Bird flu: 'tis the season

Howdy Revere, happy holidays...

An excellent H5N1 Nov/Dec '08 global overview. Though I feel your lighthearted tone incorrectly suggests a seasonal "business as usual" bird and human infection and fatality pattern. I disagree. The current situation is more widespread than in previous years...

The only constants are, as you write, the things we don't know 'bout the H5N1 virus. Plus, of course, Indonesian political interference in medical science (see below re: WHO's failure to recognize 15-year-old Dewi Sartika's H5N1 infection).

Oh, and Molecular Biology Evolution have just released an abstract on "recombination" as an evolutionary mechansim in H5N1 (again, see below). So, in spite of all that isn't known 'bout H5N1, we (((NOW))) know that an increasing number of science honcho folk agree on the veracity of "recombination"!

Excerpt from an e-list email sent to Jim McMenamin, of Health Protection Scotland:

Sunday, December 14, 2008

Howdy Jim, I'm an unpaid freelance transgenic pathogen research analyst living in Perth, Australia.

Reading international avian flu, public health, and science blogs/websites which track and compile reports on animal and human H5N1 infections/deaths comprise a large part of my daily routine within this unpaid role. Today, whilst reading the Lancet article from you and your colleagues (see below), I was struck by the complete irony of the final sentence when applied in context to the excerpted paragraph below: "We declare that we have no conflict of interest".

Indeed, you and your colleagues may have no conflict of interest, when it comes to "case definitions" and the "testing of cases and contacts". But others evidently do. Indonesia's Health Minister appears to have influenced the WHO's latest updated Indonesian human H5N1 cases/deaths data -- the WHO have failed to acknowledge lab tests (see CIDRAP News article linked in my reader posting on H5N1 Blog below) which were carried out on 15-year-old Dewi Sartika, indicating she was H5N1 positive prior to her death...

H5N1 Blog -- "Hong Kong sets the standard" (December 12, 2008)
http://crofsblogs.typepad.com/h5n1/2008/12/hong-kong-sets-a-standard.ht…

Cheers Then:*) Jonathon

PS: Please sign the attached Greenpeace Australia-Pacific petition asking federal Health Minister Nicola Roxon to introduce labelling and testing laws for GM food.

The Lancet -- "Minimum dataset for confirmed human cases of influenza H5N1" By Jim McMenamin, et al. The Lancet, Volume 372, Issue 9655, Page 2022, 13 December 2008

Excerpt: "However, [an Avian Influenza Management System] database on its own is insufficient; for consistency and comparability, protocols agreed and tested beforehand are necessary for important issues such as case definitions, identification and follow-up of contacts, what happens to contacts who become cases, and the testing of cases and contacts.

The European Centre for Disease Prevention and Control (ECDC) has suggested that individual countries should populate WHO/ECDC international databases with H5N1 cases. The UK is well placed to provide the international community with data for any internationally agreed minimum dataset. We look forward to continuing dialogue with ECDC and hope that other countries consider our system when designing their own.
We declare that we have no conflict of interest."

***********************************************

To: "Nicola Roxon, Federal Australian Minister for Health and Ageing"

Sunday, December 7, 2008

Dear Minister Roxon (Federal Minister for Health and Ageing), as you or at least staff from your office in the capital city of Australia already know, I'm an unpaid freelance transgenic pathogen research analyst living in Perth, WA.

In 1997, midst a 29-year-old THC sabbatical celebrating the completion of a university arts degree, I was watching -- shortly before a WA police service queerbash-packrape (see Jim McGinty email excerpt below) -- an SBS tv news item on human H5N1 in Hong Kong (six folk died in this outbreak in Hong Kong's Special administrative Region from mid-late '97).

So how did H5N1 get here?

"Horizontal Gene Transfer and Recombination" as an evolutionary mechansim -- fueled by the unstable viral-promoter, CaMV 35S, in genetically modified crops -- has more than a wee bit to do with why a bird virus is stealthily evolving into an antiviral resistant human to human transmissible virus.

[Further info on the recombination process but -- as far as this MBE abstract goes -- not the H5N1 viral protein changing cause (GM viral promoters?), "Homologous Recombination as an Evolutionary Force in the Avian Influenza A Virus" by He, C.-Q., Xie, et al. Mol Biol Evol 2009 26: p. 177-187.

Canada's Prof. Joe Cummins was the first to warn, in the 1990s, against using the CaMV 35S promoter or any viral genes in plants cos it had been shown that such viral transgenes in plants could gene flow recombine with historically natural DNA viruses to generate super infectious cross species (transgenic) viruses.

"Subsequently, the CaMV 35S promoter has been found to substitute for the promoter of many plant and animal viruses to produce infectious viruses." * Remixed excerpt ISIS Press Release 29/11/04 -- "Fluid Genome & Beyond"

Re: Greenpeace Australia-Pacific -- Sign the petition asking federal Health Minister Nicola Roxon to introduce labelling and testing laws for GM food

Minister Roxon,

In light of the hyper-evolution of deadly diseases such as H5N1... And also cos of the fact European Union environment ministers are now sceptical of agro-biotech [unscientific self-promotion via sweet smelling, well designed press releases -- refer to Greenpeace EU on the EU-GMO-authorisation-system], we, the undersigned, call on the Federal Government, to keep its promises and to protect public health and consumer choice by introducing, and strictly enforcing, legislation to ensure that:

All GM foods are clearly labelled, including highly processed products such as oils, starches and sugars from GM crops; and meat, milk, cheese and eggs from animals fed GM feed...

Cheers Then:*) Jonathon

Great article. We need to keep pandemic preparedness at the forefront of every business manager's mind. It won't go away so better start preparing.

For free references, resources and to join their free pandemic preparedness email eCourse program, go to Bird Flu Manual Online or, if you need more comprehensive tutorials, tools and templates, consider Bird Flu D-I-Y eManual for your pandemic influenza preparedness.

revere; in your best estimate, does h5n1 pose the threat to humanity we feared? It seems to just 'be hanging around."

My biggest concern with h5n1-containment will suffer as the economies of the world continue to tank.

Grace: Depends what you mean by "my best estimate." If you mean, do I think it is a serious enough threat I would be willing to devote significant resources into preparing for the consequences should it happen, my answer is definitely "yes."

I do not see it showing evidence of being more of a threat this year than last year but it is unpredictable. It could have some small change, whose nature we don't know, that would turn it into a vicious tiger or possibly a pussy cat. It certainly has the plausible potential to be something terrible and we have no discernible reasons to think any differently this year than we thought three years ago.

That's the best I can do for an answer with the information we have.

Hi Revere,

I have to disagree, the situation downstream of the Hidden falls of the Tsango in Tibet, Known down south as the BrahmaPutra (Assam) is everything but business as usual.

Some family clusters, many under surveillance all this despite rude censorship from gov back by money makers.

As time will tell, they have the most serious problems on H5N1 I have encountered in 5 years.

Snowy

Revere, Where is the resistance to N1H1 and H5N1 to oseltamivir coming from?

We know that very few doctors proscribe it. For a biological organism to become resistance requires them to be exposed to the drug. Where is the beef?

The Doctor: Resistance doesn't necessarily depend on exposure to the drug. It can be hitch hiking with genes that confer some advantage or even be neutral. We see the same thing with resistance to adamantane antivirals which spread fast and stayed in areas where these M2 inhibitors weren't prevalent.

Revere. With respect, that may be the current answer but it makes no sense.

There must be a selective advantage for the resistance to establish itself...as it must overwhelm the existing non-resistant strains/subtypes that previously had the selective advantage.

It is a little unbelievable as well that by chance, the resistance mutation is somehow connected to another mutation (piggybacking) that produces selective advantage.

It seems to me that we are operating on one scientific level and influenza specifically is on a whole different level existing beyond our current capability...

...in other words, there is another answer, we just can't see it.

Tom: Consider sickle cell disease in humans. Most mutations are probably bad or neutral and it is possible this is the case here. Or there may be an explanation we can't see. But not necessarily.

Revere.

A neutral mutation could not run around the world as fast as this has.

In my mind there must be a selective advantage.

It is just too much to believe that this could happen to two different famillies of antivirals in a relatively short time frame by coincidence...at least I have never observed nature to work this way.

Maybe the virus has contacted either an unknown source of antiviral...maybe fed to poultry...then not breaking down in the environment...

...or maybe there is another molecule in the environment naturally occurring or produced by a chemical interaction between some of the multitude of synthetic molecules that we have created that occurs only in developed western countries as this seems to be where this type of mutation originates.

