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The Contingency Planning Exchange

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Home > Events > Bulls, Bears, and Birds Conference, 2005 > Speakers > David Fedson

 

International and National Vaccine Planning Efforts
David Fedson, MD, Former Professor of Medicine, University of Virginia School of Medicine, and Former Director of Medical Affairs, Aventis Pasteur MSD

Speaker biography  |  Slide thumbnails  |  Slide show  |  Video

Klaus [Stöhr, of the World Health Organization], how many people do you have on your staff in the WHO influenza program in Geneva? You've got how many?

Twelve. You're going to have to take off your shoes to get above 20, I guess. So you've got a staff of 12 people in Geneva working on global pandemic preparedness, and that's another number that I think all of you ought to pay attention to, and you are not allowed to say that. But I can drag that information out of you.

I would like to spend a few minutes talking in a much more focused way on one of the many, many issues that concern all of you who have come to this meeting today, and that's developing vaccines and perhaps other agents for an imminent pandemic.

Now, since you all represent -- or most of you at least -- economic institutions, I thought that you would appreciate a quote from Herb Stein, who back in the 1970s said, "Things that can't go on forever won't," and of course he was talking about the economic cycle. But I think you could say the same thing about influenza and inter-pandemic annual influenza epidemics. Will they go on forever? Absolutely not. They won't go on. They can't go on forever.

Rob Webster, writing in a wonderful paper, which all of you should read, on the threat of the next pandemic, wrote a couple of years ago, "Influenza experts agree that another influenza pandemic is inevitable, and may be imminent, and the world will be in deep trouble if the impending pandemic strikes this week, this month, or even this year." I think this is a given, and I think we all understand this.

Now, what will we have [on hand] to confront an imminent pandemic? Here I'm really talking about essentially what weapons we [will] have to fight this war. I think that's one way and a useful way to think about it. What's specific weapons will we have to fight this war?

Well, we've had a lot of information on antiviral agents, anti-neurominadase inhibitors, and I will not dwell on those. We have the current inactivated vaccines, and we must focus on those, because for an imminent pandemic we don't have anything else.

We don't have live, attenuated vaccines, [and] we don't have cell culture-produced vaccines. We don't have cross-protective vaccines, and if the pandemic is coming in the next week, the next month or the next year, we have got, as a Texas politician would say, "You've got to dance with the one that brung ya." You've got to use the resources that you've got at hand.

And I would like to say something at the very close of my remarks about the potential for other existing agents, which we already have in our pharmacies.

Now, let's look at an example of developing a pandemic vaccine by going back to the United States and the situation in 1976, when within four to five months of the isolation of a swine influenza virus from one fatal case, publicly-funded vaccine trials were completed. These trials involved over 6,200 children, younger and older adults.

They involved testing for different vaccines. Each one tested at three dose levels. One to two doses were studied. The serologic, the antibody tests were all completed in one laboratory, and at the end of four to five months, the information was obtained [from] immunologically naïve subjects. In other words, people who had never seen this virus before.

Very large doses of hemoglutinin antigen, the key antigen, the key substance which gives you your immunity when you give the vaccine, very large hemoglutinin doses of a whole virus -- not a split or a subunit manipulated vaccine -- will be required for a successful immunization, and two doses were better than one. This we knew, and we knew it in four to five months when we faced an imminent pandemic threat.

Now, if we translate that into what we are faced with today, and we look at it in the United States, I think we start by calculating what is the arithmetic of pandemic vaccine supply. How many doses of vaccine will we need? And the arithmetic is unforgiving. It is unforgiving. This is not molecular biology. This is arithmetic.

We have to say, for the United States, that everyone will require two doses if it's something like an H5 pandemic. The domestic need for pandemic vaccine, therefore, will be 600 million doses. Arithmetic: 300 million X 2.

The domestic vaccine production capacity that we have in the United States in the sole facility is 60 million doses of the trivalent inactivated vaccine we make every year. At the same strength of the hemoglutinin antigen, that translates into 180 million doses of that sort of vaccine.

Now a supply of vaccine formulated in that way would be enough to vaccinate, over a sort of six-month routing production cycle, 90 million Americans. Now, a strategy that leaves millions of Americans unvaccinated will be socially and politically unsustainable.

