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Must a Pandemic Strain of Influenza decrease in lethality?
This is a question that has been addressed several times on this forum, but new data prompts me to consider the question once again. We now know that H5N1 truly is a highly lethal virus in humans. The recent release of seroprevalence data has established this as fact. The arugment that a flu virus must avoid killing its host has been discussed extensively. My conclusion is that this is not true because virus is shed before the host becomes ill, so there is no selective pressure to spare the host. Additional recent evidence, and a rethinking of the genomic structure of influenza viruses provides additional reasons to think that H5N1 may be able to retain a very high level of lethality when/if it becomes a pandemic strain.
Influenza is an unusual virus in that its genes are separated into 8 distinct segments. The hemagluttin gene (HA) is responsible for entry of the virus into the host cell. It is also likely that this gene is important for initiating a pandemic as it must acquire the ability to infect the upper respiratory system in order to be transmitted efficiently between humans in respiratory droplets.
Viruses evolve via 3 mechanisms - random mutation, reassortment and recombination. Reassortment involves exchange of entire viral genomic segments while recombination involves exchange of subsegments. However, regardless of how H5N1 evolves, because of its segmented genome, HAs can change independently of other H5N1 genes. Recent studies demonstrate that this viral gene swapping occurs much more often in influenza viruses than was previously thought. Thus, H5N1 could acquire an HA adapted for efficient spread of virus without affecting the other genes in its genome. Thus, the question of which genes contribute to its virulence become key in understanding its potential lethality as a pandemic strain.
Both the polymerase gene complex and NS1 are thought to be major contributors to the high lethality of H5N1. They are not on the same genomic segment as HA. So, there is no reason to think that a change in the HA gene that permitted efficient human to human spread would affect the lethality of the virus, at least that part of the lethality that is due to genes other than HA.
There is still much we don’t understand about influenza viruses, so there may constraints in its behaviour that put an upper limit on its lethality in pandemic strains. But if so, we have no evidence of them that I am aware of. We have concrete reasons to think that the virus may be much more lethal than the 1918 virus. Yet, all our official planning is based on the assumption that a 2.5% fatality rate is the maximum. I would argue that, based on the available evidence, not only is a much higher fatality rate the true worst case scenario, it’s the most likely scenario if H5N1 becomes a panflu.
Recent posts:
22 May 2006 anonymous – at 10:00
anonymous – at 02:48 there is a common argument that the CFR (case fatality rate) will decrease in a pandemic. The virus can better spread when the host lives. This is a common observation with other viruses. It was clearly observed in the 1918 pandemics.
However, H5N1 could be different. We didn’t so far observe any decrease in CFR, neither in chickens nor in humans. We do have asymptomatic ducks, and less severe desease in some animals, though. But when H5N1 goes efficient h2h, can we assume that selection would favour less lethal strains and mutations ? Will people who recover spread more virus to others than people who die ?
lugon – at 04:26 This has been dealt with at Forum.MustAPanFluDecreaseInLethality.
Short answer: no, CFR doesn’t have to decrease. It might, and we all wish it would.
If selection does favour less lethal strains, then that’s one more reason to buy time and try to make it happen in slow motion - or at least in a slower motion - in order to let the not-so-evil strains advance faster than the really evil ones. If we can.
Please go to that other thread. Admins, could we close this one? Thanks!
anonymous – at 04:56 yes, it has been discussed before. But I am missing arguments why H5N1-survivors are more likely to spread virus to others than non-survivors. Are we more likely to isolate (handle,bury) non-survivors more carefully than survivors ? What’s the difference here between 1918 H1N1 and possible 2006 H5N1 ? Also, many experts still argue that H5N1 would go down in lethality when it goes pandemic. So this is controversy. You can’t just say : “short answer is:no , now close the thread”
anonymous – at 05:08 lugon, that thread is long and not very much on topic. I can’t follow monotreme’s argument in the first post. It seems valid for 1918 H1N1 too, yet the lethality did decrease. I’m not so much interested in whether it “must” decrease, (of course it needn’t) but how likely it will decrease. Yes, virus is shed before infection, but also later. How much more virus is shed by survivors ? That’s the critical question.
lugon – at 05:39 I was suggesting to close this thread, and only to avoid duplication. We can of course continue here, and close the other (or at least redirect new posters to this one).
There is controversy. But there wasn’t much of it before, at least not that I was aware of. In my opinion, before it was more or less blindly accepted that lethality must come down. Now we (or at least I) are not so sure. So yes, the possibility space has widened.
And the probability space is as muddled as it was before. My personal opinion is we must act on possibilities, and looking for probabilities takes away energy I need for other tasks.
The possibility space includes:
a hard pandemic soon a mild pandemic soon a hard pandemic later a mild pandemic later
I believe even “a mild pandemic later” (say lethality 0.3%) would be highly disruptive in a globalised world that depends on travel. I would be surprised, gladly surprised, if it were different. Call it a 95% or higher if you like.
I believe a highly lethal, highly disruptive, “sooner rather than later” pandemic is possible. I don’t know how likely. If it is 10% this year (and I don’t know) then that’s enough. 5% is still enough. 1% is still enough.
Give me a limit where it’s not enough. Then ask that question.
Sorry if I sound upset. I am, at times. I reply because I feel your arguments are valid, but I don’t see how we could move forward from this “probabilities? I don’t know! but how come? I don’t know” loop.
I feel we can make a strong case for preparation without probabilities. See this thread.
How much more virus is shed by survivors? I don’t know what will happen when there’s a pandemic. I would guess non-symptomatic carriers (before falling ill or those who don’t fall ill at all) shed less but for a longer time. I don’t know what the net (pun implied) effect would be. (Any expert in simulations here?) Social distance and so on do make sense in any case. To what degree? We’ll have to find out as we go along, if we can.
anonymous – at 06:03 you address the individual preparations done here, not the important decisions on government basis. When it comes to billions of $, you definitely want some numbers to justify your decisions.