I remain completely amazed at how every rule seems to have been proven wrong in the past three years including the one that says the virus would have to disarm itself to become immune to antivirals...

...Oh well!!

It is understood that the disease influenza is a disease caused by a RNA virus that can infect both mammals and birds. In fact, this particular virus can mutate to where it can be shared between the two life forms and multiply within each one of them.

Unlike coryza, influenza expresses symptoms more severely, and usually lasts two weeks until one recovers who has the flu. Influenza, however, poses a danger to some with compromised immune systems, such as the chronically ill. In cases such as this, influenza can in fact progress to deadly pneumonia. Symptoms of influenza usually start to express themselves 36 hours after being infected with the virus.

The flu vaccination contains three viral strains of suspected viruses for flu outbreaks during a particular winter season, as determined by the World Health Organization. Yet the strains chosen are speculated influenza viruses, as this does not eliminate the chance of a new and dominant influenza viral strain that possibly could cause a pandemic. It takes manufacturers about 6 months to make and formulate the influenza vaccination. We hope.

Dan Abshear

To The Doctor, TomDVM and Revere re where is this oseltamivir resistance in H5N1 coming from....may I propose one possibility?

The Doctor stated that the use of oseltamivir is not widespread enough to have caused this widespread resistance by exposure to the drug, but there is at least one place in the world where tamiflu has been used in a broad swath prophylatically whenever there is a known human case of H5N1, and that's indonesia. The question is how is the resistance in H5N1 showing up in other places far from Indo.

Could the answer be that the naturally selected resistant virus in the humans in Indonesia treated with tamiflu is passed on to birds (H2B) and then from there B2B and into wild birds who migrate and spread the resistance?

Another possible route might be that the tamiflu given to large numbers of people in Indonesia gets into the food chain somehow, perhaps excreted in bodily wastes into the water, and from there it travels back into birds which have the virus. This could select for a resistant strain of the virus, which then could be carried and spread by migratory birds around the globe.

The plateau pika is a rodent like species of the Qinghai/Tibetan plateau that could be serving as a reservoir for H5N1 and other influenza viruses. It is very common and often poisoned as a pest and is also prey for other larger predators including raptors in the region. It's also interesting that this corridor between China and India is used by the Bar-headed Goose.

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Influenza A virus (A/plateau pika/Qinghai/04/2007(H5N1)) segment 1 polymerase PB2 (PB2) gene, complete cds
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Dan: We cover these matters rather thoroughly here. If you click on Bird flu and Vaccines and many other categories in the left sidebar you will see hundreds of posts on the biology and epidemiology of influenza A. While the list of "knowns" you give is correct, none of them bear on the list of unknowns, unfortunately. As one leading flu epidemiologist said to me some years ago (and I have to agree with him), "I knew much more about flu 20 years ago than I do now."

It is a little unbelievable as well that by chance, the resistance mutation is somehow connected to another mutation (piggybacking) that produces selective advantage.

No, the piggybacking idea is probably true for a lot of viruses. Most viruses do not have very much genetic information, and they mostly (mostly, not all) rely on host endonucleases to splice, if they even have splicing sites at all. Since every gene they own is connected to every other gene (they use proteases and host chaperones to assemble themselves post-translation), things mostly do piggyback when it comes to viruses.

Flu viruses are actually unique in that they have segmented genomes (7-8 little pieces of RNA instead of one big piece) and they have a couple of RNA splicing sites for the host to process. But it is, literally, "a couple" as in, two. And you have to picture all these wee little segments of RNA flapping about in the cell of their own accord, waiting to bump into the assembly proteins and get packaged. So, imagine a person is infected with more than one flu virus--they caught one from the kids' daycare, they caught another from a co-worker--the loose bits can, and do, recombine, making hybrid viruses. Thus does resistance spread hither & yon easily compared to other bugs, in the presence of sporadic and half-assed selection pressure.

Lora.

Thanks for the excellent description...I have saved it. /:0)

These are highly complex issues and probably this is a little early for a fully examined response but I'll give it a try anyway.

So here's the thing.

We have a real threat potential of a pandemic in the near term future. We have a general apathy (human nature) and limited resources...

...all of the resources are and have been spent on antivirals (mainly Tamiflu) and vaccine research that is reported daily in the press with great fanfare...

...this is partially based on the opinion or the time which was...that fto achieve resistance for Tamiflu, a pandemic virus would have to lose all virulence.

As it turns out...seasonal influenza has achieved resistance pretty much all antivirals and done so by increasing rather than decreasing virulence.

In general, we are also seeing an increased trend towards virulence of all influenza strains including seasonal as well as exotic.

We also know that these resistant subtypes emerge in developed western countries...the latest occuring in Australia while pandemic exotic influenza's emerge in third world countries and most often in China.

We also have had the experience with the pattern antibiotic resistance follows...where there is no resistance when the antibiotic is introduced and then slowly over decades, resistance develops eventually leading to what we all should have been able to predict...superbugs resistance to a broad class of antibiotics.

We also know how the fundamentals of producing antibiotic resistant bacteria in the lab and in the field...In the lab, we grow colonies of bacteria on reduced concentrations of the antibioitic in question and then pick up those colonies that grow through the antibiotic...In the field we eilther give patients too low a dose of treatment or we stop the treatment too soon before all of the bacteria are killed.

We also know that seasonal influenzas are 'slow' replicators relatively when compared to the supercharged, hyperactive exotic, pandemic potential strains.

So every country in the world stockpiled Tamiflu a couple of years ago because it was the panacea, not only as a treatment for pandemic influenza but also as a preventative that could be taken for weeks by heathcare workers...and lastly, the World Health Organization decided to use a Tamiflu blanket, placed around any outbreak of any size whatsoever in high risk countries such as Indonesia.

Meanwhile, daily I read of wild claims (scientifically completely untrue but politically expedient and also as it turns out unchallenged by the scientific community) about pandemic influenza's...ie. even though distinct vaccines are failures, now they are advertising a 'cure quality'
preventative...one shot fixes all...against all forms of influenza including the supercharged next pandemic strain.

So having said all that...here's the thing. /:0)

By your description, it should be obvious that neither antivirals or vaccines could work when influenza has harnessed it's own genetic instability so unbelivebably well (ie. all other pathogens with this amount of genetic instability would be doomed to failure from the get go).

A second issue I have with your description, is that under your scenario, then there should have been resistance to antivirals even before they were introduced in the first place, if they did not play a role in the achievement of resistance...as is the historical model with antibiotics.

The fact is that there was no resistance before they were introduced...therefore, logically they must have played a role in the formation of the resistance...as one coincidence might be okay but we have seen the same thing happen with both classes of antivirals...within the same relatively short time frame.

In the end, there had to be a molecular mimic influence that caused the development of the resistance in my opinion...and of course that would be a given, if you introduced an antiviral that didn't break down in the environment and could passage through and influence a wide variety of other animal vectors.

I believe we must face facts...that antivirals and vaccines will never beat influenza...and although we should spend a percentage of resources on research we should concentrate our effort for the next grouping of pandemics on established and effective and proven alternative therapies.

For what its worth...I also believe that antibacterial vaccines against lung infections are relatively effective probably because of the slowness of penetration of infection and growth once penetration has occured...

...influenza on the other hand, penetrates and has escaped to the rest of the body in pandemic influenza within the lag period for the immune system to respond...whether someone is vaccinated or not...and this is a further problem to their 'expedient magic pills'.

The alternative treatments I know work are bacterial vaccines (pneumovax) and oral electrolyes and anti-fever and very short term antishock therapies. For very little money, because they are all off-patent, we could save all of the lives that can be saved in a pandemic.

Thanks again for the explanation.

I would appreciate your feedback on this.

Sorry, a comment I forgot to make was that the day they\ WHO decided to use the Tamiflu blanket...the usefulness of this treatment was removed because they copied exactly the model that is used in the lab to produce resistant strains.

I believe that the continued emergence of new subtypes and strains is completely due to this misguided policy and a second misguided policy of thinking that you can make the problem go away by using a partially effective vaccine in poultry that does nothing but make the problem disappear...ie. like putting your fingers in front of your face...and believing it is gone because you can no longer see it.

All of our attempts have been a failure and H5N1 has been out of control for more than two years.

Sorry, I forgot one more thing and will get out of the way.

What I meant by piggybacking...was that for these resistance viruses to run around the world, they had to replace-overwhelm the existing subtypes...and they could only do this if they had selective advantage.

