In the world of opera a diva is a prima donna, often problematic in behavior, but in the world of bird flu, DIVA stands for differentiating infected from vaccinated animals (DIVA). The bird flu DIVA relates to a problematic behavior of vaccinating poultry: after you've artificially induced them to produce antibodies against bird flu, you are faced with the trying to tell if a bird with antibodies against bird flu got it artificially or naturally. Since antibody detection is the main screening method for poultry infection with avian influenza virus most countries won't accept imports of vaccinated birds. This economic obstacle to vaccination could be eliminated if there were a way to tell natural immunity (indicating infection in the flock) from artificial immunity (from a flock presumably protected by vaccination). There are several methods to differentiate vaccination from natural infection which we review briefly (see paper by Suarez in Biologicals, 33:221-226, 2005 for more details).
One DIVA method depends on whether the poultry vaccine has been prepared from whole virus or just a part of the virus (a subunit such as part of the hemagglutinin protein). Since natural viruses have a number of other proteins that can provoke an antibody response, although smaller and non-specific, these responses can be used to indicate natural versus vaccine (i.e., subunit only) cases. But most vaccines are whole virus vaccines. In that case a vaccine with heterologous neuraminidase subtype can be used. For example if the vaccine is to protect against the H5N1 subtype, a vaccine using H5N2 will still protect the bird because the H5 protein is the major antigen. Then DIVA can be performed by seeing if there are antibodies to N2 or not. Another strategy is to use response to an internal protein like NS1 as a marker. In infected cells this protein is made in large quantities but is not packaged in the virion, so the reaction to NS1 is much larger in naturally infected than vaccinated birds. A fourth method is low tech but often effective. A few unvaccinated (sentinel) birds are kept in every flock. If they become sick or produce antibodies, this is a signal it is natural infection.
So why isn't it a no-brainer to use vaccination and DIVA? I see two main obstacles. The first relates to the fundamental question of whether vaccination fully protects poultry. Partial protection is a good thing in the sense it might markedly reduce viral shedding, but if it doesn't make the birds sick you can have vaccinated birds still able to infect unvaccinated ones and possibly infect people unknowingly. Moreover one of the things that raises the index of suspicion for diagnosing human bird flu cases is the presence of infected poultry in the vicinity. If that trigger is removed, it is possible human case would be missed more frequently, given the high prevalence of flu-like illness that isn't bird flu.
The second obstacle is practical. In a country like Vietnam, which uses vaccination to control avian influenza in poultry, there are an estimated 8 million households with small poultry flocks. Even worse, there is a 17 day lag period between initial infection of a flock and detection of infection through DIVA (7 days for the virus to spread sufficiently in the flock and another 10 days for seroconversion). Thus information at time of sale from these small holdings is not feasible (information from Dr, Dung Do in communication to ProMed).
In a disease where nothing seems to be certain, this at least is: there are no quick fixes.
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Okay, so I will give you a needle and a syringe...and one assistant...and I will put you in a barn with 200,000 chickens in one large pen...that are very upset and dying as you administer the vaccine to each bird...one by one...two hundred thousand times...and I want you to repeat the same process 6 times a year in the same flock.
What percentage of the flock do you think will be vaccinated each time?
The way around this is to use a modified live virus that can be released as a mist in the same flock and the birds vaccinate themselves...What are the problems with this method?
If I had to pick two reasons why we are where we've got in a short period of time...it would be vaccine and antivirals fed directly to birds...we would have been better without either 'technology'.
What is different about poultry vaccine compared to human vaccine?
Humans have a much higher body weight so presumably need significantly more vaccine per shot. Chickens have a fairly short life and China has 12 billion of them yet it is able to produce enough vaccine for all of them; why then is there such a problem in converting this capacity for human vaccine production?
Another consideration when embarking on poultry mass vaccination is the strain selection pressure. The Chinese were not happy at being blamed for the emergence of the Fujian strain, but which ever strain you choose for your vaccine is going to subjected to negative selection pressure leaving the field open for less closely related strains to take advantage. With influenzas propensity to mutate out of any box you try and create for it this is likely to lead to accelerated strain divergence.
