There is currently no vaccine for a pandemic strain of H5N1 avian influenza, and if a pandemic strain does emerge it will take at least 6 months to get the first batches of one. Currently the productive capacity for influenza vaccines is so overmatched by the needs of a global population, only a tiny fraction of those that will need it could be immunized.
The current experimental (and relatively ineffectual) vaccines for H5N1 are not for a pandemic strain but for a strain current in southeast asia that is still poorly transmissible from person to person. It is thought an easily transmissible strain will look sufficiently different to the human immune system that the experimental vaccine will be even less effective, maybe even useless. So what to do?
One suggestion is to make and then deploy whatever vaccine we can make prior to a pandemic, even if it is mismatched. The reasoning is that there is some evidence of enough cross-reactivity to make a substantial difference in mortality. Use of adjuvants may increase this, but at the expense of increasing adverse reactions. If there is cross-reactivity it would save lives two ways, the obvious one and by slowing spread enough to allow more communities to prepare. This is supported by some modeling studies:
Separate modelling studies at the University of Washington in Seattle and at Imperial College London suggested that inoculation against H5N1 ahead of any pandemic, even with imperfect vaccines, could significantly cut the eventual death toll. Wait for a pandemic to strike and it will be too late. The first global wave of illness is expected to be over before enough vaccine specific to the pandemic strains has been made, and by then the virus could well have mutated into a different strain. (New Scientist)
I see two serious problems with this, however. The first is that if you are going to stockpile a vaccine you have to make it first, and the world's productive capacity is meager and largely occupied with producing vaccines against strains we are fairly confident will cause seasonal outbreaks next year. Diverting that capacity, already inadequate on a global basis, would also have a substantial opportunity cost in terms of lives and sickness, if and until a pandemic struck from the H5N1 subtype.
The second problem involves proper timing. The ideal time to use a stockpiled mismatched vaccine would be as soon as you were sure a pandemic was underway or about to start. But then there is the additional problem of timely distribution. Along with an anemic productive capacity, most countries, including the US, have underdeveloped public health systems. In the US it would not be easy to vaccinate large numbers of people in a hurry. The lead time for a pandemic that started in another part of the world could be only weeks and most likely would be not more than a couple of months.
This probably means starting vaccinations before the pandemic is underway and being right about it, too. And there's the rub. Flu vaccines are quite safe, relatively speaking. There are the occasional side effects and on very rare occasions, dire or fatal ones. But they are so uncommon we wouldn't even know about them without a good surveillance system. However if you are going to vaccinate a hundred million or more people in the US and many times that around the world, you will see problems, both real and spurious. For example, many people die suddenly each day in the US for a variety of reasons, usually cerebral hemorrhages (strokes) or myocardial infarctions or arrhythmias (heart attacks, sudden cardiac death). It is inevitable that dozens of these will happen in temporal proximity to receiving a vaccination, although there will be no connection. And in some cases there may be serious adverse reactions directly attributable to the vaccination itself. If this is rare, say one in a million, the lives saved will almost certainly be outweighed by this risk if there is a pandemic, even a mild one. But it means that with a hundred million vaccinees, 100 or more will die as a result of the vaccine. Both the spurious and the real events will make news and give many people pause, perhaps scuttling or seriously crippling an important vaccination campaign if it occurs outside the setting of people sickening and dying from flu itself. The issue of lawsuits for this can be dealt with. The psychological effect cannot.
So stockpiling a mismatched vaccine is something to think about. But it isn't a "no brainer" by any means.
- Log in to post comments
What to do
Focus on better antivirals. Get sick but don't die. The US is currently getting submissions for allocation of 200 million to spend on development of Antivirals. Tamiflu and Relenza are the major two at the moment. Biota the inventor of Relenza is in the final stages of releasing LANI, a much more potent NI.
Why the drug companies can't keep us with demand Especially (GSK and Relenza) is criminal. Govt needs to step in and get it sorted.
cpg: Antivirals have some defects. There is the supply problem, then the problem of distribution, then the fact that they must be taken daily (and the inhaled version only protects the respiratory tract; if there is another mode of entry it won't work), then the fact that they don't work very well as treatment, even if given in time.
Antivirals are useful on the margin but won't work for avoiding or slowing a pandemic.
Revere wrote: "But it means that with a hundred million vaccinees, 100 or more will die as a result of the vaccine."
Granted, 100 deaths is a "small" price to pay for a successful outcome in the rest of the vaccinated population. But to the families of those 100 people, it will *feel* like 100 million deaths.
I am very nervous to get myself, my husband, and my children vaccinated but will do so because, as I understand it, we will be at almost as great a risk in the ensuing four or five post-pandemic seasonal flu seasons as we would be during the actual pandemic.
It's a no-win situation.
Another concern is that stockpiling a mismatched vaccine will decrease the pressure to get a truly effective vaccine and production regime in place.
