It's not even three months since the first H1N1 swine flu cases were diagnosed in San Diego, but already there is a significant amount of science published on the subject. Lots of genetic sequences from various isolates, clinical descriptions of hospitalized and fatal cases and now animal experiments. Two teams, one in The Netherlands and one in the US, have infected ferrets and mice with pandemic H1N1 isolates from Europe, the US and Mexico and compared transmissibility, virulence and pathology with seasonal H1N1 strains. The two papers were published yesterday in the journal, Science (papers here and here).
There were four different pandemic isolates tested in ferrets. The group in Holland used virus from the first Dutch case, a three year old child who had traveled with family to Mexico and had an uncomplicated case that resolved with full recovery. The US isolates were from another uncomplicated pediatric case in California, a seriously ill 29 year old female from Mexico who recovered, and a fatal pediatric patient from Texas. Different seasonal H1N1 isolates were compared to these swine flu isolates by each team.
The experimental set-up was similar but not identical. Ferrets -- rodents rodent-like carnivores considered excellent models for human influenza -- were inoculated intranasally and co-housed with uninfected ferrets. In some cases contact was allowed, in others, air flow but no contact was allowed. Seasonal flu transmitted efficiently for both research teams and swine flu did just as well for the Dutch team, slightly less well for the American team. Differences in isolates and physical set-up may be the reason for this difference, but while more was made of the slightly less facile transmission by the American team, the swine flu virus was plainly transmissible in the ferret model in both cases. The US team also employed sophisticated glycan microarray analysis which seemed to show slightly less avid binding to human receptors for the swine flu. Their interpretation was that their isolates were not fully adapted to humans and one could expect the virus to change to allow better transmissibility and perhaps more virulence. While lab and animal studies may show some difference, the epidemiological evidence seems quite clear. This virus is capable of rapid and efficient spread. It is already fully transmissible.
These studies also hint at a greater virulence for the swine flu virus compared to seasonal flu virus. Examining the pathology in ferrets (and in the US experiments mice were also used), the new virus will infect cells deeper in the lungs. The US team also found it in the intestinal tract, consistent with the clinical observation that nausea and vomiting is a common presenting symptom.
It has been claimed that the genetics of this virus are very stable and that essentially all isolates so far are "essentially" identical. But the three US isolates had differences in 6 different gene segments and the Mexican isolate exhibited lethality for half the animals compared to none for all the other isolates and the seasonal H1N1 (Table 1). None of the swine flu isolates had the E627K mutation in PB2 which was thought to be characteristic of human adapted viruses. Now it is clear that it isn't a necessary condition. The fact is the early isolates do exhibit amino acid differences and we are not yet sufficiently knowledgeable about which ones are important to declare them functionally identical.
There is nothing super alarming about these experiments, but there certainly is nothing reassuring, either. Even if this virus only has the same virulence as a seasonal virus, it can infect more people and younger, healthier people. Epidemiologically it will look very different and have a different impact.
It's unlikely this will be like a 1918 flu virus. But it doesn't have to be to cause a major problem. Constantly comparing it to 1918 isn't the point. The point is that this is an influenza pandemic, and that's bad enough.
Medicine & Health
Comments
Ferrets are not rodents! They are related to weasels, stoats, badgers etc (none of which are rodents).
Other than that thank you, as always, for the useful and informative information
Posted by: Ralph | July 3, 2009 8:11 AM
+1 - Ferrets are carnivores!!!
But yes, this is an interesting flu. And I've had the "it's mild" "yes, but it's still a 'flu..." chat so many times. It may be mild, but I still passed out while attempting to urinate, on it... and the fact I could stand at all makes it a mild flu...
Posted by: Charlie B. | July 3, 2009 8:45 AM
Ralph, Charlie: Yes, I meant to say rodent-like. My error. Thanks for catching it.
Posted by: revere | July 3, 2009 8:56 AM
But not long ago, some comments here compares the current flu witht that of 1918. So, now it becomes unlikely?
Posted by: passerby | July 3, 2009 9:16 AM
Revere: I especially appreciate your explanation of these studies as it is being widely reported in the MSM that they showed the swine flu was "weaker" and not an "efficient" transmitter of the disease.
In another news report, the BBC is today warning Internet users to NOT buy Tamiflu online without a prescription, that it's become the new Viagra in spam ads, and that what unsuspecting buyers are receiving are either sugar pills or -- and this is terrifying -- rat poison. (http://news.bbc.co.uk/2/hi/health/8131911.stm). Might be worth a moment of your time to help spread this warning.
Meantime, keep up the excellent work and be well!
Posted by: River | July 3, 2009 9:20 AM
And one more news story:
Reuters is now reporting that Hong Kong has its first case of Tamiflu-resistant H1N1 (http://www.reuters.com/article/rbssHealthcareNews/idUSHKG30741920090703).
