One of the greatest public health fears is an influenza pandemic. Epidemiologists have worried that the avian flu virus, formally known as H5N1, could mutate enough to sicken and pass among humans, who would not have an immunity to it. A universal flu vaccine would prevent such a threat: like some childhood shots, it would confer lifelong protection—and eliminate seasonal flu injections as well. For the Insights story, "Beating the Flu in a Single Shot,"appearing in the June 2008 Scientific American, Alexander Hellemans talked with Walter Fiers of Ghent University in Belgium. Fiers discovered a key protein on the influenza virus that could serve as a target for a universal vaccine; the drug has shown promise in an early clinical trial. Here is an edited excerpt of the interview, translated from Dutch.
Before you started working on the influenza virus, you were actually decoding genomes in the 1960s. Did this then-new technique help you in tackling the influenza virus?
My first research project was the determination of the sequence of nucleotides, a technique which was still in its infancy. The problem we were faced with in 1960-62 was that the determination of the genetic code—and the linking of code words to amino acids was based on synthetic polynucleotides. This did not explain which of the 64 possibilities of combinations occur in nature. This was our first project: the determination of the sequence of a real gene as it occurs in nature, and this was from the genome of the bacteriophage MS2.
Why did you choose this virus?
If you want to resolve a problem, you have to return to the simplest form in which this problem can be solved—this is reductionism. So we looked for a very small virus. We looked for the smallest possible genome: a bacteriophage with RNA. We elucidated the nucleotide sequence of a gene, and this was published in 1972. The bacteriophage MS2 contains four genes, and we published the complete genome in 1976.
So this was the first genome to be sequenced?
This was the first complete genome that we have sequenced. From there, with the technology we developed, at that moment, it was the largest molecule from which the primary structure was determined. Subsequently, researchers have switched to DNA-containing organisms and now have reached humans. But the automation required for this was far beyond our capabilities.
You switched from studies of bacteriophages to the influenza virus in the 1970s. Why?
Because it had an enormous medical relevance and importance. The problem we had then, which we still have today, is the phenomenon of drift and shift. If it were not for drift—the accumulation of point mutations—and shift—the interchange of genes from animal and human strains—we would have had a vaccine based on serological data. Because of drift and shift, the World Health Organization [WHO] makes a prediction every year about the strain that is the most likely to cause an epidemic in the Western world. Based on this information one makes a vaccine the classical way, growing them in eggs, something that was started just after the Second World War, around 1950. And this is still being done the same way.
How do organizations, such as the WHO, predict these mutations?
On the basis of an epidemic that spreads out in other parts of the world. For example, epidemics that happen in the Northern Hemisphere usually mirror what previously happened in the Southern Hemisphere. And if we know against which epidemics our population here has acquired immunity, we can then see whether there are other advancing epidemics that will not be stopped by the local immunity, making it probable that it may cause an epidemic here.
Every year in February, the WHO reports which new strains are the best candidates for an epidemic. Sometimes they don't change, but sometimes they all change.
Do these seasonal vaccines have certain disadvantages?
Yes, the disadvantages are enormous. Currently, the preparation of classical vaccines is very expensive; you need huge numbers of fertilized chicken eggs, a whole infrastructure.
Secondly, we sometimes miss the strain that becomes active. Research has shown that when all the data are taken together, the prediction rate is about 80 to 90 percent. But there are examples where large vaccination programs have taken place where the wrong strain was targeted. And the great disadvantage is that if a pandemic arrives, we will not be prepared.
Why do researchers think that a pandemic could be likely?
All the information that we have seems to indicate that for the 1918 flu—the mother of all the pandemics, which killed 50 million people—could have been caused by a virus strain from birds. Now we know that influenza is common among all kinds of birds, but it could also come from another animal. There is the possibility that the bird flu will adapt itself for human-to-human transmission. This has not happened, but there have been some 250 people killed by the H5 strain in different areas of South Asia. There is a larger than 50 percent mortality if humans are infected. If you have 500 million of these viruses, you have a larger probability that among these viruses there is one or two mutants that have the required combination for spreading among humans. This is justifiably a great danger.
