Virology Discussions with Dr Taubenberger Part 3

by: SusanC

Fri Nov 24, 2006 at 19:47:42 PM EST

originally posted in old forum as "Conversations with a Virologist"

anon_22 – at 11:19

This thread is a continuation of the Talking to JKT thread, with the title changed to reflect a continuous learning process rather than specific events or comments.

And this is cross-posted from the News Thread for visibility.

HIGHLY RECOMMENDED free videocast from NIH:

Oct 5, Dr Jeffery Taubenberger delivered the annual NIAID Kinyoun Lecture on Influenza Viruses: Past and Future Threats. Dr. Joseph Kinyoun is considered the founder of NIH from its origin as the Laboratory of Hygiene, established in NY in 1887. NIAID has an annual lectureship named after him and it is a big honor to be asked to give it.

The videocast for the lecture is available here.

For those of you who are techno-phobic, here’s the link to test if your PC has the required componente to play it. Go to and click on ‘test plugin’. You may need to download and install the free Real Player.
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De jure – at 12:27

Anon_22: That’s a good videocast. It got me to thinking the need for autopsy material of H5N1 victims is even more important than I originally thought. Taubenberger’s presentation also made me realize that efficient H5N1 H2H transmission is even more difficult than I originally thought (specifically the negligible effect when changes are made at the 190 and 225 positions). However, if I had one question to ask JKT right now, it would be what are the differences between the H1s in H1N1 and H5N1. Monotreme pointed out that they are very different, but I believe if we knew just how different, we might get answers to whether prior exposure and seasonal flu vaccinations will make a difference in slowing H5N1 down if it does go pandemic (whether it will be a 1918 or a 1968 pandemic). Again, though, there needs to be more world-wide collaboration on getting autopsy materials.
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lugon – at 12:42

There’s also this from Albert-László Barabási, who knows a lot about networks. Worth exploring - his book “Linked” is good but I haven’t been able to re-borrow it to summarise it for us all.
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lugon – at 12:44

you can look at the outline of the book, plus photos for every chapter, at http://www.nd.edu/~a...
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anon_22 – at 13:04

De jure – at 12:27

The N1 neuraminidase question:

This paper, hot off the press, A preliminary panorama of the diversity of N1 subtype influenza viruses, chen, gives an overview of this subject. I haven’t read it yet, but it looks interesting.

Abstract N1 subtype influenza viruses have caused many epidemics and even a few pandemics in humans, pigs and fowls including 1918 human H1N1 pandemic, which killed 20–50 million people and the current avian H5N1 pandemic in the Eastern Hemisphere, which has caused great economic losses and posed a severe threat to human public health. To elucidate the whole diversity of N1 influenza viruses from a dynamic view, 202 neuraminidase (NA) sequences of N1 subtype influenza isolates were selected and analyzed in this study. Our results showed that N1 influenza isolates could be divided into three distinct lineages (Human, Classic Swine and Avian), which largely circulated in the humans, pigs and fowls respectively, though viruses in the Avian lineage could infect mammals and even there was a sublineage in the Avian lineage wholly isolated from pigs. The Avian lineage and the Human lineage, which have existed at least for decades, possibly began divergence around in 1890 through regression analysis. Both of the Human and Avian lineages could be further divided into some sublineages, and the correlation between these lineages (or sublineages) and their isolation places, isolation time, hemagglutinin (HA) subtypes, host species, virulence, or epidemics were discussed. The panorama of the diversity of N1 influenza viruses presented in this study provided a framework for the studies on the evolution and epidemiology of N1 influenza viruses.

De jure – at 12:27 Taubenberger’s presentation also made me realize that efficient H5N1 H2H transmission is even more difficult than I originally thought

Yes, but looking at it from the molecular biologist point of view and looking at it from the epidemiologist point of view could result in totally different interpretations. Read my post at 19:48 on the previous thread for revere’s thoughts on what the current outbreaks look like.
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Grace RN – at 13:21

re: “De jure – at 12:27 Taubenberger’s presentation also made me realize that efficient H5N1 H2H transmission is even more difficult than I originally thought

At first I found that reassuring, until he mention the virulence of the inactived vaccine injected into animals and it still killed them….

And the reveres’ comment is gravely concerning as well.
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anon_22 – at 13:26

Oh, and the truth is probably somewhere in between. :-)
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anon_22 – at 13:27

Now THAT must have answered everybody’s questions completely.

LOL
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De jure – at 13:44

Anon_22 at 13:10: I remember somberly considering this observation. The question that would still need to be answered would be this: is it a newly emerging disease that transmits oral-fecal, or will it ever go H2H efficiently via respiratory spread? If its the latter, I guess we’d all be affected eventually. I wonder what Revere would have to say further on this subject.
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seacoast – at 13:49

Don’t know where else to comment on this, so I am putting it here ~ The Trust for America’s Health Report : “Pandemic Flu State of Science”, October, 2006. This is excellent and well written with information that can be understood by the lay person. This will be added to my hand-out information for Pandemic Awareness Week. If I am breaking any copy-rights laws, so be it, this is too important to worry about. I am sweeping a thirty mile radius where I live with information that is readiable, believable, and understandable. I am also going to the media, big and small.
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Dennis in Colorado – at 13:59

See http://healthyameric... as the link to the report Seacoast referred to above.
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anon_22 – at 14:34

Still on De jure’s statement :-)

Taubenberger’s presentation also made me realize that efficient H5N1 H2H transmission is even more difficult than I originally thought (specifically the negligible effect when changes are made at the 190 and 225 positions).

I think you may be making a grave error in unconsciously, automatically, assuming some equivalence between transmission and receptor binding.

I think we need to figure out what we mean when we use the word ‘transmission’, first of all, and after that ask the question is ‘efficient’ transmission strictly on the molecular level sufficient for a pandemic to occur.

On the first question, what exactly is transmission? If it was a race for the virus to achieve a goal, where is the finish line, as far as transmission goes? When it enters a cell? When it replicates? When it causes disease? When new viral particles escape from the host cell to enter other host cells? When the virus has successfully established itself inside the host organism?

But surely when we talk about the virus’s ability to cause disease, we are talking about pathogenesis, right? Where does ‘transmission’ end ‘pathogenicity’ begin? Surely, for practical purposes, transmission is meaningless to the virus unless it can replicate and re-infect over and over again, which would by definition require a degree of pathogenicity?