Now, developing then a vaccine for a pandemic, what do we need to do? The underlying principle of all of the development must follow these rules. We have to use existing facilities to produce the maximum number of doses of a monovalent vaccine that is acceptably immunogenic for a population, and not optimally immunogenic for an individual.

Our public health needs demand this. Now we can use different approaches. We can increase the antigen content above the 15 micrograms (mcg) of hemoglutinin per dose, which has been tried already. But you can see, obviously, if we do that, we then reduce the number of doses that would be available subsequently, and [would], of course, reduce the number of people who could be vaccinated.

Or we can take an antigen-sparing strategy, try to reduce the amount of antigen that we can produce in our one production facility, either by giving an intradermal inoculation or we can add something called an adjuvant.

Now all you need to know about an adjuvant is that it's a substance, in most instances alum, which we use in our childhood vaccines to augment the antibody response and to prime the immune system so that we can actually be guaranteed that we will have an adequate immune response in the vaccine recipients.

Now, these are the approaches that we can take. I would like to contrast what's been going on in other countries with what's going on in the United States, and I think we really need to take a look at the European approach to clinical trials of what are called pandemic-like H5N1 vaccines.

Now the European companies in five European countries -- the UK, France, Germany, the Netherlands, and Italy -- and the governments in those countries are following an antigen-sparing approach, and they've been committed to this for many years. This is a low dose hemoglutinin, alum adjuvant vaccine.

Furthermore and very importantly, European regulators will not require Phase III clinical efficacy trials for these vaccines. For the vaccine companies to develop vaccines in which they can show that their vaccines, which are alum adjuvanted, are safe and that they induce an acceptably immunogenic antibody response, that's all that will be required to obtain a license for these test vaccines.

And once the pandemic comes and the true pandemic virus is isolated, they simply slot that new virus into their process, which has already been approved by regulatory authorities. They will have a license for the pandemic vaccine literally in 3 to 4 days.

Now the vaccine companies in Europe need public funding for these trials, and European governments have been amazingly slow in providing that public funding. So that the trials that need to be undertaken, specifically the trials that are large enough to give people the assurance and feel comfortable that these are the vaccines they will want to use, have simply not been undertaken.

Now, if we contrast that with the U.S. approach to clinical trials of pandemic vaccine, we can see the happy talk that comes out of NIAID saying that they're testing H5N1 vaccines, produced by Sanofi, Pasteur, and Chiron. The vaccines that have been tested and will continue to be tested now have been formulated at 7.5, 15, and 45 mcg and 90 mcg of hemoglutinin per dose. But they do not contain an adjuvant.

Now we heard recently, in early August, that two doses of this vaccine were immunogenic only at 90 mcg of hemoglutinin, which [means that] giving two doses to recipients would be enough to vaccinate, with our current production capacity, only 5.0% of all Americans. Are you happy with that kind of development?

A new alum adjuvanted H5N1 vaccine is being formulated, and I have learned this recently, at 45, 15, and 7.5 mcg of hemoglutinin, but this would be enough to vaccinate only 10%, 30%, or 60% of all Americans. Is that kind of vaccine development strategy something that is sustainable for the American population?

But there's another hooker here and that's the FDA. The FDA is on record as saying, "Simple changes in the antigen content of a non-adjuvanted vaccine -- current vaccines contain 15 mcg of hemoglutinin per strain or 45 mcg in total for the three strains -- licensing a pandemic vaccine like this will be very simple and will require only some antibody data and safety data in order to get a license."

But an adjuvanted vaccine will be considered a brand new vaccine, and clinical evidence of efficacy during the inter-pandemic years will be required.

Now vaccine companies have no commercial incentive to pay for the development of adjuvanted inter-pandemic vaccines full stop. They have no incentive as businesses to do this, and they won't do that. Now, if the FDA does not change its position, the U.S. will not be able to develop an adjuvanted pandemic vaccine.

That is the only conclusion that you can adopt if you take a look at what is the FDA's stated position. You have got to be aware of this fact, and therefore, we won't have an adjuvanted vaccine for the American people.

So what is our current situation? The Europeans and the Australians and the Canadians and the Japanese know what to do -- an alum-adjuvanted low-dose vaccine -- but they have been very slow to figure out how to do it, namely to provide the public funds. The European community at large is completely out of the picture because they can't get their act together to do anything at the kind of speed required.