By the way, there is a DIVA Avian flu vaccine availible that is used in Mexico and Central America (2 billion doses sold for Low Path AI)) and has an emergency use vaccination registration in the US, and can be administered to chicks in the hatchery before they are dispersed to the houses, and has a very rapid onset of immunity and has been demonstrated to stop the spread of vaccine from vaccinated -intentionally exposed birds, to unvaccinated sentinal birds.
it is also being used in Viet Nam.
Future already here?
Bob: You might go to the link at ProMed where the Vietnamese respond to why they are not using DIVA. The info is from two weeks ago, so is current.
Then there is the vaccine itself. Quoting B. Webster from two years ago
"If the vaccine they are using is so good, then why are we seeing so much bird flu there?"
Tom so you advocate a complete slaughter, no vax, vax with off antigen or do nothing? Does off antigen vax create big problems for us later because like humans lack of coverage, time in motion, and above all does it prevent the bug from mutation.
I saw something the other day that was sent about Tamiflu being fed to birds over in Thailand and Vietnam. The same stuff we were supposed to give to people and in fact we shipped it to them and it has made it into their feed.
There is an obvious problem with low dose Tamiflu being eaten by humans via the chicken/turkey/duck chains.
Revere's previous post about pee getting into the waterways and making superbugs would apply to chickens too. So we have Tamiflu running all over the ground in an infected BF area and we are making it worse by vaccinations?
Revere, if someone is sick would you vaccinate them if they already had Tamiflu on board or would the possibility of a mutation be raised if they did.
I get a really bad feeling about this and I thing we have been gamed by the SE Asians. We cant make them account for the Tamiflu but if its out in the poultry I perceive that as being a big problem.
Randy: Not sure I understand your question. If they are sick with flu, I wouldn't vaccinate them. The infection is a better "vaccine" than any other, although it might kill them, too. A vaccination wouldn't help if you are already sick. Is that what you meant?
Does it really matter where antibodies have come from anyway, already?
I mean ..... poultry is already pretty riddled with bacteria, and bacteria are harder to destroy than viruses. If you cook it long enough to kill the bacteria (and aren't the last ones to die actually the most benign ones, which will just speed things along downstairs a bit, so to speak, but have no long-lasting effects?) then it should already be free of flu virus .....
AJS: Yes, it matters a great deal. The problem is one for the poultry industry. If the virus gets into their flocks they lose a great deal. The issue isn't directly about human health, although there are issues there, too.
Yep thats part of it. But what if those morons and I use the term generously in light of current events if they are feeding Tamiflu to poultry. Doesnt that likey give rise to very potent viruses in the future.
I read that many want Japan and others to quit prescribing Tamiflu and the others just as a matter of cause for ordinary flu. I dont know if thats right or wrong but your read on it would be great info.
Randy: Regarding use of Tamiflu for seasonal flu, that seems to me to be a reasonable use, just as the use of antibiotics for bacterial infections is. While it is true this increases selection pressure, it doesn't cause mutation, and the mutants that arise may or may not be genetically fit. "Ordinary" flu can be quite nasty, as the current estimates of excess mortality indicate. So I don't think saying don't use it in seasonal flu is an obvious solution. Thiss isone of the uses of modeling, to do some "what if" calculations. Not sure if this has been done. Everything takes time and there are few hands to do the work.
Randolph. There are two school's of thought in veterinary medicine and usually authorities go one way or another...in the case of H5N1 they are attempting a combination which is worse than either one alone.
...There are 1) the test and slaughter proponents 2) the 2) vaccinate proponents.
You would guess right if you put me in the test and slaughter proponents...as this keeps everything above board and it is easy to see where the disease is...and when your job is done.
There is a whole lot of problems vaccinating chickens that you wouldn't have with other animals including humans...as a result...it is never 100% and if you can't get 100% coverage then the vaccination control system fails abysmally and totally!!
I have a feeling that H5N1 is manmade...probably unintentional but manmade just the same...
