The vaccine news: how good?

The human bird flu vaccine news from pharma giant GlaxoSmithKline sounds good and it probably is. Probably. There is a lot we don't know yet as the results have not been published in the open medical literature. Here's what GSK is claiming.

First, they claim to have produced a vaccine that raises antibodies in 80% of the test subjects (400 Belgians) with a very small amount of viral material (antigen), 3.8 micrograms given twice (7.6 micrograms, total). Previous attempts to make vaccines against H5N1 have required much more antigen. Because our ability to produce viral antigen in eggs is very limited compared to the demand, being able to use less antigen is critical.

Second, GSK was able to use a low dose with the help of a proprietary additive (an "adjuvant") to boost the immune response. The good news is the adjuvant was so effective. The downside is it is proprietary (we do not yet know the make-up). Anyone wishing to make a similar vaccine would have to license the adjuvant from GSK. Moreover, the additive is not approved for use in the US, so there will be regulatory issues to solve first. In an emergency those hurdles might be short-circuited, which is reasonable. We wouldn't want to prevent vaccine use for reasons of paperwork. On the other hand, the reasons for the regulatory requirements relate to safety. Vaccine licensing is more about safety than it is about efficacy. If the adjuvant has such powerful biological properties with respect to immune response, it might have other effects as well, including adverse ones. GSK is saying their vaccine has no more side-effects than usual seasonal flu vaccines, but we haven't seen the data yet, nor do we know if GSK has fully analyzed it.

Third, GSK says the vaccine shouldn't be much more costly than ordinary flu vaccine, although it has yet to cost out the production in quantity. They are talking with the Gates Foundation about subsidizing the cost for poorer nations.

Fourth, GSK says it could ramp up production by the end of this year and go full scale in 2007, perhaps producing hundreds of millions of doses.

So that's what we know, and it sounds good. What don't we know? For starters, GSK has not released the data to the scientific community, so questions remain. Even with the data, we don't know how effective the vaccine would really be in protecting against getting the flu. The antibody response is said to have been measured by hemagglutinin inhibition rather than a neutralizing assay. It isn't known with certainty whether the measured response is sufficient, more than sufficient or insufficient to protect people from infection. The reported response is a measurement of a laboratory value in the subject's blood, not actual protection against infection. We also do not know how protective the vaccine would be against a somewhat different H5N1 that had mutated to become easily transmissible from person to person. GSK still has not worked out how to scale production up, what that will cost or what the ultimate rate of adverse effects will be. Unlike the questions about protective effects, however, those should be determinable and determined shortly. It will also partly determine exactly how many doses can be produced in a year.

Whatever the number (and let's take GSK's claim of several hundred million for the sake of argument) the amount of vaccine still falls short -- far short -- of the demand should there be a pandemic in the next 18 months, assuming the rate of adverse effect, cost and efficacy were all as good as claimed. Several hundred doses is not enough for Europe and the US, let alone the rest of the world. To meet a global demand GSK will have to allow rival companies to make the vaccine in their facilities, leading to a whole new set of complications. Even given the best of will, such arrangements are difficult to work out quickly. Moreover, the world's productive capacity rests entirely in the developed world. Some way to share this scarce resource in the setting of intense pressure to retain the vaccine until local needs are met must be worked out, too. It hasn't been.

Even assuming all of this turned out optimally (yeah, right!) there is the problem of distributing, delivering and administering the vaccine in a timely way. Even rich, developed countries like the US have rickety and underfunded public health systems. Vaccines aren't any good in a warehouse. They have to be in a person's body and be there before the virus is.

We are in a race with a mutating virus. The vaccine finish line is still a fairly long way off and no one knows where the pandemic strain H5N1 finish line is, or even if it exists. Societies with sane and rational priorities would have started running long ago instead of waiting until, or even past, the last minute. None of the technology now being employed so frantically is new. We could have been working on this for a decade or more and had most of it worked out by now, ready for any eventuality. Instead we ignored it.

