FDA will probably declare experimental bird flu vaccine safe. Too bad it might not work.

The bird flu news hasn't been that good this week. New outbreaks in Afghanistan, Kuwait, Vietnam's previously quiet north, continuing infestations in Russia, and human cases in Egypt and Laos (although confusion over the Egyptian case) (see rundown in CEDRAP News here and here). How about some good news? Like, tests have shown the experimental vaccine now being considered for licensing by the FDA is safe. Of course there is also other news about the vaccine:

The federal government is weighing approval of a bird flu vaccine that is even less effective than previously thought.

Sanofi Aventis SA, the maker, believes the benefits of the vaccine outweigh its risks. However, in a clinical trial, the two-shot series appears to provide protection to just 45 percent of adults who received the highest dose. An earlier, interim analysis of the same study suggested it prompted a protective immune response in 54 percent of patients, when measured 28 days after getting the second shot. The New England Journal of Medicine published those results in March 2006.

The Food and Drug Administration released the more recent analysis ahead of a Tuesday meeting of outside experts asked to review the vaccine. The FDA said the 452-person study showed the vaccine against the deadly bird-flu strain called H5N1 is indeed safe, but it remained unclear whether it would be effective. (AP)

Ouch. But maybe not as bad as it looks. Or maybe even worse than it looks. That's because we have no way to judge the effectiveness of the vaccine in the absence of a controlled trial where people are randomly administered the vaccine and then challenged with H5N1 virus. Obviously that's not going to happen. The alternative, an observational study of vaccine effectiveness during a real pandemic is possible but only after the fact. So what are the claims of effectiveness, even as poor as 45%, based on?

The only measure we have at the moment is the ability of the vaccine to raise "neutralizing antibodies" in the blood of human volunteers given the experimental vaccine. Those antibodies are thought to confer protection to a viral challenge. How high the antibody level has to be for this is unknown. We are guessing based on seasonal flu data and animal studies. This is better than no information at all and may (or may not) be accurate. It could even be that there is more protection than the antibody levels indicate -- or less.

In the recently published animal studies (mice) of cross-reactivity with human and avian N1 antigen-based DNA vaccines (discussed on our post here), we pointed out there was a difference between detectable levels of antibodies in the mice (12.5%) and the level of protection (50%). The numbers are small and the relationship between what happens in mice and humans notoriously uncertain, but it points up an important gap in our knowledge relevant to this vaccine story: we don't really know the accuracy of our measure of vaccine effectiveness for these experimental H5N1 vaccines.

But given current practices, the news here is certainly not good. The amount of viral antigen needed to protect less than half the subjects required two doses of 90 micrograms each. That's twelve times as much antigen as in the current seasonal flu shot, although current flu vaccines have antigen for three different flu viruses (two influenza A and one influenza B), so plausibly these results represent only a factor of four lower productive capacity to make this vaccine. Other vaccines have now been produced with much better ability to produce comparable antibody levels with less antigen, so why the government would put in an order for this vaccine is a bit of a mystery. This vaccine uses egg-based technology and seems doomed to be too ineffective and result in too little productive capacity to make it worthwhile investing in at this point.

That seems to almost assure the US government will invest in it.

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"Other vaccines have now been produced with much better ability to produce comparable antibody levels with less antigen, so why the government would put in an order for this vaccine is a bit of a mystery. This vaccine uses egg-based technology and seems doomed to be too ineffective and result in too little productive capacity to make it worthwhile investing in at this point.

That seems to almost assure the US government will invest in it."


(May I add, too many people seem to think once you get a vax - as if they think they'll see one the first year - you are magically protected and good to go out into the fray? Not a few weeks after a second dose...)

Use that weekly presidential radio address to remind citizens to be frugal, get out of debt and put things aside in their pandemic pantry, or their families will just be tragically out of luck...
Invest in some ethics and backbone and start having open community discussion on how people are going to stay alive during a panflu year...

By crfullmoon (not verified) on 27 Feb 2007 #permalink


"That seems to almost assure the US government will invest in it."