To compare the R_0 of H5N1-survivors in a pandemic with that of H5N1-deaths, it’s easier to think about the differences from 1918. What’s the infection-time, the estimated number of people infected before onset of symptoms , defore death, after death, before recovery, after recovery. What can we do to improve these numbers ? (only ethical suggestions) Clearly, the more severe an illness is, the more we should avoid infection. Not only for our own immediate health but also for disruption of the spread of the dangerous strain. Should we go so far to “support” mild strains in a pandemic ?
lugon – at 06:37 I wrote: Give me a limit where it’s not enough. Then ask that question.
Anonymous wrote: you address the individual preparations done here, not the important decisions on government basis. When it comes to billions of $, you definitely want some numbers to justify your decisions.
Yes, some numbers: a 1% possibility of a civilization breaker. A 5% possibility of major disruption. A 20% possibility of major health-care disruption.
Do you really think they are not paying attention? It’s just that they don’t know what to do.
Or maybe numbers would bring people on board faster?
Please, do create a page on the wiki titled “the numbers game”, outline why this is so crucial, what you’ve understood about what others say about this, your summary of who has said what regarding numbers, and what we should be doing next.
It’s not that I dismiss your work in this area. It’s just that I find it terribly frustrating. I feel it doesn’t take us any further, at all! An important, yet impossible question.
I suggest you settle it as best you can. I’m moving on to other things. Thank you.
lugon – at 06:39 My numbers are not official: just a way to say “if it’s this or higher, then it’s worth the investment; and it is this or higher”.
Most of the investment would not be monetary, by the way: just plain old talking about it, organising around it, planing for it.
Nikolai---Sydney – at 06:42
And I, too, feel this has been fine-combed on the previously
cited thread. There is no question in anyone’s postings but
that this is a vital question, but there is question as to
whether we need or even wish to rehash it.
anonymous – at 07:36 the old thread is lengthy and the subject of the thread was missed in most of its posts. Alas, the same is happening here already. If lugon and nikolay-sidney don’t like the discussion, they can just skip it. No need to close the thread. Even if it were discussed before, which I can’t see, there are lots of examples in the archive where repitition was no reason to close a thread.
anon_22 – at 08:18 anon,
Go and post your questions on that thread. For the benefit of everyone, it is better for threads of EXACTLY the same question to stay in one place.
lugon – at 08:38 I repeat: I was suggesting to close this thread, and only to avoid duplication. We can of course continue here, and close the other (or at least redirect new posters to this one).
Anonymous - at 07:36 wrote: the subject of the thread was missed in most of its posts. Alas, the same is happening here already. So here’s the subject again: But when H5N1 goes efficient h2h, can we assume that selection would favour less lethal strains and mutations? Will people who recover spread more virus to others than people who die?
My answer to the three questions (well, actually, one assumtion and two questions):
We don’t know if H5N1 will go efficient h2h or not. We don’t know if it will happen, when, or how would the resulting pandemic virus (which H5N1 currently isn’t) behave. If someone asks about probabilities, I will skip it because I badly want to use my limitted time working on something which, in my mind, will be more useful. I think selection favours less lethal strains and mutations … in the long run. But that doesn’t necessarily happen short term. Sometimes it happens, sometimes it doesn’t. The deeper mechanisms escape me: I’d sincerely like to know more about how “selective pressure” works. But the practical conclusion, for me at this stage, is another “I don’t know”. Will people who recover spread more virus to others than people who die? Let me see …
Three groups of people here:
People who will die have a more severe form of the disease than those who will recover. More severe may or may not mean more virions inside the patient, and likewise for shedding. More severe may mean more contacts with care-givers, or less time to contact anyone, or contact with protected care-givers. People who will recover will have a less severe form. They may shed less virions, but for a longer time, and maybe to care-givers who are less protected. Some may even go to work even when ill, at least in the last days of disease when they are a bit better. People with little or no symptoms. They probably shed a small amount of virions, to anyone who is around.
I guess the factors are:
amount of shedding per time-unit number of time-units the patient is alive number of people who are around the case degree of protection by those who are around the case
What info do we have on each? What would happen in a pandemic?
How all of this adds up I don’t know.
crfullmoon – at 10:29
Don’t know either; so many unknowns.
People who die may not have had a worse form of virus; they may have had no caregiver preventing dehydration, ect.
And, dead from many causes not the virus itself, will add to the “surge” of bodies to be buried. Don’t see places buying enough PPE now for surge mortuary needs (and I think places will need to bypass the funeral industry somehow, to get all the extra losses buried. But, live infected people spread virus more than dead ones, who may need contact precautions, (and I’m not sure about surface water contamination - get cemetery departments planning and stocking up at home now, so bodies are getting buried promptly -and with id/paperwork done- but aren’t getting buried where/how they shouldn’t be).
What is anyplace’s HIV rate? This is not even known for sure, because so many don’t get tested. But they and others with low immune systems, (probably can get numbers of transplant or cancer treatments) if they survive, may shed virus for longer, and be more likely to give time for more strain mutations?
Getting people prepared, and, officials able to tolerate erring on the side of caution; don’t tell people not to wear masks, don’t be in a hurry to tell them a wave is over and to stop taking distancing/infection control precautions, ect, might help, but, we need to educate and prepare now.
Having recovering/recovered people still try and take precautions, in case they do shed, is not unreasonable.
We (and tptb) can’t prove pandemic won’t happen, and we can’t prove it won’t drop in lethality, so, better to get preparing.
With being able to spread the virus before one feels ill, and airflight criss-crossing people ‘round the globe every hour of the day and night, a virus could do great damage even if its host dropped in its tracks, as long as it had a few days to spread without symptoms first; it wouldn’t burn itself out to fast not to give it a try. It doesn’t have to make sense long-term -its a virus, and evolution tries everything, for as long or short as possible.