Posted by: River | July 3, 2009 9:28 AM
We know this flu is a newly evolved human pathogen. We also know that it is evolving as we watch. The latest is two reports of Tamiflu resistance, predicted but not welcome.
With cheap and rapid sequencing, we will be able to watch it evolve in real time. Coupled with animal experiments, this could be a gold mine for evolutionary biology and flu genetics.
There is also a bit of irony here. Many people in the US are evolution deniers. If the pandemic goes as expected, they are about to be probably scared, possibly sickened, and some will be killed by a newly evolved and rapidly evolving novel pathogen. While claiming it is impossible because evolution is "hooey" as a distinguished commentator called it.
Posted by: raven | July 3, 2009 9:37 AM
Any flu ends up being compared to the 1918 Spanish flu epidemic in terms of virulence. Understandable, 50 million people dead and young people dying in hours and days.
It may have been a one off event. 1918 was WW I. A lot of people were on the move as refugees, workers, soldiers, and so on. These populations were also highly stressed, war does that to people physically and mentally. They were also living with 1918 standards of medicine and nutrition.
All these conditions are ideal for rapid spread of the flu. One way to increase the virulence of pathogens is rapid, serial spread in its normal host. The opposite of attenuation protocols. The war might well have selected for increased virulence.
Just a theory. What would falsify it would be a 1918 style pandemic again. Let's hope it is a correct theory.
Posted by: raven | July 3, 2009 9:49 AM
"It is being widely reported in the MSM that they showed the swine flu was "weaker" and not an "efficient" transmitter of the disease..."
That comes I believe from the press release which was carried on EurekAlert (the PR service sponsored by AAAS) but actually written by the MIT news office IIRC. It was unfortunately not well-phrased, or at least not well-headlined.
Posted by: maryn | July 3, 2009 10:01 AM
passerby: Not sure what comments here you are referring to, but raven has a valid point that 1918 is a bench mark for any flu pandemic. If H5N1 got loose it could be worse than 1918. This one is likely to be not anywhere near as bad (at least those are all the indicators at the moment). But a flu pandemic is an inherently destructive thing on its own, without comparing it to 1918, just as a hurricane is inherently destructive without comparing it to Katrina.
River: I saw the story on the Japanese resistant isolate. I didn't have anything to add after our discussion of the Dutch isolate. Emergence of H274Y mutants is not unexpected, although whether in the context of the swine flu genotype it will spread as easily as the seasonal one did we still don't know.
Maryn: Thanks for the background. The MIT group did the glycan microarray so from that point of view the PR spin made sense. But it is a pretty narrow point of view considering the Dutch data and the epidemiologic picture. When the lab says one thing and the world says another, I think we go with what the world says.
Posted by: revere | July 3, 2009 10:58 AM
So the Mexican isolate killed half of the ferrets, but the U.S. isolated didn't kill any? Does that mean that the virus really WAS more virulent in Mexico? I was under the assumption that there were far more cases than were being counted, and that's why their CFR seemed so high in Mexico the beginning.
Posted by: Curious | July 3, 2009 11:35 AM
"It's unlikely this will be like a 1918 flu virus."
I'm not sure this conclusion is valid just yet.
Posted by: Tom DVM | July 3, 2009 11:43 AM
is this a puzzle ?
> The US isolates were from another uncomplicated pediatric case in California,
> a seriously ill 29 year old female from Mexico who recovered, and a fatal pediatric
> patient from Texas.
we have to know which substrain, not which host.
Posted by: anon | July 3, 2009 12:06 PM
Curious: the sample is too small to draw a conclusion like this. It does indicate, however, that the investigators don't automatically buy the idea that all the early isolates are functionally the same, as was repeatedly claimed by CDC and others. There are always differences and it is likely most of them are not significant. But we aren't at the place where we can say this with certainty. Differences in outcome can be either from differences in teh virus, the host or the environment or a combination of these.
Tom: It wasn't a conclusion. It was a guess on the basis of what we are seeing so far. Obviously we don't know what this thing is going to do.
anon: three different isolates. Phrase this however you wish.
Posted by: revere | July 3, 2009 12:16 PM
I do find the reporting of these experiments; as showing lower transmission rates as odd, a case of wood and trees.
Currently swine flu is spreading rapidly in the US, Canada, Europe and Japan when seasonal flu normally has very low transmission rates.
Swine flu also appears to be spreading very rapidly in Argentina, Australia and Chile, in line with normal flu season rates.
The only rational conclusion is that swine flu is already significantly more transmittable than seasonal flu.
The conclusions from the ferret studies can only be that transmissibility is likely to increase significantly as the 'standard' genetic mutations kick in to make it more like seasonal flu.
I am also fascinated by the double swine flu proposition. 'US' strain relatively mild, through US and rural Mexico, then spread to Canada, Europe and most of the rest of the world.