...my bet is that H5N1 escaped a lab in the vicinity of Guandong Province...in response, the Chinese played with modified live viruses dispensed through fogging...and then what happened was that the vaccine virus reassorted and/or recombined with wild or tame strains or just plain mutated to put us in the hole we are now in.
So the only thing the vaccine has done is to drive H5N1 underground where we can no longer see it or find it...and it has also allowed selective adaption to occur in a multitude of directions...
...this is exactly why vaccines never end the problem...especially with an influenza virus that harnesses its inherent instability so successfuly .
Hope that helps explain things a bit.
Bio-Defense... goofy term because its really bio-warfare research in the Guandong Tom? I got an email on that from Hong Kong three years ago but no substantiation. You heard anything. It sure would explain a lot. The Ruskies had a wild haired flu that was rumored as late as '95 when I was into the military intelligence briefings. Now its more like a state department briefing and request for classified if you can put two and six together and come up with Margaret Chan.
Randolph.
Sorry, no inside information...just 'informed speculation'...
...this thing is just too good to be natural, in my opinion...but I don't think it was designed as a weapon...it's just that it probably slipped out of a lab...
...and we still haven't seen the sequences from China's undisclosed case of the young person in the army...my bet is that there are reasons we are not seeing it.
...and they have probably been playing with modified live virus vaccine to avoid having to inject every animal...which really opens the can of worms from a genetic shift point of view...
...and given their history, they will have vaccinating at least a portion of their military as well...and we may see some fall-out from that on the disease front...if they will admit it...which they won't.
Backyard chickens and wild birds will have a natural immunity against H5N1.
There are now domesticated chickens (backyard flock) in Indonesia showing no or minor symptoms when infected. Just like most of the water fowl.
Anyway, in time all birds that survive H5N1 will duplicate and have stronger offspring that's immune.
Only 'designed' poultry of industry (lost their natural immunity by selection for commercial traits) will stay vunerable. Unless industry creates a layer or broiler that has build in immunity as they now try to make in Australia. That's business too.
How many people in industry will care for some antibodies found in industrial breeds that are immune for any virus?
A bird that is immune will spread less virus because it's cleaned up and the virus can't duplicate in the cells (less than 1% in fully vaccinated birds (Intervet-1998)). Eventually the virus will extinct. Until... a new one shows up.
Yes, humans were the cause of the bad H5N1 strain, it could alter from a harmless fieldvirus into a deadly form for poultry and other birds. That happend in a stable with thousands. Now it's only a matter of spreading.
Fun is: it still didn't show up in the US.
It didn't show up in Australia where millions migrating birds from Asia fly to and from.
So, spreading is done by humans too. Illegal transports, disposal of infected materials etc.
Sigrid van Dort
Holland
PS. the spray (eyedrop) vaccin is on its way here. At the moment problem isn't the first jab but the second two weeks later. Costs labour, so is loss of profit.
Sigrid. You and I agree on most thing. H5N1 is an industrial agriculture disease just like Nipah. The size of Asian poultry farms exceeded a threshold...a tipping point where sufficient mass of birds was avaliable for adaption and evolution of viruses previously unseen in the world...also in my opinion being pushed by many other factors including global warming.
If we went back twenty years with backyard flocks and family farms, this would not have happened...even though I think this virus is too good to be a field strain or naturally evolved...I think this is an inadvertent man-made virus in China...and if they release enough sequences, it will be proven.
However Sigrid, the horses are out of the barn, down the lane and in the next county...it is just not going to go away...this bug has 'big' momentum...and I believe that it will be involved in the next pandemic in whole or in pieces (gene exchange with seasonal influenza by reassortment-recombination).
We have too many bullets in the revolver that we are playing russian roulette with...H3N8, H7, H9, H5 etc. etc. etc. Each of this exotic viruses has unique characteristics...none have achieved pandemic potential on their own but when you hypothetically put them all in a limited space and allow them to collide...the end result is inevitable...in my opinion of course.