If at first something doesn't work? Keep doing it, add some expensive proprietary ingredients (aka adjuvants) make it more complicated so it will take even longer and cost even more while giving you less (fewer doses) than you need. And, oh, btw? Those ingredients have not been FDA approved either, so now we have 2 things to get licensed instead of one...

The most important thing to do? Ignore the new and faster and cheaper ways of doing things.

Why? Cos they are not made by the same old vaccine makers that we are already so comfortable with. You know, there's nothing like doing business with old friends...

With the CDC conducting tests on other possiblilties for a second choice (Novavax), Placing an order at this time for a vax that is proven ineffective is a total waste of tax payers moneys..... sounds like a free plane trip for a political entity to me

For ordinary flu vaccine, the endpoint measure for 'success' should be 'prevents illness'.

For highly lethal flu vaccine, the end point measure for 'success' may also include 'prevents death'.

Neither of these criteria is what can be ethically measured. The proxy is 'neutralizing antibodies', and this proxy was developed for the 'prevents illness' criterium.

I suspect that even an imperfect vaccine such as this will be better than none, though it remains unclear whether this vaccine will do any better in the 'prevents death' category than an H1N1 vaccine would do.

WIth the available data, any purchases do seem more politically than scientifically motivated.

By Lisa the GP (not verified) on 27 Feb 2007 #permalink

PS--does anyone know if the neutralizing antibody test is performed against whole virus? Does it measure effect against both H and N, or just H?

By Lisa the GP (not verified) on 27 Feb 2007 #permalink

Revere, you write: "Other vaccines have now been produced with much better ability to produce comparable antibody levels with less antigen..."

That's interesting. Please tell us more: Which vaccines are those? What data show they do that?

The influenza vaccine uses 'antigenic drift' (mutability) to evade an immune system response, either due to natural infection or due to vaccination.

In the laboratory, the identical viral genetic sequence is used to test the efficacy of a vacine...in a sense 'freeze-framing' the virus. This is not reliable as a measure of effectiveness in the field and provides an explanation for why approved vaccines fail.

Secondly, there have been recent failures in vaccine production with seasonal vaccines under perfect conditions.

In a pandemic, humans become the target and the vector disseminating the infection to other animal species...

Then to attempt grow the virus in eggs and assume that Biosecurity will prevent the virus from entering hen areas or that adequate numbers of workers will be avaliable to produce vaccine seems farfetched.

If regulators want to provide vaccines, they are first going to have to get away from the requirement for eggs because the system has too many flaws to be successful.

In the end, there is no chance that they will provide pandemic vaccine from eggs within 12 months of the index case in a pandemic.

Bird Flu Virus in all the countries around them, but no Bird-Flu in Iran!

The Iranian Minister of Health, Kamran Baqeri Lankarani speaking to Islamic Republic News Agency, denied recent reports that the deadly bird flu H5N1 virus had invaded the city of Amol in northern Mazandaran province.

Could this be any thing to do with the effect of the radiation from all the Nuclear goings on over there???

Full report here:


Could this be any thing to do with the effect of the radiation from all the Nuclear goings on over there???


This has been another edition of simple answers to simple questions.


This flu strain is serious enough without trying to link to shabby political fashions by nonsensical speculation.

Tom is right on the vaccine from eggs on H5N1. Webster has a vaccine sitting in the freezer at St. Jude and its one wicked mother. It took months to make just a few ounces, had to be de-engineered to keep it from killing the eggs it was injected into (even then it still killed like 60%), then it was removed from the eggs, purified and then reengineered with the nasty back into it. Very, very strong vaccine.

Bottom line from this research was that it produced huge titer levels in the subject. Bad news was that it too would almost kill you if you took it. In fact the tests indicated that it would flat knock you down. Quite a few primates took the last train to the tree from what I understood. I never heard whether humans ever got it tested on them.

By M. Randolph Kruger (not verified) on 27 Feb 2007 #permalink

Um, marquer and greg, I think those of us who are regulars to the flu communities get a little jaded and a little silly at times.

I took BBFBT's post as being a bit of sarcastic humor. Sort of like my post yesterday, responding to Revere's post about incomprehensible changes to food-processor inspections, where I said sarcastically 'at least they're doing something'.

By Lisa the GP (not verified) on 27 Feb 2007 #permalink

Randolph, are Webster's results with that vaccine available anywhere?