Let's hope we didn't try to close the vaccine door after the infected bird has flown.

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Even rich, developed countries like the US have rickety and underfunded public health systems.

Even rich, developed countries, especially the US, have rickety and underfunded public health systems.

And some rich, developed countries would not have any problem administering a vaccine. Canada for one. Annual flu vaccination is routine and free in most provinces, and has a very high acceptance rate.

All around the world people are rejoicing today!

It seems that an inexpensive and effective vaccine has been developed by a British company.

According to MARIA CHENG, AP Medical Writer, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases said this about the new vaccine "The data are really very impressive," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "It changes the whole complexion of the issue that we have to face of getting enough vaccine for people who might need it in a pandemic."

But hold on here!

What is this at the end of the same article?

I mean, right at the bottom of the article and certainly not in the form of a headline?

"Creating a prototype pandemic vaccine, however, does not guarantee that countries will be protected in the event of a flu pandemic. "This vaccine will only give protection against this particular H5N1 strain and possibly other H5N1 strains," said Osterhaus. Thus, if the next influenza pandemic is sparked by a subtype other than H5, much of this vaccine may prove of little use" reads the same article. ." Because it is impossible to predict which influenza strain will spark the next pandemic, it is equally impossible to produce a vaccine that will be completely effective."

So we have this great new vaccine, which er.. "may prove of little use".

I see.


Not sure what to think now.


"Moreover, the additive is not approved for use in the US"

It's not approved in Europe either. The only approved proprietary adjuvant is MF59 from Novartis (formerly Chiron), and that's in Europe and only for elderly subjects.

What I have heard from both Klaus Stohr of the WHO and some vaccine company employees, with any new proprietary adjuvant, the regulatory process is going to take years, not months.

What is the most significant information about this? It was announced one hour ahead of the news that GSK tanked for the second quarter...HARD! Net effect on the stock was zero.

Like they say it will take years. If indeed there has been such a response then great. But like the WHO they are witholding information and that can only raise the eyebrows of the medical/research community. The stuff is based on old egg technology too. Very strange that the WHO jumped all over this and all of the insider stock sales for the last three months IAW federal law filings have all been sells.

Why would they do that in the face of what Roche is making off of Tamiflu? Get back to me on that.

By M. Randolph Kruger (not verified) on 27 Jul 2006 #permalink

Hasn't GSK been using squalene as an adjuvant? That would cause a great deal of controversy if used in this vaccine.

There is quite a difference for making 800 doses under controlled laboratory conditions and 800 million doses under controlled laboratory conditions.

I would think that regulators and companies should have reached a stage of sophistication that they could some basic respect the public...

...such that they could provide an adequate explanation that titres or a measured immune response to an antigen does not in any way indicate protection from disease.

When regulators, governments and companies learn to respect the collective intelligence of the citizens they are entrusted to protect, each of us will be better off... this point, they have been little more than 'snake-oil salesman'.

Tom DVM: my fear is that 'collective intelligence of the citizens' is very susceptible to the 'snake-oil salesman' techniques... if you don't believe that, just take a look at the government officials we have elected... Ted Kennedy, George Bush, Hillary Clinton, Newt Gingrich... and the way campaigns are run, need I say more??? Most of our elected officials are elitists who feel they are better suited to make decisions for us because the 'collective intelligence of the citizens' is less that their own intelligence... they know what it best for us...

As a side note, the wikipedia entry for 'collective intelligence' makes for some interesting reading:

"less that their" --- DOH!!! --- "less than their" --- maybe proof they're right... LOL

MRK: "It was announced one hour ahead of the news that GSK tanked for the second quarter...HARD!...all of (GSK's) insider stock sales for the last three months IAW federal law filings have all been sells. Why would they do that...?"

If that's true, then why indeed?

The corporate flacks would count on most pundits' reluctance to appear prejudiced or negative by dismissing such "great news for humanity" without hard evidence. Anything less than cautious optimism would be bad form. So if you need a short-term lift, this is a great way to do it. If it doesn't work out, no harm, no foul, right?

