Influenza viruses resistant to oseltamivir, news and updates

[Giuseppe]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

(1.1): Antiviral Res. 2008 Jul 5. [Epub ahead of print]

Adamantane resistance in influenza A(H1) viruses increased in 2007 in South East Asia but decreased in Australia and some other countries.

Barr IG, Deng YM, Iannello P, Hurt AC, Komadina N. - WHO Collaborating Centre for Reference and Research on Influenza, 45 Poplar Road, Parkville, Melbourne, Victoria 3052, Australia; Monash University Gippsland, Churchill, Victoria 3842, Australia.

The adamantanes (amantadine and rimantadine) were the initial antivirals licensed for use against influenza A viruses and have been used in some countries to control seasonal influenza and have also been stockpiled for potential pandemic use.

While high rates of resistance have been observed in recent years with A(H3) viruses, the rates of resistance with A(H1) viruses has varied widely.

In this study we analysed 281 human influenza A viruses isolated in 2007 that were referred to the WHO Collaborating Centre for Reference and Research in Melbourne, mainly from Australia and the surrounding regions, for evidence of resistance to adamantanes and a subset of these was examined for resistance to the neuraminidase inhibitors (NIs).

We found that the rates of adamantane resistance in A(H3) viruses continued to increase in most countries in 2007 but a distinct variation was seen with A(H1) resistance levels.

A(H1) viruses from Australia, New Zealand and Europe had low rates of resistance (2-9%) whereas viruses from a number of South East (SE) Asian countries had high rates of resistance (33-100%).

This difference can be attributed to the spread of A/Brisbane/59/2007-like viruses to many parts of the world with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses continue to predominate.

When these two A(H1) subgroups were compared for their in vitro sensitivity to the other class of influenza antiviral drugs, the neuraminidase inhibitors, no difference was seen between the groups with both showing normal levels of sensitivity to these drugs,
The finding of reducing A(H1) resistance rates in Australia and rising levels in SE Asia in 2007, reverses the trend seen in 2006 when A(H1) resistance levels were rising in Australia and elsewhere but remained low in most of SE Asia.

PMID: 18611414 [PubMed - as supplied by publisher]
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http://www.flutrackers.com/forum/showpost.php?p=168806&postcount=1
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[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

(1.1): Antiviral Res. 2008 Jul 5. [Epub ahead of print]


A(H1) viruses from Australia, New Zealand and Europe had low rates of resistance (2-9%) whereas viruses from a number of South East (SE) Asian countries had high rates of resistance (33-100%).

This difference can be attributed to the spread of A/Brisbane/59/2007-like viruses to many parts of the world with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses continue to predominate.

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http://www.flutrackers.com/forum/showpost.php?p=168806&postcount=1
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In the other phylograms, Brisbane/59 is 2B, while HK/2652 is 2C (Solomon Island is 2A).

In the US, 2C is also present this past season, but Hawaii has a newer version.

 

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> the spread of A/Brisbane/59/2007-like viruses to many parts of the world
> with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses
> continue to predominate.

that puts the published resistance rates in another light.
We should consider resistance-rates (H274Y) in Brisbane/59 alone
in order to track where / how it occurred / amplified !





---------edit1-------------

region
H1N1-samples
with H274Y

Africa       88   0 (00%)
NAmerica   1489 236 (16%)
LAmerica     20   3 (15%)
Europe     2896 724 (25%) 
Ozeania     186   3 (02%)
Hong Kong   581  68 (12%) 
Japan      1544  42 (03%) 
restEAsia   174   1 (01%)

 

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> the spread of A/Brisbane/59/2007-like viruses to many parts of the world
> with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses
> continue to predominate.

that puts the published resistance rates in another light.
We should consider resistance-rates (H274Y) in Brisbane/59 alone
in order to track where / how it occurred / amplified !

The japan phylogram had all three subclades labeled (2a, 2b, 2c).

 

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

INFORMATION FOR THE VACCINE AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
CBER, FDA FEBRUARY 21, 2008

The CDC's notes from this meeting, available on the web in pdf format, clearly shows a tree rooted in New Caledonia 99. See page 8 for the phylogram.