Or is that ‘virulence’ we are talking about?

Who was it who said this about ‘respect’, “I can’t tell you what it is but I sure as hell can recognize it when I see it?”

The reason why I raise these seemingly ridiculous questions is that IMO it’s important to separate ‘concept’ from ‘process’ from ‘mechanism’.

And all of that from ‘clinical manifestation of disease’, aka real-life events like pandemics.

I can’t answer any of these questions that I am raising, FYI. :-)
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lugon – at 15:06

anon_22 at 14:34 - would by definition require a degree of pathogenicity - not sure about that one, if influenza virus is transmissible during the incubation period. If we had an eternal incubation period (i.e., no disease) then we’d have a “lab only” pandemic.
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Tom DVM – at 15:43

Hi everyone. Interesting discussion…thanks anon 22.

I thought I might as well make a few comments from my perspective as a veterinarian.

First, I would ask us to remove the minutia of the genotype from the discussion for the moment and concentrate on the expression of the genotype…the phentoype which in this case = disease…and the characteristics unique to H5N1.

We have only one equivalent virus to use as a comparable, H1N1 in 1918. In fact our template for observation really comes down to, in essence, one virus H1N1…because every pandemic of the 1900′s were due to the virus or two recombinants of the virus in 1957 and 1968…and I’m not quite sure than 1968 would qualify as a pandemic.

There was no bird die-off before 1918 which means H1N1 was a low virulence avian influenza and the 1918 pandemic was a direct mutant of the strain that lived symbiotically (harmmoniously) in birds…

…previous to 1918, there had been no influenza in pigs but H1N1 has also caused disease in pigs ever since 1918 when the zoonosis worked in reverse…from humans to pigs.

Now lets have a look at H5N1.

1) It is now pandemic in bird populations as well as endemic in Asia and soon probably to be endemic in Russian, the Mediteranean and Africa.

2) It has caused huge die-offs of poultry and die-offs of wild migratory birds…while at the same time having the ability to live asymptomatically in other species.

3) No influenza has been identified with other species in the past but H5N1 has maintained the ability to live asymptomatically in some members of a species while being lethal to other members or the species…particularly in cats, there has been no known influenza in the past…this is the first on record which is extremely significant in assessing threat level of H5N1.

4) Has the ability to be asymptomatic in pigs…we do not no if this was possible in 1918 or not…but asymptomatic infections in pigs and other species while maintaining lethality and not being asymptomatic in humans represents a significant future threat to our species.

5) Has the ability to explode geographically in an extremely short period of time.

6) In 1918, there was no avian-effect so concurrent pandemics in pigs, poultry and humans could create an associated food shortage.

Therefore, in my opinion, although I’m quite sure I forgot a lot of other unique characteristics in this list…I believe this virus is a ‘freak’ the like of has never been encountered in human history.

We don’t need genomes to tell us that this virus is adapting to animals and humans at the same time. I think the genome debates cloud the issue unneccesarily because they cloud what is happening at the moment before our eyes…

…if there is no barrier…and I think that question was answered in 1997, make no doubt about it…this is not going to be a ‘picnic in the park’.
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moeb – at 15:54

well laid out Tom
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Tom DVM – at 16:01

Thanks moeb.
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De jure – at 16:09

Anon_22: Taubenberger in the videocast stated that there have only been 3 “H”s out of the 16 that have caused pandemics: H1, H2, and H3. His explanation of why the H’s from a molecular standpoint caused pandemics was interesting in that it only took a couple of changes in the hemagluttinen to switch from avian to human via the a2,6 receptors. Now, that leaves 13 other H’s. Why haven’t they ever caused pandemics? We can’t say that they might have in the past, because we’ve already concluded that the winning strain eliminates all of its competition (such as H1N1 did in 1918). Don’t get me wrong, because I’m not interpretting Taubenberger as saying that H5N1 “won’t” go pandemic; however, I am interpretting his comments as saying that this virus, because of its molecular structure, does not transmit easily from person to person. Yes, I agree with everyone here that it is extremely virulent. But so is ebola, yet I dare say we don’t have much to fear from efficient spread of that pathogen due to its structure. So, structurally, is H5N1 something that “can” spread efficiently? We’ve never really had a virologist answer that one, and that is the question of which I am most concerned. By the by, thanks for the hot-off-the-press N1 research. I look forward to reading it.
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anonymous – at 16:32

De jure – at 16:09, we’ve already concluded that the winning strain eliminates all of its competition (such as H1N1 did in 1918).

It’s anon_22′s opinion that H1N1 was the only virus, so it looks like there is no consensus about this. At least on this website. I’m very sure of standard academic theory in the scientific community.

Other thread, anon_22 – at 19:20: “…all current human flu viruses are descendants of the 1918 virus H1N1.”

Maybe anon_22 can speak to this…
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De jure – at 16:32

I should probably add why the structure of the virus is key for me. My grandfather used to teach and practice at a prestigious medical school. He was also one of the MASH doctors in the Korean War. One day he brought up the subject of what to him was mankind’s most pressing problem. He was sure that one day, probably not in his lifetime, the HIV virus would go airborne. He said once that happened we would all be in big trouble. I put great faith in my grandfather’s analyses, and worried about it for awhile. But then I started thinking yes, my grandfather knew a great deal about surgery and human anatomy (his research even contributed to the development of the heart and lung machine). However, my grandfather was not a virologist. How could he know whether the HIV virus could mutate in such a way? I’d give his analysis more weight than that of an engineer, but really, when looking at such problems, it seems best to start with an expert whose work is more relevant in the field. From a layman’s perspective, it does look like H5N1 could go pandemic, but it seems to me the virologists are saying, “we don’t know.” I can live with that, but I don’t think you can extrapolate “the pandemic is imminent” from “we don’t know.” Of course, I am prepping for a worst-case scenario, but you can’t say it will happen with certainty.
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anon_22 – at 16:45

lugon – at 15:06 anon_22 at 14:34 - would by definition require a degree of pathogenicity - not sure about that one, if influenza virus is transmissible during the incubation period. If we had an eternal incubation period (i.e., no disease) then we’d have a “lab only” pandemic.

lugon, I was going to make a general comment that this is a philosophical debate and not a factual one. But you took that to a different level, so let me answer your challenge. What is the definition of an incubation period? The time before someone is symptomatic, or something to that effect, right? Surely, you cannot talk about incubation period unless there is something to incubate ie the disease.

