Clearly, D225G strains are not reacting with the vaccine that has been used to vaccinate tens of millions around the globe. Of course, D225 does react. That sounds like a great way to select for D225G. If Vincent is right, no worries. If niman is right, it'll be Katie-bar-the-door.

Bets, gentlemen?

Clearly, D225G strains are not reacting with the vaccine that has been used to vaccinate tens of millions around the globe. That sounds like a great way to select for D225G. If Vincent is right, no worries. If niman is right, it'll be Katie-bar-the-door.

Bets, gentlemen?

Clearly, D225G strains are not reacting with the vaccine that has been used to vaccinate tens of millions around the globe. Of course, D225 does react. That sounds like a great way to select for D225G. If Vincent is right, no worries. If niman is right, it'll be Katie-bar-the-door.

Bets, gentlemen?

Clearly, D225G strains are not reacting with the vaccine that has been used to vaccinate tens of millions around the globe. That sounds like a great way to select for D225G. If Vincent is right, no worries. If niman is right, it'll be Katie-bar-the-door.

Bets, gentlemen?

I don't think I have ever heard anyone say that a LACK of linkage between cases supports evidence of transmission. That's certainly an 'interesting' stance.

A sample of 4 is statistically insignificant as well.

Hand waving about spontaneopus mutations and coincidences of 4 of 4 fatal cases are simply nonsensical exercises. Knock yourself out, If you think the 4 or 4 fatal cases in Ukraine is a coincidence along with a match of the subclade in Norway with D225G, talk to reporters. They might believe you and continue to distribute the “spontaneous mutation” nonsense to a guilible audience.

it could just have been occasional introductions from travelers without spreading.
We saw that often in Europe in May,June

> The same is true for the detection of the same polymorphism in four of four fatalities
> in western Ukraine, where cases were in the two most hard hit Oblasts and not linked

no proof for that. If it typically happens together with other polymorphisms, which are not present
in D225, that I would consider evidence for your view. Do we see this ?

> Do you think that four of four was a coincidence of SPONTANEOUS “mutations”

yes, ATM I consider that the most likely explanation. It seems to be linked to lung-samples,
but lung-viruses can't easily go into sputum and transmit.

D225G TRANSMITS. The number of nonsynonymous HA changes was ONE (D225G).

Comments (hand waving allowed)?

Another isolate from Kiev, which was wild type at position 225, was California/7-like.

The interest in D225G increased dramatically with the outbreak in Ukraine. Large numbers of previously healthy young adults began showing up at emergency rooms coughing up blood and dying within a few days. Both lungs were destroyed within a couple of days, and the large number of cases produced a significant amount of panic. Initially the infections were called a “mystery disease” but had all of the landmarks of a swine H1N1 infection.

Ukraine request help from WHO, who sent in a team of nine and sent samples off to Mill Hill in London. Most of the samples were from the hard hit regions of western Ukraine where hundreds had died.

I had looked at existing sequences and predicted the large number of hemorrhagic cases were due to a receptor binding domain and focused on position 225 which had already changed to D225E, D225N, and D225G in samples collected worldwide. I predicted the change would be D225G.
The sequences were withheld for 1-2 weeks, but were released at GISAID on Nov 18. Ten HA sequences from 10 individuals were included. One had been collected from an earlier cases in Kiev, while the other nine were from three locations in western Ukraine. Phylogenetic analysis showed that all 9 were from the same sub-clade and four had D225G. The next day more demographic data was added, and it was clear that 4 of the 10 patients had died, and all four had D225G. Three were from lung and one was from throat. The five survivors had the same sub-clade, but were wild type for position 225. The samples in the five survivors were nasopharygeal washes. The four positives were from two Oblasts and none were linked, providing STRONG evidence that D225G transmits.

there are hundreds of HA-spikes, some may have 225D and some 225G,
so such a virus could bind to both types of cells. If that combined HA-production
sheme could be encoded genetically wouldn't that make a major advance in flu-genetics ?

no forum yet, sigh

Is there more data on this statement? It would be great to review it.
Thanks

The ferret model isn't terribly convincing either. An early study on the a Mexican strain of swine flu showed an astoundingly high death rate in ferrets although the same strain in people was relatively mild. Other experiments in ferrets concerning the transmissibility of the virus also seemed to contradict observations on human epidemiology.

Equally, of course, I'm not convinced that the mutation should concern us just from genetic speculation.

As far as I'm concerned the question, as to how concerned we should be, is best answered by observation of human clinical subjects.

Below the table, you write “Different isolates of the 2009 H1N1 influenza virus have D at HA at amino acid 190 and mostly D at amino acid 225. The virus prefers to bind to alpha(2,3) linked sialic acids.” and I think you mean (2,6) here too? If not I'm very confused.

This post was mentioned on Twitter by profvrr: D225G change in 2009 #H1N1 influenza virus not a concern http://bit.ly/6qJTyi at virology blog…

The picture I had in mind was a lot simpler – you have an active upper respiratory infection with D at 225. Periodically, random mutations happen which create a G at 225 – along with a host of other mutations, of course, since the sheer number of viral RNAs synthesised pretty much guarantees that any given mutation will arise at least once. These mutant particles get released and go wherever the air flow takes them, be that up or down.

If they get coughed out and land on someone else, there's no effect as they don't transmit well. If they get inhaled deeper into the lungs, then they may set up shop there. They won't get outcompeted by the parent virus because the parent virus isn't infecting the same cells.

I wonder if new deep sequencing technology will help answer these questions. Would it let you look at the whole population of viral sequences within an infection, and/or at different locations within the lung, rather than getting a consensus sequence?

However, the question remains which selective advantages such sporadic “in-patient-mutated” virus could have over its non-mutated competitors during the course of the infection within the patient ?

As long as the “front of the infection wave” has not reached the deep lung tissue, the reproduction rate of the non-mutated version would be superior… and will thus stop before the deep lung tissue is reached.

Maybe it is only those rare cases where the “jump” happen to occur in a virus particle just at the peripheric border of the infection wave far enough down the respiratory tree to reach the first susceptible “2,3″-type cells. from which point on a “second wavefront” of the infection would be started running down the lower part of the respiratory tract.

just a thought …

How labile are flu viruses within an individual patient? Is the D225G polymorphism transmitting between patients, or is the same mutation recurring in many different patients? One could hypothesise a scenario where only virus particles with a D at position 225 are able to transmit, but the subsequent course of the infection depends on whether the the virus happens to pick up a G at position 225 within each given patient. Whether you detect a D or a G when you come to sequence a sample would depend on how long-established the infection was, how deep you were sampling within the respiratory tree, etc.

On a related note, how certain are we about what was going on in the ferrets? If I remember rightly, the study infected ferrets with H1N1 flu (i.e. with D at 225) and observed deep lung pathology. Did they then re-isolate the virus from the deep lung lesions and check whether it still had a D at position 225?

Perhaps the pathogenic factor is not whether a given strain has G at 225, but the ease (or otherwise) with which it can acquire a G as it replicates within the host.

Same goes for any other polymorphism that increases lethality but decreases transmission. If you need half a dozen nucleotide changes to get from the transmissible sequence to a lethal sequence, you're safer than if it's only a single hop away.