In Barry’s book, he makes a reference to Devaine’s experiment with injecting a rabbit with anthrax and when injecting subsequent rabbits with the blood of the previous rabbit, found the virulence increased form 10 drops (fatal dose) to a millionth of a drop by the 25th rabbit. He called this phenomenon, “passage”. The organism learns to kill more efficiently. It was later shown that passing the same blood through several pigs would have decreased its virulence in rabbits, “attenuation”. A recent investigator found cholera increased virulence 700 times compared to a lab strain after passing through humans. Some assumptions could be made here for H5N1. If given the opportunity to pass though humans in a easily transmittable form, could become more nasty. If pigs pick it up and pass it around in an easily transmissible form before humans pick it up, it may become less lethal.
rrteacher—11:09
I thought I was beyond being shocked by anything further that could come out of the possibilities for this monster virus’s pandemic impact.
I was just demonstrably wrong. The odds of such a pandemic going on for many, many years, and at increading lethality, are obviously far higher than has generally been accepted.
Monotreme, -the old thread was pretty far down out of sight, so you can’t expect new posters to read that far. It takes all day just to keep up with the current day threads, plus there’s other sites and materials competing for reading time. Just repaste up your good speeches for the same questions.Your posts are worthwhile so just keep them coming.
It doesn’t look like any numbers will get the officials moving, but even for individual prepping, imagining what will happen in the lethality rate is obviously of interest. To continue to look into the crystal ball - viruses are “Designs by Accident”.
Each host will have variety in the same virus replicating inside of them. As the environment changes, so will the varieties’ success change. A fast replicating virus can cause greater shedding faster and make the victim sicker faster. In close population density, it will beat out the slower varieties, by outnumbering them and having a higher transmission rate. But when distance increase between the population, the slower virus is more successful, it gives the victim more time to walk further, shedding viruses over more space. Large viral replication won’t equal transmission if the patient is only shedding all the virus in one location, such as a porcelain throne.
We believe close passage, poultry farming allowed low-path. H5N1 to morph up to the high-path. varieties we’ve had in the last 10 years. But notice it has stayed high-path. for 10 years. This may be a little hard to explain since the farm outbreaks can be separated quite a bit in space and time. The virulence may be tied into longevity in the environment or some other successful transmission trait. When it gains the H-2-H mutation, that’s when it might be trading off virulence for some other trait genetically. But once the pandemic is happening, the CFR rate we see then, will then be changing gradually over time. The 1918 virus’ CFR. went up in the second wave, before it went down. That could be due to hitting population densities in the war trenches and Third World slums. We have even greater population densities today.
In my speculation (to separate fact from fancy) if the human virus hasn’t dropped like a rock immediately, in order to go pandemic, then it’s not going to drop like a rock in a few weeks time. It will move slower and faster through different population densities, but basically take a full wave of fresh victims first, before getting weaker. After a third of the population has been infected and has immunity, the population density changes for the virus, less people are available for transmission. This will create more space to bridge for the virus and favor the slower varieties. However, that will be a process over time.
After a year, the 1918 virus approached more normal levels of flu virulence. For the average world population the average flu must work best, since you can’t argue with success, but that’s a population that has immunity recognition of that virus type. The regular flu has to be slower in replicating to have more time to cover more ground. A novel type does not have to be as stealthy; everyone is available for infection. How long it takes a new virus to normalize, will not be as soon as we would like. In short- if it looks very bad, in the first country that gets the pandemic, go ahead and scream into a pillow.
Hi everyone. Interesting as always.
H5N1 can do one of two things. It can remain an avian virus and never successfully become easily transmissible in people…for this to happen, we will have to be incredibly lucky at this point in its steady adaptive and geographical progression.
…or we have a pandemic.
If we have a pandemic, the facts are that there is no compelling reason or requirement for the virus to drop its virulence…it can continue to infect the same number of people and still kill you after you have transmitted the disease.
Once the virus has gone pandemic, it may maintain, increase of decrease virulence…which one happens is dependent on chance alone without any other influencing factors…it’s a crapshoot.
The pandemic will continue for 6 months, 5 years or twenty years…in other words it will continue until every person on the earth is immune by infection or vaccination. I believe the 1918 pandemic was causing smaller after-shocks or smaller waves of infection into the late 1920′s.
As the environment changes, so will the varieties’ success change. A fast replicating virus can cause greater shedding faster and make the victim sicker faster. In close population density, it will beat out the slower varieties, by outnumbering them and having a higher transmission rate. But when distance increase between the population, the slower virus is more successful, it gives the victim more time to walk further, shedding viruses over more space. Large viral replication won’t equal transmission if the patient is only shedding all the virus in one location, such as a porcelain throne.
I’m almost beginning to understand.
So if we change the environment - can we win?
lugon, the way to change the environment and to win is shelter-in-place and produce an effective vaccine as quickly as possible. Even if all human tranmsission were to stop, an impossible task, the virus would still be waiting for us in multiple animal reservoirs. No vaccine, game over.
Monotreme. Given the evidence as it is today, how long do you feel it will take for adequate amounts of vaccine (say for 50% of the population of developed countries) to be produced?
Notice I didn’t mention the word effective.
No vaccine, game over
third world will most likely have no vaccine. If the alternative is
“game over” then it would be reasonable to try everything including
war to force WHO to give them vaccine.
Will India,Pakistan,China,North Korea or other countries which feel
handicapped by WHO-vaccine-distribution-plan threaten with nuclear
strikes to blackmail for vaccine ?
Tom DVM, it depends on the technology and how much risk you are prepared to assume. Conventional technology can, maybe, produce a vaccine for 300 million people in 6 months. Cell based vaccines may shave a month off of that and could be produced in unlimited quantities, if the technology was ready for prime time. Not sure that it is. DNA vaccines would be fastest. If existing molecular biology labs were retrofitted and you were willing to take some risks of adverse side-effects, enough vaccine could be produced for the entire world in a couple of months. And new vaccines could easily be produced if the virus changed. If this could be made to work, it truly would be a magic bullet. Problem is, very little data is available on this approach.
anonymous, most of the countries you mention could have built there own factories to produce vaccine if their governments had a clue. China probably is working on vaccines. The others have no idea what’s about to happen to their people. By the time they figure it out, it’ll be too late for them to do much of anything.
