Constraints Loom for Swine Flu Vaccine

Worldwide, drug companies are scrambling to manufacture a vaccine for H1N1, also known as swine flu, which was declared a pandemic in June 2009. David Fedson, an expert in influenza vaccines and a former consultant to the World Health Organization, says the current distribution system is outmoded, and could slow or restrict the delivery of vaccines to some developing countries. "One of the reasons they’re getting it late is that thus far, the distributions of vaccines from companies to countries have been handled as a series of business deals," Fedson says. He argues there could be other drug options outside of a vaccine to improve survival rates, but more research is needed.

Swine flu became the first real test for the World Health Organization’s pandemic alert system when it emerged earlier this year. How has swine flu progressed in reality compared with expectations?

H1N1, or so-called swine flu virus, has not disappointed us at all. It’s now in virtually every country of the world and managed to make that move in just a matter of a couple of months. After six weeks or so, it became quite evident that overall, the effects of infection in populations were rather mild, and in general no more severe than a seasonal [flu]. What we’ve seen is a mild illness overall that’s infecting a very large number of people and communities in a rather short period of time. It’s caused a lot of disruption; it’s caused stress on doctor’s office visits and emergency rooms; and in several communities, in many countries, it’s caused great pressure on intensive care units, [which] have had to take care of a large number of desperately ill patients, usually young adults.

Everybody is talking about an impending swine flu vaccine. How difficult has it been to develop a vaccine and what types of issues arise when you have different versions of vaccines from different countries and companies?

Like so many things, there’s good news and there’s bad news. It seems that after playing around with the virus in the laboratories, the virologists have been able to make it grow better and been able to get these modified strains in the hands of the vaccine companies so that the growth yields in production facilities are much better than they were six weeks ago. That’s good news. The second piece of good news is that it seems that one dose rather than the anticipated two doses ought to be enough to provide a protective level of immunity. That means at any given point in time the world will have twice as much vaccine to give to people and won’t have to worry about recalling patients to come back for a second shot.

What is not good news is that the vaccine that has been tested and that people have been enthusiastic about is a preparation that does not have an adjuvant. An adjuvant is a substance that augments the immune response. Its advantage in population-based health is that when you put an adjuvant in a vaccine you can reduce the amount of vaccine virus in each dose. Instead of being able to immunize one hundred people with a given amount of vaccine, you might be able to immunize four hundred people. This is the situation that we’re faced with. It means that there will be fewer doses to go around and it means a lot of developing countries won’t get anything at all.

There are expected to be vastly more doses of flu vaccine available in the developed world. Just how big is this disparity in flu vaccine access, and what are its consequences?

This is something I’ve been writing about and talking about for six years, and I put numbers on it over two years ago. In the first six to nine months of a new pandemic period, the vaccine companies of the world, which are located in nine countries--the United States, Canada, five countries in Western  Europe, Australia, and Japan--would collectively be able to produce enough vaccine to be able to vaccinate about 840 million people. We might be able to stretch that out to 1 billion or 1.1 billion, but you can see that is not anywhere near meeting the vaccine [needs] for several billion more people. The vaccine-producing countries, the nine major countries, have 750 million people. And if every one of their citizens gets a vaccine, there will be little left over for other countries. Those other countries include Spain, Sweden, and Finland. They include the countries of Central and Eastern Europe, and certainly they include the vast populations that live in South and Southeast and East Asia and sub-Saharan Africa. Those countries are going to be left with little to no vaccine, and if they get it at all they’re going to get it late.

One of the reasons they’re getting it late is that thus far, the distributions of vaccines from companies to countries has been handled as a series of business deals. Government health authorities have made contracts with vaccine companies to supply a certain number of doses of vaccine. Although we don’t have direct evidence from this because nobody is telling us what is actually going on--there is no transparency in this process at all--I guess it makes a difference if you are first in the queue or last in the queue.

Why is that? There has been a lot of discussion, especially in the last five to six years with the emergence of avian flu (H5N1), that these pandemics are a real looming threat.  Why has vaccine distribution followed this path?