If the resistance factor in itself was not selectively advantageous...then the resistance factor would have to piggy-back on a second factor that was selectively advantageous allowing the new strain to overwhelm those that exist...this is the model going back to the 1918 pandemic.

The point I was trying to make was that it might happen once...but for this piggybacking to occur with both classes of antivirals is just too much to be random chance.

Also, when the World Health Organization decided to use their Tamiflu blanket...they knew or should have known that this molecule is relatively extremely resistant in the environment...

...and if there was ever a formula for natural weaponizing a virulent virus in nature's laboratory, these are exactly the conditions you would want.

Of course at the time the WHO had done little survelliance work on wild animal species to see if they were susceptible to H5N1 and other influenza's...and the WHO appeared to be working under the premise that Pigs were the only non-human vectors...of course once again they were wrong when they could have easily, proactively spend the few resources for the needed screening of animal populations in Indonesia to pick up the unknown animal vectors.

Also, theoretically, you would never deploy a blanket with such a resistant treatment-preventative because it could also assist in resistance achievement with other humans and also possibly interact with other manmade chemical molecules with unknown end results for public health.

The day the WHO decided in 2005 to promote Tamiflu and vaccine only...it was all over for us.

And while I am at it...one last thing.

I have heard many say that the threat is over...it hasn't achieved transmissibility over the past ten years so it won't.

I believe this argument is fundamentally flawed.

1) H5N1 has achieved lethal infections in humans...not once but independently hundreds of times that we know about...and probably hundreds of times we don't know about.

2) H5N1 has achieved the ability to be lethal and sublethal and subclinical in a multitude of different animal species. The last piece of the puzzle (to complete the natural cycle) is rats and I fully expect that they to are susceptible in the same ways.

3) The template has done nothing but expand...as in geography.

4) The estabilished genetic diversity (multiple strains-subtypes) have not only expanded in numbers but also in geography.

5) The virus is continually moving and decreasing lethalilty in some species while pretty much maintaining it in humans...which too me is a very bad sign for us.

The bottom line is that with the virus that Lora has described...

...probability must be measured in opportunity...as in given enough opportunity, the last missing factor transmissibility will be achieved with a 99.9999999999% certainty...and H5N1 can achieve the end game by direct mutation (as in 1918) or by recombination with the new subtypes of seasonal vaccines or the other variety of emerging subtypes.

H5N1 is both geographically and genetically entrenched...it will has all the opportunity it needs to go wherever it is headed...and with the mistakes previously mentioned, there is now nothing we can do to stop it.

The only question is how much time we have to prepare...and as it stands if the status quo doesn't change we will face it with no gloves, no masks, no antibioitics, no electrolytes, no antishock therapies, no anti-fever medications etc. etc. etc.

They are playing with fire...and the inability to see the truth both about vaccine failures and antiviral resistance will be seen in retrospect as the greatest scientific-strategic failure in all history.

Thanks for the time.

/:0)

Tom: The selection pressure probably doesn't have to be very great and could well relate to one of the 11 genes we know about. After all, we see many simultaneous strains and changes from year to year. H3N2 doesn't seem to have developed resistance at this point, so it is not obvious what is going on. Since this mutation became prevalent in areas without selective pressure on NA, it is a plausible assumption that it is neutral or only slightly deleterious and that some other gene linked to it is the explanation. Maybe we'll find out some day. Maybe not. But at this point I don't think we can say much with confidence.

Thanks Revere.

One last thing I forgot to mention and I promise I will get out of the way.

The only effective respiratory viral vaccine I observed as a farm veterinarian was an intranasal killed vaccine...hard to give to a bunch of snorting cows...but highly effective.

If there ever is to be a successful influenza vaccine (which I very much doubt due to influenza's ability to morph so quickly) it will have to be an intranasal vaccine.

Respiratory viruses and the pharynx and lung they enter are completely different from any other type of infection.

Giving vaccines in the muscle obviously does not stimulate local immunity before the virus enters the lungs...the time lost then in creating a response is outwitted by the speed of replication of the virus and in fact all respiratory viruses when you thing about it.

If the virus was injected into the muscle then an intramuscular vaccine would be far more likely to work as it would stimulate the same type of immune response locally in the muscle.

Finally, in my opinion which may very well be wrong...I think to allow antiviral resistance to occur theoretically by ignoring the way it has been achieved for ever with bacteria etc....and then back to Darwin...given my lifetime of experience with nature and animal disease...is implausible.

Thanks again.

While TomDVM's predictions are frightening and certainly incautious, they have more actual facts and science to back them up then the more circumspect and conservative reasonableness of revere, IMO.

We may not want to believe the worst, but the simplest logical explanation for the widespread resistance to tamiflu is the widespread massive overuse of tamiflu. The fact that H3N2 isn't resistant yet doesn't disprove that: How frequent are H3N2 infections in Indo or elsewhere that have been treated with tamiflu. If H3N2 is a relatively mild flu, then perhaps people suffering from it don't seek such treatment. Has this been researched?

If tamiflu is given to every person exhibiting ILI in an area where there has been a case of human H5N1, it is going to select for resistance not just in H5N1, but for all the other flu like viruses these individuals were infected with. Since most of the time, if the reports out of indonesia can be believed, these suspect cases were negative for H5N1, then the use of tamiflu may have promoted resistance in the influenza viruses they WERE infected with, especially with such broad scale and repeated 'blanketing". This would allow for the possibility of recombination between resistant strains of ordinary flu and H5N1, would it not?

I don't see TomDVM's conclusions as some kind of "out there" postulate, but actually very scientifically sound reasoning based on known facts regarding how resistance is created and what precisely has been being done in Indonesia to create this resistance. And the warning should be given due respect and heeded, rather than placed on the back burner as unproven. The only way it can and will ever been proven will be by scientific historians mopping up well after the fact, and by then it will be too late to save most of the world population.

By your description, it should be obvious that neither antivirals or vaccines could work when influenza has harnessed it's own genetic instability so unbelivebably well (ie. all other pathogens with this amount of genetic instability would be doomed to failure from the get go).

No, not really. We know lots of viruses have far more genetic instability than flu--lentiviruses are notorious for using host recombination/mutation events to create multiple infections in the same host during active replication. The mutation that confers oseltamivir resistance is in fact just one little point mutation, H274Y (Ives et al. 2002 Antiviral Research 55(2): 307-17). Those happen quite a lot. The thing about viruses is that they beat you by sheer numbers: one replicative round in just one cell gives you millions upon millions of chances for a successful mutation/recombination event. When you consider that the initial infective dose is pretty high, you can see how the chances aren't that bad really.

Also, when it comes to point mutations, lots of proteins are not as finicky as all that. A good portion of most proteins is structural rather than an active site, so provided the mutations stay out of the active site, they can tolerate rather a lot of wobble in the code.

A second issue I have with your description, is that under your scenario, then there should have been resistance to antivirals even before they were introduced in the first place, if they did not play a role in the achievement of resistance...as is the historical model with antibiotics.

Not necessarily. The mutation can come from anywhere. Spontaneous mutations can arise whenever. Here's an interesting paper, they don't estimate or analyse the source of mutations, but you can sorta guess-timate an indicator of the mutation rate inherent in the polymerase: Ito et al. 2001 J. Virology 75(9): 4439-4443. They were doing this specifically to generate a more virulent virus from a less-virulent one, too. They found that HA-based virulence was actually an adaptation that allowed better cleavage by host proteases.

Anyway. You know what I would love to see, to reduce the transmission frequency most often? Infinite sick days from employers. My employer does this: You get infinite sick days, but after so many of them (don't know how many, maybe 10-12?), the company's disability insurance policy kicks in to pay your salary. After a rather generous time period (I think it's about 2 years), you either file for SSI or are let go at that time. But in the meantime they hold your job for you, or else agree to give you one at the same pay rate, type of thing. Coming to work sick is dangerous, as you could infect the experiments, and the experiments are worth more than you ;-) I know it's the management instinct that people will abuse such a policy, but I think out of several thousand employees, they've had problems with only two or three. Let more people telecommute, fer cryin' out loud. You'll save the air pollution too.

Thanks Mary.

What I find difficult is untruths knowingly spread through the community by authorities and pharmaceutical companies and regulatory authorities that largely go unchallenged by the scientific community.

Thanks Lora.

"The thing about viruses is that they beat you by sheer numbers: one replicative round in just one cell gives you millions upon millions of chances for a successful mutation/recombination event."

That is my point exactly...the thing about respiratory viruses is that they evade antivirals and vaccines through this mechanism.