As always thank you for your comments folks.
could have built ? Anyway, it didn’t happen. They are dependent on other country’s vaccine in a pandemic. Will they get some/how much/enough ? Which country will get how much ? You can imagine what will happen, when Pakistan thinks their quote is too low compared with that of India. “Sorry people, there is only vaccine for 3% of the population, only the most corrupt people will get some.”
Re Anonymous — 01:14
“third world will most likely have no vaccine. If the alternative is “game over” then it would be reasonable to try everything including war to force WHO to give them vaccine. Will India,Pakistan,China,North Korea or other countries which feel handicapped by WHO-vaccine-distribution-plan threaten with nuclear strikes to blackmail for vaccine ?”
You imply that almost certainly they will. “And by direct missile and air strikes on the enemy heart: nuke Geneva! That will teach WHO a lesson. AND get tons of vaccine.’
Well, we each and all have our views and are free to express them. Operationally, however, I do not see myself modifying my plans to take this possibility into account…
WHO a lesson, won’t it.
Monotreme – at 21:58
“lugon, the way to change the environment and to win is shelter-in-place and produce an effective vaccine as quickly as possible. Even if all human tranmsission were to stop, an impossible task, the virus would still be waiting for us in multiple animal reservoirs. No vaccine, game over.”
Hi all- what I have been wondering about for ages; If there is a H2H pandemic, will the animal reservoirs be a threat to hunmans? I mean, the H5N1 in birds, pigs and cats is not a direct threat to humans right this moment? Am I correct? The threat is that a pig, bird or cat H5N1 will pick up traits that make it a human H5N1- and start spreading in the human population? At that point, it will be other humans carrying this particular new human H5N1 that would be a threat to me- not birds, pigs or a cat? The bird, pig or cat H5N1 virus would still be relatively difficult (but not impossible) for me to get. Birds are at risk from other birds-cats are at risk from other cats- pigs are at risk from other pigs- humans are at risk from other humans?
Can anyone follow my drift? Monotreme’s post has gotten me wondering-
No vaccine in 1918, right?
Assuming a bad pandemic, 2% of all people may be able to effectively SIP for long enough to come out and get their vaccine 9 months later. (I say 9 months because they will not be the first to get their shot.) From those who can’t SIP, maybe 20% will get their vaccine in the first year.
For most people in the World, this is still 1918.
And we’re asking them to cull their poultry. With no vigorous alternative.
Yes, Civ 2.0. Ask me after I get some extra sleep.
clark at 06:14
when there are lots of sick humans around, that’s also dangerous for cats and dogs, even if the virus will be specialized in humans.
The current virus is specialised in birds but still very dangerous for cats.
When people can get it from other people, then cats will probably also get it from people and other people will get it from those cats,
although probably less often - cats are smaller.
Take especial care of these saber toothed cats.
clark, a scenario where multiple strains of H5N1 evolve the ability to infect humans, separately and over time, is possible. The widespread dispersal of H5N1 in many animal reservoirs makes this quite possible, IMO.
In my opinion, if H5N1 decides to leave us alone for ten years we might have a chance to research alternatives for a vaccine.
Monotreme. The 300 million doses in 6 months, I believe was what they could produce before they found they had to double or triple the antigen in each dose.
There are some realities we have to face soon. The first is that there will be no vaccine for this pandemic if it occurs in the next five years….and secondly, the potential effectiveness and potential of significant side-effects from antivirals are up in the air at the moment…under any other conditions these antivirals would be considered highly experimental and used with extreme caution.
The bottom line is that if this thing blows in the next few years…we will have few tools that were not avaliable to the citizens in 1918. If we face this fact then we can change to utilizing techniques that worked in the past…if we rely on technologies that will not work including healthcare facilities…we are in big trouble. However, this is just my opinion and I could be wrong.
Monotreme: Are there multiple, ongoing “Manhattan Projects” for the novel production and manufacture of vaccines around the world? Or are there just sporadic efforts here and there that are promising, but nothing like a “war footing” effort?
Then there is the disruption factor for such efforts even if ALL of what was needed was in place at the start of a high CFR panflu. That hurdle in itself is formidable.
Where are we truly, and what realistically are our prospects?
You all need to ‘think’ a little more like a virus (if it were capable of thought ;-) on how to win the game of survival.
To win in the short term you want to reproduce yourself in as high a number of copies as possible and find a bunch of new hosts to repeat another round of viral replication. But to win in the long term, you need a way to hang around in SOME population on the planet (and frankly any supportive species will do, human, bird, cat, dog, pig, horse, sheep, whatever). Ordinary yearly epidemic human flu strains are thought to readily jump back and forth between humans and other species (virologists call the other species ‘reservoirs’).
As a virus, you are *utterly* dependent of having a supply of suitable hosts in which to carry out the reproduction portion of your life cycle. If you kill off too many of your hosts, your descendents will die off — this is pretty much where the smallpox virus is. So if you adapt to live in humans but you kill them off too rapidly, you will lose. Better to do what others have done — cycle back and forth between species. Note that a lot of ‘avian influenzas’ don’t make the bird hosts very sick — sometimes infected birds are just carriers and don’t get sick at all. We humans only notice ‘avian flu’ infections when birds are obviously sick or dying. Also this same process of mild or no illness sickness happens to humans with ‘human flu’ strains and virologists have struggled with why this is for decades (they have studied this well before the field of molecular biology was born and are still doing so)
Now on to the 8 ‘chromosomes’ (identified gene segments) of a flu virus.
HA (hemagglutinin) and NA (neuraminidase) are something like keys that are located on the surface of a flu virus particle or virion. The hosts’ cell surfaces have ‘locks’ if you will on their surfaces (sialoproteins) If the keys fit the locks well, the virus particle can enter the host cell, if not, well the virions can’t take over the host cells and turn them into virus making machines.
Drugs like amatandine, rimantidine, Tamiflu and Relenza all work against the NA key — this is why they are called neuraminidase or NA inhibitors. If NA inhibitors are around, they act like decoy locks filled with SuperGlue, faking out the virus to test them, get stuck, and buying time for the host’s immune system to spot them as garbage and get rid of them.