Its like the saying “if a tree fell in a forest and no one heard it did it happen?……” :-)
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anon_22 – at 16:56

anonymous ¨C at 16:32 De jure ¨C at 16:09, we¡¯ve already concluded that the winning strain eliminates all of its competition (such as H1N1 did in 1918).

Actually, I’m not sure that it always happens. I don’t know if we can draw conclusions about the few occurrences we are studying. (n<3)

It¡¯s anon_22¡äs opinion that H1N1 was the only virus, so it looks like there is no consensus about this. At least on this website. I¡¯m very sure of standard academic theory in the scientific community.

Other thread, anon_22 ¨C at 19:20: ¡°¡­all current human flu viruses are descendants of the 1918 virus H1N1.¡± Maybe anon_22 can speak to this¡­

No, it isn’t my opinion, it is a fact.

Think about the origins of the genes of our current H3N2 seasonal flu strain. After 1918, the only circulating strain was the H1N1 of 1918, or descendants of that, till 1957, when it reassorted with an unknown avian strain and acquired a new HA NA and PB1, and became H2N2. But the other 5 genes are from thae 1918 virus. Then in 1968, the HA and PB1 got swapped for new ones again. But the other 5 genes are still descendants of the 1918 virus.

So every single ‘human’ clade virus that we have characterized in the 20th century was from different clades or descendants of one single virus, and retain the vast portion of the internal genes of the 1918 H1N1.
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lugon – at 16:57

yeah, ok, sorry - got carried away (but couldn’t help pressing “enter”)

LOL

(i even thought about a virus that would make us better people, but never mind)
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anon_22 – at 16:58

anonymous

JKT explained that using PB2 as example on the videocast.
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anon_22 – at 17:36

De jure – at 16:09 Anon_22: Taubenberger in the videocast stated that there have only been 3 “H”s out of the 16 that have caused pandemics: H1, H2, and H3. His explanation of why the H’s from a molecular standpoint caused pandemics was interesting in that it only took a couple of changes in the hemagluttinen to switch from avian to human via the a2,6 receptors. Now, that leaves 13 other H’s. Why haven’t they ever caused pandemics?

Well, the short answer is probably “we don’t know”. But the thing to notice is that he was using the example of receptor binding to illustrate certain points, such as the complexity of the possible rules, which we haven’t figured out yet. But to say we haven’t figured out the rules for receptor binding, does not imply that once we figured that out, we will have solved the transmission problem, because receptor binding is just one aspect that we are paying attention to, and there could be a whole number of other issues that we haven’t even defined or discovered yet. That is what I was trying to point out at 14:34.

We can’t say that they might have in the past, because we’ve already concluded that the winning strain eliminates all of its competition (such as H1N1 did in 1918).

As I said before, I don’t know if we can generalize it and say that is always the case.

Don’t get me wrong, because I’m not interpretting Taubenberger as saying that H5N1 “won’t” go pandemic; however, I am interpretting his comments as saying that this virus, because of its molecular structure, does not transmit easily from person to person.

I actually do agree with you on this, intuitively. I was only trying to point out the problems that can arise in our thought processes that might lead us down complete blind alleys. :-)

So the caveat is this, (bit like Bill Clinton), it depends on what you mean by “does not transmit easily”, and also, as compared to what?

We can only say that up to now, it has had plenty of opportunities, and so relatively speaking, it appears to be unable to acquire that ability as compared to our expectations. Since our expectations are built on extremely shaky grounds to say the least, we don’t really know whether it is true that it is difficult for H5N1 to achieve h2h (ie that this is a function unique to H5N1), or that there was something wrong with our expectations to start with..

On top of that, we don’t know enough about the rules governing its molecular structure to know whether this apparent difficulty in acquiring h2h is due to the molecular structure and not due to something else entirely, possibly something that we don’t even know about at this moment. Call it the X factor if you will.

Yes, I agree with everyone here that it is extremely virulent. But so is ebola, yet I dare say we don’t have much to fear from efficient spread of that pathogen due to its structure.

Here we come back to the question of “as compared to what?” If we think of H5N1 as an influenza virus, and automatically use the yardstick of influenza viruses, then we have a lot to fear from influenza than from ebola in terms of its transmissibility.

But that is correct only if it is valid to use other flu viruses that spread among humans that we know of (ie H1, H2, H3) as the yardstick against which to compare H5N1. The case for that is, well, that it is a flu virus. The case against that is that our understanding of human flu viruses is built on a very narrow knowledge base ie descendants of one single virus, the 1918 H1N1. We don’t really know that a flu virus with origins totally different from these descendants of 1918H1N1 can be expected to behave in a comparable manner. (see my comments on evolutionary bottleneck in the previous thread).

So, structurally, is H5N1 something that “can” spread efficiently?

Theoretically, I think so. We might hypothesize that by saying we have seen how it can spread efficiently in poultry. But HPAI only occurs with H5 and H7 strains, and not with H1 H2 H3, the current human subtypes. So we don’t know whether the rules of spread among poultry HPAI H5 & H7, possibly a unique disease involving complex as yet unknown virus-host interactions specific to domestic poultry, can be extrapolated to human spread. OTOH, we need to remember that in 2003, H7N7 infected a large group of poultry workers in Europe, and subsequently 58.9% of family members who did not have contact with infected poultry had positive H7 serology. Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003, so we know that at least for H7 it is possible.

We’ve never really had a virologist answer that one, and that is the question of which I am most concerned. By the by, thanks for the hot-off-the-press N1 research. I look forward to reading it.

You’re welcome.
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De jure – at 17:45

Anon_22 at 13:04: I’m having trouble with your link. Do I need special access for this article? Thanks again.
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anon_22 – at 17:49

Yes, it’s a subscription site. Or you have to pay $$. :-(
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De jure – at 17:57

It seems that anything relevant to virology costs money to access, whereas you can find anything dealing with epidemiology essentially for free. Hmmmm…this is all beginning to make sense to me now. No wonder virologists are more reticent to express their opinions…they had to pay dearly for them, so it doesn’t make “cents” to give them away for free! :-)
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anon_22 – at 17:59

De jure – at 17:57

That’s funny! lol
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anonymous – at 22:55

did H5 evolve from 1958 H2 ? Do those infected with H2 in 1958–1967 have some immunity against H5 ? How can one human pandemic strain wipe out all the other strains when the main reservoir is in birds ? When we have 15HAs and 9NAs, then how many PB2a,PB1s,PAs,NPs,Ms,NSs are there ?
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08 October 2006
anon_22 – at 09:22

anonymous – at 22:55 did H5 evolve from 1958 H2 ? Do those infected with H2 in 1958–1967 have some immunity against H5 ?