The fact seems to be that successful challenge tests with laboratory animals are build on a foundation of sand.

They vaccinate the lab animals with a strain of influenza that is then frozen in development. The natural and continuous 'genetic drift' that occurs in nature is prevented. Under these artificial conditions...a positive but meaningless (in the real world) result can be demonstrated.

Secondly, the scientific community has allowed pharmaceutical companies to report unchallenged successful human trials of pandemic vaccines measured by a post- vaccination titre. A titre means nothing...lots of vaccine trials produced titres and then the vaccine was thrown out because the titre was not protective.

Thirdly, they base their seasonal influenza success on screening studies where they often measure clinical signs only or once again titres which may mean nothing.

In my opinion, there are two results of influenza vaccination to humans or poultry...pandemic or seasonal.

1) once vaccinated you can not distinguish disease titres from vaccination titres when doing their favoured screening studies...

2) vaccination with a by definition, at best, partially effective vaccine results in carriers...animals which have and can spread the disease but will not develop clinical signs...this is not good on a farm, not good in a human community, and especially not good when front-line healthcare workers are spreading the disease into the community.

We have to ask ourselves, why do the majority of healthcare workers not take the vaccine. The fact is that healthcare workers are trained to question. You can't get away with what happens in the community...authorities telling them that it works.

I would have hoped that double-blind quality irrefutable studies would have been done to convince everyone concerned including me that these vaccines work...but to this point...all we have seen is useless screening tests...the same test type that tellsw young people that alcohol is good for you.

So why don't they do easily achievable tests that would answer the question once and for all?

I can only conclude that they may be afraid of the end result.

The fact is that there is a vaccine that works....natural infection. Humans have known this intuitively for a long time.

The other fact is that the majority of those who died in 1918 died from secondary bacterial infections...and for that we do have effective vaccines and effective treatments...

...even better is that these treatments and preventatives cost a fraction of those ineffective vaccines and antivirals.

But of course vaccines and antivirals are expedient.

Lora

I agree with you on the sick thing...but I also never saw a problem with people walking around with masks on either...

...unlike the authorities with SARS who made nurses take off their masks because they were scaring people.

Tom, Mary: Disagreement is one thing. Spreading "untruths" is another. There are alternative explanations for what we see and none of the ones advanced here are beyond the pale scientifically (by either party). Tom has been consistent in his beliefs about what is happening although consistency is not a virtue if it isn't connected with what we observe. My interpretation of what Tom has been saying is that he objects more to the consequences of believing certain things than whether those things are true or not. His privilege. Mine is to make my judgments based on what I see and know in terms of science. In particular I don't believe that H5N1 having supernatural or mystical powers or unfathomable potency is a scientific explanation for anything.

Regarding the efficacy of antivirals to stop a pandemic, I agree with Tom. I have said so here numerous times. That's a different question. Vaccines remain an open question but not with the public health system in bad shape. Tom's rendition of the how they work or don't isn't based on vaccine science but I don't want to argue that here. If we want to prepare for a pandemic we need to make the public health and social service systems ready and start investing in them. That's always been the position here and I don't know why we are arguing about antivirals since neither of us thinks it's the answer to much.

If we want to prepare for a pandemic we need to make the public health and social service systems ready and start investing in them.

This is so, of course. Tell me a utopian story for a snowy day, revere: What is your dream of public health? If money was no object, what would you have? How do we determine how many medical professionals we need, of what type, and determine how they would be distributed? Would you have large central hospitals that focus sharply on a single discipline, as many Asian health systems do--take advantage of the efficiencies of scale that one large hospital doing nothing but one discipline can enjoy? And then have a distribution network of groups of GPs running clinics for the usual plumbing checks and writing referrals--and have the GP clinics do infectious disease management as well?

Or have several smaller hospitals evenly distributed amongst population density, and the smaller hospitals all do their own thing?

How would you distribute preventative care? In some nationalized systems, if you miss your annual physical, the nurse or PA tracks you down to find out why you missed it; or should we have preventative care distributed in new ways, by putting offices for basic care and disease surveillance in schools (like, grade schools and such), pharmacies, shopping malls? Should we have a sort of Doctormobile that would be responsible for each neighborhood's worth of people, making housecalls?

How can we distribute vaccines and make sure they are taken in a timely fashion? Do you think the school vaccination requirement works well enough that we could expand it to, "must be fully vaccinated (or have doctor's note) to work here," or, I dunno, something else?

I am a fan of the idea that people don't really NEED to move around a whole lot. Not as much as they do now, anyway. If your job is sitting in front of a computer and going to meetings, why would you need to be there in person? I'd like to see a lot more people telecommute, there's no real reason why not. And I'd like to see the same thing with food, I don't think food absolutely needs to be moved around all that much or processed as much as it is. Better to grow diverse foods locally, so that a local illness doesn't spread and monoculture doesn't wreck the economy--and I say that sitting under a foot and a half of snow right now (this venison stew w/ potatoes is mighty tasty).

What do you envision?

Lora: You ask pertinent and important questions. Let me answer in two ways, neither being the answers you are looking for, I suspect.

The first is that we need to rethink the public health system and if you look back over the lst week of posts here you will see I am inviting you and others to start a conversation about that. I don't think any of us (I include myself first and foremost) have done the hard job of thinking this through in some Big Picture sense. So by all means join the conversation.

The second response is slightly different. I mentioned the public health infrastructure and you responded by asking me about the health delivery system. Whether the second is part of the first or not is a question to ask, but it is certainly not all of the public health system. When we speak of attending to the transportation infrastructure we are talking about roads, bridges, rail tracks, tunnels and there will be much debate about the proper mix, what to add to them, etc. But there is general agreement that one of the first things we need to attend to is fixing the bridges that are falling down, the roads with huge potholes in them, the tunnels about to collapse, etc. So when I talk of re-invsting I am talking about repairing the damage of the last 20 or 30 years where we have de-invested (it started with Reagan and has continued almost unabated). So I am talking about the basic and routine pieces of the public health and social service infrastructure as it used to exist, for starters: substance abuse programs, surveillance, vital records, epidemiology and infectious disease units, maternal and child health, food inspection, water systems, etc. On the social service side I am talking about aid to dependents (old and young), the "safety net", visiting nurse associations, child protection services, etc.

The idea is to make our communities more robust and more resilient for whatever shocks it will suffer, whether it is a pandemic with flu virus or some other agent, a mass poisoning, mass unemployment, etc. In my view, this will go farther than antiviral stockpiles or vaccines that don't exist. I do think we should continue to work on antivirals and vaccines, but not as the mainstay of pandemic preparedness.

Maenwhile, go back to my first answer, rinse, repeat.

Hi Revere,
I find this an interesting conundrum: On one hand you are absolutely right, as a scientific purist one never jumps to any conclusions or "proves" any hypothesis: however by the strong inference method one seeks to find more and more support for it. Since there is no objective proof for Tom DVM's contentions of how the H1N1 virus acquired resistance to tamiflu, his inferences based on the known use of tamiflu blankets and the known methods of creating drug resistance in infectious organisms such as XDR TB are only that, strong inference models. As are yours.

I think the problem lies in the fact that this subject is of enormous public health importance, not idle ivory tower conjecture. When faced with the choice of whether to support the conservative view - that the resistance is the result of natural mutations that were not provoked by the use of tamiflu (coincidentally occuring almost globally and almost simultaneously) or alternatively to believe that these mutations were directly caused by the use of tamiflu and to thereby construct a model for predicting what might similarly occur/be occuring with H5N1 in Indonesia, in its ongoing evolution to become a devastating pandemic...I think the more careful, conservative and wiser choice would be to err on the side of caution and take the latter view. Why? Because the first offers us no chance whatsoever to predict or mitigate its course, it's all a crap shoot and nothing we can do. At the very least accepting the second alternative would provoke tptb as well as the general public to prepare for the pandemic with the proper tools and procedures.

One thing in your last post to "Tom,Mary" that I would have to raise a mild objection to is your intimation that either of us were attributing supernatural powers to H5N1.

as in "In particular I don't believe that H5N1 having supernatural or mystical powers or unfathomable potency is a scientific explanation for anything."

That's a straw man argument: neither of us intimated any such thing and to hint that we did so in order to discredit our points of view is not particularly fair.

A few other infected mammals in interesting regions...