This is prototypical H1N1 strain used for 5 flu seasons for vaccines, chosen because it was a 'fast grower' and seasonal vaccine efficacy study had shown it to be semi-effective, 2003-2006.

"Fast growers' are
Good for pumping out many doses of vaccines.
Bad for fostering immune escapees in:

- infants/toddlers
- the elderly
- the immunocompromised

All three are veritable 'pathogen incubators' due to less than robust immune response, plus they silently excrete active virus for a LONG TIME after symptoms have ceased. All three are LIKELY to be hospitalized and therefore present strong potential for local spread of strains carrying antiviral resistance mutations. This propensity continues as they are also likely to be seen in clinics for followup, where they have plenty of opportunity to spread infection because they also have a tendency to express disease symptoms for an extended period of time due to secondary infections.

Note to Experts who are BAFFLED but also sit on key international public health recommendation committees (and hence, unwilling to point fingers):

Do NOT employ the same strain of 'fast grower' in large-scale public vaccine mixes for many years running, especially if the strain prototype has been aptly demonstrated to mutate for drug avoidance.

<b>Be VERY AWARE that your choice patient type for vaccination is the EPITOME of host type for viral escape for vaccines and antiviral drugs.</b>

 

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

INFORMATION FOR THE VACCINE AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
CBER, FDA FEBRUARY 21, 2008

The CDC's notes from this meeting, available on the web in pdf format, clearly shows a tree rooted in New Caledonia 99. See page 8 for the phylogram.

This is prototypical H1N1 strain used for 5 flu seasons for vaccines, chosen because it was a 'fast grower' and seasonal vaccine efficacy study had shown it to be semi-effective, 2003-2006.

"Fast growers' are
Good for pumping out many doses of vaccines.
Bad for fostering immune escapees in:

- infants/toddlers
- the elderly
- the immunocompromised

All three are veritable 'pathogen incubators' due to less than robust immune response, plus they silently excrete active virus for a LONG TIME after symptoms have ceased. All three are LIKELY to be hospitalized and therefore present strong potential for local spread of strains carrying antiviral resistance mutations. This propensity continues as they are also likely to be seen in clinics for followup, where they have plenty of opportunity to spread infection because they also have a tendency to express disease symptoms for an extended period of time due to secondary infections.

Note to Experts who are BAFFLED but also sit on key international public health recommendation committees (and hence, unwilling to point fingers):

Do NOT employ the same strain of 'fast grower' in large-scale public vaccine mixes for many years running, especially if the strain prototype has been aptly demonstrated to mutate for drug avoidance.

Be VERY AWARE that your choice patient type for vaccination is the EPITOME of host type for viral escape for vaccines and antiviral drugs.

Yes, the relationship between selection of the target and the technical nicities is not a good one. In 2002 it was clead that the Fujian strain should replace Panama. However, there were technical issues for getting Fujian to grow in eggs. It would grow after one passage in a mammalian cell, but grow in a mammalian cell was in the protocal and the FDA objected, so Panama was used again and many children needlessly died.

The choice of Solomon Island for the last season was a likely factor in the emergence of Brisbane in the past season, leading to an explosion of H274Y.

 

[miso]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Thanks for the warm welcome.

Referring back to the topic of this thread and the article that spawned it.
I'm a scientist (of the lowest order, a mere BSc.) and I think I see where the problem is. Firstly , let's call a spade a spade. The topic should have been TAMIFLU resistance baffles scientists. Secondly, I'm baffled that scientists are baffled; didn't they read the published studies that showed how Tamiflu worked and the simple mutations that would make it ineffective? That stuff wasn't hidden.

 

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Oh, I'm much more interested in the match of Spanish 'Flu herald wave outbreaks (pre-1918) and significant H1N1 tamiflu resistance late 2007-early 2008. Same countries. France, Norway, Germany, the UK and US.

Coincidence, right?

The supposedly mild first wave, Spring 1918, it was reported in the US (NYC, then elsewhere by early February). It wasn't mild everywhere.

