already posted in this forum at http://www.flutrackers.com/forum/sho...80&postcount=1 -


This link is no longer good. I have merged the threads. Fla1

[HenryN]

Originally Posted by AlaskaDenise

What is that timeline? What should it be to keep pace with viral changes?

.

There is no reason to take a year to identify key sequences. H5N1 evolution involving wild birds and recombination is quite predictable.

[HenryN]

Commentary

http://www.recombinomics.com/News/03...e_Qinghai.html

[Niko]

Originally Posted by niman

Commentary

http://www.recombinomics.com/News/03...e_Qinghai.html

Commentary

H5N1 Pandemic Vaccine Selection Trails Clade 2.2 ChangesRecombinomics Commentary 13:27
March 7, 2008

The recently released human vaccine target selections by the WHO, raise concern over timely identification of targets. H5N1 is rapidly evolving and clade 2.2 is rapidly spreading. The spread of the Uvs Lake strain of clade 2.2.3 has been most glaring, yet this strain was not targeted in the February, 2008 update. The strain has spread throughout Europe and is in the Middle East. Movement into south Asia is unclear, because sequences have not been released. However, earlier sequences were clade 2.2.3, so the spread of the Uvs Lake strain to that region is certainly possible. In addition to the lack of targeting of the Uvs Lake strain, the explosion in diversity in Egypt is under-representation. In Egypt human cases have been reported in each of the last three seasons, moving Egypt to the number one position in confirmed human H5N1 cases outside of southeastern Asia.

As seen in the phylogenetic tree in Figure 1 of the report, the Uvs Lake strain, as represented by isolates from Kuwait and Krasnodar has evolved away from the 2006 clade 2.2.3 isolate from India, which has been selected as a target sequence. The evolutionary movement has been noted for some time, and the spread throughout Europe was emerging in the summer of 2007. The emergence and evolution of the strain was evident in wild bird sequences from the massive outbreak at Uvs Lake in northern Mongolia in the summer of 2006. H5N1 was isolated from a whooper swan and golden eye in Mongolia along with isolates from a duck and grebes in adjacent Tyva in southern Siberia. The sequences were 2.2.3, but were distinct from 2.2.3 isolates from Europe earlier in the year.

As seen in the recently released sequences from the 2006 outbreak in south Korea, the Uvs Lake strain migrated southeast to south Korea near the end of 2006. The sequences also migrated to southwest to Kuwait in early 2007, raising the possibility that it also migrated due south into south Asia.

Although the strain was not reported in Europe in late 2006 or early 2007, it appeared in the Czech Republic in the summer of 2007, as confirmed by the recently released sequences. However, movement into Europe was also indicated by the outbreaks in Germany over the summer. Early reports from FLI indicated the sequences in Germany were most closely related to the published wild bird sequences from Uvs Lake. The German wild bird outbreaks were followed by outbreaks in France, which were also characterized as being closely related to the Uvs Lake of Kuwait sequences. Thus, in the summer of 2007 it was becoming increasingly apparent that Uvs Lake H5N1 was widespread in wild bird populations and was spreading across Europe, displacing early clade 2.2.1 and 2.2.2 strains identified in 2006.

Public confirmation of the spread was provided by sequences from Krasnodar, which were released shortly after the September outbreak. This was followed by release of sequences from Germany, as well as sequences from Romania, which were released shortly after the fall outbreak there. More recent sequences from Saudi Arabia and Ukraine confirm the spread of the Uvs Lake strain in Europe and the Middle East, yet there is no representation in the vaccine targets selected in the recent WHO report.

Similarly, the broad diversity of sequences is under represented in the tree and selection of new targets. In early 2006, clade 2.2.1 sequences were detected in Egypt. These sequences were closely related to sequences in Israel, Gaza, and Djibouti. The sequences from the 2006/2007 had the same regional markers, but were markedly more complex due to acquisition of new polymorphisms. These new polymorphisms trace back to early clade 2.2 isolates, including an over representation of polymorphisms in Germany. This diversity is represented in part by the five Egyptian sequences on the tree. However, the initial cases in the 2006/2007 season were fatal and mapped to additional branches which are not represented on the tree in Figure 1. All patients with M230I died, yet the isolates with M230I are not represented in the tree. Included in the fatal cases with M230I were the three family members designated as the Gharbiya cluster. These patients had another receptor binding domain change, V223I, which is also not represented.

The diversity in Egypt may have contributed to the vaccine failure in some flocks. H5N1 from these isolates is also not represented. These isolates had a large number of non synonymous changes, and were geographically diverse, but primarily in northern Egypt. Similarly, a large number of isolates with M230I and V223I were also detected in the current season. Thus, this season H5N1 is more diverse and unlikely to be well represented by the target sequence from Egypt, which is from a mild case that was genetically distinct from the sequences in northern Egypt. The added diversity in Egypt, coupled with more aggressive human cases will create new challenges for effective human vaccines, which is being exacerbated by vaccine failures and growing diversity in Egypt.

Media Links

[kent nickell]

A few things I found interesting in this document (Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as human vaccines February 2008) ... especially in light of the recent swan in Japan showing 2.3.2 and 2.3.4 characteristics...

""Clade 2.3.4 viruses have been responsible for human infections in China, Lao People's Democratic Republic, Myanmar and Viet Nam.""