The United States is the odd man out, internationally, among the nine vaccine-producing countries. It knows how to do it. It provides public funds. But it has been very slow to figure out what to do -- namely a low-dose alum-adjuvanted vaccine -- and the FDA has simply been not connected to this whole process.

There is no international institution today or a process that is capable of coordinating, and more importantly managing, global pandemic vaccine development, and even going beyond that, once you develop that global vaccine production and far, far more important than anything else, the equitable distribution globally of a pandemic vaccine.

Now, why is this global perspective important? So if you take a look at this slide right here that goes from 1994 to 2003, you will see the amount of vaccine used in Western Europe, Canada and the United States and then the rest of the world. Take a look at the top of the slide, because that's where the action is occurring today.

The global use of influenza vaccine more than doubled in the decade from 1994 to 2003, but most of that growth occurred in the rapidly developing countries outside of North America and Western Europe. In 2003, those countries outside of Western Europe and North America used 38% of the world's vaccine last year. It was up over 40% within a few years. I would say half of the influenza vaccine will be used in countries that do not produce it.

Think about the political implications of that when the pandemic arrives. The countries that had been using the vaccines inter-pandemically will expect to receive supplies of pandemic vaccine. What will they do when the vaccine-producing countries nationalize their supplies -- as will happen -- and refuse to allow vaccines to be exported to other countries until their populations are vaccinated?

It means that people in the Bordeaux, France will survive while people in Barcelona, Spain will die. That's the only way you can look at it.

So, what are the underlying realities of this global supply? There's no surge capacity beyond the 300 million doses of annual trivalent vaccine production.The nine vaccine-producing countries will prohibit their exports. The have-not countries will receive little or no vaccine, and this will produce a global diplomatic and security as well as public health crisis. I think this conclusion is unmistakably clear.

So I think if we're considering questions about pandemic vaccination, [there are] three questions for Wall Street, and I think everyone else, if the pandemic is imminent:

1. Will the U.S. be able to obtain and adequate supply of pandemic for its own population? The answer today is clearly not.

2. Will the U.S. be able to provide pandemic vaccines to Mexico -- a word that does not appear in the earlier draft pandemic plan -- other have-not countries? I think not.

3. What will be the social, economic, political, and national security consequences if have-not countries cannot obtain adequate supplies of pandemic vaccine? Unimaginable.

I believe we could do something if we got our international act together for pandemic vaccines . . . if we found a way to formulate and produce a low-dose alum-adjuvanted pandemic vaccine. There are studies with pandemic-like vaccines that show you can go down to 1.875 mcg.; that's an eight-fold reduction from our current antigen content of 15 mcg. You combine 1.875 mcg antigen together with an alum-adjuvant, and you could produce in six months perhaps 7.2 billion doses, enough to vaccinate 3.6 billion people, more than half the world's population and certainly probably more vaccine than could be accommodated by the healthcare systems throughout the world.

Is that pie in the sky? Of course is it. Is it an achievable target if we were socially and politically and economically organized to do just that? I believe, absolutely, yes it is.

Now, let me just spend one slide on one aspect of a response with a weapon to fight the war that has not been considered, but which I think if nothing else, represents another direction in which our thoughts ought to be going. And that is, could a currently available drug be useful for treatment and prophylaxis of pandemic influenza?

To summarize a large body of information very succinctly, I hope, let me just say that influenza viruses induce inflammatory changes in the human host and statins. The cholesterol-lowering drug that so many high living financial people have to take if they want to survive long enough to see what the markets are doing next Monday, statins, act as antiinflammatory agents.

Now in a recent study of patients with pneumonia, patients taking statins had a 64% reduction in mortality from pneumonia. I have been advocating for over a year that what we really ought to look for is an epidemiological signal in populations that people taking statins have a reduction in the influenza-related morbidity and mortality that we experienced during inter-pandemic years, namely hospitalization and death from influenza-related conditions. And I persuaded two groups of epidemiologists to actually look in to their large administrative databases for such a signal.

All the results from these two studies suggest clearly and consistently that statins are protective against influenza-related diseases. [We apologize; the last few sentences were lost to technical difficulties]]

. . . The Americans can always be counted to do the right thing, after they had exhausted all other possibilities. Thank you.

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