What was it doing in Peking (Bejing) in March and Shanghai in April/May 1918?

1. I don't think we have the full picture of the 1918 pandemic yet.
2. It has strong bearing on the only strain to attain many of the same lethal phenotype (H5N1) characteristics, and the sudden acquisition of multiple key polymorphisms in a related, commonly circulating strain of human influenza.

Nothing to do with Tamiflu; everything to do with a change in cellular targets.

 

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Thanks for the warm welcome.

Referring back to the topic of this thread and the article that spawned it.
I'm a scientist (of the lowest order, a mere BSc.) and I think I see where the problem is. Firstly , let's call a spade a spade. The topic should have been TAMIFLU resistance baffles scientists. Secondly, I'm baffled that scientists are baffled; didn't they read the published studies that showed how Tamiflu worked and the simple mutations that would make it ineffective? That stuff wasn't hidden.

The baffled part relats to the sudden appearance and spread in countries not using Tamiflu, as well as the absence of at fitness penalty, which was widely touted when H274Y was first reported for H5N1. In addition the resistance is only in H1N1 - and virtually exclusively in the Brisbane (clade 2B) strain.

 

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Yeah, Brisbane is a VERY interesting place.

 

[Oracle]

More or less correct

More or less correct

Study uncovers cause of flu epidemics.
Mar 4, 2008
http://www.eurekalert.org/pub_releases/2008-03/ps-suc030408.php

The exchange of genetic material between two closely related strains of the influenza A virus may have caused the 1947 and 1951 human flu epidemics, according to biologists. The findings could help explain why some strains cause major pandemics and others lead to seasonal epidemics. Until now, it was believed that while reassortment ? when human influenza viruses swap genes with influenza viruses that infect birds ? causes severe pandemics, such as the ?Spanish? flu of 1918, the ?Asian? flu of 1957, and the ?Hong Kong? flu of 1968, while viral mutation leads to regular influenza epidemics. But it has been a mystery why there are sometimes very severe epidemics ? like the ones in 1947 and 1951 ? that look and act like pandemics, even though no human-bird viral reassortment event occurred.

?There was a total vaccine failure in 1947. Researchers initially thought there was a problem in manufacturing the vaccine, but they later realized that the virus had undergone a tremendous evolutionary change,? said Martha Nelson, lead author and a graduate student in Penn State?s Department of Biology. ?We now think that the 1947 virus did not just mutate a lot, but that this unusual virus was made through a reassortment event involving two human viruses.

?So we have found that the bipolar way of looking at influenza evolution is incorrect, and that reassortment can be an important driver of epidemic influenza as well as pandemic influenza,? said Nelson, whose team?s findings appear in the current issue of PLoS Pathogens. ?We have discovered that you can also have reassortment between viruses that are much more similar, that human viruses can reassort with each other and not just with bird viruses. ?

Nelson and her colleagues analyzed the evolutionary patterns in the H1N1 strain of the influenza A viruses by looking at 71 whole-genome sequences sampled between 1918 and 2006 and representing 17 different countries on five continents.

Using the genome data, the researchers constructed phylogenetic trees representing evolutionary relationships across all eight genome segments of the virus.

Big differences in the shapes of these eight trees signified that reassortment events had occurred.

The swapping of genes between two closely related strains of the influenza A virus through reassortment may also have caused the 1951 epidemic, which looked and acted in many ways like a pandemic as well. Deaths in the United Kingdom and Canada from this epidemic exceeded those from the 1957 and 1968 pandemics.

Currently, there are many types of influenza virus that circulate only in birds, which are natural viral reservoirs. Though the viruses do not seem to cause severe disease symptoms in birds, so far three of these viral types have infected humans ? H1N1, H2N2, and H3N2.

Understanding how each strain evolves over time is crucial. H3N2 is the dominant strain and evolves much more rapidly than H1N1. So the H1N1 component of each year?s flu vaccine has to be updated less often. In comparison, the H3N2 component of the vaccine has been changed four times over the past seven years.

