This is a continuation of the discussion here
This is to re-visit some of the previous discussions on receptor specificity, what we know and what we don’t know.
I’m just going to add a small but important piece of the puzzle, from studies of different strains of the 1918 virus in this paper A Single Amino Acid Substitution in 1918 Influenza Virus Hemagglutinin Changes Receptor Binding Specificity
“we show that the hemagglutinin (HA) of the virus that caused the 1918 influenza pandemic has strain-specific differences in its receptor binding specificity. The A/South Carolina/1/18 HA preferentially binds the 2,6 sialic acid (human) cellular receptor, whereas the A/New York/1/18 HA, which differs by only one amino acid, binds both the 2,6 and the 2,3 sialic acid (avian) cellular receptors.”
The South Carolina strain had specificity almost exclusively for the human 2,6 receptors, while the New York strain has more 2,3 than 2,6 specificity. Half the 1918 strains were like the first, the other half like the second. But the important point that is not obvious from reading the title etc is this: there is no difference in clinical presentation, pathophysiology, or mortality of the cases from these 2 very different patterns of receptor binding specificity.
So what does that mean? The obvious one is that receptor binding is not a simple on-off/either-or situation. Also, there may some complex relationship and possibly as yet undetermined host-virus interactions which affect the expression of such specificities.
annon 22. Thanks. All that time they were concentrating on these receptors and now the final nail in the coffin…they really don’t matter to the phenotypic expression of the virus.
It only goes to show that there are a lot of so called experts who pronounce with great confidence…and only later we find out that the ‘school of thought’ actually knows very little about influenza in the first place but for some reason is not willing to admit it.
Once again, it is re-inforced to me that we are in big trouble with this virus!!
Or, in other words, what we don’t know could fill a graveyard the size of Missouri or conversely leave us all breathless in wonderment as this grim reaper (H5N1) passes us by.
Unfortunately, the data, timing, and momentum speak to the former.
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Tom DVM – at 23:13
You’re right, although I wouldn’t quite put it like that.
With this virus, I get seriously worried when some expert expresses great confidence on the virology. Or, worse, when they express great confidence that we’re going to be fine.
Not that we’re NOT going to be fine. I have just as much problem with compulsively apocalyptic types.
The problem is too serious and the potential consequences too dire for us to not treat this whole subject with the utmost care and respect and precision.
Medical Maven – at 23:25 “Or, in other words, what we don’t know could fill a graveyard the size of Missouri or conversely leave us all breathless in wonderment as this grim reaper (H5N1) passes us by.”
Agreed!
“Unfortunately, the data, timing, and momentum speak to the former.”
Or the data, timing, and momentum require us to assume that it may be the former and act accordingly.
Anon_22 at 23:06 June 21, happy to see you have revisited this matter of receptor binding, your thoughts line up with research released in 2004 that while indeed 2,6 receptors are present on human trachea nonciliated cells, but that we also carry 2,3 receptors on the ciliated cells.
There is another recent article that details the role of the “other genes” (not HA or NA) in infectivity. In particular they found the presence of a multi-basic cleavage site is not the only determinant of infectivity. I hope to post brief reviews of a couple recent articles surrounding this subject matter over the weekend. The projects both involved mammalian experiments (not cell cultures). I’m not sure however which might be the best thread to post at.
I wonder if the mutation found in the 10 yr old and his father from Sumatra displayed one of these “lesser” genes in the sequence that can contribute to H2H, but hasn’t been identified as a “major player” yet.
beehiver,
You can post it here if it is related and we’ll discuss it. And if it seems to fit better elsewhere, we can always split the thread, but I like linking related thoughts and threads.