Without discounting anything, I'll hold off on the champagne for now, thanks.

Thinlina. Not really if you look up all of the poop they threw out ahead of the bad stock news. It said they used inactivated H5N1. Webster had to engineer the evil section out of his, then make the vaccine (egg technology) then reattach the bad boy leg of the virus and then use the vaccine against it.

His quote, "I have a vaccine that will make you very, very, very sick. But you likely will not die. " GSK, Nbarro, Fauci, Maria Cheng all were out of context quoted as this was good news. It is to a certain extent. As Revere, Tom DVM, etc said if it works, GREAT! Else get that pandemic stores list up to snuff.

By M. Randolph Kruger (not verified) on 27 Jul 2006 #permalink

Randy, thinlina: As I said in the post, there is much we don't know. On its face, this is good news because someone finally succeeded in getting H5N1 to be immunogenic enough for a feasible vaccine. We still don't know the details and the details can be important. Their stock hadn't tanked. It was down because while they did quite well it wasn't the usual obscene profit Wall Streeters are used to and they hadn't met those expectations.

So let's wait and see. It isn't bad news. It just isn't as much news as we need to make a judgment.

Just for a moment, let's catch our breath. Sure..breaking out the champagne might be premature. But consider this:

1. I've heard over and over again, that H5N1 as a possible pandemic, was most feared because it is such a novel virus. With an unusually high CFR, as the most concerning feature.

2. Many believe this vaccine news to be snake oil. With some pointing to the fact that H5N1 might not be "the one", suggesting this particular vaccine has no particular merit.

IF H5N1 is a particularly nasty virus, I'll take my chances with any other pandemic strain. Give me the H5N1 protection (even limited). From what I've seen, it sure beats nothing!

Please, let's start acknowledging the the hard work of people on the front lines. The fate of the world could well rest in their hands.

Well done GSK...keep up the good work!!

Thats just it Thinlina, no one knows what they have or what they did that was different. Hell, Russia, France, Bulgaria, US, Chinese, and Vietnam all have said they have vaccines. Do any of them work? Not scientifically and definitively speaking which is what Revere is saying. I dont want to take the wind out of GSK's sails but Sanofi did the same, Sino Vac did the same and poof, it all went away when it was put to the hard test. Revere could speak volumes on it but bottom line is the titers and whether the vaccine is as bad as the virus. You could also be right. We get this and now there's reports they think it might have merged in some way with Dengue Fever. Wonder if bug vaccine 1 works on bug virus #2?

Fast way to get shot down on this one. Everyone is right and wrong.

By M. Randolph Kruger (not verified) on 27 Jul 2006 #permalink

I have a concern - possibly ill founded - regarding the use of immune system stimulants (adjuvants) in a vaccine against a virus whose lethality is based on its ability to overstimulate a person's own immune system, causing a "cytokine storm" which in essence drowns the victim in his own body fluids.
Let's say you get this vaccine with the adjuvant, and it is against the earlier non H2H virus, so when the mutated pandemic strain hits town you are not really protected against it. Bad enough: but my question is, would the adjuvant still be activating your immune system and thus making you more likely, if you do get infected with this new mutated H5N1, to have the cytokine immune overreaction that kills you?

Also (on a slightly different tack) did you read all the articles in crof's blog today about bird flu cases in Thailand? Now that the cat's out of the bag re bird flu resurfacing in Phichit, are they simply overreacting, panicking over normal flu, erring on the side of caution...or are they having a very real sudden great upsurge in the number of bird flu cases? There is no data given on whether any of these cases are linked by familial ties or other close contact (ie, could this be the start of efficient H2H transmission? or "just" more B2H?)

By mary in hawaii (not verified) on 27 Jul 2006 #permalink

mary: I don't think the adjuvant is a risk for increasing cytokind storm, although the mechanism of storm is not exactly known. The adjuvant seems to work in a complementary fashion for humoral immunity and should be short term. I do have a concern it will boost vaccine adverse reactions, however. I commented on the new suspect Thai cases today. Whenever H5N1 is in an area there is an increase in the index of suspicion which can lead to more suspect cases, some or many of which are not true positives. This is normal and appropriate. They should be erring on the side of caution.

