The "prime and boost" vaccine trial

A paper to be presented today at the annual meetings of the Infectious Disease Society of America, but following a familiar pattern the results have been presented in a press release. The news is modestly good, but the emphasis should be on modestly.

The paper reports work that took advantage of a group of people who were vaccinated with two doses of an experimental bird flu vaccine in 1998, shortly after the first human cases in Hong Kong. The viral strain of H5N1 used then was of a lineage (or "clade") different than the ones used in the recent spate of vaccine trials from a lineage circulating in southeast asia. The two viruses are both H5N1 subtypes of influenza A but have diverged genetically in a variety of ways so they now constitute distinct clades (designated clade 3 and clade 1; clade 2 circulates in Indonesia).

Since the part of the H5N1 virus that the immune system "sees" is now altered, there has been the plausible assumption that any vaccine prepared from a non-pandemic strain would have either no or greatly lessened protective effect if the virus put on a different looking set of clothes to confuse the immune system. This presented a dilemma for pandemic flu planners, because current egg-based technologies take about 6 months to ramp up to production from the time the strain is first identified and isolated. Thus a pandemic would be underway for a minimum of 6 months before any vaccine would be available, and then only in limited quantities.

The new work, from Dr. John Treanor's group at the University of Rochester, located 37 of the former clade 3 vaccine subjects in 2005 and gave them a booster dose with a clade 1 virus vaccine. Their response was compared to subjects who received clade 1 vaccines for the first time in 2005. The "prime and boost" group had a noticeably better antibody response against clade 1 than those freshly vaccinated against clade 1.

In their trial, the Rochester team found that more than twice as many of the individuals who had received the priming dose of clade 3 H5N1 vaccine responded with substantial antibody levels to a single dose of clade 1 H5N1 vaccine than did those with no prior H5N1 exposure. Dr. Treanor says that these early but promising data indicate that priming with an antigenic variant vaccine before a pandemic occurs may be one strategy used to help control a pandemic.

"These preliminary findings need to be confirmed in larger studies, but they offer the intriguing possibility that pre-pandemic priming with existing H5N1 vaccines may boost the immune response to a different H5N1 vaccine tailor-made years later to thwart an emerging human influenza pandemic," says [NIH's Dr. Anthony] Fauci. (Eurekalert)

So here is the proposal. We make a pile of mismatched H5N1 vaccine and at a suitable time (criteria to be developed) use what we have to vaccinate high value workers, like health care workers. Then, when they are "challenged" with the actual pandemic virus (which will act like a booster) they will respond more quickly. That's the theory and the hope, anyway.

You may wonder why we don't just do this now and give it to everyone. Here are some reasons. First, there is plenty of "seasonal flu" around and we need our vaccine production capacity for what we know is happening instead of what might happen. We don't have enough production capacity to make that much of a primer vaccine, either. It would only be enough to vaccinate a tiny, targeted fraction of the population, like health care workers. Second, when you vaccinate tens of millions of people a certain small number of people die from causes unrelated to the vaccine but in close proximity to getting it. That's because people drop dead with some regularity in any given week and if tens of millions are being vaccinated, some of them will drop dead around the time they get vaccinated. Those kinds of events, for a disease that no one yet has, is pretty bad PR and could severely damage a vaccine program for when it's really needed. In addition, the vaccine itself does have a small rate of side effects and if given before a pandemic will not be protecting anyone against the disease (because there is no pandemic at that point to protect against). Third, these results are preliminary and based on small numbers. We don't know how much extra protection is being afforded or how worthwhile it is to do this. Everyone connected with this paper has stressed that much work needs to be done, yet.

Which makes us wonder what the purpose of the press release and fanfare is all about. Maybe that's an inappropriate question. These days, though, no question seems inappropriate.

What a world.

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Reminds me of the debacle over swine flu when Gerry Ford was president. Do we put a lot of effort into some sort of vaccination program or not. if we do and nothing happens, we lose credibility. On the other hand, it just might savelives if a pandemic does break out.

The way I read the article, the 'idea' was (also?) that pre-vaccination would enhance response to the actual pandemic vaccine ( vs the actual pandemic virus ), so that you could stretch the actual pandemic vaccine supply by using lower doses. Am I wrong?
If that does prove to be the case, perhaps it would make sense to gradually ( and voluntarily ) vaccinate everyone with the 'current' vaccine using whatever spare production capacity we have, over a period of years. We may not have years, of course, and you would definitely want to start with HCW and key infastructure workers.