No & No

How can one human pandemic strain wipe out all the other strains when the main reservoir is in birds ?

Well, let’s say the other strains disappeared from human circulation.

When we have 15HAs and 9NAs, then how many PB2a,PB1s,PAs,NPs,Ms,NSs are there ?

Don’t know that we have any data on that.
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anonymous – at 09:35

when even H3N2-vaccine has a chance to help against H5N1 then H2N2 antibodies should have an even larger chance because of the similarities of H5 and H2. That the other strains disappear from human circulation must mean, that we get immunity against them by the pandemic. I mean, the strains are not “fighting” each other to diminish the other one, and there is enough place on earth for 2 strains… We have almost as much data on PB2,.. as we have on HA,NA
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anon_22 – at 09:37

Tom DVM ¨C at 15:43

We have only one equivalent virus to use as a comparable, H1N1 in 1918. In fact our template for observation really comes down to, in essence, one virus H1N1¡­because every pandemic of the 1900¡äs were due to the virus or two recombinants of the virus in 1957 and 1968¡­and I¡¯m not quite sure than 1968 would qualify as a pandemic.

1968 qualified as a pandemic cos it was a global outbreak of a new human virus. But its fatality rate was not significantly higher than seasonal flu. That puts into question what De jure was asking about immunity against the neuraminidase protein.

There was no bird die-off before 1918 which means H1N1 was a low virulence avian influenza and the 1918 pandemic was a direct mutant of the strain that lived symbiotically (harmmoniously) in birds

No, only H5 and H7 are known to acquire the peculiar molecular changes in the cleavage site of the HA to cause HPAI. It is possible that H1 is inherently unable to change in that way. Again we bump into the question of whether we can even use 1918 as a template, as you said earlier in the post. Taubenberger did tell me that there are historical accounts from the mid 19th century of poultry outbreaks which seemed to be exactly the same as HPAI as we observe it now.

­previous to 1918, there had been no influenza in pigs but H1N1 has also caused disease in pigs ever since 1918 when the zoonosis worked in reverse¡­from humans to pigs.

yes

Now lets have a look at H5N1.

5) Has the ability to explode geographically in an extremely short period of time.

Well, that is for HPAI which may or may not be a model for humans. see 16:57 post second last paragraph.

6) In 1918, there was no avian-effect so concurrent pandemics in pigs, poultry and humans could create an associated food shortage.

True

Therefore, in my opinion, …I believe this virus is a ¡®freak¡¯ the like of has never been encountered in human history.

Agree

We don¡¯t need genomes to tell us that this virus is adapting to animals and humans at the same time. I think the genome debates cloud the issue unneccesarily because they cloud what is happening at the moment before our eyes¡­

Yes, just look at the clusters.
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janetn – at 10:49

Thanks for explaining such a complex subject in a way even us laypeople can get it.
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a’Akova – at 12:46

De jure – at 16:32 said “From a layman’s perspective, it does look like H5N1 could go pandemic, but it seems to me the virologists are saying, “we don’t know.” I can live with that, but I don’t think you can extrapolate “the pandemic is imminent” from “we don’t know.””

This is similar to asking a weather forcaster whether tropical depression X will obliterate a city. The best he can say is “we don’t know”. But historically some tropical depressions turn into tropical storms, and some tropical depressions turn into hurricanes, and some hurricanes obliterate cities.

The risks against which we should prepare ourselves aren’t limited to what H5N1 might do, but include any number of other disasters including hurricanes, tornados, earthquakes, volcanos, disease outbreaks, or even the odd winter storm which boxes us in without power for a couple of days.
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Grace RN – at 20:25

anon_22 – at 14:34

My comment re: H5N1 not so easily transmissable was in the context of bird-human, and to date, H-H.

Re: when, Taubenberg seen to quasi-answer,as I suppose any of us could, with the same answer-no one truly knows IF H5N1 will go pandemic, no one knows when the pandemic will occur, and no one knows how severe the next pandemic will be.

It seems I-for one-am back to the same starting point as I was in 1998 regarding the when/how bad. What I’ve learned in between-and a good deal from fluwkie and all the contributors-could spell the difference in my family surviving or not.
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anon_22 – at 21:45

Grace, I think one lesson for all of us, is to learn that there are never easy answers that someone in ‘authority’ can give to you and that you can bet your family’s lives on. We all need to make our own risk assessments, and learn to cope as best we can with uncertainties. In a weird way, there may be times when for some people it is easier if someone tells them for sure disaster is going to happen, than for them to learn to accept that no one can tell them what is the right thing to do. Examples of people who are fervently religious and will follow one single line of doctrine meticulously and unquestioningly come to mind. I don’t have anything against people who choose to do that, but I’m pointing it out as examples of how bad certainties may sometimes appeal to some people more than good uncertainties.

Just saying…..
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09 October 2006
Tom DVM – at 00:29

“but I’m pointing it out as examples of how bad certainties may sometimes appeal to some people more than good uncertainties.”

Hi everyone. Interesting comments.

I think that it might be useful to reflect on the past twelve months. Twelve months ago, H5N1 was isolated in Asia. There had been no significant clusters and no real evidence of H-H. The CFR was lower a year ago than today…

…my point is that I have not seen one bit of evidence in the past year to indicate a trend other a very serious situation faces us sooner rather than later…

…If there is evidence otherwise I would like to see it presented so that I can feel better about the trend-line.

For me it is not a matter of bad certainties being more attractive…it is all about the fact there are is no good news.
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felidsdan@msn.com – at 01:50

“The recent announcements of H5N1 bird flu in cats in Indonesia strongly signal the existence of a separate mammalian H5N1 reservoir in Indonesia that is responsible for the vast majority of human cases” An asymptomatic “carrier” that is spreading the virus through fecal matter contamination directly to humans or to their most common predator, cats. With their high metabolism and body temperature, shrews come to mind………
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lugon – at 04:02

http://www.fluwikie....
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lugon – at 04:03

Sorry, the above should be http://www.fluwikie....
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Patch – at 08:10

TomDVM @ 00:29 - …my point is that I have not seen one bit of evidence in the past year to indicate a trend other a very serious situation faces us sooner rather than later…

I can give you one (one I’m sure you’ll quickly dismiss). It’s been over a year. What is “sooner rather than later”?

