Forum: Conversations with a Virologist Part 2

This is continued from part 1

First post: 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.

I’ve stopped posting on this subject for a while cos of a problem that I got stuck on, which has now been resolved.

The problem that I had, on studying the recent paper A preliminary panorama of the diversity of N1 subtype influenza viruses, Chen et al, was whether their finding was in conflict with JKT’s hypothesis about the origins of the 1918 virus. The answer is not, they actually validated his original premise that the ancestor of the 1918 H1N1 had come into general circulation shortly before 1918.

The Chen paper is essentially an overview of all known N1 sequences. Without going into the detailed phyogenetic analysis, basically all current N1 sequences can be broadly separated into avian, human, and classical swine lineages. 3 things about this paper that bear relevance to our discussion:

1 all these different lineages could be traced back to a common ancestor, of which the Brevig/1918 (the sample from Alaska) appeared closest to the ancestral node. If you take the differences and extrapolate the rate of change backwards, you would get an intersection at around the year 1890, which is consistent with JKT’s findings from HA and NA genes of the 1918 virus.

The first chart is from Integrating historical, clinical and molecular genetic data to explain the origin and virulenbce of 1918 virus, Taubenberger et al 2001

The second one is from the recent Chen paper, showing regression analysis of N1 sequences from the classical swine and human lineages. Note how similar the 2 results are.

2 The Phylogenetic analysis showed that of the avian, human, and classical swine lineages, the avian one was the most diversified, with 11 sublineages. This is consistent with the Holmes paper that I mentioned in the first post of the Talking to JKT thread, that flu viruses in birds are actually not in evolutionary stasis, but rapidly evolving in a similar way to those in human hosts. The N1 phylogenetic tree shows this very clearly, that even within the 100 year time-frame that we are observing, there is a tremendous diversity obtained.

Note also that all HPAI H5N1 are situated in multiple sublineages, with those causing the 1997 Hong Kong human outbreaks (#8) and the current H5N1 (#11)belong to distinct sublineages.

3 Even though the N1 in human H1N1 is distinct from the N1 in H5N1, they are still descendants of a common ancester arising probably in the late 19-century, which probably wiped out all other N1′s in existence. Exactly how this happened is unknown.

But the significance is that there may indeed be some human immunity to H5N1 from prior infection with H1N1 or from vaccination. This may not be enough to prevent infection, but it may be enough to mitigate the impact.

The reason why the 1968 pandemic was milder than the 1957 one was because the N2 gene was not replaced. The difference in mortality of the 2 pandemics may reflect the degree that human immunity to the NA protein would confer protection.

However, the N2 in the 1968 was exactly the same as in 1957, so the degree of protection would be more than the degree of protection that one might expect against H5N1 from prior H1N1 infections or vaccination.

hey, I spent all that time writing this, I figure I should bump this up!! :-)

anon_22 – at 20:05

You wrote: But the significance is that there may indeed be some human immunity to H5N1 from prior infection with H1N1 or from vaccination.

I am not too sure that what you wrote gives me a lot of comfort. I would assume that people in countries have also been exposed to the N1 gene, either by having the flu or getting the vaccination. The CFR is still high…

That being said… it still makes sense there would be some type of immunity / resistence if exposed to the N1 gene in H5N1 for a certain portion of the population(s).

FloridaGirl,

Younger people would not have been exposed repeatedly to H1N1 as older people.

Uhh, so there’s a sound basis for ‘68 being mild (N2 being the same as ‘57 conferring some measure of immunity) but no basis for the present N1? (That’s kinda how I’ve understood it so far…)

Bump away! :)

Therefore more reason for younger people to get the seasonal flu vaccine.

Wolf, there is, except the effect may not be as big as 1968, since the 1968 and 57 N2 were exactly the same, whereas N1 from H1N1 and H5N1 are related but not exactly the same.

anon_22 - Thank you. I’m not sure I can completely understand everything you are saying, but I’m hoping there is SOME hope in your statement in BOLD:

But the significance is that there may indeed be some human immunity to H5N1 from prior infection with H1N1 or from vaccination. This may not be enough to prevent infection, but it may be enough to mitigate the impact.

This COULD help me sleep tonight, if I understand you correctly. Especially given the latest news about the sub-liniage of H5N1 (the Fujian strain). It seems to prove your point to some degree, doesn’t it? Does this lower your anxiety level at all?

Anxiously awaiting your reply. Thanks!

Patch,

I don’t know about lowering anxiety level cos I’m not the anxious type, but I do find the N1 immunity issue a source of some hope. And it gives me a reason for suggesting regular flu vaccinations, particularly for those of the highest risk age groups.

In simple layman’s language, then, H5N1 won’t be as dangerous as thought?

BeWell – at 22:49

In simple layman’s language, then, H5N1 won’t be as dangerous as thought?