S227N is in another human H5N1 isolate from Turkey, suggesting these changes are NOT random mutations happening in selected individuals. Two of the 4 human HA sequences from Turkey have the change.
why NOT ? It could have happened in the first selected individual by random mutation who then gave it to the second selected individual
S227N was not found in the sister of the index case. It was in the index case and probably his cousin. The other negative may have been another sibling of the index case.
the 227N didn’t jump from one person to the other by infection ?
anon_22 at 18:25, after writing up a review of an article, it seemed like it didn’t fit on this thread very well. I have opened a new thread here, called Studies about mechanisms of virulence. This article addresses mutations that showed up in an H3N2 human influenza virus once it was passaged through mice, resulting in much higher virulence.
This paper was recently published in Nature. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors
This is a similar study to the paper published last year by Stevens et al, discussed in part 1 of this thread, which also contains various bits of dummies guide to receptor binding. :-)
Essentially, what both these groups of authors did, was to use a technique that measures what kind of receptors that the haemagglutinin from a particular virus binds to. Generally, we would say that avian viruses tend to bind to alpha 2,3-linked receptors, while human viruses bind to 2,6 receptors.
What this present study used, was a whole bunch of HA from different H5N1 isolates. However, what may be controversial (and I emphasize the word may, since I’m still uncertain whether I’m right), is that 2 out of the 3 HA’s that showed some preference to 2,6 binding, (VN/3028IIcl3, and VN/30408cl7) were from human samples that showed a mixture of different HA’s, and these different HA’s were extracted by cloning in MDCK cells.
I wonder if someone can tell me whether cloning in MDCK cultures before sequence analysis would make the results unreliable.
Anyway, let’s just assume they are reliable for the moment. They then analysed the HA’s and compared them to VN1194, a human isolate previously sequenced and known to be exactly the same as an avian sequence. This gave them a number of different mutations. They then introduced these mutations into the reference HA VN1194, to see if any of these mutations would change its receptor binding preference from 2,3 to 2,6.
For VN/3028IIcl3, the mutations were Q192R and S223N. Introduction of Q192R alone, but not S223N alone, to VN1194 increased binding to 2,6 receptors, while introduction of both increased that binding even further.
For Thai/KAN, the changes were G139R and N182K. Introduction of either one into VN1194 increased 2,6 receptor binding, and an additional increase in binding was shown when both mutations were present.
For VN/30408cl7, the mutations were E75K,S123P,N193K,R167K(HA2). While N193K enhanced binding slightly, none of the others had any effect when introduced alone. Introduction of 2 of these produced varying degrees of increased binding, and 3 mutations enhanced that even further.
So what does this mean? Probaby that there are multiple ways to achieve receptor binding change, and that sometimes, but not always, these effects are additive. Beyond that, we are not very sure. Remember these are all in vitro assays, so far there hasn’t been any good animal model that we can use for receptor binding studies of this type. This means we do not know whether these laboratory tests actually co-relate with increased transmission or virulence.
They do, however, give us a sense of some of the molecular requirements that may be important for host switching. Whether these requirements are sufficient is something that we don’t know about.
Secondly, according to Taubenberger in last week’s videocast, Great Teachers - Influenza: Past Pandemics and Future Threats, it isn’t enough that we discover whether the virus binds to 2,3 or 2,6-linked terminal dissacharides (the sugars at the end of the receptor molecule) but that it appears that the internal sugar structure is also important. That is, 2 viruses that both bind to 2,6-linked terminals may nevertheless be binding to different receptors with different internal sugars. These different types of 2,6 receptors may have different distribution along the respiratory tract, so that these individual binding specificities may have additional significance beyond just whether the virus binds to ‘avian’ 2,3 or ‘human’ 2,6 receptors. He suggested as something to consider whether such receptor distribution might change with age. We may also speculate whether that could account for differences in severity of illness, for example.
I put the words ‘avian’ and ‘human’ in quotes because Taubenberger also says that both these types of receptors can be found in varying degrees in the epithelial cells of all species.
Now, I’m not saying these changes are not significant. Certainly the fact that some of them have been found in patients in Azerbaijan (2) and Iraq (1) is cause for concern.