There has been some discussion as to whether the exterior proteins (H, in particular) or the interior proteins (PB1, in particular) are responsible for the peculiar mortality rate due to this virus.

If a vaccine containing only H or only H and N had an unusual mortality rate, then this would strongly suggest that it is indeed the surface protein responsible for the high mortality rate, and not the interior proteins as has sometimes been postulated.

By Lisa the GP (not verified) on 27 Feb 2007 #permalink

Lisa-It was in an article from way back... ABC I think. I download everything about this stuff so it can be chronicled later... just in case. Had to buy a whole new hard drive to store it all and now I am into disks and memory sticks. I will see if I can find it and post the link for you.

Your assessment if memory serves me right is correct. It was postulated that the surface proteins were the bad boys because it was only moderately lethal to the eggs they used it on after they de-engineered the virus. They apparently were able to remove one leg of the protein assembly, then injected it into the eggs. You can imagine they had every chicken working to keep up. One guy on the dock over at St. Jude told me they were using clean room eggs and that couldnt have been cheap.

The samples came from that woman that was buried in the permafrost up in Alaska. It was her samples with the Walter Reed soldier lung samples that provided enough original H1N1 that it could be grown, then reengineered.

Might be the weekend before I find it in the archives. Will advise.

By M. Randolph Kruger (not verified) on 27 Feb 2007 #permalink

"I took BBFBT's post as being a bit of sarcastic humor." wrote Lisa the GP.

You were of course correct Lisa.

That was supposed to be ironic/funny/sarcastic, specially as my colleagues and I have in the past repeatedly tried to address the Iranian attitude towards transparency in the no-longer-local health matters.

Sorry marquer and Greg, I should have been more clear and less "sarcastic"!

It is just that repeated and automatic denials of any H5N1 infection by the Government officials in Iran and in other countries are sure to be counterproductive.

Of course, as it has been said many times before, there are economic and political (even religious) pressures on the Governments which may force the officials to do this.

J M Tom


Uh, there is more but its more to the Webster side of things and its contained in that cite at the tail end. Goes into the processes but this is the end results that I think you wanted. If you need the actual puppy pop from that side too, let me know and I'll continue to dig.

By M. Randolph Kruger (not verified) on 27 Feb 2007 #permalink

Sorry, J M Tom. As I went away, I thought, he can't be serious. But other people, including some of our annointed leaders, are serious about such nonsense. I can't say all of my own assertions have been accepted as uncontrovertial. I can agree that few governments have not tried either to deny or to minimize.

Just saw this, via Crofsblog: GlaxoSmithKline wants to bring a prepandemic vaccine to the market. Well, of course they do. That way they can make a killing (as it were) even if H5N1 never goes pandemic. Still, if their (hypothetical?) vaccine showed good immune response and had a good safety trial, I'd take it. Maybe not be in the clinical trial, but I'd certainly "ask my doctor about" it once it was on the market.


"If you can demonstrate long-term priming, and that that priming is likely to confer benefit and that the approach is safe, then we could put many of the concerns about pandemic influenza to rest."


That rosy prediction in the final paragraph completely overshadows the earlier admission that "this could be a couple years", especially since it's not mentioned that this is time we might not have. I'm afraid it sends the take-home message that "it's all under control, the experts are handling it." And so encourages people to tune out.

And even if we do have years still before a panflu, and even if their vaccine is safe, and effective (none of which is close to certain), are they planning to make enough of it for people outside the U.S. and Canada? Hard as it may be for a pharmaceutical company to understand, my concerns about a pandemic flu don't end with people who have health insurance, or even with people in North America.

Actually, considering many of our (their) drugs are manufactured overseas (not to mention our socks, cameras, cars, etc.), they really should be able to understand that.

Revere/Lisa-As I understand it and its based upon limited understanding but a lot more than most, if we use shitty vaccine on people just as the Chinese do on their poultry, dont we run a terrible risk of mutating it right into possibly High Path flu? 45% is about as sucky as it gets but its better than nothing is the thought I believe but shit folks the wont even consider it in the EU if its less than 70% for licensing. Is this just an attempt to make money?