?Last year the infections were dominated by H1N1 but we had no way of predicting it,? said Nelson. ?This year the vaccine failure is due to the H3N2 mismatch because researchers picked the wrong strain.?

The H1N1 virus is particularly unusual because it disappeared completely in 1957, only to mysteriously re-emerge in humans in 1977 in exactly the same form in which it had left. It is still not certain what happened to the virus during its disappearance. But since it did not evolve at all over these twenty years, ?the only plausible explanation is that it was some kind of a lab escape,? says Nelson, who is also affiliated with Penn State?s Center for Infectious Disease Dynamics (CIDD).

In recent decades, flu infections in the United States have been dominated by yet another reassorted viral strain known as H3N2. This strain caused the Hong Kong flu pandemic of 1968, which killed nearly a million people.

The Penn State researcher says the study shows that the evolution of a virus is not limited to the mutation of single lineage, and that there are multiple strains co-circulating and exchanging genetic material. The H1N1 and H3N2 strains, for instance, are occasionally generating hybrid H1N2 viruses.

?If we really want effective vaccines each year, our surveillance has to be much broader than simply looking at one lineage and its evolution, and trying to figure out how it is going to evolve by mutation,? said Nelson. ?You have to look at a much bigger picture.?

 

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

The PLOS paper is nonsense. The 1918 pandemic did NOT involve reassortment.

 

[AlaskaDenise]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

The H1N1 virus is particularly unusual because it disappeared completely in 1957, only to mysteriously re-emerge in humans in 1977 in exactly the same form in which it had left. It is still not certain what happened to the virus during its disappearance. But since it did not evolve at all over these twenty years, “the only plausible explanation is that it was some kind of a lab escape....

It was circulating in swine, poultry, & wild birds. See http://www.flutrackers.com/forum/showpost.php?p=45694&postcount=11
(from this thread: http://www.flutrackers.com/forum/showthread.php?t=12642&highlight=H1N1+1957+swine )

It may have not evolved because it wasn't working to evade a human immune system.

.

 

[tropical]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

By plain words: "we" did it (by vaccination).
Err. human est.

"The choice of Solomon Island for the last season was a likely factor in the emergence of Brisbane in the past season, leading to an explosion of H274Y."

Now, our actual "the best" antiviral bullet oselt. shield policy was crippled by ourself.

 

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

niman, the 2002/3 H3-vaccine in USA was an almost perfect match for the circulating strains.
The "Fujian flu" in USA 2003/4 is due to a surprising reassortment with a rare
HA which first showed in A/Wellington/3/19-05-2003.
So in 2002 or even in spring 2003 (when next season's vax is selected), they couldn't
foresee that the Fujian strain would dominate in the 2003/4 season.
With nowadays cell-based technology they might have succeeded to produce a
matching vaccine timely for Northern Hemisphere winter
http://en.wikipedia.org/wiki/Fujian_flu#A.2FFujian_.28H3N2.29
(you posted nonsense:
> In 2002 it was clead that the Fujian strain should replace Panama.
> However, there were technical issues for getting Fujian to grow in eggs. It would grow
> after one passage in a mammalian cell, but grow in a mammalian cell was in the protocal
> and the FDA objected, so Panama was used again and many children needlessly died.
)

AD, that was a different virus (comon origin before 1920), not related to the 1977 human H1N1.

tropical, that is highly hypothetical. Most people are not vaccinated and even vaccinated
people often get it, even when the vaccine is a good match.
New strains evolve also without "vaccine support". Early Brisbane/59 strains had no H274Y.

Hmm, if vaccine created Brisbane/59, then shouldn't it be able to wipe it out too ?
Maybe they should regularly and timely test whether resistence mutations are viable
in new strains ?!

 

[tropical]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

gsgs:
"that is highly hypothetical"
From the Dr. Niman text supposition, it seems not.
That supposition have some similarities with illnessed poultry flocks (Egipt, ...) supposedly (FT thread texts) resulted from mismatched or faulted previously injected vaccines.