The infection has spread among birds and that has certainly increased human contact and therefore, IMO, transmission to humans and a larger number of human cases. I don’t doubt things COULD get worse or I wouldn’t be here. I’m just saying……
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lugon – at 08:31

It will be gradual until it stops being gradual, but we don’t know where’s the threshold to a pandemic.
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Patch – at 09:47

lugon - @ 8:31

It will be gradual until it stops being gradual, but we don’t know where’s the threshold to a pandemic.

Or, if this (H5N1) will even lead to one.
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Medical Maven – at 10:21

My take on this thread is that it will be the wierdest outcome in the history of virology is H5N1 continues to spread, adapt, entrench, etc. and then at the end of the day humans do not pay the piper.
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Tom DVM – at 10:45

“Or, if this (H5N1) will even lead to one.”

Patch.

I think there is a close correlation between the Asian tsunami and H5N1. It is interesting to a pattern collector like me that the third last serious pandemic was in 1830 and the second last tsunami was in 1825 which was thought to have killed twenty-five thousand people in the Asian-Pacific Basin…

…There are many things we agree on…one of which is that nature time and human time are two very different things. I agree with you that the absence of a pandemic to this point, could be considered indirect evidence that we will not have one but that would be to ignore the history of both influenza pandemic and other biological/pathogen based catastrophe’s which are sort of my stock and trade…

…Then scientific community has reached consensus on one point if you reflect where we were with H5N1 a year ago and where we are now…and the consensus is that H5N1 in endemic in Asia and will soon be endemic in other parts of the world…and while H1N1 has dominated influenza’s in humans over the past century we are currently somewhere within the process of ‘a changing of the guard’…or that H5N1 will influence human health either directly or through reassortment and recombination.

I search out patterns in nature that many would think would have no relation to H5N1…like sunspots and global warming’s relationship to viral adaption and mutation (evolution). I do this because as a practising veterinarinan I could see a close relationship between pathogen, localized epidemics and environment…

…these patterns lead to intuition that I would welcome any comments and criticisms on…

1) I believe we are poised today for a pandemic, however I do not know nature’s time and I do not have the irrefutable historical data to be able to predict accurately onset times…however, I believe intuitively it will be before the end of Apr. next year (2007).

2) I believe that evolution occurs by small steps and by leaps…and I believe H5N1 has achieved the threshold by which the final adaption (summit) will most likely occur in one last leap.

3) I believe when the pandemic virus does emerge, it will be confused with Dengue Fever and will follow a step-wise process identical to what is going on in India right now.

4) I believe the pandemic will emerge from North Korea with China as a close second possibility.

5) I believe the pandemic will be as bad or probably worse than 1918 because history has demonstrated that 1918 is the rule rather than the ‘exception to the rule’…previous pandemics of equivalent lethality…1918, 1890, 1830 which equal three of the past six pandemics.

6) I believe our response to the pandemic will be relatively far less effective than in 1918 and we will have less technology (pharmaceuticals etc) to respond to the pandemic then they had in 1918 and the losses due to collateral damage will be relatively worse than in 1918 and wiil equal the direct mortality of the pandemic in scope.

7) I think we have entered a period of ‘shifting sands’ relative to pathogens and their natural weaponization and emergence…and I believe we will have approx. three pandemics within the next twenty years from influenza alone.

8) We had better ‘get smart’ in a hurry…time is running out for the human race…metaphorically of course.
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lugon – at 11:04

Or, if this (H5N1) will even lead to one.

Yes, of course. There could be another virus that comes sooner, or there could be reassortment or recombination or whatever, or it could take veeeeeeery long.

To me it looks like things are not getting any better, but of course Nature may pull some hidden brake, or there may be some hidden limit, or whatever.

We don’t know.

I (mostly) agree with Tom DVM. Sadly.
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Medical Maven – at 11:38

Tom, is that just a hunch on North Korea being the primo prospect for panflu emergence?
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De jure – at 11:57

Tom DVM at 10:45: “…these patterns lead to intuition that I would welcome any comments and criticisms on…” And Linus Pauling, who was twice awarded the Nobel prize, believed that Vitamin C was the cure-all for just about everything. Tom, it’s easy to get stuck to the flypaper, so to speak. When one locks himself or herself into one theory at the expense of looking into any other possibilities, then one is more apt to reject out of hand the data that doesn’t fit the paradigm. Yes, we are looking at a scary situation, but there does appear to be some data that lies outside of the worst-case scenario. JKT’s comments, for instance, suggest that this H5N1 virus has a structure which doesn’t readily adapt itself to easy human to human transmission. Until I saw this videocast, I was searching for what other virologists besides Webster had to say on this topic. I respect your opinions as they relate to zoontic infection patterns (humans, of course, being one of the animals in the animal kingdom!) but nobody seems to know how this virus will behave structurally in a human-to-human transmission scenario. I don’t believe anyone here is arguing that we should put off prepping because of the threat; however, it does no good to build the anxiety level unless and until you have more experts with data in hand weighing in on the situation. I would like to see more comments by JKT and others as more data becomes available (thanks again, Anon_22, for going the extra distance to provide another viewpoint). I believe we get into dangerous territory when we wed ourselves to a theory and won’t look at what other experts have to say. That is not what science is based on. I admire your courage in detailing your inner-most thoughts on this threat. Believe me, I won’t be disappointed if your predictions don’t come about. However, we just don’t have enough virologists weighing in on this subject. Don’t you find that a bit curious? I suspect you would say that they don’t want to stick their necks out or that they are being told not to panic the public. But I refuse to believe that the whole profession of virology is being restrained by the corruptible influence of politics and ego. Why haven’t more virologists taken part in any of the discussions that we’ve had on this website (or any other public forum?) I don’t know. I like a good puzzle, but I find there are too many pieces missing out of this one to come up with any definitive answers. Again, that won’t stop me from assessing the risk, but again, it doesn’t give me any definitive answers.
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Tom DVM – at 12:07

Hi Medical Maven. Well sort of. Here is how I did it. North Korea has basically one ally in the world, it’s neighbour China. North Korea has been chronically short of food for quite a long time…one very important way for China to make friends and influence allies, is to provide food to the malnournished etc.

