IT IS not a nice way to die. As the virus spreads through your lungs, your immune system goes into overdrive. Your lungs become leaky and fill with fluid. Your lips and nails, then your skin, turn blue as you struggle to get enough oxygen. Basically, you drown.
Flu can kill in other ways, too, from rendering you vulnerable to bacterial infections to triggering heart attacks. Of course, most flu strains, including (so far) the 2009 pandemic virus, cause only mild symptoms in the vast majority of people. But with 10 to 20 per cent of people worldwide getting flu every year, that still adds up to a huge burden of illness – and even in a good year some half a million die.
What if it needn’t be this way? Many once-common diseases, from smallpox to polio, have been eliminated, or nearly so, just by vaccinating children. If only we could develop a vaccine that was effective against all strains of flu, we might prevent both annual epidemics and occasional pandemics like the one now under way.
Advertisement
Recent work suggests it is possible to create just such a vaccine. In fact, the effectiveness of one potential universal vaccine will be tested in people for the first time in September. Could we be on the brink of beating flu?
The reason flu keeps infecting us again and again is that the virus is constantly changing. The first time you get infected, your immune system has to rely initially on innate, non-specific defences. But it also evolves specific defences, learning to make antibodies and immune cells that recognise that particular virus and destroy both it and any cells it has infected. This process can take a week or more, but once we have defences against a virus, we can respond to it much more quickly next time. This is why many viruses, such as measles, make us ill only once.
Flu viruses, however, evolve so fast that this “immune memory” provides only partial protection. Most of the antibodies we produce bind to the globular heads of a surface protein on the virus called haemagglutinin. The next big target is another surface protein, neuraminidase (see “Moving target”).
As flu viruses circulate through the human population, some acquire small mutations in haemagglutinin and neuraminidase that alter their shape and prevent our existing antibodies from binding as strongly. If the differences are large enough, we can be infected by one of these new strains, although our symptoms will be milder than if we had no previous immunity to flu at all.
And so it goes on. By staying one step ahead of our immune systems, the flu virus can infect large numbers of people year after year. What’s more, every few decades a flu strain acquires a new haemagglutinin – by swapping genes with a pig or bird flu strain, say – that is very different from those most people have immunity to, so we have very little protection. This is when flu goes pandemic.
Existing flu vaccines all work by mimicking natural infections. Based on global monitoring of flu strains, virologists try to predict which haemagglutinin and neuraminidase will dominate during the next flu season. The annual vaccines contain inactivated flu viruses bearing these specific proteins. If the virologists guess right, the vaccine will protect you until the virus changes enough again.
There is, however, a flaw in the whole idea of producing vaccines that mimic natural infections. “Haemagglutinin’s a decoy,” says Wayne Marasco, an immunologist at Harvard Medical School in Boston. “Those globular heads can undergo many mutations without the virus suffering any ill effects.”
Shifting the attack
Like a bullfighter’s cape, in other words, the heads of haemagglutinin deflect the immune attack away from more vulnerable parts of the virus. “There are conserved proteins that are almost identical in all flu, because they are delicate bits of machinery that do complex tasks and can’t really change much,” says Marasco. “If we can shift the immune system to attack the conserved proteins instead, flu cannot mutate to escape without crippling its own machinery.”
We do already make a few antibodies to these proteins. But it appears our immune systems decide which antibodies are most important and suppress others. For flu, haemagglutinin wins.
To refocus the immune attack, the idea is to create vaccines containing only the conserved proteins, rather than whole viruses. Most attention has focused on the M2 protein, an ion channel that protrudes from the virus’s surface and tells it when it is inside a cell. M2 also appears in abundance in the membrane of cells producing new flu viruses, so targeting it with antibodies will lead to the destruction of infected cells as well as the virus itself.
Changes in M2 are limited in a peculiar way. The RNA that codes for the M2 protein overlaps with that coding for another protein. If there are too many mutations, says Marasco, the virus cannot make working versions of either protein.
At least 10 companies have been looking into vaccines that provoke a reaction to the protruding part of M2, a 23-amino-acid sequence called M2e. Pure M2e does not elicit strong immune reactions when injected as a vaccine, so all groups have attached M2e to molecules that do provoke a strong response.
Three companies have got as far as human safety trials. Merck bound M2e to a bacterial protein, but people injected with this hybrid made antibodies only when the vaccine also contained an extra immune stimulator, or adjuvant, in quantities that caused pain on injection. Merck abandoned the project in 2007. “It was decided that further investigation was not warranted,” says spokesman Ian McConnell.
Acambis of Cambridge, UK, has coupled M2e molecules to a fragment of hepatitis virus to get the immune system’s attention. In 2008, it reported that when mixed with two adjuvants, 90 per cent of people made antibodies and there were no severe side effects. It also protected 70 per cent of ferrets, the best test animal for flu, from H5N1 bird flu.
However, work has slowed as Acambis is absorbed by a new owner, French vaccine giant Sanofi-Pasteur. “We will now try the vaccine with their proprietary adjuvant,” says Xavier Saelens of the University of Ghent in Belgium, a lead scientist on .
Pandemic situations
, a small biotech firm in Cranbury, New Jersey, has engineered a hybrid protein containing four copies of M2e bound to flagellin, a building block of bacterial flagella. “We got the same antibody reaction as the others, without the adjuvant,” says the head of the company, Alan Shaw, former head of public health at Merck.
There is, however, a big difference between showing that a vaccine is safe and stimulates antibody production, and showing it protects people from flu. VaxInnate is planning further trials, but these are on hold as health authorities deal with swine flu.