However, given that this paper and the 2005 one together gave a number of different mutations that appear to affect the binding affinity, one might think that what this shows it that there are multiple ways for the virus to achieve that kind of affinity. Beyond that, I don’t knkow if we can say to any degree of accuracy what each individual mutation means with regards to pandemic potential.
The authors of the current study suggests in the last sentence “Thus, such residues might provide useful molecular markers in assessments of H5N1 field isolates for their capacity to replicate in humans—an essential indicator of pandemic potential.” One of the authors, Suzuki, presented some of this data in June in Paris, and he was advocating the use of glycan assay as screening test for pandemic potential of the virus.
Personally, I don’t know that we have enough information to know what exactly we are screening for. I think they should do a lot more of these studies, to delineate all the different mutations etc, and study the significance a lot more. Rushing into using this as screening aka something that you are going to depend on to make important decisions, maybe, is IMHO a little premature, and may lead us to false sense of security if these ‘tests’ are negative.
But then I could be wrong. Any input from someone with more knowledge or info is welcome.
Makes sense to me
Thursday, 16 November 2006, 00:49 GMT
BBC Clues to pandemic bird flu found
Many are worried H5N1 will mutate and pass from human-to-human
Scientists believe they have identified some of the key steps needed for avian flu to develop into the deadly pandemic strain of the disease. An international team says it has found two genetic mutations that would need to occur to the H5N1 virus for it to potentially spread to humans. Writing in the journal Nature, the scientists said the findings would help them to detect pandemics strains.
A22-
MDCK passage is truer for human host viral strains.
A22-
Many paths to the pandemic strain are possible as are multiple pandemic strains to begin the process.
You’re right . . . we DON’T know the individual nucleotides and their functions, much less the combinations. Our best studies only move us toward a shorter list of items to surveil. The eventual PF51 may look nothing like what we are postulating.
NS1 – at 23:30
MDCK passage is truer for human host viral strains.
So does that mean its ok, this particular paper?
I didn’t read it yet? Are they looking at avian hosts for the strains or human hosts?
If they are investigating polymorphisms likely in human hosts, then using the Darby kidney cells is the soundest experimental design.
human, for the test strains.
I’m more interested in Niman’s work in the past 48 hours. Very much more interested.
I’ve been able to confirm a significant portion of his findings.
NS1 – at 23:45 wrote:
I’m more interested in Niman’s work in the past 48 hours. Very much more interested.
He may have some commentary shortly.
Updated:2006–11–16 10:38:05 MYT
e.sinchew-i.com
“She broke down three times in tears during a live radio programme in 2003 at the height of the SARS epidemic in Hong Kong which took 299 lives. Her poignant outburst of emotion over the death toll is etched in many memories, particularly because it jarred with her tough image.
Dr Margaret Chan, who is nicknamed “Iron Lady” despite her soft-spoken demeanour, had shown steely resolve when dealing with the SARS disaster.
Now confirmed as head of the World Health Organisation (WHO), the 59-year-old has come a long way since she was confronted with the avian flu outbreak in 1997 and then SARS—both economy-crippling catastrophes—as Hong Kong’s director of health.
These events showed her competence as a health official.
But a majority of the Hong Kong public at those times saw her gritty performance as more show than substance and criticised her for some poor judgments.
In 1997, Dr Chan was accused of misleading the public when she famously said “I eat chicken every day, so do not worry” after bird flu took its first human casualty. Five deaths were to follow. Three years ago, a Legislative Council report slammed her for “inadequate” handling of the SARS outbreak, with a huge loss of life as a consequence.
Perhaps having had enough of the brickbats, she retired in 2003 after 25 years in government to join the WHO as a department director.”
Burundi,
Niman produced the commentary earlier today in two parts.
The other thing I forgot to point out in my 23:15 post is that the 3 strains that showed some alpha 2,6 binding are all Clade 1 viruses, that were responsible for outbreaks in 2004 and early 05. Human cases since then are from clade 2 viruses.