This means that poultry products unsuitable for Chinese citizens will have found its way to North Korea and that would include live chickens.

We know that China has covered up significant H5N1 outbreaks probably from 1996-present and we know that in the intervening time, there production of poultry has more than doubled.

This circumstancial information leads me to believe that you can’t consider China without its twin sister North Korea in all of this…and since there is only one country in the world more secretive than China and that is North Korea…the pandemic will likely start there or start in China. Any attempt to control it in China will fail as the pandemic will accelerate in North Korea.

On another matter, where would we think that North Korea got its nuclear technology if not from China…a countries with established spy networks developed the atomic bomb after world war…

…North Korea is a closed country both intellectually and socially…it would be pretty hard for a country in the Middle Ages to develop nuclear energy without the help of their closest ally.
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De jure – at 12:16

Tom, and I thought you suspected North Korea because reportedly Kim Jong Il’s favorite cartoon character was Daffy Duck…well, I guess we can all be glad that at least it wasn’t Foghorn Leghorn.
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Tom DVM – at 12:24

One other thing. Dr. JFT is a very focused researcher who along with a large team, has done the world a great service and pulled off what to me is one of the greatest scientific feats of all time: one that will no doubt be rewarded with a Nobel Prize a few decades from now…

…but one that is so focused can by definition not see the whole picture and I’m sure that Dr. JFT would be the first to say it if given an opportunity…

…Dr. Webster has to be considered the number one authority because he has, as I understand it, been studying primarilly influenza for fifty-years. Dr. Osterhaus is a brillant virologist. He identified and proved that SARS was in fact the corona virus. However, he spends time on many different kinds of viruses.
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Tom DVM – at 12:32

De jure.

Sometimes (more often than not) generalists see things more clearly than specialists. If one only concentrates on influenza in birds for instance, they would miss the mutations and other changes including widening habitats going on with parasites to animals and plants, bacteria, fungi, and viruses that did not begin very long ago but is consistently accelerating at this time…

…you can’t understand one of them (H5N1) without understanding all of them.

I have no doubt that global warming, sunspot activity and other unknown pressors are acting here and have been for some time. Medical Maven says that we are in for unprecedented levels of sunspots until 2012 and therefore, there is not going to be a trend change until that time…and we will deal with lag effects for probably ten years after that until 2022 approx.

I think flu wiki is a leader because of a wide range of generalists from every concievable angles are pushing each other to greater heights…the ‘hive mind’ at work…credits to whoever first coined the phrase here.
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diana – at 12:32

I thought Kim Jong was ill? In his case if we are lucky, terminally? Who would replace him? I also thought China was trying to reign him in. Perhaps the information I have been reading is wrong. I really haven’t been keeping track since there are so many new stories that I get from the internet, since newspapers and T.V. and radio seem to trim news to their own agendas. The internet of course is a hotbed of misinformation as well as news that regular channels don’t deem fit for us to read.
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De jure – at 12:36

Tom at 12:24: Who does see the whole picture? That’s my point. If we were to use a connect-the-dots puzzle as an example for this situation, most folks who have spoken out on the issue would say we have enough dots to connect. I believe JFT might say we are missing the head, face, torso, etc. of the beast, while most others have simply inferred where the dots would be based on what they think the head, face, etc. look like. I get what you’re saying. I think the beast could look how you’ve drawn it (terribly ferocious, as you’ve described). However, we might need another professional group to tell us where the rest of the dots are (e.g. virologists). Would I wait for their opinion? No. By the way, how is your prepping coming along? I agree that JFT, Webster and Osterhaus are exemplary in their fields. I wonder, why is Dr. Osterhaus not as vocal as Dr. Webster on this issue, would you imagine?
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Klatu – at 12:52

Mammalian H5N1 Evolution in Indonesia

Recombinomics Commentary October 7, 2006

“The recent announcements of H5N1 bird flu in cats in Indonesia, coupled with results from expanded sequencing of poultry strongly signal the existence of a separate mammalian H5N1 reservoir in Indonesia that is responsible for the vast majority of human cases.

This separate reservoir creates significant problems, because most of the attention has focused on infected poultry, and the mammalian reservoir has been significantly under investigated and under reported.

Therefore, a review of the evolution of this mammalian reservoir is useful. Although Indonesia did not acknowledge H5N1 infections until 2004, the first isolates were from birds in 2003. Sequence analysis of the 2003 and 2004 isolates indicated the H5N1 was Clade 2 and had a number of genetic markers that were specific for Indonesia.

The first human case was reported in July of 2005, and the sequence of the isolate, A/Indonesia/5/2005 had the Indonesia specific markers, but also had a number of unique polymorphisms, including one that created a novel HA cleavage site, RESRRKKR. However, the second human isolate, A/Indonesia/6/2005 had the more common HA cleavage site, RERRRKKR, and was similar to bird isolates. Subsequent human isolates in 2005 had the novel cleavage site, but several had an additional silent change, so although the cleavage site matched the first sequence at the protein level, there were a number of changes at the nucleotide level that divided the sequences with the novel cleavage site into two groups.

However, as the number of sequences increased in early 2006, it became increasingly clear that the human sequences were separating from the poultry sequences, all of which had the common bird cleavage site. The first match of the human sequences was from H5N1 from a throat swab of a cat in Indramayu near a residence were two siblings died from H5N1 infections. The sequence of the cat isolate not only matched the more recent human sequences, but was very close to the sequences of the isolates from the two siblings, A/Indonesia/283H/2006 and A/Indonesia/286H/2006, as well as other human isolates from Indramayu, A/Indonesia/292H/2006 and A/Indonesia/304H/2006. New isolates in 2006 collected from patients in East and West Java were sequenced and all were matches of more recent sequences such as the four human and one cat isolate from Indramayu.

In May of 2006 however, there was a new cluster in the Karo regency in north Sumatra. This outbreak was the largest to date and involve secondary and tertiary transmissions of H5N1. Consequently a meeting was call by WHO and consultants in Jakarta in June. Included in the presentation was a phylogenetic tree that summarized the H5N1 Indonesian isolates as of June 12, 2006.