By M. Randolph Kruger (not verified) on 27 Feb 2007 #permalink

Apparently, GSK can't sell it in Canada unless they can show that it is effective. However, they are working on those pesky little obstacles.

"Now one of the issues in Canada, as I understand the regulatory situation, is that currently there are not regulations in place to allow a traditional approval of a vaccine if there are no data speaking to its efficacy," Innis said.

"That's an issue that perhaps the Canadian authorities are going to have to wrestle with."


Randy: No, a vaccine doesn't increase the mutation rate. It only affects selection. The question is whether the balance of risks of vaccine reaction to benefits is positive in the case of a vaccine that may not really work well. But it may confer some protection in which cse we are better off, unless, of course, we use up all the eggs and need thm to make a better vaccine because we know the pandemic strain. It is a difficult trade off problem. I'd say this one isn't worth it.

But you have ask, not worth it compared to what? Revere, you really piqued my interest about other promising vaccines (see above). Which ones have data to show they might work better?

I've heard rumors that the H5N1 medimmune-style live attenuated is good, and could be manufactured more quickly. Is that what you're refering to? Or maybe an adjuvanted prep? C'mon--let us in on your thinking here.

Rob, I think what he is saying that the buyoff between the availability, viability, and then distribution would be very limited. 45% effective in producing a favorable result. It had been touted as 70% and that was with the ad-J's in it. Now its 45% and favorable result in the instance of H5N1 is very likely only that it keeps one alive. Doesnt mean you wont get sick and it wont be like it just takes a day off of the illness time like the current vaccines for flu, you just get to live. You might have seriously torn up lungs, organ damage, and still be near invalid status for upwards of six months. There wont be any of this "survivor" shit where they are going to be helping out. They will be drains on the resources that are still in place.

I dont know what Webster has in his refrigerator but I am confident in saying that if he says its dangerous, then I have to go with that. I believe the quote was that if you took this vaccine that," you would get very, very, very ill but likely would survive." He then went on to say, "it would take weeks to recover from this."

I dont know whether he was speaking of the flu, the vaccine or both. Sounds to me like its a damned if you do, damned if you dont. The official vaccine of choice now is to just be prepared as so many have stated. You cant get it unless you are in contact with an infection vector. Face the fact that if it comes in at a 10% level its just piling on and be prepared for it. Its really all we can do and in the US there are going to be far more casualties simply because our society is multi-level integrated... too far from the basic necessities and the people are so single tasked. Plumbers would make as much as a doctor.

By M. Randolph Kruger (not verified) on 28 Feb 2007 #permalink

I took part in the SA vaccine trial (as a guinea pig, not as a researcher). They had a bunch of us sign on for an additional extended trial (due to the dosage problems). Basically, they had a bunch of the non-responders come back for 3rd and 4th doses of vaccine, hoping that the boosters would increase immunity.

My reason for signing on? Partly the cash (nice to have a few extra hundred dollars at Christmas) but mostly because I hoped that even if I don't get protective immunity from the vaccine, that I'll have enough immunity that I don't die when the birds*%t hits the fan. At the end of the day, 45% making enough antibodies to inactivate the virus (granted, that's in vitro, but still) is still better than zero.

If 45% are in fact protected from infection and retransmission that would, to me, justify mass preventative (voluntary) vaccination. Lower R0, lower overall numbers needing scarce medical treatment, etc. You don't need 100% to get herd immunity. But the vaccine is targeted at an old strain and might not be effective at all against current strains. OTOH, maybe *any* previous exposure to H5 would "prevent death" or lower CFRs. (N1 we get in seasonal vaccine or seasonal infection, right?)
Given an opportunity, I'd get vaccinated with this one. Little to lose ( no ill effects in trials ) and *maybe* a big gain. Not to say I'd advocate mass production of this particular vaccine. It is an old one and there have been much better trial results with improved and proprietary adjuvants. The question of devoting a lot of resources to this particular vaccine is a valid one.

MRK: You're right: the Revere who wrote this entry is saying manufacturing a stockpile of this vaccine isn't worth it. I don't know whether that's correct or not. I do know it's a tough call.