Although they have found those mutations in Clade 2 human isolates from Azerbaijan and Iraq, my sense is the more we find different mutations for receptor binding, the less we will know what exactly the requirements are for host switching, even just from the point of view of receptor binding.
For example, why do some strains exhibit one mutation and other strains exhibit other mutations to achieve what we assume (probably incorrectly) to be the same purpose, aka binding to ‘human’ receptors?
Also, remember again that these are in vitro tests. We don’t really know whether those strains that show increased binding to 2,6 terminals were clinically consistently more virulent or more transmissible.
For example, if, let’s say, that some of these mutations are consistently found in strains that cause more human cases or more clusters, or more virulent either in animal studies or in human cases, then that would give us more information about the significance of the mutation. In that sense, the Stevens paper, summarized in part 1 of this thread, did a better job cos they used a particularly virulent strain for the study.
The moral of this part of the story is that we cannot draw conclusions solely based on molecular findings, we need to have correlation with epidemiological data.
IMO it would be a good idea to use this kind of tests to survey a larger number of samples from different clades, to see if there is any consistency between the molecular findings and the actual behavior of a particular virus in humans.
Note that survey is not the same as screening. The first is collecting information for analysis to see if there is an pattern that can be used; the latter is when you already know what finding means what and you are using those findings to test new samples to discover those strains that might have higher pandemic potential. We should do more of the first. We don’t have enough data or correlation between molecular and clinical findings to use as basis for screening tests.
As far as pandemic potential is concerned, it is likely that the requirements include a complex set or combinations of mutations, most likely involving the internal genes as well. No one knows what combination we are looking for.
We need more research; or faster research…
anon_22 – at 11:32: We need more research; or faster research…
But I don’t think we have time. Do you think we have time?
Niman’s commentary today gives me the distinct effect of watching a runaway train that is about to crash. We can see it happening, we can discuss what track it is on and its velocity, but what can we do about it from our front row seat?
From Niman - (Commentary 11/16/06 http://tinyurl.com/yhcmso):
The co-circulation of N186K, Q196R, S227N, and M230I in Qinghai strains which also have PB2 E627K remains a cause for concern, as WHO continues to hoard H5N1 sequences and continues to isolate H5N1 in chicken eggs, selecting against H5N1 isolates with the acquisition of these mammalian polymorphisms (the second sequence submitted to Genbank from the patient in Thailand has lost N186K).
The guy’s been standing on the railroad tracks, waving his arms and jumping up and down for some time now, asking, pleading, begging for those sequences. Still, they are not forthcoming. If they were, would it help now? (That’s not a rhetorical question - I’d really like to know the answer).
What can science, even fast science, do to stop this train now?
Pixie – at 11:49
Well, no one knows if we have time, and how much. That’s something we will all have to live with for a long time, I suspect.
From this paper, I don’t get a sense of “a runaway train that is about to crash”. I do, however, worry a lot more about the dominant strain in China. It still feels scary if one particular virus has done something ‘right’ for itself as to conquer everything else. The most important bit of information is how many human cases there are/were in China, and, of the reported ones, how many of them were infected by that strain?
That’s where the need for data is most urgent, IMHO.
This is copied from the duplicate thread.
Grace RN – at 11:08 OK, what does this mean?
I mean it. Very confused about the findings AND implications.
“H5N1 influenza A viruses have spread to numerous countries in Asia, Europe and Africa, infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects1, 2. Human and avian influenza A viruses differ in their recognition of host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acid-2,6-galactose (SA2,6Gal), whereas the latter prefer those ending in SA2,3Gal (refs 3–6). A conversion from SA2,3Gal to SA2,6Gal recognition is thought to be one of the changes that must occur before avian influenza viruses can replicate efficiently in humans and acquire the potential to cause a pandemic. By identifying mutations in the receptor-binding haemagglutinin (HA) molecule that would enable avian H5N1 viruses to recognize human-type host cell receptors, it may be possible to predict (and thus to increase preparedness for) the emergence of pandemic viruses. Here we show that some H5N1 viruses isolated from humans can bind to both human and avian receptors, in contrast to those isolated from chickens and ducks, which recognize the avian receptors exclusively. Mutations at positions 182 and 192 independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. Analysis of the crystal structure of the HA from an H5N1 virus used in our genetic experiments shows that the locations of these amino acids in the HA molecule are compatible with an effect on receptor binding. The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates.”