When transmission takes place between birds, they don't have an equivalent immune response like humans. Consequently, the virus doesn't change. With humans you will not have the same conservation of the virus. On the contrary, I'm strongly convinced that if in Hong Kong, or somewhere else, a pandemic started to develop, it will quickly spread throughout the world, but there will be no immune defenses because nobody had been previously exposed.
So your solution is a universal vaccine.
You need a vaccine that is not invalidated by drift and shift. We've researched this via many years and PhDs. At the end of the 1980s and during the early 1990s we started thinking that a new approach that proved successful might lead to a universal vaccine.
If you have a pathogen—a virus—that infects man, most people will survive. The recovered person now has convalescence serum—that is, a serum that contains antibodies against the pathogen. With the antibodies we look for which viral proteins are their targets. If we identify these, we can create a vaccine, which targets these proteins. But in the case of drift, you need another strategy.
We found that besides the large HA (hemagglutinin) and NA (neuraminidase) there is a small protein, M2e, which does occur on the virus in very small quantities. So people didn't view it as important, but for us it was very important because it does not elicit anti-M2e in the majority of recovering people.
In other words, the virus's M2e does not naturally set off an immune response in humans. How do you get the immune system to target that small protein, then?
We have made it highly immunogenic by implanting it on a viruslike particle, so that if we present this in this way to the immune system, it is very immunogenic. M2e is only slightly present on the virus, but in the lung epithelium cells where the virus ends up and starts multiplying, in the invaded cells, M2e becomes abundant. The target is not the virus, but the virus-infected cell. If you, at an early stage, can kill off these cells, than you will counteract the infection.
Why doesn't the virus's M2e gene vary the way the HA and NA genes do?
In part, because of the absence of immune selection, which plays a role in the introduction of drift, so there are not many antibodies. But there is also the fact that M1 and M2 [to which M2e is attached] are coded by two overlapping genes. M1 has very important functions at several levels, which strongly restricts the variability of both M1 and M2. Any mutations in them will impede the virus from reproducing.
So the universal vaccine acts on the M2e protein segment, which cannot undergo changes. What are the other advantages of a universal vaccine?
With the universal vaccine we can, just like for polio, give an immunization—and then again, a month later, another immunization, and perhaps a year later another one. You have more possibilities to induce a full-blown immunity.
Would you say that the phase I trial done by Acambis, based in Cambridge, U.K., and Cambridge, Mass., has been successful?
Yes, our technology has been licensed to Acambis, which has done the trial and has published the results in a press release. The results are promising: 90 percent of the vaccinated people were found to be seropositive. But we don't know whether the antibodies that are induced are antibodies that protect. We have done the equivalent trial with ferrets. We can give them a "challenge"—that is, infect them with H5N1, and we found that they were well-protected.
Ferrets are known to mirror what happens to humans. If you give a flu virus to ferrets, they develop an analogous pathology to humans.
What are the plans for a phase II trial?
First, you will have to do the trial with a large number of people. Second, you will have to find an area where there is a large probability that an influenza epidemic will take place. We are thinking of countries from the Southern Hemisphere. We have to be lucky in pinpointing such an area, and it will require the inoculation of thousands of people.
Another possibility, but we are less attracted to this, is giving people a challenge, where one infects people with a virus. Often one can recover from a virus infection. But an induced infection is less convincing than if we would do a real field trial.
In your view, another requirement for a vaccine to stave off a pandemic is that it should be administered via nasal drops?
For me it is clear that if there will be a pandemic, the chance that this happens is not in the rich West, but in the developing world. The first victims will be found in the enormous cities, in the poverty around these cities. We will have to vaccinate these people quickly, and medical workers injecting people is too slow.
The solution is to administer the vaccine nasally; nose drops can be administered by anyone. We have noticed that with intranasal administration with mice we obtain titers [antibody concentration] as high as with intramuscular injection. We expect that this will also work when applied to humans. But we still have a lot of work ahead of us.
This story was originally printed with the title, "Beating the Flu".