gsgs

hattip Tetano

Vopr Virusol. 2013 Jan-Feb;58(1):11-7.
[New cold-adapted donor strains for live influenza vaccine].
[Article in Russian] [No authors listed] Abstract

Cold-adapted (CA) strains A/Krasnodar/35 and B/Victoria/63 were isolated using passages
of A/Krasnodar/101/59 and B/Victoria/2/87 wild type strains at low temperatures.
The resulting CA strains possessed TS and CA phenotypes and had a reduced ability
to reproduce in mouse lungs and nasal turbinates. They displayed a high protective efficacy
in experiments on mice. The two CA strains reproduced well in chick embryos and MDCK
cell line without change of TS and CA markers. The CA A/Krasnodar/35 strain during passages
at low temperature acquired 13 mutations in the 6 internal genes, 8 of those mutations led to
amino acid changes. The CA B/Victoria/63 strain acquired 8 mutations in the internal genes,
6 of which led to amino acid changes. The intranasal vaccination of mice with the CA A/Krasnodar/35
strain led to a transitory suppression of various lymphocyte subpopulations, as well as to an increase
in the number of some other cell types. The CA strains in question may be used in the future as
attenuation donors for live influenza vaccines.

PMID: 23785755 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/23785755

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makes you wonder whether it's possible to use duck or chicken viruses
("warm adapted" to the temperature of 41C in birds)
and then cold-adapt them in the lab, so they transmit better in humans.
That would be much easier than the passaging in ferrets
as used in the debated Fouchier experiments

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so, I'm currently more concerned about one or multiple severe pandemics in the next decades
than I was in 2006.
And the reason is : influenza research.

Shame on me, that I didn't realize this risk earlier, I was even hoping on influenza research
to protect us from a naturally occurring pandemic.,

I somehow missed the discussion about the publishing of the 1918 virus, I had only
entered flublogia in Dec.2005.

Then in 2011 I didn't feel so concerned yet about the H5N1 research, yes, they made it
transmissible, but still less efficient and only in ferrets.

I knew, that they could implement single mutations in the lab into existing viruses
but wasn't really aware that they could "easily" create whole viruses just from the sequences alone.
(reverse genetics)

Now Wimmer et.al. are creating these viruses with hundreds of computed mutations,
some labs are checking all the 256 possible combinations of reassorting 2 strains.
Then they are passaging the viruses in cells and animals to improve them,
but are usually selfrestricting or not publishing this. (Fouchier: no, we are not
planning to increase the passages now...)

We've had 4 pandemics now that we can watch, where we have the sequences
and reconstruct how it emerged : 1957,1968,1977,2009 plus several new
introductions into swine or poultry, which may follow a similar mechanism.
Although we have the 1918 virus, that doesn't really count since we have no previous viruses,
we don't really know where it came from, how it emerged.

Now, If some advanced lab had all the flu-sequences that were available in 2008,
but nothing from 2009 or later and they didn't know about mexflu, and they had
lots of money and animals and humans or some good human imitations to test,
would they have found the mexflu virus with its pandemic potential ?

I think, yes. And in some decades we will probably be able to find such viruses with
pandemic potential.
How many viruses and reassortments would they have needed to test to find mexflu ?
More than 10 but less than 10000, probably less than 1000, IMO.

In 1957 or 1968 it should even have been easier to find these potentially pandemic viruses
in wild birds and the way how they might reassort with existing flu.
The diversity was lower then.
Just one new HA and PB1 from wild birds out of the pool of maybe some hundred circulating ones

And 1977 was almost trivial to predict, the strain existed already.

Now, all these pandemics were not so bad e.g. when compared with 1918,
but but from what we know from all the studies, manipulating the virulence
should be much easier than manipulating the transmissibility.
It's also easier and cheaper to test.

It should even be possible to introduce some mutations so to make existing seasonal
strains more virulent. Sounds easier to me than screating a new pandemic strain.
Ok, we have immunity to seasonal strains but this is somehow limited, it didn't prevent
new variants as in the Fujian 2002-2004 H3N2-semi pandemic.
And we could use old strains, H3N2 from the 80s, H1N1 from 1918 etc., or H2N2 from 1957
against which immunity is no longer so good.