There has been a real absence of public health leadership in the vaccine-producing countries. They will tell you they are doing the best they can, but Winston Churchill in the early days of World War II once said, "It is not enough to say we are doing our best. You have got to succeed in doing what is necessary." What is necessary is to develop the kinds of vaccine production systems that allow you to produce billions of doses of vaccines in a period of say, three months. There are technical ways that could have been achieved. For example, we know from the experience of using live attenuated influenza vaccine in children, which we have been doing in the United States for eight or nine years, that it would be possible to make a live-attenuated pandemic vaccine. That would have the advantage of not requiring a needle for administration; you could simply give drops into the nose of children and adults who you are vaccinating, and you could produce this in the egg-based production facilities that vaccine companies use to make their traditional vaccines. The advantage of using a live-attenuated vaccine is that you increase the number of doses of vaccine you produce in any given time period by a factor of perhaps eighty to one-hundred fold. You can just imagine what difference that makes in terms of the number of people you could immunize in a given time period. You could literally make billions of doses in a period of three months.

The second approach would be to take recombinant-protein vaccine against influenza, which is close to licensure in the United States and should have been licensed at least a year ago if not earlier. You could produce that in pharmaceutical bioreactors. You could simply commandeer the pharmaceutical bioreactors that already exist for a few months. Again, you could produce enough inactivated adjuvanted recombinant-protein vaccine to vaccinate billions of people, and you could do that within two months. In order to do this, it would have required that political leaders sit down with the corporate executives who run these companies and say, "This is what we are going to do, and we are going to make it worth your while so you don’t lose your shirts." Now, it really would have depended upon it had we been faced with an H5N1 [avian flu] pandemic.

Now we’re faced with H1N1. There is no incentive for government leaders to stick their necks out and do something risky that might risk ruffling the feather of business executives. So they are content to sort of sit back, be silent, let contracts be honored, let companies do their business, let health authorities scramble to find a vaccine company that might be able to give them vaccine doses in three months instead of six months. Consequently you have this global public health free-for-all when it comes to vaccine distribution.

Officials from the WHO have asked drug makers to donate some vaccines to the developing countries and appealed directly to wealthy countries for aid. China has also been asked to donate some of its vaccine. So far the response has been far lower than the need (NPR). Why has the response been so lukewarm?

The WHO doesn’t have any [power]. It can simply make pleas and try to use moral persuasion to change people’s minds, but it doesn’t have an army. The WHO is not like a country, which has an elected leader whose responsibility is to protect his or her own people. Countries that produce vaccines will make very certain that they have enough doses to meet their domestic needs before they let vaccines go to any other country. Canada, for example, which has a production facility, will supply at least 31 million doses for the Canadian people before it allows any vaccine to leave Canada. Australia will do the same thing: 21 million doses for Australians before it begins to supply, through its contracts, the United States. Of course, by doing so, Australia will be supplying no vaccine to its near neighbor, Indonesia, which has more than 200 million people and no production capacity.

What can be done for developing countries? You note in a recent paper that vaccines will fail to meet the needs in a pandemic anyway and that realistic alternatives such as anti-inflammatory drugs might be needed.

[Editor’s Note: Many flu-related deaths are not caused by the flu, but by secondary bacterial pneumonia infections, causing an inflammation of the lungs. Thus, some public health experts argue that it is important to look at methods that improve patient survival, not just flu prevention via vaccination.]

It turns out that none of the influenza scientists really know anything at all about host response factors to serious illnesses, like sepsis or crush injury, that occur in people who have had major motor vehicle accidents. In all of these other clinical illnesses, you have a certain range of host responses that in severely ill people lead to what is called multi-organ failure and in many people eventually death. Now, the scientists who study sepsis and these related conditions know an awful lot about the host response. We have learned enough from the molecular biology to know that you can modify that host response and improve survival. But is this something that the influenza scientists know anything about? No. Is it something that influenza scientists want to know something about? No. Is it something that the influenza scientists who have been running the WHO programs want to know about? No.

In fact, the WHO staff have refused on several occasions to convene even a small technical consultation in order for these issues to be discussed among scientists who really know the issues, and to explore the possibility that inexpensive, generically produced agents that are manufactured in huge amounts in countries like India and China might actually be used to treat the severely ill people with H1N1 influenza and perhaps save lives.  But none of this work has been done. So in the absence of sufficient supplies of vaccines and antivirals, what can WHO tell the global community? "Sorry folks, you have to depend upon nineteenth-century public health technologies because we don’t have anything for you."