Influenza A virus (A/cat/Dagestan/87/06(H5N1)) (Submitted (20-JUL-2006) Laboratory for Diagnosis of Avian Diseases, Federal Centre for Animal Health (FGI ARRIAH), Yur'evets, Vladimir 600901, Russia)

---------

Influenza A virus (A/cat/Germany/606/2006(H5N1)) (isolation_source="naturally infected cat's brain")

(In the course of the epidemic among wild birds on the island of Ruegen, three stray cats and one stone marten (Martes foina) were also found to be infected with HPAIV H5N1, presumably from scavenging on carcasses of dying or dead wild birds. Apparently, these animals succumbed to the infection. (Journal of General Virology (2007), 88, 554558))

Mary: One problem with responding to two people at once (my error) is that comments directed to one person are attributed to another. So I apologize for that. My comment about abilities beyond science are based on comments by Tom over the years similar to this one (this is a quote from a comment of his):

It seems to me that we are operating on one scientific level and influenza specifically is on a whole different level existing beyond our current capability...

Tom's position, as I understand it (although it has a number of internal contradictions) is that:

i. vaccines will never work for influenza (he also says that vaccines depend on "local immunity"; not true)
ii. seasonal influenza is resistant to all antivirals. This is also not true, although even if true is not particularly relevant since there are so far only two classes of antivirals. It says nothing about antivirals any more than saying MRSA exists says antibiotics will never work for staph.
iii. virulence is increasing for all influenza strains, seasonal or not. I know of no evidence for this.
iv. Tom seems to think that antivirals cause resistance mutations. Almost every evolutionary biologist I know of does not subscribe to the (Lamarckian) idea of directed mutation. Maybe we will find out that it occurs. But that has never been suggested for antiviral resistance by any scientist in the world I have ever heard of.
v. the idea that seasonal flu subtypes are "slow replicators" (compared to what?) is also something I haven't seen evidence of.
vi. countries stockpiled Tamiflu for a relatively simple reason. In the face of a possibly imminent pandemic, there were no other possibilities with any evidence of efficacy. Many of us (not just Tom) pointed out the problems with this, but there were no other responses on the horizon except for what I have been harping on, strengthening community robustness to withstand the shock of a pandemic and manage its consequences. Even in that context, pandemic stockpiling was a rational response, just not one that should have been solely or even mainly relied on. Just one other arrow in the quiver.
vii. the same for vaccines. We have made a lot of progress in vaccine technology, progress that Tom's view would not have encouraged since he takes a negative view of vaccination as a preventive measure for flu. He believes this because flu changes so rapidly. But we make vaccines against features that do change rapidly. People are now trying to make vaccines against features that are relatively highly conserved. He mistakes older techniques for the only techniques.
viii. Tom has raised here a number of times his suspicion that the reason there are no randomized trials of flu vaccine is that the drug companies or WHO or whoever is his target knows they don't work and therefore won't test them. This is a misunderstanding I have addressed on numerous occasions in response to his comments but let me try again, in shorthand. First, there are RCTs of flu vaccine, quite a number. There aren't many with good data on the older age group, which is the special target of CDC and we and others have pointed this out. Second, doing an RCT is not simple. In fact it is very, very difficult, and in the case of a vaccine generally accepted as the standard of practice, using a placebo vaccine would have some severe ethical problems. The real world of drug trials is much messier than any idea one gets from an introductory text book.
ix. vaccine trials are going on now. Tom reiterates a point we have made often here, that guessing efficacy by a surrogate like neutralization antibody titers is just a guess about the relation of those titers to actual ability to protect against disease. What does he suggest? That we test them by starting a pandemic or deliberately infecting volunteers with H5N1?
x. Tom is certain that H5N1 will evolve to be easily transmissible (99.9999999999% certainty). His privilege. Since we don't know what makes H5N1 easily transmissible this is just a statement of opinion, based on zero science. Tom is a veterinarian. Has rabies evolved to be easily transmissible through the eons of its existence?
xi. Tom assumes that the majority of health care workers don't get vaccinated because they question whether it works or not. I've spent my entire working life in health care institutions and I've worked at every level. Health care workers are just like everyone else. I have no idea and know of no convincing evidence (or any evidence but I haven't done a systematic search) that their vaccination rates are lower than that of the general public but whether it is or isn't has nothing to do with whether they have a deeper insight into influenza vaccine technology or are sterner questioners. They are just like everyone and each has reasons to get vaccinated or not that is pretty much like most other people.
xii. it is my understanding that resistance to antivirals has spread very fast and quickly in areas where it was under essentially no selective pressure. The same thing happens with other phenotypic features. There is an extensive science of evolutionary dynamics that describes how this happens with neutral, almost neutral or even unfit genes, given other conditions.
xiii. Tom has stated that the only effective "vaccination" is natural infection for flu. But of course the reason we need vaccines every year is that there is nothing effective about it at all because we don't make antibodies to a conserved feature of the flu virus, the same reason Tom thinks we can't make a vaccine. Here's his exact quote:

The fact is that there is a vaccine that works....natural infection. Humans have known this intuitively for a long time.

I think I'll stop here. Tom has a position. He is smart, well informed and no shrinking violet in expressing it or responding to my opinions. I'm no shrinking violet, either.

Thank you Revere. Your very excellent and complete explanation of the issues and reasoning is very much appreciated and sheds a great deal more light on the subject for lay people such as myself. Even though I am sure you have discussed all the above ad infinitum in various posts, it really helps to have it all laid out like this in one.

Whatever the cause of the tamiflu resistance in H1N1 - and I continue to think that Darwinian (not Lamarckian) selection factors may be at work, since H1N1 is the most common of the influenzas in North America and Europe, and thus most likely to have been treated with tamiflu over the past several flu seasons - the problem is that drug resistance has occured and thus raises a serious alarm, both in and of itself as well as the portent for what might well occur in indo if/when the tamiflu blanket is no longer effective in damping down this incipient pandemic.

Mary: . .. since H1N1 is the most common of the influenzas in North America and Europe, and thus most likely to have been treated with tamiflu over the past several flu seasons

Actually 16 of the last 20 flu epidemics since the 1968 pandemic have been dominated by H3N2, which is the main seasonal subtype (see http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2495036).

H3N2 seasons also tend to be worse than H1N1 seasons.

Speaking purely from a biological prospective, the fact that H5N1 and for that matter H1N1 has become highly resistant the Tamiflu and amantadine does indeed favor natural selection over the proposal that it could simply be a random mutation. Why, simply because it is so widespread within these two viral groups.

As I understand it, resistance to an antimicrobial in fact begins just as Revere stated above, as a random mutation within a very small number of organisms exposed to that drug. This is the selection pressure. That the resistant organism flourishes and becomes the dominant type in the future is due to the present of the resistance genetic factors found within those few organisms.

If there is no selection pressure, then the strains with the resistant gene have no advantage over the others and their numbers would remain muted within the population. Given the fact that H5N1 and H1N1 are predominately resistant to Tamiflu, the most logical explanation is that this drug must have been used in really extraordinary quantities, much greater than what has been used in the developed world by organized medicine to treat people. The use in people outside the developed world has been small simply because it costs so much.

Whats more, it would have been necessary to provide the drug to a very large number of hosts infected with the disease to have caused a selection pressure significant enough to result in a virtual complete resistance of these two viral groups. Those treated with the drug do not need to be humans. In fact they probably were not. Poultry and swine would work as well or even better.

Roche publishes its sales of Tamaflu on a regular basis. While the drug quantities shipped are large, these supplies are pretty much accounted for in various national stockpiles, prescription records and commercial inventory. The quantity of oseltamivir used on a scale adequate to result in the extremely rapid and widespread resistance is considerably greater than any missing Tamiflu tablets that might have been diverted from official records.

While a lot of Tamiflu has been used in Indonesia, it has been given to people only, not livestock and the quantity given clinically have simply been to small to result in worldwide Tamiflu resistance. Indo is also off the beaten path of wild waterfowl migration. For these reasons, they are not a likely source of the resistance.

Given the above conditions, the simplest explanation that explains the facts is that osetamivir was produced secretly in massive quantities on a national scale and placed in food destined for poultry and swine. This action could only be the result of a coordinated national policy to have the impact it has had so quickly.

We know of one country that pursued a policy like this before with respect to amantadine. That country was the PRC and it resulted in the worldwide resistance of influenza to that antimicrobial. The PRC has the means and opportunity to do the same with oseltamivir. By being located astride the wild waterfowl super flyway, the spread of the resistant viral strains across the world rapidly also plausibly explains how this occurred so quickly. What possible motive would they have to take a step like this especially since their experience with amantadine must surely have informed them that taking such an action might have the same devastating affect on oseltamivir. One possible motive is to prevent unrest in the 1 billion poor Chinese that live in the countryside and whose income and prosperity are tightly connected to agriculture. It is the unrest within this group that is a constant threat to the rulers in Beijing. Another possible motive was to try and tamp down the outbreak of bird flu within the country as much as possible in the year leading up to the 2008 Olympics, something the Chinese wanted very much to see be a success.