If any of these vaccines do prove effective, they will be relatively easy to manufacture. Nearly all conventional flu vaccines are made by growing the virus in chicken eggs, a slow process that is even slower with some strains – including 2009 H1N1 flu. Vaccines consisting of a single protein, however, can be grown using widely available equipment, which is much faster and cheaper. Then again, if you only need to be vaccinated once, it matters less how long it takes to make the vaccine.
Sarah Gilbert at the University of Oxford and colleagues have taken a different approach to other groups. They have modified a virus called MVA, a variety of the virus used for decades as a smallpox vaccine, to produce the entire M2 protein. Gilbert’s aim with this live vaccine is not so much to induce antibodies as white blood cells called T-cells – to get so-called cell-mediated immunity.
T-cells have proteins on their surface that, like antibodies, recognise specific viral proteins, so they can identify and destroy infected cells. T-cells, however, bind to smaller parts of viral proteins, making it harder for a virus to dodge all the various T-cells targeting it with just one or two mutations.
The idea of provoking a cell-mediated response to flu is controversial, though, in part because it takes longer to start mass-producing T-cells than antibodies. Many researchers think a T-cell response would limit disease severity but would not stop you falling ill. “For a vaccine to prevent flu, you need antibodies,” says Saelens.
“The data say otherwise,” responds Gilbert. Studies at the UK Common Cold Unit in the 1980s showed that people with the highest cell-mediated immunity before exposure to flu didn’t get sick or shed virus. “This was true even in people without antibodies,” she says.
Work to be published soon, by John Oxford of Barts and The London School of Medicine and Dentistry, also shows that infected volunteers with high cell-mediated immunity get few or no flu symptoms. “T-cells certainly limit the severity of disease,” he says. “But I’d love to test a vaccine that induces antibodies to M2e too.”
Oxford is a director of , a company with the only facility in the world where people can be experimentally exposed to flu. RetroScreen will be testing Gilbert’s vaccine this September – the first-ever trials designed to see if a potential universal flu vaccine can prevent infection or reduce disease severity. If tests are successful, the vaccine might be approved within three years.
“The first-ever trials designed to see if a universal vaccine can prevent infection or lessen disease severity will start in September”
There are other targets for universal flu vaccines besides M2. The stalk of haemagglutinin, beneath the globular heads, contains the machinery that releases the virus’s genes into a cell. In February, Marasco and colleagues reported that they had found 10 antibodies that bind to a conserved pocket on the stalk (see video, top). At the same time, Dutch company reported that a similar antibody protects mice from both H5N1 bird flu and the 1918 H1N1 pandemic virus – two lethal, and very different, strains.
Such antibodies could be manufactured and used to treat flu directly, says Marasco, although the need for safety testing means none will be ready in time for the current pandemic. His team is also working on a universal vaccine designed to trigger antibodies to the pocket in the stalk.
Some think any universal flu vaccine should provoke immunity to at least two different targets, to make it even harder for the virus to escape. “It is risky to base a vaccine on just one,” Marasco says.
If any of the efforts to create a universal vaccine succeed, the benefits will be enormous. Even if flu slowly evolves to resist universal vaccines, and they need to be updated every now and then, they will still be a big step forward. Health authorities could combine flu with the other childhood vaccinations, greatly reducing the overall disease burden. An effective universal vaccine that is cheap enough to be widely used worldwide could even eliminate annual flu epidemics and occasional pandemics, though unvaccinated people will still occasionally catch the virus from birds and other animals that carry flu.
That is a huge prize, one you might think that countries and researchers around the world would be working together to achieve. But there is no concerted effort. The World Health Organization is coordinating efforts to develop a vaccine against 2009 H1N1 flu, but the focus is on strain-specific vaccines made with the technology companies have already invested in.
What research there is on universal vaccines is disjointed. It is hard to compare different candidates, for instance, as each group measures effects in a different way.
Part of the problem is that the science is so new. “We’ve really only had encouraging data in the past few years,” says Shaw. There are also commercial barriers: the better a vaccine works, the less you sell. Companies have little incentive to invest in products people will only take once or twice.
Ironically, efforts to find a universal flu vaccine are now largely on hold as the world deals with one particular virus – yet we would have been much better prepared for a pandemic if we had a universal vaccine. When the dust settles, hopefully that will change.
Wanted: A faster vaccine
Until we have a universal flu vaccine, we have to make vaccines for each new strain as it evolves. This approach could still prevent flu pandemics, if only we could make vaccines fast enough.
Nearly all flu vaccines are made from whole viruses grown in chicken eggs. But companies cannot readily scale up the process from the 400 million doses of regular flu vaccine they make each year to the billions needed in a pandemic.
Protein Sciences of Meridien, Connecticut, instead makes the main flu protein, haemagglutinin, by infecting insect cells grown in vats with a baculovirus modified to carry the flu gene. Pure haemagglutinin doesn’t usually elicit much of an immune response, but Protein Sciences has got round this by putting three times as much in a dose as normal.
Its seasonal flu vaccine has cleared all three phases of human trials and is closer to licensing than any vaccine not made from whole virus. In June, won a $35 million US government contract to develop and supply a pandemic vaccine.
Many other companies hope to mass-produce flu proteins using mammal or insect cells. “But it’s not faster than eggs, and it’s more expensive,” claims Alan Shaw of VaxInnate, which instead uses bacteria.
In addition to its universal vaccine (see main article), VaxInnate has grown the haemagglutinin from 2009 H1N1 in E. coli. “Nobody else can match this for speed,” says Shaw. “The first batch of E. coli-based vaccine is enormous, and you can start a new batch every four days.” But clinical trials have been delayed by the pandemic.