I wouldn’t say that, since our ability to predict how dangergous H5N1 is is rather limited. ie we don’t know whether it will become pandemic, whether the CFR will drop and by how much. Given these large variables, any possible small gain in immunity from N1 may be rather insignificant. Or it could be significant enough to make the difference between life and death. We just don’t know. This is more a theoretical discussion than a quantitative observation.

Sorry to disappoint you. :-)

Not disappointed at all. I’m an irregular reader of FW, just got done with a week of “graping” so I’m catching up here. (Canned 35 qts of grape juice and 40 pints of grape jam.)

Am a non-medical professional, so I read up and try to understand as best I can. I appreciate the expertise here!

Anon_22 - Not that you need my blessing, but your work/information contained here in this thread has led me to hold your opinion in much higher regard. Again, not that you need my respect, but I sincerely appreciate someone who is able to explore both sides of this issue.

All too often, it appears we see the glass as half empty and proving it becomes our only vision.

Again, thank you! Very interesting information!

Hi Anon-22!!

You are so smart! Thank you from all you do!

Would the poeple that have thus far, had H5N1 be more unlikely to have been vaccinated against flu? Does this years flu vaccine, have N1 in it? We have all gotten it, one advantage to ALL being high risk….I guess… If the human outbreaks have been in areas of mostly unvaccinated people, we may not know how the H5 would effect vaccinated people??? I’m so tired tonight, but sure would like one small sliver of hope…SOMEWHERE!

mom11 – at 23:59

Does this years flu vaccine, have N1 in it?

Look at the WHO Recommendations for Influenza Vaccine Composition Northern hemisphere: 2006-2007

It is recommended that vaccines to be used in the 2006–7 season (northern hemisphere winter) contain the following:

• an A/New Caledonia/20/99(H1N1)-like virus;
• an A/Wisconsin/67/2005 (H3N2)-like virusa;
• a B/Malaysia/2506/2004-like virusb

Thanks Anon_22!

I’ll go read this! Did you get your shot??

NOt yet, will do so next week.

Fascinating - thanks Anon-22!

Well, I would hate to rain on anyone’s parade. /:0)

Patch. I think we can deal with the realities here and still conclude that the cup is half full. Maybe it is the scientific threads that I read here…but I rarely see anyone being overly pessimistic. Science isn’t about reassuring people it is about the ‘cold hard truth’ of the matter…let the chips fall where they may…sort of thing.

Based on anon 22′s excellent studies, maybe we should be looking at 1968 as another wave of the 1957 pandemic or alternatively we should be looking at both 1957 and 1968 as waves of the 1918 pandemic.

It is interesting that N1′s apex is 1890 considering a pandemic of approx. virulence to 1918 occurred in 1890.

My thinking like everyone elses here as evolved since I came on flu wiki eight months ago.

The conclusion I have come to is that a catastrophic event occurred sometime before 1918. This event produced the completely unique virus H1N1 that has dominated the field of play for the last century. In 1997, a ‘kissing cousin’ of H1N1, also a completely unique virus has emerged…and at some point in the near future it will dominate the next century squeezing the offspring of H1N1 out of the picture.

We have been in a quiescent period in respect to pathogens in our lifetimes that came to an end in 1980 with the emergence of Aids and Ebola and has ended with H5N1.

The pandemic in 1918 was not an extraordinary event but a normal event that may take place more than once a century…in the eighteen-hundreds, there were two pandemics similar to 1918 in 1830 and 1890.

I have a problem with the statement that a vaccine that has the poorest performance of probably any commonly used vaccine is not going to work on seasonal influenza, will work on the incredibly virulent ‘China virus’..this conclusion defies all logic, in my opinion.

TomDVM at 11:41:

A posterity post for sure. I too was surprised by the confirmation of a N1 apex in 1890. This means that the older people experiencing protection in 1918 wasn’t as likely to be due to a mild earlier flu as suppossed, but to exposure in 1890. Like you my thinking has evolved, and I don’t see how the seasonal flu vaccine will change the prognosis if exposed to H5N1. Another clutching at straws scenario?

Contemplating a viral pandemic as a normal event is disquieting but the evidence is present to support it. Clean water, plentiful food, safe housing and drugs and medical care have given us an illusion of being victorious in disease. HIV was the wakeup call and some type of flu will be the curtain call in healthcare at least.

Get ready for the new world? Or get the new world ready?

Thanks for writing all this out, anon_22

anon_22 – at 20:05 said “But the significance is that there may indeed be some human immunity to H5N1 from prior infection with H1N1 or from vaccination.”

What percentage of people in Vietnam and Indonesia would have had H1N1 infections at some time in their lives ? (Given that most of them weren’t alive in 1918, it would most likely be a modern strain.)

anon_22 ¨C at 20:05 wrote

3 Even though the N1 in human H1N1 is distinct from the N1 in H5N1, they are still descendants of a common ancester arising probably in the late 19-century, which probably wiped out all other N1¡äs in existence. Exactly how this happened is unknown.