I don't know if this will be the case, but it seems that such a stockpile could provide a false sense of security to politicians, allowing them to declare the problem solved. It allows governments to say "we had a stockpile, we did all we could" and abnegate their responsibility. Of course, it's not as if many governments are really pushing to solve the problem as it is, so this may not be a real concern.
In the US, the need for a national vaccine research and production facility is obvious. If the goal of the US government were to truly prepare for bioterrorism, rather than simply send taxpayer money to private companies, such a facility would exist now. It's clear that pandemic preparation has no market solution, as no market exists until disaster has already struck. But ideology and short-sightedness seem to prevent that understanding.
Nancy: The calculation you would make in this case is indeed a risk-risk trade-off, but the same can be said every time you take an aspirin, tylenol or antibiotic.
Anon: The issue with a publicly financed and operated vaccine initiative is widening what we will allow as a solution. Currently, especially under this administration but it is also true of many liberal or centrist democrats, public sponsorship is not on the table. This is a mistake and is a case of ideological blinders. We used to have public provision of vaccines and we still do for roads, the military and much else. We need to widen our vision to include vaccines.
I've been looking at the numbers in my little area. If the vaccine has an efficacy of 70% and the R0 of the pandemic strain is 4, I have to vaccinate more people than live here to stop transmission. So I guess that is why HHS has developed priortiy groups for vaccination. Vaccine as a personal protective measure rather than as herd immunity.
St. Jude's seems to have had some success with cross-strain protection of ferrets (a good animal model for human flu) from H5 using inactivated whole-virus vaccine, despite minimal antibody levels, as reported in the Journal of Infectious Disease by way of CIDRAP.
http://www.journals.uchicago.edu/JID/journal/issues/v194n2/35777/35777…
Epitope: The post was stimulated by the St. Jude work. My points are independent of its results. Indeed it depends on those results be accurate. If they aren't, then stockpililng is a no brainer because you wouldn't do it.
I have read some disturbing words about the effects of squalene when it is used as a vaccine adjuvent. It sounds like the wily consumer will not only have to be aware of which vaccine does what but also what else is in the shot.
Hi, Revere
If the St. Jude's results are accurate, it might be good to make such a vaccine available to high-risk populations, and introduce it gradually in the population.
If they are accurate, it also may bode well if there is a relatively mild sentinel wave of infection, since that might confer cross protection against later, more virulent strains. Might (possibly) be good news.
The article indicates that it was accepted for publication four months ago. I wonder what they have learned since?
Ellen: The squalene controversy has been going a long time. Started, I believe, with Gulf War syndrome. No resolution to it. There is only one approved adjuvant in the US (alum) but I think it likely in an emergency that current standards for safety and efficacy will be "abridged." Any time you are administering tens of millions of anything, very small risks add up to substantial numbers of bodies. It's a real dilemma.
Epitope: If the St. Jude's work is valid (and I have nor reason to think otherwise, they are very competent scientists) and assuming the ferret model is good for humans, it still doesn't alleviate the problems I noted. Even targeting it to "high risk" groups (meaning?) unless a lot is used it will have little effect on eventual mortality or speed of spread. If a lot is used, then we are in the problem I pointed out in my post.
Public confidence is key. Leaving vaccine development and production entirely in the hands of profit-driven companies -- which the public knows have been innoculated from any penalties for harm resulting from their own negligence -- is not going to inspire public confidence.
It strikes me that, assuming one did opt for mass-vaccination with a pre-pandemic strain, that it would be possible to manage (although not eliminate) the psychological effect with appropriate public risk communication (nods to Sandman and Lanard). Of course, it's unlikely that the U.S. government, under any administration, would manage this task, but I'm thinking of ways they might:
Instead of saying the vaccine is perfectly safe, they could acknowledge the risk, there by innoculating themselves (pun intended) from outrage later. They could say, "some people will die," but argue that the risk from a possible pandemic would be greater. They could say it was every person's choice to weigh the risks themselves, while visibly vaccinating themselves and their families.
They could acknowledge that a pandemic might not happen, and stress that this pre-pandemic vaccine would have only partial effectiveness. They could advocate other society-wide preparations in the same breath as advocating vaccination.
They could also explicitly use the creation and distribution of a pre-pandemic vaccine as a means of expanding capacity and getting the kinks out before the need for a second round of vaccines made with the pandemic strain. They could acknowledge that even with these preparations, it would take months to produce any meaningful amount of a pandemic vaccine, which would add to people's reasons to take the pre-pandemic vaccine.
I'm not saying they should definitely go with a pre-pandemic vaccine, I don't know enough about the science or the public health structure to advocate that. (I sort of wish they would, but that's an emotional response, based on the need for some control and at least partly on wishing they were really doing something.) But if they did do it, they could do it well, or poorly.
What do you think about the IBM/Scripps idea to predict the pandemic virus's shape with modeling?
bob_c: I'm a fan of modeling (since we do it) and I think structural modeling is going to be very valuable (I hope so; spent the afternoon planning some work along those lines with a bionformatics grad student). However I doubt anyone can predict the pandemic strain with modeling at this juncture because we don't understand the connection between the structure and the biology well enough. Maybe someday.
