On the future of flu vaccine and anti-viral usage

[Giuseppe]

Re: On the future of flu vaccine and anti-viral usage

I feel outraged by this wave of denialism.

I was tracking this stuff for years, spending time and money to run blogs, to contribute for free to forums, ProMed, and other more or less known web spaces, only to stop at this joint and see all things wasted and lost away after the publication of a (controversial) review.

What was the matter of my engagement after all? To play the game of Pharma Cos? As I can read in the media, the answer is YES, YOU DID!

[JJackson]

Re: On the future of flu vaccine and anti-viral usage

Giuseppe I am sure you are wrong about our efforts being a waste.

The MSM are commercial entities who will always slant/sensationalise their articles, and especially the headlines, to push sales. The 3.5 million hits this site got last month are a measure of the number of people willing to make the effort to look for information beyond the headlines and hype. Considering the fairly esoteric nature of the site's subject matter I think that is laudable.

As to the Cochrane analysis I do not think the point of the review was to encourage cuts. They are not political in that way they preform rigorous analysis of data and let the chips fall where they may. The timing of the report was almost exclusively based on when they eventually got the data, it should have been done years ago. The data showed what I expected it to show and was very much in line with all the other data and observation studies I have seen.

I would like to clarify the very last sentence of my last post which, on rereading, was not very clear.

In addition to which a truly novel flu, without either an H or N from a seasonal strain, would be wholly reliant on an innate immune response with no adaptive component which would probably greatly outweigh NI effect.

It occurs to me the "greatly outweigh the NI effect" could be taken to mean I was advocating not using NAIs when I think pre and post exposure prophylaxis is where NAIs are most effective. What I was thinking when I wrote it was about the action of the NAIs.
At a the cell level NAIs can not prevent infection what they do is bind to a pocket on the head of the NA and prevent it from performing its primary function, which is to cleave any HA to host cell bonds that are made to the infected cell that it just budded from, and now needs to escape from, in its search for a new target. It is unrealistic to expect every one of the NA spikes on each of the tens of thousands of released virions to have its NA blocked so some will find new host cells. What it will do is slow the rate of exponential spread and greatly increase the chance that the immune system can get the upper hand. The later treatment starts the more cells are already releasing virions ergo the more NAs for the NAI to find and block and the more chance that some virions make a clean getaway.

Considering the case of an infection with a novel flu the NA NAI battle is exactly as before the problem is in this case the immune response is less effective due to the chance that none of the 5 primary antigenic sites on the HA and 4(?) on NA will have any pre existing antibodies. With an H or N from any seasonal flu at least some of these sites will illicit a reaction from anyone who has previously had flu.
My comment was based on the likelihood that this depressed immune reaction was likely to sufficiently dampen the NAIs good works in slowing the infection and so increase the chance of transmission.

re. gsgs's list.
It shows what you would expect, that NAIs are very good for prophylaxis or when used early but become progressively less effective as they have more and more NAs to mop up, this does not make them useless just progressively less effective.

[Giuseppe]

Re: On the future of flu vaccine and anti-viral usage

Last night, a conversation erupted again on Twitter about Cochrane Review. Among the Others, the renowned researcher Jeremy Farrar said that:

Helen Branswell @HelenBranswell
.@JeremyFarrar

Do you think the Cochrane review's take on whether NAIs - this isn't just about Tamiflu - are useful is the full picture?

Jeremy Farrar @JeremyFarrar
@HelenBranswell

Useful but not yet whole story.RCTs have not yet asked all the right questions & we need to use all the evidence

...

[gsgs]

Re: On the future of flu vaccine and anti-viral usage

not just to prevent them from leaving the cell
also to prevent them from penetrating the mucus

http://www.virology.ws/2014/01/08/cutting-through-mucus-with-the-influenza-virus-neuraminidase/

hmm, didn't we discuss this and wasn't it jjackson and wasn't
there a problem that I forgot and can't find now

[gsgs]

Re: On the future of flu vaccine and anti-viral usage

but I wonder how much the "useless" conclusion, the formulation
is influenced by the previous trouble.

once people make a statement, choose a position in the debate,
they become less likely to deliver arguments that are against it,

[JJackson]

Re: On the future of flu vaccine and anti-viral usage

not just to prevent them from leaving the cell
also to prevent them from penetrating the mucus
http://www.virology.ws/2014/01/08/cu...neuraminidase/

hmm, didn't we discuss this and wasn't it jjackson and wasn't
there a problem that I forgot and can't find now

This may be what you are referring to, if so you have a good memory as it was 4 years ago. Link to the post from which this was part of the comments.

JJackson ? 4 years ago If I understand correctly the Neuraminidase prunes sialic acid residues from glycoproteins. This is useful in allowing a clean get away after budding and also to stop binding of virions to each other. How does the virus prevent its NAs from removing the residues it needs to bind onto the glycocaylx before fusion? Wouldn?t its NAs be freeing it as fast as it could bind?
Reply

profvrr Mod JJackson ? 4 years ago Always an interesting question. The idea is that during entry, the HA
binds and the particle enters before the slower-acting NA can remove
the sialic acid. This idea has some support from the HA assay;
initially virions bind red blood cells but after approximately 30
minutes the NA cleaves off sialic acid and reverses the HA. See
http://www.virology.ws/2009/05....