"Maybe they should regularly and timely test whether resistence mutations are viable in new strains ?!
They should, but with their technic of 6-9 months procedure duration of seasonal vaccine production, the achieving result would be practicaly the same actual, probably.

 

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

it could become faster with cell-based vaccines.
But there is also the problem of exclusive publication
of results, which somehow(I don't really understand this)
often leads to a delay of years.

That the selection of Solomon as H1N1 vaccine did
significantly contribute to the dominance of Brisbane/59
-
is it reported/mentioned elsewhere ?

 

[tropical]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

it could become faster with cell-based vaccines.
But there is also the problem of exclusive publication
of results, which somehow(I don't really understand this)
often leads to a delay of years.

That the selection of Solomon as H1N1 vaccine did
significantly contribute to the dominance of Brisbane/59
-
is it reported/mentioned elsewhere ?

Maybe the "baffled" issue now becames more knowed.

Such research report does not be necessarily published yet.
If the above Dr. N. supposition is right, the collected lab material analised trails until now would pointed in that direction.

The problem of exclusive publication of results was seen at the time in the begining of AIDS spreading also.
The US researcher/founder versus French researcher/founder controversy, which leads to an important (1 year?) delay of a joint statement (naming of the virus/strain ...) and anti-viral countermeasure aknowledgements (if I well remember).

 

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

By plain words: "we" did it (by vaccination).
Err. human est.

"The choice of Solomon Island for the last season was a likely factor in the emergence of Brisbane in the past season, leading to an explosion of H274Y."

Now, our actual "the best" antiviral bullet oselt. shield policy was crippled by ourself.

By plain words: "we" did it AGAIN (by vaccination).
In the 2002/2003 season, it was clear that the H3N2 Fujian strain (Fujian/411/02) was becoming dominant, but because of technical reasons, Panama/2007/99 was used again in the vaccine for 2003/2004 leading to many unnecessary deaths due to Fujian infections.
This past season, there is no public evidence for H1N1 Solomon Island in the US (MMWR/CDC mis-characterizations not withstanding). The choice of Solomon Island/3 instead of Brisbane/59 allowed H274Y to expand globally.

 

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

niman, the 2002/3 H3-vaccine in USA was an almost perfect match for the circulating strains.
The "Fujian flu" in USA 2003/4 is due to a surprising reassortment with a rare
HA which first showed in A/Wellington/3/19-05-2003.
So in 2002 or even in spring 2003 (when next season's vax is selected), they couldn't
foresee that the Fujian strain would dominate in the 2003/4 season.
With nowadays cell-based technology they might have succeeded to produce a
matching vaccine timely for Northern Hemisphere winter
http://en.wikipedia.org/wiki/Fujian_flu#A.2FFujian_.28H3N2.29
(you posted nonsense:
> In 2002 it was clead that the Fujian strain should replace Panama.
> However, there were technical issues for getting Fujian to grow in eggs. It would grow
> after one passage in a mammalian cell, but grow in a mammalian cell was in the protocal
> and the FDA objected, so Panama was used again and many children needlessly died.
)

The Fujian story is WELL known. Fujian/411/2002 emerged at the beginning of the 2002/2003 season. The meeting notes of the vaccine selection committee from early 2003 is public. Peter Palesse was pushing for a switch from Panama/2007/99 to Fujian/411/02, but the virus would not grow in chicken eggs unless it was first passaged in mammalian cells (like the VERO cells used by Baxter in their pandemic vaccine). However, the FDA representtaive at the meeting objected to the passage through a mammalian cell because that wasn't in the approved protocol. Palesse argued that one passage wouldn't matter because the passage virus would then be grown in eggs and killed, so risk from one cell passage would be minimal. Industry reps argued that a technical failure in the growth of Fujian could jeapordize the entire vaccine for 2003/2004 season for the northen hemisphere, so Panama was used for 2003/2004 and the number of children deaths were so high that monitoring such deaths was subsequently incorporated into the influenza analysis.

This story is VERY well known and is useful when estimating how easy it would be to roll out a pandemic vaccine against an emerging influenza strain.