Reaching for leaves on tall trees does not make a giraffe's neck long, but there seems to be a misapprehension here that antivirals make a virus resistant. They don't. The mutations are independent of the antivirals. Genetic variation is a separate mechanism and natural selection works on the variation, it does not cause it. A mutation that confers resistance may or may not confer a selective advantage. If there is little antiviral use, then there is little selective pressure. If there is no selection pressure and the mutation becomes prevalent it may be because it is linked to another genetic feature that confers an advantage and is itself neutral (new mutations abound). But if it becomes prevalent in places where there is no pressure, then that suggests it is a neutral mutation. Indeed, if it stays prevalent in a place where there is little Tamiflu use, it is neutral for that time and place. It provides no selective advantage. But it is still there.

Influenza vaccines have been with us for how long...thousands, tens of thousands, hundreds of thousands or even maybe millions of years...

...and in all that time there doesn't appear to have been any mutations developed against antivirals that of course didn't exist at the time.

The reason we know that no resistance had developed because there was no existing resistance when the antivirals were introduced.

Then antivirals were introduced and they were advertised as the new panacea...to be used as treatments and preventatives...and in fact they were used on domestic animals-poultry as well as humans...

...and then it was noticed that they don't breakdown in the environment and could passively interact with other humans and animals through many cycles.

And yet...we are to believe that the above factors played no role whatsoever in the fast development of resistance after the antivirals came into widespread use?

Tom: There may well have been that same mutation appearing thousands of times during that period. We have no way of knowing. The point again: antivirals don't cause resistance mutations. They don't as far as anyone knows, at least. Maybe you think differently, but that is not current biology (since Darwin). These mutations are selected for, at best.

Darwin only goes around mountains that exist.

Revere. Given the time it took to write the aboveI felt I owed you a response.

It follows:

1) i. vaccines will never work for influenza (he also says that vaccines depend on "local immunity"; not true

You are quite rightnever is a long time.

I think that the current technology protects maybe 5-10% of those vaccinated.

Why? The target moves faster than the vaccine production lag time.

The thing about viruses is that they beat you by sheer numbers: one replicative round in just one cell gives you millions upon millions of chances for a successful mutation/recombination event. Lora above

I believe that most cases of influenza are actually food poisoining and I believe that many persons in the past, have died in old folks homes from food poisoning misdiagnosed as influenza.

As a result, I do not believe we will have influenza vaccines that will work for the forseeable future.that would be thirty years and by my estimationor the next three pandemics.

There maybe different interpretations of local immunity. I was taught that the immunity was concentrated in areas of greatest riskthat being the gut and the oro-nasopharynx and lungsand that this immunity is qualitatively as well as quantitatively different from areas under a protective layer of skin for example.

My field experience also backs this up. Intramuscular vaccines for respiratory viruses have not been very successful in preventing disease in my opinion. Based on this, I believe the vaccine must be a topical one on mucosa mimicing the pathway the virus follows to infect the host. The result is hopefully, an improved response time.

2) ii. seasonal influenza is resistant to all antivirals. This is also not true, although even if true is not particularly relevant since there are so far only two classes of antivirals. It says nothing about antivirals any more than saying MRSA exists says antibiotics will never work for staph.

I understand that resistance has occurred in all subtypes of influenza and all classes of antiviralsmaybe a little more successful in some than others.

Reasons that antivirals will not be a factor in the coming H5N1 influenced pandemic

The thing about viruses is that they beat you by sheer numbers: one replicative round in just one cell gives you millions upon millions of chances for a successful mutation/recombination event. Lora above

Despite this, I have always mentioned that reasearch should continue at responsible funding levels.

3) iii. virulence is increasing for all influenza strains, seasonal or not. I know of no evidence for this.

Seems pretty obvious given the changes in seasonal influenza in the past ten years and the emergence of a number of exotic subtypes that have infected humans for the first time.

I can not conceive a bigger threat potential or a more lethal virus than H5N1.

4) iv. Tom seems to think that antivirals cause resistance mutations. Almost every evolutionary biologist I know of does not subscribe to the (Lamarckian) idea of directed mutation. Maybe we will find out that it occurs. But that has never been suggested for antiviral resistance by any scientist in the world I have ever heard of.
.

As one leading flu epidemiologist said to me some years ago (and I have to agree with him), "I knew much more about flu 20 years ago than I do now." Revere above.

5) v. the idea that seasonal flu subtypes are "slow replicators" (compared to what?) is also something I haven't seen evidence of.

I understand that one main difference between H5N1 and seasonal influenza is exponentially higher replications ratewhich partially explains its ability to overwhelm human physiology. I didnt think this would be new information to anyone.

6) vi. countries stockpiled Tamiflu for a relatively simple reason. In the face of a possibly imminent pandemic, there were no other possibilities with any evidence of efficacy. Many of us (not just Tom) pointed out the problems with this, but there were no other responses on the horizon except for what I have been harping on, strengthening community robustness to withstand the shock of a pandemic and manage its consequences. Even in that context, pandemic stockpiling was a rational response, just not one that should have been solely or even mainly relied on. Just one other arrow in the quiver.

Other possibilities?

Most deaths in 1918 were due to secondary bacterial infection.

Antibacterial vaccines (pneumovax) are effective oral broadspectrum off-patent antibiotcs are also effectiveoral electrolytes are also effective, anti fever drugs are also effectiveoral antishock drugs are also effective if used appropriately. These preventatives-treatments all treat seconday bacterial infections.

All are off-patent and comparatively cheap in comparison to alternatives.

In my opinion, putting all their eggs in two convenient baskets was not responsible regulation or planningbut of course it was the line of least resistance.

7) vii. the same for vaccines. We have made a lot of progress in vaccine technology, progress that Tom's view would not have encouraged since he takes a negative view of vaccination as a preventive measure for flu. He believes this because flu changes so rapidly. But we make vaccines against features that do change rapidly. People are now trying to make vaccines against features that are relatively highly conserved. He mistakes older techniques for the only techniques.

Point well takenHowever, I have not seen anything to indicate progress to completion in the next decade.

As I stated above, I have always believed in continued research with an ethical porportion of financial resources given the ever increasing threat potential of an H5N1 pandemic

8) viii. Tom has raised here a number of times his suspicion that the reason there are no randomized trials of flu vaccine is that the drug companies or WHO or whoever is his target knows they don't work and therefore won't test them. This is a misunderstanding I have addressed on numerous occasions in response to his comments but let me try again, in shorthand. First, there are RCTs of flu vaccine, quite a number. There aren't many with good data on the older age group, which is the special target of CDC and we and others have pointed this out. Second, doing an RCT is not simple. In fact it is very, very difficult, and in the case of a vaccine generally accepted as the standard of practice, using a placebo vaccine would have some severe ethical problems. The real world of drug trials is much messier than any idea one gets from an introductory text book.

You are quite rightI think epidemiology has become a tainted, unregulated professionand there have been a lot of unchallenged studies forthcoming from industry epidemiologists taken at face value from the scientific community contrary to the scientific method.

A relatively large porportion of epidemiology of the past fifteen years is the mostly snake oiland those who sell them salesman rather than scientistsand I expect you dont like it any more than I do!

I dont have a problem with screening studies. I have a problem with unethical reporting of the limitations of these studies. Every week there are reports of successful pandemic vaccines because they illicit an immune response when responsible scientists should know that this doesnt mean a damn thing when it comes to protection against a field virus.

In the same way, we continually see very good results to viral challenge in laboratory animalswhen it is not disclosed that natural field antigenic drift is artificially prevented such that the challenge comes from the 100% identical virus that the vaccine was made from.

The general public may buy this crap but frontline healthcare workers obviously are notthats a major problem when the salesman are smoking what you are supposed to be selling.

All I want is responsible reporting and an immediate response to industry mistruths.

The real world of drug trials is much messier than any idea one gets from an introductory text book.Good One!!!!!!!!!.Ill take a wise general practioner any day.

This is an animal diseasehow many human specialists have spent time studying the behavior of animal diseases in the real worldnot the laboratory?