We are going to have a pandemic. We are going to have a pandemic soon. And we will be very lucky if the attack rate is under fifty percent and the mortality rate is ten percent of under...but that is also just speculation on my part...whether it is 'informed' or not will depend on future history.
Thanks.
Tom DVM; Your idea about using a live attenuated vaccine mist is interesting
I have been grappling with the problem of how we could vaccinate enough people with a specific efficacious pandemic vaccine assuming that it could be produced in sufficient quantities soon after outbreak to control an H5N1 pandemic. While there are numerous barriers to this happening, one of them that seem almost impossible to finesse is the cultural one. The basic problem is many people in the developed, developing, and third world don't trust Western medicine and vaccines in particular. In fact it was in researching publications on the efficacy of seasonal flu vaccination in 2004 in preparation for writing a pamphlet for patients on the value of this practice that I became aware of the re-emergence of H5N1 in SE Asia and began my bird flu quest.
Cultural resistance to vaccination is an important barrier to establishing effective herd immunity within the world population sufficient to halt a pandemic. Many including me think that H5N1 will become pandemic and when it does so it will happen in a developing or third world nation. If so, the problem of vaccinating a critical mass of folks necessary to stop viral spread is a real showstopper. The issues of having enough vaccinators available and of maintaining adequate refrigeration of the vaccine on the ground within these areas alone is almost insurmountable.
Tom's mention of misting poultry raises the interesting possibility of misting people with vaccine from aircraft. If this were done with a live attenuated H5N1 specific vaccine, then those that become infected would be protected from the wild strain and would likely pass it on to 1 or 2 folks they came into contact with. In this way, people living within large geographical regions could be vaccinated very quickly. This gets around many of the problems presented by locally producing, transporting, refrigerating, and administration of vaccine to a large population of folks living in the developing or third world.
Of course it also removes the right of the individual to choose not to be vaccinated and possibly the right of a nation to control its airspace. The unilateral use of this method of vaccine delivery by one or more nations from the developed world in the third or developing nations and even within their own population, no matter how well intentioned would result in a predictable hew and cry of protest from many.
It is ironic that if this technique were employed and successful, many of those shouting the loudest would also have been those who would have died if this intervention had not occurred.
In my practice of medicine I place a great emphasis on preventive medicine. While I believe these efforts have been of benefit to my patients, I have yet to be called at 2:30 AM by one of them thanking me for preventing the heart attack, stroke, or hip fracture they were destined to suffer at that time were it not for my intervention and their compliance with my recommendations over the past few years.
Human and national rights are very important but in certain circumstances the good of all people the world over must be placed above the rights of the few. I realize that this notion will inflame some. In my opinion however, the outcomes we can expect worldwide from both the direct effects on human health of a severe influenza pandemic and the indirect effects of civil disorder that will flow from this catastrophe are so tumultuous that they justify an extreme action like this.
Grattan Woodson, MD
Doctor,
How would we come up with an adequate supply of vaccine to mist so arbitrarily? Would you just mist densely populated areas?
Interesting idea. I wonder if we are capable of producing enough vaccine for this method of delivery?
Hi Patch and Dr. Woodson.
You might be interested in the approach described in the article:
Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza.
by Olav Albert Christopherson and Anna Haug
Microbial Ecology in Health and Disease
Dec 2006: Pages 113-132
"The abstract of the article by Moxnes and Christophersen in the previous issue of this journal outlines the principles of a harm reduction strategy which could be the only feasible one (for obtaining significant harm reduction) in a situation where neither enough vaccines nor efficient treatment are avaliable, or when it will not be logistically possible to reach a target population with vacines within the short time interval that might be avaliable before the superpathogen iself arrives and perhaps will kill nearly everybody."...
...Vaccines should be used if avaliable (and if they are efficacious enough), but if vaccines are not abaliable or for logistic reasons cannot be used, one may instead - as the only realistic alternative - release a counter-pandemic with a 'vaccine' virus that has antigenic properties identical or very similar to the superpathogen, but which is no more virulent than ordinary (seasonal) influenza virus."