JJackson profvrr ? 4 years ago Thanks but that then begs the question why when a new virion is budded does it not immediately bind and restart the fusion process before the NAs cut it free. On both occasions you have a virion adjacent to cell what is the difference why is there a net benefit to having NA cleaving sialic resisdues? There obviously is one or neuraminidase inhibitors would not work. I saw this http://www.ncbi.nlm.nih.gov/pu... and assumed it was due to nuraminidase having an inhibitory effect on cell infection although that effect was significantly outweighed by the benefits when budding


profvrr Mod JJackson ? 4 years ago The NA protein is inserted into the plasma membrane before the virion
buds from the surface. Its presence may lead to removal of sialic
acids, which would prevent re-binding of the newly synthesized
particle. In theory at least; there are no data that directly answer
your question. The results in the paper you cite are consistent with
the idea that NA has some inhibitory effect during infection as would
be expected. Clearly there are significant differences between
infection and budding that are not fully understood.

Re. the mucus
Yes you are right the sialic acid residues in the mucus are going to imped the virions progress to the cell but there is no particular time constraint in that the NAs can keep cleaving the bonds until the HA binding site finds a residue on a cell and start endocytosis (assuming the delay did not put it in the path of a macrophage). The presence of NAIs would inactivate some of the NAs and slow its progress further. The situation at budding would be slightly different in that a failure to make a quick escape would leave the virus open to either being dragged back into the dying cell or being destroyed by the white blood cells which would have been attracted by the cytokines released during its forming cell's apoptosis.

[JJackson]

Re: On the future of flu vaccine and anti-viral usage

but I wonder how much the "useless" conclusion, the formulation
is influenced by the previous trouble.

once people make a statement, choose a position in the debate,
they become less likely to deliver arguments that are against it,

Pissing off Cochrane by delaying release for the better part of 3 years can not have helped Roche's cause but Cochrane's rational is explained here

The final section states

Mechanism of action for beneficial effects
These findings all suggest that the low immune response with low levels of pro-inflammatory cytokines, which is induced by the action of oseltamivir carboxylate, may reduce the symptoms of influenza unrelated to an inhibition of influenza virus replication. The potential hypothermic or antipyretic effect of oseltamivir as a central nervous system depressant may also contribute to the apparent reduction of host symptoms. Statements made on the capacity of oseltamivir to interrupt viral transmission and reduce complications are not supported by any data we have been able to access.
The mechanism of action proposed by the producers (influenza virus-specific) does not fit the clinical evidence which suggests a multi-system and central action.

[Giuseppe]

Re: On the future of flu vaccine and anti-viral usage

It would be more honest to say that oseltamivir may have an immuno-modulatory effect, similar at a certain extent to ribavirin for other viral infections, with the actual mechanism not well understood.

Oseltamivir has been suggested - in fact - as combination therapy for measles encephalitis, as well.

As said by J. Farrar - see above - NAIs are useful and RCTs had not ask all right questions so far.

Some other drugs have not a completely understood mechanism of action, for example the widely used anti-depressants and anti-psychotic drugs (though essential to treat condition such as major depression, schizophrenia, parkinsonism, etc.), as well as statins, non-steroidal anti-inflammatory compounds.

We need a Comprehensive re-evaluation of the medical countermeasures for influenza and other viral emerging diseases since current treatment regimes are not enough to protect populations from viral pandemics.

Throw away neuraminidase inhibitors may be not wise at this point.

From another point of view, over-reliance on NAIs may have slowed the progression of other compounds clinical trials (for example the protease inhibitor Favipiravir), because the almost complete monopoly in the market by oseltamivir/zanamivir manufacturers.

gm

[JJackson]

Re: On the future of flu vaccine and anti-viral usage

Did Farrar say what questions he would like them to address?

[Giuseppe]

Re: On the future of flu vaccine and anti-viral usage

Did Farrar say what questions he would like them to address?

I haven't see a clear response. He was cautious, but seems to refer to severe hospitalized 2009 H1N1 pandemic patients.

[JJackson]

Re: On the future of flu vaccine and anti-viral usage

I suspect he was also thinking about H5N1 as he is with the Oxford Uni. unit in Vietnam and works on emerging infectious diseases. I know they were using a 10 day Tamiflu course at one stage for H5N1 patients. There was a WHO organised conference a few years back gathering together clinicians who were treating H5N1 patients with a view to discussing their various treatment regimes so as to come away with a 'best practice' recommendation. I can not find a list of participants now but suspect he was one of them.

[gsgs]

Re: On the future of flu vaccine and anti-viral usage

not what I had in mind ...
only some relevant human places have mucous, or it is thinner or
it only works for some subtypes or whatever.

The time limit is the immune system, so a delay is useful - it's a race

maybe we should just eat or inhale sialic acid as antiviral
to enhance the receptor-mucus

-----------------------------------------------
rememberance maybe slowly comes back ... wasn't it, that in the mucous it only worked
with alpha 2-3 receptors ?

-----------------------------

http://jvi.asm.org/content/78/22/12665.abstract

(2004) oseltamivir affected the earliest stages of infection preceding virus replication.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842836/

(2013)

The distribution of terminal Sias in α2-6 and in α2-3 linkages varies along the respiratory tract,
and changes with age and developmental stage [19,23].

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169242/