9) ix. vaccine trials are going on now. Tom reiterates a point we have made often here, that guessing efficacy by a surrogate like neutralization antibody titers is just a guess about the relation of those titers to actual ability to protect against disease. What does he suggest? That we test them by starting a pandemic or deliberately infecting volunteers with H5N1?

Like I said, industry (and there are now many types of industry in public health) must report the limitation of their research ethicallyand when they dont, we all have a responsibility to attack until they learn not to bend the truth.

There must be a way to do an ethical double-blind quality study allowing for personal choicethis could be easily accomplished with healthcare professionals since they are evenly split on whether to receive the vaccine or not. Using healthcare workers has been successful in the past with a number of excellent ethical studies.

10) x. Tom is certain that H5N1 will evolve to be easily transmissible (99.9999999999% certainty). His privilege. Since we don't know what makes H5N1 easily transmissible this is just a statement of opinion, based on zero science. Tom is a veterinarian. Has rabies evolved to be easily transmissible through the eons of its existence?

Has H5N1 burned itself out in the ten years since its emergence?

Lora above saidThe thing about viruses is that they beat you by sheer numbers: one replicative round in just one cell gives you millions upon millions of chances for a successful mutation/recombination event.

Under these conditions what do you think the probability is that a pandemic potential virion has been reproduced many hundreds or thousands or tens of thousands times in the past three years?

This particular pathogen has the unique threat potential to decimate the human racevery few other things that humans have ever faced reach this threat level. Ignoring the risk may be human naturebut that doesnt make it prudent.

Selective tunnel vision is also human nature and it always seems to slap you up side the head once in a while to keep you honestthis has happened to me many times when it comes to animal diseases turning left when you thought they were going to turn right.

I dont think we can continue to ignore this threat.

11) xi. Tom assumes that the majority of health care workers don't get vaccinated because they question whether it works or not. I've spent my entire working life in health care institutions and I've worked at every level. Health care workers are just like everyone else. I have no idea and know of no convincing evidence (or any evidence but I haven't done a systematic search) that their vaccination rates are lower than that of the general public but whether it is or isn't has nothing to do with whether they have a deeper insight into influenza vaccine technology or are sterner questioners. They are just like everyone and each has reasons to get vaccinated or not that is pretty much like most other people.

Tom assumes that the majority of health care workers don't get vaccinated because they question whether it works or not.

Exactly, no front line professional would choose to get a debilitating disease rather than receive an effective preventative

I dont remember hearing any reports of anyone refusing the Polio vaccination.

12) xiii. Tom has stated that the only effective "vaccination" is natural infection for flu. But of course the reason we need vaccines every year is that there is nothing effective about it at all because we don't make antibodies to a conserved feature of the flu virus, the same reason Tom thinks we can't make a vaccine. Here's his exact quote:
The fact is that there is a vaccine that works....natural infection. Humans have known this intuitively for a long time.

Mothers have known this intuitively for a long time. I remember that everyone survived mumps, meazles and chicenpox.

However, it should be remembered that those who were infected in the first wave were only partially protected against the second and third waveso when it comes to influenza, even the best vaccination (being infection) only produces fleeting immunity.

Take a good look at Zimbabwe and its latest cholera outbreak.if an H5N1 pandemic starts under the current leadership and preparation levelsthat will be the fate of us all!

Tom: My response:

i. You say the target moves faster than the vaccine lag time. Yes and no. The targets change every couple of years and it is hard to predict them. But not faster than the currently (slow) time it takes to make a vaccine. That is why people are trying to make vaccines that target features that don't change fast and that are much quicker to scale up to production (e.g., 30 days)

ii.

I believe that most cases of influenza are actually food poisoining and I believe that many persons in the past, have died in old folks homes from food poisoning misdiagnosed as influenza.

influenza diagnosed as food poisoning? Since one is respiratory and the other gastrointestinal I have no idea what you are talking about except that you may have fallen prey to the common confusion between "stomach flu" and influenza, which virtually every FAQ about flu warns against.

iii. Local immunity. The immune system is complex and has many parts. There is innate immunity, which is immediate and non-specific. There is then adaptive immunity, cellular (T cell based) and humoral (B cell based). The B cells are in the marrow and lymph tissues and make antibodies that circulate in the blood. These are the things that vaccines stimulate. Humoral immunity is not local.

iv. You state a lot of opinions. Please cite evidence, especially if you are complaining that the current views aren't based on evidence (which most are; just not enough evidence).

v. antiviral resistance in all subtypes. No. H3N2 (the main seasonal subtype) isn't showing resistance and there is still little resistance to zanamivir. Many strains are not even resistant to the adamantanes (M2 inhibitors). Most subtypes have never been looked at for resistance. Remember, the subtypes represent different NAs, so an antiviral for one NA might or might work or and resistance to one NA might be sensitive in another (as in N1 and N2 with Tamiflu).

vi.

my point: virulence is increasing for all influenza strains, seasonal or not. I know of no evidence for this.
Your response: Seems pretty obvious given the changes in seasonal influenza in the past ten years and the emergence of a number of exotic subtypes that have infected humans for the first time.

A request for evidence is, "seems pretty obvious"? What is the evidence that seasonal influenza is more virulent than in the past? We've just had four mild flu seasons. Changing the subject to H5N1 isn't an answer.

vii. Your response to my pointing out you are standing evolutionary theory on its head is to say we will learn in the future you are right?

viii.

I understand that one main difference between H5N1 and seasonal influenza is exponentially higher replications rate?which partially explains its ability to overwhelm human physiology. I didn?t think this would be new information to anyone.

Maybe this is true. I hadn't heard it. Do you have a reference?

ix. As for putting all our eggs in two baskets (vaccines and antivirals), I agree. In particular, I think we should be exploring the statin connection further, something I have written about here frequently. We also need a decent health care system and public health system, without which it won't make much difference if we have effective therapies. Therapy is not public health, but I hope we get some good ones. I don't know that we disagree except your view is so consistently nihilistic I find it unhelpful and unconstructive at a time when help and constructive suggestions are badly needed.

x.

You are quite right?I think epidemiology has become a tainted, unregulated profession?and there have been a lot of unchallenged studies forthcoming from industry epidemiologists taken at face value from the scientific community contrary to the scientific method.
A relatively large porportion of epidemiology of the past fifteen years is the mostly snake oil and those who sell them salesman rather than
scientists and I expect you don?t like it any more than I do!

Since I am a professional epidemiologist I must disagree. I think I know the field better than you do and think it is like most fields in science, with its good points and bad points. Veterinary medicine is a field that has been t severely ainted with connections to agribusiness. Where did we get the antibiotics in food from except the veterinarians? Epidemiology makes news because it deals with things people are interested in and familiar with. Except for that, it is the same as other sciences. There is good epidemiology (quite a lot of it in fields you don't read about) and not so good epidemiology. Just like veterinary medicine. You talk about "screening studies" as if you knew what they were. If so, please tell me as it is not any known type of epidemiological study design. Can you even name, without a search, a single epidemiology journal? Your broad brush characterization is silly and uninformed.

xi. No one is advocating ignoring the threat. But some of us are advocating a reasoned, measured assessment, and if you have already decided that your pet threat is the one that everyone has to pay attention to, then you can join the crowd that thinks that XDR TB is the big threat, HIV AIDS, climate change and contaminated sludge -- yes, I know people who think that is the biggest public health threat facing the planet. You are another advocate for your own personal preoccupation and when confronted with evidence you tell me that being a practicing vet "in the field" makes you smarter than everyone else. I'm not buying it. I can find practicing vets that will tell me almost any thing, including that it's good to feed antibiotics to farm animals (I know several of those and I'm sure you do, too).

xii. Zimbabwe? Cholera is completely preventable and completely treatable. I don't know what it has to do with influenza. Since you don't think you can do anything about influenza anyway, what does starting in Zimbabwe have to do with it? Natural infection is the best vaccine? Than how come people get flu again? Rabies is a virus. It hasn't burned itself out in tens of thousands of years. It has not become a pandemic. As for how health care workers act, some evidence would be welcome. I don't have any data to show what you are saying is right or wrong. But I have worked in health care institutions for 50 years (starting in high school) at every level, and I think I know them better than you do. It isn't enough to just assert an opinion.

Thanks Revere.

Zimbabwe has a treatable disease with nothing at all to treat it with.

Those that could be treated due to secondary bacterial pneumonias in the next pandemic, won't be treated because there will be no antibiotics...or anything else except placebo's...because...unless I have missed something...all our eggs are still in two baskets...

If a pandemic started next week...how many persons in the United States could be treated with antibiotics? I think that is an important question...don't you?