link:http://www.nature.com/nature/journal/v444/n7117/abs/nature05264.html
DennisC – at 11:23 Grace RN – at 11:08
It means that in some of the existing circulating strains H5N1 have acquired mutations that allow them to live higher up in your throat instead of way down in the lungs. That is because it has a sequence that allows it to live at a lower temp (34C) instead of the warm temps (higher “core” body temps) and it can attach to the sugars in the throat and upper lungs (mucus = those polysaccharides) instead of the sugars lining the lower lungs.
It also means we were very lucky in Egypt, Turkey and Iraq since some H5N1 seen there have the mutation but we stopped before it could spread and pick up more human binding mutations.
In addition, it means that its sequences now share longer sequences with circulating strains including the ever-present type B flu. The longer the sequences the faster it can “mate” (hydrogen bond to the RNA sequences) and the faster it can now pick up more human binding regions. And that can all be done without effect the regions that give it the large CFR’s.
None of that is good.
Excuse me I am no MD nor do I play one on TV. I will now go crawl under a rock and play dumb and let others correct my misunderstandings.
DennisC – at 11:27 Oh yes, being higher in the lungs/throat means it is easier to cough or sneeze the stuff up. That leads to faster spread (higher R0)if it doesn’t kill to quickly.
Klatu – at 11:27 Commentary
Additional H5N1 Acquisitions of Human RBD Polymorphisms Recombinomics Commentary November 15, 2006
two of these changes, lysine at position 182 and arginine at position 192, were present in the HA’s of clade-2 H5N1 viruses isolated from two individuals in Azerbaijan and one individual in Iraq,clade
“The above comments from today’s Nature paper describe patients infected with the Qinghai strain of H5N1. The paper identified acquisitions in human H5N1 isolates that enhanced binding to human receptors, either individually or in combination.
The above comment is somewhat ambiguous. It is not clear if all three patients had both receptor bind domain (RBD) changes described above, or both changes were found among the three patients. The statement cannot be independently confirmed, because the sequences from these patients are still being hoarded by WHO, and have not been made public.
The hoarding of the sequences by WHO, weakens their complaints about China not sharing samples or sequences, when WHO and consultants at St Jude, Hong Kong University, and Weybridge are hoarding thousands of H5N1 sequence collected this year, including human cases as indicated above.
The hoarding labs have failed to understand how these changes are acquired and continue to call them random mutations.”
Long story short
One interpretation of Dr. Niman’s commentary regarding the Nature article is, a great deal of information continues to be withheld from the public and other scientists by China & WHO. Without the facts we’ll never get a handle on the evolution of the various viral clades and sub-clades. Weapons of Mass Confusion, continue to serve political/commercial interests.
Sound familiar?
crfullmoon – at 11:29 “host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acid-2,6-galactose (SA2,6Gal), whereas the latter prefer those ending in SA2,3Gal”
Can’t recall where I saw this, but, don’t human, (and other mammals) have both these kinds in the epithelial layer of the respiratory tract? Even if humans don’t have as many “avian” receptors?
Recognizing human receptors just underlines “still looking like no chance of pandemic going away”? I’d think all too soon they’ll have to stop worrying about potential, and start dealing with fallout from actual pandemic. Just don’t think humans are going to get their collective acts together to start making vaccines that will hit a moving target; systems are too fragile for that. Sure hope I’m wrong.
Grace RN – at 11:30 Dennis C.
OK, thanks.