Kevin: You are right except that it will be 6 months before there is a pandemic vaccine with current technology, so most people's exposure will be to an infecting virus. We don't have much spare capacity and even with proven vaccines many people choose not to get vaccinated. That's why it is likely to be the targeted, high risk population.

With that US swine flu vaccination program in the 1970's, is there strong evidence of some people developing Guillain-Barré syndrome as a direct result of the vaccine?

Or is that anti-vaccine hype?

Does this have any relevance to the vaccines of today?

Try the more dangerous new vaccines first, on the war profiteers, and, the bureaucrats who thought the public shouldn't be told, then, if it looks safe, the front-line hcw. (Front-line health care workers being harder to replace.)

The moderately protected war profiteers and "don't cause panic" bureaucrats (..."each prisoner pent"...)are then drafted into the "Mortuary Reserve" Corps, which will be needed in their communities to find, document, and bury the bodies.

I also don't think I want to hear many journalists/media talking heads going on about the catastrophe, since too many of them have not been educating themselves and asking the right questions, that would have helped the public understand the situation and prepare.

By crfullmoon (not verified) on 13 Oct 2006 #permalink

Our real problem is that its the lack of education from the middle class on down. The middle class on up will make it thru this likely without a scratch. If the middle class was advised every day of the kill count and percentages of mortality then maybe something would get done. Now we wouldnt want to alarm the public unduly would we?

I dont know about you guys but thats the job of the media and its just not killed enough people yet to get on their radar more than once or twice. Nor are they about to run out and say the sky is falling until it really, truly, incontrovertibly is and then the oh shit factor sets in. Oh shit, I need to be at the grocery store. Oh shit, I need to clean out the bank account. Oh shit, will they turn the power off? Oh shit, we might get cold here and on and on.

No, it plays to the Gulf War scenario perfectly and not unlike that, Wolfie Blitzer will be pulling the ratings. The screams, the cries for help, the cries for food because man its all about the ratings. I wonder how an H5N1 pandemic will rank in the Nielsens? Pretty much going to tell them what people really will watch on TV finally because the BS is going to be long and deep.

Its time for some big butt, well respected politician to go out and give it to them straight, hard and dirty. At that point in time the markets will fall 500 in a week, and temporarily he will be a pariah. Shortly after that when the bird bug does come, he will be regarded as a statesman. Statemen if they were in existence in Thailand, China, Vietnam, Indonesia would have stood up and said this stuff is going to kill you almost with a certainty if you get it. Get prepared. But the only ones I see doing anything is Thailand and with zip for money to do it.

I fear for the US, but I absolutely cringe at whats going to happen in SE Asia. They have so many people, but its like a target for a bio-nuke. It will be absolutely terrible. And who's talking about it but us? I just hope the internet remains up and running else the primary means of communication will shut down in the world.

By M. Randolph Kruger (not verified) on 13 Oct 2006 #permalink

This is rather speculative. The sample
size is woefully small, and small strain
differences can be important.

It cannot be ruled-out that a prime and
boost strategy is a recipe for original
antigenic sin. Those primed may fare
worse, in other words.

This is not to fault the researchers, or
PR. There are a lot of things we just
don't know.

By Red Crayon (not verified) on 13 Oct 2006 #permalink

why not let the people decide whether they want the vaccine or not ? Despite the possible side effects.
Offer some insurance against the side effects.

As for the producing capacities, isn't it just a question
of money ? If you pay more, you can find someone to produce
the vaccine. So,how much do they calculate is it worth
to provide the population with that option ?
How much would one dose cost with insurance against side effects under the actual circumstances ?

anon: The insurance companies cannot calculate this because they cannot fix the risks. It is also a matter of technology, eggs, etc., not just money. And the drug companies can make a lot more money making impotence drugs than vaccines.

If it is just the market determining this, then you are condemning most of the globe to go without vaccine.

Revere,

"If it is just the market determining this, then you are condemning most of the globe to go without vaccine...

