A few weeks ago an FDA advisory committee recommended approval of Sanofi-Aventis's prepandemic H5N1 vaccine, despite data that it required very large amounts of viral antigen (90 mcg) in two doses. At the time it seemed there were far better vaccines available or about to be available. What set this vaccine apart was that Sanofi had been making it to fill an order placed by the US Department of Health and Human Services (DHHS) and there was enough for 3.75 million people in the US stockpile, although because of elapsed shelf life that was down to about 3 million. Ninety micrograms is a lot of viral antigen -- more than is practical for large production. Moreover the vaccine only raised sufficient neutralizing antibodies to less than half of those receiving the vaccine.
Another vaccine maker, GlaxoSmithKline, has an experimental vaccine with a booster chemical (an adjuvant) that allows much less viral antigen to be used. Now comes news that the GSK adjuvant might be acquired by DHHS for use in the Sanofi vaccine, allowing the existing Sanofi stock to be stretched pending availability of better vaccine. The GSK adjuvant is unlicensed and unapproved, and in this connection, untested, so it isn't clear how much viral antigen would be needed in the newly adjuvanted vaccine stock. The adjuvant fortified vaccine would thus have to undergo a repeat trial for safety and efficacy. Meanwhile, Sanofi is said to be working on its own adjuvant.
The US pandemic stockpile includes more than the Sanofi vaccine. It also has the oral antiviral agent, Tamiflu, made by Roche, and the inhaled drug, Relenza, made by GSK, both neuraminidase inhibitors effective against H5N1. GSK was also developing Relenza in an intraveous form that might be used in critically ill patients. Since there is no current market for the drug (very few patients critically ill with H5N1), GSK has stopped developing it.
"We asked people if they were going to buy any and they said `No, we want it to be there just in case," [GSK's chief operating officer David Stout] said. The company faced "huge, expensive clinical programs without any buyer."
"It's just on hold," he said. (John Lauerman, Bloomberg)
If GSK doesn't want to develop it, perhaps they should turn the development over to another company willing to take the risk. Or here's another idea. DHHS is willing to pay good money for a failed vaccine. Why not pay much less money for a stockpile of i.v. Relenza to be used in a critical care setting.
Just a thought.
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I don't see anything in the data that would give one hope that any current antiviral will be effective a few weeks into a pandemic...
...and having studied and treated animals with similar viral pneumonias accompanied by a cytokine storm, I don't think you are going to get relenza where it needs to go, unless they change it from an inhaled delivery system.
Tom: In a few days I will start a series of posts on what happens with antiviral resistance. You will be sorry you asked and exhausted by the answer.
I look forward to it.
Maybe when you are done with the series of posts on antiviral resistance, we could discuss the existing literature on the efficacy of seasonal influenza vaccines and then on the challenges and potential efficacy of pandemic vaccines?
Thanks
Besides Rummy getting a little richer can anyone point to any study that shows that ANY of those touted antivirals keeps you alive at the very least, or actually puts you back onto the streets any soone? So far I have been monitoring what each person was given and it seems really that what I believe to be steroids or have a mix of steroids/anti-inflammatory types is about the only thing that has helped.
Anyone got anything on Tamiflu/Relenza being anything more than expensive?
Randy,
Were you the guy GSK called to determine the demand for i.v. Relenza? Heaven help us!
Miso-So I spill a bean or two. Revere got side posted by me about a year ago that Tamiflu was being stockpiled in the P.I. in response too what looked like HPAI about to run amok. Body bags in quantity. So far the stuff has done nothing but been distributed, used where necessary and well we havent seen the need for too many body bags.
The Tamiflu is ageing and with that heat down there it cant be too good for it even in a storehouse. but I digress a bit. My point about all of this antiviral stuff that they keep touting as being useful is that so far it looks like its really useless. No one can point a finger at any study, data or more importantly people walking out of hospitals that were wheeled in there that this stuff was given to. Neyope, just havent seen it. So at what point in time do we drop the facade and tell the truth about this stuff and really what HPAI would do if it really got the bat under the ball? I dunno, but I can tell you that it will already be too late for many people and not just because of the drugs that arent there. It will be food, water IMO that will be in shortest supply and here in the US and developed world that will take the hit the most. Sure, underdeveloped countries will also take a hit but I think it will de-evolve our society to something around the level of the turn of the 1800's. Dark Ages? I doubt it but you cant eat a X-Box.