The tree, which had the human sequences in green and the Karo cluster shaded in pink, clearly showed the match problem. All of the sequences with the novel cleavage site were on the lower portion of the tree and there were no poultry sequences on these two lower branches. Moreover, all of the recent human sequences from Java were on the lowest branch, which was even further from the poultry isolates. Thus, the human isolates were evolving away from the poultry isolates, suggesting the existence of a separate mammalian reservoir.

However, all of the human isolates were from July, 2005 or later, while most of the bird isolates were from earlier dates. Therefore 91 samples were schedule for shipment to Australia for virus isolation and sequencing. The samples were from infections between September, 2005 and March, 2006.

As sequences from these more recent and geographically dispersed isolates began to be published, it was becoming increasingly clear that the vast majority of the human infections on Java were not from domestic poultry. Each human sequence mapped to the lower portion of the tree and which was more distinct from the bird sequences.

The second set of new bird sequences included an isolate with the novel cleavage site. It was from a duck on Indramayu isolated in 2006. However, that isolate match the upper branch of the human sequences, which were composed of six isolates from three patients in 2005. Thus, although every human isolate in 2006 was matching the lower branch, the one duck sequence matched the upper branch.

The third set of poultry sequence had two matched with the lower branch. However, the two matches were from chickens in central Sumatra from 2005. Thus, none of the poultry isolates matched the lower human branch, while all human isolates, as well as the cat isolate, matched the lower human branch.

  * These data again supported a separate reservoir for the human sequences, and the only matches on Java were from the one cat, and all human isolates. The recent announcement indicates more H5N1 has been detected in cats, but the sequences of those isolates have not been released. Swine H5N1 sequences have been reported, but none match the human sequences.

The match failures pose a major problem because testing of humans is largely limited to patients how have been near dead or dying poultry. However, the poultry association has not been linked to the human infections, so an expanded testing of patients with symptoms is warranted. Similarly, more sequencing of H5N1 from other reservoirs is warranted by the match failures between mammalian and avian sequences.”

http://www.recombino...

The following may help connect another dot.

http://www.fao.org/d...
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De jure – at 13:04

Dr. Niman, IMHO, is a brilliant man but refuses to admit that he could ever be wrong, about anything. It reminds me of the old saying, “I thought I was wrong about something once, but I was mistaken.” Without any other virologists weighing in on this debate, we as a fluwikie group will either be great visionaries, or complete imbeciles. Oh well. Reminds me of another saying: “‘tis better to be a live dog than a dead lion.”
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Medical Maven – at 13:04

Tom, if there is some “evil eye” on some mountain top ready to radiate panflu to the rest of the world I have no doubt that North Korea would be a prime candidate. Forget about Africa being the “Heart of Darkness”, it is that Hermit Kingdom lurching along, something straight out of the Middle Ages as you said. And maybe ready to grace us with a plague out of the Middle Ages.
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OnandAnon – at 13:33

It would not be the first time in history, by far too many, that epedemiologists followed the wrong clue for too long because of what everyone “knows”, witness the search for H. Influenzae during 19181–1925.

It may be that there is another mammalian reservoir for this flu. If so, that would seem to be bad news, no?
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Klatu – at 13:36

De jure – at 13:04 wrote:

Dr. Niman, IMHO, is a brilliant man but refuses to admit that he could ever be wrong, about anything.

Lets chew on the following….

“Next influenza pandemic may not be due to H5N1″

Chinese Medical Journal, 2006, Vol. 119 No. 17 : 1458–1464

CONCLUSION

“In Netherlands/Germany in 2003, the highly pathogenic H7N7 influenza viruses that was lethal to poultry infected the eyes of more than 80 people and killed one person; H6 and H9 have spread from a wild aquatic bird reservoir to domestic poultry over the past 10 years.

H9N2 viruses have also been associated with human infections in the mainland of China and Hong Kong. Avian influenza H10N7 seems to have crossed the species barrier from poultry to people for the first time. Hence, it is possible that the next influenza pandemic may not be due to H5N1.

http://tinyurl.com/k...
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Klatu – at 13:42

Given a choice, I prefer to be a breathing, “visionary - imbecile”. My 2-cents. Consider the sources and follow the money, before you make up your mind.
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Dude – at 14:04

Hi all, the graphs of the individual cases are on singtome (Individuals info for graph(1)(1).10.06.2006). I tend to let the data speak for itself. All of our study about the H5 binding site and the N1 properties etc. have great import but limited focus. We don’t have enough science yet! So, to ask a scientist to speculate, you get a perfectly reasonable answer given the context. I keep stressing on my posts, that we need to look at what we can also say about what we do know. Floridagirl deserves the credit for taking my idea and putting so much effort into making it easy for us to see what is happening. Look and see what your thoughts are about this presentation of the data. I also put up a series of graphs in which I extrapolated the case onset dates from her data and plotted all of the cases worldwide. Don’t get concerned about 9 cases in one day etc. Sometimes the data had no information that allowed us to pinpoint the exact date and I simply distributed the unknowns on the 15th of the month. So there is a small bias in there that does not affect the overall import of the data. All cases plotted for each year are (2003individualcases, 2004individualcases, etc.)
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Grace RN – at 14:49

Pandemic are recurrent events, and unstoppable at this point in time. Earthquakes are recurrent events, with a field of scientists as desperate as we are looking for a way to predict them to help reduce loss of life etc.

That said; all that is left is to live in awareness of such possibilities, plan for the worst, hope for the best and enjoy each microsecond we have. Try to help others do the same.

In 100 years our great-great grandchildren might laugh saying- oh no-not able to predict and prevent such things?! Such backward times they lived in ….