This approach makes sense because there is precedence in medical history and in the fact that a small amount virus go a long way through controlled cirulation in a controlled population.
In the case of a full blown pandemic, you wouldn't have the concern about vaccine drift to pathogenicity because the virus would already be dispensed and fully armed naturally...in that case the vaccine strain would not increase the risk.
Sort of a "back-fire" virus. I've heard of this principle before.
I'm not sure about the last paragraph. Why would genetic drift to a more virulence (or pathogenicity) not occur?
It too, is an interesting idea. I'm sure there are problems with introducing a live virus, but certainly a better alternative to H5N1 at current virulence.
Hi Patch.
What I meant to say and didn't was that...the main complaint against modified live influenza vaccines is that they can revert or morph into a more virulent form.
However, in the midst of a pandemic, there is already a virus that is running around the world in a fire-storm so since the more virulent form is already present...releasing a virus to provide a fire-break can't make things any worse.
The advantage for this strategy is that the vaccine strain can pass from person to person in a group and in a controlled manner through quarantine and isolation...therefore, very little equivalent vaccine is needed for large groups of people.
Understand Tom.
Recombination, with the more virulent H5N1 (as well as drift) would be of concern I would imagine. I don't know if there is a way to genetically engineer a back-fire virus that would prevent recombination with H5N1 specifically.
But again, an interesting idea. It would certainly address your personal concerns with the efficacy of vaccination.
Should a severe pandemic come to pass, I'm sure we'll be do more "out of the box" thinking. The urgency of the situation could make us stumble. These are good questions to toss around before any type of emergency.
FYI-the military has started vaccinating now, in July for "Asian Flu".
There are references being made to the Asian flu as being the Asian Avian Flu. Is this right anyone? Are they vaccinating the military against it and just dropping the Avian out of it.
It is legal for them to use soldiers as guinea pigs and have in the past. They do have to volunteer as a rule but they can do it under military law.
Patch-under US law it is also legal for them to experiment on us as well. The specific wording is that they can "after notification of local health officials" It doesnt specify who those officials are. I take that to mean that anyone inside of the health department at a state and local level. There was a stink a few years ago under Clinton when aircraft were observed spraying something over some cities and people got sick with something. Never specified what that was. Could they mist spray a city with vaccine and stop BF? I dont know. Might be worth trying but how to keep it active and not drying out on the way down.
Here is something else.
http://www.vaccines.mil/documents/1066MIP-PandemicInfluenza%2025%20May%…
Randy: Asian flu was the colloquial name for H2N2, the subtype of the 1957 pandemic. It is not a contemporary flu strain, so if this is what is meant I think it is curious. H3N2 was usually called Hong Kong flu. Beyond that I don'thave a clue.
Patch. Here's the thing. At the point when the pandemic potential virus is exploding across the world...you wouldn't worry about recombination or reassortment of the vaccine modified live virus because...things couldn't get much worse.
I wouldn't suggest this if the mortality rate was .05% or even 2.5 % like the pandemic in 1918...
...but we have to face some facts...if H5N1 does not magically disappear it is going to have an effect at some point in the future...it hasn't gone away in ten years and it doesn't look like it is going away anytime soon...
...in the ten years it has increased its lethality from 33% CFR in Hong Kong 1997 to 80% in Indonesia today...
...the level of care being offered in Indonesia today, will not be avaliable in a pandemic in the United States or Canada...and that is a fact not a prediction.
It is entirely possible, from many professional sources, that H5N1 can go pandemic with greater than a 50% CFR - Case Fatality Rate - Death Rate.
For this potential eventuallity, we must explore the option of having a 'controlled burn' with an attenuated H5 virus vaccine...
...and I will line my family up first to get it.
Thanks for the great discussion.
/:0)
Tom,
I understand. Basically, it's a "It can't get any worse than this" type thinking. That may very well be.
I'm in agreement that H5N1 could go pandemic with higher CFR's than 50% even. CFR's we are seeing today include at least SOME level of care. In a pandemic situation, that level of care will likely not exist. On the other hand, it is also possible, (some even believe reasonable) that CFR will decrease.