I do not see how to really control this knowledge, how to prevent it from being used for evil purposes.
We can maybe delay it by secrecy and hope to be prepared, to have countermeasures
by this timely advantage of knowledge. But eventually presumably most labs and countries
will learn it and it will be cheap (less than a billion $, maybe only some millions) and commonly
known how to create pandemic flus.

It's a mystery with so many planets out there why we found no signs of intelligent life yet.
It had been speculated that intelligent life is doomed to fail, that it will destruct itself
eventually. This was the subject of many books during cold war and the authors
mainly thought about nuclear wars as the cause. But manmade diseases and accidental
lab-escapes should be a better candidate. It almost killed the American native population
and only recent measures and protection stopped that.
Then we had the plague in medieval Europe and other diseases which now are controlled
by vaccines and antivirals (for some reason this doesn't work so well for flu)

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and another "promising" method how to help creating pandemic viruses:

http://jvi.asm.org/content/87/13/7200.abstract
one major hurdle for avian viruses is their poor polymerase activity in human cells
overcome this by mutations in segments 1,2,3,5,8
broad spectrum of polymerase adaptive mutations can act collectively to overcome this defect

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it can't be so difficult now, with all that knowledge.
And maybe they already found some candidates but won't publish it,
after they "learned" in 2011 about the possible negative feedback
for their research from the press, the public and the regulators.
At that time there was discussion of measures among the researchers
how to better handle this in future, how to not alert the press.
(Who cares about the possible pandemic disasters ? Not their problem.
Only maybe useful to get attention and funding )

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"the [research-] system is broken"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557753/
(2006)
http://www.fiercebiotech.com/story/h...ken/2008-04-24

================================================== ====

I've been wondering why such research is nationalized, but then published and everyone benefits.
There must be some system in place which "rewards" the publishing and encourages the
national funding systems.

why not internationalize the research in the first place under the auspices of UNO,WHO ?

I think it boils down to the virologic details, the reassortment papers and such.
We need an independent expert discussion and risk assessment on that.
Unbiased (influenza) virologists who are willing to read the papers
and think about it. And I think programmers should also be involved
since it depends on estimating the mutation and reassortment
potential from the database analysis. This is not what virologists
are usually being taught. It's a pattern-recognition and process
optimizing thing, how to find "good" reassortment candidates
in the huge pool of virus genes. Of course, the labs must test
the candidates them and that's where we have the danger of lab-escapes.
How likely are those viruses with pandemic potential, how many are there,
when will we find them ? That's not what you can answer with classical virology.
And protein-folding simulation and (mice,ferrets,...) human transmission
simulation doesn't exist yet either.

And we need a plan, what we should do when such highly transmissible and virulent
viruses are being found in some country. (ok, that's political)

interesting, that you don't dispute the possibility / likelyhood of such weapons becoming available
but rather concentrate on the possible consequences ...

Would the USA attack Iraq,Syria,Iran,Lybia,El Qaida,... if they only suspected them of having or working
on such viruses ? Accidental bombing of the labs,instituions, storage places, transportation
containers might already release them and start the pandemic.

There you have your boomerang.

influenza scientists are biased, they are funded by NIH. They don't want their business to get
a bad image of potential abuse. NSABB members and debbaters had to rely on influenza scientists
because they didn't understand the complicated matter so well. (they revised their first decision)
http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/apr1312letter.html

Meanwhile we have H7N9, now H6N1, several new papers and methods to construct/manipulate
the viruses came out despite the moratorium.
It becomes clearer that virulence manipulation is easier than transmission manipulation.
still the debate and safety requirements was only about the old papers and H5N1.

It is not clear how this research can lead to better vaccines and antivirals, it mainly leads to
better prediction only.

History has no examples for bioterrorism yet, but then the technics,
i.e. inverse genetics, are rather new and the development speeds up only now.

Critics claim that the majority out of 200 non-influenza virologist were against these experiments,
but this is not independently verified.

http://www.scienceforums.net/topic/64418-blog-post-ajb-h5n1-and-the-ethos-of-research/?hl=nsabb

http://blogs.scienceforums.net/ajb/?p=1323

I think there is a big motivation to construct such pandemic viruses, not only for terrorists
but also for governments. And the "excuses" arguments are given to them by the defenders
of the research in this debate : they need to know how to defend against natural pandemics
or manmade pandemics created by someone else.
Now, who can control their biosafety ? Think of countries like China (already), Russia (who knows),
Israel,Syria,Iran,Pakistan,India (in some years (or decades ?)) secretly doing this research.