Secondly, in my opinion, there will be no public health in a pandemic...so all of this treatments must dispensed (therefore oral treatments only) backed up with phone advice if even that is avaliable.

Also, I think maybe it is time your colleagues got together and regulated your profession.

Influenza (stomach flu) has been commonly diagnosed in this way...that was my point.

Animal diseases are different than human diseases. H5N1 acts like an animal disease.

The continued use of antivirals as preventatives etc. will mean in short order...they will be useless...not a big deal if you have covered yourself with adequate stockpiles of the other things mentioned...

...in other words...antivirals are blunt tools...not cures as they have been sold for the last three years.

From my observations in nature and with farm animals...those with primary viral infection will die and there will be nothing we can do about it...that would be about 5% of those who get sick...The ones we can save are the 15% in the middle that die from the secondary infections...those are the ones I am aiming at...and they won't be treated in a hospital or probably even be touched by a doctor or nurse.

H5N1 is not my 'pet threat'...food safety is.

I am a retired veterinarian.

I read alot but am not very good at saving references...Sorry.

I have never believed that I am 'fear-mongering'...I just talk like I would to a group of colleagues...if that is too much for some...sobeit.

A couple of points I dug up that might add something to this conversation. First, there has been some indication of H3N2 developing resistance to tamiflu in Japan, where the drug has been used the most and for the longest period.

"Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir [18]. This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children [7]. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected."

Second, it is neither indonesia nor China that may be the source point of developing resistance, but Japan, since it has used the antiviral the longest and treated the most people.

"Roche points out that Tamiflu has been used to treat 50 million people since 1999....[1] The majority of these have been in Japan, where an estimated 35 million have been treated.[2]"

Thirdly, since tamiflu has only been in use since 1999, the statistics regarding which flu has been the most common in outbreaks is only relevant to the last decade, not the last 40 years. To validate that point, one also has to take a look at which countries H3N2 was most prevalent, and which countries H1N1 was most prevalent in during that decade, and then compare with in which countries H1N1 resistance has occured. If there is no correlation, so be it.

Finally, I do not understand why Revere continues to insist that Darwinian natural selection pressures - which is clearly what Tom DVM, The Doctor and myself are talking about - are examples of "Lamarckian selection" akin to giraffes developing long necks by reaching for leaves. None of us has intimated any such thing: Obviously naturally occuring mutations are the key, but as Darwinian theory holds, a change in the environment (in this case, antiviral medication that attacks or renders inoperative a certain key protein of the virus) can favor those viruses that have mutated a different sort of protein not affected by that antiviral. These virus particles are thus able to complete their infection of a host cell, replicate and make more of their nasty little mutated selves because they are not stopped from doing so by the antiviral. Simple, darwinian natural selection. Why do you keep saying it is otherwise????

H1N1 is now resistent to Oseltamivir, for the first time since 1918.
H3N2 is now (since some years) resistant to Amantadine for the first time since 1968.
Both just after those drugs are being widely used.

coincidence ?
How likely is it that such happens by chance ?

maybe 1:100 - 1:1000

> There must be a selective advantage for the resistance to establish itself...
> as it must overwhelm the existing non-resistant strains/subtypes that previously
> had the selective advantage.

synonymous mutations do this too, no selective advantage in sight.
Just, which strain happens to be circulating at the right place at the right time.
Almost random, unpredictable factors seem to decide which strain becomes dominant
worldwide. Local weather, date of holidays, family gatherings in SE-Asia in May-Sep.,
maybe swine breeding,slaughtering timings

http://www.setbb.com/fluwiki2/viewtopic.php?p=1201&mforum=fluwiki2#1201

~28% of established mutations went away later, 72% stayed until now

~74% of established mutations were at 3rd base , likely synonymous

> Grace: Depends what you mean by "my best estimate."

what's ambiguous about "estimate" ?

> If you mean, do I think it is a serious enough threat I would be willing to devote
> significant resources into preparing for the consequences should it happen,
> my answer is definitely "yes."

depends what you mean with "significant resources"
How much should we spend individually and by government ?
Are the ~$10B appropriate ? How would you decide ?

> I do not see it showing evidence of being more of a threat this year than last year
> but it is unpredictable.

it being "unpredictable" , do you see it showing evidence of being more of a threat
last year than this year ?
do you see it showing evidence of being the same of a threat last year as this year ?

> It could have some small change, whose nature we don't know, that would turn it into a
> vicious tiger or possibly a pussy cat. It certainly has the plausible potential to be
> something terrible and we have no discernible reasons to think any differently this year
> than we thought three years ago.

except, that we have 3 years more now which we observed it, 3 years in which it
wasn't tiger-like

> That's the best I can do for an answer with the information we have.

come on, you can do better. But you anticipate it's not good for your career
to be open on this

> Could the answer be that the naturally selected resistant virus in the humans in
> Indonesia treated with tamiflu is passed on to birds (H2B) and then from there B2B and
> into wild birds who migrate and spread the resistance?

no. We would see it in the sequences. N1 in H5N1 is different from N1 in H1N1

> Another possible route might be that the tamiflu given to large numbers of people
> in Indonesia gets into the food chain somehow, perhaps excreted in bodily
> wastes into the water, and from there it travels back into birds which have the virus.
> This could select for a resistant strain of the virus, which then could be carried
> and spread by migratory birds around the globe.

much more Tamiflu is given to the people in Japan,USA,Europe.
No Tamiflu found in the water. Wild birds are not involved
in current human H1N1.

> i. vaccines will never work for influenza (he also says that vaccines depend on "local immunity"; not true)

vaccines so far never stopped an influenza epidemic AFAIK

> ii. seasonal influenza is resistant to all antivirals. This is also not true, although even if true is
> not particularly relevant since there are so far only two classes of antivirals.
> It says nothing about antivirals any more than saying MRSA exists says antibiotics will never
> work for staph.

some evidence that flu could be particularly successful to circumvent such problems.
Maybe flu has more freedom, more directions to evade antivirals

>iii. virulence is increasing for all influenza strains, seasonal or not. I know of no evidence for this.

new successful strains are often more virulent than existing ones.
H1N1 in 2000 (?) , Fujian-H3N2 in 2003 , Brisbane-H1N1 in 2007

> iv. Tom seems to think that antivirals cause resistance mutations. Almost every
> evolutionary biologist I know of does not subscribe to the (Lamarckian) idea of
> directed mutation. Maybe we will find out that it occurs. But that has never been
> suggested for antiviral resistance by any scientist in the world I have ever heard of.

so the cause is indirect. But since flu replicates in 6 hours the effect can be observed
as quickly as if mammals would "adapt" to situations

>v. the idea that seasonal flu subtypes are "slow replicators" (compared to what?) is also
> something I haven't seen evidence of.

replicating in 6-10h , I read.
H5N1 acquires ~45 mutations per year , human H3N2 only ~35

such resistance doesn't "begin". It was there, since the (Brisbane/59) strain emerged.
But first only in small numbers.
Selection would just increase the prevalence of the resistant strains.
The mutation needn't occur in the treated person and then spread.
Treated persons are more likely to spread resistant strains, just because
they are more likely to have resistant strains.
Untreated persons spread both.
For the virus being resistant only gives a small advantage, but that
may be decisive over many generations.

Apparantly there are yearly bottlenecks in flu-evolution, when just some
small "events" in SE-Asia decide which strain will be worldwide
dominant the next season(s).
These bottlenecks may unfortunately involve large amounts of treated people (?)

swine are being treated with Tamiflu in China ??
We had PCCR since 2007 in China but transmission of flu H2S2H
is presumably not so frequent as just H2H2H2...

Hi Mary, Tom DVM, The Doctor, Anon, etc...

Have you all had a chance to read the University of Colorado article, "Avian Flu Becoming More Resistant to Antiviral Drugs, Says CU-Boulder Study" January 7, 2009!?!

http://www.colorado.edu/news/r/fe1c8e0ea11c9071a41bab551f261600.html

Excerpt: "The rise of resistance to adamantanes -- which include the nonprescription drugs amantadine and rimantadane -- appears to be linked to Chinese farmers adding the drugs to chicken feed as a flu preventative, according to a 2008 paper by researchers from China Agricultural University, said [Andrew] Hill..."

The above excerpt is a clearcut example of "simple darwinian natural selection" is it not!?!

I'm not sure what the researchers are saying regarding the evolutionary processes causing H5N1 drug resistance to adamantanes, the term "novel genetic mutations" is used often in connection with "recombination"!?!