'Mexico City' strain, much higher cfr, almost killed off by the very effective lock down the Mexicans imposed, just at the end of the normal flu season. Possibly now re-emerged in Argentina.
Posted by: kagiso | July 3, 2009 12:26 PM
Do we know the genetic identity of the Hong Kong isolate which was reported today as being resistant to Tamiflu? I am interested how it is related to the other two reported resistant strains in Denmark and Japan.
Posted by: Tye | July 3, 2009 12:32 PM
the researching process must somehow benefit from delay
and secrecy. I don't exactly understand how.
In this case it was even quick as compared to others.
But still it probably costs many lifes and infections
due to badly educated preparations of countries.
We need to know:
Which strains are more virolent than others ?
How does it spread ?
How/when does immunity set in and stop the wave ?
Will it kill other flu ?
Preliminary results are welcome.No need to wait
for a finished paper.
Posted by: anon | July 3, 2009 1:20 PM
Don't compare to 1918? Why not... that was an H1N1 virus. And none of us should rest easy on our new C-Change health status. H1N1 has a trick of changing the game in the human host without mutation. It hi-jacks a high immune system and turns it on it's self. The false neg.'s for this flu are growing, the resistance is most likely world wide. The Hong-kong case from San Fran.
Finding more differences in the circulating A-H1N1 likely and that is very much the nature of H1N1. Tranmisability, if you are shedding live virus for 10 plus days says it all. And the pop.'s may be shedding numerous subtle variations of the H1N1.
So far what we really know is... that it's fatal to the strongest age groups, Sheds for a long period, & now resistant to Tamiflu. It can take hold in the upper,& lower respiratory and the GI system. The 1918 went on to attack other organs. The false neg.'s indicate it may be getting better at hiding from the immune system.
Who number's Whoey!
Posted by: RKHatfield | July 3, 2009 2:24 PM
RKH: Everything you said is also true of seasonal flu. Anyone can speculate about what might happen. This could turn into a monster, true. It could just disappear. At this point it seems to be behaving like the other pandemics of the 20th century other than 1918, which was an outlier. What would you like me to say? Run for your life? Hide under the bed? Or take a deep breath and roll up[ your sleeves to work with your neighbors and local officials to make the ride less rough should it come to that? If you want either of the first two, you are in the wrong place. if you want the third, that's always been our position here for better than 4 years. As for WHO, their data come from governments. They have no control over it. The US government often doesn't even bother to pay its dues. It has no standing. If you voted to pay less taxes, you also voted to screw all of us should a pandemic come. As a society, we have no right to complain about CDC or WHO or our local governments. We impoverished them. Now it's time to pay the piper.
Posted by: revere | July 3, 2009 2:45 PM
Not a 1918 type pandemic.
Well, the virus certainly doesn't have to be a 1918 type killer to be destructive. You are correct in that assesment.
After all, the human population is not living in a 1918 societal envrionment. Many things that could an probably will effect the epidemiology of any new pathongen are vastly different..,
Posted by: Neil | July 3, 2009 4:14 PM
Not to belabor a point, but the scenario kagsio proposes (and that these animal studies might suggest) that there are actually two strains out there blows my mind. It seems unlikely, though, doesn't it -- since after all, viruses know nothing of borders. It seems like we would have had at least a localized outbreak of those more severe cases here ... especially on the border towns.
I think it's far more likely that either something enviromental -- poor diet, poor air quality, poor health care -- or something genetic that is wreaking havoc in areas like Mexico, BA, and the aboriginal groups in Canada.
Only time will tell, I suppose.
Posted by: Curious | July 3, 2009 4:57 PM
Curious: virulence has three pieces: the host (not just genetics but medical and social history), the environment (which might alter viral load or inocuation, among other things) and the virus itself. In this case all three factors differ. Note that even in a single person, the flu virus varies genetically -- it is more like a quasi-species than a single strain. The isolate is characterized by an average genetic sequence, the consensus sequence, that represents most of the virus in the person's body.
Posted by: revere | July 3, 2009 5:36 PM
Interesting news about swine flu animals experiments,i am very scared with swine flu .Currently swine flu is spreading rapidly in the US and Japan when seasonal flu normally has very low transmission rates.
Posted by: Avenir labs | July 4, 2009 12:55 AM
Revere you wrote "It may have been a one off event. 1918 was WW I. A lot of people were on the move as refugees, workers, soldiers, and so on. These populations were also highly stressed, war does that to people physically and mentally. They were also living with 1918 standards of medicine and nutrition."
But in fact while there is not a labeled WW, multiple wars are going on all over the globe, Somalia, Gaza, Iraq, Afganistan, etc as well as small conflicts. A lot of people are on the move as refugees and workers, probably far more than in 1918. The world is more globalized and the human and domestic animal populations much more dense. I think the conditions for a pandemic are much more ripe now than then.