In drug resistance, the virus changes the keys (here either hemagglutinin OR neuraminidase or both could be changing), and goes on to infect the host cell anyway. This is destined to be an endless game of tit for tat and HA and NA changes are not all that unexpected
The other 6 flu viral ‘chromosomes’ all have to do with the takeover of the host cell: they help to replicate more viral genetic material (viral polymerase does this), to make proteins for the structure of more virus particles (including HA & NA), to help direct proper virus particle assembly, and to get the particles made and released again. If any of these processes are too efficient (i.e. they take over too many of the host cell’s resources), they make the host ill, possibly killing it before the cycle of viral replication can be completed. So there is such a thing as a ‘too lethal’ virus strain.
The problem is virologists don’t know nearly as much about these other 6 gene segments and how they work. Needless to say there aren’t as many drugs that target viral gene replication, viral protein replication, or virion particle assembly. This is an area that sorely needs research, study, brainstorming etc. Virologists have known about this for decades but frankly unless you have something immediately and brutally lethal to people (think of HIV/AIDS), there isn’t much incentive to fund that sort of research. Most people are okay with getting a mild flu infection that makes them mildly ill every couple of years or so — sure it’s inconvenient, but it’s tolerable.
For H5N1 to ‘win’ long term, it has to eventually die back the way 1918 H1N1, 1957 H2N1, and 1968 H3N2 did. Some of us would survive a 1918 or worse pandemic H5N1 strain that can at least infect us — if too many of us die, the virus loses both short and long term. But I don’t think that intensive study of the HA & NA genes is the way to go — these genes are bound to be highly changable. Where we need to be studying H5N1 from a molecular virology level is the other 6 segments — could we perhaps develop drugs that select for H5N1 strains that infect humans and make them not so efficient that they too rapidly eat their way out of their human house and home? The world already puts up with a lot of inconvient flu infections, why couldn’t H5N1 be one of those sooner rather than later?
There’s also a better understanding of the human immune response to flu that needs to be addressed with research — one place I know that works on that is the flu group at Baylor College of Medicine in Houston TX USA — they also will be studying vaccine issues, like can ‘half doses’ of a future H5N1 flu vaccine offer any protection from lethal H5N1 flu infection (if that is possible, a lot more people could be spared).
Believe me, this is a very complex problem that has been studied for decades and from a huge variety of approaches. No offense to Monotreme and niman, but molecular sequences are but one prong of the attack on flu.
E.C.anonymous. I am from Ontario Canada. Last fall a number of world experts met at Trent University in Peterborough, at a closed meeting, to request an investment of twenty million dollars for a research effort to specifically invent more anti-virals, I assume in the families you mentioned. The effort was to be coordinated at Trent University.
This modest request, by those involved including Dr. Osterhaus personally, was ignored and the research project has not started as yet.
East, what do you think, will be the CFR in a H5N1-pandemic ? 1957 was H2N2. Those who had N1 are a bit immune against H5N1, since N1 is also a target of the immune-system. If I were H5N1 I would first kill all humans and then switch to another host, too dangerous these humans with their research ;-) Seriously, killing 10% or 20% of humans doesn’t make a big difference for the longterm future of viruskind. But for mankind it might. They are involved not only with evolution but also with politics and politics is always shortterm. OK, the longterm strategy of the virus is not so interesting here. But shortterm, would virulent H5N1-viruses be less effective in spreading than mild ones ? A long incubation time would probably be good for the virus and bad for us. Can we do something against it ? Is the idea of “creating” mild strains somewhere being considered ? I never heard about it.
have viruses killed a species in the past ?
anonymous – at 12:06
I don’t believe there is any evidence for that. I do wonder about the American Passenger Pigeon though, even thoug it is claimed that it was loss of habitat and hunting the was its demise.
Tom DVM – at 11:51
It’s tough to get money for medical research either from a federal government, a corporation or a private foundation. Most schools now teach graduate students (in addition to science) courses in grantsmanship knowing full well that if these students can’t write a successful grant application, their careers are pretty much over before they’ve started.
In the US National Institutes of Health scheme of grant funding, there are separate pools of funding for cancer research and HIV/AIDS research. Every virologist, microbiologist, immunologist — whatever kind of -ologist you are, you will somewhere in your grant application try to tie your research to cancer and/or HIV/AIDS to improve your odds of getting funding. And of course how much funding is available in the general pool is dependent on what Congress is willing to spend on it. It’s a tedious crappy process, and it’s one of the things that made me give up on grad school (and curing the common cold which was more my area of research, although respiratory viruses in general fascinate me).
From the corporate side, if it doesn’t look like your research can make back some money in say less than five years time, you won’t get to keep your job at a publically traded company — they’re all about the shareholders who want their payoff yesterday. And you’ve seen for yourself how little yearly influenza vaccine gets made — it’s not profitable for companies to make it. About 15 years ago, when I was still a grad student, there were 4 companies in the USA that could make flu vaccine, now there are just 2 (sanofi pasteur & Chiron). And of course they still make flu vaccine in eggs in injectable form— the folks at the company behind FluMist (which is an inhaled vaccine which for my money is the long term way to go, because it more closely mimics natural infection than an injection) are but a tiny group of people who are thinking different. The company (MedImmune) is a small one (the big guys won’t touch it because frankly too few people are jeopardized by yearly flu infection so there aren’t big profits to be made, at least so long as influenza only kills 30,000 people in the USA each year…)
You can do this sort of ‘special appeals’ thing to various governments for money when you get the public riled up — this is how the separate pools of money became available to first cancer researchers and then HIV/AIDS researchers. But there is no outcry for defeating respiratory viruses, except of course for something like a SARS outbreak or an actual pandemic the size and severity of the one in 1918. But when the public health crisis is over, the funding usually dries up, never mind that flu researchers learned a lot about ties between flu infection and say certain types of diabetes cases. People are not as impressed with basic science as they are with its applications. Basic science is a tool like a hammer, something that is necessary and versatile, but what really impresses people is the mansion, not the lowly hammer used to build it. But it’s awfully hard to get a mansion without first inventing and using and funding a hammer.