This debate only considered what is possible now and what biosafety is used
in those involved worldwide leading hightech labs.

And it's not just the information from those 2 papers. It's the whole process
with advances as quickly as in computer science.
We are learning how to create pandemic viruses with desired virulence.
It is foreseeable that we will succeed soon. Years or decades.
Then, how can this be controlled ? I don't see how. It will probably be cheap
and repeatable by hundreds of labs. The viruses can be traded and smuggled
easily. So our only chance would be vaccines,antivirals,NPIs and for that
we would need any time-advantage that we can get.
Before those pandemic viruses become available.

see also:

http://thisbluemarble.com/showthread.php?t=53122
http://www.flutrackers.com/forum/showthread.php?t=177126
http://www.flutrackers.com/forum/showthread.php?t=203696
http://www.urban75.net/forums/threads/man-made-influenza-pandemics.311894/
several blog posts at virology.vs and TWiV, e.g.:
http://www.virology.ws/2013/05/17/further-defense-of-the-chinese-h1n1-h5n1-study/

but no real internet discussion yet, with experts, about this important topic

I think gallstones don't react on pressing, they cause pain when

they obstruct the duct. Typically after eating fatty meals.

However, when the gallbladder is infected or sore you might feel it

with the finger pressing below the last right rib upwards

I just wanted to point out that I want to engage the experts,scientists,politicians.

And not just those of them who are envolved and have a possible bias.

I'm aware of all the other threats, but I've particularly followed the pandemic threat

since 2005 - http://www.setbb.com/fluwiki2/viewforum.php?f=10&mforum=fluwiki2

while (shame on me) the threat of manmade pandemics only

got my attention and research in 2011.

Currently I'm more concerned of this one, than the other threats.

youtube and general public attention reminds me a bit to those people often running around

in comics in public places with big "the end is near" signs.

I'd like educated people reading the papers, digging into the details and discussing the threat.

I'm missing this. The NSABB-discussion in 2012 was formalized, with general opinion papers

and meetings, no internet discussion, and many people were biased by profession.

It's also already outdated by the new papers and emerging viruses.

The moratorium ended, but nothing was achieved, no independent risk-assessment.

but rather see this just as some "project" of mine

there had been discussion in 2011-2012 about two papers about how to manipulate

the deadly H5N1-influenza virus so it could be transmitted from human to human,

maybe just like normal flu.

The USA NSABB first recommended to not publish the papers in full, but finally agreed

to publish them.

A "moratorium" followed, during which international researchers agreed to

not research this further.

This has ended earlier this year and research resumed.

There was an editorial in Nature

http://www.nature.com/news/h5n1-viral-engineering-dangers-will-not-go-away-1.12677

and a letter to Obama's bioethics commission signed by leading virologists.

http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/mar2913ethics.html

Another Chinese paper in this direction was published with mixed reactions.

http://crofsblogs.typepad.com/h5n1/2013/05/uk-appalling-irresponsibility-in-chinese-h5n1-experiments-senior-scientists.html

"gain of function" (GOF) research is apparently gaining in speed and we may be

close to understanding how these influenza pandemics occur, what mutations

and reassortments and species-jumping mechanisms trigger them.

That will help us to take countermeasures, but it may also enable evildoers

to create devastating pandemics or threaten with it.

And it bears the danger of these viruses escaping the labs unintentionally,

especially in low-security 3rd world countries.

I'm missing a public discussion about this, a risk assessment.

Most normal people aren't even aware of this danger.

what would be a good place to discuss this, to engage the experts into

public discussion and risk assessment ?

cats have other genes, other cells, other receptors...

until recently their were none cats with flu, now a few with H5N1 and H1N1.

Dogs can get horse-flu H3N8 (until ~2003?)

I've been downloading sequences from genbank and building

and analysing flu-databases. Anyone interested to share tasks,

exchange tools,data ?

I also downloaded all the 14 virus-files in Feb. , >300MB

I extracted and aligned 399 HIV-1 C and made a mutation picture

I'm currently extracting Dengue viruses

(I haven't done anything but flu until last week)