But part of the arguement this Revere gave is that there are better candidates, specifically that "[o]ther vaccines have now been produced with much better ability to produce comparable antibody levels with less antigen..." I want to know which vaccines he is talking about.

Maybe he's busy, and will get to it later. Or maybe it was more of a rhetorical device, not to be taken literally. But it's a clarification I hope he'll get around to making.

It's all a matter of perspective. If H5N1 hits, even 20% effectiveness will be seen as useful. It could be the difference between 100,000 dead and 1,000,000 dead. Besides, SA is risking loads and loads of cash on this and the FDA is saying "something is better than nothing." Wow! That actually sounds logical!

By HPLC_Sean (not verified) on 28 Feb 2007 #permalink

"Plumbers would make as much as a doctor."

MRK, you can get your plumbers to prep?
I am someone people don't expect can know so much about something they don't want to think possible, and aren't hearing enough about from the msm.

What percentage of the population lives alone and has no one to bring them a glass of water if they're sick?

I don't see there being survivors if the strain goes as is now, and survivors could come down with the next wave, too, probably.
Any prepanflu vax, if it does help, won't be enough; people will still need to eat, and not freeze to death, have potable water, security from mauraders, (better mce preparations) nonpanflu health emergencies cared for, ect.

By crfullmoon (not verified) on 28 Feb 2007 #permalink

Rob: I am battling through one of my usual 3 day migraines (I am entering day 2 after a sleepless night), so I haven't responded earlier. Here's what I remember at this point (withoug doing a thorough search). GlaxoSmithKline did a trial in Belgium (I posted on it here) but at the time it hadn't been published. I'm not in a position to chase down whether it has yet or not. GSK is seeking interest from the Canadians according to a story yesterday by Helen Branswell. I believe there are other vaccines that have also showed good response (e.g., the recent CSL announcement that caused the Indonesian upset). There are probably others. The Sanofi was one of the earlier ones and seems one of the poorest. DHHS has let a large contract to them and now they are saying they will fulfill it and use the vaccine. I am duious about this decision since I think there are better vaccines out there already.

Thanks--that gives me plenty to go on. Get well soon (I been down that migraine road, and it ain't the scenic route).

Here is my read on it folks. Logistically speaking to field a vaccine that works takes time. Time in motion and the number of hits you have to take to get this 45% effectiveness is two I believe. So how long would it take to vaccinate 10 million people? Then there is the distribution of this vaccine and who gets it. There is also the cost of doing all of this stuff. You are going to take it and put it into the hands of the healthcare workers who will be at the most risk to become infected for a 45% response? Infected people will be walking into the middle of the sheep, get vaccinated and then we will have a big test to see if its truly 45% effective in a population. Give it all to the healthcare workers as far as I am concerned because we will need them for sure and they will need whatever protection we can give them.

Its better than nothing I agree but not much.

By M. Randolph Kruger (not verified) on 01 Mar 2007 #permalink

Taking Midrin Revere?

TBBFBT -Now thats the way of the world and commerce at its finest. Listen, they had better come ups with something to give people hope if this starts whacking 5 to 10 at a pop every couple of days. If they dont then all Hell is going to break loose in the economies of the world. No one is going to be doing a thing but futures and hedge funds when it comes and shorting the hell out of the market. I could see a drop of 3-5000 points if the CFR's start manifesting themselves at even 10%. Thats one hell of a lot of customers that wont be around to buy things. It would be a huge opportunity if you were sitting on cash and around at the end of the day. Would take about 5-10 years to recover if it was 5-10%, a generation if its 10-20%, likely not more than two generations overall in the markets as they adjusted if it was 30%. Anything past that it wouldnt matter anyway as the entire world economy collapsed.

This to the glee of many would take the drug manufacturers with them. GSK getting an approval does not a cure make. Snake oil? What in heck is Tamiflu and has anyone survived BF yet from taking it? All I have seen is people hurling themselves out of windows and acting like tarantulas on speed. Then there is that mutation thing from peeing it out into the sewage treatment. Very interesting. Superviruses developed in sewage treatment plants by Tamiflu. They'll need a cure of course and who they gonna call ....Big Pharma!

By M. Randolph Kruger (not verified) on 01 Mar 2007 #permalink