One thing I was thinking about recently and pardon me if this goes off topic, but I am curious to know, if the fatality rate in poultry has declined, with 10 years of drift/recombination. It would appear not.
I ask, because everyone assumes, like H1N1, that drift/recombination and immunity would tone down H5N1, just has it did in 1918-19 with Spanish Flu. But are we seeing that in birds today? It seems to me, to be just as deadly now, as it was in 1997, but I'm not sure. I know there are models that suggest virulence will decline over time, but I wonder if we are seeing that in birds?
But then again, is H5N1 a true avian epidemic and following the model in that way? I'm not sure I know the answer to that. If you use the birds as a case study, with the idea that it's an epidemic, there are a lot of birds out there that, for whatever reason, aren't being infected. What kind of attack rate does it have in birds? I've heard about these backyard flocks and that "alot of birds died" but what percentage? I've never really paid attention. And what about wild birds and all the speculation that migration would spread it like wild fire. It didn't happen. Perhaps this particular virus has a low attack rate? (At least currently).
Is H5N1 a true epidemic in birds? I suppose so, but how communicable is it?
I'm probably way off base, but just thinking about it.
"One thing I was thinking about recently and pardon me if this goes off topic, but I am curious to know, if the fatality rate in poultry has declined, with 10 years of drift/recombination."
Great question. I would assume that the fatality rate in domestic poultry is 100%.
I still believe the CFR will drop substantially.
I am hoping for a CFR no worse than 10% and a collateral damage mortality of no worse than 10%.
I have trouble with those numbers, I avoid even thinking about anything worse.
The problem is that the experts are now almost unanimous on the pandemic without lower CFR.
Time will tell...I hope it just vanishes.
Sorry, that should have read...The problem is that experts are now almost unanimous on the possibility of a pandemic without lower CFR.
Thanks for considering my post Tom. I do respect your opinion.
I also appreciate your correction. Because as you know, I'm squarely on the fence. We are still in the "possibility" phase, thankfully.
I am trying to find out the specifics of the vaccinations. We always got an annual shot in like November so when we went back home and got the flu we would be back up and running a couple of days later. I NEVER ever got a flu shot in July, even if I was behind. I can remember one once in March and one in September, but never anything in between. Very strange. If it is would it be that liter bottle sized vaccination? I think I read that it was a two pass shot but that even though it was off antigen it would provide some protection.
Kind of like Vietnamese and Chinese chickens....right!?
A year or two ago much seemed to be being made of the drop in CFR if it went pandemic and the argument that selection pressure would lower the CFR, as it is not efficient for a disease to kill off its host species. There are a few problems with this argument. Firstly this perceived wisdom assumes we are talking about a species which is not the case here it may be true for the waterfowl which are the natural hosts but does not apply to poultry or humans which would be dead end hosts. Secondly if it goes pandemic and we become the natural host then the attenuation should occur over time but the problem is the over time bit. The selection pressure does not kick in until the host population is thinned to a point that new hosts are becoming tricky to find, i.e. there are not many live humans who have dont have antibodies.
On the misting idea I agree it could be the only realistic method of creating enough antibodies in the general population given the time constraints once efficient h2h is underway. What I can not see is any political mechanism with the authority to authorise this kind GM experiment.
What would be required? From a political point of view a near unanimous UN General Assembly & Security Council resolution. From a scientific standpoint a virus that efficiently transmits between humans that is ready to go except for the pandemic specific surface antigens. The efficiently transmitted bit is a problem, if it is too efficient and the pandemic strain is high CFR but initially not that efficient we risk creating a recombined super efficient pandemic. If it is not efficient enough it may get out performed and sidelined. Massive containment efforts to buy time at the outset of the pandemic would be needed followed but wide spread seeding of GM virus at widely spread geographical loci. While most nations pandemic plans are based on pandemics similar to 57 / 68 scenarios with 1918 as a worst case scenario there is little chance of the idea gaining any political support and it will be too late if our worst fears about H5N1 do turn out to have been justified once the pandemic starts.