Facade - a showy misrepresentation intended to conceal something unpleasant ,window dressing
deception, misrepresentation, deceit - a misleading falsehood
The problem with adjuvants is that we just don't have a lot of data or experience with them. If people worried about thiomersal before, they should worry a lot more about these 'proprietary' adjuvants. For those who don't know, for 'proprietary', read 'secret formulation'.
These are supposed to be miracle chemicals (they don't quite call it a drug, and it's not a vaccine) that is supposed to 'tweak' or 'nudge' our innate immune response - the part of our immune system that helps protect us against, well, just about anything foreign, basically, in a non-specific way. Given as accompaniment (condiment? side-order?) to a vaccine, it is supposed to improve our response to the vaccine, and produce more effective specific responses to the pathogen.
Being no expert, I've spent the past few months chasing down information on adjuvants. The thing that worries me most (quite apart from the lack of safety data) is that those touting them don't seem to have very good ideas of exactly how they work either, especially at the molecular level. In fact, come to think of it, the cutting edge of immunology is still 'discovering' new bits and pieces of the different cytokines, chemokines, and other molecules with even more exotic names or acronyms that comprise our immune system.
Now, let me ask you, how do you know where to look for side effects if you don't know the extent of the responses a particular chemical induces? "Whereof one cannot speak", I would suggest, one cannot determine safety.
One might say that we don't have to know how something works to be able to use it; we still don't quite know how aspirin works. True. However, drugs (like aspirin) and vaccines fall into different categories risk-wise. Vaccines (and their accompaniments) are biologically active materials, sometimes living, designed to have far reaching, long term, and hopefully permanent effects after 1 or 2 doses.
By the same logic, so will the side effects.
And I agree with you about stockpiling IV Relenza.
Susan: If adjuvants are used in US vaccines, their identity will have to be disclosed and safety tested in clinical trials. Better to do it now than wait until there is urgent pressure. The main reason many of us worried about thimerosol was the presence of mercury, a known neurotoxin. So far the evidence hasn't shown definite adverse effects, but I personally don't think mercury additives have any place in a pediatric formulation on general principles. Regarding other adjuvants, they should be treated just like any other pharmaceutical and tested for safety an efficacy.
revere,
The testing of adjuvants is a very complicated issue, mainly because of their nature. They tend to have different and sometimes completely opposite effects depending on what vaccine you combine them with. The nature of their effects can even vary between different doses of the same vaccine AND different adjuvant doses, or different batches of the same formulation. Which means you have to test each formulation every time, which is why using the GSK adjuvant with the Sanofi vaccine is a STORY.
The other problem is, again, we have very little experience with these kinds of adjuvants in humans, so it's hard to know what to look for. MF59 is the only licensed one (apart from alum, which I'm not including in this current category of discussion) and it has only been used in elderly subjects. Similar formulations have been used in veterinary vaccines for a number of years, and we KNOW that they have very bad safety profiles. For more times than I am comfortable with, I've heard vaccine experts mention adjuvants and refer to the fact that since we are talking about humans the 1% mortality that you see in poultry vaccines is obviously not acceptable.
(btw, and this is for everyone, pay attention when somebody says 'acceptable' safety profile; it may be time to read the small print.)
There is no agreement on what endpoints to test for, since their mechanism of action is so different from anything else we've used before. Adjuvants are almost an entirely new class of biologically active substances not quite belonging to any category: ie they sort of act like vaccines but they are not, but they are more biologically active than your usual drugs or 'inactive' types of chemicals such as fillers or preservatives.
They will probably just test them like other drugs or vaccines, but I do not have a comfortable feeling that we will be able to discern the real challenges till maybe a number of years after they have been widely used. And that, in essence, is my concern. But then, as I said, I'm no expert, so take it for what it's worth.
Susan: I agree with you that testing is fraught with difficulties, but not necessarily more so than many other pharmaceuticals and biologics. Adjuvants will be tested for safety in a particular formulation (combination of dose and antigen). Like all vaccines, we should have postmarket surveillance solidly established (not a given) but beyond that I don't see this as the problem you do.