OK I read this and then I went back and followed the threads about this concept of a global virus extinction and replacement by H1N1. While I have a strong grasp of science (chem engineer) I cannot quite get my head around this. Let me restate this and tell what I am missing.

1. The data indicates a convergence for N1 mutations for “all” existing strains around 1890. What do we know about the other subtypes of Ha and Na?

2. H1N1 “replaced” the pre-existing strains. What strains just H1N1, all H?N? subtypes.

3. In what hosts? It seems that you are saying in all(human, pig and bird). This seems odd as I can’t see any driving force to cause the repacement in animals (birds) with subclinical infections.

Thanks for all the great information. Re your previous thread that went off the rails, my father had a saying; “Good science results from the abrasion of ideas not personalities”. Dad was real smart!

CASafetymgr – at 20:06

H1N1 “replaced” the pre-existing strains.

In humans, that is. From 1918 to 1957, H1N1 was the only circulating human strain.

The data indicates a convergence for N1 mutations for “all” existing strains around 1890. What do we know about the other subtypes of Ha and Na?

I don’t believe anybody has done any research on other subtypes. This recent paper on N1 is only an overview, so that tells you how little has been done.

a’Akova – at 19:34

What percentage of people in Vietnam and Indonesia would have had H1N1 infections at some time in their lives ? (Given that most of them weren’t alive in 1918, it would most likely be a modern strain.)

I don’t know. I’ll have to do a literature search for anything like that. There may be some data but I doubt there will be any specifically for Vietnam and Indonesia.

There are a couple of other papers which I’ve only received in the last 24 hours, which will have more bearing on some of these questions. I need to find time to write them up. I just got off a 13 hour flight. :-) So hang on to your questions for a bit, and I’ll try to get some more info in the next couple days.

I just realized I went through 12 time zones in the last 3 days.

Where is the jetlag?

<anon_22 is nonplussed>

anon_22 – at 06:27

Where is the jetlag?

You have gone full circle and finally caught up with yourself;-)

anon_22 – at 06:27

Where is the jetlag?

It caught a later plane, has been lost by the baggage handlers and will call you in a few days asking to picked up from Heathrow ‘cos it’s run out of money ;-)

Okieman – at 08:07

uk bird – at 08:51

LOL.

I love both your answers!

anon_22

I (actually I’m sure it’s “we”) appreciate your work in researching this and breaking it down to English. I can’t imagine the time it takes to get your arms around this well enough to explain it to us, but thanks for taking the time.

The biggest question for me is, if the world would have “some” immunity, why aren’t current cases showing some type of immunity…at least to the virulence??

Or….is it possible, that the reason it hasn’t become an efficient H2H virus, is because most of the world DOES have some immunity?

Patch,

We are talking about relative immunity. There are lots of people exposed and not infected. Right now we don’t know how much of that has to do with the virus not being very ‘fit’ and how much of that has to do with immunity.

But in an established pandemic, you would expect almost everyone to be susceptible, to varying degrees. So that varying degree may depend on a minimal amount of immunity.

I have to emphasize this is speculation, as we won’t know until we find out. And I hope we never find out. :-)

Perfectly explained. Please keep us informed.

Thanks! And best wishes!

anon_22:

Do we know if there are any groups that have been vaccinated with regular vax as soon as cases/clusters have been discovered in any countries/areas where there have been H5N1 outbreaks?

anon_22 Thank you for all your hard work. Appreciate your ability to put this, and all your work, in understandable language. Do not know how you do all that you do, including traveling around enough to make my head spin. Know you did not make the DCMDVA group meeting because you were about tapped out, so please, take good care of yourself, we need your expertise and reasoning!

Tom DVM – at 11:41 (31 October 2006): “The pandemic in 1918 was not an extraordinary event but a normal event that may take place more than once a century…in the eighteen-hundreds, there were two pandemics similar to 1918 in 1830 and 1890.”

Not true. As I said in a prior post, the 1918–1919 pandemic had no equal. See Marble (26Sep2006 23:28)

Marble, I think you are right.

Cross posting from the News thread

HOT OFF THE PRESS - Samples of 1918 first wave virus found

Taubenberger’s team at the NIH working on pre-1918 autopsy samples from London have found 3 samples that tested positve for flu from January - July 1918. This result was only obtained 4 days ago, ie Nov 8, and they haven’t characterized it yet.

Taubenberger mentioned it in his latest NIH videocast Great Teachers - Influenza: Past Pandemics and Future Threats

Also, 31 cases from 1908–17 tested positive by RT-PCR (for the matrix gene) for influenza RNA, of which 15 were positive for H3. They have not been able to characterize the NA gene yet, but tests for N1, N2, N3, N4, N6, N8 were all negative.

COMMENT

I was so excited when I first heard this from his email that it was a bit hard to keep that to myself until I was sure that he had gone public with it. :-)

I hardly need to point out how important it would be if we can find out the characteristics of the virus going round in the first wave.

Let’s hope that RT-PCR comes back as H1. Then we’re in business.

Or at least they are….