Is their a predictable percentage of people that would have to opt to take the vaccine to lower the rate of general transmission?

Can we "meter out" the response of our bodies' TNF or Interferon response to lower the chance of cytokine storm?

By Trina Bashore (not verified) on 28 Jul 2006 #permalink

thinlina: The vaccines so far (except for FluMist) are killed virus vaccines so there is no extra danger from that. The question of GBS is another one. We don't know how much risk there is from this, although it has always been very rare.

I don't mean only Guillain Barre syndrome but all myelitis, encephalitis etc. induced by vaccines/virus infections.

If the H5N1 kills and debilitates by directing the cytokine response towards neural tissue (mimicking the tissue somehow?), and the vaccine is made of killed whole viruses, then why wouldn't the killed viruses direct the immune response towards neural tissue? (sorry my english)

Thinlina: To say the virus is neurotropic means it infects neural tissues, not that a systemic reaction affects the nervous system.

Yes, but it's not the virus itself that kills. It's the immune response that kills and debilitates.

Thinlina: That's a misconception. The infection itself causes disease and sometimes can trigger an overactive cell mediated immune response that makes it worse or is fatal (cytokine storm). The virus itself can and does induce apoptosis leading to cell death.

Or do you mean, revere, that in it was i.e. hepatotropic, it would tempt the cytokine reaction in there, locally? Or nefrotropic and so on? And the killed viruses can't go to the brain so they allure the injection site cytokine storm?

I mean, is the killing effect due to local cytokine response against the virus particles or is the killing effect due to an autoimmune reaction because of the virus similarities towith neural tissue?

revere, you seem to have sent your letter first :)
But what's the mechanism by which the virus induces the overactive cell mediated immune response?

And do we *know* that the overactive immune response is because of the virus itself and not an virus-induced autoimmune response? Or do we just *suppose*?

Thinlina. I'm sure this is a complicated intracellular process but could it be that the relative viral intracellular load in H5N1 (H1N1) infections vs. seasonal influenza stimulates a bigger immune response or is just a bigger target for a normal immune response...

...too many cells infected...killed by the immune response ...physiological reaction to left over dead intracellular contents results from the large number of cells killed...contributes to the patients death.

Tom DVM, do we know that that is the case? No autoimmune aspect? :
"However, experts believe that in many cases infection causes a derangement of the immune system which leads to an indirect autoimmune attack on the spinal cord, rather than a direct attack by the organism. One theory to explain this abnormal activation of the immune system toward human tissue is termed "molecular mimicry." This theory postulates that an infectious agent may share a molecule which resembles or "mimics" a molecule in the spinal cord. When the body mounts an immune response to the invading virus or bacterium, it also responds to the spinal cord molecule with which it shares structural characteristics. This leads to inflammation and injury within the spinal cord.
Vaccination is well known to carry a risk of the development of acute disseminated encephalomyelitis (ADEM) which is an acute inflammation of the brain and spinal cord. This was particularly common with the older antirabies vaccine which was grown in animal spinal cord cultures; the use of the newer antirabies vaccine grown in human tissue culture has almost eradicated this complication. This is also thought to occur as an immune system response."

Thinlina. I'm sure the cytokine response is multi-factoral but I don't think you need an autoimmune component if the virus is present in a huge number of cells drawing the immune response to it...

...this would in effect mimic an autoimmune process without being one.

When it comes to the vaccine, killed or otherwise, you can get an autoimmune reaction to the vaccine not with the first shot but after the booster...the first shot primes the immune system then the second vaccines is deciminated around the body from the injection site...and the over sensitive immune response targets anywhere the vaccine has attached itself...that is a classical immune response.

I had this exact reaction in 1981 to an experimental human diploid rabies was not a pleasant experience.