Posted by: K | July 4, 2009 5:14 AM
K: I didn't write that nor do I believe it. I have argued against that many times here. That was a commenter here. My view is the same as yours on this point.
Posted by: revere | July 4, 2009 8:33 AM
I'm raven, not Revere.
You can't compare the normal background of conflicts and wars today with World War I. The scales and intensities are completely different. War in Iraq? Really. There aren't millions of soldiers in fixed trenches during a grim winter, just the occasional car and suicide bombers.
If you look where the 1918 flu was first seen and most prominent, in was among the war participants, USA and Europe.
Some more data points.
1. The 1918 flu was first seen in a "herald wave" in the spring that seemed milder than the killer flu that came through later. It is possible that war conditions acted as a virulence selector, rapid, serial spread through stressed normal hosts.
2. We have had two other pandemics, Asian and Hong Kong that were not 1918 style killers.
Not many data points, but we have to make do with what we have.
I wouldn't say that a 1918 class pandemic is not possible, just not typical. Virulence is selected for in pathogens for maximum spread of the pathogen, not maximum lethality or maximum benigness.
I also wouldn't plan for future pandemic responses based on 1918 being an outlier. We should prepare for the worst and hope for the best.
Posted by: raven | July 4, 2009 10:46 AM
raven: But we have many more people, much bigger conurbations, air travel and factory farms. It's no11918. It's 2009. The times are different in many ways. It's hard to say what the consequences are.
Posted by: revere | July 4, 2009 11:13 AM
Revere sorry, Not sure how I read Raven as Revere. Apologies.
Raven, one of the biggest difference between 1918 and now is that war was fought on first world land in WWI while now war is fought on 2nd and 3rd world land and it feels different to us. Not one grand conflagration but many many smaller ones. It is easy to ignore all the events going on in the world that we do not have direct participation in.
Most important however is 3 billion people now live on 2 dollars a day or less while only 1.8 billion total were alive in 1918. Significant increases in confined animal populations have occurred as well and the conditions of that confinement are dangerous to humans and animals. The poverty of 1/2 the world's population along with regional conflicts has huge numbers of people in movement, in refugee camps, and unable to get good medical care.
WWI in its horror was a unique event but I believe current conditions are even more ripe for a 1918 pandemic.
Posted by: K | July 4, 2009 12:57 PM
Feed the ferrets GMO potatoes, if they can digest starch.
Posted by: Phillip Huggan | July 4, 2009 2:17 PM
As a boomer, I can't remember a time when there wasn't a war starting or ending somewhere. There seems to be a constant background of it somewhere.
If you think the third world is poor and backward now, imagine what it was like in 1918. Before my time but IIRC my history, there were still the occasional mass famines here and there.
My comment was only addressing flu pandemics.
For newly emerging diseases, the situation might be very different. Both SARS and HIV/AIDS came out of poor, underdeveloped countries. One was stopped and one got away from us.
We will just have to wait and see but so far nothing like 1918 is in sight. But as Revere and others say often, any flu is a bad flu. I've warned a few people in high risk groups such as long standing asthma and those on immunosuppressives for autoimmune diseases to watch out and be prepared. Strangely enough, so far no one has really paid much attention. I guess right now it is out of sight, out of mind.
Posted by: raven | July 5, 2009 1:48 AM
I have found when instructing particularly stupid animals it doesn't help after years of clear concise instructions and warnings, sometimes all that's left is rubbing the animal's nose in the mess they have made.
i.e.,
Gilead *CHING CHING* and Roche *CHING CHING* documented H274Y resistance in the first clinical trials of Tamiflu *CHING CHING* and yet declared them a success without researching *CHING CHING* the consequences of such a major flaw *CHING CHING* .
It's hard to believe *CHING CHING* that something more important *CHING CHING* that the safety and reliability of Tamiflu *CHING CHING* could be ignored by medical professionals *CHING CHING* when it should have been a reminder every time Roche *CHING CHING* delivered a free Tamiflu *CHING CHING* pen, a free flight to an exotic Roche conference destination*CHING CHING* , or a free pallet of Tamiflu *CHING CHING* to the World Health Organisation *CHING CHING**CHING CHING* warehouse.
*CHING CHING* is the hypnotic sound made by Roche and Gilead cash registers.
Posted by: miso | July 5, 2009 6:25 AM
Can anybody predict, reasonably on scientific basis, that for how long this pandemic may last?
Posted by: Aniket | July 7, 2009 1:48 AM
Aniket: I don't believe this is predictable except in the most general terms: it could be over soon (unlikely) or go on for 3 or 4 years (not the most likely but possible). It won't keep going for years and years, unless you consider it becoming seasonal (likely) being that case.
Posted by: revere
| July 7, 2009 10:14 AM