So is the implication=this season’s flu bug could perhaps meet H5N1 in some exotic corner of the planet and go…where no one wants it go ie efficient H2H?
Klatu – at 11:36 The song remains the same.
DennisC – at 11:39 Grace RN – at 11:30 some exotic corner …go ie efficient H2H
That is what it looks like to me. It has all the pieces now. They just all have to come together in one place. And that place could be a single person- exotic or not. It just needs to do a few H2H cycles without being “contained” and it is good as there.
I think I will sign off for a while and order some more powdered eggs, tea, and books.
DennisC – at 12:34 you can get the Nature article here:
http://tinyurl.com/y5l5w8 but it costs $30.
You can read the abstract for free.
Leo7 – at 13:51 I think the barrier between human and animal has now been breached too many times. The protection it once offered us seems to be in question with the zoonotics. You could read the report that the chickens have adapted better than the humans, and that infulenza B in the future won’t be referred to as mild.
And here is the ABSTRACT:
‘’‘H5N1 influenza A viruses have spread to numerous countries in Asia, Europe and Africa, infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects1,2. Human and avian influenza A viruses differ in their recognition of host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acida2,6- galactose (SAa2,6Gal), whereas the latter prefer those ending in SAa2,3Gal (refs 3–6). A conversion from SAa2,3Gal to SAa2,6Gal recognition is thought to be one of the changes that must occur before avian influenza viruses can replicate efficiently in humans and acquire the potential to cause a pandemic. By identifying mutations in the receptor-binding haemagglutinin (HA) molecule that would enable avian H5N1 viruses to recognize human-type host cell receptors, it may be possible to predict (and thus to increase preparedness for) the emergence of pandemic viruses. Here we show that some H5N1 viruses isolated from humans can bind to both human and avian receptors, in contrast to those isolated from chickens and ducks, which recognize the avian receptors exclusively. Mutations at positions 182 and 192 independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. Analysis of the crystal structure of the HA from an H5N1 virus used in our genetic experiments shows that the locations of these amino acids in the HA molecule are compatible with an effect on receptor binding. The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates.’‘’
Niman made one point (another flu site CE) that the methods used by the CDC and WHO has been to isolate the H5N1 on chicken eggs and that tends to select against the human changes in favor of avian binding sites.
I find that interesting.
DennisC-
That passage in unrelated species trick combined with goldilocks testing really made the early phases difficult to understand. No amount of complaining on the science communities part has changed their actions.
They are still working the information control panel, aren’t they?
they also use dog-kidney cells. But maybe they only report one of the results to public and keep the other secret. Who knows.
see here for the full article
(courtesy to niman)
That was not the full article. I doubt that even niman would risk copyright violations.
Re-posted from the ‘Rumors’ thread.
I want to jump in here and make a few comments about threat assessment, since quite a few people seem to be very alarmed by the Nature article, and some of you are nonplussed by the dissonance in the reactions of different people.
I think the problem has to do with the approach to new information or new data, eg the Nature article. The question of whether the mutations are significant has to be put in the context: significant for what? Let me just put that question here for you to consider while I run through the rest of my arguments, and then I will get back to it specifically.
When you get some new data, the question that comes up immediately should be, does this change anything about anything that I know? The answer to that question lies with what you already know before now, ie the ‘background’ upon which this new data has to be evaluated.
In this context, we are talking about the binding of H5N1 to alpha2,6 linked receptors, which from previous studies we general accept as being prevalent in humans and not birds, so that a switch from alpha 2,3 binding to 2,6 may indicate an increased ability to bind to human cells, thus facilitating human infections.
There are indications that the issues are a lot more complex than just simple switching, eg there may be different types of 2,6 or 2,3 receptors, or that we don’t know if receptor binding is the most critical step of transmission or infection, since we know practically nothing about all the other things that need to happen for transmission or infection to occur. Let’s just leave all that aside for a virology thread later, and just accept this simple paradigm as accurate.