Vaccine development for 2.3.4 includes A/Anhui/1/2005 (CDC), A/Japanese white-eye/Hong Kong/1038/2006 (SJ/NIAID), A/duck/Laos/3295/2006 (FDA) and for 2.3.2 A/Common Magpie/Hong Kong/5052/2007 (SJ/NIAID)

As Dr. Niman has pointed out the virus in the swan in Japan appears to have significantly changed from these isolates....

Also of interest is a collaboration between CDC and NIV (National Institute of Virology, India) for a 2.2 A/Chicken/India/NIV 33487/2006

[HenryN]

Originally Posted by AlaskaDenise

Are the recommendations be based partly on unpublished sequences?

.

The sequence of the clade 2.3.2 target has not been released

http://www.recombinomics.com/News/05...orrection.html

[HenryN]

Originally Posted by AlaskaDenise

Are the recommendations be based partly on unpublished sequences?

.

There are more withheld sequences in the WHO list than I initially realized.

[HenryN]

Commentary

http://www.recombinomics.com/News/05...Hong_Kong.html

[JJackson]

Is it just me...

I feel sub Clade 2.3 seems to be more prominent/active/getting more ink/etc. than it used to. Is it becoming more of a threat or is it the Indonesia political problems just leave us without 2.1 data?
2.2 exploded after Qinghai and obviously is big in terms of territory but was its perceived prominence just due to the fact it was heading west and became seen as more 'our problem' so got more than its fair share of (predominantly western) attention. I always thought of China as the real 'home' of flus and have been suspicious of extended periods of silence as being poor surveillance or poor reporting.

[HenryN]

Originally Posted by JJackson

Is it just me...

I feel sub Clade 2.3 seems to be more prominent/active/getting more ink/etc. than it used to. Is it becoming more of a threat or is it the Indonesia political problems just leave us without 2.1 data?
2.2 exploded after Qinghai and obviously is big in terms of territory but was its perceived prominence just due to the fact it was heading west and became seen as more 'our problem' so got more than its fair share of (predominantly western) attention. I always thought of China as the real 'home' of flus and have been suspicious of extended periods of silence as being poor surveillance or poor reporting.

Its movement into long range migratory birds in Japan (and Korea) has put it on the front page (and lack of data from China doesn't say much since it is an Olympic year)..

[JJackson]

Thanks.
Do you think there is one section of the tree that is, genetically, significantly more active with high rates of recombination/reassortment compared to others and if so do these active points shift?
We use the H & N to name the serotypes but across the full 8 strands are there areas in the world with very rich diversity (high potential for radical changes with recombination) compared to others (that was my assumption behind the China = 'home' of flus comment)?

[gsgs]

reassortment between different serotypes only seems to happen
in China. Once the viruses leave China, there is only some
"fine-tuning"

[HenryN]

Originally Posted by gsgs

reassortment between different serotypes only seems to happen
in China. Once the viruses leave China, there is only some
"fine-tuning"

Please cite reference for the above statement.

[HenryN]

Originally Posted by JJackson

Thanks.
Do you think there is one section of the tree that is, genetically, significantly more active with high rates of recombination/reassortment compared to others and if so do these active points shift?
We use the H & N to name the serotypes but across the full 8 strands are there areas in the world with very rich diversity (high potential for radical changes with recombination) compared to others (that was my assumption behind the China = 'home' of flus comment)?

Each tree is for a single gene segment and has nothing to do with reassortment. The length of a branch reflects number of changes.

[gsgs]

genbank.

give a counter-example !



for H5N1 we have reassortments with H6N1,H9N2 in China 2004
(paper mentioned earlier can't find the URL so quickly)

but no such reassortment outside China

when we count 4 strains outside China (Qinghai,Indo,Vietnam,
Fujian) then we should count 10-20 strains inside China
with same distance between strains/clades


See also the recent papers about human flu
(Holmes et.al full genome, Smith et.al HA)


new strains and pandemics form in SE-Asia

[HenryN]

Originally Posted by gsgs

reassortment between different serotypes only seems to happen
in China. Once the viruses leave China, there is only some
"fine-tuning"

The only reported human / bird reassortant (H7N2 and H3N2) was in New York.

[HenryN]

Comemntary

http://www.recombinomics.com/News/05...Migration.html

[gsgs]

OK.
http://www.recombinomics.com/News/04..._Concerns.html

but just only one isolate, it didn't spread. Dead end.

In China evolution and creation of new strains happen.
For H5N1 and human flu.

For other avian serotypes also outside China.
Reassortment and evolution in Canadian
mallards etc.

For birds however Eurasian and American strains
don't mix.

[HenryN]

Originally Posted by gsgs

OK.
http://www.recombinomics.com/News/04..._Concerns.html

but just only one isolate, it didn't spread. Dead end.

In China evolution and creation of new strains happen.
For H5N1 and human flu.

For other avian serotypes also outside China.
Reassortment and evolution in Canadian
mallards etc.

For birds however Eurasian and American strains
don't mix.

Detection of H7N2 in humans is VERY poor. In 2003 the H7N7 appeared to spread to 1000's based on H7 antibody, but the vast majority of those cases was NOT detected by PCR.

[HenryN]

Commentary

http://www.recombinomics.com/News/02..._Concerns.html