My thoughts are...... You should get started now. Make a trivalent vaccine of the most different stains that are currently present. It will certainly take more time than we will have.......
Also..... Correct me if I am wrong. But isn't one of the reasons we are in such a hurry to develop other methods of creating a vaccine(s) because early attempts at creating an H5N1 vaccine using the egg based method killed the majority of chicken eggs that were being used?
So..... lets start now......
floridagirl: No, the problem with the vaccines isn't it killed the eggs but that it didn't raise antibodies very well. Non egg-based vaccines can be made more quickly and we aren't limited by the egg supply. However we don't have any production facilities for non egg vaccines and your suggestion would cut an already insufficient vaccine production capacity by two thirds since we'd need six eggs for each dose (two eggs per strain per dose, currently). And what about the seasonal vaccine? We won't make any?
Doesn't compute, I'm afraid.
The biggest current problem with a prepandemic vaccine IMHO is this: there are ways to improve production capacity but they are require investment and commitment. At the moment, vaccine companies are unwilling to invest large sums of money for a vaccine which may never be used, and if used, probably only for a short time (until the pandemic one comes along), so they want governments to make a commitment ie place orders.
Currently government contracts for prepandemic or even pandemic vaccine are more in the category of 'intention to buy' ie you make it and deliver it, I'll pay for it.
Governments are unwilling to put actual money down until a) they are sure there is a need which will bring us too close to the pandemic and there won;t be time, and b) the vaccine(s) can be shown to work which won't happen before you have a pandemic strain to test it against.
So companies won't increase investment/research/production until the money is there, governments won't pay until the vaccines are needed and shown to work.
Bit of a chicken-and-egg situation. A rather unfortunate but probably accurate analogy.
anon_22: I think the problem is somewhat different. It isn't that the drug companies want a guaranteed profit. Governments are willing to give them that. They want obscene profits, and they can get that by investing in other things (like Viagra). They are completely unwilling to settle for the usual "defesne contractor" profits -- they said so in my presence, publicly. And the are told by Senators like Joe Lieberman that they don't have to settle for such measley monies.
revere, yes to your answer about profits.
But the point I am making is not about that. Its about money on the table NOW. At least that's the situation in Europe, and I believe but I'm not sure that the US is the same.
The one sentence that summarizes it all is this: The decision to purchase a pandemic vaccine has not been taken, period. Let alone a prepandemic one.
Companies complain that they are being coerced into making millions of doses which may not have any market (cos the government has not promised they will definitely buy it), have a very short shelf life, and is a one-off product.
Governments say there is no certainty that (whichever one you are talking about) the vaccine will work, so there's no way we will put money down.
They are at a stalemate.
It's NOT killing chicken eggs? I thought it was.....Then why not add a 1-egg dose of available prevalent strains to the current flu vaccine and have governments guarantee purchase of their entire stock of flu vaccine for the next 2 years. Provide 1 year's money up front with the 'extra' (from companies not having to waste manufactured doses) required to go to expanding capacity. Do the same next year.
The U.S. can *give* a vaccine to each medicare recipient who is willing to take it. The money THAT saves the system (on not having to treat pneumonia patients in emergency rooms, etc.) goes into buying the extra capacity next year. Make some vaccine available free to essential workers, and sell the rest (at cost plus a small profit) to hospitals, clinics, companies that want to vaccinate workers, etc. Put the small profit into buying extra capacity next year.
After all, H5N1 hasn't gone pandemic over the last several years, and might not for several more. It could go through lots of mutations before breaking out, if it ever does. Meanwhile, it's just a very-low-transmission-risk flu with a high kill rate, right? So the risk for adding killed virus to the current flu vaccine (without a bunch of iffy adjuvents) isn't any higher than changing the killed virus strains like they do every year, right? So we can gradually build up partial immunity each year, while expanding capacity and refining delivery.
I know everyone wants a whole loaf, but right now the cupboard is bare. I'd be happy for half, a slice, heck, just give my water and power guys crumbs! I do NOT want to get drafted to deliver minimum care in an overflow facility with no power or running water!!! Because frankly, that's where I think we're headed.
OK Reveres.... It took me almost 2 hours, but I finally found an article that says you are correct.... in that H5N1 can now be made in eggs. I figured you should know.... but I had not read anything that dealt with the leathality to eggs. I suppose that news is better than what we had..... Maybe there is still hope!
excerpt:
"Until recently, no commercially viable human
vaccine against an H5N1 virus could be produced because these
highly pathogenic viruses are lethal for embryonated eggs."
Commentary
Vaccine Development for an Imminent Pandemic
Why We Should Worry, What Must We Do
[Human Vaccines 2:1, 38-42, January/February 2006]; ©2006 Landes Bioscience
www.landesbioscience.com
floridagirl: It's done with reverse genetics (internal genes of egg adapted vaccine strain PR8, plus H5 and N1) and the H5 is rejiggered to shorten the high path cleavage site.