So while the leading lights come up with proposals and ask for money, the world waits and hopes. I have to wonder not only will they ever be successful in convincing TPTB to do something already, but how much more could have been accomplished if any of these funding entities had listened years ago?
Maybe a virus was one of the underlying causes of the dinosaurs’ demise. -An avian flu that became virulent to the warm-blooded dinosaurs… but not to mammals, reptiles, amphibians, fish and of course - the birds! -Even sea-dinosaurs perished.
Funny how the mass extinction took only a couple of years and whole categories of beasts were spared.
I wonder if anyone has tried to study that angle? -not sure bones could tell that story.
anonymous – at 12:02
East, what do you think, will be the CFR in a H5N1-pandemic ?
If you’ve got the answer to that one, well maybe you should be out playing the stock market and positioning yourself to rule the world ;-)
I honestly don’t know what CAR will be much less CFR.
“1957 was H2N2.”
Yeah my bad - darned typo!
“Those who had N1 are a bit immune against H5N1, since N1 is also a target of the immune-system.”
Well this is the logic I had applied in taking the yearly flu shot. It is called ‘trivalent’ because it contains at least one strain of H1N1, H2N2, and H3N2. With a little bit of luck I will have some small immunity thanks to having gotten 2 different H1N1 contain shots over the last 2 years (I lived with and took care of someone who was over 65 and also someone who was recovering from chemotherapy for cancer, so I was on the priority list to get shots)
“If I were H5N1 I would first kill all humans and then switch to another host, too dangerous these humans with their research ;-)”
Oh so that’s what this is, it’s a conspiracy to rid the world of medical researchers LOL!
“Seriously, killing 10% or 20% of humans doesn’t make a big difference for the longterm future of viruskind. But for mankind it might. They are involved not only with evolution but also with politics and politics is always shortterm. OK, the longterm strategy of the virus is not so interesting here. But shortterm, would virulent H5N1-viruses be less effective in spreading than mild ones ? “
Absolutely. A kissing cousin of H1N1 is usually out there somewhere giving grief to the children, the pregnant women, the elderly, and the immunocompromised. That of course is not most of us, who if we get sick, recover (and conveniently let loose many more H1N1 virions, waiting to make more of themselves…)
“A long incubation time would probably be good for the virus and bad for us.”
Actually that’s not necessarily true. It takes some time for a reasonably well-working immune system to detect an infectious agent, find it, tag it for destruction (this is a major role of antibodies) and destroy it (T cells B cells and macrophages along with ‘natural killer’ cells all play a role in killing of infectious agents and also cancer cells)
“Can we do something against it? Is the idea of “creating” mild strains somewhere being considered? I never heard about it.”
Sure you have — you just don’t know them by their name — vaccine strains. You either take a virus and kill it and inject it back into someone or you grow up a strain and let it live but weaken it (the old way was by chemical treatment, but now some really sophisticated genetic engineering is a possibility) and either inject that or put it into an inhalable form and it goes up someone’s nose.
The idea is to make antibodies (in the case of injection there are 2 types the body makes IgG and IgM, while in the nose there is an additional third kind that is possible, IgA). The antibodies usually don’t have to be an exact match, just ‘close enough’ so that if someone does encounter the havoc-causing strain, the antibodies prevent infection. These antibodies of course target HA and/or NA and they are what prevent the virus particles from entering the cell (think of antibodies as like a whole defensive line piling themselves on top of a rival team’s football/rugby player, a virus particle — all that has to happen is for the referee, or here the rest of the immune system, to see the pile up, clear the field, and declare that play ‘over’.)
Anyhow, the vaccine studies will involve giving the participants vaccine and then exposing them to H5N1 (that exposure is called a ‘challenge’, as in challenging or testing one’s immune system) and seeing whether or not they get sick and if they do, how sick they get — hopefully they don’t get ARDS and wicked diarrhea and secondary bacterial infections and/or die. If they only get mildly ill, or don’t get sick at all, you’ve got a viable vaccine. If some get violently ill (or die), you have to start all over again.
By the way if you take the yearly trivalent flu shot in 2005, you took a live attenuated vaccine — I don’t think sanofi pasteur or Chiron use killed virus to make vaccine anymore.
TreasureIslandGal. Some researchers are continuing to try to prove that a distemper virus similar to the one in dogs, killed off the Wooly Mammoths. I believe the research has been going on in Siberia for more than ten years without success but that could be because the technologies are not avaliable to identify the virus.
E.C.anon. Wow!! I guess I wouldn’t know about the stuff you are describing. Seems to me that the twenty million dollars they were asking for seemed like a good deal to me because I have little faith in the existing primitive anti-virals.
I used an intra-nasal vaccine for Infectious Broncho Rhinotracheitis in cattle for many years. I could walk into a barn in the middle of an outbreak and garuntee the farmer that I could cure it with one vaccination…hard to believe but true.
The evidence clearly indicates that existing intramuscular influenza vaccines are pretty much useless. I have always wondered why they didn’t use intranasal vaccines for respiratory pathogens because they preload the specific part of the local immune system in the nasopharynx that the pathogen encounters naturally. In the case of influenza, it would also assist in the oral cavity as that is probably the next best location for virus entry.
Anyway, thanks for the lesson.
Shoot…it’s posting slow and I’m sitting here looking at a stupid mistake. The condition was Infectious Bovine Rhinotracheitis (IBR)
You know…it would be really nice if all you anonymouses would pick a name that best describes you…it does get confusing keeping you separated by your writing styles.
I know we can’t produce a vaccine until we know what we are vaccinating against, but can’t we start building several production facilities in the meantime.
I don’t know how much a facility would cost; 10 million? More?
A small fraction of the Billions they intend to spend.
Tom DVM – at 14:40 wrote
“I used an intra-nasal vaccine for Infectious [Bovine] Rhinotracheitis in cattle for many years. I could walk into a barn in the middle of an outbreak and garuntee the farmer that I could cure it with one vaccination…hard to believe but true.”