Sorry, should have read...that is a classic autoimmune response.

"I had this exact reaction in 1981 to an experimental human diploid rabies was not a pleasant experience."

Do we know, what was the mechanism of deadliness of the flu virus during the second wave of 1918 pandemic?

It's important to remember this is an infection, that is, the virus uses the host cell to make copies of itself and in the process the host cell suffers. The virus initiates a programmed cell death process and the cell kills itself in this case or if it doesn't dies because it is using its machinery to make virus, not things vital to its own survival. Some viruses also set in motion immune reactions, either innate or adaptive, that themselves are harmful although they also set in motion processes that are beneficial. We don't know how the influenza virus is able to set off one of these (so called cytokine storm, which is not a scientific term but a metaphor) or what determines why it happens in some people and not in others.

It's , however, kind of hard to believe that the neural damage H5N1 has been reported to do would be caused by only the virus killing the cells via apoptosis.

Thinlina: There is more we need to understand, but it isn't at all hard to imagine. When you infect cells you also cause inflammatory damage in the area and if the tissues affected are vital tissues you get serious health effects. The polybasic cleavage site in HA is essentially the key that allows the virus to infect a wide range of tissues, including neural tissue.

So you don't think there is an autoimmune aspect, revere?

thin: please read what I say carefully. The virus causes an infection which kills cells. That is the primary lesion. In some people there is additional involvement of the immune system, both good and bad. If a cytokine storm ensues it can be serious, often fatal. It is not the primary lesion of the infection but something that can happen afterwards. It is not a classic autoimmune reaction but it is a case where the immune system reacts in a way that is harmful. I hope that clears things up and we can move on.

Yes I know that what you were writing. But I want to continue a little bit further. You don't have to answer if you don't want to, and I'm not attacking, just asking. You know us little blondes with sometimes nonsense questins? ;)

If it was just a secondary immune reaction against the lesioned host cells, then why don't all the e.g. VZV patients get any autoimmune problems? VZV goes wide and makes a lot of lesions first time. Still it rarely causes autoimmune responses (or does it?).

Well, just my two pennies. We don't have to make a number out of this ;)

Couldn't resist the tenptation...:) I didn't man only this kind of a reaction, but also the like encephalitis, myelitis, distal neuropathy. :
"Neurochem Res. 1992 Sep;17(9):887-91.

Molecular mimicry and the autoimmune response to the peripheral nerve myelin P0 glycoprotein.

Adelmann M, Linington C.
Department of Neuroimmunology, Max-Planck-Institute of Psychiatry, Planegg-Martinsried, Germany.

In the Lewis rat immunisation with the myelin P0 glycoprotein can induce an inflammatory demyelinating disease of the peripheral nervous system, experimental allergic neuritis (EAN), which has many clinical and histopathological parallels with the human disease the Guillain-Barre syndrome. In view of the reported association of GBS with a number of infectious agents we have investigated whether "molecular mimicry" may occur between microbial antigens and the P0 protein that could possibly trigger a similar pathogenic autoimmune response in man. A computer search of the available protein sequence data bases identified several absolute sequence homologies between P0 and viral proteins that involve five or more consecutive amino acid residues. Four of these sequence homologies involved viral pathogens previously associated with the Guillain-Barre syndrome, namely Epstein-Barr virus (EBV), cytomegalovirus (CMV), Varicella zoster virus (VZV) and human immunodeficiency virus I (HIV I). Although, sequence homologies were also found between viral peptides and the neuritogenic determinants of P0, residues 56-71 and 180-199, these homologies proved incapable of eliciting EAN in the Lewis rat. These observations are discussed with reference to the role that molecular mimicry between T cell epitopes on pathogen derived antigens and the P0 protein may play in the pathogenesis of the Guillain-Barre syndrome. PMID: 1383842 [PubMed - indexed for MEDLINE]"

I assume they could scale up production in a pandemic

I think we can have one dose with an old strain
and the 2nd with the pandemic strain