[I’m hoping that’s what they say, at least]
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De jure – at 14:59

Katu at 13:36: I agree completely. I’ve always said it wouldn’t surprise me if we see H7N7 before H5N1, due to its ability to efficiently spread. Whatever strain emerges as the next human pandemic, it won’t be pleasant. And one can’t argue with the growing numbers of H5N1 victims. But we still don’t know if the outbreaks in Indonesia, China, etc. will explode or not. I think now as compared to a year ago that there is a higher chance that it will happen, but I’m no expert. Lots of folks probably thought that at one time or another (especially around ‘67) that the Soviets were poised to nuke us. Who knows, they still might. There were plenty of circumstances to indicate there was a high probability that this would happen, so much so that many good citizens built bomb shelters (with good money, I might add). I’m not saying they were foolish for doing so. I might have done the same. But I would have only done so after getting all of the info that I could, preferably from those who knew something about missile accuracy, nuclear detonations, etc. Up until now, we haven’t really had (with the exception of Dr. Niman) any virologists say WHY they don’t know if H5N1 could transmit efficiently. For that matter, we really don’t know why Dr. Webster feels the way he does. So here we have JKT explain that based on what virologists know about lethal flu strains, H5N1 doesn’t work like the others in human to human infectivity (based on positions 190 and 225 in the hemagluttinin sequence). Now I’m not willing to bet that H5N1 will never learn how to go H2H efficiently (especially not on the CDC’s lukewarm, unsuccessful and probably dangerous attempts to get it to reassort with H3N2). Yes, I’m still prepping, but there are major questions that still need to be answered.
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anon_22 – at 15:14

This is a great discussion! I have reservations about some of the stuff that Niman says as you all know but I do think he has a point about Indonesia. Monotreme and I have been speculating about mammalian hosts for a little while, and it seems to me the more we fail to find poultry isolates that match the human ones, the more urgent is the need to look for alternative reservoir(s). The hypothesis about cats is a perfectly reasonable one, which one can’t prove one way or the other for the moment, but it is entirely compatible with what we are seeing and what we do know about H5N1. The larger the number of human cases, particularly with recent increased anxiety from Indonesian authorities, it would be very odd not to be able to find significant no of matching bird sequences.

I don’t think there is anything that JKT is saying that is incompatible with that. I’m sure he probably speculates as much as any of us about this in private.

I just wish we have more a) bird samples clearly identified as being obtained from the immediate area of specific human cases, and samples from b) cats, and c) pigs. Intuitively, I’m more inclined to lean towards cats as more likely reservoirs than pigs at the moment, one simple reason being Indonesia is a largely muslim country, so pig farming shouldn’t be prevalent at all, except in non-Muslim islands like Bali, where we are not seeing human outbreaks!

In addition, we already know for sure that H5N1 a) can infect cats, b) can be asymptomatic in cats, c) can be transmitted from cat to cat. None of which has been clearly demonstrated in pigs, apart from rare isolates for which we have no history!
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Medical Maven – at 15:23

De jure at 14:59-I may be missing something, but with H5N1 being so unlike other influenzas, would it be so strange for its “infectivity” to be out of the mold also? And that we know even less about the possible trajectories for this influenza virus as opposed to the other viruses that we have become familiar with and studied? I just saw another recent article about how the “experts” are deviating more and more from the standard wisdom that the Black Plague was spread by fleas. It more likely a rogue virus, just like H5N1 seems to be. LIke Tom DVM repeatedly points out it is a “freak”, and he gives the reasons why.

So we are dealing with a “freak”. Trust your instincts, (as I know you are), and be afraid, very afraid.
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anon_22 – at 15:23

So what do we actually know for sure?

1. pandemics happen
2. they tend to kill lots of people
3. influenza A viruses can infect new species every now and then, and when they do, eg pigs, they can persist
4. H5N1 can infect humans
5. H5N1 can go h2h
6. H5N1 can infect cats and cause fatal disease
7. H5N1 can, after jumping the species barrier from bird to cat, immediately go cat2cat efficiently, killing a lot of them!
8. The number of human cases continue to increase
9. The proportion of human cases that are in clusters appear to increase steadily (not erratically!)
10. in other countries with human outbreaks except for Indonesia, the human H5N1 sequences have a high degree of correspondence to the avian ones
11. Indonesia has the most no of human cases, highest fatality, and apparent difficulty in eradication (which may or may not be directly related to inadequate culling of poultry).
12. Indonesia also has the unique problem of having an increasingly odd mismatch between avian and human sequences
13. Indonesia is a Muslim country, ie there shouldn’t be a large swine reservoir

A question that often reoccurs to me when the subject of the H7 outbreak in Holland is why did it stop. I realise the symptoms were just a conjunctivitis and not in the lungs but when so many of the family members of the poultry workers were infected why or where did it stop.
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cottontop – at 16:30

TomDVM

you have put chills down my spine! I just don’t want to accept what you’ve been saying, but I respect your attention to pattern. My father was like that, and damned if he didn’t get it right. I “hear” alot of my father in your words, and I respected this man, for all his wisdom. You seem level headed, rational enough, to look, and get a feel for the situation. I dearly wish my father and I could discuss this. It’s right up our alley. Instead of talking to you, I’d be talking to him. So you’ve sorta filled a “void” for me, with your voice. You sound alot like him. (Just a thank you. I don’t feel so alone, for him not being here to guide me.)
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Pixie – at 17:40

Thanks Klatu - The FAO report you posted is interesting. Looking at the chart on slaughterhouses by geographical area, it seems that the areas that had the greatest number of ruminent processing plants (goats, sheep, cattle) are also the areas in which we are seeing human infections:

  * East Java - 229
  * West Java - 157
  * Central Java - 79
  * South Sulawesi - 42

The relationship between the much larger number of ruminent processing plants (and thus probably livestock) in these areas and human infections may simply be a function of larger and denser human populations in those areas vs. the other 23 areas listed on the chart. I have no theory at all forming from this - I just thought the data was interesting. Klatu’s FAO link: http://tinyurl.com/m...
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anon_22 – at 19:17

Krazer – at 16:08

A question that often reoccurs to me when the subject of the H7 outbreak in Holland is why did it stop. I realise the symptoms were just a conjunctivitis and not in the lungs but when so many of the family members of the poultry workers were infected why or where did it stop.

Most of the family members were asymptomatic. Which means that the virus had acquired some limited h2h ability, but not enough fitness to survive the host immune response. And they culled millions and millions of poultry, after which they put in more stringent biosecurity measures.
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Tom DVM – at 23:28

cottontop. Thanks for your most kind words.

About that comment…”you have put chills down my spine!”

I treat everyone here as a trusted colleague…I believe the truth sets you free…and I believe that everyone understands that I am only giving one opinion…

… an essential part of the ethical equation is that we continue to question each other and build and re-build hypotheses such that we can follow an interesting scientific dilemma with the hopes of being of some help.

In science, hopefully chills are quickly replaced by genuine intrigue and interest. /:0)

I know that is the case with you and I hope you will continue to contribute. Thanks again.
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Tom DVM – at 23:31

anon 22 15:23.

You just did it again…clear, concise and complete.