The way I see it, respiratory viruses are best fended off by IgA immunity (which is predominantly made in all those places where the human body meets the outside would — the nose, the eyes, the mouth, the throat, the stomach, the intestines, and in women in the vaginal area) They are adapted to best reproduce themselves at a lower temperature: in the human body that means that you 34 degree Celsius nose and mouth are more comfy than your 37 degree Celsius bloodstream where you get mostly an IgG response. I assume it’s the same way in animal respiratory viruses (although offhand I don’t know the normal body and nasal temperatures of cattle, sorry!)
Also in humans, since we got some protective responses to injected intramuscular vaccines and since that form of delivery dates back to the 1600s (cowpox being injected to protect against smallpox is the first example of vaccination), I think this is why vaccination for flu has been done this way. But MedImmune is seeing some great results with FluMist — it has just been shown that in infants FluMist actually protects better than a shot so the approval for who can take an inhaled vaccine for yearly flu will now be infant-45 years old.
I had an interesting experience with one of my cats recently. I took him in to get his ‘everything but rabies’ shot, the one that has Feline Rhinotracheitis in it. The inexperienced vet tech helping the vet accidentally hit the plunger on the syringe and squirted vaccine all over Kitty. So the vet loaded up a second syringe and hit the mark on the second try.
Well darned if Kitty didn’t get the sniffles a day or two later! It was a three or four day bout, but he got better and there are no problems to report since (which I assume means the cat’s immune system is making antibodies). Could it be that the FIP agent in the vaccine is actually live and not killed? Also I wonder if the cat isn’t actually better protected having taken vaccine in both his nose and bloodstream?
For what it’s worth both cats are indoors-only and take this shot religiously every year.
Hi Tom!
I correspond with Dr. Mittel at Purdue. He is waiting for FDA approval to begin human testing of his vaccine. He believes that there are pharmaceutical companies here in the US, as well as other parts of the world, that may have present capabilities to manufacture his novel vaccine. He has a tentative manufacturer. If I am relaying all this accurately…His vaccine uses 1/100 of the antigen used in the egg-based vaccine. He could manufacture enough doses for the entire US, in approxiamtely 60 days. The plan would be to sell the vaccine to the US citizens and use profit from those sales, to provide vaccine for parts of the world that will have none. His vaccine should cover 5 years of viral shift. I told him the only way I knew how to describe it, would be a universal H5 vaccine, H7, or whatever is warranted. His vaccine can be stockpiled and shelved, prior to a pandemic beginning or we could be pre-vaccinated. I believe he has used an earlier strain from Vietnam and was going to be working with a more recent one.
If you e-mail me, I have his contact information. He is a very kind, thoughtful person and very approachable. I also have some of his research data, if you are interested.
To anonymous at 14:38
The Sanofi vaccine is a killed, split-virion variety. Current trials at the University of Rochester (see NEJM) indicate that up to 12 times as much antigen is required to gain an effective immune response as for the seasonal trivalent vaccine. Trials are underway in Europe of a whole-virion vaccine that generates an immune response with perhaps a third as much antigen. However, I believe that whole-virion vaccines are not recommended for young children due to a propensity for pyrogenic side effects (fever/inflammation).
Sarge, it makes perfect sense to me that the Rochester H5N1 takes a lot more antigen. Live attenuated virus generally gets a better immune response than killed, but with an unknown like H5N1, live attenuated virus is not something you would want to take a chance on regardless of age.
Here’s hoping this Phase I trial of the Rochester vaccine goes well:
Split H5N1 Virion Vaccine Trial Press Release
I’m encouraged by the European whole-virion results (even though it might not be useful in young children). I figured that whole would be more efficient than split. Any clue when the European will go to Phase I like trials?
To East Coast anonymous:
I haven’t heard many details of the European trials, so I don’t know if they are ready for phase 1. The Rochester trials are somewhat discouraging, but the manufacturers are trying a variety of antigen-sparing strategies, among them adjuvants (alum) and different injection routes (sub-q vs. IM). I belive you are correct that live-attenuated with a bug a virulent as this is a gamble they would be reluctant to take, the numerous advantages cited by the previous posters notwithstanding.
Many promising new technologies are being investigated, but time is our enemy.
Sarge – at 16:19
I figured they’d at least be trying the ‘usual response-improving suspects’ adjuvants and different methods of injection (sub-q is subcutaneous or just under the skin for the newbies reading this, IM means ‘intra-muscular’ which means deeper into a muscle)
If only some of the alternate technologies could have been funded and looked into earlier…but then it’s just this sort of ‘no crisis, no interest’ mentality that’s the culprit.
I really hope the epidemiologists can get more out of the Indonesian investigations than we have so far but I fear the ‘crime scene’ in the Karo cluster has been so muddied, we may have a heck of a time calling the exact period of H2H2H…and beyond transmission should this go much further.
East Coast - at 16:38
I am told by those knowledgeable that alum is probably the least effective adjuvant, but one that is fairly well accepted.
If it wasn’t for government funding (as inadequate or ill-directed as it may be to some of the participants), we probably still wouldn’t be attempting any new vaccines or increasing the production capacity. As was pointed out by others above, the availability of government funding is directly proportionate to the amount of fear, panic and political pressure of, and applied to, the appropriators.
Someone above (Oremus at 14:48) asked how much a facility costs. Round numbers for an industrial-scale cell-culture facility is something like $500 million. (Heck, a baseball stadium costs $250 million.)
I know something about crime scenes - and you are right, this one is pretty murky. it’s like trying to process a scene that has had half the town tramp through before you got there, moving the body, taking away evidence and depositing trash along the way. Add to that the problem of a (hypothetical) police chief declaring to the media from the front porch that, despite 12 cases with identical victim profiles, modus operandi and, temporal and geographic clustering, no we don’t think there is a serial killer loose. Move along now, there’s nothing to see here…
East Coast anonymous – at 14:01 “Basic science is a tool like a hammer, something that is necessary and versatile, but what really impresses people is the mansion, not the lowly hammer used to build it. But it’s awfully hard to get a mansion without first inventing and using and funding a hammer.”
Very nice metaphor!
anonymous – at 12:06 have viruses killed a species in the past ?