Incredibly succinct statement! The U.S. fed gov hopefully will fund further research into the "prime-and-boost" H5N1 vaccine strategy. After all, what's the point of pandemic preparedness funding (ie. H.R. 4939) if money isn't placed into areas of pragmatic preventative research!?! Below is an excerpt of a letter I sent to John Treanor et. al...

To: "John Treanor, Professor of Medicine, and of
Microbiology and Immunology"

Web: The University of Rochester Medical Center @
http://www.urmc.rochester.edu/gebs/faculty/John_Treanor.htm

Saturday, 14 Oct 2006

Re: "prime-and-boost" H5N1 vaccine strategy

Dr Treanor, the study conducted by yourself and Nega Ali Goji, M.D., shows incredible promise because it makes plain and obvious sense.

Hopefully, the U.S. government will release a portion of the $2.3 billion earmarked for pandemic preparedness funding included in the FY 2006 Emergency Supplemental measure (H.R. 4939) and fund further research into the "prime-and-boost" H5N1 vaccine strategy...

[Check out the seven bill versions of H.R. 4939 @ Thomas Library of Congress @ http://thomas.loc.gov/ ]

By Jon Singleton (not verified) on 15 Oct 2006 #permalink

>anon: The insurance companies cannot calculate this
>because they cannot fix the risks.

sure they "can" and they do. Sometimes they make errors, though.

>It is also a matter of technology, eggs, etc., not just money.

money has been invented to measure technology,eggs,etc. in - money.

>And the drug companies can make a lot more money making impotence
>drugs than vaccines.

so vaccines are too cheap

>If it is just the market determining this,

And if it's not just the market determining this, then we
will magically have enough vaccine for the whole world ?
The market, that's the system of the country. It's called capitalism.
Either the market or subventions. (1)The government pays subventions
and then buys the cheaper vaccine or (2)the government buys vaccine
at market prices - the amount spent would be the same.

>then you are condemning most of the globe to go without vaccine.

are you suggesting here that USA should share its produced vaccine
with 3rd world countries ?

anon: What's your evidence that insurance companies have calculated the risk? They are not forced to underwrite insurance if they are unsure of the risk.

You believe too much in the power of money. There are some things money can't do. The problem with vaccines is not that they are too cheap but that they are insufficiently profitable unless we distort the market. Most of the world cannot afford vaccines at any price but especially at the price that Big Pharma requires to invest in it compared with other posible types of much more profiatble investment. To cure that problem you have to throw the market overboard with subsidies.

The Market is not capitalism. It is a theoretical fiction used by economists, including Marxist ones (try reading Vol. 1 of Das Kapital; it is entirely market based). It assumes various things that are clearly untrue, such as perfect information and resources by consumers, lack of collusion by producers, etc., etc.

I am not suggesting the US make vaccine for everyone. I am suggesting international laboratories throughout the world making vaccines for everyone, supported by an international agency.

>anon: What's your evidence that insurance companies have calculated
>the risk? They are not forced to underwrite insurance if they
>are unsure of the risk.

if they are unsure about the risk, they just require more premium.
Insurances cover all sorts of risks, vaccine-side effects is not
so hard to estimate, they can do tests and have data with previous vaccine.

>You believe too much in the power of money.
>There are some things money can't do. The problem with
>vaccines is not that they are too cheap but that they are insufficiently
>profitable unless we distort the market.

I don't understand. When they are more expensive, then they are
more profitable for the producer.

>Most of the world cannot
>afford vaccines at any price but especially at the price that
>Big Pharma requires to invest in it compared with other posible
>types of much more profiatble investment.

only more profitable because vaccine prices are too low.

>To cure that problem you have to throw the market overboard with subsidies.

or just pay higher prices for the vaccine you order.
That's the same effect.

>The Market
>is not capitalism. It is a theoretical fiction used by economists,
> including Marxist ones (try reading Vol. 1 of Das Kapital; it
>is entirely market based). It assumes various things that are
>clearly untrue, such as perfect information and resources by consumers,
> lack of collusion by producers, etc., etc.
>I am not suggesting
>the US make vaccine for everyone. I am suggesting international
>laboratories throughout the world making vaccines for everyone,
> supported by an international agency.

the question is just, what are you willing to pay.
With $100 billion, you could probably have enough prepandemic vaccine
with 10 H5N1 strains for all US-citizens in less than a year.
including some insurance for side effects.