So we assume that a switch to 2,6 is bad news. Fine. The next question is, does it change your risk perception? Why should it change your risk perception? (I’m not saying it shouldn’t, just bear with me while I develop the argument.)
To change your risk perception, you need to ask yourself what was your risk perception based on before you know about this new data? In this instance, did you assume there had never been any H5N1 viruses that could bind to ‘human’ receptors?
If you did, let me tell you that that was a mistake.
So far, H5N1 has infected >200 people. Suppose magically we have all the samples from all these people available, and we were to run the glycan assays with all of them, would you have expected some to be positive for 2,6 binding? If the glycan assays are any good, and at this point they look like pretty solid science to me, would you have expected that to the extent that the virus did succeed in infecting all these people, that at least some of these samples would have been positive for 2,6 binding?
If not, how solid is the receptor binding theory?
See, you can’t have it both ways. You can’t accept totally the assumptions behind the receptor binding concept, and expect out of 200+ human infections that did happen, none of the viruses were able to bind to human receptors.
Since no such data was available before, the fact that we find some now, really may not indicate any increase in current risk. Or it may. We just can’t draw those conclusions based on this particular finding.
Remember, we are talking about new data in the background of no or almost no previous data. Apart from the Stevens paper in which they examined one H5N1 sample, I don’t think anyone else has studied this virus in this particular way. At least I haven’t seen any.
So then when should we be alarmed by new data? Let me give a few examples, hypothetically.
Suppose someone had already run such tests for a fairly large sample of H5N1 human isolates, and we knew already that x% of human samples previously showed binding to ‘human’ receptors, and now all of a sudden the percentage has gone up.
Or suppose, out of all the different mutations that they found that could promote 2,6 binding, now you have one mutation or one particular combination of mutations that is now turning up more frequently.
For me, that would cause me to think something has changed, and the risk might have increased.
Now suppose this particular mutation or set of mutations is also associated with increased virulence (higher CFR), or increased transmission (bigger or more frequent clusters), or both, then that would be really really bad news.
Now to go back to the original question, how significant are these mutations? For me, they are significant for many reasons.
1) It tells us something we didn’t know before. It validates the previous work by Stevens and others, and it gives us an additional set of ‘background’ data with which future data can be compared.
2) To the extent that some of these mutations are found in isolates from actual human infections, those particular mutations are likely to be significant. This is still based on an extremely small number of samples, so we would keep our eye out for similar results in future studies.
3) It tells me that glycan assay is a useful tool that should be used and maybe standardized so that different researchers can compare findings.
Finally, I would have preferred that they didn’t find such mutations, that all tests came back negative.
But then, it would have caused me to question the validity of either the assay or the receptor binding theory, or both.
I hardly understand computer code so this may be completly of, but,, As I understand it, this two adaptations make the virus get to some part of the human lung. While doing so the rest of the virus is the same old evil one, killing 60% of infected?
My question then is.- is it posible to create a pre-vacine that makes imune system target those spesiific parts? Lets say we make a virus that is 98% nonsens, and 2% bad mutation, could it not then work as a broad vacine preventing any influensa or strain from becomming a pandemic virus? Is this what”universal vacine” is all about?
urdar-Norway – at 19:43
My question then is.- is it posible to create a pre-vacine that makes imune system target those spesiific parts? Lets say we make a virus that is 98% nonsens, and 2% bad mutation, could it not then work as a broad vacine preventing any influensa or strain from becomming a pandemic virus? Is this what”universal vacine” is all about?
These mutations are found in a handful of samples at the moment. We don’t know whether the other 200+ infections were from viruses with exactly these mutations. Most likely not. So we can’t just target these individual mutations.
The choice of which strain to use to make a vaccine is an extremely difficult one, based on many factors, not just receptor binding. And receptor binding is not the only important component. It is likely to be one of a number (we don’t know how many) issues that involve more than just the surface genes. And we are nowhere near able to make universal vaccines yet.