Something wiped out dinosaurs. Avian influenza? Who knows?
What I’d like to know is, how long ago did Influenza A and Influenza B diverge into two separate lines? What percent of their genome is different? What does the time of divergence tell us about the decision to stay with people/mammals, versus the decision to jump back and forth between birds and mammals?
I feel the need to throw in on thought I dont have the slightest clue on, but here it goes. It seems to me that you allways discuss the evolution of the virus as a 1 virus( the flock of them) vs 1 man contekst… In my wiew evolution is also about 1 cell vs 1 cell.. Is there not some factors inside a bodys imune system that could alter the evolution?. Like a mechanism that makes influensa viruses less lethal over time after meeting all the differnt cells, and their imune system, that in the end makes the virus faster spreading but less destroing? Is not the race for survivial also happening everytime a virus enter a host cell, and that surivival is dependent of accsess to spread, but not to destroy?
thankfull for any scientific feedback ;)
wetDirt. An interesting question. I would not have thought of it and couldn’t speculate on an answer…makes sense though to have a common ancestory.
Urdar-Norge. Also a good question. I think Racter said it on the earlier thread. The evolutionary pressure begins once the flu virus figures out how to open the door to another species…us.
Others might argue but I think the door has been open for more than a year since the clusters and H-H transmission first occured…and I would say the evolutionary pressures have also been working for some time…Indonesia demonstrates a steady progression in the evolution and adaption of H5N1 to humans…
It has been constant in one direction…I don’t know why we would expect it to stop now and go the other way.
As you said, this fight to adapt is occuring in each virus and each cell it enters.
The end game for the virus is to live in harmony with humans and the immune system, and the fact that H1N1 from 1918 has been doing exactly that thing for 100 years is a pretty good example of how effective viruses are at the adaption-evolution game.
Mom11. Thanks for all the information about Dr. Mittel’s work at Purdue. Let’s hope that it works.
I have said in the past that if the virus injects itself into the blood stream then it would make sense to use an intramuscular vaccine but in the case of respiratory viruses the intramuscular vaccines don’t do a very good job of stimulating the localized immune system in the nose-lungs etc. An intra-nasal vaccine exactly mimics the entry point of the natural infection and stimulates the local immune system at this point. Respiratory infections seem to be the most difficult to vaccinate against with intramuscular vaccines.
Thanks for offering the further information. I am going to be a little busy in the near future and wouldn’t be able to follow up so maybe I will get back to you later…thanks again.
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Sea Urchin – at 18:06 Q. “anonymous – at 12:06 have viruses killed a species in the past ?
A. Something wiped out dinosaurs. Avian influenza? Who knows?
LOL - Sorry, that’s a funny one to me ‘cause avians are descendants of dinosaurs. So it’d be like Generation Y taking out Generation X… Alas, perhaps the “nuclear winter” caused by the coment strike helped the “raptor flu” along? :)
Sea Urchin – at 18:06 Q. “anonymous – at 12:06 have viruses killed a species in the past ?
A. Something wiped out dinosaurs. Avian influenza? Who knows?
LOL - Sorry, that’s a funny one to me ‘cause avians are descendants of dinosaurs. So it’d be like Generation Y taking out Generation X… Alas, perhaps the “nuclear winter” caused by the coment strike helped the “raptor flu” along? :)
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Well, so I Googled it out myself:
Origin and evolution of influenza virus hemagglutinin genes.
Suzuki Y, Nei M.
Institute of Molecular Evolutionary Genetics and Department of Biology, 328 Mueller Laboratory, The Pennsylvania State University, University Park, PA 16802, USA. yis1@psu.edu
Influenza A, B, and C viruses are the etiological agents of influenza. Hemagglutinin (HA) is the major envelope glycoprotein of influenza A and B viruses, and hemagglutinin-esterase (HE) in influenza C viruses is a protein homologous to HA. Because influenza A virus pandemics in humans appear to occur when new subtypes of HA genes are introduced from aquatic birds that are known to be the natural reservoir of the viruses, an understanding of the origin and evolution of HA genes is of particular importance. We therefore conducted a phylogenetic analysis of HA and HE genes and showed that the influenza A and B virus HA genes diverged much earlier than the divergence between different subtypes of influenza A virus HA genes. The rate of amino acid substitution for A virus HAs from duck, a natural reservoir, was estimated to be 3.19 x 10(−4) per site per year, which was slower than that for human and swine A virus HAs but similar to that for influenza B and C virus HAs (HEs). Using this substitution rate from the duck, we estimated that the divergences between different subtypes of A virus HA genes occurred from several thousand to several hundred years ago. In particular, the earliest divergence time was estimated to be about 2,000 years ago. Also, the A virus HA gene diverged from the B virus HA gene about 4,000 years ago and from the C virus HE gene about 8,000 years ago. These time estimates are much earlier than the previous ones.
PMID: 11919291 [PubMed - indexed for MEDLINE]
Now, one problem with the method is that the rate would be different if recombination was the mechanism, because while random mutations accumulate and drift at a linear rate with time, moving whole chunks around, and swapping them in and out much like shuffling cards, means that you can hardly estimate a rate, unless you use only noncoding areas of the genome where changes don’t mean anything. So can anyone enlighten me?
It seems to me like everyone believes the vaccine is the cure, Why aren’t we spending more on anitviral med research? In the last couple weeks we’ve had a vaccine come out for cervical cancer and now shingles. Seems to me the technology has been around but the legal protections weren’t. Now we have both. The Roche vaccine first reports were scary—too much to inject and the effect was hardly noticeable. Adding aluminum is just great-except aluminum is so very toxic to the brain! Live weakened vaccine mists for the respiratory tract sound good, but the ones we did have seemed to cause more health problems than flu. My point is…antiviral research would be better for everyone’s health. Another point i’ve pondered is—are vaccines now becoming resistant like antibiotics? Measles and mumps epidemics in the vaccinated!! New strains-missed vaccinations—don’t think so. Maybe we’re coming full circle to survival of the fittest. It’s not a happy thought is it? Going out for some sun.
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